Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1-4

The Drug Discovery Process Hugo Kubinyi Weisenheim am Sand, Germany HISTORY AND CURRENT SITUATION Early drug discovery...

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The Drug Discovery Process Hugo Kubinyi Weisenheim am Sand, Germany

HISTORY AND CURRENT SITUATION Early drug discovery was dominated by natural products and their derivatives [1–3]. Accumulated experience from folk medicine and subsequent systematic search uncovered the active principles of many plants. These sources were complemented by active principles from microorganisms, with antibiotics being the Þrst. Recently, microorganisms turned out to be a source for other important drugs. About half of all therapeutics are natural products, their derivatives, or synthetic compounds that were derived from natural products [4]. The father of the Bayer chemist Felix Hoffmann suffered from rheumatic disease. The prescribed salicylic acid had a bitter taste and unpleasant side effects. In 1897, Hoffmann synthesized acetylsalicylic acid (ASA) for the Þrst time as a pure, chemically stable compound. Today, we would call this a prodrug approach, and indeed the goal had been to produce a better and more tolerable salicylic acid analog. Heinrich Dreser, the Bayer pharmacologist at that time, was not happy about the new compound. Whereas he favored heroin, the diacetyl derivative of morphine, as an “effective and well tolerated antitussive,” he tried to stop the development of ASA because in animal experiments he had seen some cardiac side effects. Being clinically tested without his consent, the excellent antipyretic and analgesic activities of ASA immediately convinced clinicians and patients. The drug, then called Aspirin, was introduced into therapy in 1899. Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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THE DRUG DISCOVERY PROCESS

ASA is one of the greatest success stories in drug discovery and most probably is the leader in the number of pills consumed in the past 108 years. In the 1970s the mechanism of action was elucidated: it irreversibly blocks cyclooxygenase, the enzyme responsible for the biosynthesis of pain-mediating prostaglandins. At that time, it was also recognized that ASA prevents thrombocyte aggregation via the same mechanism, by inhibition of thromboxane biosynthesis, because platelet cyclooxygenase cannot be regenerated during the lifetime of a thrombocyte. Thus, ASA has been a serendipitous drug discovery, as so many others in the history of drug research [1, 5, 6]. A period of thirty years, from about 1950 to 1980, marks the “golden time” of drug research. Many highly valuable drugs were discovered in a few decades, applying rational approaches to develop neurotransmitter, steroid, and peptide analogs [7]. Nonselective as well as selective receptor agonists and antagonists resulted (e.g., the antihistamines). Despite the fact that these early H1 antagonists had strong sedative side effects, they were celebrated as “miracle drugs.” The many new technologies developed in the past twenty years should increase the number of new drugs that can be used in human therapy. Presently, however, the opposite is the case. Since 1995 there has been a steady decline in the number of new drugs entering the market (Table 1). The year 2005 showed a marked decline after a short recovery in 2004 [8]. In contrast, research costs in the pharmaceutical industry doubled about every seven years, from 1991 to 1998 and again from 1998 to 2005, up to about $40 billion US per year—constituting the “productivity gap” in drug discovery. Research costs for a new drug are now estimated to be in the range of $800 million US [9]. However, considering all failures in drug research and comparing worldwide research and development costs with the number of NCEs, this Þgure becomes even higher, approaching almost $2 billion US per new drug. Several reasons have been advanced for the decline in new drugs. We already use safe and efÞcient drugs to treat (most often symptomatically) the “simple” diseases. Our demands for the safety of new drugs are increasing; today,

TABLE 1. New Drugs Approved by the FDA in the Years 1996–2005 [8] Year

NCEsa

Biologicals

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

53 39 30 35 27 24 17 21 31 18

3 6 7 3 2 5 7 6 4 2

a NCEs, small molecule new chemical entities.

Total 56 45 37 38 29 29 24 27 35 20


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several established drugs, from ASA to corticosteroids and other active agents, would have problems getting FDA approval. In many diseases, especially cancer, the development goes from nonspeciÞc cytotoxic agents to drugs that speciÞcally interact with certain signaling chains (e.g., the kinase inhibitors). However, kinases are a group of about 500 homologs with very similar binding sites, thus obstructing the design of speciÞc inhibitors. Drugs for the treatment of chronic diseases have to be given for many years and drugs for the prevention of a certain disease have to be given to healthy people. Such therapeutics must be absolutely safe, whereas more severe side effects can and have to be accepted in the case of anticancer drugs. As discussed later, early combinatorial chemistry and high-throughput screening produced large numbers of “hits” that were not suited as lead structures—they were too large and too lipophilic. In lead optimization, afÞnity to a target was often overemphasized, neglecting selectivity, bioavailability, other ADME parameters, and toxicity. Another reason for the poor yield in new drugs might be their long development time. Several new technologies in drug discovery, like structure-based and computer-aided design, virtual screening, and fragment-based design, are just starting to produce interesting results. On the other hand, molecular modeling goes back about twenty-Þve years and QSAR has existed for more than forty years. Although both approaches had no direct impact on drug discovery, they stimulated drug research in indirect ways: QSAR helped medicinal chemists to understand the inßuence of lipophilicity and dissociation constants [10] and molecular modeling forced chemists to consider molecules as threedimensional (sometimes chiral), ßexible objects [11]. The Þrst drugs that resulted from structure-based design are already on the market; many more will (hopefully) follow. The pipelines of the pharmaceutical and biotech companies are full of drug candidates from such rational approaches. The decline in new drug approvals is only one facet of the problem. The other one is that several drugs were approved and introduced into the market but had to be withdrawn shortly afterward, due to insufÞcient efÞcacy or toxicity problems. Well-known examples from recent years are terfenadine, cisapride, mibefradil, cerivastatin, rofecoxib, and ximelagatran, some of which were already blockbuster drugs or at least bearing the potential to become blockbusters [12]. In all cases, the reason for withdrawal was an unfavorable balance between beneÞcial and adverse toxic effects. The decline in drug approvals is in strong contrast to the hope that resulted from genomics, proteomics, system biology, and many other experimental and computer-aided new technologies. Whereas the FDA and other agencies considered lowering the barrier for clinical phase I studies, even to the point of accepting pre-phase I studies in humans, a strong question mark was put on such a procedure by the severe toxic reactions experienced by some healthy volunteers who were treated with a monoclonal antibody in a phase I study in early 2006 [13]. Since the most important steps in drug discovery are lead structure search and optimization, the focus is mainly on these two issues.

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DRUG TARGETS Gene technology and especially information on the human genome sequence created a lot of hype. Originally, there were estimates of about 100,000 or more human genes, which after 2001 had to be corrected to only about 30,000–35,000; recent estimates are even closer to 20,000–25,000. Drews counted 483 targets of current therapies and he speculated that in total there might be about 5,000–10,000 drug targets [14]. Hopkins and Groom arrived at a much smaller number of 600–1,500 drug targets in their estimate of the “druggable genome” [15]. However, the term “druggable genome” is misleading: the relatively small number of genes within our genome codes for hundreds of thousands of different proteins, due to alternative splicing, post-translational modiÞcations, and protein complex formation. If only a small percentage of them are involved in disease, a much larger number of potential targets results [16]. Gene technology contributes to drug research in different ways. Sequence determination of the coding regions of a gene provides the sequence of the corresponding protein, which often allows the prediction of its function, sometimes even its fold and three-dimensional (3D) structure. Proof of a new therapeutic approach can be performed in knock-out or other transgenic animal models or by silencing genes with siRNA technology. One of the major beneÞts of gene technology is the fact that almost any protein can be produced in cell culture. Thus, instead of animals or animal proteins, human proteins are used in screening. Production of larger amounts of a human protein enables its crystallization and 3D structure determination by protein crystallography or structure determination by NMR. In this way, gene technology supports drug research, without a patient having to take any genetically produced or modiÞed products: this is probably the greatest beneÞt of gene technology for humankind. There is an ongoing discussion on the extent to which a certain drug should be speciÞc for just one target or should act on several targets (in earlier times belittled as “dirty drugs,” but today praised as compounds with “rich pharmacology”). There is no answer from theory; experience shows that in many cases high selectivity might be favorable, whereas successful CNS-active drugs often modulate some to many targets. Even kinase inhibitors for tumor therapy are not completely selective. The recently approved drug sunitinib (Sutent, SU 11248; Sugen, PÞzer) for the treatment of renal and gastrointestinal tumors is a highly promiscuous inhibitor of a large number of different kinases [17]; possibly its therapeutic value results just from this lack of selectivity. A related question is: Do we lose too many potential drugs by target-based screening? The very Þrst antibacterial sulfonamide, sulfamidochrysoidine, would not have been discovered in vitro because it is a prodrug; clopidogrel has to be activated by CYP3A4 oxidation; acyclovir is monophosphorylated in virusinfected cells by a viral thymidine kinase and only afterward do cellular kinases convert the monophosphate to the biologically active triphosphate; and omeprazole acts only in acid-producing cells, after acid-catalyzed rearrangement.


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So are whole animal experiments better suited than target-based screening? There is no going back to mice and guinea pigs as primary test models. Chemical biology, which aims to discover new leads by searching for phenotypic changes in cells, for example, embryonic stem (ES) cells or Saccharomyces cerevisiae, or small animals, like Caenorhabditis elegans, Drosophila, and the zebraÞsh, Danio rerio, is a step in the right direction. Some results from chemical biology approaches are synthetic small molecules that induce the differentiation of embryonic stem cells. A high-throughput phenotypic cell-based screen identiÞed a pyrrolopyrimidine that differentiates ES cells to neurons by modulating glycogen synthase kinase-3β (GSK-3β) [18]. Cardiac muscle cell formation from stem cells is induced by cardiogenol C, which was discovered in a 100,000-member heterocycles library [19]. The same group described the dedifferentiating agent reversine that (seemingly) converts adult murine myotube cells to mesenchymal progenitor cells, which can then be induced to form either bone or fat cells [20, 21].

THE SEARCH FOR NEW LEADS One reason for the decline in the number of new drugs, which has not been mentioned so far, is a shortage of new lead structures that can be optimized into therapeutically useful drugs. A lead structure must have some biological activity, albeit weak and even nonselective, and there must be chemically related analogs, which indicate that structural modiÞcation modulates biological activity as well as other properties. The compounds should not react irreversibly with its biological target (although some important drugs, like acetylsalicylic acid, the penicillins and cephalosporins, and omeprazole, are irreversible enzyme inhibitors). Drug candidates most often become larger in size and more lipophilic. Thus, a lead should have a molecular weight 60, elevated lactate dehydrogenase (LDH) levels, Eastern Cooperative Oncology Group (ECOG) performance status of 2–4, Ann Arbor stage III or IV, and more than one extranodal site. IPI = International Prognostic Index.

scores, patients are assigned to one of four risk groups, each with a different expected long-term survival (Table 5). For patients younger than age 60, a simpliÞed system based on the Ann Arbor staging system has been developed: LDH level and ECOG performance status. Both the Ann Arbor staging system and the IPI can help determine the appropriate therapeutic approach for individual patients. However, one of the criticisms of the IPI is that many patients fall into the intermediate category, thereby reducing its clinical usefulness for predicting survival. Etiology Risk Factors. In the majority of NHLs cases, the cause is unknown. Although several factors have been implicated in this disease’s development, only a minority of cases can be traced to environmental, bacterial, or viral risk factors. Chemical/Physical Agent Exposures. The strongest known risk factor for NHL is exposure to environmental toxins; clinicians are able to attribute 2–10% of NHL cases worldwide to such exposures. IdentiÞed toxins include creosote,

78

AGGRESSIVE NON-HODGKIN’S LYMPHOMAS

lead, paint thinner, oils and greases, dark-toned hair dyes, and most notably, agricultural pesticides, whose contaminants dioxin and phenoxyacetic acid are the most well-documented risk factors. Pockets of increased incidence of NHL have been reported in agricultural communities in the United States and Europe (Scherr PA, 1992; Persson B, 1999). Although it might be assumed that NHLs associated with agricultural chemicals would decline along with the downward trend of farming in industrialized countries, the increased use of pesticides and herbicides in home gardens and on golf courses, playing Þelds, and beaches has increased the risk of exposure in residential and recreational environments. Patients with a history of exposure to such agents exhibit chromosomal abnormalities, including frequent translocations within genes that mediate immune functions. In 1997, researchers identiÞed a strong dose-response relation between lipid-corrected serum polychlorinated biphenyl (PCB) concentrations and risk for NHLs: people who had the highest PCB concentrations had as much as a 12fold higher risk of developing NHLs (Rothman N, 1997). Still, the nature and biological plausibility of the association are not clearly understood. In addition, increasing evidence indicates that exposure to nuclear radiation heightens the risk for developing NHLs, but data on this risk factor are sparse. The development of NHLs has also been reported among patients who are receiving therapy for other neoplasms, such as Hodgkin’s disease. The incidence of NHLs in patients treated for Hodgkin’s disease was found to be 32 times that of the general population (Dorreen MS, 1986). Additionally, data from the Surveillance, Epidemiology, and End Results (SEER) database have shown that in the United States, patients who have Hodgkin’s disease die at an increased rate from NHLs compared with the general population (Diehl L, 1999) Infectious Agents. Both bacterial and viral pathogens have been associated with the development of NHLs: •

•

The presence of the Helicobacter pylori bacterium is strongly associated with gastric lymphomas. Infection with H. pylori results in chronic gastritis, and conversely, primary gastric mucosal-associated lymphoid tissue (MALT) NHL cases frequently show evidence of H. pylori infection. Studies have indicated that patients with primary gastric lymphoma were approximately six times more likely to be positive for H. pylori than case-matched controls. Studies of treatments directed against H. pylori have suggested that in many cases, eradicating the bacteria induces a positive clinical response in the lymphoma, further implying a causal role for the bacteria (Wotherspoon AC, 2002). Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus originally isolated from aggressive adult T-cell lymphomas found predominantly in Japan. The virus is transmitted through the exchange of body ßuids. Although HTLV-1 is endemic to several regions of Japan, available data indicate that infection with the virus correlates only weakly with the development of NHLs: only about 50% of all NHL cases in these areas are

ETIOLOGY AND PATHOPHYSIOLOGY

•

•

79

associated with the virus. This Þnding suggests that HTLV-1 may predispose a person to develop a T-cell lymphoma but is not directly able to predict lymphoma development. Epstein-Barr virus (EBV) is a herpes virus that readily transforms B lymphocytes into immortal cell lines in vitro. EBV also causes mononucleosis and is strongly associated with neoplasms, including aggressive NHLs such as Burkitt’s lymphoma. The data suggest that EBV-associated NHLs result from virus-mediated changes to the cell surface, enabling infected cells to escape normal cell regulation. However, exposure to EBV without subsequent development of lymphoma is common, strengthening the argument that EBV predisposes patients to, or enables, development of NHLs rather than directly causing it. In addition, the data suggest that infection with EBV is a potent catalyst for the development of NHLs among people with other risk factors—particularly HIV patients and patients who are receiving immunosuppressive therapy after solid organ transplantation. Before the advent of new antiretroviral therapies, the NHLs (particularly those of the central nervous system [CNS], i.e., primary parenchymal lymphoma and leptomeningeal lymphoma) had been occurring with rising frequency among HIV patients. Indeed, CNS NHL is now considered an AIDS-deÞning illness. HIV patients are believed to have as much as a 60to 100-fold higher risk of developing NHLs than people who do not have HIV. The etiology of HIV-associated NHLs is complicated by the underlying immune system dysfunction and the various infections that accompany AIDS: infected patients have uncontrolled B-cell stimulation and proliferation, increasing the likelihood of genetic errors during lymphocyte proliferation. HIV patients are also at higher risk (as are all immunodeÞcient persons) for lymphomas associated with EBV. Thanks to antiretroviral therapy, however, the incidence of NHLs in AIDS patients has plateaued or is declining in most Western countries that have strong AIDS programs.

Medical Immune Suppression. The high level of immunosuppression induced in solid-organ and bone marrow transplantation can result in a post-transplant lymphoproliferative disorder (PTLD), in which lymphocytes proliferate abnormally. PTLDs can range in severity from a benign mononucleosis-like illness to NHLs; they originate most often in B cells and are associated with EBV (Loren AW, 2003). Because a suppressed immune system is less able to control viral infection, the result is unchecked proliferation of virally infected cells that may progress to NHL. Patients who receive heavy immunosuppressive therapy after organ transplantation have a 25- to 50-fold higher risk of developing a lymphoid malignancy, usually of a highly aggressive type. Prior history of blood transfusion has been associated with increased risk of NHL development (Cerhan JR, 1997). One study suggests that at worst, blood transfusion doubles the risk of NHLs, and at best, the risk does not increase after a transfusion (Vamvakas EC, 2000).

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Non-HIV Autoimmune Disorders. Autoimmune disorders such as Sjögren’s syndrome (a chronic autoimmune disorder affecting the glands that produce tears and saliva), Hashimoto’s thyroiditis, and rheumatoid arthritis are all risk factors for NHLs. In many cases, chronic inßammation promotes the development of MALT and other lymphomas; patients with Sjögren’s syndrome, for example, have a 6% increased risk for NHLs. The relationship between NHLs and autoimmune diseases remains unclear. The inherited immune deÞciency syndrome ataxia-telangiectasia, an autosomal recessive multisystem disorder, is associated with a heightened risk of developing lymphomas. The gene that is mutated in this disease (the ataxia-telangiectasia mutated gene, known as ATM ) is located on chromosome 11, and multiple mutations have been described (Stankovi T, 2002). The ATM protein is a protein kinase implicated in the integration of different cellular responses to DNA damage. Diet and Family History. Studies suggest that high dietary intake of meats and fat from animal sources is associated with an increased risk of NHLs (Chiu BC, 1996; Zhang S, 1999). A greater intake of vegetables, particularly cruciferous vegetables (e.g., broccoli, caulißower, Brussel sprouts), may reduce the risk of NHLs in women (Zhang SM, 2000). Some studies have shown that tobacco use is also associated with NHLs. A history of adult-onset diabetes mellitus (type 2 diabetes) and a history of cancer appear to be risk factors for NHLs in older women (Cerhan JR, 1997). Patients with Wiskott-Aldrich syndrome, an X-linked recessive disorder, have a 100-fold greater risk than the general population of developing NHLs (RemoldO’Donnell E, 1996). Cytogenetic Abnormalities. NHLs are associated with an array of cytogenetic abnormalities, many of them chromosomal translocations (Table 6). Such abnormalities occur when part of one chromosome is translocated onto another chromosome, possibly resulting in activation of an oncogene or disruption of a tumor suppressor gene. MCL, which accounts for approximately 6% of all NHLs in the United States, is characterized by a translocation t(11;14)(q13;q32) that involves chromosomes 11 and 14 (Swerdlow SH, 2002). In this translocation, the cyclin-D1 gene (also known as bcl-1, PRAD1, and ccnd-1 ) is juxtaposed with the enhancer of the immunoglobulin heavy (IgH ) chain gene (Vega F, 2003). The enhancer drives expression of cyclin-D1, and the resulting high levels of cyclin-D1 protein push cells through the cell cycle, accounting in part for the aggressive clinical course of MCL. Diffuse large B-cell lymphoma (DLBCL) is heterogeneous, both in biology and clinical course, and has been associated with a wide variety of molecular abnormalities. Two of the more common abnormalities involve the bcl-2 and bcl6 genes. The t(14;18)(q32;q21) puts bcl-2 under the control of the IgH enhancer (as described for MCL), leading to overexpression of the antiapoptotic bcl-2 protein. High levels of bcl-2 protein promote abnormal cell survival and override the normal propensity for cell death. bcl-6 encodes a transcription factor involved

CURRENT THERAPIES

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TABLE 6. Oncogenes, Immunophenotypes, and Cytogenetic Characteristics of Common Aggressive Non-Hodgkin’s Lymphoma Subtypes

Subtypea

Oncogenes Frequently Involved

Diffuse large B-cell lymphoma

bcl-2, c-myc, bcl-6

Mantle-cell lymphoma

bcl-1, PRAD1

Peripheral T-cell lymphomasb Anaplastic large T/null-cell lymphoma

Not known

Precursor T-cell or B-cell lymphoblastic lymphoma

Variable

Burkitt-like lymphoma Burkitt’s lymphoma

bcl-2, c-myc

ALK

c-myc

Typical Immunophenotype CD5+/−, CD10+/−, CD19+, CD20+, CD22+, CD79a+, CD45+/−, surface immunoglobulin (sIg) +/− CD5+, CD10+/−, CD11c-, CD19+, CD20+, CD22+, CD23-, CD43+, CD79a+, sIg+ CD2+, CD3+, CD4+, CD5+, CD7+, CD8+/− CD3+/−, CD15+/−, CD20-, CD25+/−, CD3-, CD30+, CD43+/−, CD45RO+/−, CD68-, EMA+/− T cell; CD1a+/−, CD2+, CD3+, CD4+/− CD5+, CD7+, CD8+/−, TdT+. B cell; CD10+/−, CD19+, CD20+/−, CD22+, CD79a+, CD34+/−, sIgCD19+, CD20+, CD22+, CD79a+, CD5-, CD10-, sIg+/− CD19+, CD20+, CD22+, CD79a+, CD10+, CD5-, CD23-, sIg+

Characteristic Cytogenetics t(14;18)(q32;q21), t(8;14)(q24;q32), t(3;14)(q27;q32) t(11;14)(q13;q32)

Trisomy 8q t(2;5)(p23;q35)

Variable

t(14;18)(q32;q21) t(8;14)(q24;q32) t(8;14)(q24;q32) t(2;8)(q11;q24) t(8;22)(q24;q11)

a Revised European-American Lymphoma (REAL) classification subtypes. b Excludes angiocentric nasal lymphoma and human T-lymphotropic virus type 1-associated lymphomas,

which are more common in non-Western countries.

with cellular differentiation and has been found translocated to many different gene partners. Further analysis is required to determine the prognostic signiÞcance and impact of the various cytogenetic abnormalities associated with NHLs.

CURRENT THERAPIES Combination chemotherapy is the mainstay of treatment for aggressive nonHodgkin’s lymphomas (NHLs); it can cure 30–40% of patients. A series of regimens developed during the 15 years between 1978 and 1993 aimed to improve on CHOP, the most widely used regimen, which consists of the following agents: •

Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics).

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• • •

Doxorubicin{hydroxydoxorubicin} (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics). Vincristine (Eli Lilly/EG Labo’s Oncovin, generics). Prednisone (Merck’s Decortin, generics). In 1993, a large, randomized trial found that three of the regimens developed to compete against CHOP conferred no additional beneÞt, so CHOP remains the standard Þrst-line treatment for aggressive NHLs (Fisher RI, 1993). As a result of this trial and others described in this chapter, the alternative regimens discussed in the following sections are reserved largely for second-line use.

Researchers continue to modify CHOP, either increasing doses, reducing intervals between cycles, or adding or substituting drugs to try to improve response and survival rates and/or reduce toxicities. To date, only the addition of the immunotherapy rituximab (Genentech/Biogen Idec/Chugai’s Rituxan, Roche’s MabThera) to CHOP (forming CHOP-R) has conferred a signiÞcant beneÞt in a large trial. Table 7 lists the leading regimens available to treat aggressive NHLs. Other regimens used by a minority of clinicians include the following: •

•

•

ACVBP, which comprises doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics); cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics); vindesine (EG Labo/Cell Pharm/Crinos/Clonmel’s Eldisine, Ciclum Farma’s Enison, Shionogi’s Fildesin); bleomycin (Bristol-Myers Squibb’s Blenoxane/Nippon Kayaku’s Bleo, generics); and prednisone (Merck’s Decortin, generics). EPOCH, which incorporates etoposide (Bristol-Myers Squibb’s VePesid/ Etopophos, PÞzer’s Lastet, generics); vincristine (Eli Lilly/EG Labo’s Oncovin, generics); doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics); cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics); and prednisone (Merck’s Decortin, generics). ICE, which combines ifosfamide (Bristol-Myers Squibb’s Ifex, Baxter’s Holoxan/Mitoxana, Shionogi’s Ifomide, generics); carboplatin (BristolMyers Squibb’s Paraplatin/Carboplat, generics); and etoposide (BristolMyers Squibb’s VePesid/Etopophos, PÞzer’s Lastet, generics).

Table 8 presents the results of trials that have examined the addition of rituximab to several existing regimens. In general, these trials have been small, and although response rates have been high, larger trials are needed to establish the impact of these combination regimens on survival and their role in the treatment of aggressive NHLs. Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) Overview. CHOP, the mainstay of treatment for aggressive NHLs, incorporates cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s

CURRENT THERAPIES

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TABLE 7. Current Regimens/Classes Used for Aggressive Non-Hodgkin’s Lymphomas Regimen Components Regimen CHOP

Agent

Availability

Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics)

Dose Cyclophosphamide: 750 mg/m2 , day 1, IV

Doxorubicin (Pfizer’s US, F, G, I, Doxorubicin: 50 Adriamycin/ S, UK, J mg/m2 , day 1, IV Adriblastine, Kyowa’s Adriacin, generics) Vincristine (Eli Lilly/EG US, F, G, I, Vincristine: 1.4 mg/m2 , day 1 (maximum 2 Labo’s Oncovin, S, UK, J mg), IV generics) Prednisonea (Merck’s US, F, G, I, S Prednisone: 100 Decortin, generics) mg/m2 /d, days 1–5, PO Repeat every 21 days. CHOP-R Cyclophosphamide US, F, G, I, Cyclophosphamide: (Bristol-Myers S, UK, J 750 mg/m2 ,day 1, IV Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics)

DHAP

Common Toxicities Fever Infection Myelosuppression Lung toxicity Alopecia Cardiac toxicity Neurological toxicity

Fever Infection Myelosuppression Lung toxicity Alopecia Cardiac toxicity Neurological toxicity Respiratory symptoms Chills Hypotension

Doxorubicin (Pfizer’s US, F, G, I, Doxorubicin: 50 Adriamycin/ S, UK, J mg/m2 , day 1, IV Adriblastine, Kyowa’s Adriacin, generics) Vincristine (Eli Lilly/ US, F, G, I, Vincristine: 1.4 mg/m2 , day 1 (maximum 2 EG Labo’s Oncovin, S, UK, J mg), IV generics) Prednisonea (Merck’s US, F, G, I, S Prednisone: 100 mg/d, Decortin, generics) days 1–4, PO Repeat every 21 days for 8 cycles of CHOP. Rituximab US, F, G, I, Rituximab: 375 mg/ (Genentech/Biogen S, UK, J m2 /d, day 1 of each of the 8 cycles of Idec/Chugai’s CHOP, IV Rituxan, Roche’s MabThera) Cisplatin (Bristol-Myers US, F, G, I, Cisplatin: 100 mg/m2 , Myelosuppressionday 1 related infection Squibb’s Platinol AQ, S, UK, J Acute lysis syndrome generics)

84


TABLE 7. (continued) Regimen Components Regimen

Agent

Availability

Cytarabine (Pfizer’s US, F, G, I, Cytosar-U/Aracytine, S, UK, J Nippon Shinyaku’s Cylocide, generics) Dexamethasone US, F, G, I, (Merck/Banyu’s S, UK, J Decadron, generics) ESHAP

Methylprednisolone US, F, G, I, (Pfizer’s Medrol/ UK, J Medrone/Medrate, generics) Etoposide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics) Cytarabine (Pfizer’s US, F, G, I, Cytosar-U/Aracytine, S, UK, J Nippon Shinyaku’s Cylocide, generics) Cisplatin (Bristol-Myers US, F, G, I, Squibb’s Platinol AQ, S, UK, J generics)

MACOP- Methotrexate B (generics)

Leucovorin (generics)

US, F, G, I, S, UK, J


Doxorubicin (Pfizer’s US, F, G, I, Adriamycin/ S, UK, J Adriblastine, Kyowa’s Adriacin, generics) Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics) Vincristine (Eli Lilly/EG US, F, G, I, Labo’s Oncovin, S, UK, J generics)

Dose

Common Toxicities 2

Cytarabine: 2 mg/m , day 2

Dexamethasone: 40 mg/d, days 1–4 Repeat every 21–28 days. Methylprednisolone: Myelosuppression 500 mg/d, days 1–4 Nausea and vomiting Non-neutropenic sepsis Etoposide: 40–60

mg/m2 /d, days 1–4 Cytarabine: 2 g/m2 , day 5 Cisplatin : 25 mg/m2 /d, days 1–4 Repeat every 21–28 days. Myelosuppression Methotrexate: 400 mg/m2 once weekly, Infection weeks 2, 6, and 10, Cardiotoxicity IV Neurotoxicity Leucovorin: 15 mg/m2 every 6 hours × 6 (24 hours after methotrexate), PO Doxorubicin: 50 mg/m2 per week, weeks 1, 3, 5, 7, 9, and 11, IV

Cyclophosphamide: 350 mg/m2 per week, weeks 1, 3, 5, 7, 9, and 11, IV

Vincristine: 1.4 mg/m2 per week, weeks 2, 4, 6, 8, 10, and 12, IV

CURRENT THERAPIES

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Agent Bleomycin (Bristol-Myers Squibb’s Blenoxane, Nippon Kayaku’s Bleo, generics Prednisonea (Merck’s Decortin, generics)

MINE

BEAM

Availability

Dose

Common Toxicities


Bleomycin: 10 units/m2 per week, weeks 4, 8, and 12, IV US, F, G, I, S Prednisonea : 75 mg/d; dose tapered over the last 15 days, PO Repeat every 12 weeks. Mesna (Bristol-Myers US, F, G, I, S Mesna: 1,330 mg/ Neutropenic fever Squibb’s Mesna/ UK, J m2 /d, days 1–3, Sepsis IV Bleeding associated Mesnex, Baxter/ with thrombocytoShionogi’s Uromitexan) penia Ifosfamide (Bristol-Myers US, F, G, I, Ifosfamide: 1,330 Squibb’s Ifex, Baxter’s S, UK, J mg/m2 /d, days 1–2, IV Holoxan/ Mitoxana, Shionogi’s Ifomide, generics) Mitoxantrone (Serono/ US, F, G, I, Mitoxantrone: 8 mg/ Wyeth/Wyeth-Takeda’s S, UK, J m2 , day 1, IV Novantrone, Baxter’s Onkotrone) Etoposide (Bristol-Myers US, F, G, I, Etoposide: 65 mg/ Squibb’s S, UK, J m2 /d, days 1–3, IV VePesid/Etopophos, Repeat every 21 Pfizer’s Lastet, days. generics) Neutropenic fever Carmustine (Bristol-Myers US, F, G, UK Carmustine: 300 Squibb’s mg/m2 , day 1, IV Sepsis Bleeding associated BiCNU/Carmubris) with thrombocytopenia Etoposide (Bristol-Myers US, F, G, I, Etoposide: 400 Squibb’s S, UK, J mg/m2 /d, days 2–5, IV VePesid/Etopophos, Pfizer’s Lastet, generics) Cytarabine (Pfizer’s US, F, G, I, Aracytine: 400 Cytosar-U/Aracytine, S, UK, J mg/m2 /d, days 2–5, IV Nippon Shinyaku’s Cylocide, generics) Melphalan US, F, G, I, Melphalan: 140 (GlaxoSmithKline’s S, UK, J mg/m2 , day 6, IV Alkeran)

a Prednisolone is substituted for prednisone in countries where prednisone is unavailable.

US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan. IV = Intravenous; PO = By mouth; SC = Subcutaneous.

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TABLE 8. Findings of Clinical Trials Investigating the Combination of Rituximab with Currently Used Regimens in Patients with Aggressive Non-Hodgkin’s Lymphomas

Clinical Setting

Regimen

Number of Patients

Relapsed/refractory DHAP-R for 4 45 aggressive B-cell cycles lymphomaa Relapsed/refractory R-ESHAP plus 11 (DLBCL 10 DLBCL or MCL GM-CSF for 6 patients, MCL (including prior RT or cycles 1 patient) ASCT)b R-ESHAP: 2-4 8 Aggressive B-cell cycles of ESHAP, lymphoma in first 8 infusions of relapse, or partially rituximab sensitive to followed by anthracycline-based HDT-ASCT for treatmentc responders 39 Relapsed, refractory or R-EPOCH for 4-6 cycles transformed aggressive CD20-positive B-cell lymphomad R-ICE 31 Previously treated patients with aggressive NHLse Previously untreated Hyper-CVAD-R for 56 stage IV mantle-cell at least 6 cycles lymphomaf

Previously untreated and previously treated mantle-cell lymphomag

Fludarabine, mitoxantrone, and rituximab

20

Overall Response/ Complete Response (%)

Survival Data

48/28

—

84/67

—

87.5/75

—

69

Median overall survival: 14.5 months Projected 2-year survival: 49% —

81/55

—/89

—/88

Two-year failure-free survival: 72% Two-year overall survival: 90% All patients remained alive after a median follow-up of 16.4 months

a Mey UJM, 2003. b Venugopal P, 2003. c Piliotis EG, 2003. d Jost LM, 2001. e Kewalramani T, 2001. f Romaguera J, 2003. g Mohrbacker A, 2004.

Note: Full source citations appear in ‘‘References’’ ASCT = Autologous stem-cell transplantation. DHAP-R = Cisplatin, cytarabine, dexamethasone, and rituximab. DLBCL = Diffuse large B-cell lymphoma. GM-CSF = Granulocyte-macrophage colony-stimulation factor. Hyper-CVAD-R = Cyclophosphamide, doxorubicin, vincristine, dexamethasone, and rituximab. MCL = Mantle-cell lymphoma. R-EPOCH = Etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone with rituximab. R-ESHAP = Methylprednisolone, etoposide, cytarabine, cisplatin, and rituximab. R-ICE = Ifosfamide, carboplatin, etoposide, and rituximab. RT = Radiotherapy.

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Endoxan/Endoxana, generics); doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics); vincristine (Eli Lilly/EG Labo’s Oncovin, generics); and prednisone (Merck’s Decortin, generics). Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cyclophosphamide (Figure 1) is an alkylating agent and a cyclic phosphamide ester of mechlorethamine that is activated in the liver. Alkylation of DNA causes both strand breaks and the formation of cross-links between strands of DNA. Both of these events result in aberrant DNA replication and transcription of RNA. Cyclophosphamide, like other alkylating agents, is cell-cycle nonspeciÞc. However, rapidly proliferating cells are more susceptible to the action of alkylating agents because of the reduced time available for DNA enzymes to repair the cytotoxic damage. Doxorubicin (Figure 2) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic

FIGURE 1. Structure of cyclophosphamide.

FIGURE 2. Structure of doxorubicin (R = OCH3 , R1 = OH, R2 = H, R3 = H, R4 = OH).

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•

•

effect. Another doxorubicin mechanism that leads to cell death is known as DNA intercalation, in which the anthracycline molecule inserts itself between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures such as proteins and DNA. Vincristine (Figure 3) is a vinca alkaloid. Vinca alkaloids act by binding with microtubular proteins of the mitotic spindle, thereby leading to mitotic arrest or cell death. Vinca alkaloids exert selective toxicity to tumor cells by acting on proliferating cells. Prednisone (Figure 4) is a glucocorticosteroid. Glucocorticosteroids reduce the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Corticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. Adding corticosteroids to chemotherapy regimens may augment their efÞcacy.

N

OH CH3

NH H3CO H3CO

N

O

H N R

CH3 OAc O

H HO H3CO

FIGURE 3. Structure of vincristine (R = CHO).

CH2OH

O

H 3C

C

O OH

H3C

O FIGURE 4. Structure of prednisone.

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Clinical Performance. In 1993, the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a prospective, randomized Phase III trial that compared CHOP with three regimens that had seemed to offer improved survival over CHOP in Phase II trials (Fisher RI, 1993). The trial involved 899 treatment-naive patients in advanced stages of intermediate-grade or high-grade NHL. Patients in each arm received a maximum of eight cycles of therapy. The three investigational regimens were as follows: • •

•

m-BACOD: consisting of low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone; ProMACE-CytaBOM: consisting of prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue; and MACOP-B: consisting of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin.

The median ages of the groups ranged from 54 to 57 years. Approximately 25% of the patients studied were aged 65 or older (Fisher RI, 1993). At three years, 44% of all patients were alive and without disease; investigators observed no signiÞcant differences in disease-free survival among the groups: 41% in the CHOP and MACOP-B groups and 46% in the m-BACOD and ProMACE-CytaBOM groups (p = 0.35). Overall survival at three years was 52%: 50% in the ProMACE-CytaBOM and MACOP-B groups, 52% in the mBACOD group, and 54% in the CHOP group (p = 0.90). Researchers found no subgroup of patients in which survival was superior in a non-CHOP arm. No signiÞcant differences occurred in the response rates of the four treatment groups. The rates of objective antitumor responses were 80% in the CHOP group, 82% in the m-BACOD group, 83% in the MACOP-B group, and 87% in the ProMACE-CytaBOM group. The rates of complete response were 44% for CHOP, 48% for m-BACOD, 56% for ProMACE-CytaBOM, and 51% for MACOP-B. The rates of partial response were 36% for CHOP, 34% for m-BACOD, 31% for ProMACE-CytaBOM, and 32% for MACOP-B (Fisher RI, 1993). In patients with Ann Arbor stage I or localized stage II aggressive NHLs, the addition of radiotherapy to CHOP chemotherapy increased survival compared with CHOP alone. In a Phase III trial, conducted by SWOG, 401 patients with localized aggressive NHLs were randomized to receive eight cycles of CHOP alone or three cycles of CHOP and 4–5.5 Gy involved-Þeld radiotherapy (Miller TP, 1998). Five-year survival was 82% in the combined modality arm and 72% in the CHOP-only arm. Fewer life-threatening toxicities were observed in the radiotherapy/CHOP arm (31% of patients) than in the CHOP-only arm (40%). The CHOP-14 study from the German Non-Hodgkin’s Lymphoma Study Group used moderately increased doses (300 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, 0.7 g/m2 vincristine) and reduced the interval between

90


courses to 14 days (Pfreundschuh M, 2002). This schedule yielded a moderate increase in survival compared with standard CHOP and is favored by some clinicians. Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab (CHOP-R) Overview. The CHOP-R regimen incorporates cyclophosphamide (BristolMyers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics); doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics); vincristine (Eli Lilly/EG Labo’s Oncovin, generics); prednisone (Merck’s Decortin, generics); and rituximab (Genentech/Biogen-Idec/Chugai’s Rituxan, Roche’s MabThera). Rituximab has been approved in the United States for patients with low-grade or follicular, CD20+, B-cell NHLs who have relapsed or are refractory to treatment; and Þrst-line treatment of diffuse large B-cell, CD20-positive, nonHodgkin’s lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens. In Europe, rituximab is approved for CD20+ diffuse large B-cell lymphoma (DLBCL). Although the Þrst published Phase III trial examining CHOP-R in aggressive NHLs involved just elderly patients, clinicians have extrapolated these Þndings as a basis for treating patients of all ages. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the overall regimen activity: •

•

•

Cyclophosphamide (Figure 1) is an alkylating agent and a cyclic phosphamide ester of mechlorethamine that is activated in the liver. Alkylation of DNA causes both strand breaks and the formation of cross-links between strands of DNA. Both of these events result in aberrant DNA replication and transcription of RNA. Cyclophosphamide, like other alkylating agents, is cell-cycle nonspeciÞc. However, rapidly proliferating cells are more susceptible to the action of alkylating agents because of the reduced time available for DNA enzymes to repair the cytotoxic damage. Doxorubicin (Figure 2) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect. Another doxorubicin mechanism that leads to cell death is known as DNA intercalation, in which the anthracycline molecule inserts itself between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures such as proteins and DNA. Vincristine (Figure 3) is a vinca alkaloid. Vinca alkaloids act by binding with microtubular proteins of the mitotic spindle, thereby leading to mitotic arrest or cell death. Vinca alkaloids exert selective toxicity to tumor cells by acting on proliferating cells.

CURRENT THERAPIES

•

•

91

Prednisone (Figure 4) is a glucocorticosteroid. Glucocorticosteroids reduce the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Corticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. Adding corticosteroids to chemotherapy regimens may augment their efÞcacy. Rituximab is a mouse/human chimeric monoclonal antibody (MAb) directed against the cluster of differentiation (CD) 20 molecule. CD20 is a calcium channel that interacts with the B-cell immunoglobulin receptor complex (Bubien JK, 1993) and is expressed on both normal and malignant B cells, making it an ideal target for MAb therapy in B-cell disorders. Rituximab has been proposed to deplete B cells following binding to CD20 in several ways, including antibody-dependent cellular cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), and alteration of calcium ßux and factors involved in apoptosis (Lin T, 2003). CD20 regulates the activation process for cell-cycle initiation and differentiation. CD20 antigen is present in normal and malignant pre-B and mature B lymphocytes, including B lymphocytes found in more than 90% of DLBCLs. Rituximab causes lysis of the B lymphocytes via activation of the complement cascade; antibodydependent, cell-mediated cytotoxicity; and inducing apoptosis. Because the CD20 antigen is absent in hematopoietic stem cells, rituximab treatment does not deplete these cells.

Clinical Performance. A randomized Phase III clinical trial compared the efÞcacy and safety of CHOP-R and CHOP in 399 treatment-naive elderly patients (aged 60–80; median age of 69) who had DLBCL (CoifÞer B, 2003). In this landmark trial, patients were randomly assigned to receive eight cycles of CHOP every three weeks or eight cycles of CHOP-R, whereby rituximab was administered on day 1 of each cycle of CHOP. The rituximab infusion was interrupted in the event of fever, chills, edema, congestion of the head and neck mucosa, hypotension, or any other serious adverse event and was resumed when such event was no longer occurring. Adding rituximab to CHOP resulted in higher response rates and improved event-free and overall survival (CoifÞer B, 2003). The rate of complete response (including unconÞrmed complete response—greater than 75% reduction in tumor size after therapy but a residual mass and indeterminate bone marrow status) was signiÞcantly higher in the CHOP-R group than in the CHOP group (76% versus 63%). Complete responses were seen in 52% and 37% of patients and unconÞrmed complete responses in 23% and 26% (sic) of patients, respectively. At median, two-year follow-up, event-free and overall survival times were signiÞcantly higher in the CHOP-R group without any clinically signiÞcant increase in toxicity. Two-year survival stood at 70% in the CHOP-R group versus 57% in the CHOP group (p = 0.007). Investigators attributed the longer survival in the CHOP-R group to a lower rate of disease progression during therapy and fewer relapses in patients who had a complete response. A total of 19 patients (9%)

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had progressive disease in the CHOP-R group compared with 43 patients (22%) in the CHOP-alone group. Three-year follow-up data presented at the American Society of Clinical Oncology (ASCO) meeting in 2003 demonstrated that three-year overall survival stood at 62% in the CHOP-R group versus 51% in the CHOP-alone group and that three-year event-free survival was 53% and 35%, respectively. In one of the studies with Þve years of follow-up, the GELA trial, R-CHOP improved overall survival by 47 percent compared to CHOP alone (a hazard ratio of 0.68, which is equivalent to a 32 percent decrease in the risk of death). U.S. Intergroup Trial 4494 is a randomized trial investigating CHOP-R versus CHOP as Þrst-line therapy in elderly patients (60+) with DLBCL, followed by rituximab maintenance therapy or observation. A corresponding press release reported on the respective trials, as follows: Wednesday, Aug 17, 2005 Genentech and Biogen Idec File Supplemental Biologics License Application for FDA Review of Rituxan for Front-Line Treatment of Intermediate Grade or Aggressive CD-20-Positive, B-Cell, Non-Hodgkin’s Lymphoma —Filing Based on Data from Three Phase III Trials in more than 1,800 Patients— South San Francisco, Calif. and Cambridge, Mass.—17 August 2005—Genentech, Inc. (NYSE: DNA), Biogen Idec, Inc. (Nasdaq: BIIB) and Roche (SWX Zurich) today announced that the companies completed the Þling of a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) for an additional indication for Rituxan® (Rituximab), in previously untreated (front-line) patients with intermediate grade or aggressive, CD-20-positive, B-cell, non-Hodgkin’s lymphoma (NHL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens. As part of the Rituxan sBLA Þling, the companies have requested Priority Review designation from the FDA. Rituxan is currently approved for use in relapsed or refractory, low-grade or follicular, CD-20positive, B-cell, non-Hodgkin’s lymphoma. The sBLA Þling is based on efÞcacy and safety data from three randomized, controlled, multicenter studies of Rituxan in combination with CHOP or other anthracycline-based chemotherapy induction regimens in 1,854 previously untreated patients with intermediate grade or aggressive, CD-20-positive, B-cell, non-Hodgkin’s lymphoma. All three trials evaluated the efÞcacy endpoint of overall survival. “These three Phase III studies add to the body of data regarding Rituxan in the treatment of non-Hodgkin’s lymphoma,” said Hal Barron,

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M.D., Genentech senior vice president, development and chief medical ofÞcer. “We are pleased to be Þling these data with the FDA, and we are committed to working closely with the agency during the review process.” “The addition of Rituxan to CHOP represents the Þrst signiÞcant improvement in intermediate grade or aggressive CD-20-positive, Bcell NHL treatment since the development of the CHOP regimen more than 30 years ago,” said Burt Adelman, M.D., Biogen Idec’s executive vice president, Development. The studies included in this Þling are ECOG 4494 (a National Cancer Institute-sponsored intergroup trial led by the Eastern Cooperative Oncology Group), GELA/LNH 98–5 (the Group d’Etude des Lymphome d’Adulte) and MInT (MabThera International Trial M39045). Study E4494 was designed to evaluate the efÞcacy and safety of Rituxan combined with induction CHOP chemotherapy in 632 patients 60 years of age or older with intermediate-grade or aggressive, CD20-positive, B-cell, NHL. The LNH 98–5 trial conducted by GELA was designed to evaluate the efÞcacy and safety of Rituxan in combination with induction CHOP chemotherapy in 399 patients 60 years of age or older with Diffuse Large B-Cell Lymphoma (DLBCL). Based on the results of this trial, in March 2002, Rituxan, which is known as MabThera® in Europe received approval from the European Union health authority to treat aggressive NHL. The M39045 (MInT) trial was designed to evaluate the efÞcacy and safety of Rituxan in combination with CHOP or other anthracyclinebased induction chemotherapy regimens in 823 patients between the ages of 18–60. Rituximab maintenance consists of four doses weekly every six months for two years. Investigators presented Þndings of a similar study at the American Society of Hematology (ASH) annual meeting in 2003. Here, the addition of rituximab to CHOP did not inßuence the overall response rate in the induction phase (78% for CHOP-R, 77% for CHOP alone). Investigators performed additional “weighted analyses” to remove any effects of subsequent maintenance therapy. These analyses found that patients who received CHOP-R experienced a signiÞcant prolongation of time to treatment failure (a 59% increase in median failure-free survival and a 45% increase in overall survival) compared with patients who received CHOP alone. Although a signiÞcant prolongation in time to treatment failure was observed in patients who received rituximab maintenance therapy, this beneÞt was predominantly conÞned to patients who received CHOP alone during the induction phase. A large international study (the MabThera International Trial [MInT]) has investigated the combination of rituximab and CHOP-like chemotherapy in

94


previously untreated younger patients with aggressive NHLs. The study was closed early when a preplanned interim analysis of the study data by an independent data and safety monitoring committee (DSMC) showed a statistically signiÞcant improvement in time-to-treatment failure for patients receiving rituximab (Roche’s MabThera) plus chemotherapy. At a median observation time of two years, overall survival among patients who received rituximab in combination with chemotherapy was 95%, compared with 85% for those who received chemotherapy alone. Among patients treated with the combination, 19% failed treatment versus 42% of CHOP patients. CHOP-R patients had a signiÞcantly higher complete response rate (85% versus 65%) (Pfreundschuh MG, 2004). A retrospective analysis of 294 patients older than age 16 who were treated for DLBCL in Canada during the 18-month period on either side of rituximab’s introduction in 2001 found that outcomes improved dramatically after rituximab’s debut (Sehn LH, 2003). Nine percent of patients received experimental treatment with rituximab during the pre-rituximab period; 85% received treatment in the post-rituximab group. Two-year overall survival (OS) for all patients was 53% and 77%, respectively (p = 0.0001); for patients aged 60 or older, OS was 40% and 67%, respectively; and for patients younger than 60, OS was 69% and 87%, respectively. In a trial presented at ASCO in 2004, 122 patients with newly diagnosed stage III or IV MCL were randomized to receive treatment with either CHOP or CHOP-R (Hiddeman W, 2004). The CHOP-R group experienced a signiÞcantly higher rate of both overall and complete responses (94% versus 75% and 34% versus 7%, respectively). Time-to-treatment failure was signiÞcantly longer in the CHOP-R arm as well. Grade III and IV granulocytopenia was more frequent after CHOP-R (63% versus 53%, p = 0.01), but severe infections were few, thus mitigating the clinical relevance of this difference. Investigators at the Memorial Sloan Kettering Cancer Center in New York performed a retrospective analysis of outcomes of newly diagnosed DLBCL patients receiving rituximab-CHOP-14 (CHOP-R-14) (Halaas JL, 2004). Of the 49 patients included in the analysis, the median age was 52; 71% had advancedstage disease. According to the International Prognostic Index (IPI), 30.6% of the patients had low-risk disease, 22.4% low-intermediate-risk, 28.6% highintermediate-risk, and 18.4% high-risk. The investigators found that administering CHOP-R-14 is feasible in terms of toxicity. Most cycles were delivered on time and at full dose, except for vincristine, whose dose was reduced in one-third of the cycles. Ten patients were hospitalized a total of 21 times; neutropenic fever occurred in 3.6% (9/252) of cycles given. Eighty-two percent of the patients achieved a complete response or unconÞrmed complete response, and one patient had refractory disease. Progression-free survival at 18 months was 89%. Cisplatin, Cytarabine, and Dexamethasone (DHAP) Overview. The DHAP regimen incorporates cisplatin (Bristol-Myers Squibb’s Platinol AQ, generics); cytarabine (PÞzer’s Cytosar-U/Aracytine, Nippon

CURRENT THERAPIES

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Shinyaku’s Cylocide, generics); and dexamethasone (Merck/Banyu’s Decadron, generics). Mechanism of Action •

•

•

Cisplatin (Figure 5) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA that results in the inhibition of transcription and/or DNA replication mechanisms. Cytarabine, an analogue of deoxycytidine, is a pyrimidine antagonist antimetabolite. Antimetabolites interfere with the production of normal nucleic acids. Cytarabine activates the enzyme cytarabine triphosphatase and causes the substitution of arabinoside for a sugar molecule, thereby inhibiting DNA synthesis. Cytarabine undergoes intracellular metabolism into its active, triphosphate form: cytosine arabinoside triphosphate. This metabolite damages DNA via multiple mechanisms, which include the competitive inhibition of DNA polymerases, resulting in inhibition of DNA repair, and direct mis-incorporation into DNA. The latter mechanism is probably the most important for inducing cell death. Cytotoxicity is highly speciÞc for the S phase of the cell cycle. Dexamethasone (Figure 6) is a glucocorticosteroid. Corticosteroids reduce the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Corticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. Adding corticosteroids to chemotherapy regimens may augment their efÞcacy.

Clinical Performance. Of the 90 patients with progressive, recurrent, intermediate-grade NHLs who were treated with six to ten cycles of DHAP in

FIGURE 5. Structure of cisplatin.

OR O HO

OH

F O

FIGURE 6. Structure of dexamethasone (R = H).

96


a Phase II trial, 34% achieved a complete response and 27% achieved a partial response (Velasquez WS, 1988). At a median follow-up of 11 months, only eight of the complete responders had relapsed. The two-year overall survival was 25%. Investigators observed a signiÞcant difference in response and survival rates for patients with low tumor burden and normal lactate dehydrogenase (LDH) compared with patients with both high tumor burden and elevated serum LDH levels. In the former group, 67% achieved a complete response and 61% survived for two years; in the latter group, no patients achieved a complete response and only 5% survived for one year. Patients with either high tumor burden with normal LDH or low tumor burden with elevated LDH achieved intermediate survival rates, compared with the survival rates of the Þrst two groups. Myelosuppression-related infection was the most frequent serious complication of this regimen (31%) and the cause of death in ten patients. Seven deaths occurred within two weeks of therapy. Details of a multicenter Phase II trial evaluating the safety and efÞcacy of DHAP in combination with rituximab (DHAP-R) for the treatment of patients with relapsed/refractory aggressive B-cell lymphoma are shown in Table 11. Methylprednisolone, Etoposide, Cytarabine, and Cisplatin (ESHAP) Overview. The ESHAP regimen incorporates methylprednisolone Medrol/Medrone/Medrate, generics); etoposide (Bristol-Myers VePesid/Etopophos, PÞzer’s Lastet, generics); cytarabine (PÞzer’s U/Aracytine, Nippon Shinyaku’s Cylocide, generics); and (Bristol-Myers Squibb’s Platinol AQ, generics).

(PÞzer’s Squibb’s Cytosarcisplatin

Mechanism of Action •

Methylprednisolone (Figure 7) is a more soluble salt of prednisolone. Prednisolone is a glucocorticosteroid. Corticosteroids reduce the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Corticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. Adding corticosteroids to chemotherapy regimens may augment their efÞcacy.

OR O HO

OH

O

FIGURE 7. Structure of methylprednisolone (R = H).

CURRENT THERAPIES

R

O O HO

97

O O OH O O O O CH3O

OCH3 RO

FIGURE 8. Structure of etoposide (R = H, R1 = CH3 ).

•

•

•

Etoposide (Figure 8) is an epipodophyllotoxin. Epipodophyllotoxins cause single-strand breaks in DNA and inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is speciÞc to the cell-cycle phase; its predominant activity occurs in the late S phase and G2 phase. Cytarabine, an analogue of deoxycytidine, is a pyrimidine antagonist antimetabolite. Antimetabolites interfere with the production of normal nucleic acids. Cytarabine activates the enzyme cytarabine triphosphatase and causes the substitution of arabinoside for a sugar molecule, resulting in the inhibition of DNA synthesis. Cytarabine undergoes intracellular metabolism into its active triphosphate form: cytosine arabinoside triphosphate. This metabolite damages DNA via multiple mechanisms, which include the competitive inhibition of DNA polymerases, resulting in inhibition of DNA repair, and direct mis-incorporation into DNA. The latter mechanism is probably the most important for inducing cell death. Cytotoxicity is highly speciÞc for the S phase of the cell cycle. Cisplatin (Figure 5) is a platinum agent. Platinum agents generate highly reactive, charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA that results in the inhibition of transcription and/or DNA replication mechanisms.

Clinical Performance. Researchers at the M.D. Anderson Cancer Center in Houston, Texas, reviewed the Þndings from 122 patients with relapsed or refractory NHLs who received treatment with one cycle of ESHAP (Velasquez WS, 1994). The Þrst 63 patients were randomized to treatment with or without cisplatin (ESHA or ESHAP); however, because of the marked differences in response rates between the two treatment arms (33% versus 75%), the ESHA arm was discontinued and all subsequent patients received ESHAP. Of 122 patients receiving ESHAP, 37% had a complete remission and 27% had a partial remission, for an overall response rate of 64%. The median duration of complete response was 20 months. At three years, 28% of patients remained

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in a state of complete response. The overall median survival duration was 14 months; the survival rate at three years was 31%. At 40 months, 10% of all patients were alive and disease-free. Response and survival rates were similar in patients with low-grade (34 patients), intermediate-grade (67), transformed (18), and high-grade (3) lymphomas. Investigators observed a signiÞcant difference in survival for patients with normal LDH levels and low or intermediate tumor burden and patients with low tumor burden and elevated LDH levels (55% threeyear survival rate) versus patients with elevated LDH levels and intermediate or high tumor burden (60 years of age with aggressive non-Hodgkin’s lymphoma: results of the completed NHL-B-2 trial of the DSHNHL. Blood 2002:100:774. Pfreundschuh MG, et al. Randomized intergroup trial of Þrst-line treatment for patients ≤60 years with diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) with a CHOPlike regimen with or without the anti-CD20 antibody rituximab—early stopping after the Þrst interim analysis. Proceedings of the American Society of Clinical Oncology. 2004. Abstract 6500. Philip T, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. New England Journal of Medicine. 1995;333:1540–1545. Piekarz R, et al. Analysis of molecular markers and targets in trials of depsipeptide, FR901228, a histone deacetylase inhibitor with clinical activity in T-cell lymphoma. Proceedings of the American Society for Clinical Oncology. 2002. Abstract 88. Piekarz R, et al. Cardiac effects of depsipeptide, FK228, in patients with T-cell lymphoma. Proceedings of the American Society for Clinical Oncology. 2003. Abstract 806. Piekarz RL, et al. Depsipeptide (FK228) in patients with cutaneous T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy. Proceedings of the American Society of Hematology. 2003. Abstract 2366.

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Bladder Cancer

ETIOLOGY AND PATHOPHYSIOLOGY Background Bladder cancer (BC), the seventh most common malignancy in the world, is primarily a disease of men older than 65 and is rarely diagnosed before the age of 40 (Ferlay J, 2001; Herr HW, 2001). The link between BC and smoking, as well as occupational exposure to certain carcinogens, is well established. Cigarette smoking is the most important cause of BC, accounting for up to 50% of BC in men and 33% in women (IARC, 1987). The development of BC is associated with the excretion of carcinogenic metabolites in the urine (Van der Meijden APM, 1998). The bladder urothelium may have direct contact with these carcinogens, which damage the urothelial cells that line the inside of the bladder and increase the chances of developing cancer (Silverman DT, 1992). High consumption of ßuids, however, may reduce the exposure by diluting the urine and reduce the contact time through increased frequency of urination (Braver DJ, 1987). The ultimate recurrence and progression of tumors may require multiple insults to the uroepithelium. In addition, further molecular alterations, such as genetic mutations, may be necessary for tumor progression (Lee R, 2000). Predicting future tumor behavior is a major task when treating BC (Zlotta AR, 2000); researchers are just beginning to understand the genetic events that occur in BC. Determining the prognostic signiÞcance of each genetic alteration and designing new therapies that directly target these alterations is a signiÞcant Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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143

challenge for researchers who are working to prevent BC and improve treatment outcomes. Pathophysiology Anatomy of the Bladder. The normal human urinary bladder (Figure 1) is a hollow, balloon-shaped organ that has a muscular wall that allows it to expand and contract. It is located in the lower abdomen and collects urine from the kidneys via thin tubes called ureters; the urine is stored until it is excreted through another tube called the urethra. The urinary bladder has three layers: the epithelium and the subepithelial connective tissue, the muscularis, and the perivesical fat (Fleming ID, 1997). A layer of urothelial cells (transitional cells) lines the inside of the kidney, ureter, bladder, and urethra. This layer is known as the urothelium or transitional epithelium. Under the urothelium is a thin region of connective tissue called the lamina propria. The next deeper layer is a wider region of muscle tissue called the muscularis propria. Beyond this muscle tissue, another region of fatty connective tissue separates the bladder from other, nearby organs (American Cancer Society [ACS], 2004). Figure 2 shows the extent of primary BC with tumor staging according to the tumor, node, metastasis (TNM) system. Pathogenesis and Natural History. BC is a disease in which cancer cells form in the tissues of the bladder. It appears that alteration in cell-cycle regulation is a key event in determining the biological behavior of BC (Cote RJ, 2003). Normal cellular proliferation takes place in an orderly fashion through the cell cycle. Cell-cycle-associated protein complexes composed of cyclins and cyclindependent kinases (Cdks) regulate normal cellular proliferation. Several tumor suppressor genes (TSGs), together with their protein products (p53, pRb, p16, and p14), act at the G0/G1 checkpoint to prevent the loss of cell-cycle control and

FIGURE 1. Structure of the normal human urinary system.

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FIGURE 2. Extent of primary bladder cancer with tumor staging according to the TNM system.

tumor progression (Quek ML, 2003; Williams SG, 2001). Mutations in a single TSG are unlikely to be the only factor resulting in carcinogenesis; alterations of one of the several pathways within the cell cycle are likely to be responsible for the progression of BC (Williams SG, 2001). The natural history of BC correlates with several prognostic factors, including histological grade, the depth of penetration into the bladder wall (stage), the appearance of vascular/lymphatic invasion, and the presence of carcinoma in situ (CIS) (Lee R, 2000). The biological foundation underlying the different types of BC within each of these categories is not fully understood. Some tumors, for example, appear to have favorable histology, but they progress and express aggressive activity despite theoretically curative treatment, while other tumors appear to have unfavorable histology but are less aggressive (Lee R, 2000). Two risks have been attached to all superÞcial tumors: a risk of recurrence with no worsening of the stage or grade, and a risk of progression leading to muscle-invasive and metastatic disease (Chopin DK, 2002). Low-grade, lowstage tumors pose less risk of progression than do high-grade, high-stage tumors (Chopin DK, 2002). CIS is by deÞnition a high-grade tumor; it is found in more


145

than half of bladders with multiple papillary tumors (Herr HW, 2001). Primary CIS constitutes 1–2% of newly detected cases of BC (Herr HW, 2001). CIS is believed to be a predominant precursor of invasive tumors (Herr HW, 2001). A previous study described three types of CIS. Type 1 CIS is an early stage of BC; tumors are not very aggressive and are unifocal. Type 2 CIS causes bladder irritative symptoms, and tumors are multifocal. Type 3 CIS increases the risk of recurrence, progression, and cancer-related death, and tumors are associated with one or more other tumors (Lamm DL, 1992). Multiple pathways of human bladder carcinogenesis have been proposed. We brießy describe one of these pathways below. When BC arises, the initial step is intraepithelial neoplastic transformation (Lee R, 2000). The transformed urothelial cells acquire growth advantages that allow them to expand and achieve dominance over normal urothelial cells. Assuming that tumorigenesis is a multiple-step process, papillary forms of BC arise via the ampliÞcation of cyclin D1, upregulation of vascular endothelial growth factor (VEGF), and loss of heterozygosity of chromosome 9. In contrast, p53 or Rb inactivation and platelet-derived endothelial cell growth factor (PDECGF) expression are implicated in the development of invasive forms of urothelial carcinoma, also known as transitional-cell carcinoma, or TCC (Lee R, 2000). Metastatic BC is a fatal disease; the most common sites of metastases are regional lymph nodes, lung, liver, bone, and skin. Less common sites are the brain, meninges, and the organs within the peritoneal cavity (Al-Sukhun S, 2003). The distribution of metastasis is particularly important when considering treatment because the sites of involvement appear to correlate with prognosis (Al-Sukhun S, 2003). Classification. The three major types of cancers that affect the bladder are urothelial carcinoma (TCC), squamous-cell carcinoma, and adenocarcinoma (Cote RJ, 2003). More than 90% of BCs are TCCs derived from the uroepithelium (Herr HW, 2001). About 3% of BCs are pure squamous-cell carcinomas, and 2% are adenocarcinomas (Herr HW, 2001). The remaining 5% are a mix of transitionalcell and squamous-cell carcinomas or adenocarcinomas. Nearly all squamous-cell carcinomas and adenocarcinomas of the bladder are invasive. Signs and Symptoms. Hematuria, the appearance of blood in the urine, is the key symptom of BC (Van der Meijden APM, 1998). Hematuria is either visible or microscopic. Hematuria occurs in 80–90% of cases, but urinary frequency, bladder irritability, and reduction in overall bladder capacity are also common (Herr HW, 2001). Rarely, metastatic bone lesion pain or local progression of disease is the presenting sign (Herr HW, 2001). Screening asymptomatic patients for hematuria does not seem to have any effect on overall survival; it does, however, increase the probability of diagnosing the disease at an earlier stage (Herr HW, 2001). Prospective studies are ongoing to assess the role of screening in high-risk populations.

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BLADDER CANCER

Staging. Physicians in the seven major markets generally stage BC according to the internationally recognized TNM (primary tumor/regional lymph nodes/ distant metastasis) classiÞcation system developed by the American Joint Committee on Cancer (AJCC) (see Table 1). BC staging is determined by the depth to which the tumor invades the bladder wall. For speciÞc deÞnitions of the BC TNM staging system and one- to Þve-year survival rates, see Table 2. SuperÞcial BC can be classiÞed as low-risk, intermediate-risk, or high-risk according to the likelihood of progression. Table 3 lists the risk of progression and cancer-related death according to tumor stage and grade. Clinically, BCs are classiÞed as superÞcial, muscle-invasive, or metastatic disease (Herr HW, 2001). SuperÞcial tumors conÞned to the bladder mucosa, submucosa, or lamina propria account for 70–80% of newly diagnosed BCs. About 20% of BCs invade the muscle layer (invasive BC) and up to 5% have de novo metastases (metastatic BC) (Cote, RJ 2003; Al-Sukhun S, 2003; Herr HW, 2001). SuperÞcial BCs consist of papillary tumors that can be low-grade or highgrade (Ta, grade 1–3) and CIS (Crawford ED, 2003). In patients who have CIS TABLE 1. AJCC TNM Classification System for Bladder Cancer Primary Tumor (T) TX T0 Ta Tis T1 T2 pT2a pT2b T3 pT3a pT3b T4 T4a T4b

Criteria Primary tumor cannot be assessed. No evidence of primary tumor Noninvasive papillary carcinoma Carcinoma in situ: ‘‘flat tumor’’ Tumor invades subepithelial connective tissue Tumor invades muscle Tumor invades superficial muscle (inner half) Tumor invades deep muscle (outer half) Tumor invades perivesical tissue Microscopically Macroscopically (extravesical mass) Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall Tumor invades the prostate, uterus, vagina Tumor invades the pelvic wall or abdominal wall

Regional node status (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension N2 Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node, more than 5 cm in greatest dimension Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis AJCC = American Joint Committee on Cancer. TNM = Tumor, node, metastasis.


147

TABLE 2. Definitions for the TNM Staging Classification of Bladder Cancer

AJCC Stage

Bladder Cancer Survival by One-Year Two-Year Three-Year Four-Year Five-Year Stage (%) (%) (%) (%) (%)

Definition

0a

Ta, N0, M0

0is

Tis, N0, M0

0

94.00

88.09

82.25

76.63

I II

70.35

T1, N0, M0

I

91.33

82.50

75.24

68.59

62.44

T2a, N0, M0 T2b, N0, M0

II

75.07

58.03

49.01

42.48

37.88

III

T3a, N0, M0 T3b, N0, M0 T4a, N0, M0

III

64.84

45.02

35.74

30.44

26.04

IV

T4b, N0, M0 Any T, N1, M0 Any T, N2, M0 Any T, N3, M0 Any T, any N, M1

IV

41.65

23.37

16.85

13.35

11.46

Overall

84.96

74.82

67.85

61.96

56.39

AJCC = American Joint Committee on Cancer. TNM = Primary tumor (T), lymph node spread (N), distant metastasis (M). Note: Survival data from National Cancer Data Base (NCDB). Data accessed August 15, 2004.

TABLE 3. Risk of Progression and Cancer-Related Death According to Tumor Stage and Grade

Risk Group Low

Intermediate

High

Types of Tumor Single pTa G1 pTa G1–G2 (not recurring in less than three months) Multifocal pTa G2 pTa with multiple recurrences pTa G3, single pT1 G2 pT1 G3 Diffuse pTis Multifocal pT1 pT1 recurring in less than six months

Risk of Disease Progression at Five Years (%)

Risk of Cancer-Related Mortality at Ten Years (%)

7.1

4.3

17.4

12.8

41.6

36.1

Adapted from Rischmann P, 1998. Full source citations appear in ‘‘References.’’

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associated with papillary tumors, the potential for developing muscle-invasive disease is 42–83%, compared with 20–34% in patients who have isolated CIS (Hudson MA, 1995). Overall, the risk of bladder muscle invasion for noninvasive disease (pTa, 9%) is half that for invasive disease (pT1, 18%) (Kurth K, 1992). CIS (pTis) makes up less than 5% of all bladder tumors (Chopin DK, 2002). Left untreated, CIS will progress to invasive disease in Þve years in more than 50% of patients (Herr HW, 2001). The risk of CIS progression increases with widespread disease. Grading. Bladder tumors are classiÞed as low-grade (G1) or high-grade (G2, G3) according to the World Health Organization (WHO) classiÞcation (Epstein JI, 1998). Grading is of major importance for noninvasive tumors (superÞcial tumors) because almost all invasive neoplasms (T1 or greater) are high-grade (Herr HW, 2001). Grade 1 tumors are much less likely (6%) to progress than grade 3 tumors (30%) (Kurth K, 1992). Researchers have found that over 20 years of follow-up, the risk of progression increases to 14% for pTaG1 tumors and 45% for pT1G3 tumors; the risk of recurrence, however, is the same (approximately 50%) regardless of the aggressive nature of the tumor (Herr HW, 1997). Also, tumors of similar grade may behave very differently; additional markers are therefore crucial for identifying patients at risk for disease progression or recurrence (Zlotta AR, 2000). For invasive (muscle-invasive/metastatic) tumors, however, stage is the most important independent prognostic variable for progression and overall survival (Herr HW, 2001). The healthy epithelium has normal nuclear polarity, no pleomorphism, and a thickness of less than Þve to seven layers (Herr HW, 2001). Low-grade papillary carcinomas are relatively benign tumors that closely resemble the normal urothelium: normal nuclear polarity in more than 95% of the tumor; no, or only slight, pleomorphism; and more than seven layers of urothelium. In addition, low-grade papillary carcinomas rarely progress to a higher stage. High-grade papillary tumors show loss of polarization of the nuclei or moderate or prominent pleomorphism (Herr HW, 2001); progression to higher-stage lesions is therefore frequent. Prognostic Factors. For BC, the Þve-year survival rates range from approximately 11% for patients with advanced disease to approximately 70% for patients diagnosed with localized disease (National Cancer Data Base, 2004). The biggest challenge for researchers is to identify the group of patients whose disease has the potential to evolve into muscle-invasive disease and, subsequently, metastatic disease. Studies have found improved median survival in patients with metastasis limited to the lymph nodes, skin, and possibly the lungs; substantially worse prognoses have been documented in patients with liver, bone, and visceral metastasis (Geller NL, 1991; Loehrer PJ, 1992). The pattern of growth is important; superÞcial tumors are associated with better prognosis. Additionally, histology (TCC versus squamous-cell carcinoma and adenocarcinoma) is an important factor in treatment outcome. Evidence shows that patients with metastatic adenocarcinoma or squamous-cell carcinoma do not


149

generally respond to chemotherapy and have a worse median survival compared with TCC patients (Saxman SB, 1997). Etiology Risk Factors. Most known cancer risk factors can be categorized as processes that increase a person’s exposure to mutagens; interfere with or prevent normal DNA repair; and/or increase the proliferation rate of cells (e.g., as a result of repetitive injury and tissue repair). Cigarette smoking is the principal known risk factor for BC, though occupational exposure to arylamine N -acetyltransferases (NATs), polycyclic aromatic hydrocarbons (PAHs), and aromatic amines is also associated with its development (Hung RJ, 2004; Yu MC, 1998). Workers who have an increased risk of developing BC include painters, truck drivers, and drill press operators (Silverman DT, 1989). Other industries that pose an increased risk to workers include the dye, rubber, and leather industries. Cigarette Smoking. Cigarette smoking is by far the most important risk factor for BC: 25–65% of all cases are attributable to this habit (Lee R, 2000). Smokers are two to four times more likely to develop BC than the general population (Lee R, 2000). Researchers have found that the duration and intensity of cigarette smoking independently increases the risk of developing BC (Castelao JE, 2001). The latency period from initial exposure to the development of the urothelial tumor is a median of 18 years (Herr HW, 2001). However, study results of the effect of cigarette smoking on BC have been inconsistent. One study found a positive correlation between smoking history and histological grade, stage, number, and size of bladder tumors (Thompson IM, 1987). In another study, tenyear survival data showed that 40% of smokers died of their disease compared with 27% of nonsmokers, even though no correlation between smoking history and histological grade or stage was observed (Raitamen MP, 1995). A subsequent study found no difference in BC risk between smokers of Þltered or low-tar cigarettes and smokers of nonÞltered or high-tar cigarettes, implying that lowtar cigarettes are no less mutagenic to human bladder urothelium than high-tar cigarettes (Castelao JE, 2001). The risk of TCC is related to the type of tobacco smoked; air-cured “black” tobacco is associated with higher risk because of its greater concentration of carcinogenic byproducts than is found in ßue-cured “blond” tobacco (Lee R, 2000; Silverman DT, 1996). A marker of arylamine exposure found in cigarette smoke (3- and 4-aminobiphenyl [ABP]-hemoglobin adduct) may play a role in smoking-induced bladder carcinogenesis (Yu MC, 1998). The 4-aminobiphenyl (ABP)-hemoglobin adducts, and the adducts of several other aromatic amines, are higher for smokers of black tobacco than for smokers of blond tobacco. Further, the urine of people who smoke black tobacco is more mutagenic than the urine of those who smoke blond tobacco (Silverman DT, 1996). The exact roles that pipe tobacco, cigars, and smokeless tobacco play in BC are unclear; however, most of the evidence suggests that pipe smokers are at increased risk for developing BC (Silverman DT, 1996).

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Smoking cessation has been found to reduce the risk of developing BC by 30–60% (Silverman DT, 1996). A reduction in smoking-related incidence of BC to a rate equal to that of the nonsmoking population comes ten years after cessation of smoking (Herr HW, 2001). The effect of reduced smoking is proportional to the length of time since quitting (Castelao JE, 2001). Other Risk Factors. Compared with smoking, other risk factors play a minor role in BC development. Nevertheless, they can potentiate a smoker’s risk of developing BC. •

•

•

Genetic susceptibility and carcinogen exposure. Glutathione S-transferases, including GSTM1, GSTP1, and GSTT1, play a role in detoxifying metabolites of carcinogens in tobacco smoke. GSTs are also involved in detoxifying the reactive metabolites of polycyclic aromatic hydrocarbons (PAHs) (Hung RJ, 2004). The data available for GSTP1 polymorphism and BC risk are inconclusive (Toruner GA, 2001; Harries LW, 1997; Katoh T, 1999). GSTM1 and GSTT1 polymorphisms may modulate individual susceptibility to BC (Hung RJ, 2004). Aromatic amines. The aromatic amines are urothelial carcinogens metabolized by arylamine N -acetyltransferases (NATs). Two types of NATs—NAT1 and NAT2 —are involved in the activation and detoxiÞcation of aromatic amines (Hein DW, 2000). The lack of two functional NAT2 alleles leads to a slow acetylation phenotype, while NAT1 *10 and *11 are associated with faster enzyme activity. A meta-analysis of NAT2 showed an increased risk of BC among smokers with slow acetylators (Marcus PM, 2000[a,b]). Data available for NAT1 in fast acetylators and BC risk are less conclusive (Hung RJ, 2004). Sulfotransferase 1A1 (SULT1A1 ) and cytochrome P450 1B1 (CYP1B1 ) are also involved in metabolizing PAHs and aromatic amines. Recent Þndings show that the risk of BC may be modulated by GSTM1, GSTT1, NAT2, and SULT1A1 polymorphisms, possibly in combination with exposure to aromatic amines (Hung RJ, 2004). Additionally, both GSTM1 and GSTT1 deletions appear to play a more signiÞcant role in bladder carcinogenesis among younger subjects. The GSTM1 null genotype also has a strong effect in heavy smokers, suggesting that GSTM1 null genotype is not an independent risk factor but acts synergistically with smoking on BC risk (Hung RJ, 2004). The Þndings show no association between NAT1 polymorphisms and BC risk. GSTM1, GSTT1, NAT2, and SULT1A1 polymorphisms may therefore modulate individual susceptibility to BC (Hung RJ, 2004). Gender. Approximately 75% of BC patients are men (van der Meijden APM, 1998). However, the risk of BC may eventually become higher in women. A population-based, case-control study involving 1,514 BC patients and 1,514 matched controls found that the risk of developing BC is higher in women than in men who smoked comparable numbers of cigarettes (Castelao JE, 2001). Researchers found that women who smoke have more elevated


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levels of 3- and 4-ABP-hemoglobin adducts than do men who smoke comparable amounts. Arylamines (including ABPs) found in cigarette smoke play a major role in smoking-induced bladder carcinogenesis; consequently, women may have a higher risk of developing BC (Castelao JE, 2001). Diet. A prospective health professional follow-up study in 47,909 men over a ten-year period found that the intake of cruciferous vegetables (e.g., broccoli, cabbage, caulißower, brussels sprouts) is inversely associated with BC risk (Michaud DS, 1999[a]). The data have reached statistical signiÞcance was speciÞcally reached in the cases of broccoli and cabbage. This inverse association was strongest among nonsmokers. The data suggest that a diet in cruciferous vegetables may substantially reduce BC risk (Michaud DS, 1999[a]). Researchers proposed that an increase in cruciferous vegetable intake protects the bladder epithelium from carcinogens by enhancing detoxiÞcation of xenobiotics prior to excretion (Michaud DS, 1999[a]). The prospective evaluation of ßuid intake in the health professional follow-up study found a clear link between increased ßuid intake and a decreased risk of BC. The Þndings from this U.S. study suggest that high intake of water may reduce the risk of developing BC by approximately 50% (Michaud DS, 1999[b]). A recent population-based, case-control study involving 1,592 BC patients and 1,592 controls (matched by sex, date of birth [within Þve years], and race) found a strong inverse association between BC risk and intake of dark green vegetables, after adjusting for nondietary risk factors, including cigarette smoking (Castelao JE, 2004). The study also found a strong inverse association between BC risk and intake of citrus fruits/juices—or, in terms of nutrients, total carotenoids and vitamin C (Castelao JE, 2004). Consumption of fried meat and fat in high quantities is associated with increased risk of BC (Herr HW, 2001; Silverman DT, 1996). Arsenic. Ingestion of arsenic in drinking water is a strong risk factor for several forms of cancer, including BC. Long-term arsenic exposure is associated with a greater risk of developing BC. A recent study found that higher levels of arsenic exposure are associated with higher levels of chromosomal instability in patients with bladder tumors (Moore LE, 2002). The study also found that deletions in part or all of chromosome 9q are increased in tumors from patients exposed to high levels of arsenic. Most of the chromosomal alterations associated with arsenic exposure were also associated with tumor stage and grade, possibly suggesting that bladder tumors from arsenic-exposed patients may behave more aggressively and result in a higher mortality rate than tumors from unexposed patients (Moore LE, 2002). The molecular mechanisms by which arsenic causes cancer are uncertain, but researchers hypothesize that arsenic probably causes increased genetic instability in BC, possibly by deregulating the cell-cycle control pathways via epigenetic mechanisms or by reducing the cell’s ability to respond properly to or to repair DNA damage (Moore LE, 2002).

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Familial predisposition. Persons with family members who have BC are at increased risk of developing the disease (Silverman DT, 1996). The risk is high in patients with environmental exposure such as heavy cigarette smoking, implying that both genetic and environmental interactions play a role in BC. Race. White men are twice as likely as black men to be diagnosed with BC, and the diagnosis rate is higher in urban than in rural areas (Herr HW, 2001). The higher incidence in whites than in blacks is limited to localized cases; in more advanced tumors, the risk for whites and blacks is similar (Silverman DT, 1996). Asians and Hispanics have the lowest rates of BC, and BC risk is very low in American Indians (Silverman DT, 1996). Age. The incidence and mortality of BC increases with age; approximately two-thirds of all cases occur in people aged 65 or older (Silverman DT, 1996). The median age at diagnosis is between 68 and 69 years (ACS, 2004). BC is rarely diagnosed in people younger than 40 (Herr HW, 2001). Schistosoma haematobium. Exposure to S. haematobium, a parasite found in many developing countries, is associated with increased risk of both squamous-cell carcinoma and TTC of the bladder (Herr HW, 2001). Cyclophosphamide. High doses of cyclophosphamide, an alkylating agent used in the treatment of both malignant and nonmalignant diseases, increases the risk of BC. Cyclophosphamide was found to produce bladder tumors in both rats and mice (Silverman DT, 1996). Patients who are taking higher doses or taking cyclophosphamide for long periods of time are at increased risk for developing BC. Radiation. Ionizing radiation causes BC, but this exposure contributes very little to the incidence of BC in the general population (Silverman DT, 1996).

Genetic Mutations. Studies of different stages and grades of BC have shown that mutations in proto-oncogenes and TSGs may be critical to the development and progression of bladder tumors. In general, loss of TSGs—the p53 on chromosome 17 and the retinoblastoma [Rb, on chromosome 13]) are common in patients with invasive disease, while aberrations of 9q occur mainly in superÞcial tumors (Herr HW, 2001). Deletions of several chromosomal arms—including 9p, 9q, 11p, 13q, and 17p—have been noted in BC (Cote RJ, 2003). Deletions of chromosome 9 are the most common abnormalities associated with BC (Quek ML, 2003). In fact, chromosome 9 alterations may represent an early event in TCC, because deletions of this chromosome are found in both low- and highgrade BC (Quek ML, 2003). The majority of chromosome 9 deletions involve the 9p21 locus, which encodes three distinct proteins: p16, p14, and p15. All three proteins act as negative cell-cycle regulators and are therefore considered potential TSGs (Quek ML, 2003; Williams SG, 2001). Additionally, deletions on the short arm of chromosomes 3 (3p) and 8 (8p) have been found in high-grade, muscle-invasive BC, though the relevant genes have yet to be identiÞed (Quek ML, 2003; Williams SG, 2001).

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Abnormalities in Rb and p53 genes are pervasive in many types of cancer, including BC, and are often important in the cascade of events that leads to the malignant phenotype. When either p53 or Rb gene product is missing or altered, negative checks on cell growth are deactivated; the “switch” is turned on, and uncontrolled cell proliferation ensues. The pervasiveness of these genetic abnormalities has led researchers to suspect that these genes act as “master switches” that control tumor formation. Table 4 brießy describes the oncogenes and TSGs implicated in BC and their clinical signiÞcance. Evidence suggests that p53 and pRb proteins have a cooperative negative effect on both progression and survival in primary BC. A marked increase in progression and decreased overall survival have been observed in BC patients with both p53 and pRb alteration (Cordon-Cardo C, 1997). Studies have shown that patients with p53 wild-type or pRb wild-type tumors are at signiÞcantly decreased risk of developing BC recurrence and mortality, compared with patients in whom both proteins are altered (Shariat SF, 2004). Altered expression of p53 and pRb/p16 and p21 is associated with an increased risk of BC progression and death (Shariat SF, 2004). Recurrent Disease. Generally, superÞcial BC is fairly benign. Approximately 10–30% of patients with superÞcial tumors will progress to muscle-invasive or metastatic disease, despite frequent recurrences; recurrence rates after initial successful treatment range from 30% to 85%, with grade progression occurring in 10–30% of patients and stage progression occurring in 4–30% of patients (Crawford ED, 2003). Despite complete eradication of the primary tumor, approximately two-thirds of patients will develop tumor recurrences within the Þrst Þve years of follow-up (Crawford ED, 2003). In contrast, invasive tumors are highly malignant and have a less favorable prognosis (Al-Sukhun S, 2003); for example, approximately 50% of patients treated locally for invasive tumors relapse with metastases within two years of treatment (Williams SG, 2001). Therefore, the prevention of invasive disease and of noninvasive superÞcial disease continues to be the ultimate goal for researchers interested in preventing BC and improving treatment outcomes. CURRENT THERAPIES Unless noted otherwise, our deÞnition of bladder cancer (BC) is mainly interchangeable with that of transitional cell cancer (TCC) of the urothelium. BC and TCC are not pathologically the same. However, we have grouped all forms of BC together when evaluating clinical data because TCC encompasses more than 90% of all BCs (Herr HW, 2001), and because other pathological types of BC are treated similarly (staging and grading being more important determinants of treatment and patient stratiÞcations in clinical trials). Treatment options for BC patients include surgery, radiotherapy, intravesical pharmacotherapy, and systemic chemotherapy. Treatment decisions are guided primarily by the stage of disease, although the pathological grade of the disease

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TABLE 4. Select Genetic Mutations in Bladder Cancer Gene/Protein

Function

Tumor suppressor genes p53 The p53 protein normally prevents the propagation of DNA damage by causing cell arrest at the G1/S checkpoint through the induction of p21 and inducing apoptosis. Mutations in the p53 gene remove this regulatory control, allowing mutation-carrying cells to progress through the cell cycle. Mutated p53 results in the nuclear accumulation of the abnormal protein with a prolonged half-life (Al-Sukhun S, 2003). Generally, an intact p53 regulatory mechanism is thought to be necessary for the activity of DNA-damaging cytotoxic agents.

p21

pRb/p16

p21 is an important target of the p53 protein. The p21 protein is both a p53-inducible and p53-independent cyclin-dependent kinase inhibitor that can arrest the cell by inhibiting DNA replication (Shariat SF, 2004; Zlotta AR, 2000). The retinoblastoma tumor suppressor gene (Rb) encodes a protein (pRb) that acts downstream of p53, also causing cell arrest at the G1/S checkpoint. The p16 gene regulates pRb function by inhibiting CDK4 enzyme activity. Inactivation of this gene therefore has the downstream effect of disrupting pRb-mediated cell-cycle control.

Comments A recent study found altered expression of p53 in 56% of patients undergoing radical cystectomy (45 out of 80) (Shariat SF, 2004). Altered expression of p53 was independently associated with disease progression. p53 was the strongest predictor of BC outcome, followed by p21, suggesting a fundamental role of the p53/p21 pathway in BC progression (Shariat SF, 2004). Tumors negative for both p53 and p21 proteins, even in high-risk superficial BC, seem to have favorable prognosis in terms of recurrence (Zlotta AR, 2000). A previous study found that accumulation of p53 protein in the tumor cell nuclei is associated with an increased risk of recurrence and decreased overall survival in patients with transitional-cell carcinoma (TCC) confined to the bladder (Esrig D, 1994). Altered expression of p21 was found in 49% of patients undergoing radical cystectomy (39 out of 80) (Shariat SF, 2004). The p21 protein seems to be associated with the early stages of BC progression. pRb or p16 proteins were altered in 54% of patients undergoing radical cystectomy (43 out of 80) (Shariat SF, 2004). Altered expression of p53, pRb/p16 and p21 is associated with an increased risk of BC progression and death (Shariat SF, 2004). While p21 seems to be associated with the early stages of BC progression, p53 and pRb/p16 seem to be associated with the later stages. Several other studies have shown significant association between loss of the Rb gene, tumor stage, and tumor grade; the data suggest that this loss is more commonly associated with invasive BC (Al-Sukhun S, 2003).

TABLE 4. (continued) Gene/Protein Oncogenes E2F3

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Function

Comments

E2F3, a candidate BC oncogene located on chromosome 6p22, is the latest oncogene to be implicated in BC. E2F3 protein is involved in controlling cell division. E2F3 appears to provide growth advantage to tumor cells by activating cell proliferation in a subset of bladder tumors (Oeggerli M, 2004).

Overexpression of E2F3 protein was found to be associated with cell proliferation and development of BC (Feber A, 2004). A high level of E2F3 protein was associated with tumor stage and grade (Feber A, 2004). Researchers have also found that a high level of E2F3 protein expression is associated with high grade, advanced stage, and E2F3 gene amplification (Oeggerli M, 2004). E2F3 was found to be frequently amplified and overexpressed in invasive BC (stage pT1-T4) (Oeggerli M, 2004). Mutations of the H-ras gene have been implicated in the development and progression of BC. Alterations in codon 12 and 61 of the H-ras gene were found in up to 20% of BC (Quek ML, 2003). cH-ras overexpression is correlated with early recurrence in patients with superficial BC; however, subsequent studies have not found this prognostic effect (Quek ML, 2003). Myc genes are overexpressed in high-grade bladder tumors, but correlation with progression or survival has not been found (Al-Sukhun S, 2003). Further studies are needed to determine the true prognostic role of c-myc gene expression in BC. Some studies found a positive association between overexpression of c-erbB-1 and high-grade, high-stage BC, thereby identifying this receptor as an independent prognostic factor in patients with advanced BC (Al-Sukhun S, 2003). Several studies have found that overexpression of HER-2/neu in patients with BC is correlated with higher-stage tumors, increased tumor progression, greater incidence of metastases, and reduced overall survival (Quek ML, 2003; Williams SG, 2001). Other studies found that HER-2/neu provide no additional prognostic value compared with previously established markers of grade and stage for TCC.

cH-as

The ras family of genes encodes for the signal transduction proteins involved in transmitting growth-promoting signals.

c-myc

The myc family of genes are nuclear transcription factors that activate genes that drive cell growth.

Epidermal growth factor receptor (c-erbB-1)

Receptor tyrosine kinase is involved with epithelial cell growth and division. Overexpression of the growth receptor on the surface of cells enhances their metastatic potential.

Epidermal growth factor receptor (c-erbB-2, HER-2/neu)

Receptor tyrosine kinase is involved with epithelial cell growth and division. Overexpression of the growth receptor on the surface of cells enhances their metastatic potential.

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TABLE 4. (continued) Gene/Protein

Function

bcl-2

The bcl-2 (B-cell lymphoma/leukemia-2) gene encodes a protein that blocks apoptosis. Overexpression of bcl-2 allows cells to escape apoptosis.

Survivin

An apoptosis inhibitor that is expressed during fetal development but is normally undetectable in adulthood.

Cyclin D1

Cyclin D1, a key cell-cycle regulator during the G1/S phase, is a putative proto-oncogene overexpressed in several cancers, including TCC of the bladder.

MDM2

MDM2 gene inhibits the cell-growth arrest mediated by wild-type p53 protein.

Other relevant events in BC Ki-67 The Ki-67 biomarker is a proliferation antigen detected by immunohistochemical staining. Tumors with positive Ki-67 represent actively growing tumor cells.

Comments Bcl-2 expression in bladder tumors is associated with a less aggressive phenotype (Shiina H, 1996). However, others have found bcl-2 overexpression to be significantly associated with disease progression and upstaging of the tumor during radiotherapy in patients with invasive BC (Pollack A, 1997; Rodel C, 2000). Previous studies found survivin in 78% of patients with BC but not in normal urothelium, and its expression correlated with increased rate of recurrence (Swana HS, 1999). Urine detection of survivin appears to be a marker for diagnosing patients with new or recurrent BC (Smith SD, 2001). In contrast, recent findings suggest that survivin expression does not correlate with early relapse; rather, its expression seems to be associated with the histological grade of tumors (Gazzaniga P, 2003). The cyclin D1 gene (CCND1) variant A allele may be associated with an increased risk of TCC of the bladder, especially in men without a history of smoking (Wang L, 2002). Recent findings suggest that while CCND1 polymorphism cannot serve as a prognostic marker for BC, the CCND1 variant A allele may increase the risk of CIS incidence in patients with superficial BC (Ito M, 2004). The role of MDM2 in regulating p53 protein levels in transitional carcinoma of the bladder is unclear. MDM2 gene amplification is not common in BC (Williams SG, 2001). Researchers have found that the proliferation markers, including Ki-67 and proliferating cell nuclear antigen (PCNA), correlate with grade, stage, and risk of recurrence (Gontero P, 2000; Bush C, 1991; Cheng G, 1997). The Ki-67 nuclear antigen also appears to be associated with invasive cancers and worse prognosis. It appears to be the most promising single marker in predicting BC recurrence and progression (Kausch I, 2002).

TABLE 4. (continued) Gene/Protein E-cadherin Basic fibroblast growth factor (bFGF) Vascular endothelial growth factor (VEGF) Matrix metalloproteinases (MMPs)

Function The presence of E-cadherin is essential for full adhesive function of the cell (Pirinen RT, 2001). bFGF promotes vascular repair and angiogenesis both in vivo and in vitro.

VEGF is essential in the regulation of endothelial cell proliferation and angiogenesis, both of them key contributors to the growth of cancer and vascular diseases. MMPs are involved in tumor-associated degradation of the extracellular matrix.

CD44

CD44, a widely expressed adhesion molecule, is involved in cell-cell and cell-matrix interactions as well as signal transduction through ras in response to hyaluronic acid (Quek ML, 2003).

Thymidine kinase (TK)

TK is an enzyme that plays a key role in the complementary, or alternative, salvage pathway of pyrimidine synthesis.

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Full source citations appear in ‘‘References.’’

Comments The loss of E-cadherin is associated with increased invasion and metastasis in BC (Cresswell J, 2002). Higher levels of bFGF have been found in the urine of BC patients than in the urine of controls. Urinary bFGF levels were also correlated with pathological stage in patients with muscle-invasive BC (Quek ML, 2003). Higher levels of VEGF have been found in the urine of BC patients than in the urine of controls. VEGF levels were also correlated with tumor recurrence in patients with Ta and T1 disease (Quek ML, 2003; Williams SG, 2001). Elevated levels of MMP-2 and MMP-9 have been found in the serum and urine of patients with muscle-invasive TTC and correlated with a decreased disease-free survival (Quek ML, 2003). Additionally, elevated levels of MMP-9 have been found in TTC compared with normal urothelium and correlated with increasing tumor stage (Quek ML, 2003; Williams SG, 2001). Increased CD44 expression has been found in superficial TTC, with a fall in expression at the time of muscle invasion. Data suggest that CD44 status is a prognostic marker in urothelial cancer and may be a potential target when screening BC patients (Quek ML, 2003). A recent study found that TK activity is correlated with both stage and grade of BC and that increased TK activity predicted early recurrence in Ta and T1 BC (Mizutani Y, 2003). TK may therefore be used as a prognostic marker in patients with BC.

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is also important. Physicians across the major markets now stage BC according to the tumor, node, metastasis (TNM) staging system. However, only three clinically relevant stages of cancer can be correlated with the TNM staging system: superÞcial BC (SBC), muscle-invasive BC (MIBC), and metastatic BC (MBC). Advanced BC (ABC) usually comprises cases in the MIBC and MBC categories. SBC can be further subdivided into low risk, intermediate risk, and high risk of progression or recurrence, which further takes into consideration pathological grading of disease, size, and number of lesions (G1 being a low grade and G3 being a high grade). The subdivisions of SBC guide decisions on the use of intravesical therapy in conjunction with surgery. The overall aim of SBC treatment is to prevent recurrence and progression to incurable disease; the main decision here is whether, in addition to transurethral resection (TUR), intravesical pharmacotherapy is warranted. The aim of MIBC treatment is to determine which tumors can be treated curatively with surgery and which require an integrated systemic approach to achieve cure. The aim of MBC treatment is to prolong survival and palliate disease symptoms because, at this stage, the disease is too advanced for the majority of patients to be cured. Combination chemotherapy is the standard approach for MBC. Table 5 lists the most common chemotherapy regimens used to treat BC. We discuss them in the following sections. Gemcitabine/Cisplatin Overview. The combination regimen of gemcitabine (Eli Lilly/Spaly Bioquimica’s Gemzar) (Figure 3) and cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics) (Figure 4) is the new gold-standard therapy for the treatment of MBC. Gemcitabine/cisplatin (GC) is indicated for the treatment of ABC (muscle-invasive stage IV tumors with or without metastases). GC is also one of the most widely used regimens for the treatment of non-small-cell lung cancer. Gemcitabine and cisplatin have complementary mechanisms of action; in preclinical studies, gemcitabine was found to be synergistic with cisplatin (Bergman AM, 1996). GC is increasingly replacing methotrexate/vinblastine/doxorubicin/cis platin (MVAC) and cisplatin/methotrexate/vinblastine (CMV) and has been investigated in several settings, including as Þrst-line therapy in metastatic disease and in neoadjuvant and adjuvant settings. In some cases of BC, the patient is too ill to tolerate the side effects of cisplatin. In such cases, researchers have substituted carboplatin for cisplatin. Carboplatin is a platinum agent, like cisplatin, but is less toxic. We discuss the results of studies examining this substitution in this section as well. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the overall regimen activity: •

Gemcitabine is an antimetabolite. Antimetabolites block normal DNA synthesis, thus stopping cell replication. Gemcitabine exhibits cell-phase speciÞcity, primarily killing cells that are undergoing DNA synthesis

TABLE 5. Current Regimens/Classes Used for Bladder Cancer Regimen Components Regimen

Agent

Availability

Dose

Gemcitabine (Eli Lilly/Spaly Bioquimica’s Gemzar)


Gemcitabine: 1,000 mg/m2 IV days 1, 8, 15.


Cisplatin: 70 mg/m2 IV day 2. Cycle repeated every 28 days

Gemcitabine, single agent

Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics) Gemcitabine (Eli Lilly/Spaly Bioquimica’s Gemzar)


Gemcitabine: 1,200 mg/m2 IV days 1, 8, 15. Cycle repeated every 28 days.

MVAC

Methotrexate (generics)


Methotrexate: 30 mg/m2 /d IV days 1, 15, 22.

Vinblastine (Eli Lilly’s Velbe, Eli Lilly/Shionogi’s Exal, generics) Doxorubicin (Pfizer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics) Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics)


Vinblastine: 3 mg/m2 /d IV days 2, 15, 22. Doxorubicin: 30 mg/m2 IV day 2.

Gemcitabine/cisplatin



Cisplatin: 70 mg/m2 IV day 2. Cycle repeated every 28 days.

Grade III/IV Toxicities Neutropenia Anemia Thrombocytopenia Nausea/vomiting Alopecia Neutropenia Thrombocytopenia Nausea/vomiting Edema Respiratory Leukopenia Neutropenia Neutropenic fever Thrombocytopenia Mucositis Nausea/vomiting Alopecia

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TABLE 5. (continued) Regimen Components Regimen CMV

Bacillus ´ Calmette-Guerin (BCG)

Mitomycin, single agent

Agent

Availability

Dose

Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics)


Cisplatin: 70 mg/m2 IV day 2.

Methotrexate (generics) Vinblastine (Eli Lilly’s Velbe, Eli Lilly/Shionogi’s Exal, generics) Organon’s Tice BCG/OncoTICE, Sanofi-Aventis’s Theracys/ImmuCyst, Nippon Kayaku’s ImmuCyst, Japan BCG’s Immunobladder, generics

US, F, G, I, S, UK, J US, F, G, I, S, UK, J

Methotrexate: 30 mg/m2 IV days 1, 8. Vinblastine: 4 mg/m2 IV days 1, 8. Cycle repeated every 21 days. BCG: 1 instillation per week for six weeks (induction therapy). May be repeated once if tumor remission has not been achieved and if the clinical circumstances warrant. Thereafter, intravesical BCG vaccine administration continues at monthly intervals for at least 6–12 months.

Mitomycin (generics)



Mitomycin: 20 mg (prophylactic protocol) and 40 mg (ablative protocol) for six to eight weeks (induction therapy).

Grade III/IV Toxicities Leukopenia Thrombocytopenia Neutropenic fever

Urinary frequency Hematuria Cystitis Dysuria Urgency Urinary tract infection Flu-like syndrome Fever Shaking/chills Malaise/fatigue Cardiac Cramps/pain Dysuria Cystitis Urinary frequency Urgency Hematuria Cramps/pain Chills Fever Malaise/fatigue Rash/itching

TABLE 5. (continued) Regimen Components Regimen Doxorubicin, single agent

Agent Pfizer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics

Epirubicin, single agent Pfizer’s Ellence/Farmorubicin, Pfizer/Kyowa’s Farmorubicin

Thiotepa, single agent

Amgen/Wyeth Lederle’s Thioplex, Sumitomo’s Tespamin, generics

Availability

Dose

Grade III/IV Toxicities

US, F, G, I, S, UK, J Doxorubicin: 50–80 mg administered Dysuria intravesically, weekly for 4–8 weeks. Frequency May be repeated at monthly intervals. Hematuria Urgency Cystitis Nausea/vomiting Bladder cramps/pain US, F, G, I, S, UK, J Epirubicin: 100 mg administered Chemical cystitis intravesically immediately after Fever transurethral resection (single dose). Dysuria Or 50 mg weekly for 4–8 weeks. US, F, G, I, S, UK, J Thiotepa: 60 mg administered Dysuria intravesically, weekly for four weeks. Urinary retention May be repeated if necessary, but Chemical cystitis second and third courses must be (rare) given with caution because Hemorrhagic cystitis bone-marrow depression may be (rare) increased. Myelosuppression

US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan. IV = Intravenous.

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NH2 N HO

O O

OH

N F F

FIGURE 3. Structure of gemcitabine.


•

(S phase) and blocking the progression of cells through the G1/S-phase boundary. The agent is metabolized intracellularly by nucleoside kinases to its active form. Cisplatin is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA that result in inhibition of transcription and/or DNA replication mechanisms.

Clinical Performance. A randomized, multinational Phase III trial compared GC with MVAC in 405 chemotherapy-naive patients with locally advanced or metastatic TCC of the urothelium (von der Maase H, 2000). The primary objective was comparison of overall survival; secondary objectives were comparisons of objective tumor responses, duration of responses, times to disease progression, times to treatment failure, toxicity, changes in performance status and weight, and evaluations of quality of life and medical resource utilization. Patients were randomized to receive either a maximum of six cycles of GC (203 patients) or a maximum of six cycles of MVAC (202 patients) between November 1996 and September 1998. Investigators observed no signiÞcant difference in median overall survival (GC, 13.8 months; MVAC, 14.8 months); time to disease progression, (7.4 months for both arms); or time to treatment failure (GC, 5.8 months; MVAC, 4.6 months). Investigators assessed overall response rates in 164 patients in the GC arm and 151 in the MVAC arm and found similar response rates: GC, 49.4% (81 patients) with 12.2% complete response (CR) and 37.2% partial response (PR); MVAC, 45.7% (69 patients) with 11.9% CR and 33.8% PR. One-third

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of the patients in both arms achieved stable disease. The median durations of response were 9.6 months for the GC arm and 11 months for the MVAC arm. GC caused more grade 3 or 4 anemia (GC, 27%; MVAC, 18%) and thrombocytopenia (GC, 57%; MVAC, 21%) but did not result in a greater number of transfusions. MVAC caused more grade III or IV neutropenia (MVAC, 82%; GC, 71%) and neutropenic fever (MVAC, 14%; GC, 2%) and signiÞcantly more neutropenic sepsis (MVAC, 12%; GC, 1%). Grade III or IV mucositis (MVAC, 22%; GC, 1%) and alopecia (MVAC, 55%; GC, 11%) were also signiÞcantly more common in the MVAC arm. The drug toxicity–related mortality rate was lower for the GC arm (1%) than for the MVAC arm (3%), but the difference was not statistically signiÞcant. Quality of life was maintained during treatment in both arms, but more patients on GC did better regarding weight, performance status, and fatigue. Based on this study, GC provided a survival advantage similar to that of MVAC, but with a better safety proÞle and tolerability. Investigators concluded that GC should be considered the new standard of care for patients with locally advanced or metastatic TCC (von der Maase H, 2000). Results of a neoadjuvant Phase III Egyptian trial presented at the American Society of Clinical Oncology (ASCO) in 2003 showed that the GC regimen is effective and well tolerated when used as neoadjuvant therapy in MIBC (stages T2–T4, N0–N2) (Khaled HM, 2003). A total of 58 patients were randomized to receive three cycles of GC chemotherapy preoperatively, and 56 patients had only radical cystectomy between November 2000 and June 2002. Patients with a CR received three additional chemotherapy cycles followed by radical radiotherapy. The overall response rate was 56% (28 patients) in the GC arm: 30% CR and 26% PR. Eight patients were not evaluable for response. Bladder preservation was feasible in 11 of the patients achieving CR. In the radical cystectomy–only arm, 52 patients underwent radical cystectomy and 4 were found unresectable on exploration. Researchers observed a trend toward increased overall one-year survival for neoadjuvant GC (69%) compared with cystectomy alone (54%). The overall survival for all patients in the study was 63%. Occasional grade III or IV toxicity was observed. The investigators found neoadjuvant GC to be effective and tolerable in MIBC and helped achieve organ preservation in a signiÞcant subset of patients. There is also insufÞcient evidence to support the routine use of adjuvant chemotherapy for the treatment of patients with locally advanced BC because the trials have employed small sample sizes and confusing methodologies (Sylvester R, 2000). However, adjuvant chemotherapy is generally used more often than neoadjuvant chemotherapy. In a retrospective study presented at ASCO 2004, 25 patients with locally advanced BC were treated with adjuvant chemotherapy between 1997 and 2002 (El-Khoueiry AB, 2004). The researchers determined that adjuvant GC chemotherapy was both feasible and effective. Over a median follow-up of 25 months, 44% had grade III or IV hematologic toxicity and 8% had grade III nonhematologic toxicity. The median time to recurrence was 49.7 months, and median overall survival exceeded 49.7 months. Eight

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patients died. Other Phase III trials are ongoing in the United States to investigate the effect of adjuvant chemotherapy. Carboplatin-based regimens are widely used as an alternative to cisplatin-based regimens in unÞt patients. “UnÞt” refers to those with poor performance status and poor renal function. Thirteen trials involving 327 patients with advanced urothelial cancer found that single-agent carboplatin elicited objective responses in 14% of patients: 3% CR and 11% PR (Mottet-Auselo N, 1993). A Phase II dose-Þnding study evaluated the combination of gemcitabine and carboplatin in unÞt patients with advanced BC (Bellmunt J, 2001). Researchers reported an overall response rate of 44%: 6% CR and 38% PR in 16 patients ineligible for the cisplatin-based regimens. At evaluation, six patients had stable disease and three had progressive disease. The gemcitabine/carboplatin regimen appears to be active and well-tolerated and shows acceptable toxicity in this patient population. This encouraging result prompted the European Organization for the Research and Treatment of Cancer (EORTC) to conduct a randomized Phase II/III trial, which is ongoing, to compare gemcitabine/carboplatin with methotrexate/carboplatin/vinblastine in patients ineligible for cisplatin-based chemotherapy. The trials are still open at the time of composing this reference. Gemcitabine, Single Agent (under open trials at the time of composing this reference) Overview. Single-agent gemcitabine (Eli Lilly/Spaly Bioquimica’s Gemzar) has also demonstrated promising activity against advanced or metastatic urothelial cancer. The agent is generally used for patients with poor renal function who cannot tolerate cisplatin-based therapy. Mechanism of Action. •

Gemcitabine is an antimetabolite. Antimetabolites block normal DNA synthesis, thus stopping cell replication. Gemcitabine exhibits cell-phase speciÞcity, primarily killing cells that are undergoing DNA synthesis (S phase) and blocking the progression of cells through the G1/S-phase boundary. The agent is metabolized intracellularly by nucleoside kinases to its active form.

Clinical Performance. Overall response rates for gemcitabine obtained from two Phase II trials in previously treated patients were 22.5% and 29%, respectively (Lorusso V, 1998; Gebbia V, 1999). Two studies evaluating gemcitabine in previously untreated patients conÞrmed its relatively high single-agent activity (Stadler WM, 1997; Moore MJ, 1997). These studies achieved overall response rates of 28% (Stadler WM, 1997) and 24.3% (Moore MJ, 1997). A Phase II study assessed the ablative efÞcacy of intravesical gemcitabine at a concentration of 40 mg/mL (2,000 mg in 50 mL saline solution) in 39 patients with intermediate-risk SBC (Ta, T1, G1, G2) (Gontero P, 2004). Gemcitabine was

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administered weekly for six weeks on a single marker tumor left in the bladder after a complete TUR of all other lesions. A complete response was achieved in 22 (56%) of the 39 patients. Investigators observed no progression among the 17 nonresponders. Side effects generally did not exceed grade I toxicity. Researchers concluded that the ablative effect of gemcitabine produced a higher number of responses than the minimum required by the protocol to indicate a signiÞcant probability of drug efÞcacy. The durability of response should be tested in Phase III trials. MVAC Overview. The regimen known as MVAC is a combination of methotrexate (generics) (Figure 5), vinblastine (Eli Lilly’s Velbe, Eli Lilly/Shionogi’s Exal, generics) (Figure 6), doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics) (Figure 7), and cisplatin (Bristol-Myers Squibb’s PlatinolAQ, Nippon Kayaku’s Randa, generics). For more than 15 years it has been the most widely used regimen for the treatment of patients with locally advanced or metastatic BC (Culine S, 2002). Randomized trials show MVAC to be superior to cisplatin alone, as well as to cisplatin in combination with cyclophosphamide and doxorubicin. However, the regimen is associated with signiÞcant toxicities, which are especially problematic for older patients, who often present with comorbidities and who constitute a signiÞcant proportion of the population with TCC (von der Maase H, 2000). Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

Methotrexate, a structural analogue of folate, is an antimetabolite. Antimetabolites block normal DNA synthesis by inhibiting several key enzymes. Methotrexate inhibits the enzyme dihydrofolate reductase. This inhibition interferes with the maintenance of the reduced folate pool. Reduced folates are essential for de novo synthesis of thymidylate and purine nucleotides, a requirement for DNA synthesis and cell replication. Thus, by inhibiting dihydrofolate reductase, methotrexate stops the replication of rapidly proliferating cells such as tumor cells.

H2N

N

N CH3

N

N N H N

NH2 O

COOH COOH

FIGURE 5. Structure of methotrexate.

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CH3

N

HN

OH

H3CO O

H

N H

H3CO

CH3

OH N R1

R3 H

R2

FIGURE 6. Structure of vinblastine (R1 = CH3 , R2 = CO(OCH3 ), R3 = OCO(CH3 ).


•

•

Vinblastine is a vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death. Doxorubicin is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA re-ligation enzyme, anthracyclines exert their cytotoxic effect. Another doxorubicin mechanism that leads to cell death is known as DNA intercalation, in which the anthracycline molecule inserts itself between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures such as proteins and DNA.

CURRENT THERAPIES

•

167

Cisplatin is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA that results in inhibition of transcription and/or DNA replication mechanisms.

Clinical Performance. Investigators at the Memorial Sloan-Kettering Cancer Center in New York Þrst described the standard schedule for MVAC in 1985 (Sternberg CN, 1985). Among 83 evaluable patients with advanced BC, 69% achieved an objective response, including a CR rate of 37% (Sternberg CN, 1988). In a multicenter French study of 70 patients with advanced BC, investigators reported an objective response rate of 57% (38 of 67 patients), with a CR rate of 19% (Boutan-Laroze A, 1991). Randomized trials have conÞrmed the superiority of the MVAC regimen, in terms of objective response rates and overall survival, over single-agent cisplatin or cisplatin combined with cyclophosphamide and doxorubicin. A randomized trial investigating MVAC compared with cisplatin alone found MVAC to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival (Loehrer PJ, 1992). Of the 269 patients with advanced urothelial cancer enrolled between October 1984 and May 1989, 246 were randomized to receive cisplatin alone (126) or MVAC (120). The response rate was far better for MVAC (39%) than for cisplatin (12%). The progression-free survival (10 months versus 4.3 months) and overall survival (12.5 months versus 8.2 months) were signiÞcantly greater for the MVAC-treated patients. However, the MVAC regimen was associated with more toxic side effects, particularly leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Long-term follow-up of the Phase III intergroup study of advanced urothelial cancer patients treated with MVAC conÞrmed that, with the MVAC regimen, survival is superior to cisplatin: 3.7% of MVAC patients experienced more than six years of disease-free survival compared with only 1.6% of patients treated with single-agent cisplatin (Saxman SB, 1997). A randomized, multinational Phase III trial compared GC with MVAC in 405 chemotherapy-naive patients with ABC (von der Maase H, 2000). (See the previous section on the GC regimen for details of the trial.) The researchers concluded that the standard of care for patients with ABC should be changed from MVAC to GC because the latter provides a survival advantage similar to that of MVAC but has a better safety proÞle and tolerability. In the trial, the drug toxicity-related mortality rate was lower for the GC arm (1%) than for the MVAC arm (3%), though the difference was not statistically signiÞcant. To improve survival rates achievable with the MVAC regimen, the EORTC conducted a randomized Phase III trial comparing high-dose-intensity MVAC (HD-MVAC) and granulocyte colony-stimulating factor (G-CSF) versus classic MVAC in advanced urothelial tract tumors (Sternberg CN, 2001). The trial randomized 263 chemotherapy-naive patients with metastatic or advanced TCC to either HD-MVAC (two-week cycle) or MVAC (four-week cycle) between June 1993 and November 1998. Using an intent-to-treat analysis over a median

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follow-up of 38 months, the overall response rate in the HD-MVAC arm was 62%: 21% CR and 41% PR. The overall response rate in the MVAC arm was 50%: 9% CR and 41% PR. Progression-free survival was signiÞcantly better with HD-MVAC. The median progression-free survival time was 9.1 months in the HD-MVAC arm and 8.2 months in the standard MVAC arm. The two-year progression-free survival was 24.7% for HD-MVAC compared with 11.6% for standard MVAC. Researchers concluded that, with HD-MVAC, it was possible to deliver twice the doses of cisplatin and doxorubicin in half the time, resulting in fewer dose delays and less toxicity (Sternberg CN, 2001). The clinical beneÞts, however, are not considered large enough to justify adopting this regimen as standard therapy (Hussain SA, 2003). However, both the HD-MVAC and GC regimens have emerged as promising candidates to end the dominance of MVAC in the treatment of advanced BC (Culine S, 2002). A randomized Phase III intergroup study compared neoadjuvant chemotherapy plus cystectomy with cystectomy alone in patients with MIBC (stage T2–T4a) (Grossman HB, 2003). The primary objective was the comparison of survival; the secondary objective was to quantify the effect of neoadjuvant MVAC on tumor stage (downstaging of the tumor). Patients were randomly assigned to radical cystectomy alone (154 patients) or three cycles of MVAC followed by radical cystectomy (153 patients with adequate renal function) between August 1987 and July 1998. Radical cystectomy included a bilateral pelvic lymphadenectomy, and urinary diversions were performed. Investigators found a signiÞcant and clinically meaningful improvement in survival among patients who received neoadjuvant chemotherapy. Over a median follow-up of 8.7 years, 90 deaths occurred in the MVAC and cystectomy arm; over a median follow-up of 8.4 years, 100 deaths occurred in the cystectomy alone arm. The estimated risk of death was reduced by 25% in the MVAC and cystectomy arm compared with the cystectomy-alone arm. Using an intention-totreat analysis, the median survival was 77 months among patients in the MVAC and cystectomy arm and 46 months among patients in the cystectomy alone arm. Approximately 57% of patients in the MVAC and cystectomy arm were alive at Þve years, compared with 43% of patients in the cystectomy-alone arm. Investigators reported that 38% of the surgical specimens of patients in the MVAC and cystectomy arm were pathologically free of cancer (pT0) at the time of surgery, compared with 15% of patients in the cystectomy-alone arm. The overall adverse effects were moderate: at least one-third of patients had severe hematologic or gastrointestinal toxicities, although all the patients recovered and no treatmentrelated deaths occurred. Furthermore, MVAC did not adversely affect a patient’s chance of undergoing radical cystectomy; nor did it increase the risk of death or complications related to the surgery. MVAC can therefore be administered safely before radical cystectomy to patients with locally advanced BC. Investigators concluded that the use of neoadjuvant MVAC followed by radical cystectomy is associated with improved survival in patients with locally advanced BC.

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CMV Overview. The regimen known as CMV combines cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics), methotrexate (generics), and vinblastine (Eli Lilly’s Velbe, Eli Lilly/Shionogi’s Exal, generics). CMV is superior to methotrexate and vinblastine (Mead GM, 1998) and has shown response rates similar to those of MVAC. It was widely used in Europe for patients with metastatic TTC of the bladder before the introduction of the GC regimen. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

•

Cisplatin is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA that results in inhibition of transcription and/or DNA replication mechanisms. Methotrexate, a structural analogue of folate, is an antimetabolite. Antimetabolites block normal DNA synthesis by inhibiting several key enzymes. Methotrexate inhibits the enzyme dihydrofolate reductase. This inhibition interferes with the maintenance of the reduced folate pool. Reduced folates are essential for de novo synthesis of thymidylate and purine nucleotides, which is required for DNA synthesis and cell replication. Thus, by inhibiting dihydrofolate reductase, methotrexate stops the replication of rapidly proliferating cells such as tumor cells. Vinblastine is a vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death.

Clinical Performance. A multicenter randomized trial conducted by the British Medical Research Council Advanced Bladder Cancer Working Party compared modiÞed methotrexate and vinblastine (MV) with CMV in patients with advanced or metastatic TCC (Mead GM, 1998). The trial enrolled 214 patients between April 1991 and June 1995. A total of 108 patients were randomized to receive six cycles of CMV and 106 patients to receive six cycles of MV. Of the 88 evaluable patients in the CMV arm, 10% achieved CR and 36% achieved PR. Of the 93 evaluable patients in the MV arm, 7% achieved CR and 12% achieved PR. The hazard ratio (relative risk of dying) was 0.68 in favor of CMV. This Þnding translates to an absolute improvement in one-year survival of 13%: 16% in MV and 29% in CMV. The median survival was 7 months for CMV and 4.5 months for MV. CMV was associated with more toxicity than MV. In the CMV arm, Þve treatment-related deaths occurred, as did grade III leukopenia and thrombocytopenia. Neutropenic fever occurred in 11 CMV-treated patients and grade I renal toxicity in 19 CMV-treated patients, compared with only 2 and 4, respectively, among MV-treated patients. Investigators concluded that adding cisplatin

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to methotrexate and vinblastine should be considered in patients with TCC, taking into account the increased toxicity. The study strengthened the belief that cisplatin is an essential component of combination chemotherapy regimens for patients with adequate renal function. ´ Bacillus Calmette-Guerin Overview. Used for more than 20 years, bacillus Calmette-Guérin (BCG) (Organon’s Tice BCG/OncoTICE, SanoÞ-Aventis’s Theracys/ImmuCyst; Nippon Kayaku’s ImmuCyst, Japan BCG’s Immunobladder, generics) remains the most active agent for SBC therapy (Bassi P, 2002). BCG is approved for both intravesical use in the treatment and prophylaxis of primary and recurrent carcinoma in situ (CIS) of the urinary bladder and for prophylaxis following TUR of primary or recurrent stage Ta and/or T1 papillary tumors. Intravesical BCG is certainly the best available intravesical agent for the treatment of CIS (Bassi P, 2002; Baselli EC, 2001). Mechanism of Action. •

BCG is a potent stimulator of host defense mechanisms and can induce tumor regression in immunocompetent hosts. Its exact mechanism of action is unknown, though it appears that repeated instillation of BCG triggers a strong inßammatory reaction in the bladder, which correlates with an antitumor response.

Clinical Performance. A Southwest Oncology Group (SWOG) study compared BCG with 20 mg mitomycin C (Figure 8) using a six-week (followed by monthly) treatment schedule. However, the study was terminated at the Þrst interim analysis because of the highly signiÞcant advantage of BCG (Lamm DL, 1991). Overall recurrence fell from 32.6% with mitomycin C to 19.5% with BCG, while the median time to recurrence was prolonged from 20 months to more than 36 months. Another SWOG study evaluating maintenance therapy in 660 patients with rapidly recurring stage Ta or T1 lesions or CIS demonstrated a long-term diseasefree advantage for BCG maintenance therapy compared with BCG induction therapy alone over an average follow-up of 3.2 years (Lamm DL, 1995). Patients

FIGURE 8. Structure of mitomycin C.

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with CIS were treated with three additional weekly BCG treatments at three months, and their CR increased from 73% to 87%. In patients with stage Ta and T1 BC who were disease-free, BCG maintenance therapy (three weekly treatments of BCG at six-month intervals) resulted in a long-term disease-free status of 83%, compared with 50% in the induction group. An excellent 86% survival observed at four years in 391 randomized patients receiving induction therapy improved to 92% in patients receiving maintenance therapy. This result supports the superiority of continued maintenance treatment in patients with BC. Symptoms associated with BCG include urinary frequency and burning, mild malaise, and low-grade fever. The most dangerous complication is systemic sepsis and/or hypersensitivity reactions characterized by chills, fever, hypotension, and progressive multisystem organ failure (Lamm DL, 2000). Clinical trials frequently study the sequential administration of BCG and mitomycin C. A prospective controlled study presented at ASCO 2004 found that, in the treatment of high-risk BC, intravesical sequential BCG and electromotive delivery of mitomycin C are superior to BCG alone (Di Stasi SM, 2004). The trial randomized 175 patients with T1 BC into two arms following TUR and multiple biopsies. Arm 1 received six weekly instillations of BCG at 81 mg; arm 2 received sequential BCG and electromotive (intravesical electric current; 20 mA for 30 minutes) of mitomycin C at weekly intervals. Nonresponders received repeat courses at three months, and all complete responders underwent maintenance regimens of monthly instillations. The median follow-ups for arm 1 and arm 2 were 64 and 71 months, respectively. The recurrence rate was 47% for arm 1 and 28% for arm 2, and the rates of progression were 20% and 14%, respectively. The time to progression was 17 months for arm 1 and 46 months for arm 2, and the Þve-year mortality rates were 9.3 and 1.1, respectively. Researchers reported no treatment-related deaths, episodes of serious illness, or bladder contractures. These results demonstrate that intravesical sequential BCG/electromotive mitomycin C is superior to BCG alone in the treatment of high-risk disease. Researchers recently reported a meta-analysis of comparative studies in SBC that demonstrated a statistically signiÞcant superiority for BCG compared with single-agent mitomycin C in the prevention of tumor progression, but only if BCG maintenance therapy was provided (Bohle A, 2004). (See “Other Intravesical Agents” further on for details of this meta-analysis.) Additionally, the combination of BCG and interferon-alpha-2b (IFN-α-2b [Schering-Plough’s Intron A]) has been developed based on reported evidence of synergistic activity between the two agents. The two agents are said to be biocompatible and can be administered simultaneously. By combining IFN-α2b with a markedly reduced dose of BCG, researchers reduced toxicity while maintaining anticancer efÞcacy (Keane TE, 2001). This regimen is an effective alternative for patients at high risk of disease recurrence and/or progression and in whom BCG therapy has previously failed. A 56% disease-free survival was achieved at 24 months (O’Donnell MA, 2000). BCG and IFN-α-2b combinations are being studied in clinical trials.

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Interim results from a national multicenter Phase II trial of BCG in combination with IFN-α-2b in BCG-naive (BCG-N) and previous BCG failure (BCG-F) patients with SBC provides a benchmark for the efÞcacy and safety of the combination of BCG and IFN-α-2b (O’Donnell MA, 2004). Between May 1999 and May 2000, the trial enrolled 490 patients with primary or recurrent SBC, stage Ta, T1, CIS, and all grades. Approximately 50% of the patients had CIS or stage T1, and more than 75% had intermediate- to high-grade disease. The BCG-N group (259 patients) received a six-week induction course (six treatments provided once weekly) of standard-dose BCG plus 50 million units of IFN-α-2b followed by three-week maintenance cycles of reduced-dose BCG (1/3 to 1/10) plus 50 million units IFN-α-2b at 3, 9, and 15 months after induction. The BCGF group (231 patients) was treated similarly, except induction therapy began at a lower (1/3 to 1/10) BCG dose. Over a median follow-up of 24 months, the simple tumor recurrence rates for the BCG-N and BCG-F groups were 40% and 52%, respectively, and disease-free rates were 57% and 42%, respectively. Progression to muscle invasion occurred in 5% and 4.3%, respectively, while metastasis occurred in 2.3% and 2.6%, respectively. About 3.9% of patients in each group underwent cystectomy, and two patients died of BC in each group. Serious adverse events occurred in 5.5% of the patients; infection-related serious adverse events were less prevalent in the BCG-F group (2.6%) than in the BCG-N group (5.4%). Moderate-to-severe local side effects during induction were higher in the BCG-F group (6.2%) than in the BCG-N group (16.9%) but equilibrated during maintenance therapy. The study could not determine the incremental value of IFN. Therefore, randomized Phase III trials need to establish if there is any beneÞt to adding IFN to BCG. Other Intravesical Agents Overview. Mitomycin (generics) is the most common chemotherapeutic agent for patients with low- or intermediate-risk SBC. Studies comparing BCG with mitomycin have been controversial: mitomycin has proved equivalent or superior to BCG for reducing recurrences in patients with papillary disease in some studies and has shown efÞcacy in treating CIS and higher-grade lesions in others (Dalbagni G, 2000). Postoperative instillations of mitomycin C can reduce recurrence rates in newly diagnosed patients with SBC. Physicians generally administer adjuvant mitomycin to patients with low- or intermediate-risk SBC and adjuvant intravesical BCG to patients with high-risk disease. Mitomycin is used in patients with SBC who are unable to tolerate BCG therapy because of toxicity or whose disease is refractory to BCG (Baselli EC, 2001). In this section, we also brießy discuss three other intravesical agents used to treat BC: doxorubicin (Figure 7), epirubicin (Figure 9), and thiotepa. None has demonstrated efÞcacy superior to that of BCG. Mechanism of Action. •

Mitomycin and thiotepa are alkylating agents. Alkylating agents cross-link with DNA during cell reproduction, thereby preventing synthesis of secondgeneration DNA. Mitomycin is nonspeciÞc to the cell-cycle phase.

CURRENT THERAPIES

O

OH

173

O OH OH

H3CO

O H3C HO

OH

O

O NH2

FIGURE 9. Structure of epirubicin. •

Doxorubicin and epirubicin are anthracyclines. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism that leads to cell death is known as DNA intercalation, in which the anthracycline molecule inserts itself between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures such as proteins and DNA.

Clinical Performance. Researchers recently reported a meta-analysis of comparative studies on tumor progression in SBC (Bohle A, 2004). Tumor progression was deÞned as progression to a higher tumor stage or the development of metastatic disease. The main objective was to compare the therapeutic efÞcacy of adjuvant intravesical BCG with adjuvant intravesical mitomycin C on progression of stage Ta and T1 BC (all grades). In nine clinical trials, 1,277 patients were treated with BCG and 1,133 with mitomycin C. With an overall median follow-up of 26 months, 7.67% of patients in the BCG group and 9.44% of the patients in the mitomycin C group developed tumor progression. Of the nine studies analyzed, the combined result of the Þve studies on BCG maintenance showed a statistically signiÞcant superiority of BCG over mitomycin C. In the remaining four studies without BCG maintenance, the combined result indicated no statistically signiÞcant difference between the two treatments. This meta-analysis demonstrates that adjuvant intravesical BCG is statistically superior to adjuvant intravesical mitomycin C for the prevention of tumor progression, but only if BCG maintenance therapy is provided. Another intravesical agent used to treat BC is doxorubicin (PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics), though evidence suggests that its efÞcacy is inferior to BCG’s regardless of tumor grade or stage (Baselli EC, 2000). Furthermore, treatment with doxorubicin causes serious toxicity from chemotherapy-induced cystitis, resulting in permanent bladder contracture in a small but signiÞcant and unpredictable number of patients (Lamm DL, 1988). Epirubicin (PÞzer’s Ellence/Farmorubicin, PÞzer/Kyowa’s Farmorubicin) is approved for adjuvant treatment (in combination regimens) of patients with early

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node-positive breast cancer and has demonstrated an ability to alter the natural history of primary SBC. Administration of a single dose (100 mg in 100 mL of saline) of epirubicin immediately following TUR in patients with primary SBC produced a statistically signiÞcant recurrence-free rate of 66% after two years (Rajala P, 1999). Its adverse effects are usually limited to chemical cystitis. However, long-term reduction of tumor recurrence (greater than or equal to Þve years) has been difÞcult to conÞrm (Lamm DL, 2000). Another chemotherapeutic agent used to manage SBC is thiotepa (Amgen/Wyeth Lederle’s Thioplex, Sumitomo’s Tespamin, generics), but few clinicians recommend it as a Þrst-line alternative to BCG despite its approval for the treatment of superÞcial papillary carcinoma of the urinary bladder (Baselli EC, 2000). More important, direct randomized comparison has demonstrated that BCG prophylaxis is superior to thiotepa, doxorubicin, or mitomycin C in patients with SBC (Lamm DL, 2000). Nonpharmacological Approaches Surgery is the mainstay of treatment for SBC. In particular, TUR of all visible tumors remains the ultimate method for diagnosing and initially managing SBC (Baselli EC, 2001). Tumor specimens taken during TUR are analyzed histologically to determine their pathological grade, and this procedure is essential for determining the clinical stage of the bladder tumor. Patients with SBC, many of whom are at risk for disease recurrence and progression, can be managed with adjuvant intravesical therapy following TUR. If recurrence develops or pathologic assessment places the patient at a higher risk for recurrence and/or progression to MIBC, then adjuvant intravesical maintenance therapy is warranted (Baselli EC, 2001). As we have discussed, studies show that mitomycin and other adjuvant intravesical chemotherapy regimens are inferior to BCG, especially in patients at high risk of tumor recurrence. Cystectomy should be considered in patients who fail to have their disease eradicated following a reasonable course of intravesical treatment or at the Þrst sign of tumor progression (Bochner BH, 2001). Radical cystectomy is the standard treatment for patients with MIBC in the United States and Europe (Rodel C, 2002). Studies have investigated the longterm effect of radical cystectomy in the treatment of invasive BC. A study involving 1,054 patients with TTC of the bladder uniformly treated with radical cystectomy with bilateral pelvic iliac lymphadenectomy and urinary diversion (with or without adjuvant radiation or chemotherapy) supports the aggressive surgical management of invasive BC (Stein JP, 2001). Over a median followup of 10.2 years, results demonstrated that excellent long-term survival can be achieved with a low incidence of pelvic recurrence (9%). The chance of survival at Þve years without evidence of disease was 69%, and overall survival at Þve years was 60%. In addition, investigators note that quality of life after cystectomy has improved because lower urinary tract options have evolved into an orthotopic form of diversion, thus allowing most patients to store urine without the need for catheterization.

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Radiotherapy may be used to either cure locally advanced BC or provide palliative treatment (Nilsson S, 2001). A new, promising treatment to preserve the bladder is extensive TUR followed by intense chemoradiotherapy. Researchers have found that this method offers a Þve-year survival rate similar to that of radical cystectomy (Nilsson S, 2001). Researchers have also found that radiochemotherapy is more efÞcacious than radiotherapy. In a study involving 428 patients with MIBC (T2–T4) or high-risk T1 BC, 126 patients were treated with radiotherapy and 302 with radiochemotherapy after TUR of the tumor (Rodel C, 2002). Over a median follow-up of 60 months, the researchers found radiochemotherapy to be more effective than radiotherapy in terms of CR and survival. The ideal treatment for MIBC would be therapies that preserve the bladder and eradicate the tumor without compromising survival. EMERGING THERAPIES Little progress has been made over the past decade in the drug treatment of bladder cancer (BC), primarily because recruiting sufÞcient numbers of patients to Phase III BC trials is notoriously difÞcult. There are several reasons for this difÞculty. First, the incidence of BC is relatively low compared with that of other cancers, such as non-small-cell lung cancer and colorectal cancer. Second, because the average age of the patient population is 70 years, many patients are not Þt enough to meet trial entry criteria. Third, many pharmaceutical companies believe that the cost of conducting trials outweighs the potential beneÞts of assessing a drug for a market such as BC, which is small compared with those for breast cancer, non-small-cell lung cancer, and prostate cancer. Consequently, signiÞcant clinical data are lacking for most agents in clinical development for the treatment of BC. Table 6 summarizes the drug therapies in development for BC. Unless indicated, our deÞnition of BC is largely interchangeable with transitional cell cancer (TCC) of the urothelium. BC and TCC are not pathologically the same, but we grouped all forms of BC together when evaluating clinical data because TCC represents more than 90% of all BCs, and because other pathological types of BC are treated similarly (staging and grading being more important determinants of treatment and patient stratiÞcations in clinical trials). Epidermal Growth Factor Receptor Inhibitors Overview. Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase expressed in a variety of human malignancies, including BC. The EGFR, also known as c-erbB-1, belongs to the EGFR subfamily of receptor tyrosine kinases, which includes c-erbB-2/HER-2/neu. The natural ligands for EGFR, tumor growth factor–alpha and EGF, have both been immunohistochemically demonstrated to be present in BC (Mellon JK, 1996). The expression of EGFR has been studied extensively in human BC tissue in which a broad range (0–100%) of expression has been observed (Small EJ, 2003). Part of the variation may be explained by the different EGFR antibodies used, the criteria employed to deÞne overexpression, and the stage of BC studied.

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TABLE 6. Emerging Therapies in Development for Bladder Cancer Compound Lapatinib United States Europe Japan Gefitinib United States Europe Japan Trastuzumab United States Europe Japan Erlotinib (Tarceva) United States Europe Japan Paclitaxel United States Europe Japan Vinflunine (Javlor) United States Europe Japan Irinotecan (Camtosar) United States Europe Japan Celecoxib United States Europe Japan

Development Phase

Marketing Company

— II —

— GlaxoSmithKline —

II — —

AstraZeneca — —

II — —

Genentech/Roche/Chugai — —

II — —

Genentech/Roche/OSI Pharmaceuticals — —

IIb IIb —

Bristol-Myers Squibb Bristol-Myers Squibb —

— III —

— Pierre Fabre —

II — —

Pfizer — —

III — —

Pfizer — —

Apoptosis stimulators Mycobacterial cell-wall complex (Regressin) United States III Europe — Japan — Arsenic trioxide (Trisonex) United States II Europe — Japan — Tipifarnib (Zarnestra) United States II Europe — Japan —

Bioniche — — Cell Therapeutics — — Janssen Pharmaceutica/Johnson & Johnson — —

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TABLE 6. (continued) Compound

Development Phase

Marketing Company

Antifolates Pemetrexed (Alimta) United States Europe Japan Immunotherapies IDM-2 (Bexidem) United States Europe Japan

II — —

Eli Lilly — —

— II/III —

— Immuno-Designed Molecules —

Alkylating agents Apaziquone (EOquin) United States Europe Japan

— II —

— Spectrum Pharmaceuticals —

Expression of EGFR at any level was seen in the majority of invasive (T2, T3, or T4) BCs and averaged 64% across 250 patients from select studies for which tumor-stage subset data were available (Small EJ, 2003). The frequency of EGFR expression in metastatic sites has not been studied extensively, although in one study, 65% of metastatic samples expressed EGFR, similar to what was seen in the corresponding primary tumor (Bue P, 1998). A separate study indicated that the frequency of EGFR expression was 78% in 33 patients with T3 or T4 tumors (Neal DE, 1990). A signiÞcant positive correlation has been noted between the primary tumor stage (T3 or T4 versus T1 or T2) and the proportion of metastatic tumors expressing EGFR. EGFR-positive BCs are signiÞcantly more likely to recur after resection, to progress to muscle-invasive disease (MIBC), and to cause death. Therefore, EGFR expression is a prognostic factor in BC. A vast amount of research and development (R&D) is ongoing in the area of EGFR inhibition, signifying its commercial viability. Two main approaches are being investigated for therapeutic intervention in BC: the speciÞc inhibition of EGFR tyrosine kinase and monoclonal antibodies (MAbs) directed at the external domain of the EGFR. No randomized data exist demonstrating the efÞcacy of EGFR inhibitors in the treatment of BC. Nevertheless, the extensive R&D in this area as a whole and the rationale for developing these agents to treat BC warrants their inclusion. Mechanism of Action. The binding of EGF to the receptor activates the receptor’s intracellular enzymatic portion and, in turn, triggers a cascade of intracellular events that stimulate growth and survival of the tumor cell. Researchers believe that overexpression of EGFR and overactivity of its downstream signal transduction pathway are signiÞcant factors in the growth of tumors in a subset of

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BC patients. Likewise, the HER-2 gene is overexpressed in a variety of cancers, including BC, and can lead to dysregulated cell growth. In addition to its effects on cell proliferation and the cell cycle, EGFR activation may inßuence several cellular processes, including angiogenesis, apoptosis, motility, adhesion, invasion, and metastasis. Lapatinib. GlaxoSmithKline’s lapatinib is an orally administered EGFR tyrosine kinase inhibitor that has the added beneÞt of blocking ErbB-2/HER2 tyrosine kinase. The compound is in Phase II trials for BC in Europe. Preliminary Phase II data were presented at the 2004 European Society for Medical Oncology meeting (WulÞng C, 2004). The trial evaluated single-agent lapatinib as a second-line treatment for patients with advanced BC (ABC, locally advanced or metastatic, incurable by surgery alone) after Þrst-line treatment with a platinum-based regimen (63%) or other treatments (37%). Of the 58 patients enrolled, only 30 patients were evaluable for the preliminary analysis; 3 patients (10%) had a partial response (PR), but only one PR was sustainable for eight weeks or longer. Eight patients (27%) had stable disease (SD). A clinical beneÞt (SD for six months or more) was observed in three patients. Survival data are premature. Six patients experienced serious adverse events (grading not given), of which one was determined to be treatment-related. The rationale also exists for combining two EGFR inhibitors that target two speciÞc EGFRs, but no signiÞcant clinical data on this approach have emerged. Gefitinib. GeÞtinib (AstraZeneca’s Iressa) is an orally active, quinazolinederived selective EGFR tyrosine kinase inhibitor that blocks signal transduction. GeÞtinib launched in the United States and Japan as a monotherapy for the treatment of non-small-cell lung cancer after patients fail on both platinum-based and docetaxel chemotherapies. The compound is also undergoing numerous other clinical trials in various other cancer indications, including BC. No signiÞcant clinical data exist for geÞtinib in BC. However, numerous preclinical data and preliminary Phase II data provide the rationale for further development and commercial viability. GeÞtinib’s dose-dependent growth-inhibitory and apoptotic effects on several human BC cell lines correlate with the degree of expression of EGFR (Meye A, 2001). Preclinical studies in athymic mice indicate potentiation of cytotoxic agents by geÞtinib in human tumor xenografts derived from various cancer cell lines (Sirotnak FM, 2000). In this system, geÞtinib alone had growth-retarding effects, which signiÞcantly enhanced the antitumor activity of platinum compounds, taxanes, and other cytotoxic agents. It is noteworthy that geÞtinib’s tumor growth-inhibitory activity in combination with chemotherapy is evident even without high levels of EGFR expression. A Phase I trial of geÞtinib (250 or 500 mg) in combination with 1,250 mg/m2 gemcitabine (Eli Lilly’s Gemzar)/cisplatin (generics) has been completed (Small EJ, 2003). No signiÞcant increase in toxicity attributable to chemotherapy was apparent. Furthermore, large variations in the pharmacokinetics of gemcitabine were not observed at the two dose levels of geÞtinib, suggesting that a clinically signiÞcant pharmacokinetic interaction does not occur.

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Because a Þxed-dose-rate infusion of gemcitabine appears to be more effective than standard dosing for the treatment of pancreatic cancer, the Cancer and Leukemia Group B (CALGB) initiated a Phase II study, called CALGB 90102, to test the efÞcacy of cisplatin, Þxed-dose-rate gemcitabine, and geÞtinib in the treatment of patients with BC that had metastasized to lymph nodes or other sites. A total of 27 patients with N2, N3, or M1 disease (performance status 0–2) were enrolled before the study was halted because the dose-limiting toxicity (DLT) exceeded preestablished stopping rules. Preliminary data were presented at the 2004 American Society of Clinical Oncology (ASCO) meeting (Philips G, 2004). The DLT events observed were two grade V (one neutropenic infection, one cerebral vascular accident) and three grade IV nonhematologic toxicities (one hyperuricemia, one fatigue, one dyspnea). Researchers also observed grade 3 diarrhea and skin rash in two (8%) and four (16%) patients, respectively. Of 24 evaluable patients, 12 responded to treatment, representing an overall response rate of 50%. Median time to progression was 6.9 months. This regimen was associated with excessive toxicity, possibly because of the Þxed-dose-rate infusion of gemcitabine, so the researchers now use a standard gemcitabine dosing schedule. CALGB has also initiated a trial for patients with metastatic BC who have renal insufÞciency and therefore cannot tolerate cisplatin. This trial is using carboplatin instead of cisplatin, in combination with gemcitabine and geÞtinib, because carboplatin is better tolerated in patients with renal insufÞciency. Trastuzumab. Trastuzumab (Genentech/Roche/Chugai’s Herceptin) is a recombinant humanized MAb that binds to the HER2 receptor. In addition to binding the extracellular domain of the receptor, trastuzumab may also induce antibody-dependent cytotoxicity against target tumors. Single-agent trastuzumab is indicated for the treatment of patients with metastatic breast cancer (CaB) whose tumors overexpress HER2 and who have received prior chemotherapy for their disease. Trastuzumab is undergoing Phase II trials in the United States for BC. The HER-2 proto-oncogene encodes a transmembrane receptor tyrosine kinase with substantial homology to the other members of the class I receptor tyrosine kinase family, namely EGFR, HER3, and HER4. The degree of HER2 receptor expression in tumors is represented using a scale of 0 (low or negative) to 3 (strongly positive). High expression of the HER2 receptor is demonstrated in 25–30% of CaB patients, making them eligible for treatment with trastuzumab. High HER2 expression increases the proliferative rate of tumor cells, resulting in poor prognosis. Studies indicate that HER2 expression rates in BC specimens range from 2% to 74% (Small EJ, 2003); part of the variation may be explained by the different HER2 antibodies used, the criteria employed to deÞne overexpression, and the stage of BC studied. Both overexpression without gene ampliÞcation and heterogeneity in HER2 expression are more common in BC than in CaB (Underwood M, 1995; Lee SE, 1994). A recent analysis of a well-deÞned set of MIBC

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specimens found a 28% incidence of HER2 positivity by immunohistochemistry, whereas the incidence of 3+ (high HER2 expression) tumors in the primary specimens was 18% (Jimenez RE, 2001). This study also demonstrated that HER2 overexpression in the primary tumors consistently predicted its overexpression in regional or distant metastatic sites. Conversely, some HER2 -negative primary tumors also expressed HER2 in their corresponding metastases. A higher percentage of HER2 positivity was found in lymph-node metastases (53% were 2+/3+, 31% were 3+) when compared with the primary sites. These data provide rationale for developing trastuzumab for the treatment of BC. At the time of composing this reference, no clinical data exist for trastuzumab in treating BC, but the CALGB has opened a trial of trastuzumab for the treatment of BC. The Phase II study will evaluate trastuzumab, paclitaxel, carboplatin, and gemcitabine in patients with locally recurrent or metastatic urothelial carcinoma overexpressing HER2. Erlotinib. Erlotinib (Tarceva) is under development by OSI Pharmaceuticals in alliance with Genentech and Roche. This orally active quinazoline derivative is in Phase II U.S. trials for the prevention of BC recurrence after surgery. Like geÞtinib, erlotinib is an oral, once-daily small molecule that inhibits the intracellular tyrosine kinase domain of the EGFR, thereby blocking receptor activity. This compound’s lead indication is non-small-cell lung cancer, for which it is awaiting U.S. and European approval. No clinical data exist on erlotinib in BC. A Phase II randomized study of adjuvant erlotinib and a green tea extract (polyphenon E) for preventing recurrence and progression of BC in former smokers with resected high-grade superÞcial BC (SBC) is ongoing. At the time of composing this reference, the clinical trial with green tea extract is ongoing. Patients are stratiÞed according to disease stage (Ta versus T1 versus carcinoma in situ [CIS]) and randomized to one of three treatment arms: arm I patients receive erlotinib and placebo once daily; arm II patients receive oral green tea extract and placebo once daily; and arm III patients receive placebo. In all arms, treatment continues for nine months in the absence of disease recurrence or unacceptable toxicity. Patients are followed every three months for 15 months and then every six months for three years. A total of 330 patients (110 per treatment arm) have been expected to be enrolled for this study within three years. Microtubule-Targeting Agents Overview. Microtubules—major structural components in cells—are the target of a large and diverse group of anticancer drugs, including taxanes, epothilones, and vinca alkaloids. Taxanes are potent antitumor agents; members of this class are marketed for numerous forms of cancer. As single agents and combined with other chemotherapeutic agents, taxanes have shown activity against a range of solid tumors. The most promising taxane in development for the treatment of BC is paclitaxel (Bristol-Myers Squibb’s Taxol, generics). In fact, it is already used off-label

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based on results of multiple clinical trials showing promising efÞcacy. In a Phase II clinical trial, Sonus is investigating an emulsion formulation of paclitaxel that incorporates the company’s Tocosol drug delivery technology. In a related development, Bristol-Myers Squibb is investigating the epothilone ixabepilone in early clinical trials for BC. Ixabepilone has anticancer effects similar to those of taxanes. Although clinical data for BC are not yet available for ixabepilone or for paclitaxel delivered via Tocosol, we do not completely exclude them from the list of potential BC agents. Mechanism of Action. Microtubules are protein polymers that are responsible for various aspects of cellular shape and movement. The major component of microtubules is the protein polymer tubulin. Taxanes and epothilones promote microtubule polymerization and inhibit tubulin depolymerization, arresting mitotic cell division at the metaphase/anaphase transition and inducing cell death. Vinca alkaloids inhibit microtubule polymerization at high drug concentrations. Importantly, considerable evidence indicates that, at lower concentrations, taxanes and epothilones have a common mechanism of action: they suppress the dynamics of microtubules without appreciably changing the mass of microtubules in the cell. The drugs bind to diverse sites on tubulin and at different positions within the microtubule and exert a variety of effects on microtubule dynamics. However, by their common mechanism of suppressing microtubule dynamics, they all block mitosis at the metaphase/anaphase transition and induce cell death. Paclitaxel. Paclitaxel is used commonly to treat other cancers. For BC, paclitaxel has reached Phase III clinical evaluation in the United States and Europe. Phase III data comparing carboplatin/paclitaxel (CP) with methotrexate/ vinblastine/doxorubicin/cisplatin (MVAC) in ABC patients are not encouraging (Dreicer R, 2004). Eighty-Þve patients were randomized to the respective treatment regimens (41 to CP and 44 to MVAC). Response rates and overall survival were similar in both treatment arms. Patients treated with CP had an overall response rate of 28.2%, compared with 35.9% for the MVAC arm. Median progression-free survival among MVAC-treated patients was 8.7 months, compared with 5.2 months for CP-treated patients. At a median follow-up of 32.5 months, the median survival for patients treated with MVAC was 15.4 months versus 13.8 months for patients treated with CP. Patients treated with MVAC had more severe worst-degree toxicities than did patients treated with CP. No signiÞcant differences with regard to quality of life, as assessed by the Functional Assessment of Cancer Therapy–Bladder (FACT-BL) instrument, were observed. An international collaborative group that includes the European Organization for Research and Treatment of Cancer (EORTC) and the Southwest Oncology Group (SWOG) is conducting a randomized, multicenter Phase III trial to compare GC (gemcitabine [Eli Lilly’s Gemzar)]/cisplatin [generics]) with the paclitaxel/cisplatin/gemcitabine (TCG) regimen in previously untreated ABC patients. The trial, with a sample size of 630 patients, was closed in mid 2004.

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Results are still anticipated. A U.S. trial is evaluating adjuvant doxorubicin and gemcitabine followed by paclitaxel and cisplatin versus adjuvant cisplatin and gemcitabine in patients with completely resected locally advanced BC. Clinical trials evaluating paclitaxel combined with cisplatin or carboplatin and/or gemcitabine have yielded some promising results. A Phase II trial provided evidence for the therapeutic beneÞt of paclitaxel and carboplatin as a Þrst-line treatment of ABC (Redman BG, 1998). Patients (performance status of 2 or less) received paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5) every 21 days. Thirty-Þve patients were assessable for response. Researchers administered a total of 184 cycles (median, six cycles per patient). They observed 7 complete responses (CRs) and 11 PRs, giving an overall response rate of 51.5%. Median response durations for CR and PR were six and four months, respectively. Overall median survival was 9.5 months. Nine patients required one dose reduction, and seven patients required two dose reductions; only one episode of febrile neutropenia and sepsis occurred. Myalgias and arthralgias of grades I/II occurred in 16 patients and usually lasted two to three days after treatment. No treatment delays because of toxicity were noted. Researchers have also evaluated the triplet combination of carboplatin, paclitaxel, and gemcitabine in patients with ABC (Hussain M, 2001). Patients (performance status 2 or less) received the same 21-day regimen as in the previously discussed trial but with the addition of gemcitabine (800 mg/m2 ) on days 1 and 8. Forty-nine patients (44 men and 5 women) were enrolled, 47 of whom were assessable for response. A total of 272 cycles were administered (median, six cycles). Fifteen (32%) patients experienced a CR and 17 (36%) patients experienced a PR, for an overall response rate of 68%. Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a one-year survival rate of 59%. Major toxicities were grade III and IV neutropenia in 17 and 19 patients, respectively; grade III and IV thrombocytopenia in 15 and 6 patients, respectively; grade III and IV anemia in 10 and 2 patients, respectively; grade III neuropathy in 4 patients; and diarrhea in 2 patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Paclitaxel and cisplatin have been evaluated in the treatment of metastatic BC (Burch PA, 1999). Cycles (135 mg/m2 paclitaxel; 70 mg/m2 cisplatin) were repeated every 21 days until progression or a maximum of six cycles. Twentynine patients (performance status 2 or less; 26 males and 3 females) with untreated metastatic BC participated in the study. Researchers observed an overall response rate of 72% and a CR rate of 34%. Eighteen patients progressed; median time to progression was eight months. When these data were released, 14 patients were still alive, and their median survival was 13 months. Grade III/IV toxicities included anorexia (two patients), nausea (Þve patients), vomiting (four patients), and fatigue (one patient). Six patients experienced grade II or higher neurotoxicity. Paclitaxel and cisplatin have also been evaluated as neoadjuvant therapy in locally advanced BC to determine whether those who experience a CR can avoid

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radical cystectomy. Some encouraging Phase II data are available (Mel JR, 2001). In this trial, patients received paclitaxel (175 mg/m2 ) and cisplatin (75 mg/m2 ) every 21 days for three cycles. Patients were then re-staged by computed tomography, cystoscopy, and multiple biopsies. Patients with a PR, stable disease (SD), or progressive disease (PD) underwent radical cystectomy. Patients with a CR underwent radiation therapy to avoid radical cystectomy. Forty-four patients (40 males, 4 females; performance status 2 or less) were evaluable for response and toxicity evaluations; of this group, 20.5% were stage II and 79.5% were stage III. Researchers observed 24 (54.5%) CRs, 11 PRs (25%), 6 SDs (11.4%), and 4 PDs (9.1%). After a median follow-up of 15.5 months (median response duration was 14 months), four patients had local relapses and four patients had distant relapses. Neutropenia was the main hematologic toxicity (grade III/IV neutropenia occurred in 31.8% of patients). No toxic deaths and no febrile neutropenia occurred. Other grade III/IV toxicities included nausea and vomiting, which occurred in 9.1%. Toxicity did not cause any treatment delays. Based on the aforementioned trials, paclitaxel is likely to play an important role in BC treatment, especially among patients with recurrent or nonresponding disease. Vinflunine. Vinßunine (Pierre Fabre’s Javlor) (Figure 10), a semisynthetic vinca alkaloid derived from vinorelbine, is in Phase III clinical trials for the treatment of BC in Europe and other, non-major-market territories. The Phase III study will enroll 330 patients who have either not responded to treatment with a platinumbased regimen or relapsed afterward. These patients will be drawn from 90 centers in 18 countries, including Mexico, Argentina, South Africa, and most countries in Europe. The main criterion for evaluation is overall survival. Results of a Phase II study of vinßunine in patients with ABC who had progressed after at least one line of platinum-containing therapy were presented at the 2003 ASCO meeting (Bui B, 2003). Among 48 evaluable patients, researchers observed 9 PRs (19%), 23 SDs (48%), and 16 PDs. Grade III/IV neutropenia, leukopenia, anemia, thrombocytopenia, constipation, myalgia, and vomiting occurred in 67%, 45%, 14%, 6%, 12%, 4%, and 6% of patients, respectively.

N

CF2CH3

N N H CH3O2C CH3O

CH3 N

OCOCH3 HO CO2CH3 CH3

FIGURE 10. Structure of vinflunine.

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Although vinßunine has shown some promising results in the aforementioned Phase II trial, Phase III data are needed. No effective treatment in the second-line setting exists for BC, particularly for patients whose disease is refractory to or who cannot tolerate gemcitabine-based therapy, so any therapy that could demonstrate even a marginal beneÞt over best supportive care would be a welcome option. Topoisomerase I Inhibitors Overview. Cytotoxic agents targeting topoisomerase I are commonly used to treat cancer. Camptothecin (CPT, generics; an alkyloid agent derived from the Campotheca acuminate tree) (Figure 11) was the Þrst topoisomerase I inhibitor to enter trials for the management of cancer. However, unacceptable toxicity, including severe myelosuppression, enteritis, and hemorrhagic cystitis, led to the discontinuation of initial trials. A new generation of topoisomerase I inhibitors has emerged, including irinotecan (PÞzer’s Camptosar, Yakult/SanoÞ-Aventis’s Campto, Daiichi’s Topotecin) (Figure 12), discussed further on. Mechanism of Action. Topoisomerase I catalyzes the conversion of DNA strands into single-strand DNA breaks—a process necessary to relieve chain

FIGURE 11. Structure of camptothecin (R1 = R2 = R3 = H).

H3C O

O

O N

N N O N

HO H3C

FIGURE 12. Structure of irinotecan.

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tension during the DNA replication required for cell division—by nicking and then reannealing the DNA strand. Camptothecin analogues exert their cytotoxic effect by binding to topoisomerase I and stabilizing the intermediate enzymeDNA cleavable complex, generating DNA strand breaks that are lethal to the cell. Irinotecan. Irinotecan (PÞzer’s Camptosar, Yakult/SanoÞ-Aventis’s Campto, Daiichi’s Topotecin) (Figure 12) is a parenteral topoisomerase I inhibitor approved for the treatment of metastatic colorectal cancer. It is in development for a number of cancers, including BC. At the time of composing this reference, no data on irinotecan for the treatment of BC are available. Two Phase II trials are under way in the United States. One trial is evaluating single-agent irinotecan in the second-line setting; the other is evaluating the combination of irinotecan and gemcitabine in ABC. Given irinotecan’s demonstrated clinical activity in colorectal cancer and many other solid tumors, it has potential in the Þeld of BC as well. Cyclooxygenase-2 Inhibitors Overview. Nonsteroidal anti-inßammatory drugs (NSAIDS) that inhibit cyclooxygenase-1 and -2 (COX-1 and -2) are active in preventing cancers (Sabichi AL, 2004). However, the use of nonspeciÞc NSAIDs such as aspirin (generics) in cancer prevention and treatment is limited because of the risk of upper gastrointestinal (GI) side effects. The recent disclosure that a COX-2 inhibitor increased the risk of heart attacks and strokes will make clinicians less likely to prescribe agents in this class for a relatively curable cancer. Mechanism of Action. The mechanism of anticancer activity of COX-2 inhibitors is not fully understood, although it may involve anti-inßammatory effects. COX-2 is expressed strongly in invasive BC. The degree of COX-2 expression correlates with tumor grade and stage (Yoshimura R, 2001). COX-2 immunostaining is positive in 31–80% of invasive bladder cancers (Shirahama T, 2000). Thus, high levels of COX-2 may promote tumorigenesis through enhanced angiogenesis, increased tumor invasiveness, resistance to apoptosis, and reduced host-immune surveillance. Celecoxib. Celecoxib (PÞzer’s Celebrex) (Figure 13) is already approved in the United States and is awaiting European approval as an adjuvant to surgery in treating familial adenomatous polyposis (FAP), a precursor to colorectal cancer. No randomized data on the role of celecoxib in BC treatment or prevention exist. However, the results of a study using data from a Canadian database containing prescription and physician service claims were disclosed at the 2003 ASCO meeting (Sheehy OE, 2003). Study patients were newly diagnosed with SBC and had surgical endoscopic treatment for bladder malignancies or cystectomy. Patients must have had one follow-up visit for diagnostic and therapeutic urethro-cystoscopy after the initial procedure. Eligible patients were grouped into

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O

H2N S O

N

N CF3

H3C

FIGURE 13. Structure of celecoxib (R1 = NH2 , R2 = CH3 ).

cohorts of celecoxib, NSAIDs, acetaminophen, and non-users. Researchers compared SBC recurrence (as signiÞed by receipt of another surgical procedure to remove bladder tumor) among study cohorts. Of the 1,172 patients evaluable, 55 received celecoxib, 382 received NSAIDs, 208 received acetaminophen, and 527 received nothing. Survival analysis showed cumulative recurrence rates at one year of 61.5% among non-users and 56.7% in the acetaminophen group, but approximately 30% for the celecoxib and NSAID groups. After adjusting the aforementioned variables, the COX-regression model indicates that celecoxib and NSAID users had a signiÞcantly lower risk of SBC than non-users. A Phase III U.S. trial examining celecoxib in the chemopreventive setting is under way. The trial will compare the time to recurrence after treatment with celecoxib versus placebo in patients with SBC after resection who have a high risk for recurrence (i.e., stage Ta [grade 3 or multifocal or at least two occurrences, including current tumor, within the past 12 months] or stage T1 or CIS [any grade]). A total of 152 patients will be recruited. As mentioned above, but needs to be repeated, the recent disclosure that a COX-2 inhibitor increased the risk of heart attacks and strokes will make clinicians less likely to prescribe agents in this class for a relatively curable cancer. Apoptosis Stimulators Overview. Apoptosis, or programmed cell death, represents a universal and exquisitely efÞcient cellular suicide pathway. As the understanding of its vital role in normal development has deepened, researchers have identiÞed numerous genes that encode apoptotic regulators, some of which represent familiar oncogenes or tumor-suppressor genes. Targeting apoptosis is successful only if the therapeutic index is good enough to selectively destroy cancer cells rather than normal cells. In drug-curable malignancies, such as common pediatric leukemias and certain solid tumors, apoptosis is a prominent mechanism associated with the induction of tumor remission. Many cytotoxic agents’ ultimate mechanism of action works via the general apoptotic pathway; we introduce this category here to cover the agents described further on because it is the most appropriate class in which to group them.

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Mechanism of Action. Apoptotic cell death is triggered by intracellular cues such as DNA damage and osmotic stress, and by extracellular cues such as growth factor withdrawal, matrix detachment, and direct cytokine-mediated killing. Two central pathways are involved in the process of apoptotic cell death: one activates the caspase proteases and the other involves a mitochondrial pathway. A drug that activates apoptosis might achieve a suitable therapeutic index in several ways. First, it might activate a death cascade via a drug target that is uniquely expressed in a cancer cell. Alternatively, it might be delivered to the target tissue in a manner that is selective for the cancer cell. A third possibility—perhaps the most promising one—is to exploit a pathway that is activated by oncogenes in order to provoke apoptosis selectively in cancer cells. It is now clear that oncoproteins can interact with apoptotic regulatory pathways. Thus, overexpression of myc sensitizes cells to a wide assortment of apoptotic triggers, probably reßecting the role of apoptosis in the intracellular immunity that prevents normal cells from persisting in the body once they acquire cancer-causing genetic defects. However, many human tumors that overexpress myc are highly resistant to apoptotic triggers, probably owing to a variety of downstream lesions that blunt the death pathway. Still, the recognition that oncogenes can sensitize cells to proapoptotic treatments suggests that if such lesions can be circumvented, drugs that induce cell death could prove highly selective for cancer cells. Mycobacterial Cell-Wall Complex. Mycobacterial cell-wall complex (MCC) (Bioniche’s Regressin, Urocidin) is a DNA oligonucleotide complex that actively inhibits tumor cell growth and triggers apoptosis. Its lead indication is BC, for which Phase II trials have been completed in the United States. In February 2006, the protocol was under review by the FDA, which had cleared the company to start a smaller open-label phase III bladder cancer trial. Enrollment is planned to begin in the second quarter of 2006. Final Phase I/II data evaluating MCC in SBC were presented at the 2004 American Urological Association meeting (Filion MC, 2004). The trial involved 55 patients with CIS refractory to traditional treatments. They received MCC (4 or 8 mg) and were evaluated at 3, 6, 12, and 18 months. CRs at 12 months ranged from 43% to 64% of patients. Three patients had to stop treatment with MCC. At the time these data were disclosed, Bioniche was working on the design of a pivotal, multicenter program in North America and Europe to conÞrm the efÞcacy and safety of MCC in patients with high-risk SBC. Data were also presented from a study of the immune response following intravesical administration of MCC emulsion in patients with BC (Morales A, 2004). MCC induced an immune response against both MCC and bacillus Calmette-Guérin (BCG, generics), as deÞned by antibodies in these patients. Arsenic Trioxide. Arsenic trioxide (Cell Therapeutics’ Trisenox) is in Phase II trials in the United States as a single agent in the treatment of BC. Several clinical trials are evaluating the agent for various tumor types, but lead indications are hematologic cancers.

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Arsenic trioxide has been shown to inhibit growth and induce apoptosis in preclinical models, although its mechanism of action has not been fully elucidated. Preliminary preclinical data suggest it may be active against cells expressing the multidrug resistance (MDR) gene. Dose-limiting toxicities with arsenic trioxide include weight gain and peripheral neuropathy. The most common side effects have been dizziness during infusion, skin reactions, hyperglycemia, and musculoskeletal pain. Arsenic trioxide has activity against certain solid tumor cell lines, among which BC cell lines were the most sensitive to its effects (Small EJ, 2003), providing the rationale for the completed Phase II trial. This trial evaluated arsenic trioxide in 35 patients with recurrent urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis (after failure of one previous line of chemotherapy). Bortezomib. Bortezomib (Millennium Pharmaceuticals’ Velcade) is a smallmolecule proteasome inhibitor that works through multiple pathways, including those inßuencing apoptosis and angiogenesis. Its lead indication is multiple myeloma, for which it is approved in the United States. Bortezomib is in Phase II trials in the United States for the treatment of BC. Proteasomes are enzyme complexes responsible for breaking down proteins, including those that regulate cell division, most notably nuclear factor kappabeta (NF-κβ). NF-κβ is implicated in BC (Karashima T, 2003). Bortezomib has high selectivity for the proteasome over other proteases (e.g., thrombin) and has demonstrated in vitro cytotoxicity against a wide range of tumor cell lines. Preclinical data show that bortezomib inhibited cell growth in a concentrationdependent fashion and augmented the growth-inhibitory effects of gemcitabine in vitro (Kamat AM, 2004), but no clinical data in BC seem to have yet emerged. Farnesyl Transferase Inhibitors Overview. The proto-oncogene Ras, which encodes a small GTP-binding protein, is required for both normal intracellular signaling via receptor tyrosine kinases (such as EGFR tyrosine kinases) and appropriate control of cell division. Mutated Ras occurs in up to 20% of BC cases (Quek ML, 2003), and substantial research has been invested in identifying inhibitors of Ras function. Farnesyl transferase inhibitors (FTIs) have emerged as potential therapies for the treatment of BC and other neoplastic diseases because they catalyze a critical post-translational modiÞcation step required for Ras activity. In preclinical models, unmodiÞed Ras molecules were unable to stimulate mitogen-activated protein kinase (MAPK), thereby inhibiting cell division (McGeady P, 1995). The only FTI in clinical trials for BC is Janssen Pharmaceutica’s tipifarnib (Zarnestra, previously R-115777), which we discuss further on. Mechanism of Action. Ras normally transduces intracellular signals from receptor tyrosine kinases; Ras signaling activates MAPK, thereby stimulating the promitogenic transcription factors Fos and Jun and promoting cell proliferation. Mutations of Ras stimulate uncontrolled cell proliferation by constitutive activation of MAPK. Ras function requires the addition of a farnesyl (lipid) group to

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a cysteine residue at the carboxy-terminus of the protein. This post-translational modiÞcation is catalyzed by farnesyl transferase; small-molecule inhibitors of this enzyme antagonize the modiÞcation of Ras, which in turn generates a naive form of Ras that is incapable of stimulating MAP-kinase-associated cell division. Tipifarnib. Janssen and its parent company, Johnson & Johnson, are developing the oral FTI tipifarnib. A Phase II trial will evaluate tipifarnib in recurred BC after at least one line of intravesical therapy. In the meantime, no clinical data on tipifarnib in the treatment of BC are available. Data available for tipifarnib in other cancers (pancreatic, breast, colorectal) have been disappointing, and overall, the FTIs show modest single-agent activity in various cancer trials and are associated with signiÞcant toxicity. Antifolates Overview. New-generation antifolate drugs are targeting multiple steps in the folate metabolism pathway, resulting in the inhibition of both purine and pyrimidine de novo synthesis. Of these antifolates, pemetrexed (Eli Lilly’s Alimta) is the only one in development for BC. Mechanism of Action. The folate pathway is involved in the metabolism and synthesis of the DNA precursors (purines); antifolates that inhibit this pathway interfere with DNA synthesis, causing tumor cell death. Previous generations of antifolates were directed principally at the enzyme thymidylate synthase, which is a key enzyme in the folate pathway. New generations of antifolates inhibit additional key enzymes involved in the folate pathway. Pemetrexed. Pemetrexed (Eli Lilly’s Alimta) (Figure 14) is a new-generation, multitargeted antifolate, which, at the time of composing this reference, is still in Phase II trials in the United States for the treatment of BC. Pemetrexed inhibits the enzymes involved in DNA synthesis, namely thymidylate synthase, as well as dihydrofolate reductase and glycinamideribonucleotide (GAR) formyltransferase. Promising Phase II data were disclosed at the 1998 European Society of Medical Oncology conference (Paz-Ares L, 1998). Researchers were able to evaluate 20 of 25 patients with metastatic BC (performance status less than or equal to

FIGURE 14. Structure of pemetrexed.

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2) who received pemetrexed (500–600 mg/m2 every three weeks). The median number of cycles per patient was three. Seven courses (10%) were dose-reduced and seven (10%) delayed. Grade III/IV hematological toxicity occurred in 15 patients (75%); Þve patients developed neutropenic fever. Nonhematologic toxicities included skin rash (grade III; one patient), stomatitis (grade III; one patient), and diarrhea (grade III; two patients). Two toxic deaths occurred. Seven patients (35%) experienced PR, Þve (25%) SD, and seven (35%) PD. On the basis of these results, a single-agent pemetrexed trial that delivers 500 mg/m2 with vitamin supplementation has been initiated in pretreated patients in several centers in the United States. A Phase II U.S. trial evaluating pemetrexed and gemcitabine in treating ABC patients is also ongoing. No signiÞcant data on this compound have been reported in recent years. Immunotherapies Overview. Several immunotherapies are being investigated for use in cancer treatment and/or prophylaxis, although only limited R&D is ongoing in BC. We have grouped all interesting immunotherapies in this section. Note that no signiÞcant positive data have been made available on these agents in BC. Mechanism of Action. The body’s immune system normally rids itself of aberrant cells before they have a chance to multiply, colonize, or metastasize. Immunotherapy takes advantage of these natural host defense mechanisms via the following agents: • • •

Monoclonal antibodies that target aberrant proteins on cancer cells. Cytokines that increase or activate host immune cells, such as T cells, macrophages, and natural killer cells. Vaccines that activate speciÞc host T-cell or antibody responses that attack the cancer cells.

These agents, also known as biological response modiÞers, include several marketed compounds, such as cytokines (interleukins [ILs] and interferons [IFs]), colony-stimulating factors (CSFs), monoclonal antibodies (MAbs), and vaccines. Immunotherapy is a general term encompassing a wide variety of mechanisms of action, but its fundamental mechanism is the production of an immune response to treat or prevent disease. IDM-2. IDM-2 (Immuno-Designed Molecules’ Bexidem) is a combination of anticancer agents incorporating macrophage-activated killer (MAK) cells. In March 2004, Immuno-Designed Molecules (IDM) began a Phase II/III European trial of IDM-2 in BC. IDM-2 is designed to destroy residual cancer cells after transurethral resection of SBC, much as BCG does; the MAK cells are produced by activating the patient’s own white blood cells ex vivo. MAK cells are designed to be reinjected into the patient and have the capacity to recognize and destroy cancer cells. IDM has two products based on MAK.

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The randomized trial will be carried out primarily in France, Belgium, Luxembourg, and Germany. Half of the patients will receive 12 intrabladder instillations of IDM-2 over a six-month period. The other half will receive BCG. Researchers will use an intermediate analysis of the results on the Þrst 138 patients to deÞne the exact number of patients for Phase III trials. Phase I/II data were presented at the European Perspectives on Bladder Cancer meeting in 2001 (IDM press release, November 2001). Seventeen patients with SBC (TaG3 or relapsed TaG2) having a high probability of relapse within a year received six weekly intravesical infusions of IDM-2 based on MAK obtained from autologous mononuclear cells. Five patients received maintenance therapy at three-month intervals. All patients were followed up for at least one year before IDM-2 treatment and two years after the Þrst IDM-2 injection to observe how many times their disease recurred before and after treatment. During the Þrst year after treatment initiation, eight recurrences were observed, compared with 34 recurrences during the year before IDM-2 treatment. During the second year of follow-up, ten recurrences took place. Only one patient experienced PD that necessitated a cystectomy, and only 12 minor (grade I or II) adverse events possibly related to the protocol were reported. Immunotherapy could eventually play a role in earlier stages of BC and/or after tumor resection, when tumor burden is low, to prevent or reduce the likelihood of recurrence. Although BCG is reasonably effective in this setting, there is room for a more effective agent, for an agent with a different side-effect proÞle, and, indeed, for an agent that can be used in combination with BCG. Alkylating Agents Overview. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. Many alkylating agents are already well-established treatments for various types of cancer but have not yet found a role in BC treatment. Mechanism of Action. Alkylating agents involve reactions with guanine in DNA. These drugs add methyl or other alkyl groups onto molecules where they do not belong. This action, in turn, inhibits their correct utilization by base pairing and causes a miscoding of DNA. The Þrst mechanism by which an alkylating agent damages DNA involves attaching alkyl groups to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases. A second mechanism by which alkylating agents damage DNA is by forming crossbridges—bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or transcription. Alkylating agents’ third mechanism of action causes the mispairing of the nucleotides, leading to mutations. Apaziquone. Spectrum Pharmaceuticals is developing apaziquone (EOquin) for the potential treatment of BC. A Phase II trial in Europe is ongoing.

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The pro-drug is metabolized in human and murine cells to the alkylating agent by the reductive enzyme DT-diaphorase (DTD), which is preferentially expressed in cancer cells. The Phase II trial is testing 4 mg/40 mL of the compound for six weeks in SBC patients. At the time of composing this reference, the trials are still ongoing. Encouraging preliminary toxicology data for this trial were presented at the 15th AACR-NCI-EORTC meeting in 2003 (Puri R, 2003). Two weeks after tumor removal, patients (n = 6) were administered apaziquone intravesically on a weekly schedule for six weeks. Doses commenced at 0.5 mg/40 mL and doubled until toxicity or maximum dosage (16 mg/40 mL) was achieved. All patients tolerated doses of 4 mg/40 mL, and only minor, reversible side effects were experienced at higher doses. Two patients were able to tolerate the maximum dose. No recurrences have been observed after one year in the Þrst patient treated, nor after six months for the remaining patients. Apaziquone may have an advantage over other alkylating agents because it is selectively activated by DT-diaphorase. Consequently, it is more likely to play a potential role in BC therapy. REFERENCES Aben KK, Kiemeney LA. Epidemiology of bladder cancer. European Urology. 1999;36:6 (Curriculum in Urology 6.4;1–13). Adrian PM, et al. Intravesical instillation of epirubicin, bacillus Calmette-Guérin and bacillus Calmette-Guérin plus isoniazid for intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer Genitourinary Group randomized Phase III trial. Journal of Urology. 2001;166:476–481. Advanced Bladder Cancer (ABC) Meta-Analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systemic review and meta-analysis. Lancet. 2003;361: 1927–1934. Al-Sukhun S, Hussain M. Current understanding of the biology of advanced bladder cancer. Cancer. 2003;97(suppl 8):2064–2075. American Joint Committee on Cancer Staging Manual . 5 th Edition. Lippincott William & Wilkins, Philadelphia, PA, 1997. Baselli EC, Greenberg RE. Intravesical therapy for superÞcial bladder cancer. Oncology (Huntington). 2000;14(5):719–729; discussion 729–731, 734, 737. Baselli EC, Greenberg RE. Maintenance therapy for superÞcial bladder cancer. Oncology (Huntington). 2001;15(1):85–91. Bassi P. BCG (Bacillus Calmette Guerin) therapy of high-risk superÞcial bladder cancer. Surgical Oncology. 2002;11(1–2):77–83. Bellmunt J, et al. A feasibility study of carboplatin with Þxed-dose gemcitabine in unÞt patients with advanced bladder cancer. European Journal of Cancer. 2001;37: 2212–2215. Bergman AM, et al. Synergistic interaction between cisplatin and gemcitabine in vitro. Clinical Cancer Research. 1996;2(3):521–530.

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Raitamen MP, et al. Impact of tumor grade, stage, number, size, smoking and sex on survival in patients with transitional-cell carcinoma of the bladder. British Journal of Urology. 1995;76(4):470–474. Rajala P, et al. Transurethral resection with perioperative instillation of interferon-alpha or epirubicin for the prophylaxis of recurrent primary superÞcial bladder cancer: a prospective randomized multicenter study—Finnbladder III. Journal of Urology. 1999;161:1133–1136. Redman BG, et al. Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. Journal of Clinical Oncology. 1998;16(5):1844–1848. Ries LAG, et al., eds. SEER Cancer Statistics Review, 1975–2000 [electronic]. National Cancer Institute: Bethesda, MD; 2003. http://seer.cancer.gov/csr/1975–2000. Rischmann P, et al. AFU recommendations 1998. Committee on Cancer of the French Association of Urology. Progres en urologie: journal de l’Association francaise d’urologie et de la Societe francaise d’urologie. 1998;8(3):25. Rodel C, et al. Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation. International Journal of Radiation Oncology, Biology, Physics. 2000;46:1213–1221. Rodel C, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. Journal of Clinical Oncology. 2002;20(14): 3061–3071. Sabichi AL, Lippman SM. COX-2 inhibitors and other nonsteroidal anti-inßammatory drugs in genitourinary cancer. Seminars in Oncology. 2004;31(2 S7):36–44. Saxman SB, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology. 1997;15:2564–2569. Schenkman E, Lamm DL. SuperÞcial bladder cancer therapy. ScientiÞc World Journal. 2004;4(suppl 1):387–399. Schottenfeld D, Fraumeni-JF J, eds. Cancer Epidemiology and Prevention. 2nd ed. Oxford: Oxford University Press; 1996. Schuster TG, et al. Pelvic recurrences postcystectomy: current treatment strategies. Seminars in Urologic Oncology. 2001;19(1):45–50. Schüz J, et al. Cancer registration in Germany: current status perspectives and trends in cancer incidence 1973–1993. Journal of Epidemiology and Biostatistics. 2000;5: 99–107. Shariat SF, et al. p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. Journal of Clinical Oncology. 2004;22(6):1014–1024. Sheehy OE, et al. Celecoxib associated with reduced risk of superÞcial bladder cancer (SBC) recurrence. Proceedings of the American Society of Clinical Oncology. 2003. Abstract 1539. Shelley MD, et al. A meta-analysis of randomised trials suggests a survival beneÞt for combined radiotherapy and radical cystectomy compared with radical radiotherapy for invasive bladder cancer: are these data relevant to modern practice? Clinical Oncology (Royal College of Radiologists [Great Britain]). 2004;16(3):166–171. Shiina H, et al. Immunohistochemical analysis of bcl-2 expression in transitional-cell carcinoma of the bladder. Journal of Clinical Pathology. 1996;49:395–399.

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Breast Cancer

ETIOLOGY AND PATHOPHYSIOLOGY Nosology Breast cancer (CaB) is the most common cancer in women worldwide. It arises from the epithelium that lines the lactiferous ducts (the conduits for milk) and lobules in the breast and is classiÞed as either carcinoma in situor invasive carcinoma. Carcinoma in situ(which is outside the scope of this report) is the term applied to lesions that express some characteristics of invasive cancers (abnormal nuclei, for example) but have not penetrated the mammary duct and entered the supportive tissue of the breast. Carcinoma in situ is treated by surgery with or without radiotherapy. The majority of primary breast cancers are adenocarcinomas, and approximately 50% are located in the upper outer quadrant of the breast. Invasive carcinoma (the subject of this study) usually arises in the ductal epithelium, with inÞltrating ductal carcinoma accounting for 75% of CaB cases. InÞltrating ductal carcinoma is associated with a high propensity to spread to lymph nodes and to distant organs, resulting in a poor prognosis. InÞltrating lobular carcinoma is the next most common histological type of CaB, accounting for approximately 10% of cases. Certain variants of this type of cancer are also associated with poor outcome, although metastatic disease is slightly less common with inÞltrating lobular CaB than it is with ductal CaB. The remaining types of breast cancer are relatively infrequent (accounting for less than 10% of cases), tend to remain localized or metastasize late, and have more favorable outcomes. At diagnosis, Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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CaB—by deÞnition—has begun to spread into surrounding breast tissue. Cells that separate from the tumor are the source of regional metastases (to the local lymph nodes and skin) and distant metastases (to other organs). Anatomy The main functional purpose of the breast in any mammal is the production of milk for sustaining offspring. Each breast comprises 15–20 lobes, which are composed of numerous tiny glands or lobules, termed alveoli or acini (Figure 1). The alveoli produce milk and other substances during lactation and are linked by thin tubes called the milk or lactiferous ducts. These ducts lead to the nipple in the center of the breast, which is within a dark area of skin called the areola. Adipose and connective tissues surround the lobes of glandular tissue. The amount of fatty tissue depends on many factors, including age, percentage of body fat, and heredity. Each breast is well vascularized by both the blood and the lymphatic system. The lymph vessels drain into the lymph nodes, clusters of which are found under the arm, above the collarbone, and in the chest, as well as in many other parts of the body. Both the lymphatic system and the blood system are responsible for the dissemination of tumor cells from a primary cancer in the breast. There are no muscles within the breast, but muscles lie under each breast and cover the ribs. Cooper’s ligaments connect the chest wall to the skin of the breast, giving the breast its shape and elasticity. Etiology Risk Factors. Many risk factors for CaB have been identiÞed to a greater or lesser degree of causal certainty. These risk factors fall into two classes: unavoidable risk factors and modiÞable risk factors that relate to lifestyle. Aside from

FIGURE 1. Structure of the breast.

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a genetic predisposition, the common factor in many of these risks is increased exposure to endogenous estrogen over a long period of time. In several large studies, researchers have established the signiÞcant risk factors for CaB that are detailed in Table 1. The “Germline Mutations” section details one of the most important risk factors listed in Table 1. These mutations are a focus because information about them could help clinicians target preventive therapy or prophylactic treatment to individual patients. Germline Mutations. Germline mutations are inherited and are present in all cells in the body. Experts estimate that up to 10% of all CaBs are linked to heritable factors (Sng JH, 2000). Mutations of the cancer susceptibility genes breast cancer 1 (BRCA1 ) and breast cancer 2 (BRCA2 ) are thought to be associated with most heritable cases of CaB (up to 80% of familial cases, 5–6% of the total number of cases). Other germline mutations associated with CaB include the following: •

•

• •

p53 mutations (such as in Li-Fraumeni syndrome, an inherited mutation of the p53 tumor suppressor gene causing high incidence of cancers in afßicted individuals); PTEN mutations (such as Cowden’s disease, in which sufferers have a germline mutation in the PTEN gene producing increased susceptibility to polyps and cancers); ATM (ataxia-telangiectasia mutation, which increases susceptibility to developing cancers by impairing the immune system); and Susceptible HRAS1 polymorphisms.

BRCA1, BRCA2, p53, and PTEN mutations are all highly penetrant (likely to be expressed), and women with any of these mutations are quite likely to develop CaB. For example, the risk of developing CaB for BRCA1 carriers is estimated to be as high as 85% by age 55 (Ford, D 1994); however, the risk associated is mutation-speciÞc, and as such, may be family-speciÞc. A signiÞcant fraction of the population may carry an ATM or a susceptible HRAS1 polymorphism, but these mutations have low penetrance; because few carriers actually develop CaB, it is difÞcult to determine the precise number of CaB cases triggered by these abnormalities. Population studies suggest that other, as yet unidentiÞed, genes are implicated in familial CaB. BRCA1 and BRCA2. Expressed in normal breast tissues, BRCA1 and BRCA2 are tumor suppressor genes that regulate the proliferation and differentiation of breast epithelial cells. Mutation of the BRCA genes confers a much higher susceptibility to CaB (Table 2). Familial CaB resulting from BRCA mutations tends to be aggressive and to have an early onset: the mean age at diagnosis is approximately 43 years and 47 years for BRCA1 and BRCA2 mutations, respectively. Women with BRCA mutations are also at risk of developing second primary breast tumors


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TABLE 1. Risk Factors Associated with Breast Cancer Age

Incidence of breast cancer (CaB) increases with age (McPherson K, 2000). The majority of cases occur in women aged 50 years or older (Ries LAG, 2004). Some studies have indicated that age may be a prognostic factor (Kim SH, 1998; Fowble BL, 1994; de la Rochefordiere A, 1993), and that younger women tend to have more aggressive cancer. Other studies indicate no differences. Exposure to Estrogen exposure increases with the number of ovulatory cycles. Earlier estrogen age at menarche (younger than 12 years), low or null parity, later age at menopause (older than 55 years), and later age (older than 30 years) at first full-term pregnancy are associated with increased risk of CaB (Adami HO, 1998; Huang WY, 2000). Use of oral contraceptives is also associated with increased risk, as is obesity, as high amounts of fat tissue can increase estrogen levels. Recent data from the United Kingdom Million Women Study claim an increased risk in CaB related to HRT usage—increased risk with duration of therapy and use of progesterone. However, the study has been criticized as being flawed, so any real risk of HRT remains uncertain and controversial. History of benign Evidence from clinical follow-up studies indicates a relationship between breast disease histologically proven benign breast disease and CaB risk and that risk varies according to the histological category of benign breast disease and hormonal status (Schnitt SJ, 2001). Three studies have reported that when biopsy revealed proliferative disease without atypia, subsequent risk was approximately 1.5 times greater; when biopsy revealed atypical hyperplasia (AH), risk was approximately 4.5 times greater. When patients with AH had a family history of CaB, subsequent risk approached that of patients with in situ carcinoma: approximately 8–10 times greater (Connolly JL, 1993). Race (related to African-American women aged 30–39 have higher incidence of CaB than familial risk) their white counterparts (Johnson ET, 2002). Mutations of the tumor suppressor genes BRCA1 and BRCA2 occur in 1/500 in the general population but in 1/40 in the Ashkenazi population (Winer EP, 2001). Heavy alcohol Consuming two to ten alcoholic beverages per week may confer a consumption 30–60% increase in risk of CaB (Gapstur SM, 1995). Alcohol appears to increase blood levels of estradiol. Other studies suggest an effect only in women who are also taking HRT (Ginsburg ES, 1996). Ionizing radiation Exposure to ionizing radiation increases CaB risk. Because of the long latency period for radiation-induced CaB and greater sensitivity of the developing breast to mutagenic damage, radiation exposure before the age of 40 incurs the highest risk; exposure after the age of 40 incurs minimal increase in risk. A marked increase in CaB has been reported in women who received mantle irradiation for treatment of Hodgkin’s lymphoma before the age of 15 (Winer EP, 2001). Familial risk Up to 1–6% of all cases are considered hereditary. A woman whose mother or sister had CaB has a 20% chance of developing CaB by the age of 40 and an 80% chance by the age of 70 (Colditz GA, 1996). Inherited germline Approximately 10% of CaB cases are attributable to BRCA1 and BRCA2 mutations mutations (Heisey RE, 1999; Hopper JL, 1999); mutations of these genes trigger a cascade of additional mutations that result in CaB. Lifestyle factors A high-fat, low antioxidant diet and a lack of exercise are generally associated with increased risk for most types of cancer. Note: Full source citations appear in ‘‘References.’’

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TABLE 2. BRCA1 or BRCA2 Mutation Carriers: Lifetime Breast and Ovarian Cancer Risk Genotype Normal (BRCA1, BRCA2) BRCA1 mutation carrier at age 50 BRCA1 mutation carrier at age 70 BRCA2 mutation carrier at age 70 Male BRCA2 mutation carrier

Lifetime Risk of Breast Cancer (%) 11–12 50 82 70 5–7

Lifetime Risk of Ovarian Cancer (%) 1.3 23 up to 50 up to 10 N.A.

N.A. = Not applicable.

and, particularly for BRCA1 mutations, ovarian cancer. These patients may also be more susceptible to other cancers, including stomach cancer and leukemia (Risch HA, 2001). Identifying all carriers of the BRCA genes in the general population is impractical because the test is expensive and may cause unnecessary concern to the individual and her family. However, physicians are increasingly screening and counseling women in families with a history of CaB. For those women identiÞed as high risk because of a high family incidence of cancer and conÞrmed by gene analysis, physicians usually recommend regular mammograms. Other options are prophylactic bilateral mastectomy and, for women with BRCA1 mutation who have do not wish to have any (further) children, an oophorectomy (removal of the ovaries) to eliminate this source of estrogen. The BRCA1 gene is located on chromosome 17q21. The BRCA1 protein comprises 1,863 amino acids. Scientists have identiÞed more than 300 different mutations of this gene. Two speciÞc mutations (a deletion and an insertion in the protein-coding sequence) appear in 22% of carriers; the remaining mutations are unique to different families. The BRCA2 gene is located on chromosome 13q12-13. The BRCA2 protein comprises 3,418 amino acids. Approximately 100 different mutations for the gene, with varying incidence, have been described to date. Mutations of BRCA genes in spontaneous, rather than inherited CaB, were thought to be rare, but recent evidence suggests otherwise. Alterations in BRCA1 function, as a result of a variety of causes including gene mutation, may play a signiÞcant role in the pathophysiology of sporadic CaB incidence and aggressiveness, particularly in sporadic invasive ductal carcinoma (Fraser JA, 2003). BRCA1 and BRCA2 proteins are also thought to play a role in response to DNA damage. This interaction could inßuence future treatment choice (Tassone P, 2003), although molecular proÞling data are not yet sufÞcient to have a major impact on this approach. Two recent publications report selective activity of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1- and BRCA2deÞcient cells (Bryant S, 2005; Farmer H, 2005). PARP is an enzyme responsible for repairing DNA damage. The selectivity to BRCA-deÞcient cells is a result of the cells’ deÞciency in homologous recombination, making them acutely sensitive to PARP inhibitors because DNA damage is unable to be repaired. Treatment with


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PARP inhibitors is likely to be highly tumor speciÞc in BRCA-deÞcient patients; this approach is under preclinical evaluation. A third BRCA gene, BRCA3, is also associated with germline mutations that may confer a moderate-to-high risk of CaB. The gene is localized to chromosome 13q21, but evidence of this gene’s role in the etiology of CaB remains controversial (Kainu T, 2000; Thompson D, 2002). ATM. Mutations in ATM genes are known to increase the risk of CaB. This gene’s precise function is still unknown, but its sequence is similar to that of genes that encode proteins that regulate telomere length and cell-cycle progression. Patients who are homozygous possess two mutations of the ATM gene and are at high risk of developing ataxia-telangiectasia (AT, a rare inherited disorder associated with neurological disorders (and immune system deterioration); vascular lesions of the skin and eyes (telangiectasias); and radiation sensitivity. Possibly as a result, AT patients are at Þve to seven times higher risk than the general population of developing CaB; however, most AT patients die in their teenage years or early 20s, before reaching the age at which CaB usually manifests. Heterozygous ATM mutations (only one copy of ATM is mutant) have low penetrance and a low likelihood of the gene being expressed: up to 1% of the population may have a single mutant copy of ATM, but very few women in this subgroup develop CaB. This low penetrance also complicates analysis of the number of CaB cases that are attributable to inherited ATM mutations, because they may be considered sporadic cases: researchers estimate that ATM is a factor in 3.4–10% of all CaBs and could therefore be a more important factor than the BRCA1 and BRCA2 genes. They hypothesize that two classes of ATM mutations (truncating and missense) confer different risks of developing CaB (Meyn MS, 1999). Sporadic ATM mutations are less common than inherited mutations, but physicians may still be able to exploit the ATM genotype in patients with sporadic mutations to guide treatment decisions in CaB and other cancers. Because loss of ATM function is associated with radiation sensitivity, these patients may be better treated with aggressive surgery instead of breast-conserving surgery followed by radiotherapy. Researchers speculate that radiation exposure (e.g., through mammography) could also confer a higher risk for CaB in these patients (Werneke U, 1997; Bebb G, 1997). PTEN. The protein PTEN (phosphate tensin homologue/mutated in multiple advanced cancers) is a phosphatase involved in transmitting growth-inhibiting signals initiated by the transforming growth factor beta (TGF-β) signaling pathway. A somatic mutation in the PTEN gene causes Cowden’s disease; although this mutation is rare, 30–50% of women with this aberrant allele will develop CaB and are likely to develop bilateral breast tumors. Inherited PTEN mutations probably account for less than 5% of all CaB cases. Spontaneous mutations are rare, accounting for less than 0.3% of all CaB cases.

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HRAS1 Polymorphism. A regulatory DNA region (known as the HRAS1 minisatellite region), located downstream of HRAS1, could be responsible for a predisposition to CaB. Women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of CaB. As with ATM gene mutations, the susceptible alleles have low penetrance but occur with high frequency and so are common in the general population—6% of the population may be carriers. Although rigorous studies are lacking, this mutation could contribute up to 9% of all CaB cases. Somatic Mutations. Somatic mutations occur randomly in individual cells throughout the body as a result of exposure to carcinogens or errors in DNA replication or DNA repair; a number of somatic mutations associated with CaB are listed in Table 3. Several mutations are needed to transform a cell, but in women who have an inherited mutation, fewer somatic mutations are needed. A large number of gene mutations have been identiÞed in CaB samples. This section discusses the most prevalent mutations and those that have attracted interest as potential targets for therapeutic intervention. Cell-Cycle Regulators. A number of cell cycle regulators—molecules that control the progression of cells through the cell cycle, such as cyclin D1 (CCND1), cyclin-dependent kinases, RB-1, and p16—have been shown to be mutant or have altered gene expression in some breast tumors. The protein products of these genes are key to cell-cycle regulation and are potential targets for chemotherapeutic intervention via such approaches as small-molecule, antibody, or antisense therapy. The gene CCND1 encodes cyclin D1, a protein that has a regulatory function in cell-cycle control. CCND1 is often overexpressed in CaB—13–24% of breast tumors have extra copies of CCND1, and an additional 13–50% have excess CCND1 without a gene ampliÞcation. CaB patients with estrogen receptor (ER)–negative and CCND1 -overexpressing tumors have a poor prognosis

TABLE 3. Somatic Mutations in Breast Cancer Genes BCL-2 HER1 Cyclin D1 (CCND1) p16 HER2 p53 RB-1 myc Ras PTEN DBC2 (early data on cell lines)

Prevalence (%) 63 9–51 13–50 40 10–40 22–30 15–20 5–20 12 5 60


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(Umekita Y, 2002). Data support a role for CCND1 as an ER-responsive or ERcoactivator gene in CaB; hence, it may play a role in selecting therapy in cases of sporadic CaB. Proteins needed during the S-phase of cell replication are repressed by pRb (RB-1 ), whereas p16 antagonizes CCND1. Although these genes are not prognostic factors, they are mutant in 15–20% and 40% of CaBs, respectively (Dickson RB, 2001; Han S, 2001). Human Epidermal Growth Factors. The human epidermal growth factor receptor (EGFR) HER2 is a transmembrane glycoprotein with intrinsic tyrosine kinase activity. Normally present as inactive monomers on the cell surface membrane, HER2 molecules form homodimers (pairs of HER2 receptors) or heterodimers with other HER receptors (HER1, for example). This interaction stimulates phosphorylation of the intracellular portion of HER2; strongly activates multiple intracellular signal-transduction pathways, including the Ras/MAP kinase pathway; and promotes cell proliferation. In normal cells, binding of the ligand to the extracellular portion of HER is necessary to stabilize the receptor dimers and maximally stimulate signal transduction. When EGFRs are involved in oncogenesis, they are usually overexpressed and are potent proliferative stimuli. Overexpression of HER2 is associated with several important phenomena: • • •

•

Aggressive tumors. Resistance to chemotherapy and radiotherapy. Ligand-independent cell division. Scientists believe that when HER2 is overexpressed, its homodimers can form spontaneously—in the absence of ligand—in numbers sufÞcient to stimulate signal transduction pathways that drive cell division. AmpliÞed ligand-dependent cell growth. Overexpression of HER2 ampliÞes ligand-dependent cell-growth signaling mediated through HER1, possibly by inhibiting the normal ligand-dependent loss of HER1 from the cell surface.

Scientists have known for several years that HER2 is overexpressed in approximately 25–28% of early-stage CaBs. In about 95% of cases, overexpression is caused by the presence of multiple copies of the HER2 gene. In the remaining cases, scientists believe, overexpression of HER2 is caused by abnormally high levels of transcription (production of HER2 messenger RNA) or translation (production of HER2 protein) because cells contain the normal two copies of the HER2 gene. Scientists do not yet understand why ampliÞcation of the HER2 gene occurs or why the product of the nonampliÞed gene is sometimes overexpressed, but other regulatory factors appear to be implicated in the process (Vernimmen D, 2003). HER2 protein overexpression in CaB is associated with shortened diseasefree survival and reduced overall survival in lymph node–positive disease and is therefore widely accepted as a marker for disease prognosis. The evidence

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for any prognostic signiÞcance of HER2 overexpression in node-negative CaB is less compelling. Some evidence suggests that HER2 overexpression can also predict the efÞcacy of adjuvant chemotherapy and hormonal therapy regimens used to treat CaB. For example, data published by A.D. Thor suggest that HER2 overexpression predicts response to a dose-intensive regimen of 5-ßuorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) in lymph node–positive CaB patients (Thor AD, 1998). These data revealed that patients with HER2-overexpressing tumors who were randomly assigned to dose-intensive FAC survived longer than patients assigned to intermediate or low doses. No dose-survival relationship was observed among patients with breast tumors that expressed normal levels of HER2; these patients did equally well regardless of FAC dose. Clinicians interpret these results to indicate that dose-intensive FAC should be considered only for treating tumors that overexpress HER2. Some experts have also concluded from this and related studies that an anthracycline (such as doxorubicin) should be included in adjuvant regimens for HER2-overexpressing CaB. However, scientists have yet to uncover the mechanisms that determine this apparent sensitivity to these chemotherapy agents. The development of the HER2-directed antibody trastuzumab (Roche and Genentech’s Herceptin), which blocks HER2-mediated signaling and has demonstrated a survival beneÞt in metastatic CaB, has driven the characterization of tumors for HER2 expression. There is a good correlation between degree of HER2 overexpression and response to trastuzumab. Assessment of HER2 expression, a factor for poor prognosis, at time of disease diagnosis is becoming increasingly routine in medical practice and is affecting treatment selection. The importance of the epidermal growth factor HER1 is still unclear, but if the prevalence of HER1 overexpression is as common as some studies suggest (up to 51% of all tumors), this protein may be a valuable drug target. Indeed, it is the major target for several emerging therapies, including geÞtinib (AstraZeneca’s Iressa) and erlotinib (Osi/Genentech/Roche’s Tarceva). However, despite preclinical evidence, no convincing demonstration of these agents’ clinical efÞcacy in CaB has been reported. Preclinical studies also suggest a possible preventive role for geÞtinib in a mouse model of cancer (Lu C, 2003; Konecny GE, 2003). Programmed Cell Death Regulators. Mutation of programmed cell death (apoptosis) pathway regulators contributes to tumorigenesis by allowing cells to continue dividing in the presence of growth-inhibiting conditions (absence of growth factors, hypoxia, severe DNA damage). Programmed cell death is activated by the p53 protein; the bcl-2 protein protects cells from death. In CaB, p53 gene mutations are relatively common (22–30% of all tumors), but bcl-2 gene mutations that cause overexpression of bcl-2 are more common (63% of all tumors). Both genes have prognostic signiÞcance and implications for therapy selection in CaB for the following reasons: •

p53 -negative tumors are unlikely to respond to doxorubicin treatment.


• •

•

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p53 -negative tumors are more sensitive than p53 -positive tumors to taxane treatment. In estrogen-dependent tumors, exposure to this hormone upregulates BCL-2 protein expression, which also reduces the effectiveness of doxorubicin treatment. BCL-2 —positive tumors are usually ER-expressing and p53 -positive, both of which indicate a good prognosis.

Telomere Regulation. Telomeres, the ends of the strands of DNA that protect chromosome ends, shorten with every division. When telomeres are sufÞciently shortened, programmed cell death pathways are activated. In normal cells, this mechanism limits the number of cell divisions. Telomerase, an RNA-dependent polymerase that repairs telomeres after chromosome replication, is usually not expressed in normal cells, but cancer cells often express this enzyme. Many CaB tumors (up to 90%) express telomerase (Herbert BS, 2001); the prognostic signiÞcance of telomerase expression is unclear. Experimental studies to investigate the effects of antisense on telomerase are ongoing (Zhang X, 2003). Microarray Analysis. Microarrays are collections of nucleic acid combinations representing genes that are spotted or synthesized onto a substrate and then tested against a tissue sample. Microarray analysis measures mRNA levels and, thus, gene expression. Microarray analyses enable researchers to examine many different genes and discern expression patterns: for example, in diseased versus normal tissue, or in early-stage disease tissue versus late-stage disease tissue. These gene expression patterns have recently started to be used in diagnosis, treatment decisions, and target identiÞcation for new drug development. Somatic mutations in certain genes may be predictive of clinical outcome. However, the large number of genes implicated make prediction extremely complex. Reports indicate that using multimicroarray analysis to proÞle large numbers of genes could increase prognostic value in early disease compared with conventional prognostic indicators such as age, ER status, and HER2 expression (Van de Vijver, 2002). Knowledge and implication of gene expression in patients with CaB could guide treatment decisions, especially when gene-based therapies reach the clinic. Several clinical studies have been initiated that assign patients to either standard or aggressive therapy based on a gene scan of up to 90 genes. The outcome of these studies will determine whether gene signatures will be used in the future as a routine diagnostic method and for stratifying CaB patient populations to receive the optimal treatment regimen. Several companies are developing microarray tests to enable routine characterization of gene expression that would contribute to a more detailed diagnosis and selection of appropriate therapy according to the degree of risk of relapse. For example, the Institut Paoli-Calmettes in France has tested the Breast Cancer ProÞleChip (BCPC) (Borie N, 2004). Tumor samples from 220 anthracyclinetreated patients underwent gene analysis for 9,000 different genes. Signatures for

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estrogen receptor, progesterone receptor, bcl2, EGFR, VEGFA, and ErbB2 were analyzed and found to be quantitative, sensitive, and reproducible. One recently published study describes data generated from tumor samples from 447 patients (Paik S, 2003). From a collection of 250 genes, 16 cancerrelated genes were predictive for recurrence. Researchers created a formula that generates a “recurrence score” based on the expression patterns of these genes in a tumor sample. Ranging from 1 (lowest risk) to 100 (highest risk), the recurrence score is a measure of the risk that a given cancer will recur. A further 668 tumor samples were analyzed and assigned into low, intermediate, and high risk of recurrence groups based on their gene expression proÞle. The low-risk group contained 51% of the samples (with a score of less than 18); 22% were at intermediate risk (recurrence score 18 or higher but less than 31); 27% were at high risk (a score of 31 or higher). These risk-group divisions correlated well with the actual rates of recurrence of breast cancer after ten years. There was a signiÞcant difference in recurrence rates between women in the low- and highrisk groups. In the low-risk group, there was only a 7% rate of recurrence at ten years; in the intermediate- and high-risk categories, these rates were 14% and 31%, respectively. Up to a recurrence score of 50, rates of recurrence increased continuously as the recurrence score increased. These trends held true across age-groups and tumor size. Microarray analysis has the potential to change medical practice, enabling chemotherapy to be targeted to those women most likely to beneÞt from it. It could also spare women with low risk of recurrence, and who would not beneÞt from chemotherapy, the side effects and adverse impact on quality of life. Pathophysiology A number of factors have been identiÞed that inßuence the response to treatment, progression, and subsequent prognosis of CaB. The most important and established of these factors are described here, along with more experimental parameters that could become future biomarkers or targets for drug intervention. Tumor Stage. The TNM (primary tumor/regional lymph nodes/distant metastasis) staging system (Tables 4 and 5) is widely used to guide treatment. Stage of the tumor at diagnosis is the key determinant of prognosis. The TNM system classiÞes stage of disease according to tumor size (T), nodal involvement (N), and presence of metastases (M); see Table 4 for TNM staging deÞnitions. The size of the primary tumor, the presence and extent of lymph node involvement, and the presence of distant metastases all have implications for the selection of appropriate treatment and for prognosis. In addition, evaluation of ER and PR status is obligatory when gauging a patient’s candidacy for hormonal therapy. The presence of certain germline and somatic cell mutations and HER2 protein overexpression are associated with a poor prognosis (Dickson RB, 2001). Since HER2-directed therapy (Genentech/Roche’s Herceptin, Þrst approved by the FDA in 1998) became available, HER2 expression is more often assessed during diagnosis and affects treatment selection. Stage of disease is also an important prognostic indicator.


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TABLE 4. Definitions of TNM Staging Classifications of Breast Cancer Primary tumor (T) TX T0 Tis T1 T1mic T1a T1b T1c T2 T3 T4

T4a T4b T4c T4d

Primary tumor cannot be assessed. No evidence of primary tumor. Carcinoma in situ; intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of the nipple with no associated tumor. Tumor 2.0 cm or less in greatest dimension. Microinvasion 0.1 cm or less in greatest dimension. Tumor more than 0.1 cm but not more than 0.5 cm in greatest dimension. Tumor more than 0.5 cm but not more than 1.0 cm in greatest dimension. Tumor more than 1.0 cm but not more than 2.0 cm in greatest dimension. Tumor more than 2.0 cm but not more than 5.0 cm in greatest dimension. Tumor more than 5.0 cm in greatest dimension. Tumor of any size with direct extension to chest wall or skin. (Note: Chest wall includes ribs, intercostal muscles, and serratus anterior muscle but not pectoral muscle.) Extension to chest wall not including pectoral muscle. Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast. Both T4a and T4b. Inflammatory carcinoma.

Regional lymph nodes (N) NX N0 N1 N2

N2a N2b N3

N3a N3b N3c

Regional lymph nodes cannot be assessed (e.g., previously removed). No regional lymph node metastasis. Metastasis to movable ipsilateral axillary lymph node(s). Metastasis to ipsilateral axillary lymph node(s) fixed or matted or in clinically apparenta ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis. Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures. Metastasis only in clinically apparenta ipsilateral internal mammary nodes and in the absence of clinically apparent axillary lymph node metastasis. Metastasis to ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement or in clinically apparenta ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement. Metastasis to ipsilateral infraclavicular lymph node(s). Metastasis to ipsilateral internal mammary lymph node(s) and axillary lymph node(s). Metastasis to ipsilateral supraclavicular lymph node(s).

Distant metastasis (M) MX M0 M1

Presence of distant metastasis cannot be assessed. No distant metastasis. Distant metastasis present.

a ‘‘Clinically apparent’’ is defined as detected by imaging studies (excluding lymphoscintography) or by

clinical examination or grossly visible pathologically. Source: American Joint Committee on Cancer; International Union Against Cancer; National Comprehensive Cancer Network, 2003.

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TABLE 5. TNM Staging System for Classification of Breast Cancer Stage of Disease

Tumor (T)

Node (N)

Metastasis (M)

0

Tis

N0

M0

I

T1a

N0

M0

IIA

T0 T1a T2

N1 N1 N0

M0 M0 M0

IIB

T2 T3

N1 N0

M0 M0

IIIA

T0 T1a T2 T3 T3

N2 N2 N2 N1 N2

M0 M0 M0 M0 M0

IIIB

T4

N0, N1, N2

M0

IIIC

Any T

N3

M0

IV

Any T

Any N

M1

a Including T1mic.

Note: TNM (primary tumor/regional lymph nodes/distant metastasis) is the internationally recognized classification system of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). See Table 3 for definitions of the TNM staging classifications.

Tumor Grade. The tumor’s histological grade has a bearing on its aggressiveness and on consequent treatment and prognosis. Three features of the tumor are assessed when assigning a cancer’s grade: the frequency of cell mitosis (rate of cell division); tubule formation (percentage of cancer composed of tubular structures); and nuclear pleomorphism (change in cell size and uniformity). Each of these features is assigned a score ranging from 1 to 3 (1 indicating slower cell growth and 3 indicating faster cell growth). The scores of each of the cells’ features are then added together for a Þnal sum that will range from 3 to 9. A tumor with a Þnal score of 3, 4, or 5 is considered a grade 1 tumor (well differentiated). A score of 6 or 7 is considered a grade 2 tumor (moderately differentiated), and a score of 8 or 9 is a grade 3 tumor (poorly differentiated). Poorer survival rates are associated with higher grade tumors: Þve-year survival for grade 3 tumors is 50% compared with 75% for grade 2 tumors and 95% for grade 1 tumors. Local Spread to Lymph Nodes. As described in the preceding section, the number of tumor-positive lymph nodes detected in a patient affects both the prognosis and treatment of CaB. Data from 24,740 CaB patients recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI) were used to evaluate the breast cancer survival experience in a representative sample of U.S. women (Carter C, 1989). The Þndings from this study were used in the development of the treatment guidelines drawn


217

TABLE 6. Breast Cancer Recurrence Rates and Number of Positive Lymph Nodes Number of Positive Nodes 0 1–3 4–6 7–9 10+

Recurrence at Five Years (%) 25 40 49 58 78

Source: Adapted from Nemoto T, 1980. Full source citations appear in ‘‘References.’’

up by the National Comprehensive Cancer Network (NCCN). Survival rates in the study varied from 46% (for large tumors with diameters of at least 5 cm and with positive axillary nodes) to 96% (for small tumors, less than 2 cm, with no involved nodes). Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increases, survival decreases, regardless of lymph node status; as lymph node involvement increases, survival status also decreases, regardless of tumor size. A linear relation was found between tumor diameter and the percentage of cases with positive lymph node involvement. However, for patients with BRCA1 -related CaB, this correlation does not hold true, implying that these tumors may behave differently (Foulkes WD, 2003). In a second large pivotal study, a total of 24,136 female patients with histologically conÞrmed breast cancer were studied (Nemoto T, 1980). In these patients, Þve-year survival rates were 73% for localized disease and 49% for regional disease. The number of metastatic nodes in the axilla was investigated, and it was demonstrated that patients with one or more positive nodes had reduced cure and survival rates compared with those with negative axillary nodes. With the increase in the number of positive nodes, a continuing associated decline could be seen in survival and cure. The clinical size of the tumor also correlated well with the prognosis. Along with increased tumor size came a gradual increase in the probability of axillary nodal involvement. However, axillary metastasis occurred in 25% of patients with tumor size smaller than 1 cm. When the axillary nodes were involved, the cure rate in those patients was not signiÞcantly better than for those with larger primary tumors in this study. These Þndings are summarized in Table 6. Micrometastases. Micrometastases—small clumps of cells that have separated from the primary tumor and entered other organs—command signiÞcant research interest because of the danger they pose to patients. Even patients whose cancers are completely resected may relapse months or years after initial treatment, presumably because of occult micrometastatic disease that escaped treatment. In CaB, common sites of metastasis include the lymph nodes, brain, bone, lung, liver, and skin (Pantel K, 1999). In many cases, though, these

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micrometastases do not exhibit the characteristics of rapidly proliferating cells, suggesting that they are not all destined to develop into secondary tumors. As the technology for detecting the presence of micrometastases in the blood, bone, and organs improves, physicians will be able to apply chemotherapy optimally in patients who are at the highest risk of relapse. It must be noted, however, that the inability to identify relevant markers remains a major obstacle to this approach, and even if micrometastases are identiÞed, researchers are not yet able to differentiate between those that will grow to become clinically relevant and those that will not. Patterns of Metastatic Spread. The site of metastatic disease in CaB will dictate the treatment given to the patient. The site and likelihood of developing metastatic disease depends on factors that include histological diagnosis and HER2 status (Porter GJ, 2004). Common sites of metastasis are shown in Figure 2. For example, although painful, and with a high incidence of bone complication, bone metastases are not typically life threatening. Bone is the most common site of spread in CaB: as many as 70% of patients with metastatic inÞltrating ductal carcinoma are affected. The lung or pleura, liver, and brain are also common sites of metastatic spread and ultimately the cause of death in CaB. Hormone-Receptor Activation. Both normal and cancerous breast tissue contain ERs and PRs. Activation of these receptors by the steroids estrogen and progesterone causes cell proliferation by modulating the expression of various growth factors. Even before ERs were identiÞed, physicians recognized the potential for arresting breast tumor growth by estrogen manipulation (originally by oophorectomy, and later by treatment with luteinizing hormone–releasing hormone [LHRH] antagonists or tamoxifen therapy). Oncologists can test the hormone-receptor (HR) status of breast tumors: patients with HR-positive (ER and/or PR) tumors are most likely to respond to estrogen-ablation therapies; patients with HRnegative tumors rarely respond to antiestrogen treatment. Approximately 70% of patients treated for breast cancer have ER-receptor-positive tumors, and of these patients, 60% will respond to endocrine therapy. In general, hormone expression is more common and more intense in postmenopausal women than in premenopausal women. Hormone status can also be used to assess a patient’s prognosis. HR-positive tumors are associated with slower growth and better prognosis. Patients who are HR-negative are more frequently HER2-positive (a characteristic of aggressive disease). In addition, HR-negative tumors often overexpress the signal transducer protein kinase C. This protein mitigates estrogen’s growth-promoting effect on the tumor. Between the diagnosis of early-stage disease and the development of metastatic CaB, receptor status can change—this fact has implications for the choice of treatment for metastatic disease (Holdaway IM, 1983). Cathepsin D. Cathepsin D is an estrogen-dependent lysosomal protease that is synthesized by normal tissues but overexpressed and secreted by some breast


FIGURE 2. Patterns of spread in breast cancer.

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cancers. It is suspected that cathepsin D facilitates invasion and metastasis of breast cancer; indeed, levels of cathepsin D tend to be higher in node-positive cases of breast cancer. Overexpression of cathepsin D in breast cancer is associated with high risk of recurrence and poor survival. In a study of 199 patients with node-negative disease and 198 with node-positive disease, high levels of cathepsin D proved to be a signiÞcant predictor of reduced disease-free survival in the node-negative population only (median follow-up = 64 months) (Tandon AK, 1990). Relating the level of cathepsin D to other prognostic factors in the patients with node-negative disease, the researchers found an association with aneuploidy (more or less than the diploid number of chromosomes) but no association with estrogen or progesterone receptors, tumor size, or patient age. In multivariate analyses, a high level of cathepsin D was the most important independent factor for predicting shorter disease-free and overall survival in patients with node-negative disease. Cathepsin D distinguishes node-negative patients whose disease may recur (and therefore should receive adjuvant chemotherapy) from node-negative patients, whose disease probably will not recur. Elevation of cathepsin D indicates a poorer prognosis. E-Cadherin. E-cadherin is a transmembrane glycoprotein that mediates epithelial cell-to-cell adhesion. The loss of E-cadherin can result in the disruption of cell clusters. It is therefore postulated that E-cadherin may function as a tumor suppressor protein. The loss of E-cadherin has been associated with metastasis and poor prognosis in invasive CaB and can help differentiate pathologically between ductal and lobular neoplasms of the breast. Loss of E-cadherin appears to be a later step in the metastatic process compared with angiogenesis and the loss of nm23-H1 expression. Researchers found that E-cadherin is a useful marker for identifying patients with poor prognosis; in a retrospective analysis of E-cadherin in tumor samples, the 14-year disease-free survival was shown to be 84%, 80%, and 56% in patients with high, intermediate, and low E-cadherin, respectively (Heimann R, 2000). Soluble Urokinase Plasminogen Activator Inhibitor-1. Soluble urokinase plasminogen activator inhibitor-1 (uPA) is secreted as a virtually inactive singlechain pro-enzyme (pro-uPA), which can be converted into active uPA by limited proteolysis. The binding of uPA to the receptor uPAR strongly enhances and localizes the activation of surface-bound plasminogen into plasmin, which, with broad speciÞcity, degrades most components of the extracellular matrix and basement membranes and is thought to play a pivotal role in the metastatic process. Researchers have reported that the concentration of a serum-soluble form of the receptor (suPAR) correlates with CaB patient outcome (Risbro R, 2002). In a group of patients with low suPAR, only 11% experienced a relapse during the observation period, compared with 40% in the group with high suPAR levels. Similarly, in the analysis of overall survival, only 17% in the low suPAR group experienced an early death compared with 49% in the group with high suPAR levels. Thus, suPAR may become a prognostic marker that could aid in treatment selection.

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CURRENT THERAPIES The treatment of CaB employs a multimodal approach that comprises hormone therapy, chemotherapy, biological agents, radiotherapy, and surgery. Treatment selection is tied primarily to disease stage, estrogen and progesterone receptor (ER and PR) status, performance status, and, increasingly, HER2 expression. Hormone therapy and/or chemotherapy are given in the following circumstances: • • •

Neoadjuvant therapy (prior to surgery) to reduce tumor size and facilitate surgery. Adjuvant therapy (postsurgery) to prevent recurrence (both local and distant). Palliative treatment of metastatic disease, where it might also be used to prolong survival. At this time, treatment of metastatic CaB is not considered to be curative, although treatment, and survival, can be long term in a minority of patients.

Treatment choice reßects the speciÞc patient and tumor characteristics and the likelihood of relapse. These factors include the patient’s age, menopausal status, performance status, ER/PR status, tumor histology, level of HER2 expression, lymph node involvement, and presence of metastatic disease. A large number of drugs—given alone, in combination, or in sequence—have demonstrated clinical beneÞt in CaB patients and have been adopted into clinical practice. Generally, neoadjuvant and adjuvant chemotherapy uses combinations of drugs—each with a different mechanism of action and complementary toxicity proÞle—to maximize efÞcacy while minimizing toxicity. Adjuvant chemotherapy is usually followed by hormonal therapy in patients who are ER- and PR-positive. In cases of early-stage disease, hormonal agents are used in the majority of ER- and/or PR-positive patients as long-term (routinely Þve years) adjuvant therapy. Hormonal agents are also the preferred treatment option in appropriate metastatic CaB patients because these agents’ efÞcacy is comparable to that of chemotherapy in this setting; hormonal agents also possess excellent side-effect proÞles, which are beneÞcial for long-term therapies. Traditionally, the selective estrogen-receptor modulator (SERM) tamoxifen (AstraZeneca’s Nolvadex, generics) has been the cornerstone of hormonal CaB treatment. However, in recent years, aromatase inhibitors (AIs) have become the treatment of choice for postmenopausal women with metastatic disease because of apparent superior efÞcacy. Data also show that adjuvant anastrozole (AstraZeneca’s Arimidex) is more effective than adjuvant tamoxifen at extending disease-free survival; thus, anastrozole and other AIs are challenging tamoxifen’s monopoly of the hormone adjuvant market, particularly in the United States. A meta-analysis of 47 adjuvant polychemotherapy trials clearly demonstrated the beneÞt of adjuvant cytotoxic therapy for early-stage (stages I and II) CaB patients (Early Breast Cancer Trialists’ Collaborative Group [EBCTCG], 1998),

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and this approach has been widely adopted. Patients who received chemotherapy had lower mortality compared with patients who received no chemotherapy, regardless of nodal or ER status or tamoxifen therapy. The degree of beneÞt gained from chemotherapy varied depending on patient age, menopausal status, and nodal involvement. The consensus is that certain subpopulations of patients will respond better to certain therapies, but the optimal regimens are yet to be determined, and criteria for selecting appropriate patients to receive chemotherapy remain unconÞrmed. The absolute reduction in the risk of recurrence using polychemotherapy (multiple chemotherapeutic drugs) in women younger than 50 years was 10.4% in women with node-negative disease and 15.4% in women with node-positive disease. The absolute reduction in mortality rates in women younger than 50 years with the use of adjuvant chemotherapy was 5.7% in patients with axillary nodenegative disease and 12.4% in patients with axillary node-positive disease. The corresponding absolute reduction in recurrence in women aged 50 to 69 years was 5.7% and 5.4% for patients with axillary node-negative disease and axillary node-positive disease, respectively. The absolute reduction in mortality rates was 6.4% and 2.3% for patients with axillary node-negative disease and axillary node-positive disease, respectively. More recently, taxanes have been introduced into neoadjuvant and adjuvant chemotherapy treatment regimens, primarily for high-risk (typically nodepositive) patients. To date, mature data are available from three large trials in which patients were randomized to receive either a taxane-containing regimen or a non-taxane-containing regimen. Studies show that both combination and sequential therapy (sequential lines of various single-agent chemotherapies) have their place in the treatment of metastatic CaB. Given the heterogeneity of CaB, physicians must be ßexible in their approach to treating the disease. Thus, treatment of patients with metastatic disease tends to be very individualized; optimal treatment regimens have yet to be determined. Sequential therapy may be particularly appropriate for older patients or those with reduced performance status because it enables the optimal delivery and management of single-drug therapy and potentially reduces the risk of toxicity without compromising quality of life. Newer drug combinations, such as trastuzumab/paclitaxel (Roche/Genentech/ Chugai’s Herceptin; Bristol-Myers Squibb’s Taxol, generics) or docetaxel/ capecitabine (SanoÞ-Aventis’s Taxotere; Roche/Chugai’s Xeloda), confer survival advantages over single-agent therapy in metastatic CaB and have manageable side-effect proÞles. Such combination treatments may be preferable to sequential therapy among patients who require immediate reduction in their tumor burden. In the clinic, combination regimens are favored for Þrst-line treatment of metastatic disease, particularly for patients whose cancer is rapidly progressing. Although trastuzumab is appropriate for the treatment of only 25–28% of the patients with tumors overexpressing the human epidermal growth factor receptor2 (HER2), its excellent clinical proÞle and beneÞt for this poor-prognosis group of patients make it worthy of additional mention. The availability of HER2 testing

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223

is much more widespread than in previous years, and testing to determine HER2 status is now recommended, and performed, at Þrst diagnosis, regardless of stage. Trastuzumab is approved only for the treatment of metastatic CaB (either alone or in combination with a taxane) in HER2-overexpressing patients, depending on previous treatments and performance status. However, the rationale exists for introducing adjuvant trastuzumab into earlier stages of disease (Slamon D, 2001). So far, three large clinical trials investigating the beneÞt of trastuzumab in the adjuvant and neoadjuvant settings, have conÞrmed: Trastuzumab demonstrates substantial beneÞt in adjuvant setting. It is under regulatory review in both the US and Europe. Trials are NSABP and NCCTG Trials in the US and HERA in Europe. BCIRG Trial is the 4th trial, which is less advanced. Retrospective studies of randomized clinical trials have revealed a correlation between the overexpression of HER2 and resistance to cyclophosphamide/ methotrexate/5-ßuorouracil (CMF) chemotherapy and tamoxifen. Other studies have suggested an interaction between HER2 overexpression and enhanced response to dose-intensive doxorubicin-containing regimens in lymphnode–positive patients (although cardiotoxicity is problematic with this combination). This Þnding has led to interest in combining trastuzumab with liposomal formulations of doxorubicin, reportedly associated with reduced cardiotoxicity. Optimizing trastuzumab combinations with other agents and improving the trastuzumab schedule are ongoing efforts. Ongoing clinical trials are testing different combinations and sequences of existing agents. Indeed, interest has grown in the use of platinum agents as second- and subsequent-line treatments in metastatic disease, but they have not yet been established as standard treatment. Additionally, cancer patients with metastatic bone disease have been treated for many years with bisphosphonates, to allay these complications. These agents do not have a proven direct anti-tumor effect. However, many trials are ongoing to determine whether bisphosphonates can slow disease progression and whether they can play a preventive role when given to cancer patients not yet suffering from bone involvement. Herein, the focus is on the regimens in regular clinical use. Table 7 lists the leading monotherapies and combination therapies used to treat CaB. The evaluation of new agents and regimens is a slow process. Because CaB is a slowly progressing disease, particularly in postmenopausal patients, it takes many years of follow-up in large clinical trials to conÞrm any improvement in response rate or overall survival. Furthermore, many agents or combinations of agents may be producing only modest, incremental improvements that are difÞcult to ascertain with statistical accuracy. Cyclophosphamide/Methotrexate/5-Fluorouracil (CMF) Regimen Overview. The CMF regimen—cyclophosphamide/methotrexate/5-FU (generics)—was the Þrst to become established as adjuvant chemotherapy for CaB and was standard care for premenopausal, node-positive patients until its replacement by anthracycline-containing regimens. The CMF regimen represented the

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TABLE 7. Current Regimens Used for Breast Cancer Regimen or Class CMF

FAC

FEC

Regimen Components Agent

Availability

Dose

Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics)

Cyclophosphamide: 100 mg/m2 /day on days 1–14 of a 28-day cycle for a total of 6 cycles. PO.

Methotrexate (Pfizer’s Farmitrexat, generics) 5-fluorouracil (generics)


Methotrexate: 40 mg/m2 /day on days 1 & 8. IV.


5-fluorouracil (generics)


5-fluorouracil: 600 mg/m2 /d on days 1 & 8. IV. 5-fluorouracil: 500 mg/m2 /day on day 1 of a 21-day cycle for a total of 4 cycles.

Doxorubicin US, F, G, I, (Pfizer’s S, UK, J Adriamycin/ Adriblastine, Kyowa Hakko’s Adriacin, generics) Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics) 5-fluorouracil US, F, G, I, (generics) S, UK, J

Common Toxicities • Myelosuppression. • Renal toxicity. • Alopecia. • Gastrointestinal toxicity. • Transient elevation of liver enzymes (methotrexate).

• Myelosuppression. • Cardiomyopathy. • Alopecia. • Gastrointestinal toxicity. • Skin rash, fever, chills (doxorubicin).

Doxorubicin: 50 mg/m2 /day on day 1.

Cyclophosphamide: 500 mg/m2 /day on day 1. All IV.

5-fluorouracil: 500 mg/m2 /day on days 1 & 8 of a 21-day cycle for a total of 4–6 cycles IV.

• Myelosuppression. • Cardiomyopathy. • Alopecia. • Gastrointestinal toxicity.

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225

TABLE 7. (continued) Regimen or Class


Availability

Epirubicin (Pfizer’s US, F, G, I, Ellence/ S, UK, J Farmarubicin, Kenfarma/Pfizer/ Kyowa Hakko’s Farmarubicin, generics) CyclophosUS, F, G, I, phamidea S, UK, J (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics) Doxorubicin/ Doxorubicin US, F, G, I, cyclophos(Pfizer’s S, UK, J phamide Adriamycin/ followed by Adriblastine, a taxane Kyowa Hakko’s Adriacin, generics)

Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics) Paclitaxel US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Taxol, generics)

TAC

Docetaxel US, F, G, I, (Sanofi-Aventis’s S, UK, J Taxotere)

Dose

Common Toxicities

Epirubicin: 50–100 mg/m2 / day on days 1 & 8. IV.

Cyclophosphamide: 75–100 mg/m2 / day on days 1–14. PO.

Doxorubicin: One of three doses—60 mg/m2 on day 1, or 75 and 90 mg/m2 on days 1 and 2. Every three weeks for 4 cycles.

• Granulocytopenia. • Infection. • Nausea and vomiting. • Hypersensitivity reactions. • Cardiotoxicity.

Cyclophosphamide: 600 mg/m2 IV on day 1.

Paclitaxel: 175 mg/m2. Every 3 weeks for 4 cycles after the completion of 4 cycles of doxorubicin/ cyclophosphamide. Docetaxel: 75 mg/m2. Every 3 weeks for 6 cycles.

• Anemia. • Neutropenia. • Amenorrhea. • Fever in absence of infection. • Hypersensitivity reactions. • Peripheral edema. • Neurosensory. • Skin events.

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Availability

Doxorubicin US, F, G, I, (Pfizer’s S, UK, J Adriamycin/ Adriblastine, Kyowa’s Adriacin, generics) Cyclophosphamide US, F, G, I, (Bristol-Myers S, UK, J Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics) Trastuzumab, Trastuzumab US, F, G, I, single agent (GenenS, UK, J tech/Roche/ Chugai’s Herceptin)

Trastuzumab/ Trastuzumab paclitaxel (Genentech/Roche/ Chugai’s Herceptin)

Paclitaxel (Bristol-Myers Squibb’s Taxol, generics)

Dose

Common Toxicities

Doxorubicin: 50 mg/m2.

Cyclophosphamide: 500 mg/m2.

Trastuzumab loading dose: 4 mg/kg, given on first day of treatment; maintenance dose: 2 mg/kg/day every 7 days. IV.


Trastuzumab loading dose: 4 mg/kg, given on first day of treatment; maintenance dose: 2 mg/kg/day every 7 days. IV.


Paclitaxel: 175 mg/m2 / day every 21 days. IV.

• Myelosuppression. • Neurotoxicity. • Hypersensitivity. • Cardiac toxicity. • Gastrointestinal toxicity. • Rash. • Pulmonary toxicity. • Fever. • Myelosuppression (neutropenia/ neutropenic infection). • Neuropathy/ neurotoxicity. • Hypersensitivity. • Cardiac toxicity. • Gastrointestinal toxicity. • Alopecia (paclitaxel). • Rash (trastuzumab). • Fever (trastuzumab).

CURRENT THERAPIES

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Trastuzumab/ Trastuzumab docetaxel (Genentech/Roche/ Chugai’s Herceptin)

Availability US, F, G, I, S, UK, J

Docetaxel US, F, G, I, (Sanofi-Aventis’s S, UK, J Taxotere) Docetaxel/ Docetaxel US, F, G, I, capecitabine (Sanofi-Aventis’s S, UK, J Taxotere)

Capecitabine US, F, G, I, (Roche/Chugai’s S, UK, J Xeloda)

Docetaxel, Docetaxel US, F, G, I, single agent (Sanofi-Aventis’s S, UK, J Taxotere)

Dose Trastuzumab: loading dose: 4 mg/kg in week 1; maintenance dose: 2 mg/kg weekly. Docetaxel: 100 mg/m2 every 3 weeks for 6 cycles. Docetaxel: 75 mg/m2 /day every 21 days. IV.

Capecitabine: 2,500 mg/m2 / dayb , 14 days then 7 days rest. PO. Docetaxel: 100 mg/m2 /day every 21 days. IV. Premedication required.

Common Toxicities • Cardiac toxicity. • Febrile neutropenia. • Neutropenic sepsis.

• Myelosuppression (neutropenia and neutropenic fever). • Gastrointestinal toxicity. • Alopecia. • Cardiac toxicity. • Rash/pruritus. • Hyperbilirubinemia. • Stomatitis. • Hypersensitivity (docetaxel). • Hand-foot syndrome (capecitabine).

• Myelosuppression (leukopenia/ neutropenia)/ neutropenic infection. • Neurosensory toxicity. • Hypersensitivity. • Gastrointestinal toxicity. • Rash/pruritus. • Edema. • Fatigue.

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Nanoparticle Paclitaxel paclitaxel, (Bristol-Myers single agent Squibb’s Taxol, generics)

Availability US

Dose Nanoparticle Paclitaxel: 260 mg/m2 administered every three weeks.

Common Toxicities • Thrombocytopenia. • Neutropenia. • Mild nausea. • Fatigue. • Alopecia. • Peripheral neuropathy.

Capecitabine, Capecitabine US, F, G, Capecitabine: single agent (Roche/Chugai’s I, S, 1,250 mg/m2 twice daily, Xeloda) UK, J 14 days, then 7 days rest. PO.

Gemcitabine/ paclitaxel

Gemcitabine (Eli Lilly’s Gemzar)

US, F, G, Gemcitabine: I, S, 1,250 mg/m2 /day on days 1 and 8 UK, J of a 21 day cycle. IV.

Paclitaxel US, F, G, Paclitaxel: (Bristol-Myers I, S, 175 mg/m2 on day 1. IV. Squibb’s Taxol, UK, J generics) Vinorelbine, Vinorelbine (Glaxo- US, F, G, Vinorelbine: single agent SmithKline/Pierre I, S, 30 mg/m2 /day every 7 days. IV. Fabre/Ellem/ UK, J Kyowa’s Navelbine)

Tamoxifen, Tamoxifen single agent (AstraZeneca’s Nolvadex, Pfizer’s Kessar, generics)

US, F, G, Tamoxifen: 20 mg I, S, daily. Toremifene: UK, J 60 mg daily. PO.

• Gastrointestinal toxicity. • Fatigue. • Thrombocytopenia. • Hand-foot syndrome. • Elevated liver enzymes. • • • •

Thrombocytopenia. Neutropenia. Neuropathy. Myalgia and fatigue.

• Myelosuppression (leukopenia/neutropenia). • Neuropathy. • Alopecia. • Gastrointestinal toxicity. • Fever. • Thromboembolic events. • Increased risk of endometrial cancer (2–7 times). • Hot flashes.

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Availability

Dose

Common Toxicities • Gastrointestinal toxicity. • Transient increase in bone pain or swelling.

Anastrozole, Anastrozole single agent (AstraZeneca’s Arimidex)


Anastrozole: 1 mg daily. Exemestane: 25 mg daily. PO.

Letrozole, Letrozole US, F, G, I, Letrozole: 2.5 mg single agent (Novartis’s S, UK daily until tumor Femora/Femara) (Preregistraprogression is evident. PO. tion in Japan)

Exemestane, Exemestane single agent (Pfizer’s Aromasin)


Exemestane: 25 mg daily until tumor progression is evident. PO.

Fulvestrant, Fulvestrant single agent (AstraZeneca’s Faslodex)

US

250 mg intramuscular injection every 28 days.

Goserelin, Goserelin acetate single agent (AstraZeneca’s Zoladex)


Goserelin acetate: 3.6 mg every 28 days. IV.

• Fatigue. • Asthenia. • Rash. • Hot flashes. • Headache. • Dyspnea.

• Asthenia. • Rash. • Hot flashes. • Headache. • Hot flashes. • Nausea. • Fatigue. • Headache. • Pain and inflammation at injection site. • Vasodilation (hot flashes). • Nausea and vomiting. • Hot flashes. • Impotence. • Decreased libido.

a Cyclophosphamide may be administered by IV infusion 200 mg/m2 on days 1 and 8 or 500–600 mg/m2 on day 1. b This dose is recommended, but clinicians generally use a dose of 2,000 mg/m2 /day because many patients do not tolerate the higher dose. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan. IV = Intravenous; PO = Oral.

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prototype of combination chemotherapy that signiÞcantly improved early and long-term results. For decades, six cycles of CMF was the gold standard of adjuvant chemotherapy in CaB. CMF is largely being replaced with more-aggressive anthracycline and/or taxane-containing chemotherapy regimens, and the former regimen’s use is now restricted mainly to patients at low risk of relapse or those with poor performance status, such as the elderly, who are unable to tolerate more-aggressive regimens. CMF remains suitable for patients for whom anthracycline therapy is contraindicated, such as the elderly and those with a preexisting cardiac myopathy. It also demonstrates beneÞt in patients with a relatively low risk of recurrence, such as those with tumors that are ER positive, with negative or low expression of HER2, and with negative (uninvolved) lymph nodes. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

•

Cyclophosphamide (Figure 3) is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication. Methotrexate (Figure 4), a structural analogue of folate, is an antimetabolite. Antimetabolites block normal DNA synthesis by inhibiting several key enzymes. Methotrexate inhibits the enzyme dihydrofolate reductase. This inhibition interferes with the maintenance of the reduced folate pool. Reduced folates are essential for de novo synthesis of thymidylate and purine nucleotides—requirements for DNA synthesis and cell replication. Thus, by inhibiting dihydrofolate reductase, methotrexate stops the cell replication of rapidly proliferating cells, such as tumor cells. 5-FU (Figure 5) is a ßuoropyrimidine antifolate. Antifolates exert their cytotoxic effect via a number of mechanisms. One of the most important targets for 5-FU is thymidylate synthase (TS), a key enzyme in de novo thymidine synthesis. This pyrimidine, which requires folate cofactors, is an essential requirement for normal DNA synthesis. By inhibiting TS, 5-FU inhibits DNA synthesis and causes cytotoxicity. In addition, because 5-FU is a structural analogue of uracil, it is misincorporated into RNA in place of uracil


CURRENT THERAPIES

H2N

N

231

N CH3

N

N N H N

NH2 O

COOH COOH


FIGURE 5. Structure of 5-fluorouracil (5-FU).

and so interferes with normal RNA function, an action that also triggers cell death. Clinical Performance. An early clinical trial, now with more than 20 years’ follow-up, convincingly demonstrated a survival advantage of CMF adjuvant chemotherapy compared with no adjuvant treatment. The trial recruited 386 women with node-positive CaB who were randomized to receive either no further treatment or 12 months of CMF treatment following surgery. The 20-year survival rates were 47% for those treated postoperatively with CMF versus 22% for the group receiving no chemotherapy. This beneÞt was particularly marked in patients younger than 50 years (Bonadonna G, 1995). The CMF regimen has been shown inferior to anthracycline-containing regimens in numerous studies in pre- and postmenopausal women, particularly those patients with poor prognostic factors such as lymph node involvement (see the following discussions of the FAC and FEC regimens). In the future, if patients who would beneÞt from anthracycline therapy can be identiÞed, the use of CMF in the remaining, lower-risk patients may increase and prevent unnecessary exposure of patients to anthracyclines’ cardiotoxic effects. Studies have been performed combining CMF with doxorubicin (PÞzer’s Adriamycin, generics), using various numbers of cycles and administering doxorubicin either before or after CMF. At this stage, although some data suggest an improved disease-free and overall survival following treatment with four cycles of doxorubicin followed by eight cycles of CMF, it remains uncertain whether combining both regimens offers an overall advantage. Currently, interest in the CMF regimen is waning, so further studies are unlikely. A large clinical study is under way in the United Kingdom to investigate the addition of epirubicin (PÞzer’s Ellence/Farmarubicin, generics) to CMF.

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The National Epirubicin Adjuvant Trial (NEAT) and Scottish Cancer Trials Breast Group (SCTBG BR9601) are analyzing 2,391 patients with early CaB; 2,021 eligible patients were entered into NEAT and 370 into SCTBG BR9601 between April 1996 and July 2001 (Poole C, 2003). NEAT compared epirubicin (100 mg/m2 × 4 cycles) followed by classical (c)CMF (×4 cycles) with six cycles of cCMF. The SCTBG BR9601 study compared epirubicin (100 mg/m2 × 4 cycles) followed by IV three-times weekly dose-modiÞed CMF (750 : 50 : 600 mg/m2 ) × 4 cycles) with three-times-weekly IV CMF (×8 cycles). The incidence of toxicity was higher in the patients receiving epirubicin in addition to CMF. Despite lower than predicted recurrence rates in the CMF arm, disease-free survival and overall survival were both superior in the epirubicin arm. The study indicates that this combination is an active regimen in this patient population, offering a highly signiÞcant improvement in both relapsefree and overall survival rates. These data add to the body of evidence that anthracyclines are a beneÞcial addition to adjuvant treatment and support the notion that this regimen has the potential to become an established treatment option. 5-Fluorouracil/Doxorubicin/Cyclophosphamide (FAC) Regimen Overview. Combination regimens that include 5-FU and cyclophosphamide are well established in the treatment of CaB, primarily as neoadjuvant and adjuvant therapy. Combination with an anthracycline in place of the antimetabolite methotrexate has been shown to have superior effects on long-term survival. Doxorubicin is now routinely used in combination regimens for the treatment of CaB—both in the adjuvant setting and in advanced disease. This use continues despite the increasing use of epirubicin since its introduction in 1985 (see the following section on the FEC Regimen). A consensus statement issued by the National Institutes of Health (NIH) in 2000 concluded that doxorubicin has a threshold dose effect in the adjuvant setting. Dose levels below this threshold demonstrate no clinical beneÞt, and once the threshold is reached, no further clinical beneÞt can be gained from exceeding it. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

5-FU (Figure 5) is a ßuoropyrimidine antifolate. Antifolates exert their cytotoxic effect via a number of mechanisms. One of the most important targets for 5-FU is thymidylate synthase (TS), a key enzyme in de novo thymidine synthesis. This pyrimidine, which requires folate cofactors, is an essential requirement for normal DNA synthesis. By inhibiting TS, 5-FU inhibits DNA synthesis and causes cytotoxicity. In addition, because 5-FU is a structural analogue of uracil, it is misincorporated into RNA in place of uracil and so interferes with normal RNA function, an action that also triggers cell death.

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•

•

Doxorubicin (Figure 6) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Cyclophosphamide (Figure 3) is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

Clinical Performance. Extensive evidence shows that including an anthracycline in adjuvant therapy regimens improves disease-free survival and overall survival (see the following section on the FEC Regimen). In a European study, 985 women with either node-negative or node-positive CaB were randomized to receive six cycles of either FAC or CMF (Martin M, 2003). The data indicated a nonsigniÞcant trend toward improved and overall survival with FAC. In a prospectively formed subset of node-negative patients, disease-free survival and overall survival were statistically superior in the FAC treatment arm. This advantage was not observed in the subset of node-positive patients. Although the clinical toxicity of FAC was greater than that of CMF, the levels were considered manageable and clinically acceptable. A meta-analysis of 11 randomized trials involving 5,942 patients compared anthracycline-containing chemotherapy with CMF (Kaklamani V, 2003). The investigators found a 12% reduction in recurrence with anthracycline-containing chemotherapy compared with CMF and an 11% reduction in the risk of mortality. Another important Þnding showed that anthracycline-containing regimens were superior to CMF only when they were given for a minimum of three months.

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Researchers remain unsure whether there are subpopulations of CaB patients who would beneÞt from anthracycline treatment. If these patients could be identiÞed, it would prevent other patients from being “overtreated” with toxic therapies. Retrospective subset analyses show that node-positive patients who also have high HER2 expression in their tumors (i.e., patients with poor prognosis) beneÞted the most from the FAC regimen. 5-Fluorouracil/Epirubicin/Cyclophosphamide (FEC) Regimen Overview. Combination regimens that include 5-FU (generics) and cyclophosphamide (generics) are well established in the treatment of CaB, primarily as neoadjuvant and adjuvant therapy (see the previously discussed FAC regimen). Regimens containing an anthracycline such as epirubicin, in place of the antimetabolite methotrexate, have been shown superior for long-term survival. The beneÞt of epirubicin treatment, as with other anthracyclines, in early-stage CaB may depend on patients receiving a sufÞciently high dose of epirubicin in each cycle and/or the cumulative dose. Therefore, clinicians generally extend the period between cycles or use growth factor stimulants (to support the bone marrow) rather than reduce the epirubicin dose per cycle in patients who experience serious side effects. Note, however, that the NIH consensus statement on adjuvant therapy for CaB endorses the view that increasing the dose of epirubicin (or another anthracycline) above the threshold level does not improve adjuvant treatment outcomes (Montemurro F, 2000). Studies suggest that epirubicin, the 4’-epimer of doxorubicin, has a better safety proÞle than its parent at equivalent dose levels (French Epirubicin Study Group, 1988; Italian Multicenter Breast Study with Epirubicin, 1988). Equitoxic doses are 60 mg/m2 of doxorubicin and 90 mg/m2 of epirubicin (Perez D, 1991). This evidence may encourage the use of FEC over FAC. Because of the cardiomyopathy associated with anthracyclines, these agents have a maximum lifetime dose that limits their extended use. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

5-FU (Figure 5) is a ßuoropyrimidine antifolate. Antifolates exert their cytotoxic effect via a number of mechanisms. One of the most important targets for 5-FU is thymidylate synthase (TS), a key enzyme in de novo thymidine synthesis. This pyrimidine, which requires folate cofactors, is an essential requirement for normal DNA synthesis. By inhibiting TS, 5-FU inhibits DNA synthesis and causes cytotoxicity. In addition, because 5-FU is a structural analogue of uracil, it is misincorporated into RNA in place of uracil and so interferes with normal RNA function, an action that also leads to cell death. Epirubicin (Figure 7) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect.

CURRENT THERAPIES

O

OH

235

O OH OH

H3CO

O H3C HO

OH

O

O NH2

FIGURE 7. Structure of epirubicin.

•

Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Cyclophosphamide (Figure 3) is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

Clinical Performance. A meta-analysis of 47 clinical studies involving more than 18,000 patients with early-stage CaB showed that adjuvant anthracyclinebased regimens (e.g., doxorubicin, epirubicin) are more effective than adjuvant nonanthracycline regimens (CMF was the principal comparator in the trials) (Early Breast Cancer Trialists’ Group, 1998). Anthracycline-treated patients had a 12% reduction in risk of recurrence and 11% reduction in risk of death compared with patients who received nonanthracycline regimens. The authors of the metaanalysis noted that these Þndings should be considered preliminary because the follow-up on the trials was short, the effect on survival was only marginally signiÞcant, and any increase in efÞcacy associated with the anthracycline regimens must be weighed against their increased toxicity, particularly in the adjuvant setting (Goldhirsch A, 2001). In the same analysis, the percentage of patients free from disease at Þve years ranged from 57% to 76% when an anthracycline was included in the adjuvant treatment regimen. A ten-year follow-up of a study directly comparing FEC with CMF in premenopausal, node-positive patients found that 52% of patients who underwent the FEC regimen were disease-free versus 45% given CMF. In addition, 62% of the FEC-treated patients had improved overall survival with reduced incidence of severe side effects compared with 58% of the CMF-treated group. Studies of epirubicin in metastatic CaB found that the higher dose, 100 mg/m2 , was more effective than the lower dose, 50 mg/m2 (French Adjuvant Study Group, 2001). These studies also found that in the adjuvant setting, node-positive CaB patients have a statistically signiÞcant superior Þve-year disease-free survival (66% versus 55%) and overall survival (77% versus 65%) with the 100 mg/m2

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(FEC100) regimen compared with 50 mg/m2 (both given for six cycles). This beneÞt is most pronounced in patients with more than three positive nodes (i.e., higher-risk patients). An update presented at the American Society of Clinical Oncology (ASCO) annual meeting in June 2003 showed that ten-year overall survival remains superior for the 100 mg/m2 group (54.8% versus 50.0%) (Bonneterre J, 2003). Because of an increase in the incidence and severity of toxicity, the FEC100 regimen is recommended only for patients at high risk of relapse. Doxorubicin/Cyclophosphamide Followed by a Taxane Regimen Overview. With their unique structure and mechanism of action, taxanes have demonstrated antitumor activity against a broad range of cancers. Incorporation of the taxane paclitaxel (Bristol-Myers Squibb’s Taxol, generics) into treatment regimens for metastatic CaB has demonstrated greater beneÞt than standard chemotherapy regimens. Researchers eagerly await further trials as well as follow-up of existing trials to help determine whether docetaxel is superior to paclitaxel and whether treatment with docetaxel is best given sequentially to, or concurrently with, doxorubicin or epirubicin (Hudis C, 2002). Paclitaxel is indicated for adjuvant treatment of node-positive CaB when administered sequentially to standard doxorubicin-containing combination chemotherapy. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

•

Doxorubicin (Figure 6) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA re-ligation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Cyclophosphamide (Figure 3) is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication. Paclitaxel (Figure 8) and docetaxel (Figure 9) are taxanes. Taxanes act by stabilizing the mitotic spindle microtubules, thereby preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. The Cancer and Leukemia Group B (CALGB) 9344 study enrolled 3,121 node-positive CaB patients with CaB between 1994 and 1999 at 516 study sites. Patients were randomized to receive either paclitaxel or

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237

FIGURE 8. Structure of paclitaxel.

FIGURE 9. Structure of docetaxel.

no therapy following four cycles of AC. At a median of 69 months’ follow-up, the researchers found that the paclitaxel-treated group experienced a 17% reduction in the risk of recurrence and an 18% reduction on the risk of death (Henderson I, 2003). Both of these differences were statistically signiÞcant at this analysis point. At Þve years’ follow-up, there was a 3% improvement in overall survival: 80% for those patients receiving paclitaxel versus 77% for those not receiving paclitaxel. A subset analysis of patients revealed that those with hormone receptor (HR)–negative disease beneÞted more than the HR-positive patient population from the inclusion of paclitaxel into their treatment regimen. In the National Surgical Adjuvant Breast and Bowel Project’s (NSABP) B-28 trial, 3,060 node-positive patients were randomized to receive four cycles of AC alone or followed by four cycles of paclitaxel at 225 mg/m2 (every three weeks) (Crown J, 2004). With a median follow-up of 64 months, disease-free survival was signiÞcantly improved by adding the taxane—76% versus 72%; however, this improvement did not translate into improved overall survival in this study. A second NSABP trial (B-30) is comparing the addition of docetaxel to anthracyclines and cyclophosphamide (Crown J, 2004). The three arms include a combination of docetaxel and doxorubicin; a combination of docetaxel, doxorubicin, and cyclophosphamide; and a combination of doxorubicin and cyclophosphamide followed sequentially by docetaxel (AC followed by docetaxel). Researchers hope to accrue 4,000 node-positive CaB patients into the study; half of this target number had been reached in 2004 and, at the time of

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composing this reference, the Þnal data are still not available. A quality-of-life question is being asked regarding all patients. Many other randomized trials designed to evaluate the efÞcacy of adjuvant taxane therapy are ongoing or have recently completed recruitment. Until longterm survival data are available from these trials, some clinicians remain uncertain about the role of taxanes in adjuvant therapy, particularly in light of the perceived increase in toxicities. However, in the aforementioned trial, the majority of severe toxicities were observed during the AC part of treatment: for example, 62% of patients experienced granulocytopenia during AC treatment and only 16% during paclitaxel therapy, suggesting that these perceptions are unfounded. Docetaxel/Doxorubicin/Cyclophosphamide (TAC) Regimen Overview. In August 2004, the FDA approved injectable docetaxel (SanoÞ-Aventis’s Taxotere) for use in combination with doxorubicin and cyclophosphamide for the adjuvant treatment of women with operable nodepositive breast cancer. Approval followed in Europe in January 2005 for the same indication. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

•

Doxorubicin (Figure 6) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA re-ligation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Cyclophosphamide (Figure 3) is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication. Docetaxel (Figure 9) is a taxane. Taxanes act by stabilizing the mitotic spindle microtubules, thereby preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. As reported on the Taxotere prescribing information sheet, investigators enrolled 1,491 women with node-positive operable CaB in an international, multicenter, randomized trial (TAX316). Patients were stratiÞed according to the number of positive axillary lymph nodes (1–3, 4+) and were randomly allocated to receive adjuvant treatment with either docetaxel 75 mg/m2 administered one hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm) or the gold-standard treatment of doxorubicin 50 mg/m2 followed by ßuorouracil 500 mg/m2 and cyclophosphamide

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500 mg/m2 (FAC arm). Both regimens were given every three weeks for six cycles. After the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors (ER+ and/or PR+) received tamoxifen 20 mg daily for up to Þve years. The primary end point was disease-free survival, which included both local and distant recurrences of CaB and deaths from any cause. At a median followup of 55 months, results from the second interim analysis showed that patients treated with the TAC regimen has signiÞcantly longer disease-free survival than those treated with FAC. This was equivalent to an overall reduction in risk of relapse of 25.7% (hazard ratio = 0.74, stratiÞed log rank p = 0.0047) in favor of the taxane-containing regimen. As per the Clinical Study Report by Aventis Pharmaceuticals, Inc. ((# RP56976V-316); 2004, at the time of the interim analysis, with 55 months of follow-up and based on 219 deaths, overall survival was longer for TAC than FAC, with a reduction in the risk of death of 30% (hazard ratio = 0.69). Further analysis from this trial will be presented when survival data mature. In terms of the toxicity proÞle of TAC, women receiving TAC had an increase in anemia, grade 3 and grade 4 neutropenia, amenorrhea, fever in absence of infection, hypersensitivity reactions, peripheral edema, and neurosensory and skin events compared with those receiving FAC. The toxicity, while signiÞcant, did not cause a large number of patients to withdraw from treatment. As with other anthracycline/cyclophosphamide-containing regimens, long-term serious toxicity for the TAC regimen included a low incidence of leukemia (0.4%) and congestive heart failure (1.6%) (Smith RE, 2002). The approved dose of docetaxel for the adjuvant treatment of operable nodepositive breast cancer is 75 mg/m2 administered one hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every three weeks for six cycles. Following the success of the TAC regimen in the adjuvant setting, studies have been performed to determine whether this regimen has neoadjuvant activity prior to surgery for CaB. Interim data from 907 patients, reported at ASCO 2004 (Costa S, 2004), conÞrm activity of TAC in this setting. Patients were treated with two cycles of TAC, and responders (>50% reduction in tumor volume as measured by ultrasound) were randomized to receive either four or six further cycles of TAC. Patients not responding to two cycles of TAC were randomized to receive either four further cycles of TAC or four cycles of vinorelbine and capecitabine in combination. The overall response rate in the study was 75%. Neutropenia (grades 3 and 4) was the most common toxicity and was more frequent in patients receiving TAC compared with a combination of vinorelbine and capecitabine: 8.6% versus 1%. Trastuzumab, Single Agent Overview. Trastuzumab (Genentech’s/Roche/Chugai’s Herceptin) is a recombinant humanized monoclonal antibody (MAb) that binds to the HER2 receptor. The degree of HER2 receptor expression in tumors is represented using a scale

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from 0 (low or negative) to 3 (strongly positive). High expression of the HER2 receptor is demonstrated in 25–30% of CaB patients, making them eligible for treatment with trastuzumab. High HER2 expression increases the proliferative rate of tumor cells, resulting in poor prognosis. Trastuzumab’s initial indication was as a single agent for the treatment of patients with metastatic CaB whose tumors overexpress the HER2 protein and who have received chemotherapy for their metastatic disease. In June 2004, trastuzumab also gained approval, in Europe, for Þrst-line treatment, in combination with docetaxel, for patients whose tumors overexpress HER2. Several studies have conÞrmed that patients who do not overexpress HER2 do not beneÞt from trastuzumab. Studies are underway to determine whether there is any beneÞt of continuing to treat patients with trastuzumab, as a single agent, following disease progression. Typically, if a patient suffers disease progression while on chemotherapy, the treatment is ceased. However, when trastuzumab is used in combination with chemotherapy, possibly the tumor has acquired resistance only to the chemotherapy component of the regimen. Because the side-effect proÞle of trastuzumab as a single agent is relatively benign, studies are underway to identify whether patients remaining on trastuzumab gain a survival beneÞt. Currently, several important clinical trials are evaluating the role of trastuzumab in early disease or in the adjuvant setting. An April 26, 2005, press release from Roche and Genentech announced that primary and secondary end points had been met in both disease-free and overall survival. Mechanism of Action. Trastuzumab binds selectively and with high afÞnity to the extracellular domain of the human epidermal growth factor receptor 2 (EGFR2), also known as HER2, which signals cellular growth and proliferation. Downregulation of HER2 occurs when the trastuzumab antibody attaches to HER2 protein receptors on the cell surface. This binding causes some receptors to be internalized into the cell, reducing the signal for cell growth. Clinical Performance. In a single-arm, open-label monotherapy trial, the overall response rate (complete response plus partial response) was 14% for metastatic CaB patients overexpressing HER2 (2+ and 3+) who were pretreated with trastuzumab (Cobleigh MA, 1999). The median duration of response was 9.1 months, and median survival was 12.8 months. Twenty-four percent of patients were progression-free at 5.8 months. The degree of HER2 protein overexpression correlated with the degree of treatment effect, although both HER2 2+ and 3+ graded patients populations showed a beneÞt. As an antibody therapy, trastuzumab offers substantial efÞcacy without the severe toxicities of traditional cytotoxic chemotherapies. The agent’s most serious side effect is cardiac dysfunction similar to that observed with anthracycline treatment (Seidman A, 2002; Keefe D, 2002). This overlapping toxicity proÞle raises concern, particularly in the adjuvant setting, about the administration of protocols that contain both agents. In a Phase II trial of 469 patients, sequential administration of trastuzumab and an anthracycline caused grade 3 or 4

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left-ventricular ejection fraction (LVEF) events in approximately 4% of patients (Sledge GW, 2001). Physicians consider these levels low enough to warrant investigation of this combination for adjuvant therapy. Nevertheless, extensive cardiac monitoring is mandatory for patients in the ongoing Phase III adjuvant therapy trials using trastuzumab. Four ongoing, pivotal Phase III clinical trials are investigating the beneÞt of including trastuzumab in adjuvant treatment (for eligible HER2-positive patients). They are the B-31 adjuvant trastuzumab study—North Central Cancer Treatment Group (NCCTG) and North American Breast Intergroup study number N9831; the National Surgical Adjuvant Breast and Bowel Project (NSABP) study number 31; the Breast Cancer International Research Group (BCIRG) study number 006; and the Breast International Group (BIG) Herceptin Adjuvant (HERA) trial. All the trials have been designed to test one year of treatment (the HERA trial also tests two years) against no therapy at all; they mostly build on a backbone of adjuvant chemotherapy comprising AC followed by a taxane. The HERA clinical trial is a large-scale international clinical trial designed to determine if earlier use of trastuzumab can increase the length of survival without cancer recurrence in women whose early CaB has been diagnosed as HER2 positive, which tends to be less responsive to classical treatment. The BIG and Roche are collaborating in the conduct of the HERA trial, which recruited nearly 4,500 patients between December 2001 and March 2004 and is now closed to recruitment. The Þnal analysis of study results will take place two years after the Þnal patient has been entered into the study, mid-2006. Success of trastuzumab in this setting will likely mean a high uptake by clinicians. An April 25, 2005, press release from the Data Monitoring Committees that are overseeing the combined analysis of two of these adjuvant trastuzumab trials (NSABP-B-31 and NCCTG-N9831) recommended that the results of a recent combined interim analysis, with data from more than 3,000 patients, be made public because the studies had met their primary endpoints of increasing diseasefree survival in patients receiving trastuzumab in combination with chemotherapy. The improvement in overall survival was statistically signiÞcant. Patients in the clinical trials who received trastuzumab following treatment with standard combination chemotherapy (AC followed by T) also had a 52% decrease in disease recurrence compared with patients treated with chemotherapy alone. This difference is highly statistically signiÞcant. Trastuzumab/Paclitaxel Regimen Overview. Researchers have combined trastuzumab with different chemotherapeutic agents in experimental treatment regimens. Trastuzumab in combination with doxorubicin is contraindicated, as both agents have potential for serious cardiac adverse reactions. One established combination is trastuzumab and paclitaxel, which is used to treat patients with metastatic CaB whose tumors overexpress the HER2 protein and who have not previously undergone chemotherapy for their metastatic disease.

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Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Trastuzumab binds selectively and with high afÞnity to the extracellular domain of the human epidermal growth factor receptor 2 (EGFR2), also known as HER2. Down regulation of the growth factor protein receptor HER2 occurs when the trastuzumab antibody attaches to HER2 protein receptors on the cell surface. This binding causes some receptors to be internalized into the cell, reducing the signal for cell growth. Preclinically, researchers have demonstrated trastuzumab’s synergy with several chemotherapies and hormonal therapies (e.g., treatment with trastuzumab prevents DNA repair following the impact of DNA-damaging drugs). Paclitaxel is a taxane. Taxanes act by stabilizing the mitotic spindle microtubules preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. A clinical trial comparing paclitaxel alone with paclitaxel in combination with trastuzumab as Þrst-line therapy for metastatic CaB demonstrated that the combination resulted in a marked improvement in response rate, time to disease progression, and overall survival (Slamon D, 2001). In another study, the overall response rate induced by trastuzumab/paclitaxel was shown to be independent of ER status: 44% for ER+ and 46% for ER–(Klein P, 2003). The study concluded that ER status is not a determinant of response to trastuzumab/paclitaxel therapy. In trastuzumab’s pivotal Phase III combination therapy trial, 469 previously untreated patients with metastatic CaB and HER2 overexpression at the 2+ or 3+ level received either anthracycline/cyclophosphamide (AC) or paclitaxel, plus either trastuzumab or placebo (Slamon D, 2001). The response rate for patients who received AC plus trastuzumab was 56% versus 42% in the AC/placebo group; the response rate for patients who received paclitaxel plus trastuzumab was 41% versus 17% in the paclitaxel/placebo group. For both the AC and paclitaxel treatment groups combined, the addition of trastuzumab increased the response rate from 32% to 50%, time to progression from 4.6 to 7.4 months, and overall survival from 20.3 to 25.1 months.

Trastuzumab/Docetaxel Regimen Overview. In June 2004, the European Commission approved the use of trastuzumab in combination with docetaxel in the European Union as a Þrstline therapy in HER2-positive metastatic breast cancer patients who have not yet received chemotherapy for their disease. Studies are also under way examining the role of trastuzumab in combination with docetaxel as a neoadjuvant treatment for HER2-positive patients with locally advanced CaB.

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•

Trastuzumab binds selectively and with high afÞnity to the extracellular domain of the human epidermal growth factor receptor 2 (EGFR2), also known as HER2. Down regulation of the growth factor protein receptor HER2 occurs when the trastuzumab antibody attaches to HER2 protein receptors on the cell surface. This binding causes some receptors to be internalized into the cell, reducing the signal for cell growth. Preclinically, researchers have demonstrated trastuzumab’s synergy with several chemotherapies and hormonal therapies (e.g., treatment with trastuzumab prevents DNA repair following the impact of DNA-damaging drugs). Docetaxel is a taxane. Taxanes act by stabilizing the mitotic spindle microtubules, preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. The approval of docetaxel in combination with trastuzumab is based on study results that showed that, for women with HER2-positive CaB, the combination of trastuzumab and docetaxel signiÞcantly improved median life expectancy by more than one-third (31 months with trastuzumab plus docetaxel versus 22 months for docetaxel alone) (Burris H, 2000). The study also revealed that 61% of patients treated with the combination responded to treatment, compared with 34% of patients who received docetaxel alone. Data from a small Phase II study investigating trastuzumab and docetaxel in combination as a neoadjuvant treatment for patients with locally advanced CaB reported a 72% overall response rate to the combination. A partial response was seen in 47% of patients and a complete response achieved in 25% of patients (Hines J, 2003). Docetaxel/Capecitabine Regimen Overview. Like 5-FU, capecitabine (Roche/Genentech/Chugai’s Xeloda) (Figure 10) is a ßuoropyrimidine antifolate. It is approved in the United States and Europe as a second-line treatment for metastatic CaB, both as a monotherapy and in combination with the taxane docetaxel or as a Þrst-line treatment for patients ineligible for anthracycline therapy. When combined with docetaxel, capecitabine is also approved for the treatment of anthracycline-refractory patients. In Japan, Chugai has Þled for the approval of capecitabine as a third-line treatment for metastatic CaB. Clinical studies to assess the performance of capecitabine in combination regimens and in the adjuvant setting are ongoing. In May 2003, the United Kingdom’s National Institute for Clinical Excellence (NICE) endorsed the addition of capecitabine to docetaxel treatment for patients with locally advanced or metastatic CaB who have failed or are unsuitable for anthracycline therapy.

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O CH3 HN

O F

N O H3C

HO

O

N

OH

FIGURE 10. Structure of capecitabine.


•

Capecitabine is a ßuoropyrimidine. It is converted to its active form—5FU—by thymidine phosphorylase (TP). TP is found in higher levels in cancer cells and therefore produces higher levels of the 5-FU metabolite in cancerous than in normal tissues. Fluoropyrimidines act by inhibiting thymidylate synthase (TS), a key enzyme in DNA synthesis. Docetaxel is a taxane. Taxanes act by stabilizing the mitotic spindle microtubules, thereby preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. In a randomized study involving patients with metastatic CaB, researchers administered docetaxel either alone or in combination with capecitabine (O’Shaughnessy J, 2002). The authors concluded that adding capecitabine to docetaxel treatment produced a statistically signiÞcant improvement in time to disease progression of 6.1 months compared with 4.2 months. They also observed an improvement in median survival—14.5 months with the combination regimen versus 11.5 months for docetaxel alone. Researchers at ASCO’s annual meeting in June 2003 presented data from two Phase II clinical studies involving patients with metastatic CaB. Patients were treated with docetaxel and capecitabine in combination (Mackey JR, 2003; Ramaswamy B, 2003). The Mackey study concluded that the increase in grade 3 toxicities observed with the combination (nail loss, asthenia, hand-foot syndrome) was difÞcult to manage and did not justify a change from the established dosing regimen of once every three weeks for docetaxel. The ongoing Ramaswamy study described toxicities as manageable and considered the interim response data to be good: of the 21 evaluable patients who were assessed, 14% demonstrated a complete response and 62% demonstrated clinical beneÞt. Other studies also

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observed that the combination of capecitabine and paclitaxel offers excellent efÞcacy (Gradishar WJ, 2001). Docetaxel, Single Agent Overview. The taxanes docetaxel (SanoÞ-Aventis’s Taxotere) (Figure 9) and paclitaxel (Bristol-Myers Squibb’s Taxol) (Figure 8) are both active against metastatic CaB. Clinical data have supported widespread single-agent application of these two taxanes in this population. Emerging clinical data indicate that docetaxel is more effective than paclitaxel, a Þnding that may result in docetaxel becoming the taxane of choice. Single-agent docetaxel is indicated for the treatment of CaB either after combination chemotherapy for metastatic disease fails, or if a relapse occurs within six months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. Mechanism of Action. Taxanes act by stabilizing the mitotic spindle microtubules, thereby preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death. Clinical Performance. The response rate for single-agent docetaxel in patients with locally advanced or metastatic CaB who have failed Þrst-line therapy is 30–45% compared with 16–32% for single-agent paclitaxel (Mamounas EP, 2002). Response rates are slightly higher when taxanes are used as Þrst-line therapy for metastatic disease; here, too, docetaxel shows superiority over paclitaxel (50% versus 25–33%). Clinicians have observed improved response rates when a taxane is combined with an anthracycline and given as Þrst-line therapy (55–63% for docetaxel; 40–68% for paclitaxel). In a large Phase III randomized trial, patients with anthracycline-pretreated metastatic CaB were assigned to receive either docetaxel monotherapy or the combination of the alkylating agent mitomycin (generics) and the vinca alkaloid vinblastine (generics) (Nabholtz JM, 1999). Docetaxel demonstrated superior response rates to those of mitomycin/vinblastine (28% versus 10%) and superior median survival (11.4 versus 9.1 months). A comparison of docetaxel with doxorubicin in patients previously treated with an alkylating agent demonstrated a superior response rate in the docetaxel-treated arm but no improvement in overall survival (Chan S, 1999). Nanoparticle Paclitaxel, Single Agent Overview. The taxanes docetaxel (SanoÞ-Aventis’s Taxotere) (Figure 9) and paclitaxel (Figure 8) (Bristol-Myers Squibb’s Taxol) are both active against metastatic CaB and are increasingly used in the adjuvant setting, particularly for patients with a high risk of relapse. Clinical data have supported widespread single-agent application of taxanes in patients with metastatic CaB.

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Nanoparticle paclitaxel (American Pharmaceutical Partners’ Abraxane) is a formulation of paclitaxel that is also given intravenously. The nanoparticles of paclitaxel are bound to albumin—a naturally occurring plasma protein. And, in contrast to paclitaxel, the nanoparticle paclitaxel formulation is cremophorfree and has a higher solubility. The lack of cremophor means that nanoparticle paclitaxel does not require intensive steroid premedication, and the agent is associated with a lower risk of treatment-related severe hypersensitivity and potential life-threatening anaphylaxis and a lower incidence of neuropathy. Nanoparticle paclitaxel recently gained FDA approval as a single agent for the treatment of metastatic CaB in patients who have failed combination chemotherapy for metastatic disease or who have relapsed within six months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. In April 2005, American Pharmaceutical Partners announced it would be initiating a Phase II clinical study of nanoparticle paclitaxel in one of the most widely used paclitaxel combination chemotherapy regimens. Nanoparticle paclitaxel will be used in place of paclitaxel and in combination with trastuzumab as Þrst-line therapy for HER2-overexpressing CaB. Mechanism of Action. Nanoparticle paclitaxel is a taxane. Taxanes act by stabilizing the mitotic spindle microtubules and thereby preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death. Clinical Performance. Data have been released from a Phase II study in 106 poor prognosis patients who had taxane-resistant progressive metastatic CaB and were given weekly nanoparticle paclitaxel (100 mg/m2 over 30 minutes; the typical weekly dose of paclitaxel would be administered over a minimum of three hours) (Blum J, 2003). A 15% overall response rate was achieved in this study, and 40% of patients were free of disease progression for four months; 30% were free of disease progression for six months. Nanoparticle paclitaxel was well tolerated; two patients experienced grade 4 toxicity (one thrombocytopenia and one neutropenia); common adverse events included mild nausea, fatigue, and alopecia. In a pivotal randomized controlled Phase III trial of nanoparticle paclitaxel, the safety and efÞcacy of 260 mg/m2 of nanoparticle paclitaxel was compared with 175 mg/m2 of paclitaxel, administered every three weeks (Perez E, 2005). The study was performed in 460 patients with metastatic CaB. The Phase III trial demonstrated that nanoparticle paclitaxel almost doubled the response rate (responses of speciÞc target lesions), 21.5% compared with 11.1% for paclitaxel, and prolonged time to tumor progression. The investigator reported response rates of 33% and 19% for nanoparticle paclitaxel and paclitaxel, respectively. In addition, the study conÞrmed that nanoparticle paclitaxel could be administered safely over 30 minutes without the need for steroid premedication and, despite

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being used at 50% higher dose than paclitaxel, nanoparticle paclitaxel was not associated with an increased rate of toxicities. Neutropenia (all grades) was experienced by 80% of patients treated with nanoparticle paclitaxel compared with 82% of patients with paclitaxel, with a lower incidence of grade 4 neutropenia in the nanoparticle paclitaxel arm of the study. A higher number of patients treated with nanoparticle paclitaxel experienced peripheral neuropathy (all grades, but no grade 4 reported) compared with those treated with paclitaxel: 71% versus 56%. The majority of patients experienced a rapid improvement in neuropathological symptoms. Capecitabine, Single Agent Overview. Capecitabine (Roche/Chugai’s Xeloda) (Figure 10), an orally administered pro-drug of 5-FU, has been available in all the major markets as a third-line treatment for locally advanced and metastatic CaB since 2002. Its approval was based on its activity in patients pretreated with anthracyclines and taxanes. Capecitabine is approved for the treatment of metastatic CaB as a monotherapy and in combination with docetaxel. Single-agent capecitabine is indicated for patients who are refractory to both paclitaxel and anthracyclines and for paclitaxel-resistant patients for whom further anthracycline therapy is contraindicated. In May 2003, NICE endorsed the use of capecitabine monotherapy treatment for patients who have failed both anthracycline- and taxane-based treatment. Researchers hypothesize that levels of thymidine phosphorylase (TP) enzyme expression may predict response to capecitabine. A retrospective analysis of a large Phase III trial showed that high levels of TP correlated with a favorable outcome in patients receiving 5’-deoxy-5-ßuorouridine (5’-FUDR, an intermediate form of capecitabine) but not in patients who did not receive the compound (Toi M, 2001). If similar results were obtained with capecitabine therapy, and a simple and effective test for TP expression was developed, physicians could target the use of capecitabine to patients who are most likely to respond to the agent, thus preventing unnecessary treatment. Mechanism of Action. Capecitabine is a ßuoropyrimidine. It is converted to its active form—5-FU—by TP. TP is found in higher levels in cancer cells and therefore produces higher levels of the 5-FU metabolite in cancerous tissue than in normal tissues. Fluoropyrimidines act by inhibiting thymidylate synthase (TS), a key enzyme in DNA synthesis. Clinical Performance. As a single agent, capecitabine produces signiÞcant responses in pretreated patients with metastatic disease. In a Phase II trial, 162 patients with metastatic CaB received capecitabine (1,250 mg/m2 twice per day on days 1–14 every 21 days) (Blum JL, 2001). All patients had previously been treated with paclitaxel, and the majority had also received an anthracycline (91%) and/or a 5-FU-based therapy (82%). Twenty percent of the patients

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responded to capecitabine, and an additional 43% achieved stable disease. The median time to disease progression was 3.0 months; median overall survival was 12.8 months. The most common adverse events were lymphopenia (94%), anemia (72%), diarrhea (57%), hand-foot syndrome (57%), nausea (53%), vomiting (37%), dermatitis (37%), neutropenia (26%), and thrombocytopenia (24%). These data were sufÞcient for capecitabine to receive accelerated approval by the FDA. An ongoing randomized adjuvant trial (CALGB-49907) is comparing capecitabine (alone) with AC or CMF in women over the age of 65 years. Oral, single-agent capecitabine is seen as an attractive choice for adjuvant treatment, particularly in low-risk, older, or poor performance status patients who are ineligible for more-aggressive chemotherapy treatment. Gemcitabine/Paclitaxel Overview. Gemcitabine (Eli Lilly’s Gemzar) (Figure 11) has largely replaced 5-FU as Þrst-line therapy for nonresectable or metastatic pancreatic cancer in all the major pharmaceutical markets. It is also approved for Þrst-line use, in combination with cisplatin (Figure 12), for nonresectable, locally advanced or metastatic nonsmall-cell lung cancer. Because of its favorable side-effect proÞle and convincing efÞcacy data, it is used extensively off-label as single-agent second-line or subsequent therapy for metastatic CaB. Several clinical trials are underway to evaluate the use of gemcitabine in combination with other cytotoxic agents (e.g., cisplatin, vinorelbine) as Þrst-line treatment and in anthracycline- and taxane-pretreated CaB patients. Gemcitabine in combination with paclitaxel has recently gained approval by the FDA for Þrst-line treatment of patients with metastatic CaB after they have had chemotherapy with anthracyclines. Patients contraindicated for anthracyclines are also eligible for gemcitabine/paclitaxel treatment. Mechanism of Action. Gemcitabine is an antimetabolite. It is a deßuorinated analogue of deoxycytidine with a novel mechanism of action. Gemcitabine undergoes intracellular metabolism by nucleoside kinases to its active form, leading to cytotoxicity via inhibition of DNA synthesis. Clinical Performance. In nine, mainly small, clinical studies of gemcitabine monotherapy, researchers disclosed response rates of up to 37% in the Þrst-line NH2 N HO

O O

N F

OH

F


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setting, 26% in the second-line setting, and 18% or better in the third-line setting (Heinemann V, 2003). In view of these results, gemcitabine may be regarded as a valuable alternative to the palliative treatment of metastatic CaB because its unique mechanism of action may elicit responses in heavily pretreated patients. In the large pivotal study that formed the basis for gemcitabine’s FDA approval for CaB, 267 patients (median age 53 years) received gemcitabine plus paclitaxel; another 262 patients (median age 52 years) received paclitaxel alone (Albain K, 2004). The median overall survival was 18.5 months for gemcitabine with paclitaxel and 15.8 months for paclitaxel alone. One-year survival was 71% in the group that received the combination therapy, compared with 61% for the group treated with paclitaxel alone. The study found that 55% of patients in the paclitaxel arm stopped therapy because of disease progression, in contrast to only 38% of the combination drug group. This research also found that gemcitabine provides pain relief in symptomatic patients. Vinorelbine, Single Agent Overview. Vinorelbine (GlaxoSmithKline’s/Pierre Fabre’s Navelbine) (Figure 13) is used primarily as a single-agent option for second-line (or subsequent) treatment of locally advanced or metastatic CaB when anthracycline-based treatments either have failed or are unsuitable. Vinorelbine monotherapy has a response rate of about 24% in the pretreated CaB population. Combinations of vinorelbine with other chemotherapeutic agents have failed to show clinical beneÞt. For example, in a randomized comparison of vinorelbine plus doxorubicin with doxorubicin alone, no signiÞcant differences between treatment groups were detected

N

CH3 N

N H CH3O2C CH3O

CH3 N


FIGURE 13. Structure of vinorelbine.

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in either response rate (38% versus 30%), duration of response (median 7.2 months versus 6.8 months), or survival (median 13.8 months versus 14.4 months). Vinorelbine monotherapy often Þnds application in older CaB patients because it is a well-tolerated option. In the United Kingdom, NICE endorsed this application of vinorelbine in September 2003. Mechanism of Action. Vinorelbine is a semisynthetic vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death. Clinical Performance. A noncomparative study using vinorelbine as a Þrstline metastatic treatment in elderly (>60 years) CaB patients yielded an objective response rate of 38%, median duration of response of nine months, and median time to disease progression of six months (Vogel C, 1999). The major doselimiting toxicity was hematologic. Grade 3–4 nonhematologic toxicity consisted of asthenia (7%) as well as nausea and generalized pain (5%). Neurotoxicity and alopecia were grade 1–2 and relatively infrequent. Data that directly compares vinorelbine monotherapy with other monotherapy in pretreated patients with metastatic CaB are limited. However, a randomized controlled trial compared vinorelbine with melphalan (an agent not in current widespread usage for CaB) in 179 patients who failed to respond to anthracyclinecontaining chemotherapy (Jones S, 1995). A statistically signiÞcant survival beneÞt for vinorelbine was found. The median survival time for patients treated with vinorelbine was 35 weeks compared with 31 weeks for those treated with melphalan; the one-year survival rate was 35.7% for the vinorelbine group compared with 21.7% for melphalan. Decisions on treatment selection are based primarily on an agent’s toxicity and the patient’s previous treatments. Vinorelbine exists as one of several treatment options in this setting and is normally indicated for second-line or subsequent treatment in advanced CaB. Tamoxifen, Single Agent Overview. Tamoxifen (AstraZeneca’s Nolvadex, generics) (Figure 14) is the most widely studied SERM, and its role in the treatment of CaB is well established. The agent is approved for the treatment of all stages of CaB; patients who are HR-positive are most likely to respond to treatment. Tamoxifen is not recommended for the treatment of HR-negative CaB. In 1998, the FDA approved tamoxifen as a preventive agent in women at high risk of developing CaB. Tamoxifen is administered orally; the standard dose is 20 mg daily, and in the adjuvant setting, physicians generally prescribe it for Þve years or until relapse. Mechanism of Action. Tamoxifen is a SERM. SERMs act by interfering with estrogen’s signaling of epithelial cell growth and reproduction. As a mixed ER antagonist/agonist, tamoxifen can selectively stimulate or inhibit the ERs of different target tissues: this action is responsible for its protective effect on bone.

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FIGURE 14. Structure of tamoxifen.

Clinical Performance. Tamoxifen has been in widespread routine use for several decades and, until recently, has been virtually unchallenged in both the adjuvant setting and as Þrst-line hormonal treatment for metastatic CaB. Other agents were relegated to second-line or subsequent treatments. Studies have shown that tamoxifen increases the survival of women with CaB. The Early Breast Cancer Trialists’ Collaborative Group overview of randomized trials of adjuvant tamoxifen versus no tamoxifen showed that during approximately ten years of follow-up, the proportional reductions in mortality for one, two, and approximately Þve years of adjuvant tamoxifen therapy in ER-positive patients were 12%, 17%, and 26%, respectively (EBCTCG, 2000). As a result of these data, Þve-year adjuvant treatment with tamoxifen is now recommended. In a meta-analysis of 11 trials involving more than 15,000 patients, tamoxifen was shown to be equivalent in efÞcacy to adjuvant chemotherapy (EBCTCG, 2002). Since the emergence of the third-generation potent and selective aromatase inhibitors (AIs, discussed next), tamoxifen’s dominance has been under threat. Interim analysis has shown that for adjuvant treatment, the AI anastrozole (AstraZeneca’s Arimidex) offers a small but statistically signiÞcant survival advantage over tamoxifen and an improved side-effect proÞle, with the exception of the incidence of bone fractures (Anastrozole, Tamoxifen Alone and in Combination [ATAC] Trialist Group, 2002; Buzdar A, 2003; Baum M, 2003). However, until the outcome of the ATAC trial is elucidated, tamoxifen remains the standard adjuvant treatment for ER-positive patients. This agent will likely remain the preferred therapy for premenopausal patients with CaB because the aromatase route of estrogen production is less important in these patients. Anastrozole, Single Agent Overview. Anastrozole (AstraZeneca’s Arimidex) (Figure 15) is an aromatase inhibitor, or AI, approved in all the major markets for the adjuvant treatment (with or without radiation) of postmenopausal women with HR-positive early CaB. Approval was based on study results from patients taking anastrozole as adjuvant treatment for a median of two and a half years. This study is ongoing; further

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FIGURE 15. Structure of anastrozole.

follow-up of patients will be required to determine long-term results, including the agent’s side-effect proÞle and patient survival. Until these data become available, a complete comparison with tamoxifen is not possible. (Tamoxifen has more than 15 years’ detailed follow-up involving many thousands of patients.) Anastrozole is also approved for the treatment of locally advanced and metastatic CaB—either as a Þrst-line hormonal therapy or for patients currently taking tamoxifen whose disease has progressed. Mechanism of Action. Anastrozole is a selective nonsteroidal AI. AIs act by binding to the aromatase enzyme in place of androgens, inhibiting aromatase activity. Aromatase is the enzyme that converts androgens to estrogens; its inhibition results in the reduction of plasma estrogen levels, a promoter of cell replication in some breast tumors. Clinical Performance. The interim ATAC trial results show that patients treated with adjuvant anastrozole survived longer than those treated with tamoxifen (Baum M, 2001). More than 10,000 postmenopausal, hormonereceptor-positive, early-stage CaB patients were randomized to receive anastrozole, tamoxifen, or both. Accrual to the combination arm was halted early after evidence of inferiority to tamoxifen alone. Early analyses at 33 and 47 months reported that, compared with patients taking tamoxifen, patients taking anastrozole experienced a lower incidence of hot ßashes, weight gain, vaginal bleeding, endometrial cancer, and thromboembolic events. However, anastrozole patients had a higher incidence of arthralgia symptoms and bone fractures (Burstein HJ, 2002). A subsequent update of the ATAC trial, with a median follow-up of 68 months, was presented at the San Antonio CaB conference (Breast Cancer Symposium) in December 2004 (Howell A, 2004). The data showed that differences between anastrozole and tamoxifen in disease-free survival, time to recurrence, the occurrence of new tumors in the opposite breast, and metastases were even more pronounced at 68 months than they were at 47 months. However, no statistically signiÞcant improvement in overall survival between the two arms of the study was seen. Researchers noted that in this postmenopausal population, the course of

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FIGURE 16. Structure of letrozole (R = CN).

CaB can typically span 15 to 20 years, and patients often die of unrelated causes, making it difÞcult to conÞrm an overall survival beneÞt. Nevertheless, clinicians are already changing to anastrozole, in preference to tamoxifen, especially in patients with a high risk of thrombosis. In light of these ATAC data, ASCO has stated that Þve years of tamoxifen is no longer the optimal treatment choice in postmenopausal hormone-receptorpositive patients. The Society recommends that adjuvant therapy should include an AI, either as initial therapy or after treatment with tamoxifen, to reduce risk of recurrence. Letrozole, Single Agent Overview. Letrozole (Novartis’s Femora/Femara) (Figure 16) has been approved for the hormonal treatment of metastatic CaB. The drug was Þrst launched in 1997 in the United Kingdom for the second-line treatment of metastatic CaB. That same year, the FDA cleared letrozole as a once-daily therapy for the treatment of metastatic CaB in postmenopausal women with disease progression following antiestrogen therapy. The drug is also registered as a Þrstline therapy for advanced CaB. Letrozole is now being studied extensively for the treatment of early-stage CaB, the interim data for which are discussed in this section. Mechanism of Action. Letrozole is a selective nonsteroidal AI. AIs act by binding to the aromatase enzyme in place of androgens, thereby inhibiting aromatase activity. Aromatase is the enzyme that converts androgens to estrogens; its inhibition results in the reduction of plasma estrogen levels, a promoter of cell replication in some breast tumors. Clinical Performance. Two clinical studies (551 and 555 patients) evaluated letrozole’s tolerability and efÞcacy compared with that of megestrol acetate (generics) (Dombernowsky P, 1998) and aminoglutethimide (generics) (Gershanovich M, 1998) in patients with advanced CaB who had progressed on antiestrogen therapy. Letrozole showed superiority over both agents in tolerability and efÞcacy, including response rate and duration of response.

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A study comparing letrozole with tamoxifen as a Þrst-line hormonal therapy in patients with advanced CaB concluded that letrozole is signiÞcantly superior to tamoxifen in several efÞcacy parameters, including time to disease progression (41 weeks versus 26 weeks) and overall response rate (30% versus 20%) (Mouridsen H, 2001). Letrozole’s tolerability was reportedly equivalent to that of tamoxifen. In a randomized, double-blind neoadjuvant trial, 337 postmenopausal patients with large HR-positive tumors requiring mastectomy or breast-conserving surgery (BCS) were randomized to receive either preoperative letrozole or tamoxifen for four months (Smith I, 2003). The overall response rate was signiÞcantly better for letrozole (55% for letrozole versus 36% for tamoxifen). Neoadjuvant treatment allowed BCS in 45% of the patients treated with letrozole versus 35% treated with tamoxifen. Again, the improvement observed in the letrozole group was statistically signiÞcant. Interim data from the Breast International Group (BIG) 1–98 study were disclosed at the St. Gallen Primary Therapy of Early Breast Cancer conference in January 2005 (Thurliman {Thurlimann} B, 2005). BIG 1-98 is a multinational Phase III double-blind, randomized multicenter trial that is being conducted in 27 countries and has recruited more than 8,000 postmenopausal women with early CaB who have hormone-receptor-positive tumors. The primary endpoint of the study is to determine if letrozole can reduce the risk of recurrence or death compared with tamoxifen. At a median follow-up of 26 months, the study showed that, compared with tamoxifen, letrozole reduced the risk of such events by 19%. Among the 4,003 patients in the letrozole group, 84% remained alive and disease-free at Þve years compared with 81% of the 4,007 patients in the tamoxifen group. As in other studies with AIs, the incidence of thromboembolytic events and endometrial changes were reportedly lower with letrozole than with tamoxifen. Conversely, letrozole was associated with a higher incidence of bone complications, such as fractures. Exemestane, Single Agent Overview. Exemestane (PÞzer’s Aromasin) (Figure 17) has been approved for the treatment of hormone-receptor-positive, postmenopausal metastatic CaB patients who have progressed on tamoxifen (either in the adjuvant or metastatic setting). Studies investigating exemestane for Þrst-line metastatic treatment and adjuvant treatment of CaB are ongoing. Data showing a beneÞt from switching from adjuvant tamoxifen (following two to three years of treatment) to exemestane for a further two to three years (Coombes RC, 2004) has driven exemestane’s off-label usage in high-risk early-stage patients. Mechanism of Action. Exemestane is a selective steroidal AI. Steroidal AIs act by irreversibly binding to the aromatase enzyme in place of androgens, inhibiting aromatase activity. Aromatase is the enzyme that converts androgens to estrogens; its inhibition results in the reduction of plasma estrogen levels, a promoter of cell replication in some breast tumors.

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FIGURE 17. Structure of exemestane.

Clinical Performance. In a pivotal randomized, double-blind, multicenter, multinational, comparative clinical trial, exemestane was administered once daily to postmenopausal women with advanced breast cancer who experienced disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also had received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. Three hundred sixty-six patients were randomized to receive exemestane once daily, and 403 patients received megestrol acetate (the comparator of choice at the time of the study) four times daily. In the study, exemestane reduced the relative risk of tumor progression by 16%: patients experienced a median time to tumor progression of 20.3 weeks compared with 16.6 weeks for megestrol acetate. There was no statistically signiÞcant difference in the number of women having a clinical response. Both responders and nonresponders to tamoxifen beneÞted from exemestane treatment. In an adjuvant, double-blind clinical trial, the Intergroup Exemestane Study (IES), women who had already received two to three years of tamoxifen were randomized to one of two groups (Coombes RC, 2004). Either they completed the Þve-year course of tamoxifen or they switched to the aromatase inhibitor exemestane to complete a total of Þve years of hormonal treatment. Of the 4,742 patients enrolled, 2,362 were randomly assigned to switch to exemestane, and 2,380 continued to receive tamoxifen. The study demonstrated that the women who switched to exemestane had increasing disease-free survival compared with women who remained on tamoxifen. Overall survival was not signiÞcantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group. This result was statistically signiÞcant. Fulvestrant, Single Agent Overview. Fulvestrant (AstraZeneca’s Faslodex) (Figure 18) is a low-toxicity, synthetic hormonal agent that overcomes tamoxifen resistance. In April 2002, the FDA approved fulvestrant for second-line treatment of patients with metastatic CaB whose disease had progressed despite prior antiestrogen therapy. It has now been approved in the UK and other European countries.

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H3C

OH

H O H

H

F

F

S HO

CF3 FIGURE 18. Structure of faslodex.

In addition, a European Phase III trial comparing fulvestrant and tamoxifen as Þrst-line therapy for patients with metastatic CaB has completed accrual, and AstraZeneca is planning trials in the adjuvant setting and in premenopausal women. In Japan, Phase III trials are ongoing in patients with metastatic CaB. Mechanism of Action. Fulvestrant is a selective estrogen receptor downregulator (SERD). SERDs act by binding to the cellular estrogen receptor in a competitive manner and downregulating estrogen receptors. Fulvestrant has no known estrogen-agonist effects and, because of its unique mechanism of action, shows no cross-resistance with SERMs. Clinical Performance. Two Phase III trials (one European and one North American) compared fulvestrant with anastrozole in ER-positive, metastatic, postmenopausal women in whom tamoxifen therapy had failed. The European trial compared 250 mg of fulvestrant (delivered as a single monthly intramuscular injection) with 1 mg/day anastrozole. The North American trial involved a third arm (125 mg fulvestrant), which was closed prematurely when a planned interim analysis showed that predeÞned efÞcacy criteria had not been met. In the North American trial involving 400 patients, the 250 mg fulvestrant group had a superior duration of response (19.3 months) compared with the anastrozole group (10.5 months)—a beneÞt that was not reproduced in the 451patient European trial (14.3 months and 14.0 months). Investigators suggested that this discrepancy may have resulted from differences in the frequency of follow-up (Carlson R, 2002). An update from the European trial reinforced the lack of a signiÞcant difference in survival rates between fulvestrant and anastrozole: time to death was 26.4 months for the fulvestrant group versus 24.2 months for the anastrozole group (Howell A, 2003). A combined analysis of the North American and European trials found a (nonsigniÞcant) trend toward improved efÞcacy with fulvestrant compared with anastrozole. At the annual meeting of ASCO in June 2003, researchers presented interim data from an ongoing study in Japan (Watanabe T, 2003). Thirty patients who had relapsed on antiestrogen therapy were treated with fulvestrant. A clinical beneÞt rate (complete response plus stable disease) of 60% led the authors to conclude that fulvestrant represents another treatment option for patients with metastatic CaB.

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Fulvestrant’s toxicity proÞle is comparable to that of tamoxifen and aromatase inhibitors. In the aforementioned Phase III trials, the incidence of side effects was similar in patients taking fulvestrant and anastrozole. Side effects of fulvestrant included hot ßashes (21%), vasodilatation (14%), and nausea (10%) (Jones S, 2001). Because fulvestrant has no estrogen-agonistic effects, clinicians do not expect the agent to cause endometrial cancer or to have a favorable effect on bone density and serum lipid levels. Goserelin, Single Agent Overview. Gonadotrophin-releasing hormone (GnRH) agonists—in particular goserelin (AstraZeneca’s Zoladex)—enable temporary suspension of estrogen production from the ovaries and, when used in combination with tamoxifen, result in total estrogen blockade. In terms of clinical beneÞt, this hormonal approach to the treatment of premenopausal ER-positive CaB has proven to be equivalent to chemotherapeutic regimens. Indeed, some physicians speculate that some chemotherapeutic drugs may exert their effect in part by ovarian ablation. For patients who require chemotherapy but are made amenorrheic by chemotherapeutic treatment, physicians may consider goserelin treatment unnecessary and prescribe tamoxifen alone. Mechanism of Action. Goserelin acetate is a GnRH analogue. GnRH analogues act by downregulating pituitary GnRH receptors, thereby suppressing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These actions, in turn, reduce the main source of estradiol, which is produced in the ovaries, in premenopausal women. In HR-positive tumors, estrogen has been established as a promoter of cell growth and replication. Clinical Performance. Clinical trials have shown that goserelin, when used either alone or in combination with tamoxifen as an adjuvant systemic therapy in premenopausal women with ER-positive CaB, produces recurrence-free survival rates equivalent to those of chemotherapy (Robertson JF, 2003). These data demonstrate that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early CaB. Nonpharmacological Approaches The treatment of CaB is multimodal: for the majority of patients, surgery and radiotherapy are used alongside chemotherapy and hormonal treatments. Surgery. Common surgical options for CaB are mastectomy (removal of the breast and sometimes the axillary lymph nodes) and breast-conserving surgery (BCS) (removal of the tumor and immediately surrounding tissue only, resulting in narrow margins of resection). Surgeons have also started to perform sentinel

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node biopsy during BCS to determine whether full axillary lymph node resection is necessary. More recently, the use of intraoperative ultrasound to localize nonpalpable tumors has resulted in a reduced re-excision rate due to positive margins in the excised tissue. In early-stage tumors, mastectomy and BCS have equivalent effects on survival, particularly if BCS is followed by radiotherapy. Surgical treatment for small early-stage CaB is likely to be BCS rather than mastectomy. In patients with large tumors at diagnosis, BCS may be possible if chemotherapy or hormonal therapy is given prior to surgery to shrink the tumor (neoadjuvant therapy). A minority of women at high risk of developing CaB may undergo elective bilateral radical mastectomy and, in some cases, bilateral oophrectomy. For total ovarian blockade, premenopausal women with CaB may undergo surgical oophrectomy rather than receive goserelin. Radiotherapy. CaB radiotherapy generally involves postoperative irradiation of the tumor site, chest wall, and draining lymph node regions. Its goal is the reduction of local or regional recurrence. Though toxic and timeconsuming—usually Þve days a week for six to eight weeks—postoperative radiation has been shown to reduce the risk of local recurrence. In a metaanalysis of 66 trials involving some 28,500 women, investigators found that radiation lowered the rate of local recurrence after surgery by a factor of three (EBCTCG, 1995). The effectiveness of radiation for increasing overall survival, regardless of recurrence, remains controversial. In a review of 18 randomized trials of radiation’s effect on survival, investigators found that overall survival was approximately 17% better in radiation-treated patients than in patients not receiving radiotherapy (Whelan TJ, 2000). However, in a meta-analysis of 10- and 20-year results from 40 randomized trials of radiation therapy, investigators found that although CaB mortality was signiÞcantly reduced, mortality from other causes—particularly vascular causes—increased (EBCTCG, 2000). Overall survival was statistically equivalent: 37% survival with radiation versus 36% for controls. Patient nodal status, age, and other factors strongly affected survival rates. The potential importance of these predictive factors appears particularly relevant in light of a follow-up meta-analysis, which found that radiation signiÞcantly improved overall survival of CaB patients by as much as 20% when molecular techniques were employed (Van de Steene J, 2000). EMERGING THERAPIES In the breast cancer (CaB) pharmaceutical market, the barriers to entry for new therapeutic agents are high, particularly for hormonal and cytotoxic therapies. Several classes of very well tolerated hormonal agents, administered as once-daily pills, can keep metastatic disease in check for two years or more when used in succession. When hormonal therapies and Þrst-line chemotherapy fail, several of the better-tolerated cytotoxic agents (capecitabine, vinorelbine, gemcitabine) can

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delay progression for many more months. For any new agent to gain approval in the metastatic setting, it must exhibit greater efÞcacy and/or a superior side-effect proÞle to existing agents or be relegated to third- or fourth-line use. In addition, efÞcacy is increasingly measured in terms of duration of disease control; the concept of clinical response (stable disease plus tumor response) is an important new endpoint, supplementing tumor response, disease-free survival, and overall survival. In the adjuvant market, the company developing the drug must invest in a trial recruiting more than 1,000 patients (the number required to achieve statistical signiÞcance) and then wait Þve to eight years (the amount of time required to show survival beneÞt). These conditions make entry into the CaB market time-consuming and expensive. The adjuvant market is a potentially lucrative one because of extended treatment periods and long survival times and the large number of patients involved. However, any new hormonal or cytotoxic therapy must demonstrate superiority to current therapies in both efÞcacy and toxicity proÞle. The arrival of several aromatase inhibitors (AIs) into the adjuvant market has further increased the barrier to entry for new hormonal agents. Currently, little late-stage development activity for new hormonal treatments is ongoing. One agent, TAS-108 (SRI and Tahio), is reportedly in Phase II studies in the United States and Phase I studies in Japan, with particular interest in tamoxifen-resistant disease. TAS-108 is a steroidal aromatase inhibitor under development by SRI and Taiho, for the potential Þrst-line treatment of metastatic breast cancer and secondline treatment of tamoxifen-resistant breast cancer. Data from a phase I study, showed that TAS-108 was well tolerated at doses ranging from 40 to 160 mg/day with no maximum tolerated dose achieved (Buzdar A, 2005). Toxicities associated with TAS-108 include hot ßashes, headache, and nausea and vomiting. There was evidence of antitumor activity, with stable disease noted in eight of the 16 patients enrolled, despite the fact that they were heavily pre-treated with the majority having received three or more lines of chemotherapy (63%), and three or more lines of endocrine therapy (75%). One patient had stable disease for 33 weeks and a second patient for 60 weeks. The remaining eight patients suffered progressive disease. A phase II study is ongoing in the U.S., although no data are yet available, and Phase III studies are being planned with the drug. Because biologic and other highly targeted therapies are likely to be used together with existing therapies, the barriers to market entry are lower for these agents. Clinician concerns relating to this group of drugs pertain to their burdensome cost and the potential for unusual or delayed toxicities. However, the enormous success of trastuzumab (Genentech/Roche’s Herceptin), in the treatment of metastatic HER2-positive disease and with several large ongoing trials in the adjuvant setting, has fueled enthusiasm for a targeted approach to treatment. Evaluating targeted agents in earlier disease is essential: treatment of lower tumor burden is more likely to prove successful, but research has also demonstrated that some pathways (particularly those involved in angiogenesis) may become redundant in advanced CaB.

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The complexities of hormone receptor activation and epidermal growth factor receptor (EGFR) pathways are yet to be fully elucidated. Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways (Osborne CK, 2005) in what is termed “molecular crosstalk.” In tumors with active growth factor receptor signaling (e.g., HER2 gene ampliÞcation), tamoxifen may lose its estrogen antagonist activity and acquire more agonist-like activity, resulting in tumor growth stimulation. Indeed, clinical data support this concept of tamoxifen resistance, and many clinicians now replace tamoxifen with AIs for hormone-receptor-positive/HER2-positive patients. A signiÞcant number of novel agents in clinical development have the potential to improve treatment outcomes in the future. Herein are discussed agents that show the most promise for entry into the future CaB market. Table 8 summarizes drug therapies in development for CaB. Epothilones Overview. In the wake of taxanes’ success, epothilones, a novel class of anticancer drugs whose mechanism of action is similar to that of taxanes, are under investigation. Epothilones have several potential advantages over taxanes. Because they are soluble in water, they eliminate the need for cremophor. Cremophor is present in paclitaxel formulations to improve taxane solubility and is in part responsible for the allergic response that can occur during administration. Without the need for cremophor, epothilones are easier to administer (although still intravenous) and less likely to trigger an allergic response. Most important, they appear to be effective against cancer cells that are resistant to existing chemotherapies. Given these advantages, epothilones may challenge the place of taxanes in neoadjuvant and adjuvant therapy and in the treatment of metastatic disease. Many companies are investing signiÞcantly in epothilones and have epothilones in clinical development: Bristol-Myers Squibb’s ixabepilone is the leading agent in this class for CaB treatment, so we discuss this agent in detail. Another one, epothilone D (KOS-862), is undergoing Phase II investigation for CaB by Roche and Kosan in the United States and Europe. If epothilones are shown to be signiÞcantly more effective than taxanes, they may replace the latter class, but only if the side-effect proÞle is deemed acceptable. If epothilones exhibit efÞcacy similar to that of taxanes, have a superior side-effect proÞle, and circumvent taxane resistance, they are most likely to be used when clinicians are running out of other options. Mechanism of Action. Comprising a family of 16-member ring macrolides, epothilones were originally isolated in 1991 by Holfe and Reichenbach from the fermentation broth of the soil-derived myxobacterium Sorangium cellulosum. Epothilones work via a mechanism similar to that of taxanes: they stabilize spindle microtubules formed during mitosis, thereby preventing the

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TABLE 8. Emerging Therapies in Development for Breast Cancer Development Phase

Marketing Company

Epothilones Ixabepilone United States Europe Japan

III II —

Bristol-Myers Squibb Bristol-Myers Squibb —

Modified taxanes SA-109881 United States Europe Japan

III III —

Sanofi-Aventis Sanofi-Aventis —

Other microtubule modulators Vinflunine United States Europe Japan

— II —

— Pierre Fabre (France) —

Antimetabolites Pemetrexed (Alimta) United States Europe Japan

II II —

Eli Lilly Eli Lilly —

Cell-cycle inhibitors Temsirolimus (CCI-779) United States Europe Japan

S — —

Wyeth — —

Compound

Vascular endothelial growth factor inhibitors Bevacizumab (Avastin) United States III Europe — Japan — Epidermal growth factor receptor inhibitors Lapatinib United States III Europe — Japan — Pertuzumab (Omnitarg) United States II Europe — Japan — Erlotinib (Tarceva) United States II Europe — Japan —

Genentech (US)/Roche (EU) — —

GlaxoSmithKline — — Genentech/Roche — — OSI/Genentech/Roche — —

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TABLE 8. (continued) Development Phase

Marketing Company

Gene therapy and antisense Advexin United States Europe Japan

II — —

Introgen — —

Vaccines Theratope United States Europe Japan

S S —

Biomira Biomira —

COX-2 inhibitors Celecoxib (Celebrex) United States Europe Japan

S S —

Pfizer Pfizer —

Chemotherapy potentiators Tesmilifene United States Europe Japan

III III —

YM BioSciences YM BioSciences —

Compound

S = Suspended.

microtubules’ disassembly and consequently blocking cell division. Because their chemical structure differs from that of taxanes, epothilones can circumvent taxane resistance. Ixabepilone. Ixabepilone is a semisynthetic analogue of epothilone B being developed by Bristol-Myers Squibb. Multiple trials are evaluating ixabepilone in breast cancer treatment, including two ongoing Phase III trials in the United States. The primary end point is time to progression. The second Phase III study, study CA163-048, is evaluating ixabepilone in combination with capecitabine versus capecitabine alone in 1,200 patients. Both trials are evaluating ixabepilone in patients who have received at least one previous line of chemotherapy (including a taxane and an anthracycline). A U.S. Phase II study of ixabepilone and trastuzumab (Herceptin) in patients with HER2-positive metastatic CaB is also ongoing. In June 2004, Phase II data on ixabepilone were presented at the 40th American Society of Clinical Oncology (ASCO) meeting (Low JA, 2004). A total of 42 patients with metastatic or locally advanced CaB were administered 6 mg/m2 /day IV ixabepilone on days 1 to 5, every three weeks. Prior taxane-treated patients received a median of two prior chemotherapy regimens. Grade 3 and 4 toxicities per patient were neutropenia (32%), febrile neutropenia (10%), thrombocytopenia

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(5%), fatigue (15%), diarrhea (12%), nausea/vomiting (5%), constipation (2%), myalgia/arthralgia (2%), and sensory neuropathy (grade 3: 2%). Of the 33 patients who had prior taxane treatment, 6 (18%) achieved a partial response, 12 (40%) experienced stable disease, and a further 12 had disease progression. Of the 9 taxane-naive patients, 4 had a partial response and a further 4 had stable disease. In an earlier Phase II study, seven patients with taxane-refractory metastatic CaB were treated with ixabepilone at 50 mg/m2 in a one-hour infusion every 21 days (O’Shaughnessy J, 2002). Two subjects achieved partial responses and three achieved stable disease. Grade 3 toxicities—experienced in each case by a single patient—included fatigue, sensory neuropathy, proctitis, stomatitis, and thrombocytopenia. Two patients developed grade 3 neutropenia. In another Phase II trial involving 19 taxane-naive patients with metastatic disease, 10 patients achieved a partial response and 8 achieved stable disease; the overall disease control rate (including stabilization) was 95% (Roche H, 2002). (Although this study was small, this disease control rate compares favorably with the rate [74%] achieved with docetaxel alone.) In this group of patients, grade 3 toxicities included myalgia (Þve patients), sensory neuropathy (four), fatigue (three), dyspnea (three), diarrhea (one), and febrile neutropenia (one). Seven patients experienced grade 3 or 4 neutropenia. In another Phase II study, researchers changed ixabepilone’s dosing schedule to reduce neurotoxicity: patients received a three-hour (rather than a one-hour) infusion every 21 days (Thomas E, 2003). The researchers also reduced the dose from 50 mg/m2 to 40 mg/m2 to address the incidence and severity of mucositis and abdominal pain reported in other studies. In June 2003, at the ASCO meeting, researchers presented preliminary efÞcacy data from this study, which involved anthracycline-pretreated patients. Of the 44 evaluable patients, they determined 15 partial responses and 23 cases of stable disease. The incidence of grade 3 neuropathy fell from 37% to 16%. Grade 3 neutropenia was observed in 24% of the patients. Clinical investigations of ixabepilone are also underway in patients previously treated with anthracyclines. Novel and Modified Taxanes Overview. Paclitaxel has been a highly successful agent for the treatment of a variety of solid tumors. As a result, much interest has been shown in developing new formulations and analogues to address problems with its administration. The goal is to develop more-soluble, cremophor-free formulations and analogues that enable clinicians to administer higher doses of paclitaxel for greater efÞcacy while reducing the associated toxicity. These agents may also have an improved pharmacokinetic proÞle and different mechanism of intracellular uptake. The commercial potential of these agents has recently been demonstrated with the launch of American Pharmaceutical Partners’ nanoparticle formulation of paclitaxel, ABI-007 (Abraxane). With improved therapeutic indices, modiÞed taxanes could encourage longer term maintenance use and avert toxicity concerns with available taxanes, that is, unless their cost is prohibitive.

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Mechanism of Action. Taxanes suppress microtubule dynamics and disassembly, thereby stopping mitosis at the metaphase/anaphase transition and inducing cell death. Formulation. Companies are investigating a variety of approaches to modifying taxanes. These include the following: •

• • • • •

New paclitaxel (Bristol-Myers Squibb’s Taxol, generics) analogues (BristolMyers Squibb’s BMS-184476, in Phase II evaluation for CaB and other cancer indications); Oral formulations (Ivax’s Paxoral); Liposomal formulations (PÞzer/NeoPharm’s LEP); Polyglutamated formulations (Cell Therapeutics’ CT-2103; Xyotax); Polyethylene glycol–conjugated (pegylated) formulations (Enzon’s MacroMed); and Microsphere formulations (Guilford Pharmaceuticals’ Paclimer).

Many other agents are in clinical trials for CaB. We focus our discussion on the most promising agent, SanoÞ-Aventis’s SA-109881. SA-109881. SanoÞ-Aventis is developing SA-109881, an orally and intravenously active taxoid. A Phase III trial is ongoing in the United States and Europe. As of February 2004, prior to its merger with SanoÞ-Synthélabo, Aventis was also planning to implement a Phase II screening program during 2004 to identify the tumors most sensitive to SA-109881. The Phase III trial is evaluating SA-109881 versus capecitabine as a Þrst-line treatment of metastatic CaB patients. SA-109881 will be given intravenously once every three weeks. A Phase II U.S. study is evaluating SA-109881 in chemotherapy-refractory metastatic CaB patients. Encouraging data from a Phase II trial in patients with metastatic CaB were disclosed at the 39th ASCO meeting in 2003 (Dieras VC, 2003). Patients previously treated by chemotherapy were stratiÞed into taxoid-responsive and taxoidresistant arms. At the time data were disclosed, 42 patients (21 in each arm) of the 58 enrolled had been evaluated for safety and efÞcacy. The median time between the last administration of the previous taxoids and the Þrst SA-109881 infusion was 13.6 months and 1.4 months in arms 1 and 2, respectively. A total of 175 cycles of SA-109881 were administered, with a median of 6 cycles and 2 cycles in arms 1 and 2, respectively. The safety proÞle was similar in both arms. Neutropenia was the main hematologic toxicity (59%; grade 3/4). Grade 2 toxicities were as follows: diarrhea (9%), neurosensory disorders (13%), fatigue (17%), myalgia (6%), arthralgia (6%), nausea (7%). Thus far, no cumulative toxicity or ßuid retention—a problematic side effect associated with established taxanes—have been reported. Preliminary efÞcacy results show partial response rates of 48% and 29% in the Þrst and second arms, respectively.

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These Phase II data are encouraging, especially for the Þrst-arm, given that docetaxel achieves approximately a 50% response rate as a Þrst-line treatment. If the ongoing Phase III trial results are positive, SA-109881 has potential to become a second-line treatment. Other Microtubule Modulators Overview. The success of the taxanes in CaB treatment has spurred R&D interest in many other microtubule inhibitors that do not fall within the other classes outlined here. These agents, which include Kosan Biosciences’ KOS-862, are as yet unproven in CaB because data are lacking. The only exception is Pierre Fabre/Bristol-Myers Squibb’s vinßunine (Javlor), an agent covered in detail in this section. Mechanism of Action. These agents work in a similar way to taxanes; they promote microtubule polymerization and inhibit tubulin depolymerization, arresting mitotic cell division at the metaphase/anaphase transition and inducing cell death. Vinca alkaloids inhibit microtubule polymerization at high drug concentrations. Vinflunine. Vinßunine (Pierre Fabre’s Javlor) (Figure 19) is a semisynthetic vinca alkaloid derived from vinorelbine. It is in Phase II clinical trials for the treatment of CaB in Europe and in other, non-major-market countries. Phase II data on vinßunine in metastatic CaB patients progressing after prior chemotherapy with anthracyclines and taxanes were presented at the 2004 ASCO meeting (Fumoleau P, 2004). Of the 60 patients enrolled, 45 were evaluable for efÞcacy, and 52 were evaluable for safety. Dose reduction was required in 11.4% of cycles. The relative dose intensity was 96.5%. Partial response (PR) was obtained in 16 out of 45 patients (35.6%), and stable disease (SD) in 15 patients (33.3%). By an intent-to-treat analysis, median progression-free survival was 4.2 months. From 16 out of 45 patients with a progression-free interval less than three months after taxane exposure, 7 patients (43.8%) achieved a PR. Grade 3/4

N

CF2CH3

N N H CH3O2C CH3O

CH3 N


FIGURE 19. Structure of vinflunine.

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related toxicities were neutropenia (63.5% patients), neutropenic infection (5.8% patients), constipation (19.2% patients), abdominal pain (13.5% patients), nausea (9.6% patients), and vomiting (7.7% patients). No grade 3/4 related peripheral neuropathy was observed. Although vinßunine has shown some promising results in the aforementioned Phase II trial, Phase III data are needed. The cytotoxic CaB market is already well established, so any therapy entering this market must show a signiÞcant advantage over standard treatments. Antimetabolites Overview. Although cytotoxic anticancer drugs are collectively the largest and most-established chemotherapy group, the agents in development have relatively poor clinical and commercial potential. A possible exception is pemetrexed (Eli Lilly’s Alimta). Mechanism of Action. Antimetabolites are incorporated into new nuclear material or combine irreversibly with vital cellular enzymes, such as those on the folate pathway, thereby preventing normal cellular division. The folate pathway is essential, by its provision of cofactors, to the de novo synthesis of DNA precursors (purines); compounds that inhibit this pathway interfere with DNA synthesis, thus causing tumor cell death. Previous generations of antifolates principally targeted a single pathway. For example, the antimetabolite/antifolate methotrexate inhibits dihydrofolate reductase, a key enzyme in the folate pathway, and 5-ßuorouracil (5-FU), combined with folic acid and raltetrexed (AstraZeneca’s Tomudex), inhibits thymidylate synthase, which is essential for de novo thymidine synthesis. Pemetrexed. Eli Lilly is developing a multitargeted antifolate/antimetabolite compound called pemetrexed (Alimta) (Figure 20). The compound exerts its antitumor activity by inhibiting multiple key enzymes involved in DNA synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide (GAR) formyltransferase. The company hopes pemetrexed’s multitargeted action will overcome the resistance acquired through the overexpression of any single enzyme. Pemetrexed was approved initially for malignant pleural mesothelioma in the United States in February 2004 and has since been approved in the United States and Europe as a second-line therapy for non-small-cell lung cancer (NSCLC). Pemetrexed is in Phase II trials for CaB in the United States and Europe. Phase II data on pemetrexed in combination with gemcitabine (Eli Lilly’s Gemzar) were disclosed at the 2004 ASCO meeting (Ma CX, 2004). Eligible patients must have been treated with both an anthracycline and a taxane, in either the adjuvant or metastatic setting, and with no more than one chemotherapy regimen for metastatic disease (unless a taxane and anthracycline). Fifty-nine patients were enrolled, with a median of 0–1 prior adjuvant chemotherapy regimens (0 = 8%; 1 = 92%) and 0–2 prior metastatic chemotherapy regimens

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(0 = 39%; 1 = 59%; 2 = 2%). Twenty-eight patients (48%) had also received prior hormonal therapy. Patients received a median of Þve cycles with a median follow-up of 426 days. Considering grade 3 and 4 toxicities, 48 (81%) patients had neutropenia (grade 3 = 11, grade 4 = 37), although only 7 (12%) had febrile neutropenia. Fifteen patients (25%) had thrombocytopenia (grade 3 = 13, grade 4 = 2). Grade 3 or 4 nonhematologic toxicities included 10 (17%) patients with dyspnea, 10 (17%) with fatigue, 4 (7%) with rash, 3 (5%) with nausea, and 3 (5%) with anorexia. Overall, 14 (24%) patients achieved a partial response with a median duration of at least Þve months. Nine (15%) had stable disease for six months or more, with a median of 334 days. Median time to progression was 3.8 months. Median survival was 10.3 months, and the one-year survival rate was 49%. Results of a Phase II study of single-agent pemetrexed in the neoadjuvant setting in patients with locally advanced disease were disclosed at the 2002 ASCO meeting (Gomez HL, 2002). Data were available on 59 of 61 patients: 20 patients achieved a partial response, for a preliminary overall response rate of 34%; 32 patients had stable disease; 6 patients had disease progression; and 1 patient was lost to follow-up. Based on these results, pemetrexed would not be able to compete with an anthracycline followed by a taxane regimen—a combination that elicits better response rates. A Phase II study evaluating the efÞcacy of single-agent pemetrexed as thirdline therapy in patients with metastatic CaB showed promising results in this poorprognosis group (Mennel RG, 2001). Fifty-eight patients received 500 mg/m2 pemetrexed by intravenous infusion for ten minutes every 21 days. Seventy-two percent of the patients had visceral metastases. No dose reductions or omissions were necessary in a total of 169 cycles administered; the median number of cycles was two (range = 1–18). Analysis of 42 evaluable patients revealed four partial responses with a median duration of 5.9 months. Thirty-eight percent of patients experienced stable disease with a median duration of 4.5 months. Of the patients who received vitamin supplements (folic acid and B12 ) to prevent toxicity, 10%, 30%, and 14% experienced grade 3 or 4 leukopenia, neutropenia, and elevated transaminases, respectively. A second Phase II trial involved 38 patients with locally recurrent or metastatic CaB who were treated with a higher dose of pemetrexed (600 mg/m2 every 21 days) (Miles DW, 2001). Thirty-three patients had had prior chemotherapy:

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16 adjuvant, 12 metastatic, and 5 in both settings. This trial achieved a higher response rate but at the expense of greater toxicity. The overall response rate was 28%, including one complete response. The median duration of response was 8 months, and median survival was 13 months. Of the patients, 47% suffered grade 3 or 4 neutropenia, and 16% suffered grade 3 or 4 thrombocytopenia. Nonhematologic toxicities (grades 2 or 3) included elevated transaminases (92%), vomiting (34%), and mucositis (32%). Pemetrexed could ultimately replace methotrexate in many neoadjuvant and adjuvant regimens in earlier disease. Given the drug’s signiÞcant toxicity and lack of advantage over existing agents, the agent may Þrst be approved as thirdor fourth-line therapy for advanced CaB. Cell-Cycle Inhibitors Overview. Researchers have identiÞed novel components of cell-cycle regulation as targets for chemotherapeutic intervention. Within this class are agents at all stages of development, including product failures. One failure was RO-317453, a novel oral cell-cycle inhibitor with activity against a wide range of human tumor cell lines and xenografts, including breast cancer and drug-resistant models. RO317453 causes cells to arrest in the pro-metaphase, disrupting mitotic spindle formation and apoptosis. In June 2003, at ASCO’s annual meeting, researchers presented data showing that RO-317453 was well tolerated but had limited clinical activity in patients with metastatic CaB who had failed on either taxane or anthracycline therapy (Trigo Perez JM, 2003). Roche discontinued work with this agent in September 2002. Roscovitine (Cyclacel’s CYC-202) is a cyclin-dependent kinase (CDK) inhibitor. In January 2003, Cyclacel initiated a Phase IIa clinical trial of roscovitine in combination with capecitabine in patients with advanced CaB. The study is evaluating the compound’s safety, pharmacokinetic proÞle, antitumor activity, and effect on biomarkers. However preclinical data show this compound to have low potency and unfavorable bioavailability. The agent that is the most advanced in development and that may propel this class into more clinical trials is Wyeth’s temsirolimus. We discuss this agent in more detail further on. Mechanism of Action. Progression through the cell cycle depends on numerous signaling pathways and checkpoints (e.g., the cyclin families of proteins, the CDKs). The deregulation of these key regulators of the cell cycle is observed in most cancer cells. The inhibition of these enzymes can result in cell-cycle arrest and, ultimately, cell death, usually by apoptosis. Temsirolimus. Wyeth’s temsirolimus (CCI-779) is an ester analogue of rapamycin with improved aqueous solubility and pharmacokinetic properties. Temsirolimus selectively inhibits the mammalian target of rapamycin (known as mTOR), a serine/threonine kinase, by binding to the cytosolic (FK506 binding)

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protein (FKBP), which subsequently inhibits mTOR. The inhibition of mTOR, a downstream mediator in the PI3K/Akt signaling pathway, blocks a number of signal transduction pathways that suppress translation of several key proteins regulating the cell cycle. These effects lead to a cell-cycle block at the G1 phase, preventing progression to the S phase. In breast cancer, the PI3K/Akt signaling pathway can be activated by membrane receptors, including the HER (or ERBB) family of growth factor receptors, the insulin-like growth factor receptor (IGF-R), and the estrogen receptor (ER), revealing the potential for synergy with other agents. In March 2002, based on promising clinical data, the FDA designated temsirolimus for fast-track development for second-line treatment of renal cell carcinoma (RCC). Temsirolimus is undergoing a U.S. Phase III trial for metastatic CaB. The U.S. multicenter, randomized, double-blind, placebo-controlled Phase III trial under way is examining 30 mg temsirolimus administered in combination with letrozole versus letrozole alone. The study is recruiting postmenopausal women with locally advanced or metastatic CaB. The study is estimated to last for 34 months, and all subjects will have the option of participating in the long-term follow-up phase of the trial that involves follow-up every three months until disease progression; the primary endpoint is overall progressionfree survival. Phase II data were presented at ASCO 2004 (Baselga J, 2004). The trial consisted of three arms of approximately 30 evaluable patients per arm: letrozole alone, letrozole with temsirolimus 25 mg daily (daily arm), or letrozole with temsirolimus 75 mg daily for Þve days every two weeks (intermittent arm). All patients received 2.5 mg letrozole daily. At the time of composing this reference, 55 patients had been enrolled. Initially, 6 patients had been enrolled on each of these two “high-dose” (HD) schedules, but 3 patients in each arm had toxicity that resulted in dose delay/reduction or discontinuation. The protocol was amended, and doses were reduced to “low-dose” (LD) schedules: 10 mg temsirolimus daily and 30 mg temsirolimus intermittently. The most frequently occurring grade 3 and 4 temsirolimus-related toxicities were stomatitis for the HD schedules (2/6 patients, 2/6 patients) and diarrhea for the LD schedules (0 patients, 1/7 patients). No grade 3 or 4 toxicities were reported in the letrozole alone arm. Of 55 patients, 7 had been on study for more than 40 weeks. Preliminary tumor responses are available for 19 evaluable patients. Temsirolimus patients (n = 13) had 1 CR (HD schedule), 3 PRs (HD schedule), 9 SDs (6 on HD schedule, 3 on LD schedule; SD at 24 weeks or beyond for 4 patients on HD schedule). Letrozole-alone patients (n = 6) had 2 PRs and 4 SDs (SD at 24 weeks or beyond for 1 patient). Phase II data in patients with stage III/IV CaB unresponsive to taxane- or anthracycline-based chemotherapy have been released (Chan S, 2003). Temsirolimus, at 75 mg or 250 mg, was administered weekly as a 30-minute IV infusion to 34 patients. Researchers noted two objective responses in measurable

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liver metastases in the Þrst 16 evaluable patients. Two patients in the study suffered grade 3 or 4 events, and at least 30% reported grade 1 or 2 events, which often resolved without discontinuing temsirolimus. In future, agents such as temsirolimus could be approved in combination with hormonal treatments. Currently, hormonal agents are not combined with chemotherapy or targeted agents because such combinations have appeared detrimental in terms of efÞcacy and toxicity. Vascular Endothelial Growth Factor Inhibitors Overview. Angiogenesis, the formation of new blood vessels, plays a major role in many normal physiological processes and in several pathological conditions, including solid tumor growth and metastasis. Investigators have detected vascular endothelial growth factor (VEGF) expression in tumor samples from 90% of CaB patients that involve four or more nodes (n = 124) (Gown A, 2001). VEGF expression was graded 3 or 4 in 36% of patients. Further, Þve-year overall survival was signiÞcantly lower among patients with high VEGF expression: 44% versus 67%. VEGF inhibition is an area of considerable commercial interest in the pharmaceutical industry. Agents within this class in early-phase development for CaB include AstraZeneca’s ZD-6474, EntreMed’s 2-methoxyestradiol (2-ME2), and Bayer’s sorafenib (BAY-43-9006). These agents are not included in our discussion because the data are still insufÞcient. Bevacizumab is covered in detail because it is the only VEGF inhibitor that has reached Phase III trials for CaB. Mechanism of Action. VEGF is a multifunctional cytokine and potent permeability factor that is secreted in response to hypoxia (reduced oxygen). The biological effects of VEGF are mediated by the binding of VEGF to one of three endothelial surface receptors: VEGF-R1 (ßt-1), VEGF-R2 (ßk-1/kdr), or VEGFR3; binding to the coreceptor neurophilin enhances signaling. VEGF has a major angiogenesis-promoting effect. Researchers hope that blocking this receptor will, in the best-case scenario, kill the solid tumor that depends on new blood vessel formulation for its survival or at least slow tumor growth by preventing new vessel formation and thus limiting the supply of blood. Bevacizumab. Bevacizumab (Genentech’s/Roche/Chugai’s Avastin) is a humanized monoclonal antibody (MAb) that prevents VEGF from binding to its receptors. Its lead indication is colorectal cancer, for which bevacizumab gained U.S. and EU marketing approval in February 2004 and January 2005, respectively. Bevacizumab is also in development for numerous other cancers; Phase III trials are ongoing in non-small-cell lung, renal cell, ovarian, pancreatic, and breast cancer. Numerous Phase II and III trials for bevacizumab in CaB are underway, including combinations with docetaxel with or without capecitabine in locally advanced or metastatic CaB, or with erlotinib in metastatic CaB.

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The trial that led to bevacizumab’s U.S. approval for colorectal cancer involved more than 900 patients with metastatic CRC. Researchers found that the adding bevacizumab to a standard-care regimen (5-FU/leucovorin/irinotecan) produced a statistically signiÞcant prolongation of time to disease progression (6.2 versus 10.6 months) and increased survival time by about Þve months (15.6 versus 20.3 months) (Hurwitz H, 2003).These Þndings exceeded the expectations of the study design. Trials have also shown that bevacizumab is active in previously treated patients with metastatic CaB (Hillan K, 2003). A Phase III, 462-patient trial of bevacizumab in patients with refractory metastatic CaB compared a combination of bevacizumab and capecitabine with capecitabine alone. Although no improvement in progression-free survival (the primary endpoint) was observed, a statistically signiÞcant increase in the secondary endpoint—objective response rate—was revealed (9.1% versus 19.8% by independent review; 19.1% versus 30.2% by investigator assessment). The adverse event proÞle in this study was similar to the observed events in Phase II studies and included venous thrombosis, hypertension, and asymptomatic proteinuria. No increase in serious bleeding occurred in the bevacizumab arm of the study. An ongoing Phase III trial is investigating the efÞcacy of bevacizumab combined with paclitaxel as Þrst-line treatment for locally recurrent or metastatic CaB. In April 2005, Genentech/Roche reported that a preliminary efÞcacy analysis of the study data was positive (Genentech/Roche, press release, April 2005). At that point, 722 patients were evaluated. No safety data were disclosed, although the companies reported that “adverse events appeared to be similar to those observed in previous clinical trial” and that bevacizumab-related events “included neuropathy, hypertension, and proteinuria. Serious bleeding and blood clots were rare in this study.” Preliminary Phase II data of bevacizumab in combination with erlotinib were disclosed at the ASCO meeting in 2004 (Dickler M, 2004). Erlotinib (150 mg orally/day) and bevacizumab (15 mg/kg IV every 3 weeks) was given to patients with metastatic CaB following one to two prior chemotherapy regimens. The primary endpoint was response rate; secondary end points included safety and time to tumor progression. Of the 13 patients enrolled at the time, 9 were evaluable for response. One patient had a conÞrmed PR (11%), 2 had SD at nine weeks (22%), 5 had PD (56%), and 1 (11%) withdrew from the study after one cycle because of an allergic drug eruption. Two patients (15%) experienced grade 4 toxicities: pulmonary embolus 1 (8%) and neutropenia 1 (8%). Toxicity potentially related to erlotinib and/or bevacizumab included rash (grade 2, 46%), diarrhea (grade 2, 23%), hypertension (grade 3, 15%), and nausea/vomiting (grade 3,: 8%). Phase II data of bevacizumab in combination with docetaxel were also presented at ASCO 2004, but the data were preliminary and efÞcacy data were not available (Overmoyer B, 2004). In a Phase II, monotherapy, dose-escalation study, 75 patients with previously treated metastatic CaB (median = 2 regimens) were treated with bevacizumab—3 mg/kg (18 patients), 10 mg/kg (41 patients), and 20 mg/kg (16

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patients)—once every two weeks (Cobleigh MA, 2001). At 22 weeks, 17% of the patients were responding or had stable disease; after 12 months, three patients were progression-free. Bevacizumab was well tolerated. No bleeding was reported in this trial, though 7% of patients developed thrombosis, 22% developed mild hypertension, and 15% developed proteinuria. It remains to be seen whether the mortality risk associated with these complications will deter clinicians from prescribing them to CaB patients who already have a good treatment outcome from older therapies. Epidermal Growth Factor Receptor Inhibitors Overview. The ERBB tyrosine kinase family includes four related transmembrane receptors: erbB1, also known as HER1 or EGFR; erbB2 (HER2); erbB3 (HER3); and erbB4 (HER4). Each receptor contains an extracellular binding region and an intracellular kinase. The HER3 kinase is defective; thus, signaling through HER3 requires heterodimerization with another EGFR family member. HER2 has no known natural ligand and, thus, also typically requires heterodimerization. However, at high concentrations, HER2 homodimers may signal even in the absence of ligand. Ligand binding results in homo- or heterodimer formation with activation of the associated receptor tyrosine kinase. Receptor activation triggers multiple intracellular pathways, including the mitogen-activated protein kinase (MAPK) and AKT/PI3K, that result in increased proliferation, resistance to apoptosis, and increased angiogenesis. Overexpression of HER2 proteins, which occurs in 22–28% of breast tumors, is associated with poor prognosis in CaB patients. Estimates of the prevalence of EGFR overexpression in breast tumors vary widely; the American Cancer Society estimates prevalence at 14–91%. Agents that target HER2 include the MAb trastuzumab and the EGFR tyrosine kinase inhibitors (described further on in this chapter). Vaccine approaches targeting HER2 are also the subject of investigation, as described later. Many EGFR inhibitors, especially EGFR1, have not shown promise in CaB treatment. Nevertheless, this class is of immense scientiÞc and commercial interest because of the success of trastuzumab and other agents in other cancer indications. Other agents being investigated for CaB include Takeda’s small-molecule inhibitor of HER2 tyrosine kinase, TAK-165. One more agent of considerable, yet controversial, interest is AstraZeneca’s EGFR1 inhibitor, geÞtinib (Iressa). The controversy surrounds postmarketing efÞcacy data in NSCLC that have failed to show improved survival. GeÞtinib is still in development for CaB. Mechanism of Action. EGFR is part of the ERBB family of receptors, which consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Binding to the receptor results in tyrosine kinase activity and receptor autophosphylation which then initiate signal transduction cascades implicated in cell proliferation. Drug intervention, either at the EGFR or the intracellular tyrosine kinase, blocks cell signaling pathways, thereby preventing proliferation and subsequent tumor growth.

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Lapatinib. GlaxoSmithKline’s lapatinib is an orally administered EGFR tyrosine kinase inhibitor that has the added beneÞt of blocking ErbB −2/HER2 tyrosine kinase. Because of lapatanib’s dual-acting properties, the agent might be used in a wider patient population. Lapatinib is undergoing two Phase III trials for CaB treatment in the United States. One trial is comparing capecitabine with or without lapatinib in refractory locally advanced or metastatic CaB. A total of 372 patients (186 per treatment arm) will be accrued for this study within 17 months. The primary endpoint is time to disease progression. The second Phase III trial is examining paclitaxel with or without lapatinib as a Þrst-line therapy for patients with advanced or metastatic CaB. The primary end point is time to disease progression. A total of 570 patients are planned for enrollment. Preliminary Phase II data were disclosed at the 2004 ASCO meeting (Blackwell KL, 2004). The primary objectives of this study were to assess the safety and efÞcacy of monotherapy Lapatinib at 1,500 mg daily in women with trastuzumabrefractory metastatic CaB. Eligible patients had ErbB2 overexpressing CaB with disease progression following either one or two prior trastuzumab-containing regimens. Preliminary efÞcacy results regarding the initial 36 patients include 3 PRs (8+ weeks, 16+ weeks, and 44 weeks) and 5 SDs (range = 12 − 36 + weeks). For 15 patients with preliminary safety data, adverse events considered by investigators to be drug-related were all grade 1–2 except for one grade 3 rash. For these 15 patients, drug-related adverse events observed in more than one patient were anorexia, nausea, rash, vomiting, diarrhea, and weight loss. Updated data were presented in December 2004 at the 27th Annual San Antonio Breast Cancer Symposium (Blackwell KL, 2004). At that time, 48 women had been enrolled. A total of 4 women responded to therapy, including 1 woman who achieved a complete response; 7 women were progression-free at 24 weeks. Preliminary Phase II data were also disclosed at the 2003 ASCO meeting but were available for only three patients (Kaplan EH, 2003). Patients with disease progression after one or two prior treatments with trastuzumab alone or in a combination chemotherapy regimen were administered lapatinib (1,250 mg daily). Inclusion criteria were stage IIIb or IV CaB, conÞrmation of erbB-2 overexpression prior to Þrst-line trastuzumab, Karnofsky performance status greater than 70, and normal left ventricular ejection fraction (LVEF). Preliminary side-effect data included reports of rash and diarrhea. No cardiac toxicity was reported. Pertuzumab. Genentech/Roche/Chugai’s next-generation HER2-directed MAb, pertuzumab (Omnitarg), inhibits HER2 dimerization. It is in Phase II clinical trials for a range of solid cancers, including CaB. A Phase III study is planned, although not yet recruiting, that will be a multicenter, open-label extension study available only to patients who have completed 17 cycles (approximately one year) of treatment with single-agent pertuzumab in a Genentech-sponsored Phase II cancer study. Eligible patients must have shown no signs of unacceptable pertuzumabrelated toxicity in the previous trial. Genentech claims that pertuzumab is the Þrst in a new class of targeted potential therapeutic agents known as HER dimerization inhibitors (HDIs). Such agents

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may have application in non-HER2-overexpressing cancers because binding of the antibody to the dimerization domain of HER2 directly inhibits the ability of HER2 (the most common pairing partner) to dimerize with other HER receptor proteins. Inhibiting receptor dimerization prevents the activation of HER signaling pathways. Only Phase I data have been reported so far. Twenty-one patients with locally advanced, recurrent, or metastatic solid tumors who had progressed during or after standard therapy were recruited to a dose-escalating Phase I study. Three patients had CaB. Nineteen patients received at least two cycles of pertuzumab at doses ranging from 0.5 mg/kg to 15 mg/kg. Pertuzumab was generally well tolerated, and a maximum tolerated dose was not reached in the study. The most common adverse events were asthenia (62%), vomiting (52%), nausea (48%), rash (43%), diarrhea (43%), and anemia (33%). The majority of cases were grade 1 or 2 in severity. However, after cycle 2, one patient suffered a myocardial infarction resulting in grade 4 left ventricular failure. Because of the cardiotoxicities associated with trastuzumab, the authors concluded that this may be a class effect, and great care would be needed throughout the clinical development of this agent. Two partial responses were seen in this heavily pretreated population—one in ovarian cancer and one in pancreatic cancer. Interestingly, neither were in patients whose tumors overexpressed HER2 (as measured by ßuorescent in-situ hybridization [FISH]). One unconÞrmed disease regression was noted in a patient with prostate cancer. Stable disease (2.5–5.5 months) was observed in a further six patients. Pharmacokinetic analysis showed that, in line with other antibody therapies, three-times-weekly administration of pertuzumab would be optimal. Pertuzumab’s novel mechanism of action will add insight to this complex area of molecular cell biology. Were it to demonstrate efÞcacy in an HER2-negative CaB population (approximately 75% of patients), it would have wide application in this indication. Erlotinib. Erlotinib (OSI-774/CP-358774/Tarceva), another EGFR tyrosine kinase inhibitor, is under development by OSI Pharmaceuticals in alliance with Genentech and Roche. This orally active quinazoline derivative is undergoing Phase II trials in the United States. Phase II trials being carried out on erlotinib include combinations with trastuzumab as a Þrst-line therapy in metastatic CaB associated with HER2/neu overexpression and with bevacizumab-treated metastatic CaB patients previously treated with one or two lines of therapy. Data disclosed at the ASCO meeting in 2003 revealed that an erlotinib/docetaxel/capecitabine combination was well tolerated (Bruno R, 2003). Nine of the 23 patients treated to date had conÞrmed partial responses. A further 4 patients had unconÞrmed partial responses, and there were 2 unconÞrmed complete responses. Preliminary Phase II data of erlotinib in combination with bevacizumab were disclosed at the ASCO meeting in 2004 (Dickler M, 2004). Erlotinib (150 mg orally/day) and bevacizumab (15 mg/kg IV every 3 weeks) was given to patients

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with metastatic CaB following one or two prior chemotherapy regimens. The primary endpoint was response rate; secondary end points included safety and time to tumor progression. Of the 13 patients enrolled at the time, 9 were evaluable for response. One patient had a conÞrmed PR (11%), 2 had SD at 9 weeks (22%), 5 had PD (56%), and 1 patient (11%) came off study after one cycle because of an allergic drug eruption. Two patients (15%) experienced grade 4 toxicities: pulmonary embolus (8%) and neutropenia (8%). Toxicity potentially related to erlotinib and/or bevacizumab included rash (grade 2, 46%), diarrhea (grade 2, 23%), hypertension (grade 3, 15%), and nausea/vomiting (grade 3, 8%). Gene Therapy and Antisense Overview. Researchers are keenly interested in the theoretical rationale for using gene therapy and antisense approaches to treat cancer, but these approaches have been studied for years without any signiÞcant progress. Despite anecdotal reports of therapeutic responses in some patients, there is still no unequivocal proof of clinical efÞcacy. The primary obstacle appears to be the transcription rates of the gene in vivo and the gene’s delivery to tumor sites. Mechanism of Action. The primary approach to gene therapy is to either replace or activate aberrant tumor-suppressor genes or to inactivate oncogenes by inserting the gene or antisense DNA using a vector (typically an attenuated virus such as an adenovirus). Advexin. Introgen’s Advexin is an adenoviral p53 gene therapy for the treatment of multiple tumors. In about 50% of cases of aggressive CaB, the p53 gene is mutated so that protein is no longer available in sufÞcient amounts to control cell growth. Loss of p53 is associated with more aggressive and resistant tumors, as well as early metastasis and reduced survival rates. Advexin is undergoing Phase II trials in the United States as a treatment for CaB. At ASCO in 2003, researchers presented preliminary Phase II data from nine patients with locally advanced CaB (Cristofanilli M, 2003). Given by intratumoral injection, Advexin was shown to be safely combined with a two-drug standard chemotherapy regimen, doxorubicin and docetaxel. Ninety percent of the patients had major responses to the therapy. Additional data from the trial were presented at the 2004 San Antonio Breast Cancer Symposium (Cristofanilli M, 2004). The addition of Advexin to the doxorubicin/docetaxel combination achieved an average of nearly 80% reduction in tumor size and an average of nearly 70% reduction in lymph node tumor size in all 12 patients with locally advanced breast tumors. Overall disease-free survival at 25 months was 83%, and overall survival at 25 months was 92%. Patients who received Advexin and chemotherapy achieved a greater reduction in tumor size than did those who were treated with chemotherapy alone. Despite this apparent success, for gene therapy to be considered a therapeutic option, randomized trials must be conducted. They will need to compare regimens

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that include gene therapy with standard chemotherapy regimens to determine whether the gene therapy actually contributes to the regimen’s efÞcacy. Vaccines Overview. Although the concept of tumor vaccines is a viable one, these therapies remain unproven in the treatment of cancer. Even if research proves that vaccines possess activity similar to that of cytotoxic agents, their uptake may be hindered by their high costs and reimbursement problems. Biomira/Merck KGaA’s Theratope (STn-KLH) is the most clinically advanced vaccine for CaB. Other vaccines include Pharmexa’s HER2 protein vaccine, AutoVac (PX-104.1), which is undergoing Phase II trials for metastatic CaB. Mechanism of Action. Cancer vaccines are designed to stimulate the immune system to launch a response against the speciÞc target contained by the vaccine. In general, research has shown that the most effective antitumor immune responses are achieved by stimulating T cells, which can recognize and kill tumor cells directly. Theratope. Biomira’s Theratope underwent a Phase III international trial in collaboration with Merck KGaA and Chiron, but both of these latter companies are no longer involved. Merck KGaA decided to discontinue its involvement with theratope in 2004 because additional trials were likely to be required to support registration. Biomira is seeking a collaborative partner prior to further development of theratope. Theratope comprises a synthetic Sialyl-Tn (STn) antigen linked to keyhole limpet hemocyanin (KLH) protein carrier; it is administered with Corixa’s DetoxB-adjuvant. In 2000, the FDA granted theratope fast-track status as an adjunct to Þrst-line combination therapy for metastatic CaB. The working hypothesis for this vaccine is that it stimulates an immune response to the tumor-associated STn epitope, thereby producing an anticancer effect. The STn epitope, expressed as part of the mucin-1 (MUC-1) glycoprotein, is associated with most types of adenocarcinoma. Although STn is expressed in some normal tissues, scientists believe its expression to be relatively tumorspeciÞc. A randomized Phase III trial of theratope followed up 1,030 women with metastatic CaB at 120 sites in the United States and Europe who had no evidence of disease progression following Þrst-line chemotherapy. Patients received intravenous low-dose cyclophosphamide on day 3, followed by four subcutaneous injections of either theratope or a control vaccine at 0, 2, 5, and 9 weeks. The control vaccine differed from theratope in not having the active STn cancer-associated antigen—it had the protein carrier. The women also received immunomodulatory low-dose cyclophosphamide to inhibit the suppressor T-cell response induced by shed cancer mucins. Data released in June 2003 and at the 2004 ASCO meeting showed that theratope had not met its primary

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end points: time to disease progression and survival (Biomira, press release, June 2003; Ibrahim NK, 2004). However, the data did show that one subset of patients—women on hormonal treatment followed by chemotherapy—appeared to have a favorable trend toward improvement in survival. Further analyses of these data are under way. Data on subset analysis of this Phase III trial were presented at the ASCO meeting in 2004 (Ibrahim NK, 2004). Of a planned accrual of 950 patients, 1,030 were enrolled and 1,028 randomized to receive either adjuvant chemotherapy plus Theratope (n = 523) or placebo (n = 505). Median duration of follow-up was 22.2 months. Median overall survival (MOS) was signiÞcantly greater in theratope-treated patients who received concurrent hormone therapy and who had high immune responses to naturally occurring clustered STn versus low immune responses (41.1 versus 25.4 months). MOS for patients in the hormonal subset without stratiÞcation into low versus high immunoresponse to naturally occurring clustered STn (n = 350) showed a statistically signiÞcant difference between the two treatment arms: women in the theratope arm (n = 180) survived a median of 36.5 months, while those in the control vaccine arm (n = 170) survived a median 30.7 months. Survival for women not receiving hormonal therapy did not differ signiÞcantly between the two treatment arms. Cyclooxygenase-2 Inhibitors Overview. Cyclooxygenase-2 (COX-2) is involved in carcinogenesis, tumor growth, and metastasis, and it is often overexpressed in premalignant and malignant lesions. Indeed, studies in CaB patients have shown that COX-2 expression is associated with a substantially worse clinical outcome (Ragaz J, 2003). Preclinical studies provided solid evidence that inhibiting this enzyme with selective COX-2 inhibitors could prevent carcinogenesis, slow the growth of established tumors, and enhance tumor response to radiation and chemotherapeutic agents without appreciably affecting normal tissue response to radiotherapy. PÞzer’s SC-236 is under preclinical development and has been studied in vitro in HER2 /neu-transfected breast tumor cell lines, alone and in combination with other agents. Researchers concluded from this work that a tyrosine kinase inhibitor that blocked HER2 /neu and EGFR in combination with a COX-2 inhibitor may elicit a better response in patients with CaB than either agent alone. Investigators have studied the effect of celecoxib (PÞzer’s Celebrex) on breast tumors in preclinical studies (Abou-Issa HM, 2000). Both Cornell Research Foundation and Collagenex have been granted patents protecting their methods for treating cancer with COX-2 inhibitors. Recent controversy has surrounded the COX-2 inhibitor class, and they have been associated with increased cardiovascular events. Indeed, the trial that initially identiÞed this problem was conducted in (colorectal) cancer patients. Cancer patients are particularly prone to thromboembolic events. This situation has led to massive uncertainty about the future of COX-2 inhibitors. We include them in our analysis for completeness, as clinical trials seem to still be ongoing.

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O

H2N S O

N

N CF3

H3C FIGURE 21. Structure of celecoxib (R1 = NH2 , R2 = CH3 ).

Mechanism of Action. The antitumor and chemopreventive mechanisms of COX-2 inhibitors have not been fully elucidated. Researchers theorize that these agents may exert their effect via tumor necrosis factor (TNF) and nuclear factor kappa beta (NFκβ) inhibition. Celecoxib. PÞzer’s celecoxib (Celebrex) (Figure 21) is registered in all seven markets for the treatment of rheumatoid arthritis and osteoarthritis, and it has been studied extensively as a chemopreventive agent in individuals with familial adenomatous polyposis (FAP). Celecoxib is undergoing various clinical trials for CaB, including Phase III trials in the United States and Spain, investigating it both as an adjunct to chemotherapy regimens for the treatment of advanced disease and as a neoadjuvant treatment. One ongoing U.S. and Spanish Phase III study is randomizing postmenopausal women at increased risk of developing CaB to receive exemestane with or without celecoxib. More than 5,000 patients are planned for project accrual. Another ongoing U.S. Phase III trial with a projected accrual of almost 7,000 CaB patients will compare the event-free survival of postmenopausal women with receptorpositive primary breast cancer when treated with exemestane versus anastrozole as adjuvant therapy with or without celecoxib. In one ongoing Phase II trial, celecoxib is being given with letrozole in a neoadjuvant setting to 20 patients; it is being compared with letrozole or exemestane (PÞzer’s Aromasin) alone (Toi M, 2003). The combination treatment has been well tolerated; however, despite one complete response, no signiÞcant difference between the groups was observed at this early stage. Phase II data were presented at the 2004 ASCO meeting (Chow LW, 2004). Three cycles of 5-FU, epirubicin, and cyclophosphamide (FEC), with or without celecoxib (400 mg bid), were given at three-week intervals to women with histologically proven, locally advanced CaB. A total of 31 patients with a median age of 45.6 years were enrolled (15 FEC, 16 FEC plus celecoxib). Response rates were as follows: FEC, 62.5% FEC plus celecoxib, 81.3% (complete response 18.8%, partial response 62.5%). In the FEC plus celecoxib arm, mean tumor size decreased from 4.25 cm to 2.04 cm. The regimens were well tolerated, and no clinical cardiac toxicity was detected. Among tumors that showed clinical

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response (n = 9) to the FEC/celecoxib combination, a signiÞcantly higher level of COX-2 gene expression was observed versus nonresponders (n = 6). In another Phase II trial, celecoxib is being studied in combination with exemestane in patients with advanced CaB; 30 patients have been enrolled so far. According to data reported at ASCO 2003, 9 of the 13 evaluable patients (69%) remained on therapy without disease progression at six months (Canney P, 2003). Of the 19 patients evaluable for response, 6 (31%) had a partial response, 8 (42%) had stable disease, and 5 (26%) had progressive disease, giving a clinical beneÞt (partial response plus stable disease) in 73% of patients. Four patients experienced gastrointestinal toxicity, three experienced hot ßashes/sweats, and one patient reported headaches. The combination of celecoxib and exemestane shows promising early activity and acceptable toxicity. This trial will continue until 53 patients are enrolled. Chemotherapy Potentiators Overview. Potentiators of chemotherapy are agents intended to increase the efÞcacy of existing cytotoxic anticancer agents via a number of different mechanisms. Agents that inhibit the DNA repair enzymes that reduce the efÞcacy of DNA-damaging agents are under extensive preclinical study as potentiating agents. We restrict our discussions in this class to YM BioSciences’ tesmilifene because it is the most advanced in clinical development. Mechanism of Action. According to the theory of how intracellular histamine receptor ligands exert their cell-proliferative action, intracellular histamine mediates DNA and protein synthesis. This action may be caused by the downregulation of growth-inhibitory prostaglandins. Increased expression of intracellular histamine receptors may also be present in tumor cells. Antagonism of the intracellular action of histamine at intracellular histamine receptors by selective antihistamines may disrupt growth of malignant cells. Tesmilifene. YM BioSciences/Shin Poong’s small-molecule antihistamine agent tesmilifene is undergoing Phase III clinical trials in the United States and Europe as a treatment for CaB. A Phase III trial involving 305 patients with metastatic CaB has been completed (Reyno L, 2004). The trial compared the addition of tesmilifene to doxorubicin with anthracycline monotherapy. The Þnal analysis was conducted as planned after 256 progression events (median follow-up = 20.5 months). There was no signiÞcant difference between arms in response rate, response duration, or the primary end point, progression-free survival. The study was closed to additional accrual and the tesmilifene arm was discontinued. The researchers did Þnd that patients receiving the tesmilifene/doxorubicin combination had improved median survival of 23.6 months, versus 15.6 months for those receiving the anthracycline alone. Tesmilifene/doxorubicin was associated with more gastrointestinal and CNS toxicity than doxorubicin alone. No consistent inßuence on quality of life was detected.

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Despite these negative data, a registrational Phase III trial with tesmilifene in 700 patients with metastatic CaB or recurrent local disease was initiated in the United States and Western Europe in March 2004. The trial will compare the overall survival times of patients receiving tesmilifene in combination with epirubicin (PÞzer’s Ellence, generics)/cyclophosphamide with the survival period of patients taking epirubicin/cyclophosphamide alone. The primary end point of this pivotal trial is survival.

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Cervical Cancer

ETIOLOGY AND PATHOPHYSIOLOGY Background Cervical cancer (CaC) afßicts approximately 44,000 women each year in the major markets under study (United States, France, Germany, Italy, Spain, United Kingdom, and Japan), making it the fourth most common female malignancy. In many developing countries in sub-Saharan Africa, Central and South America, and south and southeast Asia, CaC is the most common lethal female cancer, and its incidence in these countries continues to increase. Developing countries now account for approximately 80% of CaC cases. The increase in incidence is primarily the result of lack of awareness of the disease and its outcome as well as lack of national screening programs for the detection of early, precancerous cervical changes, and HPV infection. In Western countries, screening programs have been credited with reducing CaC incidence by 74% (Peto J, 2004). Diagnosis of CaC is made following cytological analysis of Pap smears (described further on) and conÞrmed by biopsy. Occasionally, an incidental diagnosis of CaC may be made during a hysterectomy. For our purposes, the deÞnition of CaC refers to invasive carcinoma only. Invasive CaC is conÞrmed when cervical cancer cells are found deep within the tissue of the cervix rather than on the surface of the cervix only (known as cervical cancer in situ). A detailed diagnosis of CaC is made according to the deÞnitions of the 1994 International Federation of Gynecology and Obstetrics (FIGO) clinical staging system, detailed in Table 1, Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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297

TABLE 1. Carcinoma of the Uterine Cervix: FIGO Clinical Staging System Stage 0 Stage I Stage 1a

Stage Ia1 Stage Ia2 Stage Ib Stage Ib1 Stage Ib2 Stage II Stage IIa Stage IIb Stage III

Stage IIIa Stage IIIb Stage IV

Stage IVa Stage IVb

Carcinoma in situ, cervical intraepithelial neoplasia (CIN) grade III. The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded). Invasive carcinoma that can be diagnosed only by microscopy. All macroscopically visible lesions—even with superficial invasion—are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0 mm and a horizontal extension no wider than 7.0 mm. (Depth of invasion should be no greater than 5.0 mm taken from the base of the epithelium of the original tissue superficial or glandular. The involvement of vascular spaces—venous or lymphatic—should not change the stage designation.) Measured stromal invasion no greater than 3.0 mm in depth and extension no wider than 7.0 mm. Measured stromal invasion greater than 3.0 mm and no greater than 5.0 mm with an extension no wider than 7.0 mm. Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA. Clinically visible lesions no greater than 4.0 cm. Clinically visible lesions greater than 4.0 cm. Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina. No obvious parametrial involvement. Obvious parametrial involvement. The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are due to other causes. Tumor involves lower third of the vagina, with no extension to the pelvic wall. Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney. The carcinoma has extended beyond the true pelvis, or has involved the mucosa of the bladder or rectum (biopsy-proven). (A bullous edema, as such, does not permit a case to be designated as stage IV.) Spread to adjacent organs. Spread to distant organs.

FIGO = International Federation of Gynecology and Obstetrics. Source: Benedet JL, et al. Carcinoma of the cervix uteri. Journal of Epidemiology and Biostatistics. 2001;6(1):5–44.

which are based on criteria relating to tumor diameter and depth of invasion; invasion outside of the uterus; involvement of the pelvic wall, parametrium, bladder, kidney, and rectum; and spread to distant organs. Anatomy The uterine cervix is the lower, narrow tip of the uterus that extends into and joins the vagina, as shown in Figure 1. It is conical in shape and projects through the anterior wall of the vagina, which divides it into an upper portion, called the endocervix, and a lower, vaginal portion called the ectocervix. The endocervix is separated in the front from the bladder by Þbrous tissue called the parametrium, within which lie the uterine arteries. On the rounded extremity of the ectocervix

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Fallopian tube

Secrum

Ovary Uterus Bladder Cervix Vagina

Rectum Anus

FIGURE 1. Female reproductive system showing position of the uterine cervix.

is a small circular aperture called the external oriÞce of the uterus. Externally, the oriÞce is bounded by two lips, called the anterior and posterior lips. The cervix is made up of epithelium and underlying stroma. The stroma contains both smooth muscle and Þbrous tissues. The ectocervix is lined with squamous epithelium, which comprises several layers: basal, parabasal, intermediate, and superÞcial. The basal layer is a single row of cells on a thin basement membrane; active mitosis occurs in this layer. The superÞcial layer varies in thickness, depending on the degree of estrogen stimulation. The response of the epithelium to sex hormones is identical to that of the vagina. The endocervix is covered by mucin-secreting, simple, columnar epithelium, which lines the surface. The border of the endocervix and ectocervix is located between the stratiÞed squamous epithelium of the ectocervix and the columnar epithelium of the endocervix and is called the squamocolumnar junction. During sexual development, under the inßuence of hormones, the endocervix progresses onto the ectocervix and lies within the vagina. Under the inßuence of vaginal secretions, the endocervix undergoes transformation from columnar to squamous epithelium. The majority of cervical tumors arise at the transformation zone. Etiology Risk Factors. All sexually active women are at risk for CaC. The most important risk factor for the development of CaC is infection with human papilloma virus, or HPV, which is transmitted through genital-to-genital sexual contact. Researchers estimate that as much as 99% of CaC cases are related to persistent HPV infection. However, other, secondary factors play a role because most cases of HPV infection have no clinical manifestation and regress spontaneously. Even the majority of cases of HPV-induced cellular neoplasia or abnormalities do not progress to invasive cancer; approximately one-third of these cases will become CaC. No apparent underlying genetic or hereditary basis exists for the development of CaC. Infection with Human Papillomavirus. Papillomaviruses are small, doublestranded DNA viruses encased in a protein capsid that contain a circular genome consisting of approximately 7,900 base pairs. The HPV-16 genome (Figure 2)


Regulatory noncoding region LCR

299

Transforming proteins E6

E7

Major capsid protein L1 E1 Replication HPV 16

Major capsid protein L2 E2 Replication and transcription E5

FIGURE 2. HPV-16 viral genome structure.

TABLE 2. Prominent Proteins of the Human Papillomavirus Genome and Their Functions Protein E1 E2 E6 E7 L1 L2

Function/Comments DNA-dependent ATPase. Allows unwinding of the viral genome and acts as an elongation factor for DNA replication. Regulates viral DNA transcription and replication. Involved in transformation of the host cell by binding p53 tumor suppressor protein. Transforming protein, binds to retinoblastoma protein pRB/p107. Major capsid protein. Can form virus-like particles. Minor capsid protein. Possible DNA packaging protein.

has three regions: the upstream regulatory region (URR), the early (E) region, and the late (L) region. The E region is divided into seven areas that code for different proteins important at various stages during the life cycle and crucial for viral replication (see Table 2). E6 and E7 produce the proteins that cause malignant cellular transformation and oncogenesis and therefore represent targets for therapeutic intervention. The HPV E6 gene encodes a small 16–19 kDa basic protein, E6, which is expressed in the nuclear matrix. The E6 protein encoded by high-risk HPV types interacts with the host p53 tumor suppressor protein and disrupts p53’s normal function by causing its degradation. Absence of functional p53 protein prevents the activation of p53-mediated apoptosis and makes the cell highly susceptible to DNA damage. To associate with p53, the E6 protein requires a cellular protein called E6-associated protein (E6-AP). Like other oncogenic virus proteins, such as SV40 large T antigen and adenovirus E1A, E6 proteins of high-risk HPV abrogate the ability of wild-type p53 to activate transcription. However, the mechanism of the E6 protein’s action is different from that of SV40 large T antigen and the adenovirus E1A protein. The E6 protein causes degradation of p53, whereas the other oncogenic proteins interact with p53 and disrupt its function

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without degrading the protein. Research has shown that E6-dependent degradation of p53 occurs through the cellular ubiquitin proteolysis pathway (Werness BA, 1990). The HPV E7 gene is expressed together with the E6 gene as a part of early transcription. The E7 protein has transforming and transcriptional regulatory functions (Barbosa MS, 1989). It controls the cell cycle by interacting with the tumor suppressor retinoblastoma (Rb) protein P105 and other Rb-associated proteins, such as P107 and P130, displacing the E2F transcription factor (Chellappan S, 1992). This action results in the unregulated activation of the cell cycle in the infected cell. The E6 and E7 proteins are invariably expressed in HPV-associated tumors (zur Hausen H, 2002). The absolute requirement for continued expression of E6 and E7 genes to maintain the HPV transformed (or cancerous) phenotype makes these proteins extremely attractive targets for immunotherapy of cervical tumors. Several strategies are being used to induce host immunologic responses against these proteins, including (1) recombinant vaccinia vectors that express E6 and E7 genes, (2) soluble recombinant proteins with adjuvant, and (3) synthetic peptides that represent the appropriate epitopes. Because both transforming genes are expressed from the same messenger RNA (mRNA), this transcript has become a target for gene inhibition therapies. Natural infection of humans by HPV does not appear to provoke strong antibody responses against E6 and E7 proteins; antibody responses against E6 or E7 proteins from HPV-16 are most prevalent in patients with advanced CaC but appear to have little prognostic or therapeutic value (Frazer IH, 1996). About 100 types of HPV have been described, which have been numbered in the order of their discovery. An HPV type is considered new when at least 10% of the gene sequences in the HPV regions E6, E7, and L1 (Figure 2) differ from any previously known type. Each type of HPV has an afÞnity for particular types of epithelium. Oncogenic potential varies among subtypes, and this variation is reßected in the E6 and E7 proteins. Low-risk HPVs have a much smaller capacity than high-risk HPVs to induce malignant transformation, owing to functional differences between their E6 and E7 proteins. Approximately 30 types of HPV are known to infect the anogenital tracts of both sexes; of these, types 16, 18, 31, and 45 have the highest risk of causing CaC (Hwang TS, 2003; Munoz N, 2003). The E6 and E7 proteins of HPV types 16 and 18 are attractive targets for the development of both preventive and therapeutic vaccines and antisense therapies. Sexual Activity Under Age 18 Years. Becoming sexually active at an early age is associated with an increased risk of CaC (Zarama Marquez FA, 2003). This risk is the result of increased fragility of developing cervical cells in younger women, making the cells more liable to damage during sexual intercourse. This damage may make them more susceptible to HPV infection. Teenagers who smoke in addition to having early sexual intercourse further increase their risk of developing CaC (Zarama Marquez FA, 2003; Berrington de Gonzalez A, 2004).


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Multiple Sexual Partners. An increase in the incidence of HPV infection and CaC has been found in women who have multiple sexual partners (Zarama Marquez FA, 2003; Berrington de Gonzalez A, 2004), primarily because it increases the likelihood of sexual interactions with a male carrier of HPV. Therefore, the incidence of HPV in the male population is a factor that affects the incidence of HPV infection in women and, ultimately, the incidence of CaC. In addition, the incidence of sexually transmitted diseases (STDs) generally is higher in women who have multiple sexual partners, and cervical neoplasia may develop following a sexually transmitted infection. Teenagers are particularly at risk for STDs. Women who have only one sexual partner may still be at increased risk if their partners have many sexual contacts (Castellsague X, 2003). Cigarette Smoking. Women who smoke cigarettes have a higher risk of CaC than nonsmokers (Minkoff H, 2004; Eifel PJ, 2002; Berrington de Gonzalez A, 2004). Although certain chemicals from cigarette smoke have been found in cervical tissue, it remains uncertain whether cigarette smoke exerts a direct carcinogenic effect. Also important may be the fact that the immune system is often impaired in smokers, making these women more susceptible to infection by HPV. Immunosuppression. As with all infectious diseases, people who are immunocompromised are at higher risk of infection. Groups at high risk for HPV infection, and therefore CaC, include women who carry the HIV virus; the correlation between HIV infection and development of CaC is so strong that infected women are advised to undergo a Pap smear every six months. HIV-infected women who develop CaC tend to exhibit very aggressive disease (Ahdieh-Grant L, 2004). Socioeconomic and Ethnic Factors. The incidence of CaC is higher in economically disadvantaged women, a population that often includes ethnic groups such as African-Americans and Hispanics (Bazargan M, 2004; Singh GK, 2004). This increase in incidence results from the lack of awareness, the lack of health insurance, and the consequent low uptake of Pap screening. Other factors that discourage women from undergoing Pap screening include cultural inßuences and the stigma of HPV as an STD. Pathophysiology Following infection by HPV, preinvasive cancer may develop over a period of months to years. As much as two-thirds of cases of severe neoplasia (CIN3, carcinoma in situ) will progress to invasive CaC if left untreated (Paraskevaidis E, 2002). Progression is slow. It can take 3–30 years from HPV infection to the development of invasive cancer; on average, it takes ten years (Table 3). The degree of neoplasia is determined by the extent of mitotic activity and proliferation index of immature cells and abnormal cell nuclei. If these aberrations are detected only in the lower third of the epithelium, the lesion is designated cervical intraepithelial neoplasia grade 1 (CIN1). Lesions that also involve the

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TABLE 3. Characteristics of Progression from Cervical Intraepithelial Neoplasia to Cervical Cancer Grade of Neoplasia CIN 1–2 CIN 3 Microinvasion

Median Age

Median Time to Progression

Cases That Progress to Cervical Cancer (%)

22 28 41

7 years to carcinoma in situ 7–10 years to microinvasion 2 years to invasive carcinoma

50 66 100

CIN = Cervical intraepithelial neoplasia.

middle third or the upper third are termed CIN2 and CIN3, respectively. The designation adenocarcinoma in situ is used when normal endocervical epithelial cells are replaced by irregular columnar cells with increased mitosis but there is no obvious stromal invasion. More than 90% of invasive CaC cases are squamous-cell carcinomas, which originate in the cell lining of the lower cervix; another 5% are adenocarcinomas, which originate from glandular-type cells in the endocervix. Researchers have identiÞed several subtypes of adenocarcinoma and estimate the distribution of these subtypes as follows: endocervical (60%), endometrioid (10%), clear-cell carcinomas (10%), and adenosquamous carcinoma (20%). The adenocarcinomas tend to be more difÞcult to diagnose and are more aggressive in nature, but they are managed primarily in the same way as CaC of squamous-cell origin. The remaining 5% of invasive CaC cases are rare and include small-cell carcinomas and cervical sarcomas; both have a poor prognosis. CaC is staged in all major markets according to the FIGO guidelines, established in 1994 and subject to regular review (Benedet JL, 2003) (Table 1). This staging system has also been adopted by the National Comprehensive Cancer Network (NCCN). The network published its version of FIGO guidelines in 2003 (www.nccn.org). The American Joint Committee for Cancer (AJCC) has developed a TNM classiÞcation system for CaC that deÞnes stage groupings. Between 80% and 90% of cervical carcinomas are of squamous origin, and approximately 95% of these carcinomas originate in the transformation zone (see “Anatomy,” above). For this reason, the whole transformation zone should be sampled in a Pap smear to enable accurate interpretation. The cells taken during a Pap smear include cells from the epithelium of the ectocervix and the endocervix. The proportion of squamous-cell carcinomas to cervical adenomas is declining, resulting in an apparent increase in adenomas. This effect is attributed to the increased sensitivity of Pap smears for detecting squamous-cell carcinomas. Squamous carcinomas can be classiÞed as large-cell keratinizing, large-cell nonkeratinizing, or small-cell. Most experts believe that small-cell carcinomas have a poorer prognosis than the other types. Rarely, anaplastic small-cell carcinomas are diagnosed; these carcinomas resemble oat-cell carcinoma of the lung and frequently have neuroendocrine features. Anaplastic small-cell carcinomas of the cervix are extremely aggressive and have a poor prognosis—less than 50% survival, even for patients diagnosed with stage I disease.

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TABLE 4. Survival by Stage of Cervical Cancer FIGO Stage Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IVa Stage IVb

Five-Year Survival >95% 80–90% 75–80% 60% 40–65% >20% 5–20%

FIGO = International Federation of Gynecology and Obstetrics.

Approximately 80% of adenocarcinomas of the cervix originate in the endocervical glandular epithelium. The remaining 20% of tumors are endometreoid, clear cell, intestinal cell, or of mixed origin; these tumors are sometimes difÞcult to differentiate from cancers of ovarian or endometrial origin. CaC may invade the lymphatic system, spreading initially to local lymph nodes within the pelvis and ultimately to the aortic lymph nodes and lymph nodes in the groin. Local spread of the cancer to the outer vagina and vulva is common. Distant metastases may also arise, disseminated via the bloodstream; distant metastases typically manifest in the lungs, liver, and brain. In CaC, survival rates correlate with tumor stage. The prognosis for patients with early disease is good when they are treated with surgery and/or radiotherapy. For bulky tumors and disease that has spread to the lymph nodes, cure rates are lower, despite treatment with surgery and/or radiochemotherapy (Table 4). The outlook for patients with metastatic disease is bleak, and although treatment may result in a small survival beneÞt, it is largely palliative. The FIGO staging system incorporates additional prognostic factors. Survival correlates with disease characteristics such as the following: • • • •

Tumor diameter in early disease. Tumor bulk in advanced disease. Unilateral or bilateral involvement of the pelvic wall. Lymph node involvement (size and number).

Other prognostic factors include posthysterectomy invasion of the lymph-vascular space, which worsens prognosis and histologic tumor type (Eifel PJ, 1994; Logsdon MD, 1999). One analysis demonstrated that the risk of death associated with adenocarcinoma is almost twice the risk associated with squamous-cell carcinoma (Eifel PJ, 1995). CURRENT THERAPIES Surgery is the mainstay of treatment for early-stage, localized cervical cancer (CaC). Radiotherapy, in the form of external beam radiation (EBT), is employed

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at all stages. The utility of cytotoxic chemotherapy in patients with locally advanced, metastatic, or recurrent disease has been investigated in clinical trials with a variety of study designs. These designs include neoadjuvant chemotherapy, administered prior to surgical resection or radiation; concomitant chemotherapy and radiation, in which both modalities are administered together; adjuvant chemotherapy, in which surgery or radiation is followed by chemotherapy; and palliative chemotherapy for patients with widely disseminated tumor not suitable for palliative radiation. Cisplatin (Bristol-Myers Squibb’s [BMS’s] Platinol-AQ, Nippon Kayaku’s Randa, generics) is the agent of choice for pharmaceutical treatment of CaC. Its single-agent activity has produced response rates of 18–31% in multiple trials conducted in more than 900 patients. In advanced disease a study adding topotecan to the standard regimen of single agent cisplatin administered every 3 weeks resulted in a highly signiÞcant prolongation of survival (9.4 versus 6.5 months). In addition, this combination was found to be well tolerated and not associated with a decrease in quality of life. Interestingly, the response rate (13%) to cisplatin alone in this trial was surprisingly low and was most likely related to the new era of upfront chemo-radiation treatments. Long HJ, Bundy BN, Grendys EC et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Journal of Clinical Oncology 2005;23:4626–4633. It has been used for palliative treatment of metastatic, locally advanced, and recurrent disease for several decades. Clinicians use either single-agent cisplatin or cisplatin in combination with other agents; combination therapy increases response rates (and usually toxicity) but does not greatly affect survival. Increasingly, cisplatin is used in addition to radiotherapy and in bulky nonmetastatic disease. Cisplatin-containing regimens are now used in all but very early-stage disease, either as an adjuvant to surgery or as Þrst-line treatment in more extensive, inoperable disease contained within the pelvis (stages IIB–IVA). Five out of six trials demonstrate a survival advantage for cisplatin-based, concurrent chemoradiotherapy compared with non-cisplatin-based chemoradiotherapy or radiotherapy alone (Rose PG, 1999). The use of systemic cisplatin in addition to radiotherapy is thought to reduce the likelihood of distant as well as local relapse. The data from trials of concurrent cisplatin and radiotherapy (Whitney C, 1999; Morris M, 1999; Rose PG, 1999; Keys HM, 1999; Peters WA, 2000; Thomas GM, 1999) prompted the National Cancer Institute (NCI) to release a clinical announcement supporting the concurrent use of cisplatin-based chemotherapy with radiotherapy for high-risk, early-stage, and locally advanced CaC (Loizzi V, 2003). Women with CaC for whom treatment with radiotherapy is being considered should be offered concurrent cisplatin with their course of radiotherapy. These patients include the following: • • •

Patients with locally advanced cervical cancer. Patients with bulky, clinical stage IB (greater than 4 cm) CaC. Patients who are treated with radiotherapy.

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Patients with high-risk, early-stage CaC (node-positive or margin-positive). Patients who will be treated with radiotherapy following hysterectomy.

Neoadjuvant treatment that incorporates cisplatin is used increasingly to raise the possibility of performing curative surgery. However, numerous trials have failed to show a beneÞt from using cisplatin prior to radiotherapy in bulky stage IB and II disease—indeed, some trials have shown a reduction in survival using this regimen. Table 5 lists the most commonly used regimens for the treatment of CaC. Cisplatin Single-Agent Regimen Overview. Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) is the most-established single agent for the treatment of metastatic CaC (mCaC), producing response rates of up to 25%. U.S. national guidelines recommend its use in conjunction with radiotherapy for CaC stages Ib through IVa. This combined treatment modality is also used extensively in the treatment of earlier stages of CaC. In mCaC, response rates are signiÞcantly higher when cisplatin is used in combination with other cytotoxic agents: up to 46%. However, improved survival in mCaC patients also has been reported using a combination of cisplatin with topotecan (Long H, 2004). In an attempt to determine an optimal cisplatin combination, four combinations are being investigated in a randomized Phase III trial. Clinicians interviewed note that single-agent cisplatin is not included in this trial because of the evidence showing better response rates with combinations. Cisplatin is also becoming widely established as a radiosensitizer and in some cases is replacing both radiotherapy alone and surgery. No randomized trials have compared different cisplatin-based regimens, but a widely accepted schedule is 40 mg/m2 (maximum of 70 mg/week) intravenous (IV) given weekly with concurrent radiotherapy at 1.8–2.0 Gy daily, Þve days a week for six weeks. At this modest dose level, cisplatin is considered to be a radiosensitizer, although some clinicians claim it will still have a cytotoxic effect on both local and occult distant disease. Typically, when cisplatin is used in the absence of radiotherapy, a standard dose of 100 mg/m2 IV is given every three weeks. Mechanism of Action. Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive, charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and less importantly, protein crosslinking of DNA. These cross-links inhibit transcription and/or DNA replication


306

TABLE 5. Current Regimens Used for Cervical Cancer Regimen

Regimen Components

Availability

Dose mg/m2

Cisplatin single agent

Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics)


IV weekly (with 40 radiotherapy) 100 mg/m2 IV every 3 weeks

Cisplatin plus 5-fluorouracil (5-FU)



Cisplatin 70 mg/m2 IV day 1



5-FU 1,000 mg/m2 /day IV continuous infusion days 1–4

Cisplatin plus 5-fluorouracil (5-FU) plus hydroxyurea





Hydroxyurea (BMS’s Hydrea/Litalir, generics)

US, F, G, UK, J

Two cycles with radiotherapy and 2 cycles following completion of radiotherapy Cisplatin 50 mg/m2 IV days 1, 29

5-FU 1,000 mg/m2 /day IV continuous infusion days 1–4 and 29–32 Hydroxyurea 2,000 mg/m2 oral, twice weekly 2 hours before radiotherapy, weeks 1–6

Common Toxicities Leukopenia Nausea and vomiting Hearing loss (100 mg/m2) Neurotoxicity (100 mg/m2 ) Leukopenia Granulocytopenia Nausea and vomiting Diarrhea

Leukopenia Gastrointestinal toxicity Nausea and vomiting

TABLE 5. (continued) Regimen Cisplatin plus topotecan

Cisplatin plus ifosfamide

Carboplatin plus ifosfamide

Cisplatin plus paclitaxel

Regimen Components

Availability

Dose mg/m2

Common Toxicities

307



Cisplatin 50

IV day 1

Topotecan (GSK’s Hycamtin)




Topotecan 0.75 mg/m2 days 1–3 Repeat cycle every 3 weeks Cisplatin 50 mg/m2 IV day 1

Ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics)


Carboplatin (BMS’s Paraplatin, generics)


Ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics)




Paclitaxel (BMS’s Taxol, generics)


Ifosfamide 1,000 mg/m2 IV continuous infusion over 24 hours day 1 (with mesna 6,000 mg/m2 ) Repeat cycle every 3 weeks Carboplatin IV AUC = 4, day 1

Ifosfamide 1,600 mg/m2 IV continuous infusion over 24 hours day 1 (with mesna 6,000 mg/m2 ) Repeat cycle every 3 weeks Cisplatin 75 mg/m2 IV day 2

Paclitaxel 135 mg/m2 IV day 1 Repeat cycle every 3 weeks

Neutropenia Anemia Nausea and vomiting

Neutropenia Leukopenia Thrombocytopenia Nausea and vomiting Neurotoxicity

Neutropenia Leukopenia Thrombocytopenia Nausea and vomiting

Neutropenia Leukopenia Thrombocytopenia Nausea and vomiting Diarrhea

308 TABLE 5. (continued) Regimen Cisplatin plus gemcitabine

Paclitaxel plus ifosfamide plus cisplatin (TIP regimen)

Regimen Components

Availability

Dose mg/m2

Common Toxicities



Cisplatin 75

Gemcitabine (Eli Lilly’s Gemzar)


Paclitaxel (BMS’s Taxol, generics)


Gemcitabine 1,250 mg/m2 IV days 1 and 8 Repeat cycle every 3 weeks Paclitaxel 175 mg/m2 IV day 1

Ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics) Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics)


Ifosfamide 5,000 mg/m2 IV day 1


Cisplatin 75 mg/m2 IV day 1 Repeat cycle every 3 weeks

US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan. AUC = Area under the curve; IV = Intravenous; PO = By mouth. BMS = Bristol-Myers Squibb; GSK = GlaxoSmithKline.

IV day 2

Neutropenia Leukopenia Gastrointestinal toxicity Anemia Granulocytopenia

Neutropenia Leukopenia Thrombocytopenia Nausea and vomiting Diarrhea

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mechanisms. The principal sites of reaction are the N7 atoms of guanine and adenine. The formation of intrastrand cross-links between cisplatin and neighboring guanines has been shown to correlate with clinical response. When used in conjunction with radiotherapy, cisplatin may also act as a radiosensitizer. Possible mechanisms of radiosensitization include inhibition of repair of sublethal radiation damage and synchronizing tumor cells into a radiosensitive phase of the cell cycle. Clinical Performance. Two pivotal, randomized, Phase III clinical studies investigated single-agent cisplatin with concurrent radiotherapy. The Þrst, the Gynecologic Oncology Group’s GOG120 study (Rose P, 1999), recruited 176 patients with stage IIB, stage III, or stage IVA disease, without para-aortic lymph-node involvement, to receive treatment with a control regimen or one of two investigational treatments. The control arm (177 patients) was treated with hydroxyurea and concurrent radiotherapy. The Þrst investigational arm recruited 174 patients who received 40 mg/m2 cisplatin weekly and concurrent EBT, at 1.8–2.0 Gy daily, Þve days a week for six weeks. The second investigational arm included 173 patients who received cisplatin, 5-ßuorouracil (5-FU), and hydroxyurea with concurrent radiotherapy. The results showed that the relative risk of recurrence for patients treated with cisplatin/EBT was 0.57 (95% conÞdence intervals: 0.42–0.78), and the relative risk of death was 0.61 (95% conÞdence intervals: 0.44–0.85) compared with the hydroxyurea/radiotherapy treatment. Progression-free survival at two years was 67% versus 47%. The frequency of adverse events was similar in the cisplatin/EBT arm and in the control arm; the most important toxicity was hematologic. In the three-drug combination arm, the clinical beneÞt achieved was similar to that of the cisplatin/EBT arm, but both hematologic and gastrointestinal toxicities occurred signiÞcantly more frequently (Rose PG, 2003). The authors concluded that single-agent cisplatin should be added to radiotherapy for this patient population and should replace the older agent, hydroxyurea, in this setting. The second study, GOG123, recruited patients from 1992 to 1997 with stage IB bulky (greater than 4 cm) disease and compared radiotherapy with cisplatin (183 patients) or without cisplatin (186 patients), followed by hysterectomy (Keys HM, 1999). Patients received 40 mg/m2 cisplatin weekly for a maximum of six doses. Relative risks of progression and death when treatment included cisplatin were 0.51 (95% conÞdence intervals: 0.34–0.75) and 0.54 (95% conÞdence intervals: 0.34–0.86), respectively. The three-year survival rates were 83% for radiotherapy/cisplatin treatment and 74% for radiotherapy alone. In the combined therapy arm, patients had a higher rate of hematologic toxicity (21% versus 2%) and gastrointestinal toxicity (14% versus 5%). These data conÞrm the beneÞt of concurrent cisplatin and radiotherapy for the treatment of early-stage, bulky disease. Overall, the risk of death from CaC fell 30–50% with concurrent, cisplatinbased chemoradiotherapy compared with radiotherapy alone. Generally, the relatively low dose of cisplatin used with radiotherapy has an acceptable toxicity

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proÞle. However, clinical beneÞt from cisplatin treatment for mCaC patients is suboptimal, and new agents should be tested in this setting. Cisplatin plus 5-Fluorouracil Regimen Overview. The combination of cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) and 5-ßuorouracil (5-FU, generics) has been widely used for decades to treat advanced CaC and, more recently, earlier-stage disease. Preclinical data have shown that adding 5-FU to cisplatin and radiotherapy has a synergistic effect, thought to result from the impairment of DNA repair that renders lethal the radiation-induced tumor cell damage that is usually sublethal. These data provide the rationale for clinical investigation of this combination. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and less importantly, protein cross-linking of DNA. These cross-links inhibit the transcription and/or DNA replication mechanisms. The principal sites of reaction are the N7 atoms of guanine and adenine. The formation of intrastrand cross-links between cisplatin and neighboring guanines has been shown to correlate with clinical response. When used in conjunction with radiotherapy, cisplatin may also act as a radiosensitizer. Possible mechanisms of radiosensitization include inhibition of repair of sublethal radiation damage and synchronizing tumor cells into a radiosensitive phase of the cell cycle. 5-FU (Figure 4) is a ßuoropyrimidine antifolate. Antifolates exert their cytotoxic effect via several mechanisms. One of the most important targets for 5-FU is thymidylate synthase (TS), a key enzyme in de novo thymidine synthesis. This pyrimidine, which requires folate cofactors, is an essential requirement for normal DNA synthesis. By inhibiting TS, 5-FU inhibits DNA synthesis and causes cytotoxicity. In addition, because 5-FU is a structural analogue of uracil, it is misincorporated into RNA in place of uracil and interferes with normal RNA function, an action that triggers cell death. When used in conjunction with radiotherapy, 5-FU may also act as a radiosensitizer by synchronizing tumor cells into a radiosensitive phase of the cell cycle.

FIGURE 4. Structure of 5-fluorouracil (5-FU).

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Clinical Performance. A Phase III study, initiated in 1986 by the Gynecologic Oncology Group, randomized patients with para-aortic, lymph-node-negative, stage IIB, stage III, or stage IVA CaC to receive either cisplatin with 5-FU or single-agent hydroxyurea, both administered with concurrent radiotherapy (Whitney C, 1999). Patients (n = 177) were randomized to cisplatin/5-FU and 190 received treatment with hydroxyurea. All parameters measured demonstrated a beneÞt of cisplatin/5-FU over hydroxyurea. The relative risk of progression for patients treated with cisplatin/5-FU was 0.79 (90% conÞdence limits: 0.61–0.99) compared with the risk for the hydroxyurea-treated patients. The relative risk of mortality was 0.74 (90% conÞdence limits: 0.58–0.95) for patients treated with cisplatin/5-FU, compared with hydroxyurea-treated patients. Hematologic toxicity was more common and much more severe in the hydroxyurea-treated patients, but other toxicities were equivalent in the two arms. A second randomized Phase II study recruited 403 patients who had either large (greater than 5 cm diameter) stage IB or IIA CaC, or stage IIB, stage III, or stage IVA CaC to receive either radiotherapy alone or radiotherapy plus 5-FU and cisplatin (Morris M, 1999). Five-year survival was 73% for the chemoradiotherapy group versus 58% for radiotherapy alone (p = 0.004), and disease-free survival was 67% versus 40% (p > 0.001). The incidence of hematologic toxicity was higher in the group receiving chemotherapy; however, the data afÞrm that the survival beneÞt gained warrants the use of concurrent chemoradiotherapy. Between 1991 and 1996, 268 patients with early-stage (IA2, IB, or IIA) CaC were randomized in a clinical trial to receive either cisplatin/5-FU with concurrent radiotherapy or radiotherapy alone (Peters W, 2000). Twenty-Þve patients were ineligible, leaving 127 in the chemoradiotherapy arm and 116 in the radiotherapy arm. Because data from other studies were reported while this trial was ongoing, an unscheduled interim analysis was performed to determine any beneÞt for including chemotherapy in treatment. The four-year, progressionfree rates were 80% for chemoradiotherapy and 63% for radiotherapy. The incidence of grade 4 toxicities, primarily hematologic, was higher among the chemoradiotherapy-treated patients: 17% versus 3.5%. No chemotherapy-related deaths were reported. Cisplatin plus 5-Fluorouracil plus Hydroxyurea Regimen Overview. Data do not support a role for single-agent 5-FU (generics) in CaC as they do for cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) and hydroxyurea (BMS’s Hydrea/Litalir, generics). However, 5-FU has been studied in combination with other agents in an attempt to improve clinical beneÞt. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

Cisplatin is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to

312

•

•

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intrastrand, interstrand, and less importantly, protein cross-linking of DNA. These cross-links inhibit the transcription and/or DNA replication mechanisms. The principal sites of reaction are the N7 atoms of guanine and adenine. The formation of intrastrand cross-links between cisplatin and neighboring guanines has been shown to correlate with clinical response. When used in conjunction with radiotherapy, cisplatin may also act as a radiosensitizer. Possible mechanisms of radiosensitization include inhibition of repair of sublethal radiation damage and synchronizing tumor cells into a radiosensitive phase of the cell cycle. 5-FU is a ßuoropyrimidine antifolate. Antifolates exert their cytotoxic effect via a number of mechanisms. One of the most important targets for 5-FU is TS, a key enzyme in de novo thymidine synthesis. This pyrimidine, which requires folate cofactors, is an essential requirement for normal DNA synthesis. By inhibiting TS, 5-FU inhibits DNA synthesis and causes cytotoxicity. In addition, because 5-FU is a structural analogue of uracil, it is misincorporated into RNA in place of uracil and interferes with normal RNA function, an action that also triggers cell death. When used in conjunction with radiotherapy, 5-FU may act as a radiosensitizer by synchronizing tumor cells into a radiosensitive phase of the cell cycle. Hydroxyurea inhibits the enzyme ribonucleotide reductase, thereby blocking deoxyribonucleotide formation and DNA synthesis. Ribonucleotide reductase enzyme is closely related to proliferative status in cancer cells. It is involved in the de novo synthesis of all the precursors used in DNA synthesis. It converts ribonucleotide diphosphates to deoxyribonucleotides. Hydroxyurea is a drug that is speciÞc to the cell-cycle phase; it exerts its action during the S phase.

Clinical Performance. In a randomized Phase III study (GOG120) that recruited women with stage IIB, III, or IVA CaC from 1992 to 1997, 173 patients were treated with cisplatin/5-FU/hydroxyurea with concurrent EBT (Rose P, 1999). The control arm of 177 patients received hydroxyurea and radiotherapy; a third group received cisplatin and radiotherapy. For the arm receiving the triplet chemotherapy, the relative risks of disease progression and death were reduced 0.55 (95% conÞdence intervals: 0.40–0.75) and 0.58 (95% conÞdence intervals: 0.41–0.81), respectively, compared with the control arm. The clinical beneÞt, equivalent to that of single-agent cisplatin, was offset in part by the high incidence of adverse effects, which was double the incidence observed in the control arm and the cisplatin arm. The study concluded that although the triplet regimen had greater efÞcacy compared with hydroxyurea alone, no additional beneÞt was gained by adding 5-FU and hydroxyurea to cisplatin. Cisplatin plus Topotecan Regimen Overview. Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) has been investigated in combination with numerous other agents in an attempt to

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improve clinical efÞcacy. The addition of topotecan (GlaxoSmithKline’s [GSK’s] Hycamtin) has resulted in some encouraging Þndings (topotecan is used routinely for the treatment of ovarian cancer). Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in the inhibition of transcription and/or DNA replication mechanisms. Topotecan (Figure 5) is a semisynthetic, water-soluble derivative of camptothecin, which is a cytotoxic alkaloid extracted from plants that acts as an inhibitor of topoisomerase I (the same mechanism of action as irinotecan). Topoisomerase I is the enzyme that produces reversible, single-strand breaks in DNA during DNA replication. These single-strand breaks relieve torsional strain and allow DNA replication to proceed. Topotecan binds to the topoisomerase I-DNA complex and prevents the religation of the DNA strand, resulting in double-strand DNA breakage and cell death. Unlike irinotecan, topotecan is not a pro-drug. As a result, topotecan has different antitumor activities and toxicities than irinotecan. Topotecan is a radiation-sensitizing agent and is speciÞc to the S phase of the cell cycle.

Clinical Performance. A recently reported study presented Phase III data from a three-arm, randomized study of patients with stage IV recurrent or persistent CaC who had recovered from the effects of prior surgery, radiotherapy, or chemoradiotherapy (Long H, 2004). Between 1999 and 2002, 356 evaluable patients were randomized to receive cisplatin alone (145 patients); cisplatin plus topotecan (148 patients); or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (63 patients; this arm was stopped early owing to excessive toxicity).

CH3 N CH3 HO

O N N O HO H3C

O

FIGURE 5. Structure of topotecan.

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The response rate in the cisplatin/topotecan arm was 26%—double the response in the single-agent cisplatin arm (p = 0.0004). Median progression-free survival and overall survival were superior in the combination arm: respectively, 4.6 months versus 2.9 months, and 9.2 months versus 7.0 months. The cisplatin/topotecan combination is unique in producing a survival advantage—not just an improved response rate—compared with cisplatin, and a 24% reduction in the risk of death. However, this improvement came at the cost of increased toxicity associated with the inclusion of topotecan into the treatment—namely, neutropenia (70% versus 1%) and anemia (32% versus 23%). Despite the additional toxicities, some investigators advocate cisplatin plus topotecan as the treatment of choice in this patient population. A randomized Phase III study in mCaC is under way to compare cisplatin combined with either topotecan or one of three other cytotoxic agents. Cisplatin plus Ifosfamide Regimen Overview. Both cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) and ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics) have single-agent activity in CaC, prompting investigation whether combining the two agents improves clinical activity. Ifosfamide has been studied as a single agent and in combination with other drugs in different studies. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in inhibition of transcription and/or DNA replication mechanisms. Ifosfamide (Figure 6) is an alkylating agent pro-drug and a structural analogue of cyclophosphamide. After being metabolized in the liver to its active form, ifosfamide binds DNA and transfers alkyl groups, causing the formation of DNA cross-links and strand breaks. As a result, this agent prevents DNA replication and causes tumor cell death. The action of ifosfamide is nonspeciÞc to the cell cycle. Ifosfamide is administered almost exclusively with mesna, a compound that inactivates the alkylating activity and helps prevent the cystitis associated with this drug.

Clinical Performance. A randomized study compared single-agent cisplatin, given at 50 mg/m2 , with the combination of cisplatin at the same dose level and ifosfamide at 5g/m2 , administered every three weeks up to six courses, in 454 advanced CaC patients (Omura GA, 1997). The combination regimen achieved a higher response rate (31% versus 18%) and longer response duration (4.6 months versus 3.2 months) than cisplatin alone. However, the combination did not improve overall survival and was associated with more-toxic events.

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FIGURE 6. Structure of ifosfamide.

Another study reported in the same year evaluated cisplatin/ifosfamide as neoadjuvant chemotherapy in patients with stage IIB CaC (de Jonge E, 1997). Sixty-eight patients with previously untreated stage IIB CaC were given two cycles of chemotherapy: cisplatin at 20 mg/m2 and ifosfamide at 1.2 g/m2 on days 1–5, repeated every three weeks. Responders were subsequently randomized to either surgery or radiotherapy. A clinical response was documented in 80% of evaluable patients (95% conÞdence intervals: 69–91%). The response rate among the intent-to-treat population was 64.7%. Twenty-one patients were randomized to surgery and 23 patients to radiotherapy. One patient had grade 4 thrombocytopenia, four had grade 3 anemia, one patient had leukopenia, one had nausea, and a third suffered vomiting. The authors concluded that the combination of cisplatin and ifosfamide has acceptable toxicity and produces a clinical response rate of 80% in previously untreated patients with stage IIB CaC. Carboplatin plus Ifosfamide Regimen Overview. In some cancers, such as ovarian and non-small-cell lung cancer, carboplatin (BMS’s Paraplatin, generics) has replaced cisplatin because it has been shown to have equivalent efÞcacy but with an improved side-effect proÞle (Paccagnella A, 2004; du Bois A, 2003). To date, the role of carboplatin as a radiosensitizer has not been fully elucidated, though studies have been performed with carboplatin as either a neoadjuvant treatment for CaC or for treatment of mCaC. Carboplatin has been studied in combination with ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics). Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Carboplatin (Figure 7) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in inhibition of transcription and/or DNA replication mechanisms. Ifosfamide (Figure 6) is an alkylating agent pro-drug and a structural analogue of cyclophosphamide. After being metabolized in the liver to its active form, ifosfamide binds DNA and transfers alkyl groups, causing the formation of DNA cross-links and strand breaks. As a result, this agent prevents

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FIGURE 7. Structure of carboplatin.

DNA replication and causes tumor cell death. The action of ifosfamide is cell-cycle nonspeciÞc. Ifosfamide is used almost exclusively with mesna, a compound that inactivates the alkylating activity and helps prevent the cystitis associated with this drug. Clinical Performance. Investigators in Germany reported an analysis of patients with CaC who, following hysterectomies, were found to possess one or more “high-risk features” for disease recurrence. These patients were subsequently randomized to receive adjuvant chemotherapy (carboplatin [area under the curve (AUC) of 4] plus ifosfamide [1.6 g/m2 /day x three days] x four cycles) followed by EBT radiotherapy, with or without erythropoietin (epoetin alfa, Janssen-Cilag’s Eprex) (10,000 IU three times/week with oral iron). A total of 256 patients were enrolled in the trial, which was well-balanced for known prognostic factors in this malignancy. The investigators found that the requirement for transfusion was substantially reduced in the epoetin-treated patient population (10% versus 32%, p = 0.0004). At a median follow-up of approximately two years, the one-year and two-year relapse-free survivals (primary study endpoint) were 91% versus 86% and 81% versus 70%, respectively, both in favor of the epoetin-treated patient population (p = 0.074). Further follow-up of this study will provide important data on the signiÞcance of anemia and epoetin treatment in the risk of relapse and ultimate survival in locally advanced cervical cancer. Another study performed in Germany (Kuehnle H, 1992) investigated carboplatin and ifosfamide in combination as a neoadjuvant treatment in 34 patients with CaC. After chemotherapy, patients underwent surgery or radiotherapy according to feasibility. Nineteen patients achieved remission; three achieved complete remission. The most common toxicities were myelosuppression, grade 4 leukopenia (28%), and thrombocytopenia (13%); these effects led the authors to conclude that this combination was not recommended for standard practice in this setting. Cisplatin plus Paclitaxel Regimen Overview. Paclitaxel (BMS’s Taxol, generics) is an important anticancer agent with proven activity in a number of cancers, in particular non-small-cell lung cancer, breast cancer, and ovarian cancer. It has also been studied, in combination with cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) for the

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treatment of CaC. The combination of cisplatin and paclitaxel is in widespread use for the treatment of mCaC. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in inhibition of transcription and/or DNA replication mechanisms. Paclitaxel (Figure 8) is a taxane. Taxanes stabilize the mitotic spindle microtubules formed during cell division, thus preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death.

Clinical Performance. A Phase II study has investigated the efÞcacy of paclitaxel in combination with cisplatin as Þrst-line treatment in 47 patients with advanced or recurrent CaC (Rose P, 1999). Patients were recruited to the study between June and October 1996. Forty-one patients were assessable for response; 5 had a complete response and 14 had a partial response (overall response rate of 46.3%; 95% conÞdence intervals: 30.7–62.6%). The median progression-free survival was 5.4 months, and the median survival was at least 10 months. Interestingly, response was more frequent in disease outside of Þelds that had received prior radiotherapy, a Þnding that suggests untreated disease is more chemosensitive. Another small Phase II study (Piver MS, 1999) investigated the same combination of agents. Of 20 patients, 2 had complete responses and 7 had partial responses, and again, the response rate was improved in patients with recurrence outside radiotherapy-treated Þelds. Again also, the treatment was well tolerated, the most signiÞcant toxicity being grade 3/4 neutropenia in 55% of patients. A GOG Phase III randomized study in 280 patients reported statistically signiÞcant, superior response rates for paclitaxel and cisplatin in combination compared with cisplatin alone: 36% versus 19% (Moore DH, 2001). The median


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progression-free interval was also superior: 4.8 months versus 2.8 months. However, these responses did not translate into improved survival: 9.7 months versus 8.8 months is not signiÞcant. The incidence and degree of hematologic toxicity were higher in the combination arm and, although reversible, were deemed unacceptable by the authors in light of the modest improvement in efÞcacy. Cisplatin/paclitaxel is being investigated in an ongoing, four-arm, randomized Phase III study to determine whether response rate or survival is superior for this combination. Cisplatin plus Gemcitabine Regimen Overview. Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) is well established as the most active agent for the adjuvant treatment of CaC and for mCaC. In an attempt to improve on its duration of response and, ultimately, the survival of patients, cisplatin has been combined with new-generation cytotoxic agents such as gemcitabine (Eli Lilly/Spaly Bioquimica’s Gemzar). A meta-analysis (Mutch DG, 2003) concluded that although single-agent gemcitabine was generally inferior to cisplatin, when it was used concurrently with cisplatin and/or radiotherapy, objective response rates were high and survival was prolonged. The drug also showed promise when used with cisplatin as neoadjuvant therapy. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the regimen’s overall activity: •

•

Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in the inhibition of transcription and/or DNA replication mechanisms. Gemcitabine (Figure 9) is an antimetabolite that shares characteristics common to all nucleoside analogues, including mediated transport by membrane transporters, activation by intracellular metabolic steps that retain the nucleotide residues in the cell, and the formation of active phosphate derivatives. Gemcitabine exhibits cell-phase speciÞcity, primarily killing cells undergoing DNA synthesis (S phase) and blocking the progression of cells through the G1/S-phase boundary. It is metabolized intracellularly by nucleoside kinases to the active diphosphate and triphosphate nucleosides.

The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. The inhibition of this enzyme by the diphosphate nucleoside reduces the concentrations of deoxynucleotides, including 2 -deoxycytidine 5 -triphosphate (dCTP). Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the

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NH2 N HO

O O

OH

N F F


incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one more nucleotide is added to the growing DNA strands. After this addition, further DNA synthesis is inhibited. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). Clinical Performance. Data supporting the use of cisplatin/gemcitabine combinations come from Phase I and Phase II clinical trials. Researchers performed a meta-analysis of 15 Phase I and Phase II trials (Mutch DG, 2003) and found gemcitabine to be beneÞcial when given in combination with cisplatin. For example, one Phase II study (Burnett AF, 2000), in which 19 patients recruited between July 1997 and January 1999 received a median of Þve cycles of gemcitabine plus cisplatin therapy, produced a response rate of 41%. There was one complete response, lasting 14 months, and six partial responses. In the patients not previously radiated, the response rate was 57%; in the radiated patients, the response rate was 30%, with all responses occurring in the radiation Þeld. Ongoing Phase III studies have been designed to conÞrm the beneÞt of adding gemcitabine to cisplatin and to compare the combination with the other cisplatin combinations. Between December 1998 and June 2003, 57 patients with recurrent, bulky, stage II (21 patients), stage III (25 patients), or stage IVA (11 patients) squamouscell CaC were treated with six courses of gemcitabine (1,250 mg/m2 ) on days one and eight, in combination with cisplatin (70 mg/m2 ) on day one, every three weeks (Mutch DG, 2003). Forty-six patients were evaluable for response. The overall response rate was 50%: 15% complete responses, 35% partial responses, and 7% stable disease. The remaining 20 patients (43%) progressed during treatment. One- and two-year survival rates were 44% and 26%, respectively. Studies are also under way to investigate the effect of gemcitabine-containing doublets. A presentation at the recent American Society of Clinical Oncology (ASCO) meeting in New Orleans (Porras A, 2004) described a study that used gemcitabine (1,000 mg/m2 ) in combination with irinotecan (100 mg/m2 ) on days 1 and 8, repeating the cycle every 21 days. The overall response rate in this Phase I study with ten patients who had locally recurrent and/or metastatic disease was 33% (complete response rate 22%, partial response rate 11%). Hematologic toxicity, particularly anemia, was common, and one patient died of grade 4 diarrhea.

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The Gynecologic Oncology Group of the NCI is recruiting patients to a fourarm, multicenter, Phase III study in stage IVB CaC, as detailed on the group’s Web site (www.cancer.gov/clinicaltrials). The study is randomizing women. As of February 2006, this trial is still recruiting (aim for 600 patient in 4 years—150 in each of the 4 arms) to receive cisplatin in combination with one of these agents: gemcitabine, paclitaxel, topotecan, or vinorelbine. Physicians eagerly await the outcome of this study because it should deÞnitively answer the question about the optimal Þrst-line treatment for patients with mCaC. If the gemcitabine combination proves to be superior to the comparators, it may be established as the treatment of choice for mCaC and launch for this indication. Paclitaxel plus Ifosfamide plus Cisplatin (TIP) Regimen Overview. Cisplatin (BMS’s Platinol-AQ, Nippon Kayaku’s Randa, generics) and ifosfamide (BMS’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics) are regarded as active drugs in the treatment of CaC. Paclitaxel (BMS’s Taxol, generics) (Figure 8) also showed activity in a randomized trial, thus prompting investigation of combinations of all three agents. The TIP regimen (also known as the Zanetta regimen) is used, primarily in Europe, as a neoadjuvant treatment prior to hysterectomy. Studies have also been performed to investigate this regimen for the treatment of mCaC. The typical dose levels used in the TIP regimen are paclitaxel IV 175 mg/m2 , ifosfamide IV 5 g/m2 , and cisplatin IV 75 mg/m2 , repeated at three-week intervals. Mechanism of Action. •

•

•

Paclitaxel (Figure 8) is a taxane. Taxanes stabilize the mitotic spindle microtubules, formed during cell division, thus preventing depolymerization. This stability inhibits the dynamic reorganization of the microtubules, resulting in a mitotic block at interphase with a consequential inhibition of cell proliferation and eventual cell death. Cisplatin (Figure 3) is a platinum agent. Platinum agents generate highly reactive, charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and protein cross-linking of DNA, resulting in inhibition of transcription and/or DNA replication mechanisms. Ifosfamide (Figure 6) is an alkylating agent pro-drug and a structural analogue of cyclophosphamide. After being metabolized in the liver to its active form, ifosfamide binds DNA and transfers alkyl groups, causing the formation of DNA cross-links and strand breaks. As a result, this agent prevents DNA replication and causes tumor cell death. The action of ifosfamide is cell-cycle nonspeciÞc. Ifosfamide is used almost exclusively with mesna, a compound that inactivates the alkylating activity and helps prevent the cystitis associated with this drug.

Clinical Performance. In a randomized trial, researchers compared two neoadjuvant regimens involving 182 patients with locally advanced squamous-cell

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CaC (Buda A, 2003). Patients randomly received three cycles of ifosfamide and cisplatin (IP) or ifosfamide, cisplatin, and paclitaxel (TIP). The TIP regimen yielded a slightly higher clinical response rate (89%) than the IP regimen (78%). Optimal response (residual tumor less than 3 mm) resulted signiÞcantly more often with TIP (43%) than with IP (22%). With a short follow-up, survival also tended to be better after TIP, though TIP caused grade 4 neutropenia in 37% of patients compared with only 16% of patients on the IP regimen. Four toxic deaths were observed, two in each group. Of the 182 patients enrolled, 164 completed chemotherapy and 178 underwent surgery. The aim of a second, Phase II trial was to assess the efÞcacy of TIP for persistent or recurrent squamous-cell CaC (Zanetta G, 1999). Forty-Þve women were treated with the TIP regimen; 31 had received prior radiation. Complete response was observed in 15 patients and partial response in another 15, yielding an objective response rate of 67% (95% conÞdence interval: 51–81%). Ten complete responders underwent subsequent surgery. The median survival for nonresponders was 6 months; for partial responders, more than 9 months; and for complete responders, more than 13 months. The most signiÞcant side effect was myelotoxicity; 91% of patients experienced grade 3 or 4 myelotoxicity. One woman had life-threatening toxic effects. The authors concluded that the TIP combination is highly effective for salvage treatment, particularly in unradiated patients (Zanetta G, 2000). For radiated women, the response rate is higher than response rates observed with other regimens, but further investigation is needed. Nonpharmacological Approaches Surgery is the mainstay treatment of localized, early-stage CaC—either simple extrafascial hysterectomy (the uterus and a small rim of vaginal cuff are removed from a plane outside the peritoneum) or colonization of the cervix for tumors less than 3 mm. Early invasive tumors larger than 3 mm are commonly treated by radical hysterectomy (the uterus and upper two-thirds of the vagina are removed). Early-stage disease with small tumors may be managed exclusively by radiotherapy (EBT and brachytherapy) rather than surgery; this choice of treatment may depend on the requirement to preserve fertility. With survival rates of up to 90%, radiotherapy and surgery are about equally effective as single options for treating very small CaCs in their earliest stages. Surgery is not routinely an option for locally advanced disease, which is treated by radiotherapy, usually with concurrent chemotherapy. Select patients with recurrent disease who have received maximum radiotherapy may be managed by extensive pelvic surgery for palliation, although this procedure is associated with urinary function complications. Studies have been conducted to investigate the potential therapeutic beneÞt of concurrent hyperthermia with radiotherapy and/or chemotherapy for the treatment of CaC. A Dutch Phase III trial demonstrated a survival and local control beneÞt gained from the addition of hyperthermia to chemoradiotherapy (Jones EL, 2003). The authors evaluated response and toxicity in patients with locally advanced CaC. All patients achieved clinical complete response and durable local control;

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the three-year survival rate improved from 27% to 51% with the addition of hyperthermia. The triple-modality treatment was well tolerated. Further trials are warranted to ascertain whether hyperthermia should be incorporated into standard treatment for CaC. EMERGING THERAPIES For several decades, the mainstay of drug treatment for cervical cancer (CaC) has been cisplatin. However, to achieve a major improvement in survival of patients with advanced CaC and to reduce the recurrence for stage I, II, and III patients, a new approach to treatment is required. Given that virtually all cases of CaC are caused by persistent infection with human papillomavirus (HPV), this virus has become an attractive target for new therapies. Indeed, vaccination against high-risk, CaC-related HPV subtypes has been under investigation for several years. These vaccines can be used in three settings: • • •

As population-wide preventive vaccines administered to females before they become sexually active. For women at high risk of developing CaC due to HPV infection with high-risk subtypes and/or cervical neoplasia or carcinoma in situ. For women who have been diagnosed with CaC, possibly as an adjuvant to surgery and likely in combination with standard chemotherapeutic agents.

Only the last of these uses is covered herein because it is the only one related to the direct treatment of CaC. Other approaches being tested to improve the outcome for CaC patients include new biological agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In February 2004, the Þrst VEGFtargeted antibody, bevacizumab (Roche/Genentech’s Avastin), was approved for the treatment of metastatic colorectal cancer. GeÞtinib (AstraZeneca’s Iressa) and cetuximab (ImClone/Bristol-Myers Squibb [BMS]/Merck KGaA’s Erbitux), both EGFR-targeted agents, have been approved for non-small-cell lung cancer (NSCLC) and colorectal cancer, respectively. These developments have fueled interest in the use of targeted agents to treat CaC. Although CaC is relatively chemo-insensitive, new-generation cytotoxic agents are being tested in an attempt to improve patient outcome, primarily in CaC with distant metastases and often in combination with cisplatin. However, success has been elusive. For example, development of the protein kinase C inhibitor bryostatin (GPC-Biotech) was discontinued in March 2004 owing to lack of efÞcacy and a poor toxicity proÞle. This naturally occurring agent, isolated from the marine bryozoan Bugula neritina, had undergone Phase II testing, in combination with cisplatin, for advanced CaC. Based on data from the study, the authors concluded that the addition of bryostatin confers no beneÞt (Nezhat F, 2004). A report of a Phase I study of the natural product angiogenesis inhibitor TNP-470 (Abbott/Takeda’s Fumigillin) detailed a complete response in a patient

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previously treated with radiotherapy for stage IIIa squamous-cell carcinoma (Kudelka AP, 1998). On presentation with multiple pulmonary tumors but no evidence of local disease, she was treated with TNP-470 and remained in remission at eight months following completion of therapy. Another three patients in this trial experienced stable disease, but 14 patients progressed. A Phase II study failed to conÞrm the activity of TNP-470 in CaC. Because no further details have been released, we assume there is no further development of this agent at this time. Early clinical trials with agents such as docetaxel (Aventis’s Taxotere), an established treatment for other solid cancers, have been reported in the literature. A study of single-agent docetaxel in patients with metastatic CaC (mCaC) yielded a response rate of 19%. In the neoadjuvant setting, docetaxel produced a response rate of 34% in CaC patients, but only 17% became suitable candidates for surgery (Vallejo CT, 2003). Our research revealed no use of docetaxel in clinical practice in any of the markets under study at this time. A Phase I/II study is recruiting in the United States to examine the combination of docetaxel with carboplatin for the treatment of recurrent stage IVb CaC, based on promising Phase I data from a German study (Rein DT, 2002). Because slow progression is characteristic of CaC, retinoids have been investigated in an attempt to redifferentiate abnormal or neoplastic cervical cells. Retinoids may be used in either the preventive or therapeutic setting (Alvarez R, 2003). Also, retinoid receptors may interact with EGFRs. A study investigating the retinoid cis-retinoic acid (Ligand Pharmaceutical’s Aliretinoin) and interferon-alpha 2a (Roche’s Roferon-A) showed an overall response rate of 50% (12% complete response rate) in 32 previously untreated patients who had locally advanced, squamous-cell CaC. After a median response duration of three months, 9 of the 16 responders eventually progressed (Wilailak S, 2003; Braud AC, 2002). Table 6 summarizes the key emerging therapies in development for CaC. Vaccines Overview. Although the concept of a therapeutic tumor vaccine is viable, these therapies remain largely unproven in the treatment of cancer. Recent Phase III data subgroup analysis shows that Dendreon’s Provenge, a vaccine for the treatment of metastatic prostate cancer, has clinical activity in goodperformance status patients with less-aggressive tumor characteristics. Together with an improvement in survival (approximately eight months), this factor may stimulate renewed interest in initiating and recruiting patients for CaC therapeutic vaccine trials, particularly because CaC has an established viral cause. Provenge, shown to activate T cells, has fast-track status with the FDA and could be the Þrst therapeutic cancer vaccine to reach the market. Vaccines offer three major advantages over current treatments: • • •

They are generally well tolerated. The anticipated autoimmunity has not materialized as a clinical problem. They have convenient dosing regimens.

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TABLE 6. Emerging Therapies in Development for Cervical Cancer Development Phase

Marketing Company

— D —

— Xenova/Cancer Research Technology —

— II —

— Transgene —

Platinum agents Oxaliplatin United States Europe Japan

— II —

— Sanofi-Aventis —

Antimetabolites Capecitabine United States Europe Japan

II II —

Roche

II II —

AstraZeneca AstraZeneca —

III II —

Genentech/OSI/Roche Genentech/OSI/Roche —

II II —

Merck/KGaA/Takeda Merck/KGaA/Takeda —

Bioreductive agents Tirapazamine United States Europe Japan

II II I

Sanofi-Aventis Sanofi-Aventis Sanofi-Aventis

Efaproxiral United States Europe Japan

II — —

Allos Therapeutics — —

Compound Vaccines TA-HPV and TA-CIN United States Europe Japan MVA-HPV-IL-2 United States Europe Japan

EGFR-targeted agents Gefitinib United States Europe Japan Erlotinib United States Europe Japan EMD-72000 United States Europe Japan

—

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If vaccines are shown to be efÞcacious at any stage of CaC, they will be rapidly adopted and widely used. One approach that has attracted attention is the development of preventive vaccines targeted at high-risk subtypes of HPV. Such vaccines could be used to immunize girls prior to becoming sexually active; Phase III clinical trials are underway. The attraction of preventive vaccines would be greatest in the developing world, where the incidence of CaC is high and screening is not economically viable. Success in this arena could also lead to the replacement of Pap smear tests in countries where they are currently established, and preventive vaccination might have better penetration and compliance than Pap tests. Additionally, HPV-directed vaccines could be used for the treatment of cervical intraepithelial neoplasia (CIN) and so reduce the likelihood of progression to invasive CaC. In short, development of a successful vaccine could dramatically affect the incidence of CaC. Most vaccines in development for CaC target one or both of the two oncogenic proteins, E6 and E7, of the highly oncogenic subtypes of HPV (types 16 and 18), which are highly associated with the disease. Such vaccines have been extensively studied in the preventive setting and are designed to induce an antibody-mediated response (Adams M, 2001). Other multivalent vaccines have been developed that target as many as four HPV subtypes in an attempt to maximize protection against the most common cancer-causing agents. Given the time scale of CaC development following HPV infection, it will be some decades before a preventive vaccine will affect the incidence of CaC, even if widespread vaccination were undertaken. Endpoints of preventive studies may be either presence of HPV infection (detected by DNA analysis) or cervical neoplasia; either will enable more rapid assessment of vaccine efÞcacy than the endpoint of invasive CaC development. Longer-term follow-up is required to assess the effect of vaccination on the development of CaC and to determine its efÞcacy as a cancer preventive agent. A vaccine derived from HPV type 16 has been shown to reduce the incidence of HPV type 16 infection and its associated CIN (Koutsky L, 2002). In a doubleblind Phase III study performed in the United States, 2,392 sexually active women aged 16–23, with no history of an abnormal Pap smear test result, were given three doses of either the HPV type 16 vaccine or placebo. Participants were dosed with vaccine on day 0, at 2 months, and at 6 months; they were tested for HPV type 16 infection at enrollment, at 1 month after the third vaccination, and every 6 months subsequently. Median follow-up was 17.4 months after completion of the vaccination regimen. Of the 41 cases of new HPV type 16 infection identiÞed in the study, including 9 cases of HPV-related CIN, all occurred in women in the placebo group, thus demonstrating the vaccine’s 100% effectiveness in this study. In May 2004, GlaxoSmithKline (GSK) announced the launch of a doubleblind, placebo-controlled, Phase III clinical trial, the Papilloma Trial to Prevent Cervical Cancer in Young Adults (PATRICIA), which aims to recruit 13,000 women aged 15–25 years. The vaccine, developed in collaboration with MedImmune (MEDI517, Cevarix), targets HPV types 16 and 18 and contains a novel

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proprietary adjuvant, AS04, which contains 3’-deacylated monophosphoryl lipid A and alum to enhance the immune response. Another approach to vaccine therapy is to vaccinate women who have CIN or carcinoma in situ. In these indications, HPV infection is prevalent, and clinical trials have shown that vaccines can reverse neoplasia. If proved effective in this setting, vaccines could eliminate the need for surgery and would enjoy rapid uptake—even conservative surgery such as conization can lead to impaired fertility and the ability to carry a baby to full term. Therapeutic vaccines must induce cell-mediated immunity because antibodies cannot eliminate the virus once it has become intracellular. Transgene recently reported data from a Phase II clinical study of its vaccine, MVA-HPV-IL-2, in high-grade CIN (grades 2 and 3). MVA-HPV-IL-2 is a recombinant virus that expresses HPV type 16 proteins E6 and E7 and interleukin-2 (IL-2). Results showed clinical and histological responses in 5 of 15 patients. The company is planning a new trial to test the highest vaccine dose in this patient population. Data for MVA-HPV-IL-2 in the treatment of CaC are discussed further on. Xenova has been developing two vaccines directed against HPV: TA-HPV and TA-CIN. Preclinical studies have shown that TA-CIN can induce a cell-mediated response, in the absence of an adjuvant; this formulation has been extended into clinical study. A Phase I, double-blind, randomized, placebo-controlled, and doseescalating safety and immunogenicity trial that enrolled 40 women was completed in July 2000. TA-CIN was found to be very well tolerated; no serious adverse events were reported during the trial. It was also conÞrmed to be immunogenic (Knutson KL, 2001). We describe clinical studies of TA-HPV and TA-CIN for the treatment of CaC further on. Mechanism of Action. Cancer vaccines are designed to stimulate the immune system to launch a response against the speciÞc target contained by the vaccine. Vaccines for CaC have targeted highly oncogenic viral proteins expressed by HPV. Some vaccines also express cytokines, such as IL-2, that act as immunostimulants in order to augment the host response to vaccination. TA-HPV and TA-CIN. Xenova, in conjunction with the European Organization for the Research and Treatment of Cancer (EORTC), was codeveloping TA-HPV and TA-CIN for the prevention and treatment of CaC, however this has now been discontinued. TA-HPV vaccine targeted E6 and E7 proteins of HPV types 16 and 18. TA-CIN targeted these proteins as well as the L2 component of HPV types 16 and 18. MVA-HPV-IL-2. Transgene’s MVA-HPV-IL-2 is a recombinant virus vaccine that expresses the HPV type 16 proteins E6, E7, and IL-2. This vaccine is in Phase II development for CaC in Europe. No development is underway in the United States or Japan for this indication. The rationale behind this agent is to induce a speciÞc T-lymphocyte-mediated response against the E6 and E7 HPV

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proteins and a nonspeciÞc IL-2 immune-stimulatory response. MVA-HPV-IL-2 is also under investigation for the treatment of CIN and vulva intraepithelial neoplasia. A Phase II clinical study conducted in Mexico that investigated MVA-HPVIL-2 for the treatment of CaC in 27 patients treated with a high dose (5 × 106 units) has been reported (www.transgene.fr). Two patients had stable disease at a minimum of six months’ follow-up (primary efÞcacy criteria). However, the clinical activity observed did not reach the efÞcacy threshold outlined in the protocol, which was amended to allow patients to receive chemotherapy following disease progression during the study. Two partial responses (seven months) and two stabilizations, out of Þve patients, have been reported. Based on the results of this study, the company concluded that the efÞcacy demonstrated was not sufÞcient to justify continuing the development of MVA-HPV-IL-2 as a monotherapy. Studies of MVA-HPV-IL-2 in combination with chemotherapy have not been identiÞed. Investigation of MVA-HPV-IL-2 is continuing for the treatment of the precancerous indications, CIN, and vulva intraepithelial neoplasia. Platinum Agents Overview. Cisplatin is the backbone of chemotherapy for the treatment of CaC. In some situations, however, despite the lack of studies showing equivalence, carboplatin is used in place of cisplatin because of the former’s improved toxicity proÞle. Research is ongoing to identify novel platinum agents with improved activity against CaC. To date, nedaplatin (Shionogi’s Aqupla), approved in Japan, has demonstrated clinical beneÞt, and oxaliplatin, approved in the United States and Europe for the treatment of colorectal cancer, is being investigated. Mechanism of Action. Platinum agents generate highly reactive, charged platinum complexes that bind covalently to DNA, leading to intrastrand, interstrand, and, less importantly, protein cross-linking of DNA. These cross-links result in inhibition of transcription and/or DNA replication mechanisms. The principal sites of reaction are the N7 atoms of guanine and adenine. The formation of intrastrand cross-links between platinum and neighboring guanines has been shown to correlate with clinical response. When used in conjunction with radiotherapy, platinum agents may also act as radiosensitizers. Possible mechanisms of radiosensitization include inhibition of repair of sublethal radiation damage and synchronization of tumor cells into a radiosensitive phase of the cell cycle. Oxaliplatin. Oxaliplatin (SanoÞ-Aventis’s Eloxatin) (Figure 10), a platinumbased chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, has been approved in all the major markets for the treatment of metastatic colorectal cancer. It recently received approval in the United States as an addition to 5-ßuorouracil (5-FU) for adjuvant treatment after surgery for colorectal cancer. Oxaliplatin has shown in vitro and in vivo efÞcacy against many tumor cell lines, including some that are resistant to cisplatin and carboplatin, a discovery that suggests it has potential utility in cisplatin-refractory CaC. The retention of

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NH2

O

O

O

O

Pt NH2

FIGURE 10. Structure of oxaliplatin.

the bulky DACH ring by activated oxaliplatin is thought to result in the formation of platinum-DNA adducts, which appear to be very effective at blocking DNA function (Raymond E,1998). A Phase II study was conducted to determine the efÞcacy of oxaliplatin therapy in patients with previously treated squamous-cell carcinoma of the cervix (Fracasso PM, 2003). Patients who had received a maximum of one previous chemotherapeutic treatment were treated with oxaliplatin at 130 mg/m2 every 21 days. Twenty-three of the 24 patients entered in the study had received prior cisplatin or carboplatin. One complete response lasting 2.2 months and one partial response lasting 3.2 months were achieved. Another nine patients had stable disease. The most frequently reported drug-related toxicities were anemia, nausea and vomiting, and neurotoxicity. Three patients had a grade 3, infusion-related allergic response that was resolved mainly by increasing oxaliplatin infusion time. Oxaliplatin has only modest activity against cisplatin-resistant or carboplatin-resistant disease. Antimetabolites Overview. First launched in 1959, the antimetabolite 5-FU has proven, though modest, efÞcacy against CaC. It is used concurrently with cisplatin or immediately after radiotherapy, and it is used for the treatment of disseminated disease. The evidence of 5-FU activity provides the rationale for testing new-generation antimetabolites such as capecitabine, a tumor-activated pro-drug of 5-FU with a better side-effect proÞle. Mechanism of Action. Antimetabolites are structural analogues of naturally occurring compounds. Antimetabolites interfere with the production of nucleic acids. They work through a variety of mechanisms, including competition for binding sites on enzymes and incorporation into nucleic acids. The three categories of antimetabolites, based on their sites of action, are as follows: antifolates, purine analogues, and pyrimidine analogues. Capecitabine. Capecitabine (Roche’s Xeloda) (Figure 11) is an orally active pro-drug of the ßuoropyrimidine 5-FU approved for the treatment of metastatic breast cancer and colorectal cancer; it is under extensive investigation in other cancer indications, including adjuvant use. Capecitabine is selectively tumoractivated to its cytotoxic moiety, ßuorouracil, by thymidine phosphorylase (TP). Within normal and tumor cells, ßuorouracil is further metabolized to two active metabolites, 5-ßuoro-2-deoxyuridine monophosphate (FdUMP) and 5ßuorouridine triphosphate (FUTP). FdUMP inhibits DNA synthesis by reducing

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O CH3 HN

O F

N O H3C

HO

O

N

OH


normal thymidine production; FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate. The active moiety of capecitabine, ßuorouracil, is speciÞc to the cell-cycle phase (S phase). In one case study, a patient with mCaC who was treated with one course of capecitabine evinced a response that resulted in extended survival (Hindenburg AA, 2003). However, the patient experienced severe toxicity, including grade 4 hand and foot syndrome, a side effect commonly associated with capecitabine. An interesting study by a group of Japanese investigators has shown that TP levels in cervical tumors are elevated following radiotherapy, a Þnding that suggests CaC may be amenable to treatment with capecitabine (Oguri H, 2004). A multicenter Phase II study in the United States is recruiting patients with persistent or recurrent adenocarcinoma of the cervix to receive capecitabine as a single agent following failure of Þrst-line therapy (www.cancer.gov). Patients receive oral capecitabine twice daily on days 1–14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. No results have been reported at the time of writing this report. EGFR-Targeted Agents Overview. Cervical intraepithelial dysplasia and invasive cancers have been shown to possess increased levels of EGFR; 90% of CaC tumors reportedly overexpress the receptor (Boiko I, 1998). In addition, levels of expression correlate with the stage of cancer and degree of HPV infection (Kersemaekers AM, 1999). Interestingly, evidence is accumulating for a nicotine-induced upregulation of EGFR in CaC cell lines, with a resultant increase in cell proliferation (Mathur RS, 2000[a]). These observations suggest that EGFR is a valid therapeutic target for CaC therapies as well as a potential marker for the disease (Mathur RS, 2000[b]). A vast amount of research and development is ongoing in the area of EGFR inhibition. Two main approaches are being investigated: the speciÞc inhibition of EGFR-associated tyrosine kinase and monoclonal antibodies (MAbs) directed at the external domain of EGFR itself. To date, geÞtinib (AstraZeneca’s Iressa), a

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small-molecule EGFR tyrosine kinase inhibitor, has been approved for the thirdline treatment of NSCLC, and cetuximab (ImClone/Merck KGaA/Bristol-Myers Squibb’s Erbitux), an EGFR-directed MAb, has been approved for second-line use, in combination with chemotherapy, for colorectal cancer. Also, recent data have shown that cetuximab provides a signiÞcant survival beneÞt when administered with radiotherapy for the treatment of head and neck cancer, a squamouscell malignancy. This information may be relevant for the treatment of CaC, particularly CaC of squamous-cell origin, which is also treated by radiotherapy. Mechanism of Action. EGFR is a 170-kilodalton transmembrane glycoprotein encoded by the (c-erbB-1 ) proto-oncogene. EGFR comprises three domains with distinct functions: extracellular ligand-binding domain (binds to different EGFrelated growth factors); transmembrane domain (anchors the receptor in the cell membrane); and cytoplasmic tyrosine kinase domain (activates the intracellular response cascade). Therapeutic intervention of the EGFR is either by MAbs that competitively bind to the extracellular receptor or by small-molecule inhibitors of the receptor-associated tyrosine kinase. Gefitinib. GeÞtinib (AstraZeneca’s Iressa) is a small-molecule inhibitor of EGFR tyrosine kinase. It launched in the United States and Japan as a singleagent, third-line treatment for NSCLC and is in Phase II development for CaC in the United States and Europe. GeÞtinib is a competitive inhibitor of the ATPbinding site and blocks ligand-induced EGFR activation, inhibiting EGFR-driven cell proliferation. Data from a Phase II trial involving patients with advanced or metastatic squamous-cell CaC were presented at the American Society of Clinical Oncology (ASCO) meeting in 2003 (Viens P, 2003). Twenty-three patients received 500 mg of geÞtinib each day for a median of 1.8 months. Six patients had stable disease that lasted 25–114 days. Twelve patients had progressive disease; the median time to disease progression was 47 days. A Phase II study, underway in the United States, is recruiting CaC patients (and patients with epithelial ovarian cancer) to receive single-agent geÞtinib and to determine any reduction in phosphorylation of EGFR (or other molecules downstream on the same signaling pathway) and whether this reduction correlates with clinical response. At this time, it has not been possible to identify additional clinical data for geÞtinib in CaC; it does not appear to be a focus of AstraZeneca’s development strategy. The relationship between EGFR expression and response to geÞtinib took an interesting turn with the publication of two papers showing that geÞtinib responders express a mutant form of the EGFR tyrosine kinase (Paez JG, 2004; Sordella R, 2004). However, early data suggest that CaC samples do not express the mutation. Erlotinib. Erlotinib (OSI Pharmaceuticals’ Tarceva), a small-molecule EGFR tyrosine kinase inhibitor with a mechanism of action similar to that of geÞtinib,

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is under development by OSI in alliance with Genentech and Roche. This orally active quinazoline derivative is in Phase III trials in the United States and Europe and in Phase I trials in Japan with Roche subsidiary Chugai for NSCLC cancer. A Phase II, multicenter study of erlotinib is recruiting patients with persistent or recurrent squamous-cell CaC. Patients will receive oral erlotinib once daily until evidence of disease progression or unacceptable toxicity. The drug has been approved in Europe. EMD-72000. EMD-72000 (Merck KGaA/Takeda’s matuzumab) is a humanized IgG1 antibody directed at the EGFR. EMD-72000 competes for binding at the receptor with the EGFR’s natural ligands, EGF and tumor growth factor-alpha. By February 2004, a Phase II study named EMD 72000-023 had enrolled 41 CaC patients in Germany, the United Kingdom, and the Netherlands. The study is still ongoing at the time of writing. Interestingly, cetuximab (ImClone/BristolMyers Squibb/Merck’s Erbitux) has been approved for the treatment of refractory metastatic colorectal cancer; its approval was based on improved response rate but, as yet, no proven survival beneÞt. This precedent may increase the likelihood of EMD-72000’s approval for CaC, an indication with a signiÞcant unmet treatment need. Bioreductive Agents Overview. Bioreductive, or hypoxia-selective, cytotoxins represent a promising new class of drugs that may have single-agent activity or, most likely, will be combined with other cytotoxic agents or with radiotherapy. Tirapazamine is a lead compound within this class and has been under investigation for solid tumors, including CaC, head and neck cancer, and NSCLC. Data showing lack of additional activity and increased toxicity when added to standard agents have lowered the chances for tirapazamine’s success. Mechanism of Action. Bioreductive agents are unique because they exhibit selective cytotoxicity toward hypoxic cells (Peters KB, 2001). This pharmacological strategy is designed to exploit the fact that tumor cells are typically less well oxygenated than healthy cells. This characteristic contributes to tumor progression and to radiotherapy and chemotherapy resistance in a variety of ways, such as activation of certain signal transduction pathways and gene regulatory mechanisms. In the human body, metabolism of the active drug turns it into a toxic free radical when the compound undergoes one-electron reduction by cytochrome P450 reductase. In hypoxic cells, the resulting free radical induces single-strand and double-strand breaks in DNA, whereas in well-oxygenated tissues, the free radical is further oxidized and is transformed into an inactive metabolite. Tirapazamine. Tirapazamine (SanoÞ-Aventis’s Tirazone) (Figure 12) is the lead agent in a new class of bioreductive drugs known as benzotriazine diN-oxides (Peters KB, 2002). It is in Phase II trials in the United States and

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FIGURE 12. Structure of tirapazamine.

Europe and in Phase I development in Japan for the treatment of CaC. Based on promising activity in a Phase II trial, a Phase III study is underway in Australia, investigating tirapazamine in combination with cisplatin and radiotherapy for the treatment of squamous-cell head and neck cancer. The Þnal data are expected in 2007. Cervical cancers are known to be hypoxic tumors because of the development of necrotic areas in even relatively small tumors. Radiation and chemotherapy failures have been attributed to tumor hypoxia because tumor oxygenation is critical for the free-radical formation that causes DNA damage. In preclinical models, tirapazamine enhances both radiation and chemotherapy effectiveness. Data from a Phase I/II clinical study in women with locally advanced CaC have been described (Craighead PS, 2000). Patients received standard radiotherapy and cisplatin treatment to which escalating doses of tirapazamine were added. The study identiÞed a tirapazamine dose level of 290 mg/m2 , given with a cisplatin dose on days 1, 15, and 29, plus a dose of tirapazamine at 220 mg/m2 given on days 8, 10, 12, 22, 24, and 26 as the maximum tolerated dose with acceptable toxicity. Radiotherapy was given daily on days 1–5, 8–12, 15–19, 22–26, and 29–33. At six months, 13 of 15 patients had complete pelvic control of disease. The authors concluded that the use of tirapazamine with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase II testing. Results from an earlier Phase I study coordinated by the NCI in the United States were also presented (Aghajanian C, 1997). This study combined tirapazamine with cisplatin in 12 heavily pretreated patients with recurrent CaC. Tirapazamine was administered as an intravenous (IV) infusion over two hours, followed one hour later by a one-hour infusion of cisplatin at 75 mg/m2 . A maximally tolerated dose of 330 mg/m2 of tirapazamine was determined for the schedule described, and all observed responses were seen at this dose level. Despite the use of prophylactic antiemetic, the dose-limiting toxicity was nausea and vomiting. All 12 patients were evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and four patients achieved disease stabilization (33%). All major and minor responses were seen at the highest dose level tested: 330 mg/m2 . Details of tirapazamine in other Phase II or Phase III studies in CaC have not been identiÞed, and interest in its utility in NSCLC has waned. However, studies

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FIGURE 13. Structure of efaproxiral.

of tirapazamine in conjunction with radiotherapy are ongoing in head and neck cancer, and it is this radiosensitizer role that holds most interest for clinicians. Efaproxiral. In August 2002, Allos Therapeutics initiated a Phase I/II clinical trial of efaproxiral (Efaproxyn in the United States, Revaproxyn outside the United States) (Figure 13), a synthetic small molecule, for patients with locally advanced CaC who were receiving cisplatin-based chemoradiotherapy. The trial enrolled patients in the United States and Canada. Efaproxiral is an allosteric modiÞer of hemoglobin that enhances the diffusion of oxygen to hypoxic (oxygen-deprived) tumor tissues, thereby making radiation therapy more effective. Allos’s lead indication for efaproxiral is the treatment of brain metastases from breast cancer with whole brain irradiation; this breast cancer indication resulted from a subpopulation analysis of Phase III data that showed no signiÞcant improvement in survival for patients with brain metastases from other types of primary tumor. The FDA awarded efaproxiral orphan drug status for brain metastases of breast cancer and an approvable letter that states, “If the study shows effectiveness in this population (increased survival) using the pre-speciÞed analysis, and the study is otherwise satisfactory, we believe it would, together with the subset result in the earlier clinical study, support approval.” The ongoing Phase I/II clinical trial is an open-label, multicenter study of efaproxiral administered to patients with stage IIIa or IIIb CaC who are receiving a course of weekly cisplatin with both external beam therapy (EBT) or brachytherapy. The goal of the Phase I part of the study is to assess the safety and tolerability of escalating doses of efaproxiral in this combination and to determine the maximum tolerated dose (MTD) of efaproxiral in patients with CaC. The objective of the Phase II part of the trial is to further evaluate the safety proÞle and to assess the efÞcacy of efaproxiral at the MTD in combination with cisplatin and radiation therapy, to be determined by the disease’s progression rate at two years. The trial is expected to take about two years to complete enrollment. Efaproxiral is also showing promise in other indications.

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radical hysterectomy and pelvic lymphadenectomy: report of a Phase III Intergroup Study. Journal of Clinical Oncology. 2000;18(8):1606–1613. Peto J, et al. The cervical cancer epidemic that screening has prevented in the UK. Lancet. 2004;364(9430):249–256. Pisani P, et al. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiology, Biomarkers & Prevention. 1997;6(6):387–400. Pisani P, et al. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. International Journal of Cancer. 2002;97:72–81. Piver MS, et al. First-line chemotherapy with paclitaxel and platinum for advanced and recurrent cancer of the cervix—a Phase II study. Gynecologic Oncology. 1999;75(3): 334–337. Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat. World Population Prospects: The 2002 Revision, vol. II, The Sex and Age Distribution of Populations (United Nations publication, Sales No. E.03. XIII.7), 2003. Porras A, et al. Gemcitabine plus irinotecan (GI) in recurrent cervical cancer: A pilot study. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Journal of Clinical Oncology. July 15, 2004;22(14 suppl): 5118. Quinn M, et al. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. British Medical Journal. 1999;318(7188):904–908. Raymond E, et al. Oxaliplatin: mechanism of action and antineoplastic activity. Seminars in Oncology. 1998;25(2 suppl 5):4–12. Rein DT, Kurbacher CM, et al. Weekly carboplatin and docetaxel for locally advanced primary and recurrent cervical cancer: a Phase I study. Gynecologic Oncology. 2002;87(1): 98–103. Ries LAG. Surveillance, Epidemiology, and End Results (SEER). Cancer Statistics Review, 1973–2000. National Cancer Institute; 2003. Rose PG, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. New England Journal of Medicine. 1999;340:1144–1153. [a] Rose PG, et al. Paclitaxel and cisplatin as Þrst-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. Journal of Clinical Oncology. 1999;17(9):2676–2680. [b] Rose PG. Combined-modality therapy of locally advanced cervical cancer. Journal of Clinical Oncology. 2003;21(10 suppl):211–217. Rose PG. GOG 120: concurrent cisplatin-based chemoradiation improves progression-free and overall survival in advanced cervical cancer: results of a randomized Gynecologic Oncology Group Study. New England Journal of Medicine. Article in press. Schottenfeld D, Fraumeni JF, eds. Cancer epidemiology and prevention. 2nd ed. Oxford: Oxford University Press; 1996. Schreiber K, et al. Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors. Oncogene. 2004;23(22):3972–3979. Sigurdsson K. Quality assurance in cervical cancer screening: the Icelandic experience 1964–1993. European Journal of Cancer. 1995;31A(5):728–734.

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Chronic Lymphocytic Leukemia (CLL)

ETIOLOGY AND PATHOPHYSIOLOGY Overview Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world but is rare in Japan and other Asian countries. In 95% of chronic lymphocytic leukemias, the affected cells are B lymphocytes; in the remaining 5%, T lymphocytes are affected. CLL is further differentiated according to morphological, immunophenotypical, cytogenetic, and molecular characteristics, and the clinical course and treatment of these subtypes vary widely. Pathophysiology Mature blood cells (red cells, white cells, and platelets) are produced in the bone marrow from pluripotent hematopoietic stem cells. (Figure 1 shows the different lineages of blood cells and the stages involved in their maturation.) The blood cells mature and differentiate through a sequence of steps involving a series of complex—and incompletely understood—interactions with growth factors, cytokines, and other cells in the bone marrow. Once mature, the blood cells leave the bone marrow and enter the general circulation, where they have a limited life span. T and B lymphocytes (often known as T and B cells) are white blood cells, and they are vital constituents of the immune system. When the body is infected with a pathogen, T and B cells are mobilized to target and kill the pathogen. Although other immune cells are involved in this process, lymphocytes possess Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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Pluripotent stem cell in bone marrow

B stem cell

T stem cell

Pre-B cell

Prothymocyte

Dendritic stem cell

Dendritic cell

Myeloid stem cell

Precursor colony-forming cells

Neutrophil B lymphocyte T lymphoblast Megakaryocyte Basophil Erythrocyte Monocyte

Platelets

Eosinophil

B cell T cell

Macrophage

Plasma cell

FIGURE 1. The hematopoietic cascade: development of mature blood cells from pluripotent hematopoietic stem cells.

unique qualities that allow them to adapt during infection and become speciÞc to the invading pathogen. In addition, once an infection has been cleared from the body, most of these lymphocytes die, but a few “memory” lymphocytes remain. Upon future reinfection with the same pathogen, these cells are immediately activated, so each successive immune response is therefore quicker and more accurate than the one before. Cancer occurs when a series of genetic mutations, which are hereditary and/or environmental in nature, takes place in a single cell. The resulting cell proliferates without control and disrupts the normal functioning of the organ in which it originates. A lymphoid leukemia results when this process occurs in a T or B


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lymphocyte, and the expanding malignant cells disrupt the balance of normal blood cells in the bone marrow, blood, and lymphoid organs. Lymphoid leukemias can be acute or chronic and can arise from lymphocytes at different stages of development. CLL is a malignancy of small, morphologically mature but immunologically less mature lymphocytes that accumulate in the blood, bone marrow, lymph nodes, spleen, and liver. No single deÞned genetic mutation or abnormality is solely responsible for all CLL cases; instead, this disease is characterized by an array of different chromosomal deletions (described later). Investigators have also described a multitude of aberrations associated with apoptotic proteins, suggesting that in most cases, CLL cells accumulate as a result of an abnormally long life span rather than an accelerated rate of proliferation. The median age of onset of CLL is 65–68 years (Call TG, 1994), although approximately 20% of cases occur in people younger than age 55. Survival is dependent on the stage of disease and ranges from a median of 12 years in patients with the earliest stage to 2–5 years in those with advanced disease (Pangalis GA, 2002). CLL also tends to occur more in men than in women. Onset is usually insidious, and up to 70% of patients are asymptomatic. Diagnosis is often made following routine blood tests or investigations for an unrelated disease. In symptomatic patients, the most frequent clinical Þndings are fatigue, loss of appetite, weight loss, and enlarged lymph nodes. Table 1 lists laboratory features typical of CLL. CLL has no single pattern of progression—approximately one-third of patients never require treatment and die from causes unrelated to CLL; one-third have an initial indolent phase followed by progression; and the remaining third have aggressive disease at the outset requiring immediate therapy. CLL’s progressive symptoms are related to leukocyte inÞltration of the bone marrow, spleen, and lymphoid tissue. This inÞltration, together with disruptions in normal hematopoietic function, results in anemia, neutropenia, thrombocytopenia, and immunological dysfunction. The most important immunological dysfunction is the lack of immunoglobulins (hypogammaglobulinemia), a condition that occurs in up to 60% of patients with advanced disease. This condition leaves the patient more susceptible to infection, which is a primary cause of death and morbidity. Autoimmune disease, an immune response against the body’s own cells and tissues, occurs in 10–35% of untreated CLL patients. This condition is a natural complication of CLL but is also associated with purine analogue therapy (a common treatment for CLL); however, the exact frequency of treatment-induced autoimmune disease is unknown. The autoimmunity usually manifests as autoimmune hemolytic anemia. Immune thrombocytopenia, pure red-cell aplasia, and immune neutropenia occur less frequently. Autoimmunity is usually successfully treated with corticosteroids; steroid-refractory patients may have to undergo a splenectomy. In 3–10% of patients with CLL, the disease undergoes a transformation into a more aggressive condition distinct from CLL. The transformation is usually

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CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

TABLE 1. Laboratory Features Characteristic of Chronic Lymphocytic Leukemia Diagnostic Modality

Features Characteristic of CLL

Blood count

• >5,000 lymphocytes/microliter of peripheral blood. • Anemia and thrombocytopenia present at the time of initial diagnosis in approximately 20% of patients; both are usually mild, but their presence denotes a poor prognosis. • Polyclonal increases in gamma globulins (present in approximately 15% of patients). • Hypogammaglobulinemia (8%). • Autoimmune thrombocytopenia (3%). • Pure red-cell aplasia (0.5%). • Agranulocytosis (0.5%).

Blood smear

• A large number of small, morphologically matureappearing lymphocytes are visible; the nucleus is large, a nucleolus usually not evident, and only a thin band of cytoplasm is evident (a small proportion of lymphocytes may be larger with a larger nucleus and a visible nucleolus). • ‘‘Smudge cells’’ (ruptured cells) may be visible; these are lymphocytes that appear flattened or smudged in the process of slide preparation. • When leukocyte counts are extremely high (in excess of 200,000/mL), whole blood viscosity may be abnormally high.

Bone marrow biopsy

• The proportion of mature-appearing lymphocytes in the bone marrow aspirate exceeds 30% of all nucleated cells. • Infiltrative patterns of lymphocytes that may be nodular (10%), interstitial (30%), or diffuse (35%). A mixture of infiltrative patterns is observed in 25% of patients. • The infiltration pattern is significant in determining prognosis; diffuse infiltration is associated with advanced disease and poorer prognosis, whereas nodular and interstitial patterns (nondiffuse) are associated with lessadvanced disease and better prognosis.

Cytogenetic/molecular analysis

• Cytogenetic analysis is undertaken in research settings only.

Immunophenotypical analysis

• Low levels of surface immunoglobulin, only a single light chain. • Expression of one or more B-cell-associated antigens —CD19, CD20, and CD23. • Coexpression of CD5.


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into large-cell lymphoma (also known as Richter’s syndrome), and the prognosis for these patients is poor—median survival is six months. Transformation into prolymphocytic leukemia occurs occasionally, and transformation into acute leukemia is rare. Classification. The World Health Organization (WHO) published a consensus classiÞcation system that categorizes lymphoid disorders based on morphology, immunophenotype, genetic features, and clinical characteristics (Harris NL, 1994). Under the WHO classiÞcation system, CLL and small lymphocytic lymphoma (the lymphoid form of CLL) are grouped into a single entity (CLL). Advances in monoclonal antibody and ßow cytometry technology have established immunophenotyping as a routine diagnostic test for CLL. Using these methods, CLL is easily distinguished from other B-cell neoplasms because the cells aberrantly express CD5, a T-cell marker. Staging. Three major staging systems exist for the classiÞcation of CLL. (These systems are described in Table 2.) The original Rai system, published in 1975, consists of stages 0-IV and is based on the presence of lymphadenopathy, organomegaly, and cytopenias (Rai K, 1975), demonstrating a correlation between Rai stage and survival. This system was later modiÞed from the Þve-tier TABLE 2. Common Staging Systems Used in the Treatment of Chronic Lymphocytic Leukemia System Rai staging system

Stage

Definition

0 I II III

Lymphocytosis only Lymphocytosis and lymphadenopathy Lymphocytosis, spleen or liver enlargement Lymphocytosis and anemia (hemoglobin 50% tumor regression), and an additional 21 patients (52.5%) achieved disease stabilization. Median time to disease progression was approximately 3.5 months. Overall median survival was 6.75 months, with a one-year overall survival rate of 32.5%. The most common adverse events reported were nausea, fatigue, and an acnelike rash. Toxicities associated with the use of gemcitabine did not appear to be exacerbated by the addition of cetuximab. A Phase III, multicenter, randomized, open-label trial comparing gemcitabine alone with gemcitabine plus cetuximab in patients with locally advanced, unresectable, or metastatic disease started patient recruitment in December 2003 (www.cancer.gov). The objectives of the trial include a comparison of overall survival, time to treatment failure, toxicity, total response rate, and quality of life. Investigators will estimate tumor EGFR expression and establish a correlation to overall survival. The South West Oncology Group (SWOG) intends to recruit 704 patients from multiple centers in the United States and randomize them to receive either gemcitabine alone given on days 1, 8, 15, and 22 of course one and days 1, 8, and 15 of all subsequent courses, or gemcitabine plus cetuximab on days 1, 8, 15, and 22 of each course. Courses are given every four weeks and will be continued until disease progression. Patients will be followed for a total of three years. The results of this Phase III trial will be a pivotal factor in the approval of cetuximab for APC in the future. Erlotinib. Erlotinib (Tarceva), a small-molecule EGFR tyrosine kinase inhibitor, is under development by OSI Pharmaceuticals in alliance with Genentech and Roche. Erlotinib is in Phase III clinical trials for APC, alone and in combination with gemcitabine; Phase III studies in combination with gemcitabine were initiated in 450 APC patients at the beginning of 2003. The primary endpoint is a 33% improvement in patient survival, but OSI recently announced that erlotinib is unlikely to meet this goal.

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The NCI initiated a Phase I study of erlotinib with gemcitabine and radiotherapy in patients with APC in July 2003. This nonrandomized, open-label, single-center, dose-escalation study will determine the maximum tolerated dose of erlotinib when given in combination with chemotherapy and radiotherapy. Preliminary efÞcacy data will be generated from the 19–28 patients enrolled in this study. Farnesyl Transferase Inhibitors Overview. The proto-oncogene Ras, which encodes a small GTP-binding protein, is required for both normal intracellular signaling via RTKs (such as EGFR and VEGFR) and appropriate control of cell division. Mutated, oncogenic Ras occurs in up to 90% of PC cases, and substantial research has been invested in identifying inhibitors of Ras function. Farnesyl transferase inhibitors (FTIs) have emerged as potential therapies for the treatment of PC and other neoplastic diseases because they catalyze a critical posttranslational modiÞcation step required for Ras activity. In preclinical models, unmodiÞed Ras molecules are unable to stimulate MAP kinase, inhibiting cell division (McGeady P, 1995). Several companies, including Schering-Plough, Janssen Pharmaceutica, and Bristol-Myers Squibb, are developing FTIs. Mechanism of Action. Ras normally transduces intracellular signals from RTKs; Ras signaling activates MAP kinase, thereby stimulating the promitogenic transcription factors Fos and Jun and promoting cell proliferation. Mutations of Ras stimulate uncontrolled cell proliferation by constitutive activation of MAP kinase. Ras function requires the addition of a farnesyl (lipid) group to a cysteine residue at the carboxy-terminus of the protein. This posttranslational modiÞcation is catalyzed by farnesyl transferase; small-molecule inhibitors of this enzyme antagonize the modiÞcation of Ras, which in turn generates a näive form of Ras that is incapable of stimulating MAP-kinase-associated cell division. Tipifarnib. Tipifarnib (formerly known as R-115777; trade name Zarnestra) is a selective nonpeptideomimetic FTI in development by Janssen Pharmaceutica (a subsidiary of Johnson & Johnson). The agent is in Phase III trials in the United States and Europe for the treatment of metastatic PC; it is also under investigation for the treatment of other carcinomas, including breast cancer. Data from a large-scale, randomized Phase III trial of tipifarnib in combination with gemcitabine in previously untreated APC patients indicate no signiÞcant improvement in efÞcacy relative to gemcitabine plus placebo (Van Cutsem E, 2004). In this trial, 688 previously untreated patients with APC received either weekly gemcitabine (1,000 mg/m2 for seven weeks) followed by one week of rest and a further three weeks of therapy plus placebo or weekly gemcitabine plus tipifarnib (200 mg twice a day) for the duration of the trial. Treatment was given for a median of 85 and 98 days, respectively. No statistically signiÞcant differences were observed in the primary endpoint—median survival rate—between treatment groups receiving tipifarnib and gemcitabine and those receiving gemcitabine plus placebo (193 versus 182 days, respectively).

EMERGING THERAPIES

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SCH-66336. Schering-Plough’s SCH-66336 is an orally active FTI in Phase II development in combination with gemcitabine. In a randomized Phase II trial, 63 metastatic PC patients received either gemcitabine or SCH-66336 (200 mg twice a day) (Lersch C, 2001). The three-month, progression-free survival rate and length of median survival were greater in the gemcitabine group (31% and 4.4 months) than in the SCH-66336 group (23% and 3.3 months). However, SCH66336 was better tolerated than gemcitabine. Although the incidence of nausea, vomiting, and diarrhea was equivalent in the two groups, these side effects were more severe in the gemcitabine group. SCH-6336 patients also experienced less hematological toxicity. In a second trial, 25 evaluable patients with solid tumors received SCH-66336 in combination with gemcitabine. Two achieved partial responses, two had a minor response, and 11 had stable disease. One patient with PC maintained stable disease for more than 16 months. Preliminary data suggested there was no interaction between gemcitabine and SCH-66336 (Hurwitz HI, 2000). Thymidylate Synthase Inhibitors Overview. Inhibition of DNA synthesis is a common mechanism of action for cytotoxic agents. Folic acid antagonists (antifolates)—such as methotrexate (an established agent in chemotherapy regimens used to treat numerous neoplasms)—act by inhibiting the function of dihydrofolate reductase (DHFR), a key enzyme in the thymidylate cycle that is required for the production of the nucleotide thymidine. However, the use of methotrexate is associated with cellular resistance because tumors acquire mutations that allow escape from the cytotoxic effects of methotrexate. Many emerging antifolates are analogues of folates or methotrexate that have been rationally designed to overcome the cellular resistance associated with methotrexate. Some emerging folate antagonists inhibit the function of thymidylate synthase (TS), another component of the thymidylate cycle, which catalyzes the generation of thymidylate from deoxyurydilate. Mechanism of Action. TS inhibitors inhibit the conversion of deoxyuridylate to thymidylate; in the absence of de novo synthesis of thymidine, cells are unable to replicate their DNA prior to cell division and proliferation. Pemetrexed. Pemetrexed (Eli Lilly’s Alimta) (Figure 6) is a multitargeted antifolate (i.e., thymidylate synthase and dihydrofolate reductase inhibitor) undergoing Phase III clinical studies in the United States and Europe for the treatment of APC. The agent exerts its antitumor activity by inhibiting multiple components of the thymidylate cycle: TS, dihydrofolate reductase, and glycinamide ribonucleotide (GAR) formyltransferase. Pemetrexed’s multitargeted action may overcome the resistance acquired through the overexpression of any single enzyme. The compound is approved in the United States–in combination with cisplatin—for the treatment of patients with malignant pleural mesothelemia who cannot undergo surgery; Lilly has also Þled for pemetrexed’s approval as secondline therapy for NSCLC in Europe and metastatic NSCLC in United States.

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Negative Phase III data were disclosed at the ASCO 2004 meeting (Richards DA, 2004). The trial involved 565 patients with APC randomized to receive gemcitabine alone or gemcitabine and pemetrexed (GP). No statistical difference in overall survival (median 6.2 months for GP and 6.3 months for gemcitabine) was evident, although response rate was signiÞcantly better for GP (18.3%) than for gemcitabine monotherapy (9.1%), as was median time to progression (5.2 months for GP versus 3.6 months for gemcitabine). Progression-free survival (3.9 months versus 3.3 months) and one-year survival (21.4% versus 20.1%) were similar in both arms. More grade 3/4 toxicity was seen among PG-treated patients: neutropenia (45.1% versus 12.8%), thrombocytopenia (17.9% versus 6.2%), anemia (13.9% versus 2.9%), febrile neutropenia (9.9% versus 0.4%), and fatigue (15% versus 6.6%). Capecitabine. Capecitabine (Roche’s Xeloda) (Figure 7) is a ßuoropyrimidine. Fluoropyrimidines, which are structural analogues of naturally occurring metabolic products (generally folates, purines, and pyrimidines) needed for the synthesis of nucleic acids, act by inhibiting TS, a key enzyme in DNA synthesis. Capecitabine is marketed for the treatment of metastatic CRC and metastatic breast cancer in the United States and Europe. Phase III trials of capecitabine in combination with gemcitabine are recruiting patients with APC in Europe. Capecitabine is in Phase I/II trials for PC in the United States. A Phase II multicenter European study investigated the efÞcacy of the capecitabine/gemcitabine combination in patients with APC (Stathopoulos G,

EMERGING THERAPIES

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2004). A total of 53 therapy-näive patients were treated with gemcitabine (1,000 mg/m2 ) on days 1 and 8 and capecitabine (1,300 mg/m2 ) as total dose-perday on days 1 through 14 of a 21-day cycle. An objective partial response was achieved in 10 (18.9%) patients. Stable disease was reported in 22 (42%) patients, and the remaining 15 (28%) patients had progressive disease. The median duration of response was three months, and the median time to progression was 6.5 months. The median overall survival was eight months. One-year survival was reported as 34.8%. Side effects at grade 3 or 4 toxicity levels were recorded for anemia in 9%, thrombocytopenia in 6%, neutropenia in 34%, and febrile neutropenia in 4% of patients. Investigators concluded that the combination of capecitabine and gemcitabine is a well-tolerated regimen that requires further investigation in randomized Phase III trials. Preliminary data were disclosed at the 2004 ASCO meeting (Heinemann V, 2004). The trial randomized 135 patients to receive capecitabine/oxaliplatin, capecitabine/gemcitabine, or gemcitabine/oxaliplatin. EfÞcacy data were not available, but all three regimens were equally well tolerated. Taxanes Overview. Taxanes are potent antitumor agents; members of this class—such as paclitaxel (Bristol-Myers Squibb’s Taxol, generics)—are marketed for numerous forms of cancer, including breast cancer. As single agents and in combination with other chemotherapeutic agents, taxanes have shown activity against a range of solid tumors but have demonstrated variable efÞcacy against PC. Phase II studies have failed to conÞrm the high response rates observed in early studies. Mechanism of Action. Taxanes promote microtubule polymerization and inhibit tubulin depolymerization, arresting mitotic cell division at the metaphase/anaphase transition and inducing cell death. Docetaxel. Docetaxel (Aventis’s Taxotere) (Figure 8) has shown activity against PC. In a Phase II study in 40 patients with unresectable locally advanced or metastatic PC, 6 patients had a partial response and 15 patients had stable disease. The median duration of response was 5.1 months (Rougier P, 2000). Interest has developed in employing docetaxel in combination regimens with gemcitabine.

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In another Phase II combination trial, 40 patients with APC were enrolled to receive gemcitabine (750 mg/m2 ) and docetaxel (35 mg/m2 ) weekly for three out of four weeks for a median of four cycles. An objective response was obtained in 10 (27%) patients with a median duration of 17 weeks. Median survival was seven months and one-year survival was 19.3%. The authors conclude that, although the gemcitabine-docetaxel regimen was well tolerated, its ultimate role in the treatment of PC can only be determined by a randomized Phase III trial (Schneider BP, 2002).

Gene Therapy Overview. The withdrawal from clinical development of Onyx Pharmaceuticals’ Onyx-015—an attenuated adenovirus that preferentially replicates in p53 -deÞcient cells—suggests that gene therapy may not be a viable approach to the treatment of PC, especially given the disease’s complex biological nature. The gene therapies still in development are at relatively early stages. Mechanism of Action. The primary approach of gene therapy is to either replace or activate aberrant tumor-suppressor genes or to inactivate oncogenes by insertion of a gene or antisense DNA using a vector. Alternatively, some approaches deliver genes that confer cytotoxic function to the tumor site. Delivery mechanisms include attenuated viruses (e.g., adenoviruses, selected retroviruses) or encapsulated cell approaches. CYP2B1. Austrianova is developing CYP2B1, an encapsulated cell therapy/ifosfamide combination approach for the treatment of PC. It is undergoing Phase II trials and was granted orphan drug status in the European Union in 2003. CYP2B1 therapy requires angiographic implantation of encapsulated cells modiÞed to express cytochrome P-450 2B1 (CYP-B1). Found naturally in the liver, cytochrome P-450 is a family of enzymes that metabolize the pro-drug ifosfamide into an inactive intermediary compound, which subsequently spontaneously converts into two cytotoxic compounds. Both cytotoxic compounds have short half-lives, limiting the effectiveness of ifosfamide treatment. During therapy, genetically modiÞed cells are injected into an artery feeding the primary tumor. (The encapsulation procedure prevents attack by the host’s immune system.) Low doses of ifosfamide are injected into the patient, and the ifosfamide is locally activated by the genetically modiÞed cells, producing a high concentration of active ifosfamide metabolites at the tumor site. Data from a single-arm Phase I/II trial in 14 patients with inoperable PC indicate the potential of this approach. Ten patients showed stable disease, and median survival of treated patients was twice that of those treated with control therapy. (Salmons B, 2003). One-year survival in the treated group was 36% (twice that of the control group), and four of 13 evaluable patients reported improvements in pain assessment.

REFERENCES

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TNFerade. TNFerade, a tumor necrosis factor-alpha (TNF-α)-based gene therapy in development by GenVec, is undergoing Phase II trials for the treatment of PC. TNFerade is a replication incompetent adenovirus vector carrying TNF-α under the transcriptional control of the radiation-sensitive early growth response (EGR)-1 gene promoter. The combination of spatially and temporally restricted control of TNF-α expression and synergistic action with radiation therapy is expected to increase the efÞcacy of this agent and minimize the side effects associated with systemic administration of TNF-α. Data from Phase II trials were presented at the American Society of Clinical Oncology’s First Annual Symposium on Gastrointestinal Cancers in 2004. ThirtyÞve patients with unresectable PC were treated with TNFerade in combination with radiotherapy; after three months, 26 of 35 patients showed stable disease and four of these patients demonstrated tumor regression in excess of 50%. As a result, four patients were able to undergo surgical resections. Transient hypotension, the only therapy-speciÞc toxicity, occurred in one patient. TNFerade was efÞcacious at all doses used and the maximum tolerated dose was not reached (Hanner N, 2004). Rexin-G. Rexin-G, a gene-therapy-based approach targeting cyclin-G1, is in Phase II development in the United States by Epeius Biotechnologies. Rexin-G is an injectable retroviral vector encoding a mutant form of the cell-cycle-control molecule cyclin-G1, which normally regulates the passage of cells from G1 phase to S phase during the cell cycle. Cell-cycle arrest at this phase causes cells to die. Phase II data from three APC patients treated with Rexin-G indicate some efÞcacy. Patients were treated with one of two protocols. In the Þrst protocol, intravenous Rexin-G was administered for eight to ten days followed by a oneweek toxicity evaluation period. Subsequently, the maximum tolerated dose of Rexin-G was administered for eight to ten days. In the second protocol, intravenous Rexin-G was administered for six days followed by eight doses of weekly gemcitabine. All three patients experienced arrested tumor growth without experiencing dose-limiting toxicity. No signiÞcant side effects were reported. Two patients were reported to be alive with stable disease approximately Þve and 14 months from diagnosis. One patient remains alive with progressive disease 20 months from diagnosis (Gordon EM, 2004). REFERENCES Abbruzzese JL, et al. Phase II study of anti-epidermal growth factor receptor (-EGFR) antibody cetuximab (IMC-C225) in combination with gemcitabine in patients with advanced pancreatic cancer. Proceedings of the American Society of Clinical Oncology. 2001. Abstract 518. Ahlgren JD. Epidemiology and risk factors in pancreatic cancer. Seminars in Oncology. 1996;23:241–250. Alberts SR, et al. Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group Phase II Study. Annals of Oncology. 2003;14: 580–585.

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Prostate Cancer

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Typically, tumors of the prostate grow slowly. The vast majority arise in the subcapsular peripheral region of the posterior lobe—a region of the gland that is most sensitive to changes in androgen levels. Tumors generally originate as small, well-differentiated lesions and double in size every two to four years. As a tumor grows, the cells within it become more diverse, and the outlines of the lesion become less visible. By the time the tumor reaches 4–5 cm along its longest axis, the cancer is likely to have spread to other areas of the body and can usually be seen (typically during surgery) extending beyond the prostate gland. The cancer spreads, both locally and to distant sites, over a period of eight to ten years following the appearance of the primary tumor. Local spread typically involves the seminal vesicles, ejaculatory ducts, and pelvic lymph nodes. Undetected, the cancer continues to advance, reaching the liver and lungs; death generally occurs 12–15 years after the development of the primary tumor. Distant spread or metastatic deposits are most commonly in the bone, where the cancer grows at an accelerated pace, fueled by the presence of transferrin, a protein that is abundant in bone tissue (Weinzimer SA, 2001). Transferrin is a insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3). Recent research demonstrates that insulin-like growth factor I (IGF-I) is an important factor for the growth and survival of the LNCaP cell line, while IGF-binding protein-1 (IGFBP-1) induces apoptosis (programmed cell death) (Ngo TH, 2003). A low-fat Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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221

diet and exercise regimen reduce IGF-I and increase IGFBP-1, thereby substantially reducing IGF and prostate cancer (CaP) cell growth. This section discusses key features of CaP that inßuence approaches to medical treatment. Pathophysiology Biology of Prostate Cancer. The development and maintenance of the normal adult prostate are under the hormonal control of androgens acting through the androgen receptor (AR) (Heinlein CA, 2004). The androgens are converted to testosterone in peripheral tissues and the prostate gland. Testosterone diffuses into the epithelial or stromal cells, where it is converted into the functionally active androgen dihydrotestosterone (DHT) by the action of the 5-alpha (−α) reductase enzyme system located on the nuclear membrane (Cheng E, 1993; Russell DW, 1994). DHT binds to the androgen receptor, which undergoes a conformational change and is transported into the nucleus. Inside the nucleus of the cell, the androgen receptor (which is bound to DHT) binds to the target genes and initiates transcription. In this way, the androgen receptor ultimately controls the regulation of the cell cycle, cell growth, and cell differentiation (Cheng E, 1993; Russell DW, 1994). Prostate-Specific Antigen. Prostate-speciÞc antigen (PSA) is a protein produced in the epithelial cells of the prostate (Oesterling JE, 1988). In men younger than age 40, small amounts of PSA (less than 4 ng/mL) circulate in the blood; these levels rise naturally with age, corresponding to an age-dependent increase in prostate size. In general, the higher the PSA level in the bloodstream, the greater the chance of developing CaP. However, some men with CaP do not have high PSA levels, and two-thirds of men with elevated levels of PSA do not have CaP (Schro¨ der FH, 2004). High PSA levels may also indicate nonmalignant conditions, such as benign prostatic hyperplasia. Indeed, it has been suggested that PSA population screening could result in men making the wrong decision and having unnecessary, aggressive treatment (Schro¨ der FH, 2004). In practice, many clinicians believe that PSA velocity or doubling time is more signiÞcant than the absolute PSA level for determining the aggressiveness of the tumor. A recent study found that men with high-risk early-stage CaP (as deÞned by high PSA velocity) have a high risk of death from CaP despite radical prostatectomy (D’Amico AV, 2003). Recent Þndings from a population-based, case-controlled study reported at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2004 suggest that PSA screening among asymptomatic men may substantially reduce the risk of metastatic CaP (Kopec JA, 2004). Further research is needed to conÞrm these results in a randomized trial. A comparison study found that PSA screening of men at ages 40 and 45, then every two years beginning at age 50, would save more lives than the current model—annual screening beginning at age 50 (Ross KS, 2000). The former schedule prevented 3.3 deaths and involved an additional 7,500 tests and 450 prostate biopsies. The standard strategy (annual

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PSA testing beginning at age 50) prevented 3.2 deaths but required an additional 10,500 tests and 600 biopsies. Researchers based these estimates on a PSA level of 4.0 ng/mL for prostate biopsy. The earlier, less frequent schedule would save money and reduce the number of unnecessary biopsies performed each year. The study was primarily in white populations; consequently, these results may not apply to men of other races (Ross KS, 2000). Key applications of PSA as a tumor marker include the following: •

•

•

•

Screening of the general male population. Although widespread, ad hoc screening has clearly resulted in a shift toward the detection of earlier cancers, no prospective, controlled studies of PSA screening have shown that PSA measurement reduces morbidity or mortality (Barry MJ, 2001). Monitoring response to treatment. Failure to achieve PSA of close to 0 ng/mL after local treatment suggests that metastatic disease is already present. Detecting recurrence. A rise in PSA from initially low levels achieved following local treatment such as radiotherapy or radical prostatectomy (RP) likely reßects a recurrence of the tumor (Liao Z, 2004). The availability of the PSA test to detect recurrence (unique among solid tumors) has engendered a huge shift toward early treatment; patients are increasingly treated upon PSA rise rather than waiting several years until metastases are visible on imaging studies. Evaluation of response to novel therapies. The PSA Working Group has recommended a standardized method for reporting PSA response in Phase II trials: trials should report a decline of 50% or greater, versus less than 50%. The group based this standard on the Þndings of several small trials that statistically associated a 50% or greater decline with improved survival (Scher HI, 1999).

Research is ongoing to enhance the sensitivity of PSA testing by using one of the following markers as an adjunct: • • •

Human glandular kallikrein-2. Insulin growth factor-1. Binding protein-3.

Staging. In common with most cancers, prostate tumors are staged according to their degree of metastasis. The most commonly used staging scheme is the primary tumor, regional lymph node, and distant metastases (TNM) system, which is replacing the older Jewett-Whitmore system. Table 1 describes the TNM system in detail. The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) adopted the revised TNM staging system in 1992. This system was revised again in 1997 to include reference to tumor grade (the degree of abnormality of cancer cells compared with normal cells). The TNM system

223


TABLE 1. TNM Staging Classification System for Prostate Cancer Primary Tumor T1a T1a T1b T1c T1 T2 T2a T2b T3 T4 Any T Any T

Regional AJCC/UICC Lymph Distant Histopathological AJCC/UICC (1997) AJCC (2002) Nodes Metastasis Grade (1992) Stage Stage Stage N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

G1 G2, 3-4 Any G Any G Any G Any G Any G Any G Any G Any G Any G Any G

I I I I II II II III IV IV IV

I II II II II II II II III IV IV IV

I II II II II II II II III IV IV IV

TNM = Tumor, node, and metastasis. Note: The sixth edition (AJCC 2002) is for cancer cases diagnosed beginning in January 2003. Source: American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).

now uses broad tumor stage categories, including a stage to describe patients whose only sign of CaP is an abnormal PSA level, and assigns cancers to stages I through IV. TNM was further revised in 2002 to include new T subcategories of prostate tumors for cancer cases diagnosed from January 2003. Figure 1 shows the timescale for CaP’s progression through the disease stages. Grading. Histologically, nearly all CaP are adenocarcinomas, which are further classiÞed by grade. The Gleason scoring system (the most commonly used measure for grading CaP) recognizes that CaP is a multifocal disease with heterogeneous distribution within the gland. Thus, two individual scores, each ranging from 1 to 5, are given to the two most predominant histological patterns of CaP in a biopsy sample. The two scores are added together to give the Gleason sum. In the 1997 AJCC cancer staging manual, sums of 2–4 represent well-differentiated disease; 5–7, moderately differentiated disease; and 8–10, poorly differentiated disease. This system is slightly different in the 2002 edition, in which sums of 5–6 represent moderately differentiated disease and 7–10, poorly differentiated disease (AJCC, 2002). However, the Gleason score is emphasized as the grading system of choice, not the deÞnitions of the scores. Physicians collect the sample via a needle biopsy of the prostate, and the scores are based on morphological appearances corresponding to the size and pattern of the tumor. The Gleason score can help predict the chance of cancer spread. For example, published reports indicate risk of lymph node metastasis in the range of 2%, 13%, and 23% for patients with Gleason scores of Þve, six, and eight, respectively. Gleason scores based on samples taken after radical prostatectomy, rather than on needle biopsy samples, are more accurate and precise; these postprostatectomy samples are assigned Gleason scores to aid in decisions about adjuvant therapy (usually radiation).

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Timescale Localized disease (treated with surgery, radiotherapy, or "watchful waiting") 3 years Rising PSAa 7.5 years Metastases visible on imaging studies (hormone-responsive) 5.5 years Hormone-refractory disease 1 years Death

a. Micrometastatic disease or metastatic disease is present; disease usually responds initially to hormone therapy. Occurs in nearly half of patients treated with local therapy.

FIGURE 1. Prostate cancer disease progression.

Bone Metastases. The skeleton is the major site of CaP metastases. Approximately 70% of CaP metastases involve the skeleton, and the major cause of hospitalization of CaP patients is for the relief of bone pain (Coleman RE, 1987). CaP usually forms osteosclerotic lesions characterized by increased osteolysis (bone destruction) and increased bone formation (osteogenesis) around tumor deposits. Osteolytic metastases can cause severe pain, pathological fractures, lifethreatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes (Roodman GD, 2004). Growth factors potentially involved in increased bone formation include transforming growth factor-beta-2, basic Þbroblast growth factors-1 and -2, bone morphogenetic protein, PSA, and endothelin-1. A recent study found that patients with PSA 20 ng/mL or greater, locally advanced disease (T3 and T4), or Gleason score eight or higher are at high risk for bone metastases; such patients should therefore be considered for bone scan (Abuzallouf S, 2004). Agents that block bone resorption such as the bisphosphonates ease bone pain, spinal cord compression, and the risk of pathological fractures (Charhon SA, 1983; Oades GM, 2002). Bisphosphonates are not covered here because of their lack of direct antitumor effect in CaP; these agents are used only for symptom relief.


225

TABLE 2. Combined-Modality Risk Stratification for Prostate Cancer Risk Group Low risk Intermediate risk High risk

Diagnostic Markers PSA ≤10 ng/mL and biopsy Gleason score ≤6 and AJCC T1c or T2a PSA >10–20 ng/mL or biopsy Gleason score of 7 or AJCC T2b PSA >20 ng/mL or biopsy Gleason score of 8–10 or bilateral disease

AJCC = American Joint Committee on Cancer; PSA = Prostate-specific antigen. Source: Adapted from D’Amico AV, et al. Vital statistics following surgery or radiation for patients with clinically localized prostate cancer managed during the PSA era. Proceedings of the American Society of Clinical Oncology. 2003. Abstract 1528.

Prognostic Factors. The probability that an apparently early-stage CaP will recur after local therapy depends on the three most important clinical prognostic factors: the clinical stage of the cancer, its grade, and the PSA level before treatment. Preoperative or postoperative nomograms or “Partin tables” have been developed for localized cancers. These tables combine clinical stage, Gleason score, preoperative PSA levels, surgical margin status, lymph node status, and prostatic cap invasion to aid physicians in evaluating prognosis (Graefen M, 2002). Table 2 shows how PSA stage, AJCC stage, and Gleason score can be combined to stratify risk. When the cancer is conÞned to the prostate gland (stages I or II), median survival is likely to exceed Þve years. Patients with locally advanced cancer (stage III) usually are not curable, and most will eventually die of their tumor, although median survival may be as long as Þve to seven years. If CaP has spread to distant organs (metastatic stage IV disease), current therapies will not cure it, and median survival is usually one to three years. However, even in this last group of patients, some cancers spread slowly and the patient lives for many years with the disease. This scenario highlights the need for better prognostic indicators. In the 1997 AJCC cancer staging manual, poorly differentiated (Gleason score of eight or more) tumors are more likely to have metastasized by the time they are diagnosed and are associated with a worse prognosis. Furthermore, in the majority of studies, ßow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-speciÞc survival in some CaP patients. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. Among patients with hormone-refractory CaP, factors affecting prognosis include performance status, hemoglobin level, and serum levels of lactate dehydrogenase and alkaline phosphatase (George DJ, 1999). Potential new markers predictive of early relapse (for testing tumor samples after radical prostatectomy) include the following (Kumar-Sinha C, 2003): • • • • •

E-cadherin Microvessel density Ki-67 proliferation index Neuroendocrine differentiation Bcl-2 status

226 • • • • •

PROSTATE CANCER

HER2 status CDK1 Caveolin-1 P27 TGF-β

In each case, more studies are needed because available evidence of the predictive power of these markers is either conßicting or preliminary. Etiology The precise etiology of CaP is unknown, although studies suggest that CaP occurs as a result of complex interactions between exposure to environmental toxins and associated genetic changes and predisposition (Abate-Shen C, 2000). CaP appears in the prostate epithelial cells, where precancerous histological changes are common in men in their 20s and 30s; however, CaP does not become evident in most cases until after age 50. Genetic Influences. Genetic epidemiology of CaP remains in its infancy. Most studies have examined the effect of single genes/polymorphisms. Conßicting results have been reported for several of the genetic variations. Table 3 brießy describes the oncogenes and tumor suppressor genes (TSGs) implicated in CaP and their clinical signiÞcance. One key goal in treating CaPl is to map genes responsible for high-grade disease and to Þnd more-sensitive biological markers. A genome-wide linkage analysis of 326 affected sibling pairs, stratiÞed on the basis of Gleason score, has highlighted certain chromosomal regions as containing potential loci important in the development of aggressive disease (Witte JS, 2000). A second goal in understanding the microbiology of CaP is to explain how CaP cells protect themselves against the cytotoxic effects of chemotherapy. One hypothesis suggests that the ability of CaP cells to up-regulate the antiapoptotic proteins Bcl-2 and Bcl-xL is crucial. Bcl-2 blocks the proapoptotic release of cytochrome c from mitochondria; cytochrome c is increasingly expressed in CaP as a function of stage and grade (McDonnell TJ, 1992). All CaPs express Bcl-xL. Blocking the action of these proteins may explain the efÞcacy of taxanes in treating CaP (see “Current Therapies”). Chemosensitizing agents in development for CaP are also targeting these proteins. Androgen-Receptor Mutations. Withdrawal of androgens induces apoptosis in normal prostate epithelial cells (Kyprianou N, 1988). In CaP cells, scientists recognize three phenotypes: androgen-dependent, androgen-sensitive, and androgen-independent. Androgen-dependent tumor cells, like normal cells, die in the absence of androgen. In contrast, androgen-sensitive cells survive in the absence of androgen but grow faster if exposed to the hormone. The growth rate of androgen-independent (also called hormone-refractory) cells is unaffected by the presence of androgen. Androgen-independent cells predominate only in latestage, hormone-refractory, metastatic disease. (Figure 2 shows the sites of action


227

TABLE 3. Genetic Mutations in Prostate Cancer Gene/Protein

Function

Tumor suppressor genes (TSGs) p53 The p53 protein normally prevents the propagation of DNA damage by causing cell arrest at the G1/S checkpoint and inducing apoptosis. Mutations in p53 remove this regulatory control, allowing mutation-carrying cells to progress through the cell cycle. An intact p53 regulatory mechanism is thought to be necessary for the activity of DNA-damaging cytotoxic agents. CHEK2

RB1

PTEN/MMAC1

Glutathione S-Transferase 1 (GSTP1)

Comments

p53 is mutated in up to 75% of CaP bone metastases (Navone NM, 1999). Introduction of a wild-type p53 suppresses growth of human CaP cell that contains mutant p53 alleles, suggesting a functional role in suppressing prostate tumorigenesis (Isaac WB, 1991). Additionally, p53 protein expression is an independent prognostic marker for disease-free survival after radical prostatectomy (Bauer JJ, 1995). The cell-cycle checkpoint kinase 2 Studies of CHEK2 have shown (CHEK2) encodes an upstream germline mutations in patients regulator of p53 in the DNA with sporadic and hereditary damage signaling pathway. CaP. Most CHEK2 mutations detected were not present in 423 unaffected men (Dong X, 2003). The retinoblastoma tumor Reduced pRb expression is suppressor gene (Rb) encodes a associated with androgenprotein (pRb) that acts stimulated proliferation in the downstream of p53, also human CaP cell line causing cell arrest at the G1/S (LNCaP) (Taneja SS, 2001). The checkpoint. The p16 gene replacement of a mutated Rb regulates pRb function by gene with a normal wild-type inhibiting CDK4 enzyme activity. into CaP cell line (DU145) Inactivation of this gene, suppresses tumorigenecity in therefore, has the downstream nude mice (Bookstein R, 1990). effect of disrupting pRb-mediated cell-cycle control. Phosphatase and tensin homolog Loss of PTEN expression is (mutated in multiple advanced correlated with higher Gleason cancers) is a new TSG that has score and advanced stage been located on chromosome (McMenamin ME, 1999). A 10q23.3. PTEN phosphatase recent study also found that loss negatively regulates cell of PTEN and p27 is correlated interactions with the extracellular with an increased risk of matrix (Tamura M, 1998). recurrence (Halvorsen OJ, 2003). GSTP1 is involved in detoxifying GSTP1 is a promising screening metabolites of environmental marker for detecting carcinogens and protecting DNA organ-confined disease (Harden from oxidative damage. SV, 2003). Hypermethylation of GSTP1 gene is the most common (>90%) genetic alteration in CaP (Harden SV, 2003).

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TABLE 3. (continued) Gene/Protein

Function

Comments

BRCA1 and BRCA2 BRCA1 and BRCA2 are TSGs that Mutations of BRCA1 or BRCA2 regulate proliferation and have been reported in more than differentiation of breast epithelial 2% of Ashkenazi Jews; there cells. BRCA1 and BRCA2 have was an elevated risk of been implicated as a CaP developing CaP as well as breast susceptibility locus. and ovarian cancers (Struewing JP, 1997). RNASEL/HPC1 2’-5–oligoadenylate In small population studies, the (2-5A)-dependent ribonuclease L RNASEL allele with a termination (RNASEL) gene encodes a codon at amino acid position widely expressed latent 265 was detected in 0.54% of endoribonuclease involved in white men without CaP. The degradation of viral and cellular same mutation was detected in RNA. RNASEL is involved in the 4.3% of Finnish men with CaP innate immune response to and only 1.8% of control men. pathogens. The RNASEL gene Among Ashkenazi Jews, the has been linked to hereditary allele was present in 6.9% of prostate cancer 1 (HPC1). men with CaP and 2.9% of Evidence for RNASEL elderly men without CaP involvement in CaP is conflicting. (Rennert H, 2002). One study found no association between mutant RNASEL alleles and CaP. MSR1 MSR1 encodes a macrophage Germline MSR1 mutations have scavenger receptor that can bind been linked to CaP in some to many different ligands, families with hereditary CaP. including oxidized lipoproteins, Among men of European apoptotic cells, and bacteria. descent, MSR1 mutations were MSR1 is involved in the innate found in 4.4% of individuals immune response to pathogens. affected with sporadic CaP but Expression of MSR1 appears to only 0.8% of unaffected men (Xu be restricted to macrophages in J, 2002). Among the prostate that are abundant at African-American men, these sites of inflammation. values were 12.5% and 1.8%, respectively, indicating that MSR1 may be important in susceptibility to CaP in men of both African-American and European descent (Xu J, 2002). KLF6 Kruppel-like factor 6 (KLF6) is a Early LOH analyses have found zinc-finger transcription factor of that one KLF6 gene allele is unknown function that has been deleted in 77% of primary proposed as a candidate TSG prostate tumors; the retained that plays a role in the allele is mutated in 71% of those development of the majority of tumors (Narla G, 2001). Unlike CaPs (Narla G, 2001). wild-type KLF6 (which upregulates p21 independently of p53), tumor-derived mutants fail to reduce cell proliferation.


229

TABLE 3. (continued) Gene/Protein Oncogenes HER-2/neu (C-erbB-2)

Function

Comments

The human epidermal growth C-erbB-2 is overexpressed in up to factor HER2 is a transmembrane 60% of patients with glycoprotein with intrinsic hormone-refractory CaP. receptor tyrosine kinase activity Overexpression of C-erbB-2 involved in epithelial cell growth correlates with shorter survival and division. Overexpression of (Jorda M, 2002). High C-erbB-2 the growth receptor on the expression is associated with surface of cells enhances antiandrogen therapy and may metastatic potential. contribute to androgen-independent CaP (Shi Y, 2001). EZH2 polycomb The polycomb group protein EZH2 mRNA and protein are (enhancer of zeste homologue 2) significantly increased in is activated in advanced CaP. malignant CaP compared with EZH2 encodes the EZH2 protein, benign prostate; higher which represses transcription concentrations of E ZH2 mRNA (Karayi MK, 2004). and protein in clinically localized CaP predict poor prognosis (Varambally S, 2002). Other relevant genes and events in CaP E-cadherin and its The presence of E-cadherin and all Decreased expression of E-cad associated catenins are essential for full has been found in high-grade intracellular adhesive function of the cell prostate tumors. It is associated molecules (Pirinen RT, 2001). with recurrence after radical catenins prostatectomy (Kallakury BV, 2001). Androgens Androgens play a major role in the A gene-gene interaction study development of CaP. Androgens found that the combined effect augment the effect of of a high-risk polymorphism in carcinogens present and the AR CAG repeat and a stimulate cell division via the high-risk polymorphism in PSA androgen receptor (AR) (Nelson conferred a higher risk of CaP KA, 2002). The AR is a member than either polymorphism alone of the nuclear receptor (Xue W, 2000). Men who were superfamily of ligand-activated homozygous for the PSA G allele transcription factors. and had short AR CAG repeats Polymorphisms that may play a were at increased risk of CaP role in androgen metabolism and advanced disease. include AR, CYP17, CYP19, SRD5A2, and HSD3B2 (Ntais C, 2003). SRD5A2 SRD5A2 encodes the steroid Studies have shown that 5-a-reductase type 2 enzyme. populations with low This enzyme catalyses the 5-a-reductase activity have a conversion of testosterone into lower incidence of CaP (Ross the main prostatic androgen, RK, 1992). One study found that dihydrotestosterone (DHT). young Japanese men have lower 5-α-reductase activity than do young Caucasian-American and African-American men.

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TABLE 3. (continued) Gene/Protein Vitamin D

HPC2/ELAC2

Function

Comments

Vitamin D is a steroid hormone that Researchers have proposed that plays a role in regulating body vitamin D may influence CaP levels of calcium and risk. Several vitamin D receptor phosphorus, and in polymorphisms have been mineralization of bone. Its action investigated for their role in CaP, is mediated by its receptor. but results from reported studies have been inconsistent. In the case of several polymorphisms (e.g., the poly-A long allele), some studies have shown an increased risk is associated with vitamin D (Ingles SA, 1997), while others showed a protective effect. HPC2/ELAC2 is a candidate CaP In the general population, men who susceptibility gene on carry both of two common chromosome 17p that explains polymorphisms in the ELAC2 hereditary patterns of CaP in gene experience a modest families. HPC2/ELAC2 is increase in risk for CaP. suspected to be associated with Researchers estimate that these an increased risk of developing polymorphisms may play a role the disease. in 2–5% of CaP cases. Researchers found evidence that a mutated version of the gene raised CaP risk in 2 of 33 families who showed an inherited predisposition (Tavtigian SV, 2001).

LOH = Loss of heterozygosity. mRNA = messenger RNA.

of androgen-blocking therapies.) Additionally, androgen-independent progression from an androgen-dependent stage is associated with mutations or ampliÞcation of the androgen-receptor (AR) gene and activation of intracellular signal transduction pathways that stimulate the androgen-receptor gene. Scientists believe that androgen-independent cells come to predominate because androgen depletion exerts selection pressure that favors the growth of preexisting, androgen-independent clones (Craft N, 1999). This progression to androgen independence appears to involve adaptive up-regulation of genes that help cells survive and grow after androgen depletion, together with mutation of androgen receptors. Also contributing are loss-of-function mutations in the genes that code for components of apoptotic pathways. Recent research has demonstrated that in the absence of androgen, the androgen-receptor gene may be activated by protein kinase A and other nonhormonal growth factors (Sadar MD, 1999). Protein kinase A is blocked by certain antiandrogens (e.g., bicalutamide) but not others (e.g., ßutamide); thus, switching from one antiandrogen to another can elicit a response in some patients.


231

Hypothalamus

LHRH Inhibitors of LH secretion: estrogens, LHRH analogues, progestins

Pituitary

LH Testes

Inhibitors of steroid synthesis: ketoconazole

Inhibitors of ACTH secretion: predinisone ACTH Adrenal

Testosterone

Testosterone Dihydrotestosterone

Prostate cancer cell

5-α reductase inhibitors: finasteride

Androgen receptor Antiandrogens: flutamide, bicalutamide, nilutamide

ACTH = Adrenocorticotropic hormone. LH = Luteinizing hormone. LHRH = Luteinizing hormone-releasing hormone. FIGURE 2. Control of normal prostate cell growth and sites of action of drug therapies.

Resistance to androgen-depletion therapies develops not because of a loss of androgen receptors, which continue to be expressed, but because mutations occur in the androgen-receptor gene. These mutations probably provide a selective growth advantage to a preexisting clone of androgen-independent cells, which can begin to spread under conditions of androgen deprivation. Scientists believe that ampliÞcation of androgen-receptor expression is one mechanism through which cells might become androgen-independent. Overexpressed androgen receptors may be constitutively active (i.e., they stimulate cell growth even in the absence of androgen) or maximally stimulated by very low levels of androgen (if, for example, androgen blockade is incomplete). Risk Factors Age. A man’s age is his most important risk factor for developing CaP (Crawford ED, 2003). CaP incidence increases faster with age than does the incidence of any other major cancer. The probability of developing clinically signiÞcant CaP

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is less than 1 in 10,000 for men younger than age 39, but it skyrockets to 1 in 8 for men aged 60–79. Approximately 80% of men older than 80 have some histological, if not clinical, evidence of CaP. Race and AR-CAG Repeat Status. Epidemiological studies consistently show a higher incidence of CaP in Western Europe and the United States and lower rates in Asia. Black men in the United States have the highest incidence rates worldwide. These Þndings suggest that some racial groups are more susceptible to cancer-promoting events or are more exposed to cancer-promoting agents. CaP risk increases in Asian men when they emigrate to the United States (Whittemore AS, 1995). Studies of the racial-ethnic distribution of a CAG triplet repeat (repetitive DNA sequences) present in exon 1 of the androgen-receptor gene (AR-CAG) identiÞed a link between the size of this microsatellite, the relative risk of developing CaP, and the racial prevalence of the disease. The CAG sequence varies in length from 11 to 31 repeats in healthy men (Crawford ED, 2003). Short AR-CAG alleles (22 repeats or less) are common in African-American men but less so in Asian and Caucasian males. A small study in Caucasians found that the short AR-CAG genotype was associated with a two to three times higher risk of advanced disease (Ingles SA, 1997). However, subsequent epidemiological studies examining the link between short AR-CAG and CaP risk have had mixed results (Crawford ED, 2003). Family History. Studies have shown that slightly more than 40% of CaP cases have a heritable component. Accordingly, family history of CaP is a very important risk factor for the disease. In 1990, investigators reported that men with family members diagnosed with CaP are at signiÞcantly increased risk of developing the disease themselves (Steinberg GD, 1990). The presence of one, two, or three affected family members increased the risk of CaP by a factor of 2, 5, and 11, respectively. Inherited forms of CaP tend to develop at an earlier age than sporadic cases. A recent study of cancer risk among 45,000 twin pairs in Scandinavia found that 42% of CaP cases are inherited, while remaining cases are attributable to environmental factors (Lichtenstein P, 2000). Diet. A case-control study involving 1,655 CaP patients and 1,645 controls (matched by age, ethnicity, and region of residence) found a positive association of CaP risk and total fat intake for all ethnic groups combined (Whittemore AS, 1995). Saturated fat intake was associated with higher risks for Asian-Americans than for blacks and whites. Importantly, among foreign-born Asian-Americans, the risk increased with years of residence in North America and with saturated fat intake. Investigators estimate that differences in saturated fat intake account for 10% of black-white differences and 15% of white-Asian-American differences in CaP incidence (Whittemore AS, 1995). Investigators at the Fred Hutchinson Cancer Center found that men consuming 28 or more servings of vegetables per week had a 35% reduced risk of CaP when compared with those eating fewer than 14 servings per week (Cohen JH, 2000). Some studies have found that

CURRENT THERAPIES

233

CaP risk is reduced by dietary factors including antioxidants such as selenium, vitamin E, and carotenoid lycopene found in tomatoes (Chen L, 2001; Gann PH, 1999). Generally, the results of studies examining the effect of fruit and vegetable consumption on CaP risk have been inconsistent. Other Risk Factors. Researchers have examined occupation, smoking history, and sexual activity as potential risk factors for CaP, but none has been consistently associated with increased risk. However, smoking appears to elevate the risk of death in men with CaP (Roberts WW, 2003). CURRENT THERAPIES The main treatment modalities for prostate cancer (CaP) include “watchful waiting”; local therapy (prostatectomy or radiotherapy, either external beam radiation therapy [EBRT] or brachytherapy); hormonal therapy; and chemotherapy. Watchful waiting is generally reserved for elderly men, who, because of short life expectancy or slowly progressing disease, are likely to die with CaP rather than because of CaP. Local therapies alone can often cure patients diagnosed with early-stage (I or II) prostate-conÞned disease. Hormonal therapy is used primarily to delay disease progression when local therapies have failed. Chemotherapy is generally reserved for hormone-refractory disease to palliate symptoms. A growing trend in CaP treatment is the use of intermittent therapy. Hormonal therapies are often administered for three years or more as adjuvant therapy. Although their sideeffect proÞle is mild compared with that of many chemotherapy agents, they do have several undesirable effects (e.g., hot ßashes, sexual dysfunction, gynecomastia [excessive development of mammary glands]). To reduce these side effects and improve their quality of life, patients are increasingly requesting breaks from treatment. To establish the role and efÞcacy of intermittent hormonal therapy, the U.S. National Cancer Institute is sponsoring several trials, including SWOG-9346, CALGB-9594, and EU-99013. Estrogen and progestin were among the Þrst hormone agents used to treat CaP. These sex hormones have numerous side effects when prescribed to men, including gynecomastia (breast enlargement and tenderness), hot ßashes, and ßuid retention. More importantly, they have a tendency to boost cholesterol to levels that put patients at risk of cardiovascular disease. These have now been replaced by safer, more-effective therapies. The adrenal inhibitors aminoglutethimide (Novartis’ Orimeten/Cytadren) and ketoconazole (Janssen-Pharmaceutica’s Nizoral) have shown some evidence of a beneÞcial effect in hormone-refractory CaP. Aminoglutethimide is marketed for the palliative treatment of metastatic CaP on the basis of subjective improvements in symptoms and pain relief but has not demonstrated any beneÞt in terms of survival. Ketoconazole is not marketed for the treatment of CaP despite numerous clinical trials demonstrating a marginal beneÞt. These agents are not discussed in detail here because recent treatment advances have rendered them marginal to mainstream treatment choices.

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Table 4 summarizes the leading therapies available to treat CaP. Table 5 compares their efÞcacy, advantages, and disadvantages. Luteinizing Hormone-Releasing Hormone Analogues Overview. Luteinizing hormone-releasing hormone (LHRH) analogues are central to the treatment of all patients with hormone-sensitive CaP. LHRH analogues are an effective alternative to surgical castration (orchiectomy), a treatment to which very few men consent. To be approved, all LHRH analogues demonstrated, in open-label, randomized trials, testosterone suppression equivalent to that of orchiectomy. Testosterone suppression removes the main tumor growth stimulus and leads to tumor cell death. Regulatory authorities in the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan) have determined that any agent that suppresses testosterone to the same extent as orchiectomy will have the same antitumor effect as orchiectomy. Mechanism of Action. As illustrated in (Figure 2) (the major sites of hormone blockade), LHRH analogues exert their action on the pituitary. Initial administration of an LHRH analogue increases LHRH release from the pituitary, thereby triggering the production of testosterone from the testes and causing an initial tumor growth spurt (tumor ßare). This initial increase in testosterone production lasts approximately two to four weeks. Subsequently, the LHRH analogue blocks the effect of endogenous LHRH on the pituitary, causing a decline in body testosterone levels similar to those achieved with castration. However, unlike castration, the effects of LHRH analogues are reversible upon withdrawal of therapy. LHRH analogues suppress only androgen production by the testes and have no effect on androgen production of the adrenal glands. The fall in body testosterone achieved by androgen suppression alone is sufÞcient to cause cell death of androgen-dependent tumor cells. Formulation. To overcome their short duration of action, the majority of LHRH analogues are formulated as depot preparations. Numerous formulations are available that can provide a continuous plasma level of LHRH sufÞcient to suppress testosterone for 1–12 months. The majority of leuprolide preparations (including Tap Pharmaceutical’s Lupron, Takeda’s Enantone/Trenantone, Abbott’s Procrin/Ginecrin, and Wyeth’s Prostap) and triptorelin (Ferring/Ipsen’s Decapeptyl, PÞzer’s Trelstar) are formulated as microspheres, which are mixed with a viscous vehicle prior to administration. The resulting suspension is administered either subcutaneously or intramuscularly to form a drug depot. The active drug is released from the depot at a controlled rate into the circulation to achieve the desired drug levels for periods of one, three, four, or six months. Goserelin (AstraZeneca’s Zoladex) (Figure 3) is formulated into a solid implant that is administered subcutaneously into the abdominal wall via a preÞlled syringe. The implant disintegrates at a

TABLE 4. Current Regimens/Classes Used for Prostate Cancer Regimen or Class


Availability

Dose

Common Toxicities Impotence, gynecomastia, hot flashes, sweating, peripheral edema, gastrointestinal disturbances, mood changes, decreased libido Renal/metabolic disorder, central nervous system disorder

LHRH analogues

Leuprolide acetate (leuprorelin)

Goserelin Triptorelin

TAP Pharmaceutical’s Lupron, Takeda’s Enantone/Trenantone, Abbott Laboratories’ Procrin/Ginecrin, Wyeth’s Prostap, generics Bayer’s Viadur AstraZeneca’s Zoladex

US, F, G, I, S, UK

22.5 mg SC monthly/30 mg SC three times monthly/65 mg SC six times monthly

US US, F, G, I, S, UK, J

Pfizer’s Trelstar, Ferring/Ipsen’s Decapeptyl

US, F, G, I, S, UK

65 mg SC every 12 months 3.6 mg SC monthly/10 mg SC three times monthly 3 mg SC monthly/11.5 mg SC three times monthly

Buserelin

235

Sanofi-Aventis’s Superfact/Profact, Sanofi-Aventis/Mochida’s Supurecur, generics Nonsteroidal antiandrogens

F, G, I, S, UK, J

0.5 mg SC q8h for seven days, then intranasal six times each day

Bicalutamide

AstraZeneca’s Casodex


50/150 mg

Flutamide

Schering-Plough’s Eulexin/Eulexine/Drogenil, Nippon-Kayaku’s Odyne, generics


750 mg qd

Pain, headache, dizziness, itching, mental depression, paranoia Headache (in the case of nasal administration) Impotence, hot flashes, fatigue, gastrointestinal disturbances, cardiovascular disorder, renal toxicity, gynecomastia Neurological disorder, pain, infection, alopecia, rash Liver toxicity, depression

236



Availability

Dose

Common Toxicities

Steroidal antiandrogens Cyproterone Schering’s Androcur/Cyprostat, acetate Jenapharm’s Androcur, generics

F, G, UK

200–300 mg

Benign and malignant liver changes, adrenal-cortical suppression, thromboembolism, osteoporosis

Combined androgen blockade An LHRH analogue A nonsteroidal antiandrogen


monthly/three times monthly 50/150 mg qd

Impotence, gynecomastia, hot flashes, sweating, peripheral edema, gastrointestinal disturbances, mood changes, decreased libido


280 mg po tid for eight weeks, then 140 mg po tid 75 mg/m2 IV every 21 days plus 5 mg of prednisone daily continuously

Gastrointestinal toxicity

Docetaxel 70 mg/m2 on day one; estramustine 280 mg po q6h for five doses

Neutropenia, thrombocytopenia, fatigue, diarrhea, nail changes, edema, asthenia

12 mg/m2 on day 1 of a 21-day cycle; prednisone 5 mg po qd continuously

Neutropenia

Chemotherapy regimens Estramustine Pfizer’s Emcyt/Estracyt, Nihon (single agent) Kayaku’s Estracyt, generics Docetaxel/ Sanofi-Aventis’ Taxotere prednisone

Docetaxel/ estramustine

Mitoxantrone/ prednisone


Merck’s Decortin generics Sanofi-Aventis’s Taxotere

US, F, G, I, S US, F, G, I, S, UK, J

Pfizer’s Emcyt/Estracyt, Nihon Kayaku’s Estracyt, generics Serono/Wyeth Lederle’s Novantrone, Baxter’s Onkotrone


Merck’s Decortin, generics


Neutropenia, bone pain, infection, fatigue, diarrhea

US, F, G, I, S

US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan. IM = Intramuscular; IV = Intravenous; LHRH = Luteinizing hormone-releasing hormone; po = Orally; q8h = Every eight hours; qd = Once each day; SC = Subcutaneous; tid = Three times daily. Note: In most European countries, prednisolone is used in place of prednisone, which is used primarily in the United States.

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controlled rate, thus providing a constant plasma level of goserelin for one or three months depending on the preparation used. Buserelin (SanoÞ-Aventis’s Superfact/Profact, SanoÞ-Aventis/Mochida’s Supurecur, generics) is the only product formulated into a nasal spray. Owing to LHRH analogues’ short duration of action, Superfact must be administered six times a day. In contrast, Bayer’s Viadur is a nonbiodegradable implant with 12-month activity. Viadur is a titanium alloy reservoir of leuprolide that relies on osmosis to pump the active drug into the systemic circulation at a rate of 120 micrograms each day. After 12 months, the spent reservoir must be removed (Alza, 2002). Viadur requires comparatively complex surgical implantation and removal. Leuprolide. Leuprolide (Figure 4) is formulated into Þve branded products, all of which vary slightly in their presentation, but their clinical effect is identical. TAP Pharmaceutical markets leuprolide as Lupron in the United States for the treatment of both CaP and breast cancer (CaB), while Takeda markets it as Enantone/Trenantone in France, Germany, and Italy for the same indications. It is available in a one-, three-, and four-month depot preparations formulated into a suspension for subcutaneous (SC) injection. Wyeth’s Prostap is marketed in the United States and the United Kingdom for the treatment of advanced CaP. Prostap is available in both one- and three-month preparations formulated into an aqueous suspension for SC administration. Abbott Laboratories’ Procrin/Ginecrin is marketed for CaP in Spain, where it is available in one- and four-month doses. Bayer’s Viadur was launched in the United States in 2000; it is the only product marketed with a 12-month dose duration. Alza is the patent holder and sole manufacturer of Viadur, but in 2000, the company signed a commercialization agreement with Bayer to market Viadur in the United States. Viadur is marketed only for the treatment of CaP. Treatment with leuprolide stimulates testosterone secretion for the Þrst month and may cause tumor ßare, but the concurrent administration of an antiandrogen (discussed in the sections “Nonsteroidal Antiandrogens” and “Steroidal Antiandrogens”) will prevent tumor ßare. Goserelin. AstraZeneca’s Zoladex is marketed for the treatment of CaP, CaB, endometriosis, uterine Þbroids, and assisted reproduction. Goserelin is available in one- and three-month implant dosage forms. An analogue of endogenous LHRH, goserelin, like leuprolide, stimulates testosterone production for the Þrst month, but chronic goserelin administration completely blocks the production of endogenous LHRH. Because goserelin is formulated into a disintegrating pellet to achieve an SC depot, the gauge of the syringe required to deliver the intact pellet is large and therefore unpopular among some patients. It is also recommended that the SC injection be given only into the abdominal wall. Triptorelin. Triptorelin (PÞzer’s Trelstar, Ferring/Ipsen’s Decapeptyl) is marketed for the treatment of advanced CaP only. Ferring markets triptorelin in

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TABLE 5. Comparison of Current Therapies for Prostate Cancer Treatment LHRH analogues

Nonsteroidal antiandrogens

Steroidal antiandrogens Combined androgen blockade

Estramustine (single agent)

Estramustine/ docetaxel

Docetaxel/ prednisone

Mitoxantrone/ prednisone Watchful waiting

Advantages • Reversible suppression of testosterone. • More acceptable to men than castration. • 1-, 3-, 4-, and 12-month depot injections available.

Disadvantages • Chronic therapy causes testicular atrophy and is associated with decreased libido. • Loss of bone mineral density.

• No suppression of testosterone production. • Oral therapy.

• Significant risk of cardiac disorders.

• Oral therapy.

• Numerous side effects associated with adrenocortical suppression.

• Total androgen deprivation removes tumor growth stimulus. • Removal of tumor-flare risk associated with initial LHRH therapy.

• Increased number and frequency of side effects compared with single-agent treatment.

• Cytotoxic agent that also causes testosterone suppression.

• No survival advantage provided by therapy. • Significantly more toxic than androgen therapy.

• Provides a three-month survival advantage to patients with hormone-refractory disease.

• More toxic than single-agent cytotoxic therapy. • Significantly more toxic than endocrine therapy.

• Provides a survival advantage to patients with hormone-refractory disease. • Less toxic than combination chemotherapy.

• Significantly more toxic than endocrine therapy.

• Well tolerated therapy hormone-refractory disease.

• No proven survival advantage.

for

• No side effects and noninvasive.

• Appropriate only for elderly patients with slow-growing tumors. • Requirement for regular PSA testing. • Survival disadvantage for men with life expectancy longer than 15 years.

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TABLE 5. (continued) Treatment

Advantages

Radical prostatectomy

• Effective treatment of young patients. • Associated with the lowest risk of relapse of all treatments (Oesterling J, 1997).

Disadvantages

• Surgery associated with significant morbidity, including incontinence, impotence, urethral stricture, and rectal injury.

Radiation therapy • Effective treatment for inoperable tumors. • Local therapy with limited toxicity.

• Associated with morbidity caused by damage to surrounding tissue, including impotence, incontinence, proctitis, cystitis, rectal and urethral strictures, and bowel obstruction.

LHRS = Luteinizing hormone-releasing hormone.

H-5-OxoPro-His-Trp-Ser-Tyr-D-Ser(t-Bu)-Leu-Arg-Pro-NHNHCONH2 FIGURE 3. Structure of goserelin.

H-5-OxoPro-His-trp-Ser-Tyr-D-Leu-Leu-Arg-ProNHCH2CH3 CH3COOH FIGURE 4. Structure of leuprolide.

Germany; Ipsen is responsible for marketing in France, Italy, Spain, and the United Kingdom; and PÞzer owns marketing rights in the United States. An analogue of endogenous LHRH, triptorelin, like leuprolide and goserelin, stimulates testosterone production for the Þrst month, but chronic administration of the compound completely blocks the production of endogenous LHRH. Unlike other LHRH analogues, triptorelin’s marketing approval prevents the drug from being prescribed to men with bone metastases who are at risk of spinal cord compression caused by tumor ßare. Buserelin. Buserelin (SanoÞ-Aventis’ Superfact/Profact, SanoÞ-Aventis/ Mochida’s Supurecur, generics) is marketed in Europe and Japan for the treatment of advanced CaP. It is not available in the United States. The compound is available as a subcutaneous (SC) injection and nasal spray. An analogue of endogenous LHRH, buserelin stimulates testosterone production for the Þrst month. Chronic administration of the compound then completely blocks the production of endogenous LHRH.

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Buserelin is not available in depot formulation. For the Þrst seven days, patients are administered an SC injection every eight hours. Patients are then switched to the less invasive nasal spray, which must be administered six times a day. Luteinizing Hormone-Releasing Hormone Antagonists Overview. LHRH antagonists are the most recent class of hormonal therapy to enter the CaP armamentarium. Mechanism of Action. Compared with LHRH analogues (e.g., goserelin, leuprolide acetate), which produce their effect by activating and then desensitizing androgen-producing cells to LHRH, LHRH antagonists directly block the effect of the releasing hormone. Abarelix. NOTE: This drug has been discontinued. The LHRH antagonist abarelix (Praecis Pharmaceuticals/Schering AG’s Plenaxis) received FDA approval in 2003 for the palliative treatment of men with advanced, symptomatic CaP for whom the temporary testosterone “ßare” associated with LHRH analogue treatment could be dangerous and who refuse orchiectomy. However, in 2005, Praecis Pharmaceuticals has voluntarily discontinued selling Plenaxis to new patients in the United States for economic/commercial reasons. In fact, clinicians interviewed say, ßare is easily prevented by combining an antiandrogen with an LHRH analogue and that abarelix never fulÞlled an urgent unmet need. Nonsteroidal Antiandrogens Overview. The three marketed nonsteroidal antiandrogens have similar clinical activity and differ only in their marketing authorizations. The following paragraphs proÞle the two most widely used antiandrogens: bicalutamide (AstraZeneca’s Casodex) (Figure 5) and ßutamide (Schering-Plough’s Eulexin/Eulexine/Drogenil, Nippon-Kayaku’s Odyne, generics) (Figure 6). Nilutamide (SanoÞ-Aventis’s Nilandron) is indicated only for the treatment of metastatic (stage IV) CaP in combination with surgical castration and is unavailable in most of Europe. Like the LHRH analogues, the antiandrogens have no direct antitumor activity and rely on androgen deprivation to kill androgendependent tumor cells. Unlike the case for the LHRH analogues, their clinical efÞcacy has been proven in placebo-controlled clinical trials assessing tumor response. Mechanism of Action. Nonsteroidal antiandrogens prevent binding of testosterone and dihydrotestosterone (DHT) (androgens) to the androgen receptor within normal and cancerous prostate cells (Figure 2). In this way, they stop prostate cell growth. Nonsteroidal antiandrogens have a higher antiandrogenic activity than steroidal antiandrogens (discussed in more detail in the next section). Because they do not suppress testosterone production, they are not as frequently

CURRENT THERAPIES

HO O F

CH3 O

S

241

CF3

HN

CN

O FIGURE 5. Structure of bicalutamide.

CH3 H N H3C

CF3

O NO2 FIGURE 6. Structure of flutamide.

associated with impotence or atrophy of the testis. In addition, they do not have the side effects associated with steroidal antiandrogens. Nonsteroidal antiandrogens are prescribed a few days before the initiation of LHRH analogue therapy. By preventing the initial surge in testosterone levels that can cause a tumor growth spurt, they prevent tumor ßare. Formulation. Currently available nonsteroidal antiandrogens are administered orally. Bicalutamide (AstraZeneca’s Casodex) is administered once daily, while ßutamide (Schering-Plough’s Eulexin/Eulexine/Drogenil, NipponKayaku’s Odyne, generics) must be administered three times a day. Bicalutamide. Bicalutamide (AstraZeneca’s Casodex) is marketed for the treatment of stage IV CaP in combination with LHRH therapy (combined androgen blockade, discussed later) or surgical castration. High-dose bicalutamide (150 mg daily) is also marketed for the treatment of locally advanced CaP as an adjuvant to prostatectomy or radiotherapy. Patients with locally advanced CaP who are not candidates for surgical castration or other interventions (including prostatectomy, radiotherapy) can be treated with bicalutamide monotherapy. In clinical trials, bicalutamide as a single-agent therapy demonstrated a survival advantage in patients with locally advanced CaP. However, in men with metastatic disease, bicalutamide must be combined with an LHRH analogue to provide a survival advantage over castration. Two multi-center trials with identical protocols randomized 1,453 patients with locally advanced (tumor, node and metastasis [TNM] stage T3/T4 M0) or metastatic disease (TNM stage T4 M1) to either 150 mg bicalutamide each day or castration (Tyrrell CJ, 1998). Pooled analysis at a median follow-up of 100 weeks for both studies found bicalutamide was less effective than castration in patients with metastatic disease. Castration improved median survival by six weeks over bicalutamide. Bicalutamide provided a signiÞcant improvement only in subjective response: 70% versus 58% over castration in men with

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symptomatic metastatic CaP. Quality-of-life questionnaires found bicalutamide treatment offered an advantage in terms of sexual interest and physical capacity and a substantially lower incidence of hot ßashes compared with castration. Pooled analysis of two trials involving patients with nonmetastatic CaP was completed after four years of follow-up (Iversen P, 1998). A total of 480 patients with TNM stage T3/T4 nonmetastatic disease were randomized to bicalutamide 150 mg each day or castration (either orchiectomy or goserelin). Bicalutamide monotherapy was statistically equivalent to castration in the pooled survival analysis. Different end points for time to treatment failure and objective progression between the two trials prevented pooled analysis of these end points. However, one trial favored bicalutamide and the other favored castration. Men treated with bicalutamide maintained a higher sexual interest and capacity than those who were castrated. Because of its poor clinical performance, bicalutamide should not be used as monotherapy in patients with metastatic disease. Gynecomastia (breast enlargement and tenderness) occurs in up to 10% of patients. Hot ßashes, depression, decreased libido, and weight gain occur less frequently. Flutamide. Flutamide (Schering-Plough’s Eulexin/Eulexine/Drogenil, NipponKayaku’s Odyne, generics) is marketed for the treatment of advanced (stage IV) CaP in combination with an LHRH analogue or as monotherapy in castrated patients. Patients who have failed, or are not able to tolerate, other forms of hormone manipulation can also be treated with ßutamide. Flutamide in combination with an LHRH analogue is also marketed for the initial treatment of bulky tumors conÞned to the prostate or those that extend beyond the prostate capsule. Clinical data do not support ßutamide monotherapy in noncastrated patients. Flutamide as a treatment for metastatic CaP is discussed in the upcoming section “Combined Androgen Blockade.” Flutamide must be administered orally every eight hours, which is considerably more inconvenient than bicalutamide’s oncedaily administration. It is associated with hepatic injury—mainly transaminase abnormalities, cholestatic jaundice, hepatic necrosis, depression, and hepatic encephalopathy. The hepatic injury can be fatal. Steroidal Antiandrogens Overview. Chronic administration of steroidal androgens can suppress adrenocortical function (i.e., interfere with the body’s ability to regulate endogenous steroid production). These agents have been replaced by the nonsteroidal antiandrogens, which lack this complicating side effect. Mechanism of Action. Steroidal antiandrogens prevent binding of testosterone and dihydrotestosterone (DHT) (androgens) to the androgen receptor within normal and cancerous prostate cells (Figure 2). In this way, they stop prostate cell growth. Steroidal antiandrogens have less antiandrogenic activity than nonsteroidal antiandrogens, but because they have a progestin-like effect on the pituitary, they can reduce the secretion of luteinizing hormone from the pituitary.

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FIGURE 7. Structure of cyproterone acetate.

As a result, steroidal antiandrogens can reduce testosterone secretion to levels similar to those achieved by castration (Figure 2). Cyproterone Acetate. Cyproterone acetate (Schering’s Androcur/Cyprostat, Jenapharm’s Androcur, generics) (Figure 7) is marketed in France, Germany, and the United Kingdom for the treatment of CaP. It is approved for the suppression of tumor ßare with initial LHRH analogue therapy, for the treatment of metastatic CaP when alternative treatment interventions are contraindicated or not tolerated, and for the treatment of hot ßashes in castrated men receiving LHRH analogues. Numerous trials have been conducted to elucidate cyproterone’s activity in the treatment of locally advanced or metastatic CaP. The pivotal trial in this quest was conducted by the Urological Group of the European Organization for Research on Treatment of Cancer. The Phase III trial randomized 210 patients to receive cyproterone, medroxyprogesterone, or diethylstilbestrol therapy (Pavone-Macaluso M, 1986). Of the three drugs studied, patients treated with medroxyprogesterone had a signiÞcantly shorter duration of time to progression and survival than did those receiving diethylstilbestrol or cyproterone. There was no signiÞcant difference between diethylstilbestrol and cyproterone in terms of overall survival, time to progression, and tolerability. A review of the aforementioned trial and the drugs available in 1988 concluded that the safest and most cost-effective endocrine treatment for metastatic CaP was orchiectomy (Bollack C, 1988). Cyproterone’s steroidal effects are responsible for the majority of its side effects, of which the most serious are benign and malignant liver changes. Adrenocortical suppression can occur, so patients must be monitored for the duration of treatment. Thromboembolism is a considerable risk for patients with a history of thrombosis or diabetics with microvascular disease. Diabetics must be monitored continually because cyproterone can change carbohydrate metabolism. The compound is also linked to osteoporosis. Combined Androgen Blockade Overview. Combined androgen blockade (CAB)—sometimes called androgendeprivation therapy—is the simultaneous administration of an LHRH analogue

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and an antiandrogen. A huge number of randomized, controlled trials have been undertaken to assess the beneÞt of adding an antiandrogen to LHRH therapy. Mechanism of Action. The individual components of this regimen contribute the following mechanisms to achieve the overall regimen activity: •

•

LHRH analogues competitively bind to the pituitary LHRH receptors. After initial stimulation of testosterone production, total block occurs (Figure 2). LHRH analogues suppress testosterone levels to levels achieved by castration. Nonsteroidal antiandrogens prevent binding of testosterone and dihydrotestosterone (DHT) (androgens) to the androgen receptor within normal and cancerous prostate cells (Figure 2). In this way, they stop prostate cell growth.

The combination of blocking androgen production via the pituitary and blocking the effect of androgens produced from other sources, including the adrenal glands, completely removes the endocrine growth stimulus on the tumor cells. An additional beneÞt of combining treatment is prevention of the initial tumor ßare that occurs in the Þrst month of LHRH analogue therapy. The initial surge in testosterone production has no growth effect on tumor cells because the antiandrogen blocks the androgen receptors. Clinical Performance. A National Cancer Institute (NCI) intergroup trial randomized 600 patients to receive either leuprolide or leuprolide plus ßutamide (Crawford ED, 1989). Initially, patients receiving CAB appeared to have a longer time to disease progression (16.5 versus 14 months) and improved survival (37 versus 28 months), but subsequent meta-analyses showed mixed results. For example, the most recent update of the CaP Trialists’ Collaborative Group metaanalysis (CaP Trialists’ Collaborative Group, 2000) found that outcome depends on the antiandrogen used. In this meta-analysis, which comprised 27 clinical trials and 8,000 patients, CAB with nonsteroidal antiandrogens was associated with an 8% reduction in the risk of death and a 2.9% beneÞt in Þve-year survival; in contrast, CAB with the steroidal antiandrogen cyproterone acetate was associated with a 13% increased risk of death and a 2.8% reduction in Þve-year survival. The aforementioned meta-analysis implies that differences among antiandrogens may account for the discrepancy in CAB’s efÞcacy. One hypothesis suggests that activation of the androgen receptor induced by protein kinase A is differentially blocked by various nonsteroidal androgens (Klocker H, 1999; Sadar MD, 1999). Androgen-independent tumor growth may occur because growth factors such as protein kinase A activate the androgen receptor. The achievement of second-line tumor responses by a change in antiandrogen (e.g., from ßutamide to bicalutamide) supports this hypothesis. Estramustine (Single Agent) Overview. Until recently, estramustine (PÞzer’s Emcyt/Estracyt, Nihon Kayaku’s Estracyt, generics) (Figure 8) was one of two chemotherapeutic agents marketed for the treatment of CaP. Estramustine was speciÞcally designed to

CURRENT THERAPIES

O H3C

O

P

245

O− Na+ O− Na+

H O H

H

Cl N

O

Cl FIGURE 8. Structure of estramustine.

combine antiandrogen activity with cytotoxicity. Its poor clinical performance as a single agent prompted researchers to assess estramustine in combination with other cytotoxics. One such study is discussed in the upcoming section “Docetaxel/Estramustine.” Mechanism of Action. Estramustine’s exact mechanism of action is unknown. Researchers postulate that it has a dual mechanism of action. Prior to metabolism, the intact molecule has an antimitotic action, possibly achieved by the stabilization of microtubule dynamics by binding to a novel site in tubulin (Panda D, 1997). Additionally, some of the metabolites exert an antigonadotrophic effect owing to their estrogen-like activity. This antigonadotrophic effect suppresses testosterone. Clinical Performance. In a randomized, Phase III trial conducted by the Urological Group of the European Organization for Research and Treatment of Cancer, 227 patients with T3 or T4 CaP were randomized to estramustine or diethylstilbestrol therapy (Smith PH, 1986). The patients in the estramustine arm received a dose of 280 mg twice a day for the Þrst eight weeks, after which the dose was reduced to 140 mg twice a day. Patients randomized to the diethylstilbestrol arm were treated with 1 mg three times each day. Duration of response was made by assessment by palpation of local tumor response. Patients treated with diethylstilbestrol had a signiÞcantly better local tumor response, but the investigators found no signiÞcant difference between the two drug treatments in response rate of metastases, interval to local and distant progression, and overall survival. Diethylstilbestrol was signiÞcantly more cardiotoxic than estramustine, while estramustine caused gastrointestinal toxicity in 25 patients, six of whom stopped treatment. Docetaxel/Prednisone Overview. In May 2004, the FDA approved the regimen of docetaxel (SanoÞAventis’s Taxotere) (Figure 9) plus prednisone (Merck’s Decortin, generics) (Figure 10) for the treatment of hormone-refractory CaP. This regimen’s apparent efÞcacy is prompting further research in the use of docetaxel in combination with other chemotherapy agents in the hope of improving overall survival for

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CH2OH C O

H3C

O OH

H3C


this indication. In November 2004, docetaxel was approved in Europe for the treatment of metastatic, hormone-refractory CaP. Mechanism of Action. The individual components of the docetaxel/ prednisone regimen contribute the following mechanisms to achieve its overall activity: •

•

Docetaxel is a taxane. Taxanes inhibit the dynamic reorganization of microtubule networks, which is essential to vital interphase and mitotic cellular functions. Docetaxel, which achieves selective toxicity against rapidly proliferating cells, is mainly active in the S phase of the cell cycle. Prednisone is a glucocorticosteroid. This class of drugs reduces the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Glucocorticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. The addition of glucocorticosteroids to chemotherapy regimens may augment their efÞcacy.

Clinical Performance. The TAX-327 study stratiÞed 1,006 patients with histologically proven, hormone-refractory, metastatic CaP by pain and performance status and randomized the patients to one of three treatment arms (Tannock IF, 2004). The trial’s primary end point was survival, and secondary end points were PSA response, pain, and toxicity. Patients in arm A received prednisone (5 mg orally twice daily) and docetaxel (75 mg/m2 every three weeks for ten cycles); arm B patients received the same dose of prednisone plus docetaxel 30 mg/m2 weekly for Þve weeks out of six for Þve cycles; and arm C patients received

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the same dose of prednisone and 12 mg/m2 mitoxantrone every three weeks for ten cycles. Grade 3 or 4 toxicities occurred in the following percentages of patients in arms A, B, and C, respectively: neutropenia 32%, 1.5%, and 21.7%; bone pain 7.8%, 7.3%, and 9.9%; infection 5.7%, 5.5%, and 4.2%; fatigue 4.5%, 5.5%, and 5.1%; and diarrhea 2.1%, 4.8%, and 1.2%. Although the investigators stated that baseline characteristics were similar in each arm, they did not provide information regarding these characteristics (e.g., median age, baseline PSA value, performance status). The median survival times in arms A, B, and C were 18.9 months, 17.4 months, and 1.5 months, respectively. A p-value for the difference in median survival was not presented, but the hazard ratio for patients treated with docetaxel every three weeks (arm A) relative to mitoxantrone (arm C) was signiÞcantly reduced: hazard ratio 0.76 (95% conÞdence interval [CI] 0.62–0.94), p = 0.009. The hazard ratio for the docetaxel arms combined remained signiÞcantly reduced—hazard ratio 0.83, 95% CI 0.7–0.99, p = 0.04—but the hazard ratio for weekly docetaxel (arm B) relative to the mitoxantrone arm (arm C) was not signiÞcantly reduced. Patients with baseline pain intensity greater than two were assessed for their pain response, and patients with baseline PSA greater than 20 ng/mL were assessed for their PSA response. Again, patients in arm A achieved a signiÞcantly higher rate of pain response than did those in arm C (35% versus 22%), p = 0.01, and a signiÞcantly higher PSA response (45% versus 32%). Because of its impact on survival, arm A (prednisone with thrice-weekly docetaxel) is deemed the most effective treatment for metastatic, hormonerefractory CaP. Docetaxel/Estramustine Overview. Researchers have investigated estramustine in combination with many chemotherapy agents. For example, the combination of estramustine with docetaxel (SanoÞ-Aventis’ Taxotere) has achieved promising results. However, the FDA’s May 2004 approval of docetaxel/prednisone for the treatment of hormone-refractory CaP means that the docetaxel/estramustine combination is unlikely to be widely used. Mechanism of Action. The individual components of the docetaxel/ estramustine regimen contribute the following mechanisms to achieve its overall activity: •

•

Docetaxel is a taxane. Taxanes inhibit the dynamic reorganization of microtubule networks, which is essential to vital interphase and mitotic cellular functions. Docetaxel, which achieves selective toxicity against rapidly proliferating cells, is mainly active in the S phase of the cell cycle. Estramustine’s exact mechanism of action is unknown. Researchers postulate that it has a dual mechanism of action. Prior to metabolism, the intact molecule has an antimitotic action, possibly achieved by the stabilization

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H N OH

O

HN

OH

O

HN

OH

OH N H

FIGURE 11. Structure of mitoxantrone.

of microtubule dynamics by binding to a novel site in tubulin (Panda D, 1997). Additionally, some of the metabolites exert an antigonadotrophic effect owing to their estrogen-like activity. This antigonadotrophic effect suppresses testosterone. Clinical Performance. At the 2004 American Society of Clinical Oncology (ASCO) Conference, the Southwest Oncology Group (SWOG-9916) presented the results of a trial comparing docetaxel plus estramustine with mitoxantrone plus prednisone in 770 patients with hormone-refractory CaP (Petrylak DP, 2004). All patients were premedicated with 60 mg dexamethasone. Patients in the docetaxel/estramustine arm received 60 mg/m2 docetaxel by intravenous (IV) infusion on day 2 plus 280 mg estramustine orally days 1–5. Patients in the mitoxantrone/prednisone arm received mitoxantrone 12 mg/m2 IV on day 2 plus 5 mg prednisone orally, twice each day. Cycles were given every 21 days. If no grade 3 or 4 toxicities occurred, the patient’s dose was escalated to 70 mg/m2 docetaxel and 14 mg/m2 mitoxantrone. The study was designed to detect a 33% difference in survival. Arms were balanced for age, race, performance status, PSA, and symptoms. The median survival of men treated with docetaxel versus mitoxantrone was 18 months versus 15 months (p = 0.008). Median time to progression was also higher in the docetaxel arm (six months versus three months, p < 0.0001). Response rates in measurable disease were not signiÞcantly different. Grade 3 or 4 toxicities were reported in 54% of patients treated with docetaxel and 34% of patients treated with mitoxantrone. This difference arose from higher rates of gastrointestinal and cardiovascular toxicity. There was no signiÞcant difference in deaths due to toxicity (2% in the docetaxel arm versus 1% in the mitoxantrone arm). Mitoxantrone/Prednisone Overview. Mitoxantrone (Serono/Wyeth Lederle’s Novantrone, Baxter’s Onkotrone) (Figure 11) is marketed for the treatment of hormone-refractory metastatic CaP in combination with prednisone. Despite mitoxantrone’s inability to improve overall survival, it is well tolerated and thus an appropriate palliative treatment.

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Mechanism of Action. The individual components of the mitoxantrone/ prednisone (MP) regimen contribute the following mechanisms to achieve their overall activity: •

•

Mitoxantrone is an antitumor antibiotic. It is an anthracenedione and structural analogue of the antibiotic anthracyclines. Mitoxantrone’s exact mechanism of action is unknown, but it intercalates with DNA to cause interstrand and intrastrand cross-linking. Mitoxantrone also causes DNA strand breaks by binding with the phosphate backbone of DNA. The agent is cell-cycle-phase-nonspeciÞc. Mitoxantrone also impairs the strandreunion reaction of topoisomerase II. These effects result in the production of protein-linked, double-stranded DNA breaks. Although mitoxantrone is cytotoxic to cells throughout the cell cycle, cells in late S phase are most sensitive. Prednisone is a glucocorticosteroid. This class of drugs reduces the inßammatory response to tumor tissue by preventing white blood cells from functioning to produce swelling and pain around the tumor site. Glucocorticosteroids induce lysis of peripheral lymphocytes and slow lymphocyte production. The addition of glucocorticosteroids to chemotherapy regimens may augment their efÞcacy.

Clinical Performance. Many randomized trials have conÞrmed mitoxantrone’s palliative activity. In one study, 161 hormone-refractory, metastatic CaP patients with pain were randomized to receive either mitoxantrone 12 mg/m2 IV on day 1 of a 21-day cycle plus 5 mg of prednisone orally each day continuously, or prednisone 10 mg daily (Tannock IF, 1996). Patients who failed to respond to prednisone could switch to mitoxantrone. The primary endpoint was a reduction in pain by a scale factor of two in a six-point scale for the duration of two evaluations (which were at least three weeks apart) without an increase in analgesic use. The secondary endpoints were a reduction of 50% or more in duration of pain response and the use of analgesic medication without an increase in pain, and an increase in overall survival. Palliative responses were observed in 29% of patents treated with MP versus 12% (p = 0.01) of patients who received prednisone alone. An additional seven patients in each treatment arm were able to reduce analgesia requirements without an increase in pain symptoms. The median duration of palliation was longer in the MP arm: 43 weeks versus 18 weeks (p = 0.001). Eleven patients who were initially randomized to single-agent prednisone responded after mitoxantrone was added. There was no difference in overall survival. Treatment was well tolerated; only Þve incidences of cardiac toxicity occurred in a total of 130 patients who received mitoxantrone. Most responding patients experienced a reduction in PSA levels from base line. Nonpharmacological Approaches Watchful Waiting. Watchful waiting (no treatment other than observation with PSA testing) is a standard approach for men who choose to postpone or avoid

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treatment, with its associated side effects, until the cancer begins to affect quality of life (by causing pain or interfering with urinary function) or PSA velocity increases. Watchful waiting is appropriate for men with a life expectancy of less than ten years and slow-growing tumors (Gleason score of four or less and PSA level of 5 ng/mL or less). (See the section “Grading” in “Etiology and Pathophysiology” for further explanation of the Gleason score.) Between 1989 and 1999, nearly 700 men with clinically detected, well- or moderately well-differentiated stage T1b, T1c, or T2 CaP were randomly assigned to undergo watchful waiting or radical prostatectomy. The primary endpoint was death from CaP; secondary end points were overall mortality, metastasis-free survival, and local progression (Holmberg L, 2002). At a median follow-up time of 6.2 years, investigators observed no statistically signiÞcant difference in overall mortality, although a higher rate of death from CaP was seen in the watchful waiting group—8.9% for the watchful waiting group versus 4.6% for the prostatectomy group (p = 0.02). (Note that this study involved men with clinically detected disease. The difference in the two treatment outcomes may be less clear among men with smaller, PSA-detected tumors.) Investigators recently published updated results of this trial (Johansson JE, 2004). The majority of cancers in the studied cohort had an indolent course during the Þrst 10–15 years. Investigators found that after 15 years, local progression and aggressive metastatic disease are more likely to occur. The researchers concluded that patients with a life expectancy of 15 years or more should be treated with early radical therapy. Radical Prostatectomy. Radical prostatectomy (removal of the prostate, including the seminal vesicles [RP]) has been a treatment for CaP since the late 1800s. It is Þrst-line therapy for stage I and II CaP in otherwise healthy men younger than age 70 and may be undertaken as an elective procedure in robust older men. RP is rarely performed for advanced disease because of the difÞculty of excising enough tissue to secure negative margins. Although surgical mortality for CaP is extremely low (0.4–0.7%), side effects are common and include impotence and incontinence in up to 50% of patients. RP increased in popularity during the 1970s, 1980s, and early 1990s (Wingo PA, 2000), most likely as a result of reÞnements in surgical techniques (so-called nerve-sparing surgery) that reduced the frequency and severity of side effects. Transurethral resection of the prostate (TURP) is an alternative procedure available for older, less robust patients. Radiation Therapy External Beam Radiation Therapy. External beam radiation therapy (EBRT) is one of the few options for inoperable disease or for early-stage disease when comorbidities preclude surgery. EBRT reduces PSA to less that 1 ng/mL or halts PSA increase in 65–85% of cases (Oesterling JE, 1997). Radiation is usually delivered to the prostate gland, periprostatic tissue, and pelvic lymph nodes in Þve doses per week for six to eight weeks.

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The efÞcacy of EBRT may be improved if given in conjunction with hormonal therapy. In a study comparing EBRT alone with combined hormonal therapy and EBRT, the latter group had signiÞcantly better overall survival (79% versus 62%) at Þve years. Among survivors, Þve-year disease-free survival was also signiÞcantly higher in the EBRT/chemotherapy group (85% versus 48%) (Bolla M, 1997). In a retrospective study of 1,580 men treated with EBRT or EBRT plus adjuvant hormonal therapy, men with intermediate- and high-risk tumors receiving the adjuvant therapy had 20% and 40%, respectively, the risk of local recurrence at Þve years compared with men receiving EBRT alone (D’Amico AV, 2000). Brachytherapy. Interstitial brachytherapy is the transperineal placement of needles that contain permanent or temporary radiation implants, or “seeds,” into tumor and adjacent tissue. The surgeon places the needles generally with the guidance of an imaging modality such as magnetic resonance imaging (MRI), transrectal ultrasound (TRUS), or computed tomography (CT). The seeds (either slow-releasing iodine I-125 or fast-releasing palladium Pd-103) diffuse radiation into the adjacent tumor tissue, resulting in maximal doses of radiation to the tumor but, in most cases, minimal damage to much of the surrounding normal tissue (bladder, rectum). Brachytherapy is usually an outpatient procedure that requires only one visit to the hospital in stark contrast with EBRT’s 25–30 visits. Among patients with localized disease and low combined Gleason scores (2–4), brachytherapy has yielded results comparable to those of radiotherapy and/or prostatectomy: 93% of patients have negligible PSA at Þve years according to some studies (Wallner K, 1996). In a retrospective study of 1,870 men treated with RP, EBRT, or brachytherapy, investigators found no signiÞcant difference in PSA outcomes at Þve years for patients with low-risk disease, though patients at intermediate or high risk (Gleason sum of Þve or more) for disease progression experienced better outcomes with either RP or EBRT (D’Amico AV, 1998). In a retrospective review of 1,050 patients treated with brachytherapy between 1991 and 1999, 92% had negative biopsies at two years; here, too, results were best for patients with low Gleason scores and PSA levels (i.e., less than 10 ng/mL) at diagnosis (Sharkey J, 2000). Orchiectomy. The testes produce 85–90% of naturally occurring androgens, including testosterone; the remaining androgens are produced in the adrenal glands. Removing androgen from the system either pharmacologically (with antiandrogens or hormonal ablation) or with surgery (orchiectomy) shrinks the tumor and lowers PSA in approximately 80% of cases. However, because the resulting cell-death process fails to eliminate the entire malignant cell population (for still unknown reasons), this procedure does not result in a cure. Bilateral orchiectomy (surgical removal of both testes) is a straightforward procedure that is relatively inexpensive when compared with long-term drug therapy. However, because of the psychological impact of this procedure, it is generally reserved for highly select patient groups—those for whom permanent impotence is not

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a signiÞcant concern and those with life-threatening complications. Orchiectomy can be used as monotherapy or may be followed up with antiandrogen treatment for maximum androgen blockade. Antiandrogen Withdrawal. Despite the proven effects of hormonal therapy with CAB or an antiandrogen alone, resistance usually develops after two to three years and PSA levels begin to rise. Withdrawing antiandrogen therapy after long-term treatment is a widely adopted second-line approach that can actually lower PSA and stall disease progression (Dawson NA, 1995; Scher HI, 1993). Accordingly, antiandrogen withdrawal can be used as a second-line hormonal therapy. Twenty-Þve percent or more of patients respond, although the duration of effect is typically only a few weeks. EMERGING THERAPIES Prostate cancer (CaP) R&D is an extremely active Þeld; several diverse agents will likely be launched by the end of 2006, and more than 90 agents are in Phase II trials. The fact that the majority of patients have historically received treatment only from urologists has presented a major hurdle for drug developers because urologists typically lack the facilities to administer chemotherapy. This hurdle is set to disappear for two reasons. First, the recent FDA approval of docetaxel for advanced CaP will ensure that more patients are referred to oncologists in the hopes of realizing a modest survival gain. Second, the advent of nonhormonal oral therapies is enabling increasing numbers of ofÞce-based urologists to enter patients into clinical trials. The availability of prostate-speciÞc antigen (PSA) testing creates a development strategy dilemma for companies investigating agents to treat CaP. They may choose to test agents in late-stage disease where unmet need is greatest and regulatory requirements are less onerous. Alternatively, they may take advantage of the opportunity afforded by the availability of PSA testing and conduct trials of agents in the much larger group of patients who have the minimum residual disease burden (i.e., those with rising PSA levels). Although approval for patients with rising PSA is likely to be very lucrative, the long survival times (a median of eight years from rising PSA to death) make studies extremely long and expensive. Although a reduction in PSA has become a standard end point in late-stage CaP trials and PSA response may be a useful tool for making commercial development decisions, no agent has been approved on the basis of PSA response alone. Improvement in time to disease progression without proven overall survival beneÞt has formed the basis of drug approvals in Europe. At the American Society of Clinical Oncology (ASCO) conference in 2004, the FDA ran workshops to discuss CaP trial endpoints but the agency reportedly remains undecided whether surrogate end points will be considered adequate for drug approval. Table 6 summarizes the drug therapies in development for CaP. This section discusses the most promising agents in Phase II development and all drugs in

EMERGING THERAPIES

TABLE 6. Emerging Therapies in Development for Prostate Cancer Compound

Development Phase

Ixabepilone (BMS-247550) United States Europe Japan Patupilone (EPO-906) United States Europe Japan Satraplatin (JM-216) United States Europe Japan Irofulven (MGI-114) United States Europe Japan Atrasentan (Xinlay) United States Europe Japan Provenge (formerly APC-8015) United States Europe Japan GVAX United States Europe Japan Onyvax-P United States Europe Japan MLN-2704 (ATG-J591 DM) United States Europe Japan MLN-591 RL United States

Marketing Company

II — —

Bristol-Myers Squibb — —

II — —

Novartis — —

III III —

GPC Biotech GPC Biotech —

II II —

MGI Pharma MGI Pharma —

III — —

Abbott Laboratories — —

III — —

Dendreon — —

III — —

Cell Genesys — —

— II —

— Onyvax —

II — —

Millennium — —

II

Cornell University/BZL Biologics/ Millennium — —

Europe — Japan — Bortezomib (Velcade, PS-341, MLN-341, LDP-341) United States I/II Millennium Europe — — Japan — — Bevacizumab (Avastin) United States II Genentech/Roche Europe — — Japan — —

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Development Phase

Thalidomide (Thalidomid) United States II Europe — Japan — CC-4047 (Actimid) United States II Europe — Japan — Oblimersen (Genasense, formerly G-3139) United States II Europe — Japan — Trastuzumab (Herceptin) United States II Europe — Japan — Gefitinib (Iressa, formerly ZD-1839) United States II Europe II Japan II Finasteride (Proscar) United States II Europe — Japan — Histrelin hydrogel implant (Vantas) United States R Europe — Japan —

Marketing Company Celgene — — Celgene — — Genta — — Genentech/Roche/Chugai — — AstraZeneca AstraZeneca AstraZeneca Merck Merck Merck Valera Pharmaceuticals — —

PR = Preregistered; R = Registered. Note: Development phase refers to development for prostate cancer.

Phase III or later. The single exception is DebioPharm’s PL-14, for which published data concerning its mechanism of action and activity are lacking. Cytotoxic Agents Overview. CaP has historically been perceived as chemotherapy-resistant, but the FDA’s recent approval of docetaxel (Aventis’ Taxotere) for hormonerefractory CaP has reversed that perception, and docetaxel is rapidly becoming standard of care for hormone-refractory disease. To achieve success, cytotoxic agents will need to (1) improve upon docetaxel’s toxicity proÞle and/or (2) achieve increased survival, either as a monotherapy or in combination with docetaxel. The following sections proÞle the main candidates. Other cytotoxic agents in development (all Phase II) for which few data are available include amonaÞde dihydrochloride (ChemGenex Therapeutics’ Quinamed); amonaÞde malate (Xanthus’ XanaÞde, previously XLS-001); and Cell Therapeutic’s BBR3576, an aza-anthrapyrazole.

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Mechanism of Action. Cytotoxic agents’ fundamental aim is to exert selective toxicity toward cancer cells. They do so in a variety of ways. The most successful mechanism of action for CaP is microtubule stabilization, which taxanes—most notably docetaxel—cause. Microtubule stabilization prevents the disassembly of these structures, consequently blocking cell division. Epothilones have emerged as a new class of microtubule-targeting drugs. Like taxanes, epothilones induce microtubule bundling, formation of multipolar spindles, and mitotic arrest (Lee FY, 2001). Also like taxanes, they induce microtubule polymerization by binding to microtubules and stabilizing microtubule activity. Epothilones are designed to overcome some of the problems associated with taxanes, most notably, susceptibility to resistance caused by the drug efßux protein P-glycoprotein. Other R&D strategies are focusing on such diverse mechanisms as inducing apoptosis via DNA binding (MGI Pharma’s irofulven [MGI-114]), DNA intercalation (Cell Therapeutics’ BBR-3576), and binding of platinum to DNA (GPC Biotech’s satraplatin [JM-216] and oxaliplatin [DebioPharm’s Eloxatin]). The last drug has elicited responses in heavily pretreated patients (Droz JP, 2003), but the sparse data preclude further discussion of it. Ixabepilone. Ixabepilone (Bristol-Myers Squibb’s BMS-247550, formerly NSC-710428) is an epothilone tubulin inhibitor in Phase II development for CaP and Phase III for breast cancer. An ongoing U.S. Phase II trial, which hopes to recruit 80 patients, is comparing the efÞcacy of ixabepilone versus mitoxantrone plus prednisone in patients with hormone-refractory CaP who have failed taxane therapy. A pilot study of ixabepilone plus estramustine (PÞzer’s Emcyt/Estracyt, Nihon Kayaku’s Estracyt, generics) involved 13 chemotherapy-naive patients with metastatic, hormone-refractory CaP (Smaletz O, 2003). Patients received estramustine 280 mg three times daily for Þve days plus ixabepilone at one of two dose levels: 35 mg/m2 or 40 mg/m2 . Three of six patients treated at the higher dose developed grade 4 neutropenia, making the lower dose the maximum tolerated dose. A greater than 50% PSA decline was observed in 11 of 12 evaluable patients (92%). Objective responses occurred in 57% of patients with soft tissue metastases and 40% with bone metastases. At ASCO 2004, investigators presented data from several Phase II trials. A multi-center, randomized Phase II trial involved 92 patients with chemotherapynäive hormone-refractory CaP (Kelly WK, 2004). Patients received ixabepilone 35 mg/m2 by intravenous infusion over three hours every 21 days or the same dose of ixabepilone plus 280 mg estramustine three times daily for Þve days. Patients in the ixabepilone-only arm received a median of four cycles of treatment, while those in the combination arm received a median of Þve cycles. In the combination arm, 69% of patients achieved a greater than 50% decline in PSA and 44% had a partial regression of measurable disease. In the ixabepilone-only arm, 56% achieved a greater than 50% decline in PSA, while 23% had a partial response. Grade 3 or 4 febrile neutropenia occurred in 4% of patients in each arm; grade 1 or 2 neuropathy occurred in 42% of patients in the combination arm

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and 53% of patients in the ixabepilone-only arm. Grade 3 neuropathy occurred in 4% and 6% of combination-treated patients and ixabepilone-only-treated patients, respectively, and thrombosis in 5% and 2%, respectively. A retrospective evaluation presented at ASCO 2004 found no apparent crossresistance between ixabepilone and taxanes (Rosenberg JE, 2004). No difference was seen in response to second-line taxane therapy based on whether patients had received ixabepilone as part of their Þrst-line therapy. A second Phase II trial presented at ASCO 2004 investigated ixabepilone monotherapy in patients with chemotherapy-naive, hormone-refractory CaP and performance status 0–2 (Hussain M, 2004). Patients received 40 mg/m2 ixabepilone over three hours every three weeks. Forty-one patients (median age 74) received treatment. At the time of presentation, data were available for 22 patients. Forty-one percent of patients achieved a PSA response. Ten of the 22 patients had measurable disease, and 30% of these patients had an objective response (1 unconÞrmed complete response and 2 unconÞrmed partial responses). The estimated median progression-free survival was eight months, and the estimated one-year survival was 75%. The most frequent grade 3 toxicities were neutropenia (11 patients), fatigue (3 patients), and sensory neuropathy (3 patients). Grade 4 neutropenia occurred in one patient. Ixabepilone’s primary shortcomings are grade 1 and 2 neurotoxicity, which occur in about 50% of treated patients, and febrile neutropenia, which occurs infrequently but can be life-threatening. Patupilone. Patupilone (Novartis’ EPO-906), an intravenously administered formulation of epothilone B, is in Phase II trials for CaP in the United States. It is also in Phase II trials for non-small-cell lung cancer, ovarian cancer, and renal cancer. A microtubule stabilizer, patupilone is not a substrate for the multidrugresistance protein Pgp. The compound has demonstrated preclinical activity in taxane-sensitive and taxane-resistant tumors. At ASCO 2004, investigators presented Þndings of a Phase IIa trial involving 37 patients with hormone-refractory CaP with or without metastases and with PSA higher than 20 ng/mL (Hussain M, 2004). The patients received 2.5 mg patupilone weekly for three weeks followed by one week of rest for up to six cycles (with a median of three). Twenty-nine patients had received prior chemotherapy. Twenty-two percent of patients had a partial PSA response, 16% had stable disease, and 43% progressed. Four of 20 patients with measurable disease had a partial response. The most common adverse events were gastrointestinal: grade three or four diarrhea, fatigue, dehydration, abdominal pain, and vomiting were reported in 19%, 14%, 8%, 5%, and 5% of patients, respectively. Grade 2 diarrhea was reported in 19% of patients. Grade 1 or 2 peripheral neuropathy occurred in 14% and 5% of patients, respectively. Grade 2 anemia occurred in 19% of patients; no other myelosuppression was reported. Patupilone’s principal shortcoming is dose-limiting diarrhea. Neurotoxicity and myelosuppression are uncommon with this compound, unlike with ixabepilone.

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FIGURE 12. Structure of satraplatin.

Satraplatin. Satraplatin (GPC Biotech’s JM-216) (Figure 12) is a thirdgeneration oral platinum agent. Satraplatin reentered Phase III development for second-line treatment of hormone-refractory CaP in September 2003; a previous Phase III trial was halted early by the previous developer, Bristol-Myers Squibb. The ongoing Phase III trial, whose primary endpoint is time to disease progression, is known as SPARC (Satraplatin and Prednisone Against Refractory Cancer). In 2003, the FDA granted satraplatin fast-track status, and in early 2004, the Phase III trial was extended to Europe. A Phase I study protocol that will combine satraplatin with docetaxel to treat various tumor types is in preparation. Because satraplatin is orally administered and does not require hydration to prevent renal toxicity, home administration is possible. In animal models, satraplatin has demonstrated efÞcacy in tumors that are resistant to platinum agents, possibly as a result of increased lipophilicity, allowing for more passive uptake of the platinum complexes by cancer cells (Orr RM, 1994). At ASCO 2003, investigators presented Þndings from the Þrst 50 patients treated in the original Phase III trial in patients with hormone-refractory CaP (Sternberg CN, 2003). The trial was initiated by Bristol-Myers Squibb in 1998, and accrual was halted when Bristol-Myers Squibb discontinued development of the agent, although the patients were allowed to continue treatment on a compassionate-use basis. Patients received 100 mg/m2 satraplatin for Þve days plus 10 mg prednisone orally twice daily, or prednisone alone. A greater than 50% decline in PSA was seen in 8.7% of patients in the prednisone arm and in 33.3% in the satraplatin/prednisone arm (p = 0.046). Toxicity was minimal in both arms; one patient in each arm died from stomach perforation, probably related to prednisone. Median survival was 12 months in the prednisone arm and 15 months in the combination arm. The median time to disease progression was 5.2 months for the satraplatin arm versus 2.5 months for the control arm. At 6 months, 41% of patients in the satraplatin arm were progression-free versus 22% in the control arm; at 12 months, 70% of patients in the satraplatin arm were alive versus 48% in the control arm. A Phase II trial treated 39 patients with hormone-refractory CaP with 120 mg/m2 /day satraplatin for Þve of 28 days (Peereboom D, 1998). Of nine evaluable patients with measurable disease, one had a partial response and six had stable disease. Seven patients had PSA reductions of greater than 50% for a duration of 28 days; six had reductions of greater than 80%. The principle toxicities were myelosuppression, nausea, and fatigue.

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In Phase I trials, neutropenia was the dose-limiting toxicity. Other common toxicities include thrombocytopenia, severe vomiting, diarrhea, and fever. No nephro-, oto-, or neurotoxicities have been reported. Because of irregular pharmacokinetics in this trial, researchers introduced dose fractionation in subsequent trials. Irofulven. Irofulven (hydroxymethylacylfulvene, MGI Pharma’s MGI-114) is an acylfulvene in Phase II trials for CaP. MGI Pharma is investigating the agent’s activity in several tumor types as a monotherapy and in combination with other chemotherapeutic drugs. Although investigation of irofulven’s effect began in 1998, the company announced a new international, multicenter Phase II trial in April 2004. The trial will assess time to disease progression, PSA response, pain palliation, survival, and quality of life in 135 hormone-refractory CaP patients receiving one of three treatments: prednisone, prednisone/irofulven, or prednisone/irofulven/capecitabine. An ongoing Phase II program is evaluating irofulven’s activity in combination with capecitabine and a platinum agent in hormone-refractory CaP patients who have failed docetaxel-containing chemotherapy. A semisynthetic derivative of illudin S (a natural product), irofulvene is a DNA-binding agent that causes apoptosis in cancer cells. The compound inhibits DNA synthesis, inducing S-phase arrest. Its activity is independent of several common resistance mechanisms, including multidrug resistance and apoptosisinhibiting proteins. At ASCO 2004, investigators presented a summary of irofulven data from hormone-refractory CaP patients treated in two Phase II monotherapy trials and two Phase I combination trials (Cvitkovic E, 2004). In one Phase II monotherapy trial, in which irofulven was administered every other week, one of 56 evaluable patients had a complete response, eight had a partial response, and 17 achieved stable disease. One patient had a complete PSA response, eight had a partial PSA response, and 17 had stable PSA. The principal toxicities associated with irofulven were grade 3 in each case: thrombocytopenia (13% of patients), neutropenia (10%), visual disturbances (8%), vomiting (7%), and asthenia (3%). Grade 4 neutropenia occurred in 2% of patients, and grade 3 or 4 anemia in 7%. Discontinuation for toxicity was necessary in 13 of 56 patients. In a second monotherapy trial among chemotherapy-naive patients with hormone-refractory CaP, 32 patients received irofulven daily for Þve days every 28 days (Cvitkovic E, 2004). One of six patients with measurable disease achieved a partial response and another three patients achieved stable disease. Thirteen percent of patients showed a partial PSA response, and 84% had stable PSA. Of nine patients treated with irofulven/cisplatin in a Phase I study, one patient had a complete PSA response, two had partial PSA responses, and one achieved stable PSA (Cvitkovic E, 2004). In a Phase I irofulven/capecitabine combination study, one of seven patients had a complete PSA response and two had stable PSA (Cvitkovic E, 2004).

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259

Irofulven is limited by the fact that it must be delivered by intravenous infusion, rendering referral to a medical oncologist necessary in most markets, and by toxicities that are serious enough to require discontinuation of treatment in nearly 25% of patients. Endothelin-Receptor Antagonists Overview. Endothelin-receptor antagonists represent a new generation of oral, targeted, cytostatic agents. They have huge commercial potential if they can successfully negotiate the obstacles to development: demonstration of efÞcacy in terms of an end point that regulatory agencies deem is sufÞciently clinically relevant. Endothelins are part of a family of autocrine/paracrine peptides (ET-1, ET-2, and ET-3) that are potent vasoconstrictors. They are produced from precursor proteins upon cleavage by metalloproteinase endothelin-converting enzymes. An increase in ET-1 protein expression is found in both primary and metastatic CaP tumor sites. Atrasentan (Abbott Laboratories’ Xinlay), discussed further on, is the ETA-receptor antagonist that has progressed furthest in development for CaP. A second ET-A-receptor antagonist in development for CaP is AstraZeneca’s ZD4054, which is in Phase II trials, but the lack of published clinical data precludes further discussion of this agent. Mechanism of Action. ET-1 stimulates tumor-cell and osteoblast proliferation, inhibits apoptosis, and stimulates nociception. It can increase the mitogenic effect of other growth factors and directly stimulate growth of CaP cells. ET-1 has a synergistic effect on angiogenic factors (Pirtskhalaishvili G, 2000). It acts by binding to two receptors, ET type A (ET-A) and ET type B (ET-B). ET-A has the most afÞnity with ET-1 and is associated with the progression of CaP. ET-B mediates ET-1 clearance and may inhibit ET-1 secretion. The purpose of targeting the ET-A-receptor signaling pathway is to slow the progression of CaP. Atrasentan. Atrasentan (Abbott Laboratories’ Xinlay, formerly ABT-627) is an oral, small-molecule, selective ET-A-receptor antagonist that appears to slow the progression of CaP. It is in Phase III trials, and Abbott submitted a new drug application (NDA) for the drug with the FDA at the end of 2004. In June 2001, two 1,000-patient international Phase III trials began. Trial M00211 involved patients with metastatic, hormone-refractory CaP, and trial M00244 involved patients with nonmetastatic hormone-refractory CaP. In both trials, patients were randomized to receive 10 mg atrasentan or placebo once daily. An Independent Data Monitoring Committee found trial M00-211 failed to meet its primary endpoint of time to disease progression and stopped the trial early despite improvements in several surrogate markers. M00-244 has completed accrual and is ongoing. Meanwhile, a Phase II study (M01-366) is investigating the safety and efÞcacy of atrasentan among approximately 200 men with hormone-näive CaP and rising PSA (0.4–5.0 ng/mL and a doubling time of less than one year). Abbott has been granted fast-track status for atrasentan, a designation that allows the company to Þle a rolling NDA.

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Analyses of the curtailed Phase III trial involving patients with metastatic CaP (M00-211) found that atrasentan-treated patients experienced improvements compared with those treated with placebo in time to disease progression based on bone alkaline phosphatase (BAP) and the development of symptoms (Lipton A, 2003; Yount S, 2004). In an analysis of all patients (Carducci MA, 2004), atrasentan achieved a nonsigniÞcant trend in delayed time to progression (composite measure of radiological and clinical measures) and a signiÞcant delayed time to BAP progression (505 versus 254 days), as well as signiÞcantly smaller increases than placebo-treated patients in PSA and BAP. A long-term, open-label safety evaluation of atrasentan in 220 patients with hormone-refractory CaP found that prolonged administration of atrasentan at higher doses (20 or 30 mg) was well tolerated (Eliopoulos HB, 2003). The most commonly reported adverse events for subjects receiving atrasentan versus placebo were similar: peripheral edema (40% versus 44%), bone pain (31% versus 35%), anemia (25% versus 27%), asthenia (24% versus 21%), and rhinitis (23% versus 19%). No signiÞcant hepatic or renal toxicity was associated with prolonged exposure to atrasentan at higher doses. Patients with baseline renal insufÞciency or liver function abnormalities experienced no clinically signiÞcant toxicities with prolonged exposure. A Phase II double-blind, randomized, placebo-controlled, multi-center trial involving 288 patients with asymptomatic, metastatic, hormone-refractory CaP found that 10 mg atrasentan signiÞcantly increased median time to PSA progression compared with placebo (155 days versus 71 days) (Carducci MA, 2003). The primary end point was time to disease progression. The study was powered to detect a 50% improvement in median time to progression. Treatment signiÞcantly delayed disease progression only in the evaluable patient analysis (196 days for 10 mg atrasentan versus 129 days for placebo, p = 0.029). A similar effect was found in a lower-dose atrasentan treatment group (2.5 mg atrasentan) versus placebo (184 versus 129 days, p = 0.035). In the intentto-treat analysis, the improvement in time to progression did not reach statistical signiÞcance, but time to PSA progression was statistically signiÞcant (155 days for the 10 mg atrasentan group versus 71 days for placebo). According to updated results presented at the Third Annual CaP conference in Bermuda, median survival in the evaluable patient analysis was 583 days in the atrasentan group versus 500 days in the placebo group (p < 0.05) (Carducci MA, 2003; Lee D, 2003). Only one patient discontinued therapy. An analysis of the effects of atrasentan on bone deposition and resorption markers found significant differences between atrasentan- and placebo-treated patients (Nelson JB, 2003). Patients receiving 10 mg atrasentan maintained stable mean total alkaline phosphatase and BAP values compared with baseline while subjects receiving placebo experienced a 58% elevation in the former parameter and a 99% elevation in the latter. N-telopeptide, C-telopeptide, and deoxypyridinoline elevation from baseline was consistently less in patients receiving 10 mg atrasentan compared with those receiving placebo. An analysis of pharmacokinetics and pharmacodynamics found that no dose adjustment for age or body weight is

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necessary (Carr RB, 2004). Atrasentan modestly increased plasma endothelin-1 levels. Vaccines Overview. The development of vaccines is one of the most active areas of CaP research. Each of the vaccines described in the following paragraphs has demonstrated it can induce the desired immune response. The Þrst two vaccines discussed here—Dendreon’s Provenge and Cell Genesys’s GVAX—have also shown preliminary evidence of a survival beneÞt. The third, Onyvax’s Onyvax P, has shown a beneÞt in time to disease progression in early trials. Note that Provenge and GVAX are being tested in combination with docetaxel, the most potent chemotherapeutic agent used to treat CaP. Although vaccines are being tested in late-stage disease, they may ultimately Þnd their place earlier in the course of disease in patients experiencing biochemical relapse (rising PSA), either in combination with hormone therapy or alone, thereby enabling hormone therapy to be kept in reserve. In addition, patients may potentially receive more than one vaccine, either concurrently or consecutively. The following sections discuss only vaccines that have demonstrated beneÞt in terms of PSA response. Other vaccines in development include Duke University’s RNA vaccine, which is in Phase I/II trials for CaP, and ImmunoDesigned Molecules’ IDD1, which completed Phase I/II trials in 2001. IDD1 achieved some PSA responses and caused circulating CaP cells to disappear in PCR-positive patients. Mechanism of Action. All cancer immunotherapeutic approaches use elements of the patient’s immune system to kill cancer cells, but their means of doing so varies. Approaches include isolating and modifying the patient’s own dendritic cells, creating cytokine gene-transduced vaccines (tumor cells modiÞed to secrete granulocyte-macrophage colony-stimulating factor [GM-CSF]), and employing tissue-speciÞc antigens such as PSA. Provenge. Provenge (formerly APC-8015) is a dendritic cell-based vaccine in Phase III development by Dendreon. The company prepares the vaccine by isolating dendritic cells (an important element of the immune system) from a patient’s blood and then incubating them with a fusion protein comprising prostatic acid phosphatase (PAP) and a dendritic cell-targeting element, which is structurally similar to GM-CSF. The vaccine is prepared over 48 hours. When readministered to the patient, these cells “teach” the immune system to search out and destroy PAP-producing cells. Investigations have conÞrmed that the key target for Provenge therapy—PAP—is expressed by 95% of CaP tumors (Small EJ, 2003). On the basis of Phase II trials demonstrating that Provenge is safe and well tolerated and induces antigen immunity, Dendreon initiated three Phase III trials: two trials (DD-901 and DD-902B) involve patients with hormone-refractory metastatic CaP; the third trial (P-11) involves patients with rising PSA but without signs of metastases. The ongoing DD-902B trial is designed to conÞrm DD-901’s

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Þndings that Provenge improves survival and time to onset of pain in patients with a Gleason score of 7 or less (less aggressive cancers). A National Cancer Institute (NCI)-sponsored Phase II trial (P-16) is investigating Provenge in combination with the angiogenesis inhibitor bevacizumab (Genentech/Roche’s Avastin) among patients with hormone-responsive CaP. Dendreon’s Þrst Phase III trial, DD-901, involved 127 men with metastatic, hormone-resistant CaP (Kylstra JL, 2004; Lee D, 2003). Patients were randomized in a 2:1 ratio to receive three vaccinations of Provenge or placebo every two weeks for three cycles. The primary end point was the time to objective disease progression. Median patient age was 73, median Gleason score 7, and median PSA 46. The vaccine was prepared over 48 hours. A trend toward improved time to progression was observed in the Provenge arm (p = 0.061), but researchers observed a statistically signiÞcant clinical beneÞt only after a subset analysis. Among patients with a Gleason score of seven or less (approximately 75% of hormone-resistant patients), the placebo group had a median time to progression of 9.0 weeks compared with 16.0 weeks in the Provenge-treated group (p = 0.001). Seventy-eight percent of these men responded to treatment. Patients with a Gleason score of 7 or less also had a signiÞcantly increased time to onset of pain (p = 0.016). Median time to onset of disease-related pain was 18.7 weeks for the placebo arm, while the median time was not yet reached for Provenge-treated patients. The vaccine’s effect on PSA levels was minor: only 2% of vaccine-treated patients had a 25–50% reduction in PSA levels and only 5% had a greater than 50% reduction. No placebo-treated patients experienced a PSA reduction. T-cell stimulation was seven times higher in patients with a low Gleason score versus those with a Gleason score of 8 or more. Additionally, according to a preliminary analysis of the same trial reported by Dendreon in August 2002, the subset of Provenge patients who had not progressed six months after randomization achieved a greater than eight-fold advantage in progression-free survival compared with those patients who received placebo (34.7% versus 4%). The vaccine’s common side effects were grade 1 and 2. They included rigors (60% of vaccine-treated patients versus 7% of placebo patients), pyrexia (29% versus 2%), dyspnea (17% versus 4%), and fever, which were most often infusion-related and short-lived. According to Dendreon, data from the Þnal three-year follow-up of this Phase III trial showed a statistically signiÞcant survival beneÞt in patients who were treated with Provenge, regardless of Gleason score (Dendreon, press release, October 28, 2004). Although Dendreon did not provide details describing the magnitude of the survival beneÞt, the company claims this beneÞt is greater than that observed with any type of treatment in any published Phase III study in latestage prostate cancer. At the 36-month Þnal follow up, the percentage of patients alive in the Provenge-treated group was substantially greater than the percentage of patients alive in the placebo-treated group. Preliminary survival results described in a previous press release show a beneÞt for vaccine-treated patients (Dendreon, press release, January 12, 2004). Patients

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with Gleason scores of seven or less receiving Provenge had, on average, an 89% overall increase in their survival time as compared with placebo-treated patients (log rank: p = 0.047, hazard ratio = 1.89). Median survival time for patients receiving Provenge increased by 8.4 months (30.7 months versus 22.3 months). Thirty months from randomization, the survival rate for Provenge-treated patients was 3.7 times higher than for patients receiving placebo (53% versus 14%, p = 0.001). On a crossover salvage protocol, patients on the placebo arm whose disease progressed received the vaccine for three cycles. Among patients in the placebo arm who received the vaccine as salvage therapy, mean survival time was 23.9 months versus 4.6 months for those who did not receive the salvage therapy. In a Phase II trial presented at ASCO 2003, 11 patients with nonmetastatic, hormone-responsive CaP and rising PSA (0.4–6.0 ng/mL) after radical prostatectomy or radiation therapy received Provenge and bevacizumab (Rini BI, 2003). Provenge was given intravenously on weeks 0, 2, and 4. Bevacizumab (10 mg/kg) was given intravenously on weeks 0, 2, and 4 and every two weeks thereafter until toxicity or progressive disease. The median patient age was 61, the Gleason score ranged from 5 to 8, and median baseline PSA was 1.88 ng/mL. Investigators measured T-cell proliferation and cytokine production in response to PAP and dendritic-cell costimulatory/activation marker expression. Of nine evaluable patients, only three experienced a reduction in PSA doubling time and one experienced a PSA decline approaching 50%. No patient had objective disease progression. Thirty-one patients with hormone-refractory CaP were treated with Provenge in a Phase I/II trial (Small EJ, 2000). In the Phase I portion, all patients had metastases, the median patient age was 69, the performance status was 0–1, and the median PSA was 41.3 ng/mL. Sixty-six percent of patients had received chemotherapy. In the Phase II portion, the patients did not have metastases. Twelve patients in the Phase I part of the trial received increasing doses of Provenge, and six of them received the maximum dose. Nineteen more patients subsequently received treatment at the maximum dose in the Phase II portion. No treatment-related hematologic, hepatic, or renal toxicity occurred. Fifteen percent of infusions were associated with febrile reactions—two of which were grade 3; the others were grade 1 or 2. Mild myalgias occurred in two patients and mild fatigue in one. Five patients experienced mild urinary complaints. All patients developed immune responses to the recombinant fusion protein used to prepare Provenge and 38% developed immune responses to PAP. Three patients experienced a greater than 50% reduction in PSA and three experienced PSA reductions of 25–49%. Time to disease progression correlated with the development of an immune response to PAP (34 weeks median time to progression for immune responders versus 13 weeks for nonresponders) and with the dose of dendritic cells received (median 31.7 weeks for patients receiving more than 100 × 106 cells versus 12.1 weeks for patients receiving fewer cells). Seven Phase II patients had not progressed by the end of one year of follow-up. Investigators noted that the correlation of immune response to PAP with time to progression should be

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treated with caution: disease burden or aggressiveness of disease may have been confounding factors. Provenge’s limitations include the need for intravenous administration, a requirement that is likely to restrict its administration to oncologists, and the fact that the vaccine must be prepared for each individual over a 48-hour period, a requirement that will make its manufacture expensive. GVAX. Cell Genesys’s GVAX vaccine for CaP consists of tumor cells that have been irradiated and genetically modiÞed to secrete GM-CSF, a hormone that plays a key role in stimulating the body’s immune response. Unlike Provenge, the vaccine is not patient-speciÞc and is administered by intradermal injection, making it signiÞcantly more convenient to deliver and less expensive to manufacture. GVAX has completed a Phase II trial, and the Þrst of two planned Phase III trials among patients with metastatic, hormone-refractory CaP is ongoing. The ongoing Phase III trial (Vaccine ImmunoTherapy with Allogeneic CaP Cell Lines [VITAL-1]) aims to enroll 600 chemotherapy-naive, asymptomatic patients and will compare GVAX vaccine with taxane chemotherapy to determine the survival beneÞt. Patients will receive intradermal injections of the vaccine every two weeks for up to six months. The second trial (VITAL-2) will enroll symptomatic patients and compare the effect of GVAX vaccine plus taxane chemotherapy with that of taxane monotherapy on palliation of bone pain. Both trials will enroll patients at all levels of the Gleason score. In May 2004, the FDA granted Cell Genesys a special protocol assessment (SPA) for VITAL-1. The SPA is an indication that the FDA agrees that the trial’s design is adequate to support a biologics license application (BLA) and that the study Þndings will allow a deÞnitive assessment of GVAX’s effectiveness. The trial aims to achieve a 33% improvement in overall survival. The company initiated the second trial in 2005. At ASCO 2004, investigators presented mature results from a Phase II trial of GVAX involving 80 patients with hormone-refractory CaP with evidence of metastasis to the bone and other sites (Small EJ, 2004). Patients received treatment for 24 weeks in a dose-escalation trial. Doses ranged from 100 million to 300 million cells every two or four weeks; patients in the highest-dose group also received an initial dose of 500 million cells. Vaccine-speciÞc antigenic protein antibodies and a marker of osteoclast activity (type I carboxy-terminal telopeptide [ICTP]) were measured at weeks 12 and 14. At a median of 12 months, no doselimiting toxicities had been observed and median survival had not been reached. Thirty-two percent of patients in the high-dose arm achieved PSA declines following repeat vaccinations. Of all patients, 62% had stable or declining ICTP levels, suggesting osteoclast inhibition. Bone scans showed stabilization of disease in 43% of patients; two patients had completely normal bone scans. Immunogenicity appears to be dose-dependent: 87% of the patients in the high-dose group achieved an immune response to at least one cell line, compared with 72% and 40% in the medium- and low-dose groups, respectively. Investigators presented Phase II trial data for GVAX at ASCO 2002: the data showed a dose-dependent trend toward prolonged survival and longer median

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time to disease progression (Simons J, 2002). Thirty-four patients with hormonerefractory CaP and metastatic bone disease received one of two dosing regimens of GVAX. Twenty-four patients received an initial dose of GVAX (500-millioncell prime dose) followed by 12 booster doses of 100 million cells each at two-week intervals; ten patients received the same prime dose followed by treatment with a higher dose of 300 million cells at the same intervals. At two-year follow-up, 9 of the 22 lower-dose-arm patients were alive (41%; 2 were lost to follow-up). By contrast, 7 of the 10 higher-dose-arm patients (70%) were alive at two-year follow-up. Investigators reported no dose-limiting or autoimmune toxicities. In September 2002, the company reported Þnal data from this trial: the combined median survival for both dose groups was 26.2 months. A potential survival beneÞt requires conÞrmation in a Phase III trial, but the available data compare favorably with the median survival of 18.9 months achieved by docetaxel/prednisone in the same setting. In 2002, at the Targeted Therapies First International Congress, Cell Genesys reported data from a small trial in the hormone-naive setting. Some patients experienced a reduction in PSA and bone lesions. Researchers also observed a dose-response trend in terms of overall survival. On the basis of the encouraging dose-related response data reported in the Phase II trial of GVAX, Cell Genesys initiated clinical evaluation (Phase I/II) of a second-generation, high-potency GVAX vaccine in patients with hormonerefractory CaP and metastatic bone disease. This second-generation agent secretes GM-CSF at Þve- to tenfold higher levels than its predecessor. Treatment involves one of two doses of the vaccine (100 or 200 million cells) injected monthly for six months. GVAX’s limitations include its failure to achieve an immune response in all patients and the need for intradermal or subcutaneous injection, which can cause local injection-site inßammation. Onyvax-P. Onyvax’s Onyvax-P is a whole-cell allogeneic vaccine in Phase II development in the United Kingdom for CaP. The vaccine consists of three replication-deÞcient allogeneic cell lines representing cell types from different stages of the disease—primary tumor, secondary disease, and bone metastases. Onyvax plans to start a Phase III trial in the Þrst half of 2005; manufacture of the vaccine for this trial is under way at Berna Biotech. In an open-label Phase II trial involving 26 men with hormone-refractory CaP that had not metastasized to the bone, 11 patients were vaccinated monthly for one year (Pandha HS, 2004). The proÞle of the patient group was favorable: median age was 67, median PSA at presentation was 11.1 ng/mL, and performance status was 0. Each month, patients received a mixture of the three cell lines (8 × 106 of each) supplemented with bacillus Calmette-Guérin (BCG) on weeks 0 and 2, followed by the three lines alone. All 11 patients experienced a prolonged reduction in PSA velocity. Median progression-free survival was 58 weeks. The most frequent side effects were fatigue and local injection-site reaction; no serious adverse effects occurred. Clinical delay in disease progression was correlated with evidence of immunological activation. Proliferation of patient T cells occurred

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after vaccination and cytokine responses were enhanced. Responding participants showed a mixed TH1- and TH2-type response rather than simply TH1 activation. Immunoconjugates Overview. Immunoconjugation is a means of delivering cytotoxic molecules to tumor cells. The effector molecules are attached to monoclonal antibodies (MAbs), which target the agent to speciÞc antigens expressed on the tumor cell. When in circulation, the linkage between the effector molecule and antibody is stable, but, once inside the cell, it breaks down and the cytotoxic molecule is released, resulting in cell death. This method allows a higher concentration of the drug to be safely administered to the patient. This section focuses on MLN-2704, a form of the anti-PSMA (prostate-speciÞc membrane antigen) MAb MLN-591 conjugated with DM1, and on MLN-591 RL, a second form of the same antibody conjugated with yttrium-90. Other MAbs in development include Medarex’s MDX-010 (formerly MDX101), a human MAb against cytotoxic T-lymphocyte antigen-4 (CTLA-4); Medarex’s MDX-214, a human MAb speciÞc to CD89; Medarex’s MDX-070 (HuRx-Prostate), a human MAb against PSMA; MedImmune’s Vitaxin, a humanized version of LM-609 that blocks the alpha-v/beta-3 integrin receptor (vitronectin) and thus inhibits angiogenesis by inducing apoptosis in newly formed blood vessels; and Cell Therapeutics/Micromet’s MT-201, a fully human IgG1 antibody that targets EpCAM. These agents are not discussed in detail here because of the lack of clinical data. Mechanism of Action. The identiÞcation of unique proteins found predominantly in prostate tissue has allowed the development of several immunotherapeutic approaches. PSA, PAP, and PSMA have all been explored as target antigens. PSMA has several potential advantages over PAP and PSA: it is a cell-surface glycoprotein rather than a secreted protein and the higher the PSMA level, the more aggressive the cancer. In other words, PSMA levels are higher in high-grade, metastatic, hormone-resistant CaP than in low-grade, localized, hormone-sensitive disease. MLN-2704. MLN-2704 (previously ATG-J591 DM) is a conjugated form of the anti-PSMA MAb MLN-591 in Phase II development for CaP by Millennium. The FDA granted MLN-2704 fast-track designation. The immunoconjugate is designed to deliver the maytansinoid antimicrotubule agent DM1 directly to CaP cells through the PSMA-targeted humanized MAb MLN-591. PSMA is a highly prostate-restricted transmembrane glycoprotein expressed on CaP epithelial cells in virtually all CaPs. PSMA expression increases as the cancer becomes more aggressive; higher Gleason score cancers and metastatic CaPs have more PSMA on their surface than do prostate-conÞned cancers. Hormone-refractory tumors have the highest expression levels. Cornell University, Millennium, and BZL Biologics are also developing MLN-591 RL, a deimmunized, radiolabeled version of the same antibody (discussed later).

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A Phase I study involving 23 men with hormone-refractory CaP demonstrated that MLN-2704 is active in the disease (Galsky MD, 2004). Patients received a single ascending dose (18–343 mg/m2 ) of MLN-2704 administered intravenously over 2.5 hours. Repeat dosing at four-week intervals was permitted once initial safety and pharmacokinetics were established. At the time of presentation, 17 patients had received more than three doses. Investigators were able to detect free DM1 in plasma and found no autoantibodies against MLN-2704, MLN591, or DM1. One patient treated at the highest dose demonstrated a sustained, greater than 50% reduction in PSA, and one patient treated at the 264 mg/m2 dose achieved a partial response, improvement in intradermal metastatic lesions, and a 70% decline in PSA lasting at least 24 weeks. Side effects included transient elevations in hepatic transaminases, infusion-related fever and chills, nausea, and fatigue. At the highest dose, a case of uncomplicated febrile neutropenia occurred. MLN-591 RL. In development by Cornell University, BZL Biologics, and Millennium, MLN-591 RL is a radiolabeled version of MLN-591, a PSMA-speciÞc MAb. It is in Phase II development. MLN-591 is engineered using a technique known as DeImmunisation. This process is designed to allow repeat dosing by preventing the induction of T-cell responses. Currently available antibodies trigger immunogenicity because they provoke T-cell responses. To date, no immune responses to MLN-591 have been reported in human subjects who have received the antibody. In a Phase I trial involving 29 patients with hormone-refractory CaP, patients received one dose of 111 indium-DOTA-J591 to measure biodistribution and pharmacokinetics, followed one week later by 90Y-J591 at one of Þve dose levels (5, 10, 15, 17.5, or 20 mCi/m2 ) (Galsky MD, 2004). Eleven patients had previously received chemotherapy. The principal toxicity was dose-related, reversible myelosuppression (predominantly thrombocytopenia). Based on imaging data, MLN-591 RL accurately targeted the tumor in 89% of the patients with bone lesions and 69% of the patients with soft tissue lesions. Uptake of 111 In-DOTAJ951 in bone marrow did not correlate with the degree of myelosuppression. At the highest-dose level, two patients developed thrombocytopenia requiring platelet transfusions, and the 17.5 mCi/m2 level was added and determined to be the maximum tolerated dose for this trial. One patient at the 15 mCi/m2 dose level with a history of venous thrombosis died after self-discontinuing coumadin. No human antihuman antibodies were seen. None of the four patients who received a second dose experienced irreversible myelosuppression (no dose-limiting toxicities). Two patients treated at the 20 mCi/m2 level experienced major (85% and 70%) reductions in PSA lasting 245 and 258 days, respectively, and both had objective responses with 90% and 40% declines, respectively, in measurable disease. Another six patients (21%) experienced a less than 50% decline in PSA or PSA stabilization. MLN-591 RL’s limitations include its expense and the inconvenience involved in radioimmunoconjugation. Indeed, the Þrst radioimmunotherapeutic approved for non-Hodgkin’s lymphomas (ibritumomab tiuxetan [Biogen Idec/Schering

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AG’s Zevalin]) suffered from very slow uptake. In addition, because both patients who experienced major reductions in PSA and had objective responses in measurable disease received a dose higher than the maximum-tolerated dose, it remains to be seen whether the therapeutic index is sufÞciently wide. If response rates in larger trials are lower than those achieved by taxane chemotherapy, then MLN-591 RL will most likely be used as a second-line therapy. If so, researchers will have to examine the effect of prior chemotherapy on the toxicities associated with this agent. Proteasome Inhibitors Overview. The proteasome is a novel target for cancer drugs, and clinical studies in myeloma have generated intense excitement in this Þeld. Because the proteasome interacts with many proteins (as described in the next section), research into the downstream consequences of drugs that inhibit this target is ongoing. Mechanism of Action. Proteasomes are enzyme complexes involved in the disposal of damaged cellular proteins and the degradation of short-lived proteins that regulate cell proliferation, apoptosis, adhesion, angiogenesis, and signal transduction. Accordingly, inhibition of proteasomes can stimulate apoptosis and suppress tumor growth and spread. Regulatory proteins degraded by proteasomes include p53, p21, p27, NF-κB, I-κB, and bcl-2. Down-regulation of the NF-kB survival pathway, activated by anthracyclines, can reverse drug resistance. In preclinical studies, cancer cells appear more susceptible than normal cells to the effects of proteasome inhibition. Bortezomib. Bortezomib (Millennium’s Velcade, formerly PS-341, MLN-341, and LDP-341) is a small-molecule proteasome inhibitor in Phase I/II trials for CaP. The agent has been approved in the United States and Europe for the treatment of multiple myeloma and is under investigation for non-Hodgkin’s lymphomas. Bortezomib has high selectivity for the proteasome over other proteases (e.g., thrombin) and has demonstrated in vitro cytotoxicity against a wide range of tumor cell lines. Bortezomib inhibits the 26S proteasome that works through multiple pathways, including pathways that inßuence apoptosis and angiogenesis. Because NF-kB transcriptionally activates bcl-2, its inhibition may induce tumor cell apoptosis or reduce bcl-2-associated drug resistance. Bortezomib also stimulates the proapoptosis gene p53 (Williams SA, 2003). A Phase I trial involving 53 patients with metastatic, hormone-refractory CaP was designed to determine the dose-limiting toxicity and maximum tolerated dose of bortezomib (Papandreou CN, 2004). The patients’ median age was 66, their median performance status was 1, and their median PSA was 42 ng/mL. Seventy-seven percent of the patients had previously received chemotherapy; the median number of prior chemotherapy regimens was two (range zero to Þve). Patients received 0.13–2.0 mg/m2 bortezomib once a week for four of every Þve weeks. Dose-limiting toxicity of diarrhea and hypotension occurred at 2.0 mg/m2 ,

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thus making 1.6 mg/m2 the maximum tolerated dose. Other side effects included fatigue, hypertension, constipation, nausea, and vomiting. Two patients achieved a PSA response and two experienced a partial response in lymph nodes. After two cycles of treatment at the 0.5 mg/m2 dose, the adenopathy in one of these patients almost completely resolved, a resolution that lasted eight months, and the patient’s PSA remained stable. Nine patients (19%) had stable PSA. Among the patients treated at close to the maximum tolerated dose, 8% experienced a PSA response and 11% a partial response in measurable lymph node disease. A Phase I/II trial involving treatment with docetaxel and bortezomib involved 31 patients with advanced, hormone-refractory CaP (Dreicer R, 2004). In 21-day cycles, patients received 40 mg/m2 docetaxel intravenously over 30 minutes on days 1 and 8 and bortezomib at 1.3 mg/m2 intravenous push on days two and nine. Median patient age was 67 and median pretreatment PSA was 270. Nineteen patients had previously received chemotherapy, of whom 14 had received taxane treatment. Grade 3 diarrhea, peripheral neuropathy, hyperglycemia, neutropenia, and fatigue were observed in less than 5% of patients. Among the evaluable patients, 36% experienced a greater than 50% decline in PSA, and most of this group had a greater than 90% decline. Seventeen percent of patients with measurable disease achieved a partial response. Researchers are evaluating a cohort of patients receiving a higher dose of bortezomib. Bortezomib’s disadvantages include limited single-agent activity as secondline therapy and signiÞcant toxicities. Several cases of vascular leak syndrome have been reported in bortezomib trials for other tumor types. Response rates in combination with docetaxel among a population that includes taxane-pretreated patients are intriguing because they suggest bortezomib may reverse taxane resistance when combined with docetaxel. Because the trial included chemotherapy-naive patients, it is not yet possible to determine the extent of any additional activity contributed by bortezomib. Angiogenesis Inhibitors Overview. Angiogenesis inhibition for the treatment of solid tumors has received a boost from the approval of bevacizumab (Genentech/Roche’s Avastin) for the treatment of metastatic colorectal cancer. Angiogenesis inhibitors in development for CaP span a wide range of classes, including MAbs, selective metalloproteinase inhibitors, and thalidomide and its derivatives. Some agents discussed here have already demonstrated modest single-agent activity; current combination trials are designed to exploit synergies with chemotherapy. Some agents have also been investigated for maintenance use. The next sections describe the most promising of the many angiogenesis inhibitors in development—bevacizumab (Genentech/Roche’s Avastin) and Celgene’s thalidomide and CC-4047 (Actimid). One agent in Phase II development that may hold promise is squalamine (Genaera’s MSI-1246), but the lack of published data precludes further discussion of it. Mechanism of Action. Most anticancer angiogenesis inhibitors under development inhibit a single antiangiogenic pathway; the most promising pathway for

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inhibition appears to be vascular endothelial growth factor (VEGF). VEGF, a multifunctional cytokine and potent permeability factor secreted in response to hypoxia, has a major angiogenesis-promoting effect. VEGF is one of the most attractive angiogenic molecule targets for inhibiting angiogenesis. However, inhibition of a single stimulatory signal is likely to have an effect only in a subset of patients and so cannot be universally applied to all cancers, especially end-stage cancers, when multiple proangiogenic factors are expressed. A more promising approach, therefore, may be to inhibit VEGF receptors—there are only two VEGF receptors versus four VEGF ligands. Also, because the VEGF receptor is expressed on normal endothelial cells, these cells have a much lower mutation rate than that of tumor cells and therefore are less likely to become resistant to a VEGF-receptor-targeted drug. In the case of some of the molecules proÞled in this section, antiangiogenesis is only one of several mechanisms of action that contributes to the antitumor effect. Bevacizumab. Bevacizumab (Genentech/Roche’s Avastin) is a recombinant humanized MAb to VEGF. The agent, which has been approved for colorectal cancer, is in Phase II development for CaP. Roche acquired worldwide rights to bevacizumab except in the United States, where Genentech retained exclusive rights. A Phase II study sought to examine whether the PSA reduction rate achieved by docetaxel plus estramustine (69% of patients achieving greater than 50% reduction) can be improved by the addition of bevacizumab (Picus J, 2003). Seventy-nine men with hormone-refractory CaP received treatment with estramustine, docetaxel, and bevacizumab as well as dexamethasone (Merck/Banyu’s Decadron, generics). Warfarin was encouraged but not required. The median PSA level was 12.8 ng/mL, the median Gleason score at diagnosis was 8, and 92% of the patients had a performance status of zero or one. At the time of presentation at the Chemotherapy Foundation Symposium XXI, 77% of the patients had achieved a PSA response and, of 34 patients with measurable disease, 44% achieved a response and 32% had stable disease. Median time to PSA progression was 10.5 months—considerably longer than the time to progression achieved by docetaxel/estramustine (six months). Adverse events included one death due to thrombosis and one perforation of the diverticulum in the sigmoid colon. Less than 3% of the men developed febrile neutropenia, and 53% of the patients developed grade 3 or 4 rapidly resolving neutropenia. Other grade 3 or 4 toxicities included thrombocytopenia (3%), fatigue (19%), constipation (6%), diarrhea (5%), arrhythmia (7%), and hypertension (4%). In a Phase II trial presented at ASCO 2003, 11 patients with nonmetastatic, hormone-responsive CaP and rising PSA (0.4–6.0 ng/mL) after radical prostatectomy or radiation therapy received Provenge and bevacizumab (Rini BI, 2003). Median patient age was 61, Gleason score ranged between Þve and eight, and median baseline PSA was 1.88 ng/mL. Provenge was given intravenously on weeks 0, 2, and 4. Bevacizumab (10 mg/kg) was given intravenously on weeks 0, 2, and 4, and every two weeks thereafter until toxicity or progressive disease. Investigators measured T-cell proliferation and cytokine production in response

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O N O

O

NH

O

FIGURE 13. Structure of thalidomide.

to PAP and dendritic-cell costimulatory/activation marker expression. Of nine evaluable patients, only 3 had a reduction in PSA doubling time and one had a PSA decline approaching 50%. No patient had objective disease progression. Thalidomide. The FDA licensed thalidomide (Celgene’s Thalidomid) (Figure 13) in 1998 for the acute treatment of erythema nodosum leprosum. It is in Phase II trials for CaP. Thalidomide has several mechanisms of action, and those mechanisms are important to its anticancer activity but they remain controversial because of the severe side effects they can trigger (discussed later). The agent possesses several immunomodulatory activities: it is potentially synergistic with GM-CSF, enhances interleukin-2 (IL-2) activity, induces and inhibits T-cell stimulation and proliferation, and suppresses TNF-alpha and downregulated IL-6. Thalidomide also inhibits angiogenesis induced by beta-Þbroblast growth factor (β-FGF) and VEGF, and it has antimetastatic properties. In a Phase II monotherapy study involving 63 patients with metastatic, hormone-refractory CaP, thalidomide demonstrated modest single-agent activity (Figg WD, 2001). Patients received 200 mg thalidomide (low-dose arm) or 200 mg escalating to 1,200 mg (high-dose arm). Twenty-seven percent of all men achieved a PSA response of at least 40%. No patient in the high-dose arm experienced a decline in PSA of 50% or more, although 18% of the patients in the low-dose arm did. Four men were maintained on thalidomide for more than 150 days. The most frequent complications were constipation, fatigue, and neurotoxicities. An open-label study of low-dose thalidomide (100 mg daily) administered for up to six months involved 20 men with hormone-refractory CaP (Drake MJ, 2003). The study found that 15% of the men achieved a greater than 50% decline in PSA sustained throughout treatment. Among the 16 men treated for at least two months, 37.5% achieved an absolute decline in PSA; median PSA fell 48%. Recent studies have combined thalidomide with other agents to exploit potential synergies and minimize the toxicities of chemotherapy and thalidomide. Table 7 presents the details of these combination trials. Thalidomide’s principal limitation is its toxicity. The most frequently reported toxicities include constipation, somnolence, thromboembolism, and neurotoxicity. In CaP patients, the most dangerous toxicity is its potential to cause venous thromboembolism (VTE). A retrospective analysis of a randomized Phase II trial

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involving 70 men with advanced, hormone-refractory CaP found that 19% of the patients receiving docetaxel and thalidomide developed VTE, compared with none in the docetaxel arm (Behrens RJ, 2003). A prospective evaluation of thalidomide-induced neuropathy found that six of 67 patients developed neuropathy (Molloy FM, 2001). Of the 67 patients initially enrolled in the study, 24 remained on treatment for three to nine months. CC-4047. CC-4047 (Celgene’s Actimid) is the lead compound in a series of thalidomide derivatives in Phase II development for CaP. A multi-center study aims to enroll 36 patients with hormone-refractory CaP. CC-4407 is also in Phase II trials for multiple myeloma and osteoarthritis. At ASCO 2004, investigators presented data from the Þrst 22 patients in the Phase II study of CC-4407 (Sison B, 2004). Patients had hormone-refractory CaP with or without radiographic evidence of disease, castrate levels of serum testosterone, performance status 0 or 1, and a maximum of one previous chemotherapy regimen. Patients received 1 mg/day CC-407 orally. Nine of 22 patients completed at least 12 weeks of therapy. PSA fell in six patients; seven were too early for evaluation. Toxicity was generally mild and included constipation, nausea, vomiting, and fatigue. Only one grade 3 toxicity occurred—nausea. One patient on therapeutic doses of coumadin died after a central nervous system bleed. The trial is ongoing. Investigators have increased the dose of CC-4407 to 2 mg per day. Antisense Therapies Overview. Despite its promise, no antisense therapy for the treatment of cancer has yet been approved. Genta (in collaboration with SanoÞ-Aventis) and Isis are the main players in antisense approaches. This section focuses on Genta’s agent, oblimersen (Genasense), because it has been the most extensively investigated for CaP. Another antisense oligonucleotide in development is Lorus Therapeutics’ GTI-2501, which is targeted to the R1 component of ribonucleotide reductase, a highly regulated enzyme in the cell cycle of mammalian cells that plays an essential role in DNA synthesis and cell proliferation. The lack of published data precludes further discussion of it. Antisense oligonucleotides are short sequences of single-stranded DNA that can bind to a speciÞc region of corresponding messenger RNA (mRNA) sequence, thereby blocking both the expression and translation of the mRNA itself and the generation of the corresponding protein encoded by the mRNA. In this way, antisense molecules can block the expression of undesirable genes and their proteins. Mechanism of Action. Oblimersen. Oblimersen (Genta’s Genasense, formerly G-3139) is an antisense oligonucleotide designed to block the production of the Bcl-2 protein from bcl-2 (a proto-oncogene). In November 2004, SanoÞ-Aventis terminated its agreement with Genta for the development of oblimersen. The drug entered Phase II

TABLE 7. Findings of Key Trials Investigating Thalidomide for Prostate Cancer Trial Reference Frank RC, 2004

Lilly M, 2004

Design

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n = 12 Patient selection: HR CaP after HT and antiandrogen withdrawal, PS 0–2, no prior chemotherapy or angiogenesis inhibitor. Treatment: six cycles of combination treatment followed by six months thalidomide maintenance treatment. Docetaxel: 25 mg/m2 weekly every 21 days. Estramustine: 140 mg tid three days per week. Thalidomide: 100 mg or 200 mg as tolerated. n = 10 Patient selection: HR CaP Treatment: Sargramostim: (GM-CSF) 500–250 mcg daily for 14 days, then QOD for three months. Thalidomide: 200–100 mg orally daily, beginning on day 15 for three months. Note: The dose range of both drugs shown reflects protocol dose reductions due to toxicity.

Patient Characteristics

Efficacy

Toxicities (number of patients)

Comments

Median age: 76 Median PS:1 Bone metastases: 83%

67% experienced >50% PSA decline. 44% experienced >75% PSA decline. 22% experienced normalized PSA. Partial response among patients with measurable disease (five patients): 40%. Stable disease: 40%.

Grade 3 or 4: Asthenia: 2 Constipation: 1 DVT: 1

Only 2 patients entered the maintenance phase; one achieved nine months of stable disease.

N.A.

Rapid PSA response: 78%. Average PSA decrease: 50.4. Partial response among patients with measurable disease: one patient.

Grade 3 or 4: Fatigue: 2 DVT: 1 Acute MI: 1 Pleural/pericardial effusion: 1 Peripheral neuropathy: 1 Neurogenic bladder: 1

Time for PSA level to return to pretreatment levels was inversely correlated with PSA magnitude.

274

TABLE 7. (continued) Trial Reference Shevrin DH, 2003

Salimichokami M, 2003

Sarao H, 2003

Design n = 15 Patient selection: Metastatic HR CaP, normal cardiac function. Treatment: Mitoxantrone: 12 mg/m2 every three weeks. Prednisone: 10 mg/day. Thalidomide: 200 mg daily, escalating to 800 mg daily. n = 30 Patient selection: Chemotherapy-naive HR CaP Treatment: Weekly docetaxel at 35 mg/m2 for six weeks every eight weeks. Thalidomide 100 mg qd. Weekly docetaxel alone. n = 12 Patient selection: HR CaP Treatment: Paclitaxel: 80–100 mg weekly for three weeks of a 5-week cycle. Doxorubicin: 20 mg weekly for three weeks of a 5-week cycle. Thalidomide: 200–500 mg daily.

Patient Characteristics

Efficacy

Toxicities (number of patients)

N.A.

Partial response: 33%. >80% drop in PSA: three patients. >50% drop in PSA: one patient.

Median age: 65 PS: 0-1

>50% reduction in PSA Thalidomide/docetaxel arm: 66% Docetaxel arm: 32%

Median age: 65

Decrease in PSA: 90%. Grade 3 or 4: The decrease ranged from Neutropenia 0.5 to 39.5 ng/ml. (grade 3): 27% Neutropenia (grade 4): 54% Leukopenia: 63% Constipation: 12 Fatigue: 12 Nausea: 12

Comments

Grade 3 or 4: The response rate Neutropenia: 5 achieved by the Rash: 1 three-drug Venous combination is thrombosis: 1 similar to that Other: achieved by Constipation: 11 mitoxantrone/ Peripheral prednisone alone. neuropathy: 3 Somnolence: 11 Grade 3 or 4: DVT: 2 Other: Neutropenia: 2 Thrombocytopenia: 3

DVT = Deep vein thrombosis; GM-CSF = Granulocyte-macrophage colony-stimulating factor; HR = Hormone-refractory; HT = Hormone therapy; MI = Myocardial infarction; PS = Performance status; PSA = Prostate-specific antigen; qd = Once a day; QOD = Every other day; Tid = Three times daily.

EMERGING THERAPIES

275

trials for CaP in 1997, but despite demonstration of activity, it has not yet entered Phase III trials. In fact, in April 2004, oblimersen received a negative recommendation for malignant melanoma from the FDA’s Oncologic Advisory Committee. The committee stated the data presented did not provide substantial evidence of oblimersen’s efÞcacy, as measured by response rate and progression-free survival, to outweigh the increased toxicity endured by the patients receiving it. Genta subsequently announced it was withdrawing the NDA for malignant melanoma. Bcl-2 is an apoptosis regulator that, when overexpressed, inhibits the process of natural cell death that should occur when cells are damaged—for example, by chemotherapy. Bcl-2 is located in the mitochondrial membrane and prevents the release of cytochrome c, protecting the cell from entering the intrinsic apoptotic pathway and promoting survival. Inhibition of Bcl-2 allows cells to progress through the cell death pathway. CaP patients with hormone-sensitive disease have low levels of bcl-2 expression, whereas patients with hormone-refractory disease have high levels of bcl-2 expression. Bcl-2 is overexpressed in virtually all hormone-refractory, metastatic CaPs. Bcl-2 overexpression also correlates with resistance to chemotherapy. Like taxanes, oblimersen interacts with Bcl-2 to overcome this mechanism of drug resistance. At ASCO 2003, investigators reported preliminary Þndings from a nonrandomized Phase II trial combining oblimersen with docetaxel to treat 29 patients with metastatic, hormone-refractory CaP (Chi KN, 2003). The median age was 66, and the median time from diagnosis to study entry was 5.8 years. Eight of the patients had undergone chemotherapy. Patients received 7 mg/kg/day oblimersen by continuous infusion over 8 days and 75 mg/m2 docetaxel IV on day 6 every 21 days until progression or toxicity. The median number of cycles of docetaxel/oblimersen was four (range one to ten); 20 patients were continuing treatment at the time of presentation. Twenty-seven percent of the patients achieved a partial response and 48% achieved a greater than 50% reduction in PSA. Grade 3–4 neutropenia occurred in 42% of patients (18% of cycles). The PSA response rate was the same as that achieved by docetaxel/prednisone (Eisenberger MA, 2004). Five patients had grade 3–4 febrile neutropenia. The most common grade 1–2 side effects were fatigue (35%) and non-neutropenic fever (31%). Because the trial was nonrandomized, it is difÞcult to distinguish the activity of oblimersen from that of docetaxel. A Phase I dose-Þnding trial investigating oblimersen in combination with mitoxantrone in 26 patients with hormone-refractory CaP found the combination was well tolerated (Chi KN, 2001). Patients were treated at seven dose levels ranging from 0.6 to 5.0 mg/kg/day by 14-day continuous infusion every 28 days and mitoxantrone from 4 mg/m2 to 12 mg/m2 as an IV bolus on day 8. Two patients experienced greater than 50% reductions in PSA, and one patient had symptomatic improvement in bone pain. The researchers did not observe any dose-limiting toxicities, and hematological toxicities (including neutropenia, thrombocytopenia, and lymphopenia) were transient. Nonhematological toxicities included fatigue, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, none of which were severe.

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Epidermal Growth Factor Receptor Inhibitors Overview. A vast amount of R&D has been committed to the study of epidermal growth factor receptor (EGFR) inhibition. Although several EGFR inhibitors have been launched for other solid tumor types, results for CaP have been very disappointing. The two main approaches researchers have investigated are the speciÞc inhibition of EGFR tyrosine kinase (e.g., geÞtinib [AstraZeneca’s Iressa]) and MAbs directed at the external domain of the EGFR (e.g., trastuzumab [Genentech/Roche’s Herceptin] and, initially, panitumumab). Both approaches have failed to deliver results in CaP. The following sections discuss only trastuzumab and geÞtinib because of their success in treating other tumor types. Please note that Panitumumab, has now been discontinued. One agent targeting the EGFR pathway that is in earlier-stage development is pertuzumab (Genentech/Roche/Chugai’s Omnitarg). This next-generation, humanized, anti-HER/neu MAb is in Phase II development. Enrollment for the trial, which recruited men with hormone-refractory CaP who had received a taxane or epothilone, has been completed. In a Phase I trial, pertuzumab achieved a partial response in a single patient with CaP (Agus DB, 2003). The lack of published clinical data precludes further discussion of this agent. Mechanism of Action. The precise role of EGFR inhibition is not fully understood because some EGFR inhibitors are active in EGFR-negative patients as well as in EGFR-positive patients. Conßicting results on EGFR family expression in CaP have been reported, likely because of differences in testing technologies, lack of standardization of immunohistochemical assays, or different scoring systems. Estimates of the prevalence of HER-2 (ErbB-2) range from 6% to 60% (Gray CR, 2001). Several recent studies have found evidence of a role of HER-2 in the progression of CaP to hormone-refractory status, but other studies have found very low levels of HER-2 expression even in metastatic disease (Lorenzo GD, 2003; Savinainen KJ, 2002). Estimates of the prevalence of overexpression of EGFR, also known as HER-1, are wide-ranging (40–80%). Its expression is often raised in metastases compared with its expression in the primary tumor, and expression is increased in hormonerefractory CaP. Overexpression of EGFR is associated with de-differentiation, so the expression of EGFR rises along with the Gleason score. Investigators have proposed that EGFR family receptors and androgen receptors function synergistically in the absence of androgen, suggesting cross-talk between the ErbB-2 and androgen-receptor pathways. According to recent studies, mitogen-activated protein kinase and phosphatidylinositol 3-kinase can be considered the transduction pathways (Lorenzo GD, 2003). Trastuzumab. Trastuzumab (Genentech/Roche/Chuga’s Herceptin) is already marketed in the United States and Europe for the treatment of advancedstage breast cancer. It has undergone Phase II trials in the United States for patients with recurrent or hormone-refractory CaP. Researchers hypothesize that trastuzumab blocks the tumor growth stimulus delivered via the EGFR HER-2.

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In general, studies of trastuzumab in CaP have been disappointing. Preliminary results from a Phase II trial published at ASCO 2000 found that trastuzumab alone was ineffective in HER-2-negative, androgen-independent tumors. In 2002, investigators reported results from a failed trial combining trastuzumab with the farnesyl transferase inhibitor tipifarnib (Janssen/Johnson & Johnson’s Zarnestra) (Macdonald JS, 2002). A U.S. multicenter Phase II trial set out to compare trastuzumab and docetaxel, followed by a combination of both agents, in 160 patients with hormone-refractory CaP (Lara PN, 2004). Investigators screened hormonerefractory patients for HER-2 positivity and treated HER-2-positive patients with trastuzumab (4 mg/kg IV week one, 2 mg/kg thereafter) or docetaxel (30 mg/m2 weekly for six weeks followed by a two-week break). After two eight-week cycles, nonresponding patients received the combination of trastuzumab and docetaxel. Of 100 patients screened, only seven patients had 3+ or 2+ HER-2 by immunohistochemistry (IHC), and no correlation between IHC, ßuorescent in situ hybridization (FISH), or enzyme-linked immunosorbent assay occurred. Of the seven eligible patients, only four agreed to participate, so the trial was closed early for nonfeasibility. No patient responded to trastuzumab alone. Gefitinib. GeÞtinib (AstraZeneca’s Iressa, previously ZD-1839) is a once-daily oral EGFR tyrosine kinase inhibitor that acts on a range of other kinases. It does not require high levels of EGFR (HER-1) expression to be active (Arteaga CL, 2001). GeÞtinib has been approved in Japan and the United States for non-smallcell lung cancer. It is in Phase II development for CaP. In Phase I trials, the compound showed signs of activity as a monotherapy for late-stage CaP, but the results of Phase II monotherapy trials and Phase II combination therapy trials have been disappointing. A Phase I/II trial in the United States will investigate geÞtinib in combination with the sirolimus analogue everolimus (Novartis’s Certican) to treat progressive, metastatic CaP. The Þnal analysis of a Phase II trial that randomized 58 men with hormonerefractory CaP to geÞtinib (500 mg daily) or placebo had disappointing results. Comparison of PSA slopes revealed doubling times of 3.9 months for the placebo arm and 5.0 months for the geÞtinib arm. No signiÞcant differences in progression rates, time to progression, and overall survival were observed. In 2002, at the 27th European Society of Medical Oncology Congress, the disappointing results of two Phase II trials investigating geÞtinib in combination with chemotherapy in patients with hormone-refractory CaP were presented. The Þrst, 21-patient trial evaluated geÞtinib in combination with mitoxantrone and prednisone. Patients received 12 mg/m2 mitoxantrone on day 1 of a 21-day cycle to a maximum cumulative dose of 140 mg/m2 , 10 mg/day prednisone, and 250 or 500 mg/day of geÞtinib. Five patients (two of eight patients receiving lowdose geÞtinib and three of 13 receiving high-dose geÞtinib) experienced a PSA response (a decline of at least 50% lasting for at least four weeks). The second trial evaluated geÞtinib in combination with estramustine and docetaxel in 30 chemotherapy-naive patients. Patients received up to six 21-day cycles of treatment comprising 840 mg/day estramustine on days one through

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Þve, docetaxel 60 mg/m2 on day 2 as a one-hour infusion, and geÞtinib as a oncedaily oral dose of 250 or 500 mg from day 3 onward. Four patients experienced a reduction in bone pain at each dose level, and 10 of the 30 patients demonstrated a PSA response. GeÞtinib is not associated with the side effects usually seen with chemotherapy (myelosuppression, alopecia). Its side effects in the CaP trials are consistent with those recorded in the large non-small-cell lung cancer Phase II trials (IDEAL I and II) (Fukuoka M, 2002; Kris MG, 2002). They were generally mild; the most common were grade 1–2 rash, diarrhea, pruritus, and dry skin. GeÞtinib’s principal shortcoming is its failure to demonstrate clinical beneÞt either alone or in combination with chemotherapy. Hormonal Therapies Overview. Several hormonal therapies are in development for CaP. Baxter Oncology’s D-63153 and teverelix (Ardana’s Antaralix) are decapeptide luteinizing hormone-releasing hormone (LHRH) antagonists in Phase II development. Lack of data precludes further discussion of them. Toremifene (GTx’s Acapodene) is a nonsteroidal selective estrogen-receptor modulator (SERM) in Phase IIb/III development. It is being tested for the prevention of CaP among patients with high-grade prostatic intraepithelial neoplasia and for the prevention and treatment of osteoporosis caused by adjuvant LHRH analogues. This agent falls outside the scope of this study. In late-stage development for CaP are Þnasteride. Mechanism of Action. Figure 2 illustrates the major sites of hormone blockade relevant to CaP treatment. Finasteride is a steroid analogue of testosterone that treats benign prostatic conditions by blocking the activity of the enzyme 5-alpha reductase and obstructing the conversion of testosterone to dihydrotestosterone, a hormone that plays a role in benign prostatic growth and is believed to contribute to the development of CaP. Histrelin hydrogel implant is an LHRH antagonist. Unlike LHRH analogues (e.g., goserelin, leuprorelin [leuprolide acetate]), which produce their effect by activating and then desensitizing androgen-producing cells to LHRH, histrelin hydrogel implant directly blocks the effect of the releasing hormone. Finasteride. Finasteride (Merck’s Proscar) (Figure 14) was approved in 1992 for the treatment of benign prostatic hypertrophy (BPH) and is being tested as both a preventive and a therapeutic agent for CaP. In patients with BPH, Þnasteride can reduce prostate volume by 25–30%; in preclinical experiments, it has been shown to inhibit CaP cell-line growth. The focus here is on Þnasteride as a therapy to treat CaP; discussion of it as a preventive agent falls outside the scope of this study. Finasteride is in Phase II development for the treatment of CaP. A Phase II trial involving 71 patients with biochemical recurrence of CaP after primary therapy received Þnasteride (5 mg twice daily) and ßutamide (125 mg twice daily) (Barquawi AB, 2003). At a mean of 44 months’ follow-up, 38% had

REFERENCES

279

FIGURE 14. Structure of finasteride.

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Small-Cell Lung Cancer

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Lung cancer is the leading cause of cancer death in men and women in the United States, and its incidence is growing throughout the world. Recent Þndings suggest that lung cancer is increasing more rapidly in women than in men (Khuder SA, 2001). Lung cancer is divided into two major types: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). SCLC is the more aggressive form of the disease and accounts for approximately 20% of all lung cancer cases. The link between SCLC and smoking is well established. Before World War I, when cigarette smoking rates were low, lung cancer was relatively rare. The genetic pathogenesis of SCLC has yet to be fully elucidated. Researchers estimate that more than 15 genetic events occur during the development of SCLC (Wistuba II, 2001). Determining the prognostic signiÞcance of each genetic alteration and designing new therapies that directly target these alterations is a signiÞcant challenge for researchers who are working to prevent SCLC and improve treatment outcomes. In general, researchers accept the hypothesis that lung cancer develops over an extended period ranging from 20 to 30 years. Pathophysiology Pathogenesis and Natural History. The 1999 World Health Organization (WHO) classiÞcation categorizes SCLC as a neuroendocrine tumor of highly Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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aggressive nature. The neuroendocrine origin of SCLC was Þrst hypothesized because of the disease’s association with paraneoplastic syndromes, a group of endocrine disorders and neuromyopathies mediated by compounds produced by or in response to a cancer. These disorders are typically caused by inappropriate secretion of peptides (e.g., hormones, growth factors, cytokines, prostaglandins) by the tumor and by normal tissues in response to antitumor antibodies. The most common paraneoplastic syndromes observed in SCLC patients are described in Table 1. Figure 1 gives a theoretical overview of the pathogenesis of SCLC. SCLC tumors express different regulatory peptides and hormones (Table 2). SCLC-released peptide growth factors play a role in regulating cell motility and the invasiveness of cancer cells; several serve as growth factors (e.g., gastrin-releasing peptide [GRP], stem cell factor [SCF], neurotensin, vasopressin, cholecystokinin, granulocyte-macrophage colony-stimulating factor [GM-CSF], insulin-like growth factor I, and transferrin). When these growth factors interact with receptors on the surface of SCLC cells, they serve an autostimulatory role for the SCLC tumors that produced them, thus supporting continued expansion of the tumor. For example, GRP binds to GRP receptors on the SCLC cell surface very soon after being released by SCLC cells. The GRP-receptor interaction causes intracellular calcium levels to rise, in turn stimulating SCLC proliferation. Preventing the action of these autostimulatory peptides may provide a possible therapeutic target. When SCLC arises, its primary location is most commonly a central bronchial site. Typically, mediastinal lymph nodes are involved with the disease at the time of diagnosis; these lymph nodes are found in the area between the left and right lungs, where the heart, trachea, and esophagus are located. Metastasis is a common and early event in the natural course of SCLC; approximately 65% of SCLC patients have metastatic disease when they are diagnosed. The most common sites of metastases are other pulmonary locations, the liver, bones, and brain. More than 50% of people with SCLC develop brain metastases at some point in their illness. Classification. ClassiÞcation of SCLC has changed over time. The WHO, for example, classiÞed the subtypes of SCLC in 1981 as oat cell type, intermediate cell type, and combined type. Because of similarities in the clinical behavior and growth characteristics of the subtypes, the International Association for the Study of Lung Cancer (IASLC) reclassiÞed SCLC in 1988 into the following subtypes: • • •

Small-cell carcinoma (oat cell cancer). Mixed small-cell/large-cell carcinoma. Combined small-cell carcinoma (SCLC combined with neoplastic squamous and/or glandular components).

The small-cell carcinoma subtype accounts for more than 90% of SCLC cases. In this classiÞcation system, the small-cell carcinoma subtype represents cancers that do not have a non-small-cell component. Both small-cell carcinoma and mixed small-cell/large-cell subtypes respond to treatment; the combined

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TABLE 1. Common Paraneoplastic Syndromes Observed in Small-Cell Lung Cancer Patients Paraneoplastic Syndrome Cancer cachexia

Causes Complex metabolic responses to a tumor

Clinical Description

Cachexia (wasting) may be the most common paraneoplastic disorder. One database of SCLC patients indicates that weight loss of more than 10% at presentation was observed in 56% of cases. Syndrome of Overproduction of SIADH develops in approximately 10% of inappropriate hormones such as SCLC patients. The syndrome is antidiuretic arginine, vasopressin, characterized by disturbances in the fluid hormone secretion and neurophysin and electrolyte balance: hyponatremia (low (SIADH) sodium levels in the blood), increased circulating plasma volume, and high sodium content and osmolarity (concentration of dissolved substances) in the urine. Hyponatremia Overproduction of atrial Hyponatremia has been observed in 13% of natriuretic peptide SCLC patients. ANP, which is known to (ANP) and vasopressin cause natriuresis (increased secretion of sodium in the urine) and hypotension, is often found at elevated levels in hyponatremic SCLC patients. Hyponatremia is also often associated with SIADH. Lambert-Eaton Autoimmune response This syndrome, arising in approximately 6% myasthenic involving of SCLC cases, can cause muscle syndrome immunoglobulin weakness (especially in the pelvis and antibodies thighs) and autonomic dysfunction (e.g., dry mouth, impotence in males). Cushing’s syndrome Ectopic secretion of Ectopic ACTH secretion occurs in up to 50% adrenocorticotropic of SCLC patients. Cushing’s syndrome, a hormone (ACTH) condition that develops secondarily to ACTH secretion, develops in approximately 5% of patients. The syndrome is characterized by low potassium levels, high sugar levels, peripheral edema (swelling of the extremities), and muscle weakness. Paraneoplastic Autoimmune response Although more often associated with SCLC cerebellar involving antineuronal than other cancers, PCD is nevertheless degeneration (PCD) antibodies rare even in SCLC cases. PCD involves pronounced neurological symptoms, including an ataxic (uncoordinated) gait, loss of coordination in the trunk and extremities, dysarthria (imperfect articulation of speech due to loss of muscular control), and nystagmus (a spasmodic, involuntary movement of the eyeball). When it does develop, PCD is usually seen before SCLC is diagnosed.


295

TABLE 1. (continued) Paraneoplastic Syndrome

Causes

Clinical Description

Paraneoplastic Autoimmune response SCLC is the most common tumor associated encephalomyelitis/ involving antineuronal with these rare disorders. Symptoms can paraneoplastic antibodies include sensory deficiencies or pain, limbic sensory symptoms (e.g., confusion, anxiety, neuropathy depression), motor weakness, cerebellar dysfunction, and other neurological abnormalities. Cancer-associated Autoimmune response This retinopathy is observed in association retinopathy involving with several cancers but is linked primarily photoreceptors in the to SCLC. Photoreceptor degeneration eye leads to rapid vision loss, night blindness, and loss of color vision. Onset of retinopathy often occurs before cancer is diagnosed.

small-cell carcinoma subtype has a poorer prognosis. This simpliÞed classiÞcation of SCLC will promote consistency in diagnosis and advance researchers’ understanding of the clinical signiÞcance of the rarer SCLC subtypes. Signs and Symptoms. Only approximately 10% of SCLC patients are diagnosed before symptoms emerge. Typically, diagnosis of asymptomatic SCLC is a fortuitous occurrence associated with a routine chest X-ray or treatment for an unrelated condition. The remaining 90% of SCLC patients are symptomatic at diagnosis. Coughing, the most common symptom, is often ignored because most smokers are accustomed to coughing frequently. Most smokers visit their doctors only when they notice more severe symptoms, such as dyspnea (difÞculty breathing), wheezing, shortness of breath, hemoptysis (coughing up blood or bloody sputum), chest pain, weakness, fever, or unexplained weight loss. Disease that encroaches on mediastinal structures can lead to dysphagia (difÞculty swallowing) and superior vena cava syndrome (enlargement of the neck with venous distension caused by compression or invasion of the superior vena cava). Superior vena cava syndrome is present in approximately 10% of SCLC patients at diagnosis, but it does not inßuence a patient’s prognosis. In some patients, symptoms associated with paraneoplastic syndromes precede pulmonary symptoms and prompt patients to see a doctor. The three paraneoplastic syndromes most commonly reported in association with SCLC are syndrome of inappropriate antidiuretic hormone secretion (SIADH), Lambert-Eaton myasthenic syndrome, and Cushing’s syndrome; these syndromes occur in just 10%, 6%, and 5% of SCLC patients, respectively. Pleural effusion (accumulation of ßuid in the pleural sac surrounding each lobe of the lung) is seen in approximately 12% of lung cancer patients—more often in NSCLC than in SCLC. The presence of pleural effusion is associated with a poor prognosis.

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FIGURE 1. Theoretical overview of the pathogenesis of small-cell lung cancer.


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TABLE 2. Regulatory Peptides and Hormones Released by Small-Cell Lung Cancer Cells Adrenocorticotropic hormonea Atrial natriuretic peptidea Calcitonin Cholecystokininb Corticotrophina ß-endorphin Erythropoietina Gastrin-releasing peptideb,d Glucagon Granulocyte-macrophage colony-stimulating factorb Growth hormone ß-human chorionic gonadotropina Hepatocyte growth factorc Insulin-like growth factor Ib

Interleukin-10 Melanocyte-stimulating hormonea Neurone-specific enolased Neurophysina Neurotensinb Parathyroid hormonea Physalaemin Parathyroid hormone-related peptidea Somatostatin Stem cell factorb,c Transferrinb Transforming growth factors O and ß Vasoactive intestinal polypeptidea Vasopressina,b

a Hormone that produces documented paraneoplastic syndromes. b Growth factors that promote tumor formation. c Assists in metastatic activities, such as migration, invasion, and angiogenesis. d Serves as a potential tumor marker.

Prognostic Factors. SCLC has a poor prognosis regardless of good initial response to chemotherapy. Extensive-stage disease (ED-SCLC) has a Þve-year survival rate of 1–2% (Argiris A, 2001). In contrast, limited-stage disease (LDSCLC) generally has a Þve-year survival rate of 10–26% (Turrisi A, 1999; De Ruysscher D, 2000; Takada M, 2002; Sundstrom S, 2002). In search of potential new therapeutic targets, researchers are trying to identify genetic factors that inßuence disease survival (Table 3). Although stage of disease at diagnosis is the single most important determinant of SCLC patients’ outcome, prognosis may be modiÞed by several additional factors (Table 4). After stage of disease, performance status is probably the most signiÞcant prognostic indicator for SCLC patients. The most commonly used performance status assessment tools, worldwide, are the Karnofsky Scale (KS) and the Eastern Cooperative Oncology Group (ECOG) Scale (Table 5). One prognostic index, the Manchester Score, is a numerical expression that incorporates patient performance status and several other health performance measures (e.g., liver function, biochemical parameters). According to the Manchester Score scale, patients are considered to have a good prognosis if they have none or just one of the following features: extensive disease (ED-SCLC), poor performance status (KS), elevated alkaline phosphate, elevated lactate dehydrogenase (LDH), decreased sodium, or decreased bicarbonate. Staging. As in treatment of other types of cancers, the course of treatment for SCLC patients depends on the extent of the disease at the time of diagnosis. The Veterans Administration Lung Group (VALG) staging system classiÞes SCLC cases into two categories: limited-stage disease (LD-SCLC), which encompasses patients who can beneÞt from thoracic radiotherapy, and extensive-stage disease

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TABLE 3. Selected Genetic Mutations in Small-Cell Lung Cancer Gene/ Protein

Function

Tumor suppressor genes p53 The p53 protein normally prevents the propagation of DNA damage by causing cell arrest at the G1/S checkpoint and inducing apoptosis. Mutations in p53 remove this regulatory control, allowing mutation-carrying cells to progress through the cell cycle. An intact p53 regulatory mechanism is thought to be necessary for the activity of DNA-damaging cytotoxic agents. Rb The retinoblastoma tumor suppressor gene (Rb) encodes a protein (pRb) that acts downstream of p53, also causing cell arrest at the G1/S checkpoint. The p16 gene regulates pRb function by inhibiting CDK4 enzyme activity. Inactivation of this gene therefore has the downstream effect of disrupting pRb-mediated cell-cycle control. FHIT The fragile histidine triad (FHIT) gene is a candidate tumor suppressor gene located at chromosome 3p14.2. FHIT encodes the enzyme dinucleotide hydrolase. Decreased function or loss of this enzyme is thought to result in accumulation of diadenosine tetraphosphate, which promotes DNA replication. RASSFIA RASSFIA is a putative tumor suppressor gene on 3p21.3 and exhibits loss of heterozygosity in most lung cancers.

BAX

A protein that antagonizes the action of bcl-2 and promotes apoptosis.

Comments p53 gene is mutated in 78% of SCLC patients (Matthay RA, 1993).

The rb gene is inactivated in 90% of SCLC (Wistuba II, 2001). In contrast, the p16 gene, which is the other component of the retinoblastoma/p16 pathway, is almost never abnormal in SCLC.

Early studies of chromosomal analyses have shown that some portion of the short arm of chromosome 3 is deleted in almost 100% of SCLC patients (Matthay RA, 1993). FHIT is inactivated in 50–70% of lung cancer and is associated with smoking (Wistuba II, 2001).

There is strong evidence in SCLC: researchers found hypermethylation of RASSFIA in 20/26 (77%) SCLCs (Agathangelou A, 2001). Some, however, reported it to be hypermethylated in more than 90% of SCLC (Wistuba II, 2001). —


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TABLE 3. (continued) Gene/ Protein PTEN/MMAC1

Oncogenes Myc Family

c-kit

c-met

HER-2/neu (C-erbB-2)

Function

Comments

Phosphatase and tensin homolog deleted in chromosome 10 (PTEN), also called mutated in multiple advanced cancers (MMAC1), is a new TSG that has been located on chromosome 10q23.3 (Li J, 1997). PTEN phosphatase negatively regulates cell interactions with the extracellular matrix (Tamura M, 1998).

Loss of heterozygosity has been found in 91% of SCLC (Virmani AK, 1998). Mutations of the PTEN/MMAC1 gene were found in 11% of all lung cancers, indicating that the gene may play a role in the pathogenesis of a small subset of lung cancers (Forgacs E, 1998).

The myc family of genes (c-myc, Myc genes are amplified in 18–31% of L-myc, and N-myc) are nuclear SCLC tumors. Patients with myc transcription factors that activate amplification often have unfavorable genes that drive cell growth. prognosis; it is more frequently seen in metastatic SCLC cell lines than in primary tumors. It is also observed more frequently in chemotherapytreated patients (Wistuba II, 2001). c-kit is a receptor tyrosine kinase SCLC tumor cells are frequently found that encodes the stem cell factor to express c-kit. Mutational (SCF) receptor. The ligand of the activation of c-kit is evident in many SCF receptor, SCF, is a peptide malignancies and is associated with growth factor that stimulates cell 70% of SCLC (Dy GK, 2000). proliferation; many types of cancers, including SCLCs, produce SCF. c-kit indirectly plays an important role in modulating SCLC metastasis by virtue of its role in producing SCF receptors. c-met indirectly plays an important c-met, which codes for hepatocyte role in modulating SCLC growth factor (HGF) receptor, is metastasis because of HGF’s overexpressed in 87% of SCLC role in assisting cellular cases. Just as SCLC tumor cells migration and invasion as well as self-regulate their activities by the initiation of angiogenesis (the producing both SCF and its formation of blood vessels). receptor (c-kit), these tumor cells promote their reproduction by producing both HGF and its receptor (c-met). Receptor tyrosine kinase that is C-erbB-2 is expressed in more than involved with epithelial cell 10% of SCLC, and the expression growth and division. becomes more important in Overexpression of the growth advanced stages of the disease receptor on the surface of cells (Micke P, 2001). enhances metastatic potential.

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TABLE 3. (continued) Gene/ Protein

Function

Comments

bcl-2

The bcl-2 (B-cell lymphoma/ leukemia-2) gene encodes a protein that blocks apoptosis. Overproduction of bcl-2 allows cells to escape apoptosis.

Other Oncogenes

c-Jun is a transcription factor that Based on a limited body of evidence, belongs to the activator protein 1 cancer researchers suspect that (AP-1) family; the c-src gene c-jun and c-src genes are encodes a protein tyrosine kinase. inappropriately expressed in SCLC The c-Raf-1 protein kinase is a tumors. The c-raf-1 and c-myb major element of several signal genes might be implicated in the transduction pathways. The c-myb pathophysiology of SCLC as well. gene encodes a specific transcription factor that is expressed at high levels in immature hematopoietic cells.

Bcl-2 protein is overexpressed in 75–95% of SCLC cases (Kaiser U, 1996). Overexpression of bcl-2 is hypothesized to be a source of treatment resistance in SCLC tumors and is also suspected of facilitating the metastasis of SCLC cells. Studies show that cells with activated myc and bcl-2 oncogenes develop tumors rapidly and aggressively, while cells with activated myc oncogenes alone often die.

Other relevant events in SCLC Retinoic acid Retinoids are essential in the growth RAR-beta methylation occurs in 70% receptor beta and differentiation of normal lung of SCLC (Wistuba II, 2001). (RAR-beta) epithelial tissues. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), both of which are involved in regulating transcription of specific genes, which, in turn, regulate cell differentiation, proliferation, and loss. Telomerase An enzyme that extends the ends of The RNA component of telomerase is telomeres that have been up-regulated in most lung cancers shortened with successive cell (98% of SCLC). This may therefore divisions. Telomerase activity is provide a target for future therapies suppressed in most normal cells (Sarvesvaran, 1999). Recent but is expressed in many tumor evidence suggests that telomerase cells. When activated, telomerase activity occurs frequently in prevents or reverses telomere smokers and appears at a very early shortening, an action that stage in lung cancer caused by probably contributes to the smoking, and that its expression immortalization of cancerous cells can be modulated by treatment with (Soria JC, 2001). a retinoid (Soria JC, 2001).


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TABLE 4. Prognostic Indicators of Small-Cell Lung Cancer Extent of disease

Pleural effusions Performance status

Gender Age Lactate dehydrogenase (LDH) concentration Neuron-specific enolase (NSE) Alkaline phosphatase concentration Albumin concentration Albumincimia concentration Sodium concentration ACTH secretion

Weight loss Myelosuppression

Patients with limited-stage disease have a better prognosis than those with extensive-stage disease. Of patients with limited-stage disease, those with very limited disease (i.e., without mediastinal lymph node involvement) have the best prognosis. Of patients with extensive stage disease, those with a single metastatic site have a better prognosis than those with multiple sites. Pleural effusions, with or without malignant cells in the effusion, indicate poor prognosis. Performance status is one of the most significant prognostic indicators for patients with limited-stage and extensive-stage disease. Patients with poor performance status have a worse prognosis than those with good performance status. For example, compared with patients with good performance status, bedridden patients do not tolerate aggressive chemotherapy well, they have increased morbidity, and they rarely survive two years after diagnosis. Women with small-cell lung cancer have a better prognosis than men with the disease. People younger than age 70 have a better prognosis than patients who are older (elderly patients often have a poor performance status). High concentrations of LDH correlate with poor prognosis.

Some studies suggest that NSE serves as a stronger prognostic indicator than LDH. Levels of NSE are higher in extensive-stage patients than in limited-stage patients. High concentrations of alkaline phosphatase correlate with poor prognosis. Low concentrations of albumin correlate with poor prognosis. High concentrations of albumincimia correlate with poor prognosis. Low concentrations of sodium correlate with poor prognosis. Patients with ectopic ACTH secretion generally have a poorer prognosis, show poor response to chemotherapy, and experience more complications during therapy. Patients who lose more than 2 kg (4.4 lb) of weight have a poor prognosis. Low hemoglobin, platelet, and white blood cell counts correlate with poor prognosis.

(ED-SCLC), which encompasses patients who cannot beneÞt from such radiotherapy. The designation LD generally means that the tumor is conÞned to the area where the tumor started; ED means that the tumor has spread to other parts of the body. The criteria for these two categories remain controversial: the VALG deÞnition of LD includes patients whose primary tumor nodal involvement is limited to one hemithorax; the IASLC recommends that LD include all patients

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TABLE 5. Performance Status Scales Karnofsky Scale: Description

Karnofsky Scale (%)

No complaints; no evidence of disease. Able to carry on normal activity; minor signs or symptoms of disease. Some signs or symptoms of disease with effort.

Cares for self; unable to do active work. Requires occasional assistance but is able to care for most personal needs. Requires considerable assistance and frequent medical care. Disabled; requires special care and assistance. Severely disabled; hospitalization indicated although death not imminent. Very sick; hospitalization necessary; requires active support treatment. Moribund; fatal processes progressing rapidly. Expired.

100

ECOG Scale: Description

ECOG Scale

Normal activity.

0

Has symptoms of disease but ambulatory and able to carry out activities of daily living.

1

Out of bed more than 50% of time; occasionally needs assistance.

2

In bed more than 50% of time; needs nursing care.

3

Bedridden; may need hospitalization.

4

90

80

70 60

50 40

30

20

10 0

ECOG = Eastern Cooperative Oncology Group.

without distant metastasis (Micke P, 2002). P. Micke and colleagues reported that the IASLC staging system for SCLC has a higher prognostic impact and is therefore preferable in clinical practice (Micke P, 2002). Most studies indicate a 90% correlation in SCLC staging when clinicians use similar diagnostic protocols. Disagreement about staging a SCLC case is most common when patients have pleural effusions. According to one interpretation of the VALG staging system, the presence of pleural effusions is a deÞning condition of ED-SCLC. Alternatively, the presence of pleural effusions is qualiÞed by its malignancy status and extent; according to this interpretation of the VALG staging system, benign pleural effusions involving only one pleural sac are consistent with LD-SCLC. When surgery is a possibility, most physicians use the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer’s (UICC) agreed TNM (tumor/regional lymph nodes/distant metastasis) staging system to better characterize the cancer (Table 6). For speciÞc deÞnitions of the SCLC


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TABLE 6. AJCC/UICC TNM Staging Classification System for Small-Cell Lung Cancer AJCC/UICC Stage Occulta Stage 0 Stage I Stage II Stage III Stage IV

TNM Criteria TX, N0, M0 Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T4, N0, M0 Any T, N1, M0 Any T, N2, M0 Any T, Any N, M1

a Bronchopulmonary secretions contain malignant cells on multiple samples,

but no other evidence of the primary tumor or evidence of metastasis to the regional lymph nodes or distant metastasis is found. AJCC = American Joint Committee on Cancer; UICC = Union Internationale Contra le Cancer; TNM = Tumor, node, metastasis.

TABLE 7. Definitions for the TNM Staging Classification of Small-Cell Lung Cancer TNM Categories TX T0 Tis T1 T2 T3 T4 N0 N1 N2 M0 M1

Description Tumor not assessed, or assessed but not visualized No evidence of primary tumor Carcinoma in situ Tumor invades submucosa Tumor invades muscularis propria Tumor invades through muscularis propria Tumor invades serosa, nodes, and adjacent organs No lymph node involvement One to three positive nodes More than three positive nodes No distant metastasis Distant metastasis

TNM = Tumor, node, metastasis. T = Tumor (size, extent, or depth of penetration of primary tumor); N = Node (absence or presence and extent of regional lymph node involvement); M = Metastasis.

TNM staging classiÞcation system, see Table 7. In clinical practice, the TNM system is rarely needed because most SCLC patients are clearly beyond surgical intervention when they present for diagnosis. The TNM system is used more frequently in research settings than in community practice. Etiology Risk Factors. Most known cancer risk factors can be described as processes that increase a person’s exposure to mutagens, interfere with or prevent normal DNA repair, and/or increase the proliferation rate of cells (e.g., as a result of

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FIGURE 2. Contribution of independent risk factors for small-cell lung cancer in the seven major markets.

repetitive injury and tissue repair). The principal known risk factors for SCLC are related to mutagen (or carcinogen) exposure (Figure 2). Cigarette Smoking. Cigarette smoking is by far the most important risk factor for SCLC; at least 85% of cases are attributable to this habit, and some researchers attribute 95% of all cases to this risk factor. Approximately 20% of smokers develop lung cancer, and smokers are 13 times more likely to develop lung cancer than nonsmokers (Fauci AS, 1998). Environmental tobacco smoke in the home has been found to be a major source of passive smoking; large numbers of nonsmokers are being exposed to a signiÞcantly high risk of lung cancer by family members who smoke in their homes. Of all the major subtypes of lung cancer, small-cell lung and squamous cell carcinomas are most closely linked to smoking. As the number of cigarettes smoked and the time spent smoking per day increases, lung cancer risk rises sharply. Risk of lung cancer is also related to the type of cigarette smoked; low-tar or Þltered cigarettes are associated with lower risk than high-tar or unÞltered cigarettes (Blot WJ, 1996). The greatest reduction in risk, however, comes from cessation of smoking, which results in signiÞcant decrease in all lung cancer types. A study of the effect of smoking cessation found that risk reduction was highest for small-cell lung carcinoma, followed by squamous cell carcinoma, and lowest for large-cell cancer and adenocarcinoma (Khuder SA, 2001). Heavy smokers, particularly women, beneÞt most from quitting. The percentage reduction in risk after quitting depends on the duration of time smoked; shorter-term and younger smokers experience larger relative decreases in risk. The chance that risk of lung cancers in former smokers will revert to the level of nonsmokers is small (Blot WJ, 1996). Many people who quit smoking still develop lung cancer as a result of irreparable damage that occurred during their years of smoking. In a 1995 study


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conducted by researchers at the Dana-Farber Cancer Institute and Brigham & Women’s Hospital in Boston, 51% of the 685 lung cancer patients who received treatment at these institutions between 1988 and 1994 were former smokers; 22% of these former smokers had quit smoking 20 or more years before their diagnoses. Smoking is thought to contribute to cancer development by impairing mucociliary clearance in the lungs, by decreasing immunologic response, or by causing mutations in tumor suppressor genes (TSGs). Tobacco smoke is composed of two elements: the vapor phase and the particulate phase. The particulate phase, known as “tar,” contains most of the 55 known cigarette smoke carcinogens. These carcinogens require activation by carcinogenmetabolizing enzymes, principally cytochrome P450 enzymes. In recent years, researchers have made signiÞcant progress in elucidating the mechanisms by which certain tobacco carcinogens cause genetic mutations, but the relationship between speciÞc carcinogens and speciÞc TSG or oncogene mutations remains speculative. Once metabolized, carcinogens interact with DNA. If the by-products of this interaction escape the efforts of cellular repair mechanisms, they may cause a permanent mutation. Errors that occur in certain regions of an oncogene or TSG may ultimately result in cancer. Other Sources of Exposure. Compared with smoking, other risk factors—inhalation of radon or air pollution—play a minor role in SCLC development. Nevertheless, exposure to these agents can potentiate a smoker’s risk of developing SCLC. •

•

Prior Lung Disease and Carcinogen Exposure. Lung cancer risk is also high in people with a history of prior nonmalignant lung disease—most notably, asthma, pneumonia, emphysema, and tuberculosis (Alavanja MC, 1992). Benzopyrene, a known carcinogen found in tobacco smoke, has been the subject of numerous studies. Benzopyrene is thought to cause mutations to the p53 gene, a key TSG that controls tumor growth by triggering apoptosis in abnormal cells. NNK, a tobacco-speciÞc nitrosamine has been linked with mutations in the p53 gene. More recently, researchers have suggested that aßatoxins cause lung cancer. Aßatoxins are produced by fungi that invade agricultural commodities (such as tobacco) when these plants are stored in warm, damp conditions after harvesting. These products subsequently cause mutations in the p53 gene (Lane KS, 1999). The presence of aßatoxins in foodstuffs such as peanuts, corn, and grains has been monitored by the FDA since 1966, but their contamination of tobacco is not currently regulated. Diet. Researchers have found that risk of lung cancer is high in people with high dietary intake of food rich in fat and cholesterol, including whole milk and eggs (Jain M, 1990; Shekelle RB, 1991). Evidence obtained in North and South America also suggests that consumption of alcoholic beverages, mostly beer, may be associated with increased risk of developing lung cancer

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•

•

•


(Potter JD, 1992; Bandera EV, 1992). However, in Bandera’s study, the association was limited to heavy smokers. Radon-222 . An inert gas produced by the decay of radium-226, radon-222 is naturally present in rock and soil. As radon-222 decays, it emits highenergy alpha particles. If inhaled, these particles can disrupt DNA in the cells of the bronchial lining. Most evidence that correlates radon with lung cancer pertains to mining environments, where levels of the gas are relatively high. In a 1995 meta-analysis of 11 studies, the National Cancer Institute (NCI) determined that 40% of lung cancer deaths in uranium miners were caused by radon exposure. The NCI estimates that residential radon exposure could account for as much as 2–4% of lung cancer deaths (Lubin JH, 1995). The combination of smoking and radon increases the risk of lung cancer in a manner that is between additive and multiplicative; U.S. and U.K. research indicates that 50–75% of radon-linked lung cancer mortality is attributable to the excess risk posed by smoking (Lubin JH, 1995). Pollution. Because lung cancer incidence and mortality rates are highest in urban areas, researchers suspect that high levels of air pollution are a risk factor for lung cancer. The relationship between air pollution and the increased incidence of SCLC is unclear because of the difÞculty of removing confounding variables (i.e., other sources of carcinogen exposure) from the analysis. For instance, Cancer Incidence on Five Continents reports a 20–50% excess risk of lung cancer in urban areas of the world, while an Italian study conducted in Trieste between 1979 and 1986 concludes that air pollution increases the risk of SCLC only moderately when confounding factors (e.g., occupational exposure, smoking) are taken into account. Genetic Predisposition. Researchers remain uncertain of the role played by genetic factors in the pathogenesis of lung cancer. Glutathione S-transferases, including GSTM1, GSTP1, and GSTT1, play a role in detoxifying metabolites of carcinogens in tobacco smoke. The data available are often conßicting. While some studies suggest that some people with common polymorphisms of these genes may be more susceptible to lung cancer from exposure to environmental tobacco smoke, others found no association between GSTM1, GSTT1, or GSTP1-polymorphisms and lung cancer risk (Lewis SJ, 2002; Schneider J, 2004). Additionally, CYP3A is a P450 gene involved in tobacco carcinogen and steroid metabolism; CYP3A4*1B allele carriers were found to have signiÞcantly increased SCLC risk (Dally H, 2003). Further studies would be required to elucidate these connections.

Other Risk Factors. The following paragraphs discuss other risk factors for SCLC. •

Gender and Age. The incidence of lung cancer in men exceeds the incidence in women, usually by two-fold or more (Blot WJ, 1996). The difference is primarily due to a lower prevalence of smoking in women. This difference is


•

•

•

307

shrinking, however, because the percentage of women who smoke is rising. Lung cancer incidence also rises progressively with age. Arsenic. Mortality and survival studies have shown increased lung cancer mortality in male workers who are heavily exposed to inorganic arsenic for a limited time; researchers found only small-cell lung carcinoma in exposed workers. A recent study found that exposure to arsenic for Þve years is associated with an increased risk of developing lung cancer (Nakadaira H, 2002). The mechanisms by which arsenic causes cancer are uncertain, but data suggest that arsenic probably causes chromosomal abnormalities that lead to cancer. Scientists agree that chronic exposure to inorganic arsenic induces a wide range of adverse health effects, including cancers of various organs. Previous studies have also found a synergistic effect between arsenic and smoking in the development of lung cancer (Buchet JP, 1998; HertzPicciotto I, 1992; Tsuda T, 1995). Asbestos. The group of Þbrous minerals known as asbestos has a long history of industrial and commercial use. When inhaled, some asbestos Þbers are phagocytized (engulfed) by cells in the lining of the airways. This phagocytosis can release free radicals capable of damaging DNA. In addition, the asbestos Þbers themselves can cause damage by physically shearing chromosomes or disrupting mitosis. In combination with smoking, exposure to asbestos is believed to increase the risk of lung cancer as much as 50-fold. Radiation. Lung cancer is one of the major effects of exposure to high doses of ionizing radiation. Because studies have found signiÞcant incidence of lung cancer in patients receiving radiation therapy, especially smokers, it is clear that smoking and radiation have a combined effect on lung cancer. However, the precise manner in which these two factors interact is less clear.

Risk Reduction Factors. A diet that is rich in fruits and vegetables may decrease the risk of developing lung cancer by imparting high levels of antioxidants, such as vitamins C and E, carotenoids, and selenium. Such antioxidants are potent scavengers of DNA-damaging free radicals and may impede the effect of carcinogens. Researchers have found that patients who exhibit a speciÞc polymorphism in the promoter region of myeloperoxidase (MPO; an enzyme that generates reactive oxygen species and free radicals that damage DNA) have lower levels of MPO expression and a reduced risk of lung cancer (Kantarci OH, 2002). Genetic Mutations. Researchers are uncertain of the role played by genetic factors in the pathogenesis of lung cancer, but studies have shown that mutations in proto-oncogenes and TSGs are critical to the development and progression of lung tumors. The inactivation of TSGs is by far the most common mutational event observed during the development of lung cancer. The molecular changes include activation of dominant oncogenes (myc family and HER-2/neu genes) as well as loss of anti-oncogenes (p53, retinoblastoma [Rb], and an unidentiÞed gene or genes on chromosome 3). However, possible loss of DNA in multiple

308


other speciÞc sites may be present in lung cancers. Abnormalities in two particular TSGs—the Rb gene on chromosome 13 and the p53 gene on chromosome 17—are pervasive in many types of cancer. Nearly all SCLC cells have mutations in these two TSGs and/or produce abnormal Rb and p53 proteins. When either p53 or Rb gene product is missing or altered, negative checks on cell growth are deactivated; the “switch” is turned on, and uncontrolled cell proliferation ensues. The pervasiveness of these genetic abnormalities has led researchers to suspect that these genes act as “master switches” that control tumor formation. Virtually all SCLC cells have deletions in the short arm of chromosome 3 (chromosome 3p). Researchers suspect that genes in the 3p14, 3p21, and 3p24–25 regions serve as TSGs or are linked to TSGs; according to this hypothesis, deletions in these regions would permit SCLC cells to grow unchecked. Similarly, aberrations in chromosome 5 lead to nonfunctional MCC and APC genes in approximately 80% of SCLC cells (D’Amico D, 1992). These possible TSGs become inactivated through loss of heterozygosity, the usual state of having two different genetic alleles in the same location on the chromosome. Defects in chromosome 9 have been found near the site of the gene complex that encodes interferon-alpha and interferon-beta, growth factors that might play a role in SCLC pathogenesis. Table 3 brießy describes the oncogenes and TSGs implicated in SCLC and their clinical signiÞcance. The identiÞcation of genetic factors that can predict response to speciÞc therapies for SCLC and exploration of new treatment strategies could lead to individualized treatment and better results for patients with these genetic mutations. Patterns of Recurrent Disease. Although most patients diagnosed with SCLC initially beneÞt from treatment, almost all relapse with increasingly unresponsive disease. A few fortunate patients are successfully treated and live for years without recurrent disease. Even those who have “beaten” SCLC, however, are not out of the woods: SCLC patients are at increased risk of developing second cancers of the aerodigestive tract (e.g., NSCLC, esophageal cancers, head and neck cancers). For example, even SCLC patients who survive for two years after treatment have an astounding 50% chance of eventually developing a second primary tumor; overall, the risk of developing a second primary lung cancer is approximately 5% per patient per year. CURRENT THERAPIES At the time of diagnosis, small-cell lung cancer (SCLC) usually manifests as a central tumor with spread to the regional lymph nodes. The vast majority of patients also show signs of spread to distant sites. Unfortunately, despite any apparent success of local treatment (i.e., radiotherapy or surgery) in select patients, the short- and long-term prognosis for SCLC patients is very poor. Therefore, because SCLC is primarily a systemic disease, chemotherapy is the cornerstone of treatment, although radiotherapy and (to a lesser extent) surgery also play a role.

CURRENT THERAPIES

309

The majority of SCLC patients die of their tumor despite the best available treatment. Treatment is, therefore, aimed primarily at extending survival and alleviating suffering. Most improvements in survival are attributable to clinical trials that have attempted to improve on the best available accepted therapy. Patient entry into clinical studies is a common pathway to disease treatment. The Þrst small advance in the treatment of SCLC was realized in the 1960s, when cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/ Endoxana, generics), one of the cytotoxic drugs then available, demonstrated a therapeutic effect. Chemotherapeutic drugs available in the 1970s for treating SCLC—such as cyclophosphamide; doxorubicin (Pharmacia’s Adriamycin/Adriblastine, generics); and epirubicin (Pharmacia’s Ellence/Farmorubicin, generics) —are near the point of replacement with more-active and/or less toxic drugs, such as the platinum-containing agents and topoisomerase inhibitors that were introduced in the 1980s. Given all the drugs now available for the treatment of SCLC, it is possible to form many different combination chemotherapy regimens. Combinations of two to four agents produce better clinical outcomes than single agents (Schuette W, 2001). Hundreds of publications have focused on many of these regimens without demonstrating any major differences in activity. However, the regimens discussed in this section are routinely used and considered standard combination chemotherapies for SCLC (Postmus PE, 1998). Typically, four to six cycles of chemotherapy are administered over a period of four to six months. If concurrent chemoradiotherapy is administered, physicians typically use four cycles because the toxic effects of concurrent thoracic radiotherapy (TRT) are greater than those of sequential TRT. Also, because tumor burden is higher in extensive-stage disease (ED-SCLC) than in limited-stage disease (LD-SCLC), some physicians administer more cycles to ED-SCLC patients. Many clinical trials have attempted to improve survival by extending chemotherapy beyond the standard maximum of six cycles (as maintenance chemotherapy), but investigators have unanimously concluded that extended chemotherapy offers no signiÞcant advantage (Postmus PE, 1998; Giaccone G, 1993). Researchers have been experimenting with higher doses of the standard dosing regimens in hopes of Þnding a signiÞcant survival beneÞt. A landmark study compared the standard EP regimen (cisplatin [Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics] 80 mg/m2 IV on day 1; etoposide [BristolMyers Squibb’s VePesid/Etopophos, PÞzer’s Lastet, generics] 80 mg/m2 /d IV on days 1 to 3) with the same regimen at a higher dose (cisplatin 27 mg/m2 /d IV on days 1 to 5; etoposide 80 mg/m2 /d IV on days 1 to 5). Investigators found no signiÞcant differences in efÞcacy between the two regimens, but the high-dose regimen produced a signiÞcant increase in toxicity (Ihde DC, 1994). In a two-arm trial of the PCDE regimen (cisplatin, cyclophosphamide, doxorubicin, etoposide), 105 patients received the same doses of doxorubicin and etoposide throughout the six cycles of chemotherapy, but during the Þrst cycle, patients in one arm received a higher dose of cyclophosphamide and cisplatin. Investigators reported signiÞcantly higher response rates (67% versus 54%) and

310


survival (43% two-year survival versus 26%) in the high-dose group (Arriagada R, 1993). Table 8 describes the regimens most commonly used for the treatment of SCLC. Etoposide/Cisplatin Regimen Overview. The etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, PÞzer’s Lastet, generics) plus cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics) (EP) regimen is considered the standard treatment for LD-SCLC patients who have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 (Postmus P, 1998). See Table 5 for details of performance status. In most major markets, EP is used interchangeably with the carboplatin (Bristol-Myers Squibb’s Paraplatin, generics) plus etoposide (EC) regimen (discussed in the following section), but historically, EP has been the standard regimen. Both regimens are equally effective. Because EP induces nephrotoxicity and neurotoxicity, patients must be hydrated. EP causes more nausea and vomiting, but EC produces more myelosuppression. Neutropenia can be controlled with granulocyte-macrophage colony-stimulating factor (GM-CSF); thrombocytopenia is dose-limiting, and no agent is available to control this toxicity. Mechanism of Action •

•

Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins cause single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Cisplatin (Figure 4) is a platinum agent. Platinum agents inhibit tumor-cell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that cisplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle.

R

O O HO

O O OH O O O O CH3O

OCH3 RO

FIGURE 3. Structure of etoposide (R = H, R1 = CH3 ).

TABLE 8. Current Regimens Used for Treating Small-Cell Lung Cancer Regimen Components Regimen Etoposide/cisplatin (EP) regimen

Etoposide/carboplatin (EC) regimen

Carboplatin/etoposide/ vincristine (CEV) regimen

Agent

Availability

Grade III/IV Dose

Toxicities mg/m2 /d

Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics)


Etoposide, 80–100 on days 1–3; cisplatin, 80–100 mg/m2 on day 1. Both IV.

Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics) Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics)


Cycle repeated every 21 days.


Etoposide, 100 mg/m2 /d days 1–3; carboplatin, 300–450 mg/m2 on day 1. Both IV.


Cycle repeated every 21–28 days.


Carboplatin, 300 mg/m2 on day 1; etoposide, 140 mg/m2 on days 1–3; vincristine, 1.4 mg/m2 on days 1, 8, and 15. All IV. Cycle repeated every 28 days.

Carboplatin (Bristol-Myers Squibb’s Paraplatin, generics) Carboplatin (Bristol-Myers Squibb’s Paraplatin, generics)

311

Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics)


• Leukopenia • Anemia • Nausea/vomiting • Alopecia

• Leukopenia • Thrombocytopenia • Alopecia

• Leukopenia • Thrombocytopenia • Alopecia • Nausea/vomiting

312


Cyclophosphamide/ doxorubicin/vincristine (CAV) regimen or cyclophosphamide/ epirubicin/ vincristine (CEpiV) regimen

Agent

Availability

Vincristine (Eli Lilly/EG Labo/Shionogi’s Oncovin, generics) Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics)


Doxorubicin (Pfizer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics) Vincristine (Eli Lilly/EG Labo/Shionogi’s Oncovin, generics) Epirubicin (Pfizer’s Ellence/Farmorubicin, Pfizer/Kyowa’s Farmarubicin, Kenfarma’s Farmorubicina, generics)

Dose


Cyclophosphamide, 800–1,000 mg/m2 ; doxorubicin, 50 mg/m2 ; vincristine, 1.4–2 mg/m2 . All IV on day 1.


Substitute doxorubicin for epirubicin: 50 mg/m2 IV on day 1 for CEpiV.


Cycle repeated every 21–28 days.



• Leukopenia • Thrombocytopenia • Gastrointestinal • Alopecia

TABLE 8. (continued) Regimen Components Regimen Ifosfamide/carboplatin/ etoposide (ICE) regimen or Vincristine/ ifosfamide/carboplatin/etoposide (VICE) regimen

Agent Ifosfamide (Bristol-Myers Squibb’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics)

Availability

Dose


Ifosfamide, 5 g/m2 on day 1; carboplatin, 300 mg/m2 on day 1; etoposide, 120 mg/m2 /d on days 1 and 2. All IV. Etoposide, 240 mg/m2 orally on day 3. Plus vincristine, 0.5 mg/m2 on day 14 for VICE regimen. Cycle repeated every 28 days.

Carboplatin (Bristol-Myers Squibb’s Paraplatin, generics) Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics) Vincristine (Eli Lilly/EG Labo/Shionogi’s Oncovin, generics)




Grade III/IV Toxicities • Leukopenia • Thrombocytopenia • Alopecia • Vomiting

313

314

TABLE 8. (continued) Regimen Components Regimen Cyclophosphamide/ doxorubicin/etoposide (CDE) regimen or Cisplatin/cyclophosphamide/ doxorubicin/ etoposide (PCDE) regimen

Agent

Availability

Dose

Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics)


Cyclophosphamide, 1 g/m2 ; doxorubicin, 45 mg/m2 . Both IV on day 1. Etoposide, 150 mg/m2 IV on days 1 and 2. Plus cisplatin, 100 mg/m2 IV on day 1 for PCDE regimen. Cycle repeated every 21 days.

Doxorubicin (Pfizer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics) Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics) Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics)




Grade III/IV Toxicities • Leukopenia • Thrombocytopenia • Alopecia • Nausea/vomiting • Febrile neutropenia induced death, 5% in PCDE

TABLE 8. (continued) Regimen Components Regimen Cisplatin/cyclophosphamide/epirubicin/ etoposide (PCEE)

Agent

Availability

Dose

Cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics)


Cisplatin, 100 mg/m2 on day 2; cyclophosphamide, 400 mg/m2 /d on days 1–3; epirubicin, 40 mg/m2 on day 1; etoposide, 100 mg/m2 /d on days 1–3. All IV. Cycle repeated every 28 days.

Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, generics) Epirubicin (Pfizer’s Ellence/Farmorubicin, Pfizer/Kyowa’s Farmarubicin, Kenfarma’s Farmorubicina, generics)



Grade III/IV Toxicities • Neutropenia • Thrombocytopenia • Nausea/vomiting

315

316


Dose


Agent

Availability

Cisplatin/cyclophosphamide/epirubicin/ etoposide (PCEE) (cont.) Topotecan, single agent

Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pfizer’s Lastet, generics) Topotecan (GlaxoSmithKline/Merck/Nihon Kayaku’s Hycamtin)



1.5 mg/m2 /d for 5 days per week every 21 days.

• Leukopenia • Neutropenia • Thrombocytopenia • Anemia

Etoposide, single agent

Etoposide (Bristol-Myers Squibb’s VePesid/Etopophos, Pharmacia’s Lastet, Novartis Vepeside Sandoz)


100 mg orally, twice daily for five days. Cycle repeated every five days.

• Neutropenia • Infection • Nausea/vomiting

CURRENT THERAPIES

317


Clinical Performance. Many trials have evaluated the EP regimen at varying dose intensities (Ihde DC, 1994; Schiller JH, 2001[a]). In an ECOG Phase III study of 402 ED-SCLC patients, EP Þrst-line treatment provided an overall response rate and an overall survival of 35% and 9.6 months, respectively. Of the patients receiving EP, 50% experienced grade 4 neutropenia and thrombocytopenia, and 5% experienced grade 4/5 infection (Schiller JH, 2001[a]). In other randomized trials, EP has demonstrated survival rates similar to those of the ECOG trial and to survival rates of the traditional CAV regimen (cyclophosphamide plus doxorubicin [PÞzer’s Adriamycin/Adriblastine, Kyowa’s Adriacin, generics] plus vincristine [Eli Lilly/EG Labo/Shionogi’s Oncovin, generics], discussed in a later section) with much higher overall response rates—more than 80% (Fukuoka M, 1991; Noda K, 2002; Sundstrom S, 2002). A Phase III trial randomized 143 SCLC patients to receive EP or EC; 82 patients had LD-SCLC and were therefore eligible for additional thoracic irradiation. For LD patients, overall response was 73% for EP and 86% for EC; for ED-SCLC patients, overall response was 50% for EP and 64% for EC. Median overall survival was 12.5 months for patients receiving EP and 11.8 months for patients receiving EC. The differences in response rates and survival were not statistically signiÞcant, but toxicity was signiÞcantly less in the EC arm, particularly gastrointestinal toxicity, nephrotoxicity, and neurotoxicity (Kosmidis PA, 1994). Compared with the CAV regimen, the EP regimen is associated with less leukopenia, neutropenia, thrombocytopenia, peripheral neuropathy, and nonhematologic toxicities. Hepatic and renal toxicities occur equally in CAV and EP regimens (Fukuoka M, 1991; Ihde DC, 1994; Schiller JH, 2001[b]). Etoposide/Carboplatin Regimen Overview. The etoposide/carboplatin (EC) regimen is generally as popular as EP in the seven major markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan). Randomized studies have shown that compared with cisplatin, carboplatin is associated with less nephrotoxicity, neurotoxicity, ototoxicity, and gastroenteric toxicity (Rozencweig M, 1990). Because its toxicity proÞle is generally considered advantageous compared with that of EP, the EC regimen is used more often than EP for poor-PS patients, the elderly, and patients with renal insufÞciencies. Unlike cisplatin, carboplatin does not require pre- or post-treatment hydration, so administration takes no longer than one hour. Therefore, EC has the additional advantage of outpatient administration; EP can also be given on an outpatient basis, but because administration takes eight hours, EP is usually given in a hospital overnight.

318


Mechanism of Action. •

•

Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins cause single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Carboplatin (Figure 5) is a platinum agent. Platinum agents inhibit tumorcell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that carboplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle.

Clinical Performance. Carboplatin has been investigated in combinations and compared with cisplatin combinations. A Phase III trial randomized 143 SCLC patients to receive EP or EC; 82 patients had LD-SCLC and were therefore eligible for additional thoracic irradiation. Overall response to EP was 73% for LD patients and 50% for ED patients; overall response to EC was 86% for LD patients and 64% for ED patients. Median overall survival was 12.5 months for patients receiving EP and 11.8 months for patients receiving EC. The differences in response rates and survival were not statistically signiÞcant, but toxicity was signiÞcantly less in the EC arm, particularly gastrointestinal toxicity, nephrotoxicity, and neurotoxicity (Kosmidis PA, 1994). Carboplatin/Etoposide/Vincristine Regimen Overview. The carboplatin/etoposide/vincristine (CEV) regimen is used more in Germany than anywhere else. Outside of Germany, the general consensus is that CEV is more toxic than EC, with an insigniÞcant improvement in efÞcacy. However, it is associated with less life-threatening leukopenia than CAV. Mechanism of Action. •

Carboplatin (Figure 5) is a platinum agent. Platinum agents inhibit tumorcell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that carboplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle.

FIGURE 5. Structure of carboplatin.

CURRENT THERAPIES

N

OH CH3

NH H3CO H3CO

319

N

O

H N R

H HO

CH3 OAc O

H3CO FIGURE 6. Structure of vincristine (R = CHO). •

•

Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins cause single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Vincristine (Figure 6) is a vinca alkaloid. Vinca alkaloids bind with microtubular proteins of the mitotic spindle, thus leading to mitotic arrest or cell death. The drug achieves its selective toxicity against cancer cells by acting on proliferating cells.

Clinical Performance. A 316-patient ED-SCLC Phase III study showed that CEV produces an overall response rate and median survival of 83% and ten months, respectively, compared with 65% and nine months, respectively, for the etoposide/vincristine (EV) regimen alone. However, the three-drug combination was associated with higher toxicities, and survival beneÞt was more evident in patients with a better PS. Grade 3/4 hematologic toxicities of the CEV regimen include leukopenia (35%), thrombocytopenia (21%), and anemia (7%); nonhematologic toxicities include alopecia (82%) and polyneuropathy (21%) (Gatzemeier U, 1994). Cyclophosphamide/Doxorubicin (Epirubicin)/Vincristine Regimen Overview. The cyclophosphamide/doxorubicin/vincristine (CAV) regimen and the cyclophosphamide/epirubicin (PÞzer’s Ellence/Farmorubicin, PÞzer/Kyowa’s Farmarubicin, Kenfarma’s Farmorubicina, generics) plus vincristine (CEpiV) regimen were some of the Þrst multidrug regimens for treatment of SCLC; they were widely used throughout the 1970s. Because doxorubicin and epirubicin are of the same class, they are sometimes used interchangeably. However, epirubicin is more expensive and still patent-protected in some territories, so it is not as commonly employed as doxorubicin. CAV was widely used throughout the

320


1970s and set the standard against which emerging combinations were measured. CAV remains in use in most countries, but its popularity has declined since the emergence of more-active, less toxic regimens in the 1980s and 1990s, such as the platinum-containing regimens. In most countries, CAV is used primarily for patients whose disease recurs after Þrst-line therapy with platinum-based regimens because CAV is non-cross-resistant with platinum. Mechanism of Action. •

•

Cyclophosphamide (Figure 7) is an alkylating agent. These agents alkylate DNA bases, thereby producing cross-links that covalently link the two DNA strands and prevent cell replication. Doxorubicin (Figure 8) and epirubicin (Figure 9) are anthracyclines. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded



CURRENT THERAPIES

O

OH

321

O OH OH

H3CO

O H3C HO

OH

O

O NH2

FIGURE 9. Structure of epirubicin.

•

breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Vincristine (Figure 6) is a vinca alkaloid. Vinca alkaloids bind with microtubular proteins of the mitotic spindle, thus leading to mitotic arrest or cell death. The drug achieves its selective toxicity against cancer cells by acting on proliferating cells.

Clinical Performance. CAV and, to a lesser extent, CEpiV were the standard Þrst-line treatments in the 1970s and 1980s. More recently, randomized clinical trial data have led to their replacement by newer-generation, platinumbased regimens and relegation to second-line treatment. A 288-patient, three-arm study compared CAV with EP and with CAV/EP as Þrst-line treatments. CAV yielded overall response rates of 51% in LD-SCLC patients and 59% in ED-SCLC patients, compared with 77% and 78% for EP and 88% and 63% for CAV/EP, respectively (Fukuoka M, 1991). The overall response rates were signiÞcantly higher in the EP and CAV/EP arms than in the CAV arm. The CAV, EP, and CAV/EP regimens demonstrated median survival of 12.4, 11.7, and 16.8 months, respectively, in patients with LD-SCLC and 8.7, 8.3, and 9.0 months, respectively, in patients with ED-SCLC. Median overall survival was signiÞcantly greater for LD-SCLC patients treated with CAV/EP than for the other two arms, but no signiÞcant difference was evident in ED-SCLC patients. Grade 3/4 leukopenia occurred more frequently in the CAV (78%) and CAV/EP (72%) arms than in the EP arm (46%), but no signiÞcant differences were observed in thrombocytopenia. A Phase III clinical study randomized 211 patients whose disease recurred at least 60 days after Þrst-line treatment to receive either CAV or single-agent topotecan (GlaxoSmithKline/Merck/Nihon Kayaku’s Hycamtin) (von Pawel J, 1999). Both regimens are popular second-line therapies. Overall response rates in the CAV and topotecan arms were 18.3% and 24.3%, respectively. Overall survival was not statistically different between patients on the CAV regimen (24.7 weeks) and patients on the topotecan regimen (25 weeks). Symptom improvement was reportedly greater in the topotecan group than in the CAV group for four

322


out of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue. Grade 4 neutropenia occurred in 37.8% of patients in the topotecan arm and 51.4% of patients in the CAV arm. Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan than with CAV (9.8% and 17.7% versus 1.4% and 7.2%, respectively). Nonhematologic toxicities were mild and similar in both arms. Comparable results were seen in a 436-patient, randomized trial of CEpiV versus EP (Sundstrom S, 2002). The two- and Þve-year survival rates in the EP arm (14% and 5%) were signiÞcantly higher compared with those in the CEpiV arm (6% and 2%). For LD-SCLC patients, the median survival time of 14.5 months in the EP arm was signiÞcantly greater than the median survival time of 9.7 months in the CEpiV arm. The two- and Þve-year survival rates of 25% and 10% in LD-SCLC patients in the EP arm were also signiÞcantly greater than the rates of 8% and 3% in the CEpiV arm. For ED-SCLC patients, no signiÞcant survival difference between the treatment arms was evident. Median overall survival for both ED- and LD-SCLC patients combined was 10.2 months in the EP arm, which was signiÞcantly greater than the 7.8 months observed in the CEpiV arm. Hematologic toxicities are considered a major concern with the CAV regimen; characteristic toxicities are grade 3/4 neutropenia (approximately 85%), leukopenia (approximately 80%), thrombocytopenia (approximately 15%), and anemia (approximately 20%). Nonhematologic toxicities such as alopecia, fatigue, and gastrointestinal disturbances are also common side effects of the CAV regimen (Fukuoka M, 1991). (Vincristine)/Ifosfamide/Carboplatin/Etoposide Regimen Overview. The ifosfamide (Bristol-Myers Squibb’s Ifex, Baxter’s Mitoxana/ Holoxan, Shionogi’s Ifomide, generics) plus carboplatin plus etoposide (ICE) regimen and the vincristine plus ICE (VICE) regimen are used infrequently in clinical practice. ICE and (to a lesser extent) VICE are still occasionally used in the United Kingdom, however, where these regimens were pioneered. The dosing schedules for ICE and VICE are identical, except that the latter includes a midcycle dose of vincristine. Theoretically, VICE should be more effective than ICE; researchers argue that adding vincristine in midcycle prevents relapses between cycles. No randomized trials have been conducted to test this supposition. Some evidence suggests that these combinations offer better survival than other regimens (Lorigan P, 1995), but ICE and VICE produce signiÞcant toxicity, are more difÞcult to administer than other regimens (ifosfamide must be coadministered with an inert compound called mesna to prevent hemorrhagic cystitis), and are costly. Both regimens are extremely myelosuppressive; efforts to reduce myelosuppression by using stem cell support have not been successful (Steward WP, 1998). Because of their toxicity, ifosfamide-based regimens are used principally in patients with strong PS scores and good Þtness.

CURRENT THERAPIES

323

FIGURE 10. Structure of ifosfamide.

Mechanism of Action •

•

•

•

Ifosfamide (Figure 10) is an alkylating agent. These agents alkylate DNA bases, thereby producing cross-links that covalently link the two DNA strands and prevent cell replication. Carboplatin (Figure 5) is a platinum agent. Platinum agents inhibit tumorcell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that carboplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle. Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins act by causing single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Vincristine (Figure 6) is a vinca alkaloid. Vinca alkaloids act by binding with microtubular proteins of the mitotic spindle, thus leading to mitotic arrest or cell death. The drug achieves its selective toxicity against cancer cells by acting on proliferating cells.

Clinical Performance. The exact dose intensity of VICE was the subject of a European trial that randomized 300 ED-SCLC patients to receive VICE in three-weekly cycles (dose-intense regimen) versus four-weekly cycles (standardintensity regimen) (Steward WP, 1998). The two-by-two factorial design also allowed evaluation of the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on reduction of the myelosuppression associated with VICE. The overall response rate was 83% (51% complete response) for all treated patients, with no signiÞcant difference between treatment groups. Median overall survival and two-year survival rates were signiÞcantly increased in the intensiÞeddose arm (443 days and 33%) versus the standard-dose arm (351 days and 18%). GM-CSF did not reduce the incidence of myelosuppression. Neutropenia occurred in 54% of all patients, with no signiÞcant difference between treatment groups. Thirty treatment-related deaths (10%) occurred; the most frequent cause of death was infection, which accounted for ten deaths. A similar but smaller trial evaluated ICE in 50 ED-SCLC patients; patients were randomized to receive a cycle of ICE either every two weeks (dose-intense)

324


or every four weeks (standard dose). IntensiÞed ICE was given with GM-CSF (Woll PJ, 2001); this study did support the use of GM-CSF to reduce myelosuppression. Febrile neutropenia was more common in the standard-dose arm (84%) than in the intensiÞed-dose arm (56%). However, overall response rate and median overall survival were similar in the dose-intense and standard-dose arms (80% versus 76% and 327 days versus 272, respectively), although the study was not powered enough to detect any potential differences. (Cisplatin)/Cyclophosphamide/Doxorubicin/Etoposide Regimen Overview. The cyclophosphamide/doxorubicin/etoposide (CDE) regimen is widely used internationally to treat SCLC, although associated neutropenia prevents it from being given at full doses. However, as with all nonplatinum-based regimens, its use has declined since the emergence of data demonstrating the superiority of platinum-containing regimens. Nevertheless, CDE’s non-cross-resistant proÞle with platinum-based regimens makes it a useful second-line option in patients whose disease progresses after treatment with these other regimens. Cisplatin is sometimes incorporated into the CDE regimen, making the four-drug combination regimen, PCDE, which is used only in France. Mechanism of Action. •

•

•

•

Cyclophosphamide (Figure 7) is an alkylating agent. These agents alkylate DNA bases, thereby producing cross-links that covalently link the two DNA strands and prevent cell replication. Doxorubicin (Figure 8) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA religation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins act by causing single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Cisplatin (Figure 4) is a platinum agent. Platinum agents inhibit tumor-cell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that cisplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle.

Clinical Performance. Because of the dose-limiting neutropenia associated with CDE, studies have attempted to evaluate the effect of GM-CSF. One study randomized 413 patients to receive CDE either every three weeks (control group)

CURRENT THERAPIES

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or every two weeks with GM-CSF (dose-intense group) (Thatcher N, 2000). The dose intensity of CDE was increased by 50% in the dose-intense group compared with the control group. Complete response rates were 40% for the dose-intense group and 28% for the control group; overall response rates were 78% for the dose-intense group and 79% for the control group. Survival was longer in the dose-intense group: survival rates for the dose-intense and control groups were, respectively, 47% and 39% at 12 months and 13% and 8% at 24 months. In the dose-intense group, less neutropenia was observed, but more thrombocytopenia and more-frequent blood and platelet transfusions. In a multicenter clinical trial, 457 patients (79% with ED-SCLC) were randomized to receive either CDE or PCDE (Urban T, 1999). Although the objective response rate was higher in the PCDE group (72%) than in the CDE group (53%), median overall survival was similar for the groups that received CDE (266 days) and PCDE (271 days). A higher fatal neutropenia rate was observed in the PCDE group (n = 23) than in the CDE group (n = 4), mainly in patients with ED-SCLC. Researchers concluded that the addition of cisplatin to CDE is toxic to patients with ED-SCLC and does not improve overall survival. Cisplatin/Cyclophosphamide/Epirubicin/Etoposide Regimen Overview. The cisplatin/cyclophosphamide/epirubicin/etoposide (PCEE) regimen is popular in France. Because it is more toxic than double- or triple-drug regimens, its use is limited to good-PS LD-SCLC patients. In addition to replacing doxorubicin with epirubicin, the PCEE regimen is given at a slightly higher dose intensity than the previously discussed PCDE regimen. Compared with the PCDE regimen, PCEE is more hematotoxic. It is uncertain which regimen is more active because no randomized trials exist that compare PCDE with PCEE. However, the use of PCEE is limited because of the high cost of epirubicin compared with the cost of doxorubicin. Mechanism of Action. •

•

•

Cisplatin (Figure 4) is a platinum agent. Platinum agents inhibit tumor-cell replication by creating intra- and interstrand DNA cross-links. Early studies suggested that cisplatin was cell-cycle-phase nonspeciÞc; more recent studies have shown complex and variable effects on the cell cycle. Cyclophosphamide (Figure 7) is an alkylating agent. These agents alkylate DNA bases, thereby producing cross-links that covalently link the two DNA strands and prevent cell replication. Epirubicin (Figure 9) is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA re-ligation enzyme, anthracyclines exert their cytotoxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit

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cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures. Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins act by causing single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase.

Clinical Performance. One randomized French study evaluated the PCEE regimen in 117 ED-SCLC patients compared with the EP regimen in 109 ED-SCLC patients. Investigators found signiÞcant response rate and survival differences between the two arms: in the PCEE arm, the overall response rate was 76% and median survival was 10.5 months; in the EP arm, overall response was 61% and median survival was 9.3 months. Hematologic toxicity was signiÞcantly higher in the PCEE arm—22% with infections, compared with 8% in the EP arm—but the rate of toxicity-related deaths was not signiÞcantly different (Pujol JL, 2001). Topotecan, Single Agent Overview. Topotecan (GlaxoSmithKline/Merck/Nihon Kayaku’s Hycamtin) is approved in the United States and Japan as an intravenous (IV) monotherapy for patients with recurrent SCLC. Results of an international Phase III trial of the IV formulation for treatment of recurrent SCLC led to topotecan’s U.S. and Japanese launches. Results of another international Phase III trial comparing IV with oral topotecan in the second-line setting show that both forms of topotecan have similar efÞcacy. Another Phase III trial, ongoing in the United States, is comparing oral topotecan plus cisplatin with EP as Þrst-line therapy for patients with ED-SCLC. An application for European marketing as an IV monotherapy for patients with recurrent SCLC was Þled with the European Medicines Evaluation Agency (EMEA), but an EMEA panel voted against approval until more robust data are available. Mechanism of Action. Topotecan (Figure 11) is a topoisomerase I inhibitor. Topotecan binds to the topoisomerase I DNA complex and prevents religation of DNA single-strand breaks that occur naturally during DNA synthesis. Researchers believe the cytotoxicity of topotecan results from double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efÞciently repair these double-strand breaks. Clinical Performance. Japanese and U.S. approval for second-line, singleagent use of IV topotecan was based on a Phase III international trial that compared single-agent topotecan with CAV in 211 SCLC patients with recurrent disease (von Pawel J, 1999). Overall response rates of 18.3% and 24.3% occurred in the CAV and topotecan arms, respectively. Overall survival was not statistically different between patients in the CAV arm (24.7 weeks) and the

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CH3 N CH3 HO

O N N O HO H3C

O

FIGURE 11. Structure of topotecan.

topotecan arm (25 weeks). Symptom improvement was reported to be greater in the topotecan group than in the CAV group for four out of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue. Grade 4 neutropenia occurred in 37.8% of patients in the topotecan arm and 51.4% in the CAV arm. Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan than CAV (9.8% and 17.7% versus 1.4% and 7.2%, respectively). Nonhematologic toxicities were mild and similar in both arms. Clinical evaluations in the Þrst-line setting have so far yielded disappointing results (Ormrod D, 1999). Phase III data failed to show any signiÞcant survival beneÞt for EP followed by IV topotecan, compared with EP alone, in previously untreated ED-SCLC patients. Toxicity proÞles were similar in both groups (Schiller JH, 2001[b]; Johnson D, 2000). Results of a U.S. and European Phase III study showed that oral topotecan has activity and tolerability similar to that of IV topotecan in chemosensitive SCLC patients (Eckardt JR, 2003). Patients with LD- or ED-SCLC who had a documented response to Þrst-line therapy, ECOG PS < 2, and measurable, recurrent disease with a treatment-free interval > 90 days were randomized to oral (n = 153) or IV (n = 151) topotecan. Response rates for oral and IV topotecan were 18.3% versus 21.9%, respectively. Median survival and one-year survival were 33 weeks and 33% for oral topotecan and 35 weeks and 29% for IV topotecan. Quality of life results showed no signiÞcant differences between oral and IV topotecan. Oral and IV topotecan were generally well tolerated; incidence of grade 4 toxicity by patient (oral and IV) was neutropenia (47% and 64%); thrombocytopenia (29% and 18%); grade 3/4 anemia (23% and 31%); and sepsis (3% and 3%). A larger, ongoing Phase III trial has randomized ED-SCLC patients to receive oral topotecan plus cisplatin or EP as Þrst-line therapy; encouraging preliminary results were disclosed at the American Society of Clinical Oncology (ASCO) meeting in 2004 (Eckardt JR, 2004). Tolerability data for 732 patients are available so far, but no efÞcacy data have been disclosed. Principal adverse experiences per patient for topotecan/cisplatin versus EP were the following: grade 4 neutropenia

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(32% versus 58%); platelets < 25,000 (10% versus 6%); grade 3/4 anemia (35% versus 20%); febrile neutropenia (1% versus 4%); infection (9% versus 12%); all grades of nausea/vomiting (58% and 39% versus 62% and 42%). Etoposide, Single Agent Overview. Etoposide monotherapy (oral or IV) is used mainly as palliative treatment for elderly and low-PS patients who have ED-SCLC or recurrent disease. Oral etoposide is used only rarely; because oral absorption is poor, oral etoposide must be given at double the dose required for IV etoposide to achieve the same effect, but this dosing produces more toxic effects. However, IV etoposide is less convenient than the oral form, which can be administered at home. Mechanism of Action. Etoposide (Figure 3) is an epipodophyllotoxin. Epipodophyllotoxins act by causing single-strand breaks in DNA. Epipodophyllotoxins also inhibit DNA topoisomerase II to cause metaphase arrest, thereby inducing cytotoxic activity. Etoposide is cell-cycle-phase speciÞc, with predominant activity occurring in the late S phase and G2 phase. Clinical Performance. In a randomized trial of palliative treatment in advanced SCLC, oral etoposide was compared with IV chemotherapy consisting of alternating cycles of cisplatin and etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV) (Souhami RL, 1997). After 155 patients had been randomly assigned from a projected intake of 365 patients, an independent data monitoring committee examined the interim results. Survival was inferior at one year in the oral etoposide group compared with IV therapy (9.8% for oral versus 19.3% for IV), and there was a trend toward inferior overall survival. Median survival was 4.8 months for oral treatment and 5.9 months for IV therapy. Progression-free survival was worse in the oral etoposide arm (median = 3.6 months versus 5.6 months); overall response rate was also worse (32.9% versus 46.3%). With the exception of acute nausea and vomiting associated with IV chemotherapy, all aspects of symptom control and quality of life were either the same or worse in the oral etoposide group. Nonpharmacological Approaches Radiotherapy is the main nonpharmacological approach used in the treatment of SCLC and is administered in the thoracic region (thoracic radiotherapy [TRT]) or the cranial region (prophylactic cranial irradiation [PCI] or as whole-brain radiotherapy [WBRT]). TRT is used mainly in LD-SCLC and in combination with chemotherapy. No standard consensus exists on the exact timing of TRT delivery during the course of combined modality treatment, although it is becoming more evident that concurrent TRT (during chemotherapy) is more efÞcacious than sequential TRT (before or after TRT). Brain metastases are detected in approximately 10% of SCLC patients at the time of presentation and are subsequently diagnosed in 20–25% of patients during

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their lifetimes, with the likelihood of development increasing as length of survival time increases (Komaki R, 1981). In the absence of PCI, patients have a 50–80% chance of developing brain metastases during their Þrst two years of survival. Postmortem examination shows brain metastasis in 65% of SCLC patients (Rosen ST, 1983). A review of nine studies that examined the beneÞt of PCI showed that PCI reduced the frequency of brain metastases from 22% to 6% in LD-SCLC patients who had achieved a complete response. Therefore, PCI is given to all LD-SCLC patients who achieve a complete response to conventional treatment and, occasionally, to patients who achieve a very good partial response—that is, more than 75% decrease in tumor size (Armstrong J, 2002). The standard treatment for SCLC patients with brain metastases is WBRT plus chemotherapy. WBRT is sequentially administered, usually prior to chemotherapy or during chemotherapy. Because of the highly metastatic nature of most SCLC cases, surgery plays only a minor role. Some studies show that in early-stage SCLC (stages I to IIIA), surgery can achieve a high local control rate that may result in favorable longterm results (Passlick B, 2001). However, in more than 90% of SCLC patients, the disease is too systemic to be controlled by local resection; therefore, surgery is inappropriate (Beat-Ris H, 2002). EMERGING THERAPIES Commercial investment in R&D of small-cell lung cancer (SCLC) therapies is modest compared with such investment in many other tumor types, probably because of the relatively low incidence of SCLC. R&D activity in SCLC focuses chießy on investigating the activity of agents approved for other tumor types. During the past decade, median overall survival for SCLC patients has improved only by weeks. Only irinotecan (PÞzer’s Camptosar, Aventis/Prodesfarma’s Campto, Yakult/Daiichi’s Topotecin) has achieved any greater survival beneÞt over established agents. Myelosuppression—the primary toxicity of standard treatments—remains a problem with many of the cytotoxic therapies under investigation for SCLC. In common with most other cancer treatments, agents in development for SCLC are generally approved Þrst for recurrent or extensive-stage disease (EDSCLC) and later for limited-stage disease (LD-SCLC). A small number of agents with novel mechanisms of action are in Phase II trials, but currently, no clinical data are available for them. One of these novel agents is dehydrodidemnin B (PharmaMar’s Aplidin), a cyclodepsipeptide derived from the tunicate Aplidium albicans. This agent blocks cell division, induces apoptosis, and inhibits both the secretion of vascular endothelial growth factor and expression of its receptor. Phase II trials in SCLC began in May 2004 (PharmaMar, press release, May 2004). SanoÞ-Aventis’ reminertant (SR-48692) is an oral, nonpeptide, neurotensin NT1 receptor antagonist with neurotensin NT2 agonist properties. This agent entered Phase IIb trials for SCLC in February 2004. Introgen Therapeutics’ INGN-225 is an immunotherapeutic treatment in earlystage development; no clinical data are available at this time. INGN-225 entered a

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Phase I/II study in patients with SCLC in June 2003 (Introgen Pharmaceuticals, press release, June 2003); this agent stimulates patients’ own dendritic cells, which are then used as a therapeutic vaccine. Table 9 summarizes the drug therapies in development for SCLC. Conventional Cytotoxic Agents Overview. Conventional cytotoxic drugs are the mainstay of therapy for most cancers. Recent generations have been adapted to minimize toxicity proÞles and enhance therapeutic potential. Clinical trials for SCLC focus heavily on analyzing combinations of established cytotoxic drugs, aiming to improve response rate and survival time. Companies have also shown interest in developing new formulations and analogues in an attempt to reduce toxic side effects and increase the maximum tolerated dose. These agents may also have improved pharmacokinetic proÞles and different mechanisms of intracellular uptake. For SCLC, this section discusses new formulations of the vinca alkaloid vincristine (see “Onco TCS”) and the topoisomerase I inhibitor lurtotecan (see “OSI-211”). Mechanism of Action. Conventional cytotoxic agents interrupt the DNA replication and repair processes required for functional cell division. They act in several ways, including alkylation of DNA, resulting in strand breakage; inhibition of crucial enzymes required for DNA strand formation; and interference with spindle formation. Irinotecan. Irinotecan (PÞzer’s Camptosar, Aventis/Prodesfarma’s Campto, Yakult/Daiichi’s Topotecin) (Figure 12) is an injectable topoisomerase I inhibitor. Topoisomerase I inhibitors bind to the topoisomerase I-DNA complex, a nuclear enzyme that causes reversible single-strand breaks in DNA and prevents religation of the DNA strand, resulting in cell death. The drug is believed to exert its cytotoxic effects during the S phase of the cell cycle. Irinotecan is marketed worldwide for colorectal cancer and non-small-cell lung cancer (NSCLC). In Japan, irinotecan is registered for the treatment of ED-SCLC in combination with cisplatin (Bristol-Myers Squibb’s Platinol-AQ, Nippon Kayaku’s Randa, generics) and is under development for LD-SCLC. In the United States and Europe, the irinotecan/cisplatin combination (IP regimen) is undergoing Phase III trials for ED-SCLC. Japanese approval was based on the results of a 231-patient ED-SCLC Phase III Japanese trial that compared IP with the EP regimen (etoposide [Bristol-Myers Squibb’s VePesid/Etopophos, PÞzer’s Lastet, generics]) plus cisplatin (Noda K, 2002). Participation in the trial was limited to patients younger than age 70. Response rates for the IP regimen (84%) and median overall survival (12.8 months) were signiÞcantly higher than response rates and survival for the EP regimen (68%, 8.4 months). Grade 3/4 hematologic toxicities were signiÞcantly lower in the IP arm (neutropenia 65%, leukopenia 27%) than in the EP arm (neutropenia 92%, leukopenia 52%); nonhematologic toxicities were only slightly higher in the IP arm than in the EP arm (diarrhea 16% versus 0%).

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TABLE 9. Emerging Therapies in Development for Small-Cell Lung Cancer Compound

Development Phase

Marketing Company

Irinotecan (Camptosar, Campto, Topotecin) United States III Europe III Japan R

Pfizer Aventis Yakult/Daiichi

Paclitaxel (Taxol) United States Europe Japan

III III II

Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

Docetaxel (Taxotere) United States Europe Japan

II II I

Aventis Aventis Aventis

Vinorelbine (Navelbine) United States Europe Japan

II II —

Pierre Fabre/GlaxoSmithKline Pierre Fabre/GlaxoSmithKline —

Gemcitabine (Gemzar) United States Europe Japan

II III I

Eli Lilly Eli Lilly Eli Lilly

Pemetrexed (Alimta) United States Europe Japan

II — —

Eli Lilly — —

Oral topotecan (Hycamtin) United States Europe Japan

III III —

GlaxoSmithKline/Merck/Nihon Kayaku GlaxoSmithKline/Merck/Nihon Kayaku —

OSI-211 United States Europe Japan

II II —

OSI Pharmaceuticals OSI Pharmaceuticals —

Onco TCS United States Europe Japan

II — —

Inex Pharmaceuticals — —

Immunotherapies IMC-BEC2 United States Europe Japan

III III —

ImClone Merck KGaA —

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Development Phase

Marketing Company

SRL-172 United States Europe Japan

— II —

— SR Pharma —

Tumor-activated pro-drugs huN901-DM1 United States Europe Japan

II I —

ImmunoGen Vernalis —

Angiogenesis inhibitors ZD-6474 United States Europe Japan

— II —

— AstraZeneca —

Bevacizumab (Avastin) United States Europe Japan

II — —

Genentech/Roche — —

Thalidomide (Thalomid) United States Europe Japan

II III —

Celgene Celgene —

Bioreductive agents Tirapazamine (Tirazone) United States Europe Japan

II — —

Sanofi-Aventis — —

Imatinib (Gleevec/Glivec) United States Europe Japan

II — —

Novartis — —

Synthetic retinoids Fenretinide United States

II — —

McNeil Pharmaceuticals/ National Cancer Institute — —

II — —

Millennium — —

Europe Japan Proteasome inhibitors Bortezomib (Velcade) United States Europe Japan R = Registered.

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H3C O

O

O N

N N O N

HO H3C

O

FIGURE 12. Structure of irinotecan.

A randomized Phase III trial was initiated in North America to conÞrm the results of the Japanese trial (Sandler A, 2003). Based on U.S. pilot data, doses of IP were modiÞed so that patients received 30 mg/m2 cisplatin and 65 mg/m2 irinotecan on days 1 and 8, every 21 days, rather than 60 mg/m2 of both agents on days 1, 8, and 15 every 28 days. No response data are yet available, but safety data from 122 patients demonstrate that the dose-adjusted IP regimen is better tolerated than the Japanese schedule. Grade 3/4 neutropenia and anemia were reduced from 65.3% and 26.7% in the Japanese study to 32% and 5%, respectively, in the North American study. In addition, 20% of patients experienced grade 3 diarrhea in the North American study compared with 11% grade 3 and 5% grade 4 diarrhea in the Japanese trial. Another Phase III study investigating IP, using the same regimen employed by the Japanese Clinical Oncology Group (JCOG) group, is recruiting patients. This study is sponsored by the Southwest Oncology Group (SWOG), National Cancer Institute (NCI), North Central Cancer Treatment Group (NCCTG), and Cancer and Leukemia Group B (CALGB). In Phase II trials of Þrst-line therapy in patients with ED-SCLC, irinotecan is being combined with gemcitabine (Eli Lilly’s Gemzar; see “Gemcitabine” section) in 81 patients (Akerley WL, 2004), with paclitaxel (Bristol-Myers Squibb’s Taxol, generics; see “Paclitaxel” section) plus carboplatin (BristolMyers Squibb’s Paraplatin, generics) in 25 patients (Glisson SD, 2003), and with etoposide in 23 patients (Farhat FS, 2004). Poor response rates were observed in the trial of irinotecan combined with gemcitabine: the overall response rate was 29%, but survival time was eight months, which was not signiÞcantly different from results reported with the EP regimen. The triple regimen of paclitaxel, irinotecan, and carboplatin (PIC regimen) demonstrated promising results. An overall response rate of 88% included 36% complete responses (CR) and 52% partial responses (PR). Mean survival time was 453 days (approximately 15 months), and the most signiÞcant toxicities included 40% neutropenia, 24% thrombocytopenia, and 28% diarrhea. The combination of irinotecan and etoposide resulted in 24% CR and 40% PR.

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Other Þrst-line regimens being evaluated in ED-SCLC patients include alternating schedules of double-and triple-drug combinations. Phase II data presented at the American Society of Clinical Oncology (ASCO) meeting in 2004 analyzed 27 patients who received IP (60 mg/m2 irinotecan on days 1, 8, and 15, and 60 mg/m2 cisplatin on day 1) in the Þrst, third, and Þfth cycles and received doxorubicin (PÞzer’s Adriamycin)/cyclophosphamide/etoposide (ACE regimen) (50 mg/m2 doxorubicin on day 1; 750 mg/m2 cyclophosphamide on day 1; 80 mg/m2 etoposide on days 1–3) in the second, fourth, and sixth cycles of chemotherapy (Yonei T, 2004). Both regimens were repeated every three to four weeks, toxicity permitting, and granulocyte colony-stimulating factor (GCSF) was administered when patients experienced grade 4 neutropenia or grade 3 febrile neutropenia. The overall response rate was 92.6% (14.8% CR; 77.8% PR), with a median survival of 13.8 months and one- and two-year survival rates of 51.6% and 9.0%, respectively. This alternating regimen induced signiÞcant toxicities, including 96.3% neutropenia, 37% febrile neutropenia, and 25.9% thrombocytopenia. Phase II Japanese trials for irinotecan in the LD-SCLC setting have yielded promising results. A randomized trial evaluated IP alone versus IP plus etoposide (IPE regimen) after radiotherapy in 23 patients (Saito H, 2002). Trial results showed that the triple combination is too toxic; this arm was discontinued. However, based on an acceptable toxicity proÞle and response rates of 91% in the IP arm, this regimen is still being evaluated in a single-arm study. In a follow-up study to the IP versus IPE trial, the West Japan Thoracic Oncology Group evaluated the safety proÞle and response rates of EP with concurrent radiation followed by IP in 49 patients with LD-SCLC (Mitsuoka S, 2004). Median survival had not yet been reached, and the overall and CR rates were 87.8% and 40.8%, respectively. These rates are comparable to those achieved for EP with concurrent thoracic radiotherapy (TRT) (96% overall response rate; 40% CR response rate) in previous studies (Takada M, 2002). Although the oneyear survival rate of 86.4% showed improvement on PE/concurrent TRT (75%), two-year survival is equivalent (54% for EP/TRT; 51% for EP/TRT followed by IP). Grade 4 toxicities were high in the EP/TRT/IP regimen and included 84% neutropenia and 10% anemia. A Korean study evaluated the same drug regimens in a different schedule of administration (Lee DH, 2003). Twenty-three LD-SCLC patients received two cycles of IP (80 mg/m2 irinotecan, 40 mg/m2 cisplatin on days 1 and 8, every three weeks) followed by concurrent radiation and EP (60 mg/m2 cisplatin on day 1, 100 mg/m2 etoposide on days 1–3, every three weeks). After completion of this regimen, 100% of patients responded with 26% CR and 74% PR. SigniÞcant toxicities occurred throughout this regimen but particularly during the concurrent radiation/chemotherapy cycles. Grade 3/4 toxicities included 27% neutropenia and 20% febrile neutropenia during the IP chemotherapy, followed by 100% neutropenia, 60% febrile neutropenia, 60% anemia, and 52% esophagitis. One patient died of radiation pneumonitis four months after completing therapy, and 18 patients required hospitalization for esophagitis and/or febrile neutropenia.

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A carboplatin/irinotecan combination achieved a response rate and median overall survival that is approximately comparable to outcomes of currently marketed agents, such as the EP regimen, in a trial of 27 LD-SCLC patients (89%, 18.2 months) and 34 ED-SCLC patients (84%, 9.7 months) (Kinoshita A, 2002). Grade 3/4 toxicities included leukopenia (35%), neutropenia (76%), thrombocytopenia (42%), and diarrhea (13%). Irinotecan is also under Phase II investigation in combination with other chemotherapeutic agents in the second-line setting. Response rates of 68.2% were achieved in 24 patients receiving carboplatin/irinotecan, and the median survival time was 194 days (approximately 6.5 months) (Hirose T, 2003). Grade 3/4 toxicities included 58% leukopenia, 63% neutropenia, 58% thrombocytopenia, and 67% anemia. When irinotecan was combined with ifosfamide (Bristol-Myers Squibb’s Ifex, Baxter’s Mitoxana/Holoxan, Shionogi’s Ifomide, generics), an overall response rate of 52.9%, including 5.8% CR, was achieved in 34 patients (Ichiki M, 2003). This study showed a favorable toxicity proÞle: grade 3/4 neutropenia in 53% of patients and no other reported hematologic toxicities. A trial of IPE in 40 patients with recurrent disease yielded response rates and overall survival of 78% and 11.4 months, respectively (Koichi G, 2002). Patients had received chemotherapy treatment when SCLC was Þrst diagnosed. These response and survival rates are far greater than expected for recurrent disease (median survival with currently available therapies is only six months). Two abstracts presented at the ASCO meeting in 2003 described the combination of gemcitabine and irinotecan as a second-line treatment in SCLC patients. In one study, 29 patients received 1,500 mg/m2 gemcitabine and 150 mg/m2 irinotecan on day 1 every two weeks (Domine M, 2003). The overall response rate was 27.6%, including one CR in a patient with chemotherapy-sensitive disease. When the data were analyzed according to relapsed disease (chemotherapy-sensitive) versus refractory disease (chemotherapy-insensitive), 25% of patients with refractory disease responded versus 31% of patients with relapsed disease. Median survival was 9.3 months, median time to progression (TTP) was 5.3 months, and no grade 3/4 hematologic toxicity was observed. In a slightly different schedule, 26 SCLC patients received 1,000 mg/m2 gemcitabine on days 1 and 8 and 300 mg/m2 irinotecan on day 8, every 21 days (Agelaki S, 2003). Only three patients (10%) achieved a PR; two of these were refractory to previous chemotherapy and one was sensitive. Median survival was six months. Grade 3/4 neutropenia, thrombocytopenia, and diarrhea were observed in 29%, 13%, and 10% of patients, respectively; three patients experienced febrile neutropenia. Paclitaxel. Paclitaxel (Figure 13), an extract from the bark of the yew (Taxus brevifolia), was the Þrst taxane to enter the clinic as an anticancer agent. Taxanes inhibit the dynamic reorganization of microtubule networks that is essential for vital interphase and mitotic cellular functions. Paclitaxel achieves selective toxicity against rapidly proliferating cells and is active mainly in the G2/M phase of the cell cycle. This intravenously administered compound is used to treat a wide variety of cancers in major markets worldwide, but despite some Þrst-line,

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off-label use in research institutes, it is still in development for SCLC treatment. Researchers have carried out several clinical trials, but no existing data demonstrate any increase in response rates resulting from paclitaxel-containing regimens compared with standard treatments. Paclitaxel is being investigated in Phase III trials in the United States and Europe and in Phase II trials in Japan. A Phase III trial investigated whether a paclitaxel/etoposide/carboplatin (TEC) regimen could improve the outcome for previously untreated patients with SCLC compared with the standard CEV regimen of carboplatin/etoposide/vincristine (Eli Lilly/EG Labo/Shionogi’s Oncovin, generics) (Reck M, 2003). Six hundred and eight patients with stages I–IV SCLC received a maximum of six cycles of either TEC or CEV. No statistically signiÞcant differences in response rate were observed when data were analyzed for all stages or stratiÞed for stage. However, median survival was improved in the TEC arm (12.7 months) compared with the CEV arm (11.7 months), and mean one-year, two-year, and three-year survival rates were 51%, 20%, and 17% in the TEC arm compared with 48%, 16%, and 9% in the CEV arm. When survival was stratiÞed by stage, the data showed a survival advantage in the TEC arm for patients with LD-SCLC (stages I–IIIa, 18.7 months versus 16.9 months; stage IIIb, 15.7 months versus 13.2 months) but no difference for patients with ED-SCLC (stage IV). Although the rates of leukopenia, neutropenia, and febrile neutropenia were similar in both arms of the study, a signiÞcantly higher frequency and severity of anemia and thrombocytopenia in patients receiving CEV resulted in a higher incidence of platelet and red blood cell transfusions. This trial is the Þrst randomized study to demonstrate an increase in survival and a reduction in drug-related toxicities for a paclitaxel-containing regimen compared with standard therapy. The TEC regimen was compared with paclitaxel plus topotecan (GlaxoSmithKline/Merck/Nihon Kayaku’s Hycamtin) in patients with previously untreated ED-SCLC (Thompson DS, 2004). The overall response rate for TEC was 77% (13% CR) compared with 49% (6.5% CR) for the paclitaxel/topotecan arm. In addition, median survival, median progression-free survival, and the toxicity proÞle were superior in the TEC arm compared with paclitaxel/topotecan. Phase III trials that compared paclitaxel combined with the etoposide/cisplatin regimen (TEP) with the EP regimen alone yielded disappointing clinical results. In a 587-patient trial, investigators observed no signiÞcant differences in median

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survival between TEP and EP, but TEP resulted in more toxic deaths (Niell HB, 2002). Toxicities and treatment-related deaths led to early closure of a 133-patient Phase III trial (Mavroudis D, 2001). These results suggest that paclitaxel- and cisplatin-containing, three-drug combinations are too toxic in SCLC. Other noteworthy paclitaxel regimens that have been evaluated for Þrst-line therapy include paclitaxel and carboplatin in combination with either ifosfamide or topotecan. Trials have failed to demonstrate any improvement in survival or toxicity proÞle when these combinations are compared with standard treatments. The ifosfamide-containing regimen yielded a response rate of 69% and median overall survival of 9.5 months in 35 ED-SCLC patients; neutropenia was the principal grade 3/4 toxicity (Neubauer MA, 2002). The topotecan-containing regimen effected a CR rate of 51% and median overall survival of 20 months in 68 LD-SCLC patients who completed the therapy; grade 3/4 toxicity included leukopenia (60%), thrombocytopenia (42%), and fatigue (14%) (Gray JR, 2002). The paclitaxel/topotecan regimen produced efÞcacy rates similar to those of standard chemotherapy, but it was associated with a high incidence of myelosuppression and febrile neutropenia in previously untreated patients with ED-SCLC (Ramalingam S, 2004). Paclitaxel is also under investigation as a single-agent, Þrst-line therapy for SCLC. A study in NSCLC investigated the use of single-agent paclitaxel in a “dose-dense” regimen of 150 mg/m2 /week for six weeks of an eight-week cycle. Unprecedented results for a single agent in this disease were obtained, prompting its evaluation for Þrst-line therapy in ED-SCLC (Graziano SL, 2003). In 29 evaluable patients, an overall response rate of 28% was achieved (3% CR), with a median TTP and overall survival of 3.8 and 9.7 months, respectively, and a one-year survival rate of 43%. This agent induced grade 3/4 neutropenia in 24% of patients, febrile neutropenia in 6%, anemia in 9%, and thrombocytopenia in 3%. Grade 3/4 nonhematologic toxicities included sensory and motor neuropathy (27% and 12%, respectively) and fatigue and dyspnea (both occurred in 18% of patients). This dose-dense regimen achieved response rates similar to those gained in the more convenient three-weekly schedule of paclitaxel, but survival rates were comparable to those observed in patients receiving platinum-based combinations. SCLC is primarily a disease of older people, a population that can be difÞcult to treat with the same dose and schedule of chemotherapeutic agents used to treat younger, Þtter patients. Previous studies have demonstrated that administering a lower dose of paclitaxel on a weekly basis can provide greater dose intensity and less toxicity (Akerley W, 1998). A Phase II trial of weekly, low-dose paclitaxel/carboplatin attempted to improve survival and minimize toxicities in patients with ED-SCLC who were aged 70 or older or had a PS of two (Neubauer M, 2004). Sixty-six evaluable patients received 80 mg/m2 paclitaxel and area under the curve (AUC) = 2 carboplatin on days 1, 8, and 15 of a four-week cycle for up to six cycles. Response rates were 1.5% CR, 36.4% PR, 12.1% stable disease (SD), and 50% progressive disease (PD), with a median survival of 7.2 months, TTP of 3.5 months, and estimated one- and two-year survival rates

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of 30% and 4%, respectively. Grade 3/4 toxicities included neutropenia and anemia in 22% and 5.2% of patients, respectively. The response and survival rates observed in this trial are comparable to results achieved in trials that included patients with a better PS. In addition, the level of neutropenia was signiÞcantly less than reported in previous trials, indicating this regimen may be a preferred choice for elderly or poor-PS patients. Paclitaxel is also under investigation as a second-line therapy, in combination or as a monotherapy, for patients with relapsed or refractory SCLC. Patients who did not respond to Þrst-line therapy with etoposide/carboplatin (EC regimen) or who relapsed within three months of a conÞrmed prior response were eligible for therapy with single-agent paclitaxel (Joos G, 2004). Forty-four patients received 200 mg/m2 paclitaxel every three weeks for up to six cycles. Patients received a median number of three cycles; an overall response rate of 20% was achieved, with a median overall survival of four months and a TTP of three months. The most signiÞcant toxicity was febrile neutropenia, which occurred in 23% of patients. In a paclitaxel combination study, patients who had progressed after Þrst-line therapy with a platinum agent plus etoposide were treated with 80 mg/m2 paclitaxel on days 1, 8, and 15 and 1,000 mg/m2 gemcitabine on days 1 and 8, every three weeks (Dongiovanni V, 2004). Of the 31 patients enrolled in the study, Þve had LD-SCLC and 26 had ED-SCLC; their median age was 64; and they had a performance status of 0–2. Analysis of response revealed PRs in eight patients (26%), SD in Þve patients (16%), and progression in 18 patients (58%), with a median survival time of 7.4 months and a median TTP of 9.6 weeks. Toxicities included 26% grade 3 neutropenia, 22% grade 3 thrombocytopenia, 3% grade 4 thrombocytopenia, 13% grade 3–4 asthenia, and 32% grade 1–2 neuropathy. Docetaxel. An analogue of paclitaxel and a member of the taxane drug class, docetaxel (Aventis’ Taxotere) (Figure 14) is partially synthesized from an extract of the European yew (Taxus baccata). Taxanes inhibit the dynamic reorganization of microtubule networks that is essential for vital interphase and mitotic cellular functions. Docetaxel achieves selective toxicity against rapidly proliferating cells and is active mainly in the S phase of the cell cycle. It is available in all major markets for the treatment of breast cancer and NSCLC and is under investigation for a variety of other cancers. For SCLC, no randomized data are available that compare docetaxel with paclitaxel or with conventional regimens. Docetaxel is in Phase II trials in Europe and the United States for Þrst-line treatment of ED-SCLC and in Phase I trials in Japan for recurrent disease. Phase II docetaxel trials had disappointing results in terms of survival. One trial that combined docetaxel with cisplatin in 33 ED-SCLC patients showed an overall survival rate of only seven months; grade 3/4 neutropenia was low (20%) (Lianes P, 2001). Another study combined docetaxel with gemcitabine in untreated patients with ED-SCLC (Skarlos DV, 2003). Only six of 20 patients achieved a PR; the trial was closed prematurely because of the poor response rate. Median TTP was eight months, and median survival was 9.6 months; both

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hematologic and nonhematologic toxicity was acceptable. The same combination was investigated in elderly ED-SCLC patients (>65 years), and the study found a median overall survival of only four months (Thompson DS, 2004). The combination of docetaxel/gemcitabine was also investigated in the secondline setting in 22 pretreated patients with LD-SCLC or ED-SCLC (Agelaki S, 2004). No complete or partial responses were observed, disease stabilization occurred in only one patient, and median survival was 14 weeks with a sixmonth survival rate of only 28%. These results show this combination is inactive as a salvage or second-line therapy in these poor-prognosis patients. Vinorelbine. Vinorelbine (Pierre Fabre/GlaxoSmithKline/Kyowa Hakko’s Navelbine) (Figure 15), an intravenous (IV) vinca alkaloid, was Þrst launched in 1989 as a treatment for NSCLC. Vinorelbine binds to tubulin and prevents its polymerization, thus hindering formation of the mitotic spindle. The agent’s role as a component of multidrug regimens in SCLC treatment is being evaluated in Phase II trials in the United States and Europe. Vinorelbine achieved disappointing response rates in clinical trials. A Phase II trial of a vinorelbine/carboplatin regimen in 58 SCLC patients with poor prognosis reported a 55% overall response rate, including 10% CR, TTP of 18 weeks, and a 26-week median survival; 76% of the patients experienced grade 3/4 hematologic toxicity, far greater than the toxicity observed in trials of carboplatin combined with etoposide (Mackay HJ, 2003). Investigators suggest their study

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demonstrates the vinorelbine/carboplatin regimen was active, but because of the associated high toxicity, it did not warrant further study in this setting. A similar conclusion was drawn in a study of vinorelbine/carboplatin in a population of elderly patients with ED-SCLC. Therapy was highly toxic: three patients (11%) died while on treatment (Gridelli C, 2002). In the second-line setting, vinorelbine has been combined with gemcitabine in patients with relapsed or refractory SCLC (Hainsworth JD, 2003). This study determined that the activity of vinorelbine/gemcitabine is modest and limited to patients with relapsed, rather than refractory, disease. Gemcitabine. First marketed as an anticancer therapy in the 1990s, the antimetabolite gemcitabine is available in the United States and Europe for the treatment of pancreatic cancer and NSCLC. Antimetabolites block normal DNA synthesis, thereby stopping cell replication. Gemcitabine (Figure 16) exhibits cellphase speciÞcity, primarily killing cells that are undergoing DNA synthesis (S phase) and blocking the progression of cells through the G1/S-phase boundary. It is being investigated for SCLC and has reached Phase III trials in Europe, Phase II trials in the United States, and Phase I trials in Japan. In the Þrst-line setting, gemcitabine is being investigated in combination regimens. In the second-line setting, it is being investigated both as a single agent and in combination with other agents. Data from Phase II studies investigating Þrst-line gemcitabine double combinations have reported poor response rates, compared with standard chemotherapy. Eighty-one patients with ED-SCLC received 1,000 mg/m2 gemcitabine and 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle for a maximum of six cycles or until disease progression (Akerley WL, 2004). The overall response rate was 29%, with a median survival of eight months. Grade 3/4 toxicities were less than toxicities reported in other chemotherapeutic regimens: 23% neutropenia, 9% anemia, 7% thrombocytopenia, and 5% febrile neutropenia. In a randomized Phase III study involving 241 patients of unreported stage, the gemcitabine/carboplatin (GC) regimen resulted in a median survival (8.1 months) similar to that of the EP regimen (8.2 months), with more hematologic toxicities but fewer nonhematologic toxicities; GC patients required less frequent

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administration-related hospitalization than EP patients (James LE, 2002). Combination of gemcitabine with carboplatin in 69 ED-SCLC patients produced a response rate of 43%, median survival of 9.2 months, and an estimated median TTP of four months (Sirridge C, 2003). Grade 3/4 toxicities included 39% neutropenia, 33% thrombocytopenia, and 13% anemia. In a Phase II study, gemcitabine was combined with docetaxel, but the trial was closed early due to poor response rates (Skarlos DV, 2003). Gemcitabine is also under investigation as part of the triple regimen cisplatin/ etoposide/gemcitabine (PEG) in chemotherapy-naive LD-SCLC and ED-SCLC patients. A total of 54 patients received 100 mg/m2 gemcitabine on days 1 and 8, 70 mg/m2 cisplatin on day 2, and 50 mg/m2 etoposide on days 3, 4, and 5 every three weeks (De Marinis F, 2003). An overall response rate of 72.2% was achieved (including 18.5% CR and 53.7% PR), with a median survival of ten months and a one-year survival probability of 37.5%. Grade 3/4 hematologic toxicity was higher than toxicity reported for gemcitabine double regimens, with 66.7% of patients suffering from neutropenia and 53.7% suffering from thrombocytopenia. When the PEG regimen was compared with cisplatin/gemcitabine (PG regimen) in a randomized Phase II trial, both regimens were active in LD-SCLC and ED-SCLC patients, but the highest overall response rates were achieved by PG in LD-SCLC (80%) and by PEG in ED-SCLC (68%) (De Marinis F, 2002). The PEG combination showed a trend toward more grade 3/4 toxicity. Nevertheless, both combinations seem to be less toxic than standard regimens. Trials evaluating gemcitabine in previously treated SCLC patients show some activity in those who are sensitive to chemotherapy. Three of 12 relapsed SCLC patients (25%) receiving 100 mg/m2 gemcitabine and 20 mg/m2 vinorelbine on days 1, 8, and 15 of a 28-day cycle achieved a partial remission, but none of 17 patients with refractory disease responded (Hainsworth JD, 2003). Hematologic toxicities were fewer with this regimen, providing this subset of patients with an additional treatment option. In contrast, a study that analyzed gemcitabine in combination with docetaxel reported no responses, despite including patients who were sensitive to chemotherapy (Agelaki S, 2004). Two abstracts presented at ASCO 2003 described the combination of gemcitabine and irinotecan as a second-line treatment in SCLC patients. In one study, 29 patients received 1,500 mg/m2 gemcitabine and 150 mg/m2 irinotecan on day 1 every two weeks (Domine M, 2003). The overall response rate was 27.6%, including one CR in a patient with chemotherapy-sensitive disease. When the data were analyzed according to relapsed (chemotherapy-sensitive) versus refractory (chemotherapy-insensitive) disease, 25% of patients with refractory disease responded versus 31% of patients with relapsed disease. Median survival was 9.3 months, median TTP was 5.3 months, and no grade 3/4 hematologic toxicity was observed. In a slightly different schedule, 26 SCLC patients received 1,000 mg/m2 gemcitabine on days 1 and 8 and 300 mg/m2 irinotecan on day 8, every 21 days (Agelaki S, 2003). Only three patients (10%) achieved a PR; two of them were refractory to previous chemotherapy and one was sensitive. Median

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survival was six months. Grade 3/4 neutropenia, thrombocytopenia, and diarrhea were observed in 29%, 13%, and 10% of patients, respectively, and three patients experienced febrile neutropenia. Phase II data presented at ASCO 2004 described the administration of paclitaxel and gemcitabine in SCLC patients (Dongiovanni V, 2004). This study reported response rates of 20% in chemotherapy-refractory patients and 29% in chemotherapy-sensitive patients, with an overall median TTP of 9.6 weeks and overall survival of 7.4 months. Toxicities included grade 3/4 neutropenia, thrombocytopenia, and asthenia in 26%, 25%, and 13% of patients, respectively. Single-agent gemcitabine has shown modest responses as a second-line therapy in SCLC patients. Phase II data from the Eastern Cooperative Oncology Group reported an overall response rate of 11.9% in 44 patients receiving gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 29-day cycle (Masters G, 2003); the responding patients included four who were sensitive to chemotherapy and one with refractory disease. The overall median survival was 7.1 months and was not signiÞcantly different in refractory and sensitive patients. Both grade 3/4 neutropenia and thrombocytopenia were observed in 27% of patients, and grade 3/4 pulmonary and neurological toxicities occurred in 9% and 14% of patients, respectively. Pemetrexed. Pemetrexed (Eli Lilly’s Alimta) (Figure 17) is a new-generation, multitargeted antifolate that inhibits thymidylate synthase as well as dihydrofolate reductase and glycinamideribonucleotide (GAR) formyl-transferase. Lilly hopes that the multitargeted approach will overcome resistance acquired through overexpression of any single enzyme. This agent has shown efÞcacy in NSCLC and is in Phase II trials for SCLC in the United States. Phase II data presented at ASCO 2004 reported results from 17 ED-SCLC patients randomized to receive either 500 mg/m2 pemetrexed plus AUC = Þve carboplatin or 500 mg/m2 pemetrexed plus 75 mg/m2 cisplatin every 21 days for a maximum of six cycles (Socinski MA, 2004). Nine patients achieved a PR (overall response rate of 55%), six had SD, and two had PD. These regimens were well tolerated: only two patients (12%) experienced grade 3/4 adverse events, including neutropenia, nausea, vomiting, pneumonia, dehydration, and hyponatremia. At the time of composing this reference, the trial has been complete, but no survival data seem yet to be available from this study. Current response rates do not show an improvement over the EP standard chemotherapy regimen.


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Oral Topotecan. Topotecan (GlaxoSmithKline/Merck/Nihon Kayaku’s Hycamtin) (Figure 11) is a water-soluble, semisynthetic analogue of camptothecin that is approved in the United States and Japan as an IV monotherapy for patients with recurrent SCLC. This topoisomerase I inhibitor binds to the topoisomerase I-DNA complex and prevents religation of DNA single-strand breaks that occur naturally during DNA synthesis. The oral formulation of topotecan is under Phase III investigation for SCLC in both the Þrst- and second-line settings in the United States and Europe. Results of a U.S. and European Phase III study showed that oral topotecan has activity and tolerability similar to that of IV topotecan in chemotherapy-sensitive SCLC patients (Eckhardt JR, 2003). Patients with LD-SCLC or ED-SCLC who had a documented response to Þrst-line therapy, Eastern Cooperative Oncology Group PS < 2, and measurable, recurrent disease with a treatment-free interval > 90 days were randomized to oral (n = 153) or IV (n = 151) topotecan. Response rates for oral and IV topotecan were 18.3% and 21.9%, respectively. Median survival and one-year survival were 33 weeks and 33% for oral topotecan and 35 weeks and 29% for IV topotecan. Quality-of-life results showed no signiÞcant differences between oral and IV topotecan, and both were generally well tolerated; incidence of grade 4 toxicity by patient (oral/IV) was neutropenia (47%/64%), thrombocytopenia (29%/18%), grade 3/4 anemia (23%/31%), and sepsis (3%/3%). Oral topotecan was also investigated in patients with ED-SCLC in the secondline setting in combination with carboplatin (Jett J, 2004). Twenty-six patients received 1.75 mg/m2 /daily for Þve days plus AUC = 5 carboplatin on day 5, with granulocyte colony-stimulating factor for support, every 21 days for a maximum of six cycles. The trial was closed early due to unacceptable toxicities, which included three deaths due to infection caused by low absolute neutrophil count and one death due to a cardiovascular event. Other grade 3+ toxicities included 85% hematologic events and 54% nonhematologic events. PRs occurred in 62% of patients; median survival was 11.8 months with a 46% one-year survival rate. Although this regimen achieved good response rates, the levels of toxicity were too high. In the Þrst-line setting, a large, ongoing Phase III trial has randomized EDSCLC patients to receive oral topotecan plus cisplatin or EP as Þrst-line therapy. Encouraging preliminary results were disclosed at ASCO 2004 (Eckardt JR, 2004). 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Woll PJ, et al. Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized Phase II trial in small-cell lung cancer patients. Journal of Clinical Oncology. 2001;19(3):712–719. Yonei T, et al. Cisplatin plus irinotecan (PI) alternating with a three-drug combination of doxorubicin, cyclophosphamide and etoposide (ACE) in patients with extensive-stage small-cell lung cancer (ED-SCLC): a Phase II study of Okayama Lung Cancer Study Group (OLCSG). Proceedings of the American Society of Clinical Oncology. 2004. Abstract 7313.

Allergic Rhinitis

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Allergic rhinitis (AR) is clinically deÞned as a symptomatic disorder of the nose induced by an immunoglobulin E (IgE)-mediated inßammation after the membranes of the nose are exposed to an allergen (Bousquet J, 2001). In clinical settings, diagnosis of AR is usually based on the patient’s medical history, although it may be conÞrmed by allergy skin testing or serum IgE determination. Hallmark symptoms of AR include sneezing, runny nose, itchy nose, and nasal congestion; patients may also experience non-nasal symptoms such as ocular irritation and itchy palate. Sneezing, rhinorrhea, and ocular irritation usually occur immediately following exposure to allergen and constitute the early-phase (acute) response. In many (but not all) AR sufferers, the early-phase response is followed by a late-phase allergic response that results when immune and inßammatory cells are recruited to the site of inßammation (i.e., nasal tissue); the late-phase response typically takes place 3–24 hours following allergen exposure and is characterized by a recurrence of sneezing, nasal congestion, and heightened sensitivity to subsequent allergen challenge. Both the early- and late-phase allergic responses are discussed in greater detail in the following sections. Etiology Allergen Sensitization. The cascade of events leading to AR begins with initial sensitization of the cells lining the nasal mucosa to a particular allergen. Allergen sensitization occurs when a susceptible (atopic) individual is exposed Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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to sufÞcient levels of airborne allergen (e.g., pollen, animal dander, house dust mites) to prime his or her system for an exaggerated T-helper 2 (TH 2)-mediated immune response to continued challenge. Upon inhalation, the allergen (antigen) comes in contact with cells in the airway mucosa (Figure 1). Epithelial and dendritic cells, which are found in the airway mucosa, and phagocytes (e.g., tissue macrophages, granulocytes), which are found in the airway submucosa, internalize and enzymatically degrade the offending antigen into short peptide chains. The peptides associate with major histocompatibility complex II (MHC II) on the surface of these cells, which now function as antigen-presenting cells (APCs). The role of APCs is to present antigen to the lymph system—speciÞcally, to CD4+ T lymphocytes, also known as TH 0 lymphocytes. With the help of cytokines like interleukin-4 (IL-4), the TH 0 lymphocytes become differentiated into peptide (antigen)-speciÞc TH 2 lymphocytes (the phenotype commonly associated with AR). TH 2 lymphocytes then release a variety of cytokines, including IL-4, IL-5, IL-9, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-4 and IL-13, in particular, stimulate B lymphocytes (plasma cells) to produce IgE molecules. These immunoglobulins (antibodies) enter the circulation and inÞltrate airways, where they bind to high-afÞnity IgE receptors (FcεRI) on mast cells, basophils, and dendritic cells. Binding of IgE to airway cells—and mast cells in particular—sets the stage for an acute response to subsequent allergen exposure. Early-Phase Allergic Response. Subsequent allergen (antigen) exposure in the nasal mucosa of a sensitized individual results in cross-linking of IgE by antigen, which in turn causes mast cell degranulation (Figure 1). Mast cell degranulation releases a variety of presynthesized and membrane-derived mediators involved in the acute-phase allergic response. Mediators include the following: • •

Histamine, which is responsible for most acute-phase symptoms. Proteases, such as tryptase, chymotryptase, carboxypeptidase, and kininogenase.

Mediators that are synthesized de novo include the following: • • •

Arachidonic acid derivatives, such as leukotrienes B4 , C4 , D4 , and E4 ; prostaglandin D2 ; and thromboxane A2 . Cytokines, such as IL-4, IL-5, IL-13, GM-CSF, and tumor necrosis factoralpha (TNF-α). Platelet-activating factor (PAF).

Concomitant neural participation occurs as well, involving the release of neuropeptides such as substance P and neurokinin A from cholinergic and peptidergic nerves. The release of the soluble and membrane-derived mediators following mastcell degranulation initiates a host of physiological changes that lead to AR’s symptoms. These physiological effects include the following:


FIGURE 1. The allergic cascade and druggable targets.

369

370 • • • • • •

ALLERGIC RHINITIS

Increased vascular permeability and mucus production. Bronchoconstriction. Vasodilation. Activation of nociceptive neurons (via neuronal histamine [H1 ] receptors) linked to parasympathetic reßexes. Upregulation of cellular adhesion molecules (CAMs). Recruitment of immune and inßammatory cells to the site of inßammation (i.e., nasal tissue).

Many current therapies employed in the treatment of AR target speciÞc inßammatory mediators involved in the early-phase allergic response. For example, antihistamines—the most widely prescribed agents for treating AR—bind to the inactive form of the H1 receptor (one of four histamine receptors in the human body—H1 , H2 , H3 , and H4 —although H1 is the receptor through which histamine exerts most of its effects in allergic disease) and stabilize this conformation, therefore shifting the equilibrium toward the inactive state, which is unable to initiate the signal transduction cascade that ultimately results in degranulation of mast cells and basophils. Additionally, leukotriene antagonists block the ability of leukotrienes to exert their proinßammatory effects and their ability to stimulate airway secretion production, enhance eosinophil chemotaxis, and cause microvascular leakage. Thus, the resultant effect of antihistamines and leukotriene antagonists is to block the release and activity of inßammatory mediators which play key roles in the development of AR’s early-phase symptoms (e.g., sneezing, itching, rhinorrhea, and ocular irritation) (Figure 1). (Currently marketed antihistamines and leukotriene antagonists are discussed in greater detail in “Current Therapies.”) Intranasal corticosteroids are regarded as the most effective drugs available for the treatment of AR thanks to their potent and extensive anti-inßammatory effects, which include inßuencing the release of cytokines and proinßammatory mediators (e.g., IL-1, IL-4, IL-5, IL-6, IL-8, and IL-13; TNF-α; GM-CSF; and regulated upon activation, normal T-cell expressed and secreted [RANTES]), downregulating the expression of adhesion molecules and chemokines, and reducing the recruitment and accumulation of inßammatory cells (e.g., eosinophils, mast cells, basophils, APCs) to the nasal mucosa (Figure 1). Through these multiple anti-inßammatory effects, intranasal corticosteroids provide excellent relief of symptoms arising from the early-phase, as well as late-phase (discussed in the following section), allergic response. (Currently marketed intranasal corticosteroids are discussed in greater detail in “Current Therapies.”) Late-Phase Allergic Response. The late-phase allergic response is characterized by recruitment of leukocytes (e.g., eosinophils, basophils, neutrophils, T lymphocytes) to the airway tissue (submucosa, epithelium, airway lumen). There, the leukocytes accumulate and propagate the proinßammatory actions initiated by mast-cell mediators (Figure 1).


371

A number of substances have been implicated in leukocyte recruitment activity. Investigators have found that IL-5 acts as a chemoattractant for eosinophils, which play a major role in the late-phase response (as described further on in this section). In addition, IL-3 and IL-5 are chemoattractants for basophils. IL-16 has speciÞc chemoattractant activity for T cells, eosinophils, and macrophages. Studies also suggest that monocyte chemotactic proteins (MCPs)—in particular, MCP-3 and MCP-4—may play a role in recruiting inßammatory cells to the nasal mucosa during AR episodes. Other evidence indicates that leukotriene B4 acts as a chemoattractant for neutrophils and, to a lesser extent, eosinophils. Additionally, IL-4, IL-13, and TNF-α increase the expression of CAMs on endothelial cells, thereby facilitating the attachment and inÞltration of leukocytes into airway tissues. CAMs play a key role in the recruitment of immune and inßammatory cells to the airway tissue by “escorting” these cells from the bloodstream across endothelium and into tissues. CAMs—such as vascular cell adhesion molecule-1 (VCAM-1), platelet endothelial cell adhesion molecule-1, intercellular adhesion molecules 1 and 2 (ICAM-1 and -2), and E- and P-selectins—expressed on endothelial cells correspond to ligands (e.g., various integrins, L-selectin) on leukocytes; they use this relationship to guide the leukocytes’ migration to the site of inßammation. The accumulation of T lymphocytes (i.e., memory T cells) and other leukocytes—especially eosinophils—and their products in the airway tissues in the hours following allergen exposure is primarily responsible for the congestion and increased mucus production characteristic of the late-phase allergic response. Indeed, nasal eosinophilia, or the accumulation of eosinophils in the nasal tissue, is a hallmark of AR. Activated eosinophils release numerous inßammatory mediators that can damage airway endothelial cells and the extracellular matrix. They may also damage neurons if they come in contact with nerve endings in the airway lumina; such damage may result in bronchial hyperresponsiveness or airway hyperreactivity upon subsequent exposure to allergens. The following products of activated eosinophils are known to be involved in the late-phase allergic response (Pearlman DS, 1999):

•

•

•

Cytokines, such as IL-1α, IL-3, IL-4, IL-5, IL-8, IL-10, TNF-α, transforming growth factor-beta-1 (TGF-β1), and GM-CSF, which can cause autocrine enhancement, sustained inßammation, leukocyte chemoattraction, and adhesion marker expression. Basic polypeptides, such as major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and TGF, which can cause degranulation of other inßammatory cells and local tissue damage (e.g., hypersensitivity, hyperresponsiveness). Leukotriene C4 , which can promote mucus secretion, vascular permeability, and bronchoconstriction.

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Basophil activation, rather than secondary mast-cell degranulation, appears to be responsible for the increased histamine levels noted during the late-phase response because neither tryptase nor prostaglandin D2 levels (both products of mast-cell degranulation) are simultaneously increased during this phase (Christodoulopoulos P, 2000). Investigators believe that a lymphokine called histamine-releasing factor (HRF) promotes the release of histamine from basophils activated by IgE+ during the late-phase allergic response; IgE+ is a form of IgE that, when attached to basophils, speciÞcally requires HRF for basophil degranulation (and consequent release of histamine). The late-phase allergic response just described occurs in as many as 50% of all AR sufferers and is correlated with the magnitude of the initial acute reaction. That is, patients who suffer from initially severe symptoms are more likely to experience a late-phase reaction than are individuals who suffer from mild symptoms early on. The late-phase reaction usually begins within 3–6 hours of allergen challenge, peaks at 6–8 hours, and subsides 12–24 hours after allergen challenge; it will, however, persist in the continuing presence of the offending allergen. Over time, patients who experience the late-phase response tend to grow more sensitive to nonallergic triggers such as cold air and smoke, simply because they have a higher degree of nasal hyperreactivity. Researchers hypothesize that the sensory nerves (C Þbers) in the nasal mucosa of AR sufferers exhibit a heightened responsiveness to allergens and other irritants, which in turn increases their propensity for neurogenic inßammation via neuropeptide (e.g., substance P, neurokinin A) release upon activation by inhaled particles (Togias A, 2000). Ultimately, a chronic inßammatory process such as that noted in AR could result in pathologic tissue remodeling. This remodeling may involve permanent modiÞcation of the histological and functional structure of this tissue. Researchers have shown that nonasthmatic AR patients have increased subepithelial deposition of type I and II collagens within their bronchial submucosa as compared with healthy controls. As stated previously, intranasal corticosteroids provide excellent relief from AR symptoms characteristic of the early-phase allergic response—rhinorrhea, sneezing, and itching nose. However, due to their extensive and potent antiinßammatory effects—especially their ability to downregulate adhesion molecule and chemokine expression and to reduce the leukocyte recruitment and accumulation in the nasal mucosa—intranasal corticosteroids are effective in reducing nasal congestion, which is characteristic of the late-phase allergic response (Figure 1). As a result, intranasal corticosteroids are recommended for Þrst-line use in AR patient with frequent or persistent symptoms or patients suffering from nasal congestion (Bousquet J, 2001). Predisposing Factors. Atopy.. The term atopic is used to describe individuals who display an inherited tendency to develop IgE-mediated immune responses that place them at risk for developing allergies after exposure to environmental allergens. IgE is the key


373

antibody involved in potentiating both allergic and asthmatic reactions. Notably, levels of IgE are higher in atopic individuals than in nonatopic individuals. Diagnostic indicators of atopy include positive radioallergosorbent (RAST) tests, nasal eosinophilia, and the presence of ECP in nasal secretions. Although all AR sufferers are classiÞed as atopic, not all atopic individuals necessarily develop allergies. In other words, an atopic individual must be exposed to high enough levels of allergen to trigger an allergic reaction; if such a person is never exposed in this way, he or she will not suffer from the overactive immune response characteristic of AR. Studies estimate that atopy is present in 20–30% of the general population and in 10–15% of children (Fireman P, 2000; Nimmagadda SR, 1999). However, family history of atopy is one of the most important risk factors for developing AR. The risk of atopy is heightened in children with two atopic parents, especially if both parents’ atopy is manifested similarly (e.g., allergic rhinitis, asthma). Approximately 50% of children with two atopic parents are atopic themselves, and this percentage increases to 72% for children of patents with the same atopic manifestation (Fireman P, 2000; Nimmagadda SR, 1999). Lifestyle and Environment: The Hygiene Hypothesis. A widely held theory suggests that the increasingly sterile environment in which many people live in developed countries has greatly contributed to the rise in AR prevalence in these countries (as opposed to the situation found in many developing nations). In the industrialized world, rather than being exposed to a variety of childhood illnesses that allow their immune systems to mature and possibly develop immune tolerance, children tend to live in more protected environments. In these environments, they fail to encounter challenges to their immune systems (i.e., germs, microbes) that might stimulate a more mature immune response (via TH 1 lymphocytes) and possibly suppress the neonatal TH 2 lymphocytic response commonly associated with allergies (Figure 2). Researchers believe that the TH 1-like phenotype of T-cell-mediated immune responses is less likely to favor allergen sensitization than is the TH 2 phenotype. The aforementioned scenario is known as “the hygiene hypothesis.” It is based on studies indicating that exposure to microbial pathogens in early life offers protection against overzealous immune reactions to harmless offenders such as allergens later in life. In a study conducted in Italian military recruits, researchers found a negative correlation between atopy and childhood infection with hepatitis A (Matricardi PM, 1997). The same group published subsequent Þndings suggesting that respiratory allergy occurs less often in individuals who are repeatedly exposed to various orofecal and foodborne microbes (e.g., Helicobactor pylori, Toxoplasma gondii , hepatitis A) (Matricardi PM, 2000). Other studies suggest that factors such as attendance at day care facilities in infancy (Ball TM, 2000) or daily exposure to farm animals in early life (Riedler J, 2000) may help protect children from developing asthma and/or allergies in later years. In essence, researchers have found that the more exposure a child has to foreign microbes early in life, the better his or her chance of avoiding diseases

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ALLERGIC RHINITIS

FIGURE 2. The hygiene hypothesis.

involving hyperresponsive TH 2-mediated immune mechanisms (such as AR and asthma) later in life. Pathophysiology Disease Classification. Traditionally, AR has been classiÞed as either seasonal or perennial. Individuals who suffer from seasonal AR (SAR) are typically allergic to outdoor allergens (e.g., tree, grass, and weed pollens; mold spores) and experience symptoms at speciÞc times of the year when outdoor allergen levels are high. Patients who suffer from perennial AR (PAR) are typically allergic to allergens found indoors (e.g., house dust mites, animal dander, feces or skeletal debris from insects, mold spores/fungi) and can become symptomatic at any time of the year, depending on their exposure to allergens that are present in the environment year-round. Although different allergens are responsible for initiating SAR than are implicated in PAR, the symptoms and treatment approaches for both types of AR are basically the same. In 2001, the Allergic Rhinitis and Its Impact on Asthma (ARIA) report was published in collaboration with the World Health Organization (WHO) (Bousquet J, 2001). In addition to providing recommendations for the diagnosis and management of AR using an evidence-based approach, the ARIA report proposes alternative disease classiÞcation criteria—“intermittent” or “persistent” AR—to the more traditional SAR or PAR classiÞcation. According to the ARIA report, intermittent AR patients suffer symptoms for less than four days per week and for less than four weeks per year, while AR is considered persistent when the symptoms are present for more than four days per week and for more than four weeks per year. Figure 3 outlines the characteristics of SAR, PAR, intermittent AR, and persistent AR.


375

FIGURE 3. Characteristics of seasonal, perennial, intermittent, and persistent allergic rhinitis.

In addition to being classiÞed as having SAR or PAR (or intermittent or persistent AR), patients with AR are often classiÞed as having mild, moderate, or severe disease. Although disease severity is typically linked to the severity of a patient’s symptoms and the degree to which symptoms affect their life, there are no uniform, deÞnitive deÞnitions of what constitutes mild, moderate, or severe AR among various treatment guidelines that exist within the seven countries under study (United States, France, Germany, Italy, Spain, United Kingdom, and Japan). For example, according to the ARIA guidelines, AR is characterized as mild when a patient experiences no sleep disturbance, no impairment of daily activities (e.g., sports, leisure, school, work), and no trouble-some symptoms,

376

ALLERGIC RHINITIS

whereas it is moderate to severe when a patient experiences one or more of the following: abnormal sleep, impairment of daily activities, and troublesome symptoms (Figure 3). A similar classiÞcation is put forth in the European Academy of Allergy and Clinical Immunology (EAACI) guidelines (van Cauwenberge P, 2000), while Japanese allergy guidelines measure severity against three main symptoms: sneezing, nasal secretion, and nasal airßow obstruction (Nose Allergy Clinical Practice Guidelines, 2002). Link Between Allergic Rhinitis and Asthma. The link between AR and asthma has been repeatedly observed in the past 50 years, but the overall understanding of the pathogenesis of respiratory allergy has profoundly changed over the past decade. An increasing amount of epidemiological, pathophysiological, and clinical data indicate the following: • • •

The frequent coexistence of AR and asthma. The possible role of AR in the onset and evolution of asthma. The association of AR and nonspeciÞc bronchial hyperreactivity (Leynaert B, 2000; Bousquet J, 2001).

The same allergens that trigger AR can cause asthma. Studies from around the world implicate sensitivity to house dust mites as the most consistent allergenspeciÞc risk factor for the development of asthma in AR sufferers. Interestingly, asthma appears to be more often associated with PAR than with SAR, a link partially explained by the common allergen. Epidemiological studies have consistently shown that asthma and AR often coexist in the same patient (Sibbald B, 1991[a]; Houvinen E, 1999). AR has been described in more than 75% of patients with allergic asthma and in more than 80% of patients with nonallergic asthma (Sibbald B, 1991[a]; Leynaert B, 2000). Studies have also identiÞed a temporal relationship between the onset of AR and asthma: AR frequently precedes the development of the lower airways disease. In 1994, A.L. Wright and colleagues suggested that rhinitis that develops in the Þrst years of life is an early manifestation of an atopic predisposition and a risk for asthma. A study examining the coexistence of asthma and AR found, after a 23-year follow-up, that 48% of individuals with a clinical history of both diseases experienced the development of AR Þrst; 34.5% experienced the development of asthma Þrst; and 20.7% experienced the development of both diseases at the same time (Settipane RJ, 1994; Greisner WA, 1998). These data support the hypothesis that AR and asthma may be considered one entity, designated allergic rhinobronchitis or united airways disease (UAD), induced by a common inßammatory process (Simmons FE, 1994; Passalacqua G, 2000). Additionally, one study conducted by G.J. Braunstahl and colleagues demonstrated that nasal allergen provocation induced adhesion molecule expression and tissue eosinophilia in upper and lower airways, further supporting the hypothesis that local allergen exposure results in generalized airway inßammation (Braunstahl GJ, 2001).


377

FIGURE 4. The link between allergic rhinitis and asthma.

The inßammatory process that takes place in the upper respiratory epithelium (i.e., nasal passageways) of AR sufferers is fundamentally the same as that noted in the lower respiratory epithelium (i.e., bronchial tubes) of asthma sufferers. Therefore, the difference in clinical presentation of disease is due primarily to the different functions of the end organs affected by the respective conditions. In asthma, this pathway is associated with bronchoconstriction (via smooth-muscle contraction in the lower airways) rather than nasal symptoms because of the distinct histological characteristics of the tissues involved. The end result of this inßammatory process is sneezing, congestion, and rhinorrhea in patients whose upper airways are affected, and coughing, breathlessness, and sputum production in those whose lower airways are affected. Researchers have yet to elucidate the speciÞc mechanisms through which AR inßuences the clinical course of asthma (i.e., why some AR sufferers become asthmatic and others do not). Nevertheless, numerous hypotheses have been proposed. Some investigators suggest that the nasal blockage experienced by many AR patients leads to increased mouth breathing, which in turn leads to increased airway exposure to “unÞltered” allergens and ensuing asthmatic symptoms (Assanasen P, 2001). Others suggest a role for AR-related postnasal drip, on the grounds that this problem may allow inßammatory mediators to spread to the lower airways. Alternatively, as shown in Figure 4, the stimulation of sensory nerves and nasobronchial reßexes noted in AR may lead to bronchoconstriction and consequent asthma (Nolte ND, 1983).

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Whatever the mechanisms involved, the link between AR and asthma is strengthening. In fact, drugs used to treat AR often ameliorate asthmatic symptoms in atopic individuals, and drugs for asthma have demonstrated efÞcacy in AR. For example, studies have shown that the administration of intranasal corticosteroids (in sufÞciently high doses) not only decreases nasal symptoms but also improves asthma symptoms, pulmonary function tests, and bronchial hyperresponsiveness of patients with AR and concomitant asthma. Studies also support the beneÞcial effects of histamine (H1 ) antagonists, which are generally reserved for use as AR therapy, in treating patients with coexisting mild seasonal asthma symptoms. Additionally, the leukotriene antagonists montelukast (Merck’s Singulair) and pranlukast (Ono’s Onon), initially approved as therapies for asthma, are now indicated for AR. Also, the anti-IgE monoclonal antibody omalizumab (Genentech/Novartis/Sankyo/Tanox Biosystems’ Xolair) is marketed in the United States for patients with moderate to severe persistent asthma who have demonstrated reactivity to a perennial aeroallergen. (The leukotriene antagonists and omalizumab are discussed in greater detail in “Current Therapies” and “Emerging Therapies,” respectively.) In addition to providing recommendations for the diagnosis and management of AR and deÞning alternative disease classiÞcation criteria, the ARIA report emphasizes the fact that AR is correlated with—and constitutes a risk factor for—the occurrence and severity of asthma. The report endorses the view that upper and lower airways must be considered a unique entity inßuenced by a common, evolving inßammatory process, and that inßammation of the lower airway may be sustained and ampliÞed by interconnected mechanisms occurring during AR. The ARIA report suggests that the optimal management of AR may therefore partially improve coexisting asthma. Additionally, as asthma patients with concomitant AR have been shown to have higher medication costs than patients suffering from asthma alone (Yawn BP, 1999), appropriate treatment of AR in asthma patients my reduce overall treatment costs. CURRENT THERAPIES The main goal of pharmacotherapy used in the treatment of allergic rhinitis (AR) is alleviating the hallmark symptoms of the disease (e.g., sneezing, rhinorrhea [runny nose], nasal congestion, nasal itching, ocular irritation). Although the triggers and allergic response durations may differ for patients with seasonal AR (SAR) and perennial AR (PAR), the symptoms of the two types of the disease are largely the same. Thus, similar agents are used to treat both forms of the disease. Numerous therapies, including antihistamines, intranasal corticosteroids, leukotriene antagonists, decongestants, anticholinergic agents, and mast cell stabilizers, are employed in the treatment of AR symptoms. While currently available AR therapies collectively are very effective in controlling the symptoms of the disease, certain drug classes are better than others in relieving particular AR symptoms. For example, antihistamines are effective in relieving many symptoms associated with mild to moderate AR (e.g., sneezing, rhinorrhea, nasal

CURRENT THERAPIES

379

itching, ocular irritation), but these agents are less effective than intranasal corticosteroids in treating more-severe disease involving prolonged inßammation, and are less effective at controlling nasal congestion. In addition to differing efÞcacy for particular AR symptoms, current therapies also differ in routes of administration and dosing frequencies. Thus, physicians must balance desired efÞcacy with convenience when recommending pharmacotherapy to an AR patient. Table 1 summarizes the leading therapies available to treat AR in the seven major markets under study (United States, France, Germany, Italy, Spain, United Kingdom, and Japan), and Table 2 summarizes their relative advantages and disadvantages. Second-generation antihistamines and intranasal corticosteroids are the most commonly prescribed AR therapies, and there are numerous marketed products within these drug classes. Thus, the discussion here focuses primarily on agents within these two drug classes. The less numerous leukotriene antagonists are also discussed in greater detail in the following sections. Mast cell stabilizers and anticholinergics are also used in the treatment of AR symptoms. Mast cell stabilizers (e.g., cromolyn sodium [generics; also referred to as cromoglicic acid, disodium cromoglycate, or nedocromil sodium], pemirolast [Nikken Chemical’s Alegysal, generics], tranilast [Kissei’s Rizaban, generics]) are anti-inßammatory agents that address the symptoms of AR by preventing degranulation of mast cells and histamine release and, subsequently, synthesis of other inßammatory mediators. However, these agents require administration several times daily and take a period of days to weeks to reach maximum effect. Products containing cromolyn sodium are readily available over-the-counter (OTC) in all countries under study (AESGP, 2004[a]; AESGP, 2004[b]). The anticholinergic agent ipratropium bromide (Boehringer Ingelheim’s Atrovent) effectively treats rhinorrhea by inhibiting secretions from the serous and seromucous glands lining the nasal mucosa, but has no effect on any other nasal symptoms. Also, like mast cell stabilizers, ipratropium bromide requires administration multiple times daily. Because of their frequent dosing schedules and inferior efÞcacy compared with other commercially available allergy medications, mast cell stabilizers and anticholinergics are not widely prescribed for AR, so these drug classes are not discussed in detail here. Decongestants—administered orally or intranasally—are also routinely used in the treatment of nasal AR symptoms. (Ocular decongestant formulations can be used to treat eye redness and irritation associated with AR.) Therapies within this class are sympathomimetic agents that work by stimulating α-adrenergic receptors in vascular smooth muscle tissue. Oral and intranasal decongestants shrink mucous membranes and promote airßow and drainage, effectively reducing nasal congestion and, to a lesser extent, rhinorrhea. However, these agents do not address other common AR symptoms such as sneezing or itching. Consequently, oral and intranasal decongestants are most effective when used in combination with an antihistamine to treat AR. Decongestant products are readily available OTC, and many second-generation antihistamines are now formulated with a decongestant as a Þxed-combination product. Thus, this discussion of decongestants in the treatment of AR will be

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TABLE 1. Current Therapies Prescribed for Allergic Rhinitis Agent

Company/Brand

Daily Dose

Availability

60 mg bid or 180 mg qd (for patients aged 12 years or older); 30 mg bid (for patients aged 6–11 years) 5–10 mg qd (for patients aged 6 years or older); 2.5 mg bid or 5 mg qd (for patients aged 2–5 years); 2.5 mg bid or qd (for patients aged 6–23 months) 5 mg qd (for patients aged 12 years and older); 2.5 mg qd (for patients aged 6–11 years); 1.25 mg qd (for patients aged 1–5 years); 1.0 mg qd (for patients aged 6–11 months) 5 mg qd (for patients aged 6 years or older)


Second-generation antihistamines Fexofenadine +/− pseudoephedrine

Sanofi-Aventis’ Allegra/Telfast, Allegra-D 12 Hour

Cetirizine +/− pseudoephedrine

Pfizer/UCB/Daiichi/ Sumitomo’s Zyrtec/Virlix/ Cirrus, Zyrtec-D 12 Hour, generics

Desloratadine +/− pseudoephedrine

Schering-Plough’s Clarinex/ Aerius/ Neoclarityn, Clarinex-D 24 Hour

Levocetirizine

UCB’s Xyzal/Xusal


US, F, G, I, S, UK

F, G, I, S, UK

Intranasal corticosteroids Fluticasone propionate

GlaxoSmithKline’s Flonase/ Flixonase, generics

Mometasone furoate

Schering-Plough’s Nasonex

2 sprays (50 µg per spray) in each nostril qd or one spray in each nostril bid (for patients aged 12 years or older); one spray (50 µg per spray) in each nostril qd (for patients aged 4–11 years) 2 sprays (50 µg per spray) in each nostril qd (for patients aged 12 years or older); one spray (50 µg per spray) in each nostril qd (for patients aged 2–11 years)


US, F, G, I, S, UK

Leukotriene antagonists Montelukast

Merck’s Singulair

10 mg qd (for patients aged 15 years or older); 5 mg qd (for patients aged 6–14 years); 4 mg qd (for patients aged 2–5 years)

US, F, G, I, S, UK, Ja

a Montelukast is approved for the treatment of asthma in all seven countries under study. As of this writing,

however, the drug is only indicated for treating seasonal allergic rhinitis in the United States and the United Kingdom. bid = Twice daily; qd = Once daily. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

CURRENT THERAPIES

381

TABLE 2. Comparison of Current Therapies for Allergic Rhinitis Compound

Advantages

Second-generation antihistamines Fexofenadine

Cetirizine

Desloratadine

• Classified as a non-drowsy antihistamine, with no label precautions cautioning against driving while taking the drug. • Fixed fexofenadine/pseudoephedrine combination product is available in a 12-hour formulation, and a 24-hour formulation has been approved by the FDA. • Currently marketed in all seven countries under study.

Disadvantages • Label does not include PAR as an approved indication. • Only approved for children as young as age six. • Only available in oral tablet or capsule formulations.

• Indicated for both SAR and PAR. • Approved for use in children as young as six months in age. • Available in oral tablet, chewable tablet, and oral syrup formulations. • Lower-priced generic versions are currently available in most European countries. • Currently marketed in all seven countries under study.

• Not classified as a ‘‘nonsedating’’ antihistamine. • Due to the higher potential for somnolence, product label includes a warning stating that patients taking cetirizine should use caution when driving, operating machinery, or consuming alcohol or other agents that can depress the CNS. • Fixed cetirizine/pseudoephedrine combination product is only available in a 12-hour formulation.

• Classified as a non-drowsy antihistamine, with no label precautions cautioning against driving while taking the drug. • First second-generation antihistamine to demonstrate proven, consistent efficacy in relieving nasal congestion. • Indicated for both SAR and PAR. • Approved for use in children as young as six months in age. • Available in oral tablet, rapidly disintegrating tablet, and oral syrup formulations. • Fixed desloratadine/pseudoephedrine combination product is available in a 24-hour formulation.

• Currently not marketed in Japan.

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ALLERGIC RHINITIS

TABLE 2. (continued) Compound Levocetizine

Advantages • Indicated for both SAR and PAR. • First second-generation antihistamine to be indicated for PER, which reflects the new classification put forth in the ARIA report. • Has demonstrated proven, consistent efficacy in relieving nasal congestion.

Intranasal corticosteroids • Superior efficacy in relieving nasal Intranasal symptoms compared with oral fluticasone second-generation antihistamines. propionate • Significantly reduced systemic bioavailability compared with other intranasal corticosteroid products. • Currently marketed in all seven countries under study. Intranasal mometasone furoate

• Superior efficacy in relieving nasal symptoms compared with oral second-generation antihistamines. • Significantly reduced systemic bioavailability compared with other intranasal corticosteroid products. • Indicated for children as young as age two. • Only currently available intranasal corticosteroid that is indicated for the prophylaxis of nasal symptoms in SAR patients.

Disadvantages • Only approved for children as young as age six. • Product label acknowledges that no evidence from comparative clinical trials has indicated levocetirizine negatively affects mental alertness, reactivity, or ability to drive, but the label does state patients should consider their potential response to the drug if they intend to drive, operate machinery, or participate in hazardous activities, as sedating effects have been noted in clinical trials involving levocetirizine. • Only available in oral tablet formulation. • Currently not marketed in the United States and Japan. • Indicated for children as young as age four. • Must be delivered via the nasal route, which is less desirable to patients than oral formulations. • ‘‘Steroid stigma’’ precludes some patients from using this agent unless absolutely necessary. • Must be delivered via the nasal route, which is less desirable to patients than oral formulations. • ‘‘Steroid stigma’’ precludes some patients from using this agent unless absolutely necessary. • Currently not marketed in Japan.

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Advantages

Leukotriene antagonists Montelukast

• Due to its alternative mechanism of action (leukotriene inhibition), the drug is often used in combination with oral second-generation antihistamines for patients who fail to achieve adequate symptom relief with antihistamine monotherapy and who seek an alternative to intranasal corticosteroids. • Indicated for AR in children as young as age two. • Available in oral tablet and chewable tablet formulations for AR patients. (An oral granule formulation is also available, but is only indicated for use in treating asthma in children ages 12-23 months.)

Disadvantages • Efficacy is only comparable to oral second-generation antihistamines, and has been shown to be inferior to that of intranasal fluticasone propionate. • Marketed for asthma in all countries under study, but only formally approved for SAR in the United States and the United Kingdom.

AR = Allergic rhinitis; ARIA = Allergic Rhinitis and Its Impact on Asthma; CNS = Central nervous system; PAR = Perennial allergic rhinitis; PER = Persistent allergic rhinitis; SAR = Seasonal allergic rhinitis.

limited to their mention as Þxed-combination products with second-generation antihistamines; decongestants are not discussed as a separate class here. Second-Generation Antihistamines Overview. Antihistamines have been employed in the treatment of AR since the discovery of the Þrst histamine receptor antagonists in 1937 (Slater JW, 1999). First-generation antihistamines—including diphenhydramine (PÞzer’s Benadryl, generics), chlorpheniramine (Schering-Plough’s Chlor-Trimeton, generics), and brompheniramine maleate (Wyeth’s Dimetane, generics)—are very effective in treating many common AR symptoms (e.g., rhinorrhea, sneezing, itchy nose, itchy eyes). However, Þrst-generation antihistamines are highly lipophilic and can readily cross the blood-brain barrier. Once they penetrate the CNS, Þrst-generation antihistamines bind H1 receptors, as well as cholinergic, dopaminergic, and serotonergic receptors, in the brain. This action triggers undesirable and troublesome CNS side effects, including fatigue, drowsiness, performance impairment, and anticholinergic effects (e.g., dryness of the mouth and eyes, constipation, increased ocular pressure). Since 1981, numerous second-generation antihistamines (e.g., fexofenadine [SanoÞ-Aventis’ Allegra/Telfast], cetirizine [PÞzer/UCB/Daiichi//Sumitomo’s Zyrtec/Virlix/Cirrus, generics], desloratadine [Schering-Plough’s Clarinex/ Aerius/Neoclarityn], levocetirizine (UCB’s Xyzal/Xusal]) have entered the

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market, and these agents have all but replaced Þrst-generation antihistamines in the prescription AR market. Second-generation antihistamines are equally effective in controlling the common symptoms of AR, but they offer numerous advantages over their predecessors. Because second-generation antihistamines are larger molecules, possess a different ionic charge, and are more lipophobic than the Þrst-generation agents, they do not cross the blood-brain barrier as readily as the original antihistamines. Thus, they lack the unwanted CNS effects of the Þrst-generation agents. Additionally, second-generation antihistamines are highly speciÞc for histamine H1 receptors, with little afÞnity for cholinergic, dopaminergic, and serotonergic receptors. As a result, they cause mild or no sedation, do not affect performance, and have no anticholinergic effects. The discussion here focuses on four of the top-selling second-generation antihistamines—fexofenadine, cetirizine, desloratadine, and levocetirizine—as representatives of this crowded class. These four antihistamines offer comparable efÞcacy. Some of the product characteristics that differ between agents include the following: indications and age of patients for which each drug is approved; formulations in which the drug is available; and the potential to cause sedation. These characteristics are discussed in greater detail for each drug in the following sections and are outlined in Table 2. Mechanism of Action. There are four types of histamine receptors in the human body—H1 , H2 , H3 , and H4 —although H1 is the receptor through which histamine exerts most of its effects in allergic disease. The H1 receptor demonstrates constitutive activity in the human body—even in the absence of ligand binding—because two states of the H1 receptor (the active state and the inactive state) exist in equilibrium (Simons FER, 2004). Histamine preferentially binds to the active form of the receptor, shifting the balance between the two receptor states toward the active form. The active form of the receptor then initiates a G protein-mediated signal transduction cascade that results in the degranulation of FcεRI+ cells. Antihistamines bind to the inactive form of the H1 receptor and stabilize this conformation, thereby inhibiting the signal transduction cascade that ultimately results in degranulation of mast cells and basophils. H1 antihistamines, previously viewed as H1 receptor antagonists, have been reclassiÞed as inverse agonists owing to enhanced understanding of their molecular pharmacology (Simons FER, 2004). The degranulation of mast cells and basophils initiates a host of physiological changes leading to AR’s early-phase symptoms (e.g., sneezing, itching, rhinorrhea, ocular irritation). However, antihistamines are less effective at controlling nasal congestion, as histamine is not the primary mediator of this symptom. Instead, mediators such as kinins, prostaglandins, leukotrienes, and, in the latephase allergic response, leukocyte inÞltration are more intimately involved in nasal congestion. Numerous in vitro and in vivo studies have shown that antihistamines possess a range of anti-inßammatory properties, including down-regulation of adhesion protein expression, inhibition of eosinophil and other inßammatory cell migration

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and activation, and inhibition of the generation and activity of various proinßammatory cytokines and mediators (Simons FER, 2004). However, further studies are needed to determine the clinical relevance of these anti-inßammatory effects in AR patients during natural exposure to allergens at typical therapeutic doses of oral antihistamines. Formulation. Most second-generation antihistamines are delivered orally; the exceptions are azelastine (MedPointe’s Astelin, Viatris’ Allergodil/Rhinolast/ Aßuon) and levocabastine (Janssen Cilag’s [a Johnson & Johnson subsidiary] Livostin), which are administered intranasally. Because of patient preference for oral formulations, azelastine and levocabastine are used far less frequently than oral antihistamines for the treatment of AR. Fexofenadine. The oral second-generation antihistamine fexofenadine (Allegra/Telfast) (Figure 5) is marketed in all countries under study by SanoÞ-Aventis. The drug was originally launched in the United States in 1996 by Hoechst Marion Roussel (HMR). (HMR merged with Rhone-Poulenc Rorer in 1999 to form Aventis, and Aventis merged with SanoÞ-Synthélabo in 2004 to form SanoÞ-Aventis.) The drug was subsequently launched in its Þrst European market, the United Kingdom, in 1998 and in Japan in 2000. Fexofenadine, which can be administered once- or twice-daily, is indicated for the treatment of SAR and chronic idiopathic urticaria (CIU; hives) in all regions under study, and it is also indicated for dermatitis and pruritis (itching) in Japan. Fexofenadine is approved for use in children as young as age six. The drug was originally developed by Sepracor, but the company licensed its U.S. patent to the drug to HMR in 1993. Sepracor later licensed remaining worldwide patents to HMR in 1999. As a result of these agreements, Sepracor now earns royalties from SanoÞ-Aventis. In 1998, HMR launched a 12-hour version of Allegra-D, a Þxed combination of fexofenadine and the decongestant pseudoephedrine, in the United States for relief of SAR symptoms in patients aged 12 years and older. SanoÞ-Aventis received FDA approval for a once-daily, 24-hour formulation of Allegra-D in October 2004. Fexofenadine is the active metabolite of terfenadine (HMR’s Seldane/ Teldane/Triludan), one of the Þrst second-generation antihistamines to enter the

FIGURE 5. Structure of fexofenadine.

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AR market. Terfenadine has the potential to cause serious or life-threatening cardiac events such as QTC prolongation and ventricular arrhythmias when taken at high doses or coadministered with other drugs metabolized by the cytochrome P450 system (e.g., macrolide antibiotics, azole antifungals), leading to an accumulation of terfenadine in a patient’s plasma. Consequently, terfenadine was withdrawn from the French and U.S. markets in 1997 and 1998, respectively. The European Commission recommended the withdrawal of high-dose terfenadine tablets in 1998, and further recommended that additional label warnings be added to low-dose formulations of the drug. In all countries under study where terfenadine remains on the market, the drug’s follow-on compound, fexofenadine, which does not cause these cardiac adverse events, has replaced its predecessor. Like other second-generation antihistamines proÞled in this section, fexofenadine’s predominant therapeutic effects are exerted through the same means as discussed in the “Mechanism of Action” section for the drug class. Numerous studies have demonstrated fexofenadine’s efÞcacy in relieving AR symptoms. In one two-week, randomized, placebo-controlled trial, 572 patients with moderate to severe ragweed SAR were treated with one of three fexofenadine doses (60 mg, 120 mg, or 240 mg) or placebo twice-daily (Bernstein DI, 1997). At the end of the 14-day treatment period, all three fexofenadine treatment groups demonstrated signiÞcantly greater improvements in the primary efÞcacy measure—patient-assessed evening reßective total symptom scores (TSS)—compared with placebo recipients. (The evening-reßective TSS was the sum of individual symptom scores for the previous 12 hours, assessed by the patient prior to receiving their second daily dose of study medication. Symptoms included in the sum were sneezing; rhinorrhea; itchy nose, palate, and/or throat; and itchy, watery, and red eyes.) Patients treated with placebo demonstrated a mean 16.9% improvement over baseline evening reßective TSS, compared with mean improvements of 28.1%, 25.5%, and 28.1% for the three fexofenadine groups (60 mg, 120 mg, and 240 mg twice-daily, respectively). Additionally, all three fexofenadine treatment groups demonstrated signiÞcantly greater improvements over placebo in evening-reßective scores for all individual symptoms assessed; the smallest mean improvements were noted for nasal congestion. Fexofenadine was well tolerated in this study, and the incidence of adverse events was 14.2%, 6.9%, and 11.7% for the 60 mg, 120 mg, and 240 mg fexofenadine twice-daily groups, respectively, compared with 9.2% for the placebo group. The adverse events most commonly reported in the study were headache (2.8%, 0.7%, 0.7%, and 2.8%, respectively) and leucopenia (reduced white blood cell count; 2.1%, 0.7%, 1.4%, and 0.7%, respectively). Treatment with fexofenadine, regardless of dose, was not associated with any electrocardiographic abnormalities. The 180 mg once-daily dose of fexofenadine has been shown to offer efÞcacy comparable to 10 mg once-daily cetirizine (Zyrtec). In a two-week study conducted by F. Hampel and colleagues involving 495 patients with moderate to severe SAR, patients treated with fexofenadine demonstrated a mean 19% improvement over baseline reßective TSS compared with a mean improvement

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of 21.6% for cetirizine-treated patients. These improvements were considered statistically equivalent, as were the improvements for the two treatment groups on the measures of morning instantaneous TSS (sum of patient-assessed scores for symptom severity over the previous hour) and morning instantaneous scores for individual symptoms (Hampel F, 2003). Another key end point examined in the Hampel study was the difference between fexofenadine and cetirizine’s effects on drowsiness and motivation. (Although cetirizine is a second-generation antihistamine, the drug is not classiÞed as a “nonsedating” antihistamine like fexofenadine, because sedative effects have been noted with use of cetirizine in clinical studies. Cetirizine’s sedative effects are discussed in greater detail in the section devoted to this drug.) In this study, treatment with fexofenadine was associated with signiÞcantly greater improvements over baseline drowsiness scores, as measured on a 100-point visual analog scale (VAS), compared with cetirizine at all time points assessed—7 a.m., 10 a.m., and 3 p.m. Treatment with fexofenadine was also associated with a trend toward greater improvement in motivation scores, as measured on a 100-point VAS, compared with cetirizine, but the between-group difference on this measure did not reach statistical signiÞcance (Hampel F, 2003). The results from the Hampel study were comparable to those from another large-scale study comparing the efÞcacy and safety of fexofenadine and cetirizine in SAR patients. A study conducted by P.H. Howarth and colleagues determined that there was no signiÞcant difference between patients treated with fexofenadine and cetirizine on the measures of 24-hour reßective TSS, 24-hour reßective individual symptom scores, and 24-hour instantaneous TSS. Also, the incidence of drowsiness or fatigue was signiÞcantly higher for cetirizine-treated patients (8.6%) compared with fexofenadine-treated patients (4.0%); the incidence of drowsiness or fatigue for fexofenadine-treated patients was comparable to that for placebo recipients (4.3%) (Howarth PH, 1999). Fexofenadine has also demonstrated efÞcacy comparable to that of loratadine (Schering-Plough/Shionogi’s Claritin/Clarityn, generics) in improving 24-hour reßective TSS in a two-week study involving 688 SAR patients. Patients in the fexofenadine group demonstrated signiÞcantly superior improvements over baseline on the measures of nasal congestion and itchy, watery, red eyes compared with patients treated with either loratadine or placebo (van Cauwenberge P, 2000[a]). Fexofenadine has also demonstrated signiÞcantly superior efÞcacy in relieving nasal congestion compared with placebo in some studies, but this beneÞcial effect has not been consistently demonstrated in all trials. In a meta-analysis of six placebo-controlled, double-blinded, randomized studies evaluating the efÞcacy of fexofenadine in patients with moderate to severe SAR, fexofenadine-treated patients demonstrated signiÞcantly superior improvements in nasal congestion scores compared with placebo in three studies, but a signiÞcant difference was not noted in three other studies (Meeves SG, 2000; Meeves SG, 2003). The product label for fexofenadine reports that the incidence of adverse events among nearly 2,500 AR patients aged 12 years or older treated with 20–240 mg

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fexofenadine twice daily in clinical trials was comparable to that for placebotreated patients. In studies in which more than 1,300 AR patients were treated with either 60 mg fexofenadine twice-daily or placebo, the most commonly reported adverse events were viral infection (2.5% for fexofenadine-treated patients versus 1.5% for placebo-treated patients), nausea (1.6% versus 1.5%, respectively), drowsiness (1.3% versus 0.9%, respectively), and fatigue (1.3% versus 0.9%, respectively). The product label also reports the incidence of adverse events among nearly 600 AR patients aged 12 years or older treated with either 180 mg fexofenadine once daily or placebo in clinical trials, and the adverse events most commonly reported in these studies were headache (10.6% of patients treated with fexofenadine versus 7.5% of patients treated with placebo), upper respiratory tract infection (3.2% versus 3.1%, respectively), and back pain (2.8% versus 1.4%, respectively). The adverse events most commonly reported among nearly 450 pediatric AR patients (aged 6–11 years) treated with 30 mg fexofenadine twice daily or placebo were headache (7.2% versus 6.6%, respectively), upper respiratory tract infection (4.3% versus 1.7%, respectively), coughing (3.8% versus 1.3%, respectively), and accidental injury (2.9% versus 1.3%, respectively). The original U.S. patent covering fexofenadine expired in 2001. However, SanoÞ-Aventis holds numerous other patents pertaining to the drug, including method of use, formulation, composition, and process patents; the last of these patents expires in 2018. In 2001, Barr Laboratories initiated legal action challenging Aventis’s (now SanoÞ-Aventis’s) remaining patents for fexofenadine and Þled an abbreviated new drug application (ANDA) seeking FDA approval for a generic version of fexofenadine. Aventis subsequently sued Barr Laboratories for patent infringement, prompting a Hatch-Waxman 30-month stay on the launch of any generics. Since then, additional companies have Þled ANDAs with the FDA for generic formulations of either fexofenadine or the fexofenadine/pseudoephedrine combination product, and Aventis has Þled a number of patent infringement lawsuits against those companies, which include Impax Laboratories, Teva Pharmaceuticals, Mylan Laboratories, and Dr. Reddy’s Laboratories. On June 30, 2004, a summary judgment was handed down by the United States District Court in New Jersey in the patent infringement lawsuit brought about by Aventis against these Þve generic drug manufacturers (Barr Laboratories, Impax Laboratories, Teva Pharmaceuticals, Mylan Pharmaceuticals, and Dr. Reddy’s Laboratories). The judgment stated that the defendants’ products do not infringe upon three of SanoÞ-Aventis’s fexofenadine patents. Five additional patents included in the original lawsuit remain in litigation, and, in March 2004, Aventis and Albany Molecular Research (AMR) Þled lawsuits against the Þve aforementioned generic drug companies pertaining to two additional patents owned by AMR and licensed to SanoÞ-Aventis. Patents covering fexofenadine and the fexofenadine/pseudoephedrine combination product are not set to expire in Europe and Japan until 2014. Cetirizine. Cetirizine (PÞzer/UCB/Daiichi/Sumitomo’s Zyrtec/Virlix/Cirrus, generics) (Figure 6) is an oral second-generation antihistamine that has been marketed by UCB Pharmaceuticals in Europe since the late 1980s. The drug is

CURRENT THERAPIES

OH

OH

O N

O O

N

N

Cl

389

O

N

Cl

FIGURE 6. Structure of R- and S-cetirizine.

available over the counter in all Þve European countries under study (AESGP, 2004[a]). The drug received FDA approval in the United States in 1995, where it is jointly marketed by UCB and licensee PÞzer. UCB received regulatory approval in Japan for cetirizine in 1998; currently, Daiichi and Sumitomo distribute the drug in this region. However, in April 2005, UCB announced that the distribution agreement with Sumitomo will be terminated as of June 30, 2005, and that UCB will begin co-promoting Þve and 10 mg tablets of cetirizine in Japan with GlaxoSmithKline K.K. (GlaxoSmithKline Japan) beginning on July 1, 2005. Like fexofenadine, cetirizine is indicated for treating SAR and chronic idiopathic urticaria (CIU). However, unlike fexofenadine, cetirizine is also indicated for treating PAR. Cetirizine is, unlike fexofenadine, approved for use in younger patients; cetirizine is indicated for SAR in patients as young as two years of age, and PAR and CIU in patients as young as six months in age. Cetirizine is also indicated for eczema and dermatitis in Japan. Cetirizine is available in oral tablet, chewable tablet, and oral syrup formulations. This availability represents another advantage over fexofenadine, which is available only as oral capsules or tablets; chewable tablet and oral syrup formulations can be administered to young children who would otherwise have a difÞcult time swallowing oral tablets or capsules. In 2001, UCB and PÞzer received FDA approval for Zyrtec-D, a 12-hour Þxed combination of cetirizine and the decongestant pseudoephedrine, for the treatment of SAR and PAR in patients aged 12 or older. Cetirizine is the carboxylated metabolite of the Þrst-generation antihistamine hydroxyzine (PÞzer’s Atarax/Visaril, generics). Cetirizine’s predominant therapeutic effects are exerted through the same mechanism of action as other second-generation antihistamines, as discussed in the “Mechanism of Action” section for the drug class. Like fexofenadine, cetirizine’s efÞcacy in relieving AR symptoms has been demonstrated in numerous placebo-controlled studies. In one such double-blind study involving 419 adult SAR participants, patients were randomized to receive either placebo or one of three cetirizine doses (5, 10, or 20 mg once daily) for one week (Curran MP, 2004; Falliers CJ, 1991). EfÞcacy was measured by

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improvement over baseline in the patient-assessed TSS at the end of the sevenday treatment period, as well as the physician’s global assessment of treatment efÞcacy. (TSS, in this case, was the sum of individual severity scores for the following seven symptoms: sneezing, rhinorrhea, itchy eyes, itchy nose, itchy palate, eye redness, and watery eyes.) Treatment with 20 mg cetirizine daily was associated with the largest reduction in TSS over baseline (approximately 62%), compared with improvements of approximately 52%, 39%, and 26% for patients treated with 10 mg cetirizine, 5 mg cetirizine, and placebo, respectively. Additionally, signiÞcantly larger proportions of patients were deemed effectively treated (according to physicians’ global assessment of treatment efÞcacy) with cetirizine than with placebo. Overall, 73%, 79%, and 77% of patients treated with 5 mg, 10 mg, and 20 mg cetirizine daily, respectively, were deemed effectively treated, compared with only 53% of patients treated with placebo. Cetirizine treatment was shown to improve both patient- and physician-rated nasal congestion scores (which were also assessed in this study), but the difference in improvement from that of the placebo group was not signiÞcantly different. The prominent side effects in this study were somnolence (9% of patients treated with 5 mg cetirizine, 23% of patients treated with 10 mg cetirizine, 25% of patients treated with 20 mg cetirizine, and 6% of patients treated with placebo), headache (10%, 11%, 15%, and 15%, respectively), dry mouth (5%, 7%, 6%, and 0%, respectively), and fatigue (3%, 7%, 5%, and 4%). Although cetirizine is a second-generation antihistamine and is associated with less fatigue, drowsiness, and performance impairment than Þrst-generation antihistamines, the drug is not classiÞed as a “nonsedating” antihistamine, unlike fexofenadine. According to cetirizine’s product label, the incidence of somnolence in clinical studies was higher among patients treated with the drug compared with patients treated with placebo, and this trend was dose related. In controlled and uncontrolled clinical studies involving more than 6,000 adult patients (aged 12 years or older), 14% of patients treated with 10 mg cetirizine daily experienced somnolence, compared with 11% of patients treated with 5 mg cetirizine daily and 6% of patients treated with placebo. A similar dose-related trend was noted in studies involving pediatric patients (ages 6–11) treated with cetirizine in clinical studies, but the incidence of somnolence was not as high as in studies involving adults. According to the product label for cetirizine, the incidence of somnolence was 4.2%, 1.5%, and 1.3% for pediatric patients treated with 10 mg cetirizine, 5 mg cetirizine, and placebo daily, respectively. Because of the higher incidence of somnolence among cetirizine-treated patients, the drug’s product label includes a precaution stating that patients taking cetirizine should use caution when driving a car or operating machinery, and that concurrent use of the drug with alcohol or other agents that depress the CNS should be avoided to prevent additional impairments of alertness and performance. As described in the aforementioned studies conducted by F. Hampel, P.H. Howarth, and their respective colleagues, cetirizine demonstrated efÞcacy comparable to that of fexofenadine in large-scale clinical trials involving SAR patients (Hampel F, 2003; Howarth PH, 1999). However, in each of these studies, the

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incidence of drowsiness was signiÞcantly greater in patients treated with cetirizine compared with that in patients treated with fexofenadine. Cetirizine has also demonstrated comparable efÞcacy in improving AR symptoms as other second-generation antihistamines, including ebastine (Almirall/Dainippon/Meiji Seika’s Ebastel), mizolastine (SanoÞ-Aventis’ Mizollen, Schwarz Pharma’s Mizollen/Zolim), astemizole (Janssen Pharmaceutica [a Johnson & Johnson subsidiary] Hismanal, which has since been withdrawn from all markets under study), and terfenadine (Curran MP, 2004). Generic versions of cetirizine are available in all European countries under study, excluding Italy (where the drug is patent protected until 2009). Cetirizine faces patent expiry in the United States and Japan in 2007. In the United States, the FDA has already granted tentative approval for several companies’ ANDAs for generic versions of cetirizine. Desloratadine. In the face of the 2002 patent expiry for its blockbuster second-generation antihistamine loratadine, Schering-Plough launched desloratadine (Clarinex/Aerius/Neoclarityn), the principal active metabolite of loratadine, as a follow-on product. Desloratadine received its Þrst approval in January 2001 when the European Commission granted marketing authorization to all 15 European Union member states for an oral tablet formulation for the treatment of SAR in adults and children 12 years or older. Since this initial authorization, desloratadine’s European label has been expanded to include the indications of PAR and CIU. A rapidly disintegrating pill formulation and an oral syrup formulation have been approved as well, the latter of which is indicated for children as young as age two. Following a long delay due to manufacturing problems, Schering-Plough launched desloratadine in the United States in January 2002, a year after it received an approvable letter from the FDA for a tablet formulation for the treatment of SAR. The delayed U.S. approval hampered Schering-Plough’s efforts to convert as many patients taking loratadine to desloratadine as possible before the former lost patent protection and was subsequently switched from prescription to OTC status in the United States in December 2002. (Loratadine has been available OTC in Germany and the United Kingdom since the early 1990s, and was switched to OTC status in Italy in 2004. Desloratadine received FDA marketing clearance for the broadened indication of AR (encompassing SAR and PAR) and CIU in February 2002. In June of the same year, the FDA granted Schering-Plough approval to market a rapidly disintegrating tablet formulation of desloratadine for SAR, PAR, and CIU in patients aged 12 or older. In September 2004, the FDA approved an oral syrup formulation of desloratadine for treating SAR in patients as young as 2 years and for treating PAR and CIU in patients aged 6 months or older. The FDA granted approval to Schering-Plough’s Clarinex-D 24 Hour, a Þxed combination of desloratadine and the decongestant pseudoephedrine, for SAR in patients aged 12 or older in March 2005. Desloratadine was originally developed by Sepracor, which in 1997 licensed worldwide rights to the drug’s patents to Schering-Plough. As a result of this

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agreement, Sepracor now earns royalties on desloratadine sales from ScheringPlough. The drug is currently not marketed in Japan. Like other second-generation antihistamines proÞled in this section, desloratadine’s predominant therapeutic effects are exerted through the same means as discussed in the “Mechanism of Action” section for the drug class. As is the case with fexofenadine and cetirizine, desloratadine’s beneÞcial effects in treating AR symptoms have been demonstrated in numerous clinical studies, including two similarly designed, double-blind, placebo-controlled trials. In both studies, patients were randomized to receive either 5 mg desloratadine once daily or placebo for two weeks, and the mean change from baseline in the average of morning and evening reßective TSS served as the primary endpoint. (TSS, in this case, was the sum of total nasal symptom score [TNSS; sum of scores for rhinorrhea, nasal congestion/stufÞness, nasal itching, and sneezing] and total non-nasal symptom score [TNNSS; sum of scores for itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears or palate].) In one of the studies involving 328 SAR patients, desloratadine-treated patients demonstrated a mean 30.0% improvement over baseline TSS, compared with an improvement of 22.2% for placebo-treated patients. This difference was statistically signiÞcant, as was the difference between groups in TNSS improvements (31.5% versus 22.8%, respectively) and TNNSS improvements (35.9% and 26.6%, respectively) (Meltzer EO, 2001[a]; Murdoch D, 2003). Similar Þndings were found in the second 346-patient study; TSS improvements were 30.3% and 18.2% for desloratadine- and placebo-treated patients, respectively. Corresponding improvements for TNSS were 24.4% and 11.7%, respectively, and were 26.6% and 11.5%, respectively, for TNNSS. The improvements in the desloratadine groups over the placebo group were statistically signiÞcant for all measures—TSS, TNSS, and TNNSS. Desloratadine was the Þrst second-generation antihistamine to demonstrate proven, consistent efÞcacy in relieving nasal congestion (Bachert C, 2001). The drug acts as a subtype-selective antagonist of muscarinic receptors (at M1 and M3 receptor subtypes), and this antagonism may contribute to its decongestant effects. Desloratadine’s beneÞcial effect on nasal congestion was demonstrated in three large-scale, placebo-controlled studies involving 278 to 346 patients. In each of the three studies, which ranged from two to four weeks in duration, patients treated with desloratadine demonstrated a mean 21.3–23.5% improvement over baseline on the average morning and evening reßective congestion score, compared with improvements of 13.6–16.2% for patients treated with placebo. In each of the studies, the difference between the desloratadine and placebo groups was statistically signiÞcant (Geha RS, 2001). Desloratadine is well tolerated among AR patients. The product label for the drug reports compiled safety data for 3,300 AR patients aged 12 or older treated with either the recommended dosage of desloratadine (5 mg once daily) or placebo during clinical studies. The label also reports that the following adverse events occurred in more than 2% of desloratadine-treated patients and occurred more frequently among patients treated with the drug than among patients treated

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with placebo: pharyngitis (4.1% of desloratadine recipients vs. 2.0% of placebo recipients), dry mouth (3.0% versus 1.9%, respectively), myalgia (2.1% versus 1.8%, respectively), fatigue (2.1% versus 1.2%, respectively), somnolence (2.1% versus 1.8%, respectively), and dysmenorrhea (2.1% versus 1.6%, respectively). The product label for desloratadine reports consolidated adverse event rates for desloratadine-treated pediatric patients with either AR or CIU; the adverse event rates for pediatric AR sufferers are not reported separately from those for pediatric CIU patients. In general, the incidence of adverse events was lower among older children (ages 6–11 years) compared with younger children (ages 2–5) and infants (ages 6–23 months). A postmarketing surveillance study of desloratadine-treated patients found a lower incidence of adverse events than that reported on the product’s label. Among nearly 48,000 SAR patients treated with desloratadine for 1–232 days (mean 38.4 days), the overall incidence of adverse events was 0.44%. The most commonly reported adverse events deemed possibly or probably related to the drug were fatigue, headache, nausea, dry mouth, and diarrhea, each of which occurred in ≤0.07% of patients (Murdoch D, 2003). Desloratadine has market exclusivity in the United States until 2007 and is patent-protected in all European countries under study through 2010. Although desloratadine is currently not marketed in Japan, the drug’s patent in this region expires in 2005. It will likely be granted six years of data exclusivity when it launches in Japan (similar to when loratadine launched). Levocetirizine. Levocetirizine (UCB’s Xyzal/Xusal), the (R) enantiomer of cetirizine, was originally developed by Sepracor. In May 1999, Sepracor licensed all issued and pending patent rights pertaining to levocetirizine to UCB, excluding patent rights in the United States and Japan, where Sepracor retained its rights to the drug. In January 2001, UCB received marketing authorization in Germany for levocetirizine for the treatment of SAR, PAR, and CIU in patients as young as age six. The drug was subsequently approved by the other European Union (EU) member states in September of the same year. By the end of 2001, levocetirizine had launched in Germany and the United Kingdom; the drug did not launch in the other EU countries under study (France, Italy, and Spain) until 2003. In December 2004, levocetirizine’s European label was expanded further when it became the Þrst antihistamine to be approved for treating persistent allergic rhinitis (PER). The indication of PER reßects the new classiÞcation of AR put forth in the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines. (The ARIA guidelines are discussed in greater detail in “Etiology and Pathophysiology.”) As stated previously, levocetirizine is the (R) enantiomer of cetirizine. Studies have demonstrated that levocetirizine accounts for cetirizine’s afÞnity to the H1 receptor rather than the (S) enantiomer, dextrocetirizine (Devalia JL, 2001; Wang DY, 2001). According to the product label for levocetirizine, the drug has a twofold higher afÞnity for the H1 receptor compared to that of its predecessor compound, cetirizine. Like other second-generation antihistamines proÞled in this section, levocetirizine’s predominant therapeutic effects are exerted through the same means as discussed in the “Mechanism of Action” section for the drug class.

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Levocetirizine’s approval for PER was based on the Xyzal in Persistent Rhinitis Trial (XPERT), a six-month, double-blind, placebo-controlled study involving 551 patients. Study participants were randomized to receive either 5 mg levocetirizine daily or placebo, and efÞcacy was measured by two primary end points: mean improvement over baseline Total 5 Symptom Score (T5SS, the sum of individual scores for rhinorrhea, sneezing, nasal congestion, itchy nose, and itchy eyes) and change from baseline in the overall score on the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ, a disease-speciÞc measure of health-related quality of life). After four weeks of treatment (the predeÞned timing for both primary endpoint assessments), levocetirizine-treated patients demonstrated a 39% improvement over baseline T5SS and a 49% improvement over baseline RQLQ scores; corresponding improvements for placebo-treated patients were 27% and 33%, respectively. Additionally, patients treated with levocetirizine demonstrated signiÞcantly greater improvements over patients treated with placebo on individual symptom scores for sneezing, rhinorrhea, itchy nose, and itchy eyes as early as one week into the trial, and these signiÞcant differences were evident after six months of treatment. The difference between the levocetirizine and placebo groups on the assessment of nasal congestion did not reach statistical signiÞcance until 12 weeks into the trial. During the course of the entire six-month trial, 69.1% of levocetirizine-treated patients reported at least one adverse event, compared with 70.7% of patients in the placebo group. The most commonly reported adverse events among study participants were headache (24.5% of patients treated with levocetirizine versus 23.2% of patients treated with placebo), pharyngitis (19.8% versus 20.5%, respectively), inßuenza-like symptoms (14.0% versus 13.9%, respectively), fatigue (8.6% versus 7.0%, respectively), somnolence (6.8% versus 1.8%, respectively), and gastroenteritis (2.9% versus 5.1%, respectively) (Bachert C, 2004). Levocetirizine’s beneÞcial effect in treating AR symptoms was also demonstrated in a double-blind, placebo-controlled study involving 294 PAR patients. Study participants were treated with either 5 mg levocetirizine or placebo for six weeks, and efÞcacy was measured as the mean improvement over baseline for the Total 4 Symptom Score (T4SS, the sum of scores for itchy nose, itchy eyes, rhinorrhea, and sneezing); improvements over baseline for the four individual symptoms, as well as for nasal congestion, were also reported. After six weeks of treatment, patients treated with levocetirizine demonstrated a 48.1% improvement over baseline T4SS, compared with an improvement of 32.6% for placebo-treated patients. Additionally, patients treated with levocetirizine demonstrated signiÞcantly greater improvements over placebo-treated patients on all individually assessed symptoms, including nasal congestion. The improvements in nasal congestion scores were 22.3% and 8.8% for levocetirizine- and placebo-treated patients, respectively. The overall incidence of adverse events for levocetirizine recipients (60.0%) was lower than that for placebo recipients (68.1%) in this study. Headache (34.7% for levocetirizine-treated patients versus 34.7% for placebotreated patients), inßuenza-like symptoms (16.7% versus 13.9%, respectively),

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pharyngitis (8.7% versus 4.2%, respectively), and upper respiratory tract infections (6.7% versus 9.0%, respectively) were the most commonly reported adverse events (Potter PC, 2003). According to the product label for levocetirizine, which reports the pooled safety data from more than 1,700 patients treated with either the drug or placebo in clinical studies, the overall incidence of adverse events associated with levocetirizine use appears to be lower than that reported in the aforementioned studies conducted by C. Bachert, P.C. Potter, and their respective colleagues. According to the drug’s product label, 15.1% of patients treated with 5 mg levocetirizine in clinical studies experienced at least one adverse event, compared with 11.3% of patients treated with placebo; nearly 92% of these adverse events were mild to moderate. The most commonly reported adverse events were similar to those in the study conducted by Bachert and colleagues: headache (2.6% for levocetirizine-treated patients versus 3.2% of placebo-treated patients), somnolence (5.2% versus 1.4%, respectively), dry mouth (2.6% versus 1.6%, respectively), and fatigue (2.5% versus 1.2%, respectively). Like its predecessor compound, cetirizine, the overall incidence of sedating adverse events (i.e., somnolence, fatigue, and asthenia [loss of energy or strength]) associated with levocetirizine use (8.1%, as reported by the product label) is higher than that for placebo-treated patients (3.1%). The product label for levocetirizine acknowledges that although no evidence has been revealed in comparative clinical trials to indicate the drug negatively affects mental alertness, reactivity, or ability to drive, patients should consider their potential response to levocetirizine if they intend to drive, operate machinery, or participate in hazardous activities, as sedating effects have been noted in clinical trials involving the drug. Although levocetirizine is currently not on the market in the United States, the U.S. patent for this drug is not expected to expire until 2012. Levocetirizine will not face patent expiration in Europe during the study period. Intranasal Corticosteroids Overview. Intranasal corticosteroids are regarded as the most effective drugs available for the treatment of AR because of their potent and extensive antiinßammatory effects. However, physicians often prescribe oral second-generation antihistamines as Þrst-line therapy because patients generally prefer oral medications to drugs that are administered intranasally. Although they are not always as effective as oral antihistamines at alleviating ocular irritation, nasal corticosteroids provide excellent relief from other early- and late-phase symptoms, including sneezing, itchy or runny nose, and nasal congestion. As a result, agents in this class are recommended for Þrst-line use in AR patients with frequent or persistent symptoms or patients suffering from nasal congestion (Bousquet J, 2001). Intranasal corticosteroids are most effective when administered prophylactically on a daily basis. Patients may begin to experience symptomatic relief within approximately 12 hours, but several days of administration may be required

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before the maximal beneÞt is achieved. This onset of action is much longer than that of oral second-generation antihistamines, which typically ranges from 30 minutes to three hours. Several intranasal corticosteroid products are marketed for the treatment of AR: ßuticasone propionate (GlaxoSmithKline’s Flonase/Flixonase, generics), mometasone furoate (Schering-Plough’s Nasonex), budesonide (AstraZeneca’s Rhinocort/Rhinocort AQ), triamcinolone acetonide (Aventis’ Nasacort/Nasacort AQ), beclomethasone (GlaxoSmithKline’s Beconase/Beconase AQ, generics), and ßunisolide (IVAX’s Nasarel). Clinical studies have demonstrated that available intranasal corticosteroid products offer comparable clinical efÞcacy in relieving AR symptoms (Nielsen LP, 2001; Waddell AN, 2003), but agents in this class differ with respect to other product attributes, such as systemic bioavailability, dosing frequency, fragrance, and use of preservatives. Therefore, the choice of intranasal corticosteroid is often based on a balance of safety, convenience, and patient preference rather than clinical efÞcacy. As stated previously, intranasal corticosteroids are prescribed less often than second-generation antihistamines, largely because of patient preference for orally administered drugs. In addition, although clinical trials have shown that intranasal corticosteroids are very safe—even when taken over the long term—the stigma associated with steroid use leads many patients to avoid using intranasal corticosteroids unless absolutely necessary. Indeed, long-term use of oral, systemic steroids is associated with many well-known and serious side effects (e.g., adrenal insufÞciency, osteoporosis, growth retardation), and most orally inhaled steroids have been associated with suppression of the hypothalamic-pituitaryadrenal (HPA) axis because these drugs can pass into the systemic circulation and mimic the effects of naturally occurring corticosteroids. However, because of the localized activity in the nose, lower corticosteroid doses are required to achieve a therapeutic effect when the drug is delivered intranasally. Additionally, intranasal corticosteroids are associated with fewer side effects than other corticosteroid formulations because of their lower systemic absorption from the nasal mucosa and/or extensive Þrst-pass metabolism. As a result of systemic safety concerns associated with corticosteroid products, systemic bioavailability is probably the most important characteristic distinguishing one intranasal corticosteroid from another. The systemic bioavailability of currently available intranasal corticosteroids varies greatly; systemic bioavailabilities for intranasal formulations of triamcinolone acetonide, beclomethasone, ßunisolide, and budesonide are reported to be 46%, 44%, 40–50%, and 31%, respectively, while intranasal formulations of two newer corticosteroids—ßuticasone propionate and mometasone furoate—have signiÞcantly reduced systemic bioavailabilities of 0.42–0.51% and 0.46%, respectively (Salib RJ, 2003[b]). Because of their superior systemic bioavailabilities and convenient once-daily recommended dosing schedule, this section proÞles intranasal formulations of ßuticasone propionate and mometasone furoate as representatives for other agents in this class; these two agents are also the top-selling intranasal corticosteroids for the treatment of AR in the major markets under study.

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Mechanism of Action. All corticosteroids exert their therapeutic effect by binding to intracellular glucocorticoid receptors, which are found in all cells. Following translocation to the nucleus, activated glucocorticoid receptors either promote or inhibit transcription of genes that are involved in the inßammatory process. In this way, corticosteroids inßuence the release of cytokines and proinßammatory mediators, including the interleukins (IL)-1, -4, -5, -6, -8, and -13; tumor necrosis factor-alpha (TNF-α); granulocyte-macrophage colonystimulating factor (GM-CSF); and regulated upon activation, normal T cell expressed and secreted (RANTES). By lowering the levels of these inßammation mediators, corticosteroid therapy downregulates the expression of adhesion molecules and chemokines and thus reduces the recruitment and accumulation of inßammatory cells—including eosinophils, mast cells, basophils, and antigen-presenting cells (APCs)—to the nasal mucosa. By reducing the inßux of inßammatory cells into the nasal mucosa, intranasal corticosteroids effectively reduce nasal hyperresponsiveness to allergic stimuli (Mygind N, 2001; Salib RJ, 2003[b]). Other key mechanisms by which corticosteroids help alleviate the symptoms of AR include promotion of apoptosis of eosinophils, inhibition of mediator release from basophils and eosinophils, inhibition of T-helper 2 (TH 2) cell formation, inhibition of immunoglobulin E (IgE) antibodies, and reduction in mucus secretion by submucosal gland cells (Mygind N, 2001). Intranasal Fluticasone Propionate. The intranasal formulation of ßuticasone propionate (GlaxoSmithKline’s Flonase/Flixonase, generics) (Figure 7) launched in Europe in 1991. The drug was subsequently approved for use in Japan and the United States in July and October of 1994, respectively. Intranasal ßuticasone propionate is indicated for the treatment of both SAR and PAR in patients aged 4 years or older; the drug is also indicated for the management of nasal symptoms associated with nonallergic rhinitis. Intranasal ßuticasone propionate is formulated as an aqueous solution that is administered via a metering, atomizing spray pump. A nasal drop formulation of

F S H3C

HO H3C

CH3

O O CH3

H F

O

H

O F FIGURE 7. Structure of fluticasone propionate.

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ßuticasone propionate is also available in Europe for treating AR, but is not as widely used as is the aqueous solution. Like many other intranasal corticosteroids, intranasal ßuticasone propionate contains the preservative benzalkonium chloride, which can cause allergic or irritant reactions in some patients. The recommended initial dosing for adult patients is two sprays in each nostril once daily, and the dose may be reduced to one spray per nostril once daily after a few days if a patient’s symptoms continue to respond to a lower dose. The recommended initial dose for children and adolescents is one spray in each nostril once daily; two sprays per nostril once daily can be administered if a child fails to achieve adequate symptom control with the lower dose. Like other intranasal corticosteroids, intranasal ßuticasone propionate is a potent anti-inßammatory agent. The anti-inßammatory effects of these drugs are numerous (as described in the previous section). Through these multiple antiinßammatory effects, intranasal ßuticasone propionate effectively reduces nasal hyperresponsiveness to allergic stimuli. The efÞcacy of intranasal ßuticasone has been demonstrated in multiple clinical studies. In one trial involving 227 SAR patients, study participants were treated with either 200 µg intranasal ßuticasone propionate once-daily, 100 µg intranasal ßuticasone propionate twice-daily, or placebo (Nathan RA, 1991). At the end of the two-week treatment period, patients treated with 200 µg intranasal ßuticasone propionate once daily demonstrated a 46.8% improvement over baseline in physician-rated mean TNSS, compared with an improvement of 26.8% for placebo-treated patients. A greater improvement was seen in patients treated with 100 µg intranasal ßuticasone propionate twice-daily (54.9% improvement). Treatment with intranasal ßuticasone propionate—regardless of dose—was also associated with signiÞcantly greater improvements over baseline scores for each of the four individual nasal symptom scores. Patients treated with 200 µg intranasal ßuticasone propionate once daily demonstrated improvements of 33.8%, 46.0%, 56.4%, and 53.8% for physician-rated nasal obstruction, rhinorrhea, sneezing, and nasal itching, respectively. Corresponding improvements for patients treated with 100 µg intranasal ßuticasone propionate once daily were 40.8%, 53.7%, 67.9%, and 61.3%, respectively, and were 17.4%, 26.9%, 30.2%, and 34.4%, respectively, for placebo-treated patients. The efÞcacy of intranasal ßuticasone propionate has also been demonstrated in PAR patients. In one 365-patient, six-month study, patients were treated with either 200 µg intranasal ßuticasone propionate once daily, 100 µg intranasal ßuticasone propionate twice daily, or placebo (Banov CH, 1994). As in the aforementioned study conducted by R.A. Nathan and colleagues, efÞcacy was primarily measured by the improvement over baseline in clinician-rated mean TNSS (sum of scores for nasal congestion, rhinorrhea, sneezing, and itching). At the end of 24 weeks, the patients treated with 200 µg intranasal ßuticasone propionate once daily, 100 µg intranasal ßuticasone propionate twice daily, and placebo demonstrated improvements of 47%, 51%, and 33% in clinician-rated mean TNSS. Additionally, treatment with intranasal ßuticasone propionate was superior to placebo on a second primary efÞcacy end point: clinician-rated overall

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evaluation of treatment efÞcacy. At the conclusion of the study, 59% of patients treated with 200 µg intranasal ßuticasone propionate once daily and 67% of patients treated with 100 µg intranasal ßuticasone propionate twice-daily demonstrated moderate or signiÞcant improvements according to physicians, compared with only 41% of placebo-treated patients. Intranasal ßuticasone propionate has demonstrated superior efÞcacy compared with a number of oral second-generation antihistamines, including cetirizine, loratadine, terfenadine, and astemizole (Wiseman LR, 1997). In one large-scale, two-week comparative trial, 600 SAR patients were randomized to one of four treatment groups: 200 µg intranasal ßuticasone propionate once daily, 200 µg intranasal ßuticasone propionate and 10 mg loratadine administered together once daily, 10 mg loratadine once daily, or placebo. At the end of the 14-day treatment period, improvements over baseline scores for clinician-rated TNSS were 61.3%, 61.0%, 32.6%, and 33.7% for patients treated with intranasal ßuticasone propionate monotherapy, intranasal ßuticasone propionate and loratadine combination, loratadine monotherapy, and placebo, respectively. These results were statistically signiÞcant for the two groups receiving intranasal ßuticasone propionate. These two groups also demonstrated signiÞcantly greater improvements over patients treated with loratadine monotherapy and placebo on each of the individual nasal symptom scores. Patients treated with intranasal ßuticasone propionate monotherapy demonstrated improvements of 54.5%, 55.9%, 67.2%, and 69.4% on the clinician-rated measures of nasal blockage, discharge, itching, and sneezing, respectively, while the corresponding improvements for the intranasal ßuticasone propionate and loratadine combination group were 52.9%, 59.8%, 65.5%, and 67.4%, respectively. The improvements for the loratadine monotherapy group on the four aforementioned individual nasal symptoms (24.9%, 31.6%, 38.4%, and 36.9%, respectively) were comparable to the improvements demonstrated by placebo-treated patients (26.0%, 33.3%, 37.4%, and 39.1%, respectively) (Ratner PH, 1998). In this comparative study, patients treated with intranasal ßuticasone propionate (either as monotherapy or in combination with loratadine) also demonstrated signiÞcantly greater improvements on the RQLQ than patients treated with loratadine monotherapy and placebo recipients. Global RQLQ scores improved 53.6% and 57.5% over baseline for the intranasal ßuticasone propionate monotherapy and intranasal ßuticasone propionate and loratadine combination groups, respectively, while corresponding improvements for the loratadine monotherapy and placebo groups were 31.7% and 32.5%, respectively (Ratner PH, 1998). The improvements on each of the seven individual RQLQ domains (nasal symptoms, ocular symptoms, activities, practical problems, sleep, emotional issues, and other non-nasal, non-ocular symptoms) were also signiÞcantly greater for the two intranasal ßuticasone propionate groups compared with the loratadine monotherapy and placebo groups. According to the product label for intranasal ßuticasone propionate, the most common adverse events that occurred in more than 1,500 patients treated with either the drug or placebo in multiple clinical trials were headache (16.1% of

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patients treated with 200 µg intranasal ßuticasone propionate once daily versus 14.6% of patients treated with placebo), pharyngitis (7.8% versus 7.2%, respectively), epistaxis (bloody nose, 6.9% versus 5.4%, respectively), and nasal burning/irritation (3.2% versus 2.6%, respectively). The product label for intranasal ßuticasone propionate also reports the incidence of adverse events among 167 children (ages 4–11 years) treated with 100 µg intranasal ßuticasone propionate once daily. The most commonly reported adverse events among these pediatric patients were asthma symptoms (7.2%), headache (6.6%), pharyngitis (6.0%), and epistaxis (6.0%). In March 2003, IVAX Þled an ANDA with the FDA seeking approval for a generic version of intranasal ßuticasone propionate. However, following expiry of intranasal ßuticasone propionate’s patent in May 2004, GlaxoSmithKline Þled a citizen’s petition in June 2004 asking the FDA to delay the approval of any generic versions of intranasal ßuticasone propionate until the FDA issues Þnal guidelines on establishing bioavailability and bioequivalency for products that act locally rather than systemically, such as inhaler products. The FDA issued draft guidance on bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action in April 2003.. European and Japanese patents pertaining to intranasal ßuticasone propionate expire between 2005 and 2006. In May 2005, IVAX became the Þrst company to receive marketing authorization for a generic version of intranasal ßuticasone propionate in the United Kingdom, and the company plans to seek additional approvals for this generic equivalent in additional European countries. Intranasal Mometasone Furoate. Intranasal mometasone furoate (ScheringPlough’s Nasonex) (Figure 8) received European and U.S. regulatory approval in 1997. The drug is currently not available in Japan, but Phase III trials are under way in this region. Intranasal mometasone furoate is indicated for the treatment of SAR and PAR; it is the only marketed intranasal corticosteroid indicated for use in children as young as age two. Additionally, the drug is the only currently available intranasal corticosteroid that is indicated for the prophylaxis of nasal symptoms in SAR patients aged 12 years or older; it is recommended that patients begin taking the drug two to four weeks before the start of an allergy season to prevent the development of nasal symptoms. Intranasal mometasone furoate is also indicated for the treatment of nasal polyps, a complication of AR, in patients aged 18 years or older. The FDA approved a new scent-free formulation of intranasal mometasone in August 2004. Like intranasal ßuticasone propionate, intranasal mometasone furoate is formulated as an aqueous solution that is delivered via a metered-dose, manual pump spray. Intranasal mometasone furoate also contains the preservative benzalkonium chloride, which can cause allergic or irritant reactions in some patients. Similar to intranasal ßuticasone propionate, the recommended initial dosing for intranasal mometasone furoate for adult patients is two sprays in each nostril once daily, and the recommended initial dose for children aged two to 11 is one spray in each nostril once daily.

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FIGURE 8. Structure of mometasone furoate.

Intranasal mometasone furoate exerts its potent anti-inßammatory effects through the same mechanisms of action as other intranasal corticosteroids, as discussed in the “Mechanism of Action” section for the drug class. The efÞcacy of intranasal mometasone furoate has been demonstrated in numerous clinical trials. In one four-week study, the efÞcacy of intranasal mometasone furoate was compared with that of intranasal beclomethasone and placebo in 501 SAR patients (Hebert JR, 1996). Study participants were randomized to receive one of four treatments: either 100 µg or 200 µg intranasal mometasone furoate once daily, 200 µg intranasal beclomethasone twice daily, or placebo. Physician-rated improvement over baseline for TNSS on day 8—the predeÞned primary efÞcacy assessment—were 53% for the 100 µg intranasal mometasone furoate group, 59% for the 200 µg intranasal mometasone furoate group, 59% for the intranasal beclomethasone group, and 34% for the placebo group. The three active treatment groups also demonstrated signiÞcantly greater improvements in the four individual nasal symptom scores on day 8 compared with placebo recipients. The three groups treated with intranasal corticosteroids demonstrated mean improvements of 51–58% for rhinorrhea, 41–52% for nasal stufÞness/congestion, 56–59% for nasal itching, and 63–71% for sneezing; corresponding improvements for the placebo group were 26%, 28%, 31%, and 32%, respectively. Additionally, the percentage of patients who were deemed by physicians to have no or mild symptoms on day 8 was 66%, 71%, 75%, and 43% for patients treated with 100 µg intranasal mometasone furoate, 200 µg intranasal mometasone furoate once, intranasal beclomethasone, and placebo, respectively. The incidence of adverse events was comparable between the four treatment groups (from a low of 25% for patients treated with 100 µg intranasal mometasone furoate to a high of 30% for patients treated with intranasal beclomethasone). Headache, nasal burning, and epistaxis were the three most commonly reported adverse events in this study. As stated previously, intranasal mometasone furoate is indicated for the prevention of nasal symptoms in SAR patients. This beneÞcial effect was demonstrated in one eight-week study involving 349 SAR patients who were randomized

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to one of three treatment groups: 200 µg intranasal mometasone furoate once daily, 168 µg intranasal beclomethasone twice daily, or placebo (Graft D, 1996). Treatment was initiated four weeks before the estimated start of the ragweed allergy season, and the average proportion of minimal symptom days served as the primary end point. (A minimal symptom day was deÞned as a day on which morning and evening averaged TNSS was less than or equal to 2 out of a maximum score of 12.) During the ragweed season, the proportion of minimal symptom days was 83% for patients treated with intranasal mometasone furoate, 77% for patients treated intranasal beclomethasone, and 64% for patients treated with placebo. Intranasal mometasone furoate and intranasal ßuticasone propionate demonstrated comparable efÞcacy on multiple end points in a large-scale, placebo-controlled comparative trial. A total of 550 PAR patients were randomized to receive either 200 µg intranasal mometasone furoate once daily, 200 µg intranasal ßuticasone propionate once daily, or placebo for a period of three months (Mandl M, 1997). The three treatment groups demonstrated improvements of 37%, 39%, and 22%, respectively, on the primary efÞcacy end point—the change from baseline in cumulative morning plus evening TNSS on day 15, as recorded in patient diaries. The improvements for the two active treatment groups were signiÞcantly greater compared with placebo recipients but were not signiÞcantly different from one another. A signiÞcant difference between the intranasal mometasone furoate and intranasal ßuticasone propionate groups was noted on the secondary efÞcacy measure of physician-rated improvement in nasal congestion on day 29 (53% versus 45%, respectively) and at week 8 (56% versus 48%, respectively), as well as on physician-rated improvement in nasal discharge at weeks 8 and 12 (64% versus 58%, respectively). The product label for intranasal mometasone furoate reports consolidated safety data from nearly 4,000 adult and adolescent AR patients (ages 12 years or older) who were treated with either intranasal mometasone furoate or placebo in clinical trials. The incidence of adverse events was comparable between intranasal mometasone furoate-treated patients and placebo recipients. The most commonly reported adverse events in clinical trials were headache (26% of patients treated with 200 µg intranasal mometasone furoate once daily versus 22% of patients treated with placebo), viral infection (14% versus 11%, respectively), pharyngitis (12% versus 10%, respectively), epistaxis/blood-tinged mucus (11% versus 6%, respectively), and coughing (7% versus 6%, respectively). The product label also reports the incidence of the most commonly reported adverse events among nearly 800 pediatric patients (ages 3–11 years) treated with either 100 µg intranasal mometasone furoate once daily or placebo. The most commonly reported adverse events among pediatric patients were similar to those reported in adult studies: headache (17% of patients treated with 100 µg intranasal mometasone furoate once daily versus 18% of patients treated with placebo), coughing (13% versus 15%, respectively), pharyngitis (10% versus 10%, respectively), viral infection (8% versus 9%, respectively), and epistaxis/blood-tinged mucus (8% versus 9%, respectively).

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Branded intranasal mometasone furoate will not face competition from generic competitors until the end of the study period, when the drug faces loss of patent protection and/or market exclusivity in 2012 in Japan and Europe and in 2014 in the United States. Leukotriene Antagonists Overview. Although histamine is the principal mediator of the early-phase allergic response, other proinßammatory mediators—including leukotrienes—play a role in the development of an allergic reaction. Derived from arachidonic acid, leukotrienes are lipid mediators that are released from most of the inßammatory cells present in (or recruited to) the airways. Most development activity pertaining to leukotriene antagonists has been for asthma, as leukotrienes directly mediate bronchoconstriction and have proinßammatory effects. Four leukotriene antagonists have been approved for the treatment of asthma—montelukast (Merck’s Singulair), pranlukast (Ono’s Onon), zaÞrlukast (AstraZeneca’s Accolate), and zileuton (Critical Therapeutics’ Zyßo). Two of these four leukotriene antagonists—montelukast and pranlukast—have also been approved for the treatment of AR. Pranlukast, a product that is exclusive to the Japanese market, received formal approval for the treatment of AR in 2000. (The drug received approval for asthma in Japan in 1995.) In 1998, SmithKline Beecham (now GlaxoSmithKline), which had licensed rights to the drug for Europe and the United States, discontinued development of pranlukast after it had reached Phase III trials for asthma. Because of its limited geographic availability, this agent is not proÞled in greater detail here. Instead, montelukast is discussed as the representative for this class because the drug is currently marketed in all countries under study for the treatment of asthma and is either marketed or used off-label for the treatment of AR in the major markets. Mechanism of Action. Leukotrienes are potent proinßammatory mediators that are derived from arachidonic acid, an unsaturated fatty acid produced from membrane phospholipids. Leukotrienes are generated during the immediate response to antigen provocation and their concentrations increase during the late inßammatory phase of the allergic cascade. Mast cells and basophils generate a mixture of leukotrienes, which act to stimulate the production of airway secretions, enhance the migration of eosinophils, and cause microvascular leakage. Blocking the effect of leukotrienes with therapeutic intervention provides an alternative strategy for treating AR, especially in patients whose allergies involve a more pronounced late-phase response. Currently, two modes of leukotriene inhibition have been developed for respiratory conditions, including AR and asthma: •

Leukotriene receptor antagonists. Leukotriene receptor antagonists are also known as cysteinyl leukotriene receptor antagonists. Cysteinyl leukotrienes exert their biological effect by binding to receptors located on airway smooth

404

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muscles (Drazen JM, 1999). Therefore, blocking the interaction between leukotrienes and their respective receptors might inhibit the inßammatory effects. Leukotriene synthesis inhibitors. The leukotriene synthesis inhibitors include inhibitors of 5-lipoxygenase (5-LO) and 5-LO-activating protein (FLAP), which are components of the 5-lipoxygenase pathway. This pathway produces several leukotrienes (e.g., leukotriene B4 , cysteinyl leukotrienes) that can cause edema, eosinophil migration, and airway secretion (Drazen JM, 1999). Theoretically, inhibitors of this pathway might reduce airway inßammation.

Montelukast. In 1998, montelukast (Merck’s Singulair) (Figure 9) received approval in the United States and Europe for the treatment of asthma, and, in 2001, the drug received regulatory approval for asthma in Japan, where the drug is marketed by Merck’s Japanese subsidiary, Banyu. In December 2002, montelukast was approved by the FDA for the treatment of SAR in adults and children as young as age two. In March 2005, the drug was approved for the treatment of SAR in its Þrst European market, the United Kingdom. Currently, montelukast is undergoing Phase II trials in Japan for AR. Montelukast is available in three formulations—oral tablet, chewable tablets, and oral granules. Regular oral tablets are indicated for use in AR patients aged 15 years or older, while chewable tablets are indicated for use in pediatric patients ages 2–14 years of age. The oral granule formulation, which can be administered directly or mixed with soft foods, is indicated for asthma patients ages 12–23 months; currently, montelukast is not approved for use in treating AR in children under the age of two. Merck and Schering-Plough were jointly developing a Þxed-dose, once-daily combination therapy comprising Merck’s leukotriene antagonist montelukast and Schering-Plough’s oral second-generation antihistamine loratadine. In January 2002, however, the companies announced that the Þxed-combination tablet did not demonstrate a statistically signiÞcant improvement in the treatment of SAR when compared with each product administered separately in Phase III clinical trials. Although the drug is still listed in Phase III development on the ScheringPlough company Web site, no further development has been reported since 2002.

FIGURE 9. Structure of montelukast sodium.

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Montelukast is a leukotriene D4 antagonist. The drug binds to the CysLT1 receptor—which is found on airway smooth muscle cells, airway macrophages, and proinßammatory cells (e.g., eosinophils)—with high afÞnity and selectivity. By blocking the CysLT1 receptor, montelukast blocks the ability of leukotriene D4 to exert its proinßammatory effects and its ability to stimulate airway secretion production, enhance eosinophil chemotaxis, and contribute to the development of AR symptoms. The efÞcacy of montelukast in treating SAR symptoms was demonstrated in a large, double-blind, placebo- and active-controlled study. A total of 1,214 SAR patients were randomized to receive either 10 mg montelukast, 10 mg loratadine, or placebo once daily in the evening during the spring allergy season. Improvements in mean daytime TNSS (D-TNSS, as measured in the evening before administration of the next dose of study medication) served as the primary efÞcacy endpoint. At the end of the two-week treatment period, montelukast-treated patients demonstrated a mean 18.1% improvement in D-TNSS, which was statistically signiÞcant compared with the mean 13.5% improvement demonstrated by the placebo group and comparable to the 21.8% improvement demonstrated by the loratadine group (van Adelsberg J, 2003). Patients treated with montelukast also demonstrated signiÞcantly greater improvements over placebo-treated patients on a number of secondary endpoints, including the mean nighttime symptom score (mean of scores for difÞculty falling asleep, nighttime awakenings, and nasal congestion on waking); patient and physician global evaluations of treatment efÞcacy; improvements on overall RQLQ scores; mean daytime eye symptoms score (mean of scores for ocular tearing, redness, itching, and pufÞness); and composite scores (mean of D-TNSS and nighttime symptom scores). Loratadine-treated patients demonstrated signiÞcant improvements over placebo-treated patients on each of these secondary end points as well, excluding the nighttime symptoms score assessment. Additionally, treatment with montelukast was associated with a signiÞcant reduction in peripheral blood eosinophil counts compared with placebo; peripheral blood eosinophil counts remained unchanged for both the placebo and loratadine treatment groups. The incidence of adverse events was comparable among all three treatment groups—17%, 15%, and 16% for patients treated with montelukast, loratadine, and placebo, respectively. Comparable results were found in a similar study involving 907 SAR patients randomized to one of four treatment groups—10 mg montelukast, 10 mg loratadine, 10 mg montelukast and 10 mg loratadine given together, or placebo—during the fall allergy season. Primary and secondary end points used in this study were similar to the ones in the aforementioned trial conducted by J. van Adelsberg and colleagues. At the end of the two-week treatment period, mean improvements over baseline D-TNSS for patients treated with montelukast, loratadine, montelukast and loratadine, and placebo were 23.3%, 24.9%, 28.8%, and 12.9%, respectively (Nayak AS, 2002). The difference between each of the three active treatment groups was statistically signiÞcant compared with placebo for this endpoint, as well as on several secondary endpoints including nighttime

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symptom scores, eye symptoms scores, and overall RQLQ scores. In general, patients treated with both montelukast and loratadine demonstrated numerically greater, but not statistically signiÞcant, improvements on symptom scores compared with patients treated with either montelukast or loratadine monotherapy. Although montelukast has demonstrated efÞcacy comparable to that of the antihistamine loratadine in clinical trials, the leukotriene inhibitor has demonstrated efÞcacy inferior to that of the intranasal corticosteroid ßuticasone propionate in a large double-blind study. A total of 705 SAR patients were randomized to receive either 10 mg montelukast or 200 µg intranasal ßuticasone propionate once daily in the evening for 15 days (Ratner PH, 2003). Patients’ improvements over baseline in D-TNSS (as measured by a 100-point VAS) served as the primary end point of the trial, and key secondary end points included the improvement over baseline in daytime individual nasal symptom scores (D-INSS), nighttime total nasal symptom score (N-TNSS, deÞned as the sum of individual scores for nasal congestion upon awakening, difÞculty in going to sleep due to nasal symptoms, and nighttime awakenings attributable to nasal symptoms, as measured by a fourpoint scale for each symptom), and nighttime individual nasal symptom scores (N-INSS). At the end of the treatment period, patients treated with intranasal ßuticasone propionate demonstrated signiÞcantly greater improvements than montelukasttreated patients on all key primary and secondary end points assessed—D-TNSS, D-INSS, N-TNSS, and N-INSS. After 15 days of treatment, patients treated with intranasal ßuticasone propionate demonstrated a 44.0% improvement over baseline D-TNSS compared with an improvement of 31.4% for montelukast-treated patients. Improvements in D-INSS for the intranasal ßuticasone propionate group ranged from a low of 40.5% for nasal congestion to a high of 47.5% for sneezing; corresponding D-INSS for the montelukast group ranged from a low of 29.0% for nasal congestion to a high of 32.9% for sneezing. Improvements in N-TNSS for intranasal ßuticasone propionate- and montelukast-treated patients were 48.7% and 38.9%, respectively, and the improvements in N-INSS were also higher for the intranasal ßuticasone propionate group (ranging from a low of 42.4% for nasal congestion upon waking to a high of 55.1% for nighttime awakenings because of nasal symptoms) compared with the montelukast group (ranging from a low of 32.3% to a high of 44.4% for the same measures). The overall incidence of adverse events was comparable between the two treatment groups—29% and 28% for the intranasal ßuticasone propionate and montelukast groups, respectively—and the most commonly reported adverse events were headache (5% and 7%, respectively), sore throat (3% and 2%, respectively), and diarrhea (3% and 2%, respectively). The product label for montelukast reports that, among 2,200 adult patients (aged 15 years or older) treated in placebo-controlled clinical studies, upper respiratory infection was the only adverse event that occurred in 1% or more of patients and occurred more often in patients treated with montelukast (1.9%) than in placebo recipients (1.5%). The product label further reports that headache, otitis media, pharyngitis, and upper respiratory infection were the only adverse events

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that occurred in 2% or more of patients and occurred more often in montelukast patients than in placebo recipients in a placebo-controlled clinical trial involving 280 pediatric (aged 2–14 years) patients. Montelukast is patent-protected until 2012 in the United States and Europe. The Japanese patent for montelukast does not expire until after the conclusion of the study period. Nonpharmacological Approaches For patients with severe AR who fail to achieve adequate control of symptoms with typical pharmacotherapy, physicians may recommend allergen immunotherapy as a treatment option. Allergen immunotherapy aims to decrease a patient’s allergic sensitivity over time by introducing to the patient’s immune system increasingly larger doses of the substance to which the patient is allergic. Allergen immunotherapy has been shown to decrease patients’ symptoms and reduce the need for AR pharmacotherapy, even for several years after allergen immunotherapy is discontinued (Bousquet J, 1998). A consensus statement issued in August 2000 by experts involved in the American College of Allergy, Asthma, and Immunology’s Immunotherapy in Allergic Asthma conference urged more widespread use of allergen immunotherapy, especially in patients with comorbid asthma and allergy. The experts concluded that speciÞc allergen immunotherapy has been shown to be highly effective in the treatment of allergic asthma, that it can help prevent the development of new allergies and curtail progression of illness, and that it is an effective means of preventing the development of asthma in susceptible individuals. Traditional subcutaneous (SC) allergy immunotherapy, which was Þrst introduced in the early 1900s, involves a series of weekly subcutaneous injections using standardized allergen extracts that are delivered at escalating doses until a maximal dose is achieved; induction of clinical tolerance of the maximal dose usually takes three to six months. Once a patient reaches the maximal, or “maintenance,” dose, the frequency of injections tapers, eventually reaching once per month. Most allergy experts recommend that a patient remain on immunotherapy for a period of at least three years to achieve the best results. Compliance is a major issue with traditional SC immunotherapy because of the need for multiple SC injections, frequent ofÞce visits—which require that the patient remain in a medical facility for at least 20 minutes after receiving the allergy shot to be monitored for serious allergic reactions—and the extended period of time over which the patient must be treated. Although the risk of severe systemic adverse reactions is low with traditional SC immunotherapy—it is estimated at less than 1% of U.S. patients receiving such treatment (Huggins JL, 2004; Lockey RF, 2001)—the risk of death because of anaphylactic reactions is a possibility. In an effort to overcome the drawbacks of traditional SC immunotherapy, new immunotherapy techniques and formulations have been developed, including sublingual immunotherapy. Sublingual immunotherapy was Þrst introduced

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in the early 1990s by the Danish company ALD-Abelló, and this form of allergen immunotherapy involves the self-administration of allergen extract under the tongue, where it is kept for a couple of minutes before being spit out or swallowed. Like traditional SC immunotherapy, sublingual immunotherapy has been shown to provide long-lasting efÞcacy even after discontinuation, and has been shown to reduce the occurrence of asthma in AR patients (Passalacqua G, 2004). Sublingual immunotherapy is available in Europe and is gaining in popularity, but this more convenient form of allergen immunotherapy is not yet available in the United States or Japan. In November 2004, the FDA granted Greer Laboratories approval to begin Phase I safety and dosing studies with a sublingual formulation of immunotherapy for dust mites. A drawback to noninjectable routes of immunotherapy is that they are not always covered by health insurance providers because evidence to support their efÞcacy is insufÞcient. Despite the effectiveness of allergen immunotherapy, not all AR patients are appropriate candidates for this treatment, and patient selection is a key factor in the ultimate outcome and efÞcacy of such therapy. Allergen immunotherapy should only be employed in AR patients who have documented sensitivity (either with a positive skin test or radioallergosorbent [RAST] test) to speciÞc antigens, as the response to treatment is directly related to the administered allergen to which a patient is allergic. Allergens that are available for immunotherapy include a variety of pollens, pet dander, dust mites, molds, and insect venom, and typically, patients who demonstrate sensitivity to a few dominant allergens will respond more positively than patients who have nonspeciÞc hyperreactivity (DuBuske LM, 2001). For patients with sensitivities to multiple allergens, several allergens can be combined in a single vaccine; however, this combination may affect the concentration of each allergen, and certain allergens may interact with others, therefore impacting efÞcacy (Huggins JL, 2004). Optimally, allergen immunotherapy should be initiated when patients are young or have had the condition for a short period of time, as such patients may have the best response to such therapy (DuBuske LM, 2001). Additionally, allergen immunotherapy should not be administered to AR patients with impaired ability to survive a systemic allergic reaction (e.g., patients with chronic lung disease, unstable angina, myocardial infarction, uncontrolled hypertension, major organ failure), patients taking beta-blocker or angiotensinconverting enzyme (ACE) inhibitor pharmacotherapy (as these agents may mask the early signs of anaphylaxis), or young children under the ages of three or four (Huggins JL, 2004). Also, pregnant women who were tolerating and beneÞting from allergen immunotherapy prior to pregnancy can maintain treatment without dose escalation, but allergen immunotherapy should not be newly initiated during pregnancy (Huggins JL, 2004). Physicians occasionally consider surgical intervention to alleviate obstructive symptoms in very severe AR sufferers with complicating conditions, such as chronic sinusitis, severe septal deviation (causing severe obstruction), or nasal polyps that persist despite maximal pharmacotherapy. However, the need for surgical intervention is very rare in the overall treatment of AR.

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EMERGING THERAPIES Allergic rhinitis (AR) patients in the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan) and the physicians who treat them can choose from a wide selection of available antihistamine and intranasal corticosteroid products that offer good efÞcacy in controlling AR symptoms. However, novel therapies are being pursued as potential therapies for AR, including new antihistamine products, novel intranasal corticosteroids, immunoglobulin E (IgE)-mediated signaling inhibitors, and chemokine antagonists. Many of these emerging drugs—especially those with novel mechanisms of action—are in early Phase II development, and limited clinical trial information for these therapies is available in peer-reviewed journals. This chapter discusses emerging drugs in clinical development for AR and presents the latest Þndings from clinical studies for these therapies. Table 3 summarizes the drug therapies discussed in this chapter. As discussed in “Current Therapies,” immunotherapy is used to decrease a patient’s allergic sensitivity over time by exposing the patient’s immune system to increasingly larger doses of the substance to which the patient is allergic. Despite its proven effectiveness, only a small minority of the AR prevalent population actually undertakes this approach, as traditional immunotherapy requires inconvenient weekly to monthly ofÞce visits for subcutaneous injections and a considerable commitment of time is required to achieve maximal results. In recent years, advances in the Þeld of immunotherapy have notably included the advent of sublingual immunotherapy in Europe. Other novel approaches to immunotherapy include the use of synthetic CpG motifs; high-level expression systems to produce recombinant allergens in bacteria, yeast, and insect cells; and peptide-based approaches (e.g., small peptide fragments of allergens and altered peptide ligands). These novel approaches to immunotherapy may ultimately offer a simpler, more rapid way to build up immunity in AR patients compared with traditional immunotherapy approaches. However, because subcutaneous and sublingual immunotherapy preparations are not classiÞed as traditional pharmaceutical agents, these emerging immunotherapy approaches are not discussed further here. Intranasal Corticosteroids Overview. Intranasal corticosteroids are the most effective drugs available for the treatment of AR. Although they are not always as effective as oral antihistamines at alleviating ocular irritation, intranasal corticosteroids provide excellent relief from other early- and late-phase symptoms. In a meta-analysis of randomized, controlled trials published between 1966 and 1997, intranasal corticosteroids were shown to provide signiÞcantly greater relief of nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, and total nasal symptoms compared with oral antihistamines (Weiner JM, 1998). Therefore, intranasal corticosteroids are the recommended Þrst-line treatment for patients experiencing nasal congestion or if AR symptoms occur frequently or are persistent (Bousquet J, 2001).

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TABLE 3. Emerging Therapies in Development for Allergic Rhinitis Compound

Development Phase

Intranasal corticosteroids Intranasal ciclesonide United States Europe Japan 685698 United States Europe Japan NS-126 United States Europe Japan IgE-mediated signaling inhibitors Omalizumab United States Europe Japan R-112 United States Europe Japan Second-generation antihistamines Intranasal olopatadine United States Europe Japan Chemokine inhibitors Bertilimumab (CAT-213) United States Europe Japan

Marketing Company

III III I

Altana Altana Teijin

III III —

GlaxoSmithKline GlaxoSmithKline —

— — III

— — SS Pharmaceuticals/Nippon Shinyaku

—a —a III

—a —a Novartis/Sankyo

II I —

Rigel Pharmaceuticalsb Rigel Pharmaceuticalsb —

PR — —

Alcon — —

— II —

— Cambridge Antibody Technology —

a Omalizumab is currently marketed in the United States by Genentech and Novartis (Tanox also receives

royalties on sales) for use in patients 12 years or older with moderate to severe persistent asthma who have demonstrated reactivity to a perennial aeroallergen. Additionally, the drug is currently preregistered in Europe for allergic asthma. b In January 2005, Rigel Pharmaceuticals entered into a research and license agreement with Pfizer to develop spleen tyrosine kinase inhibitors for allergic asthma and other respiratory disease. The agreement between Rigel and Pfizer currently does not cover R-112, but following completion of additional Phase II studies, Pfizer will have a limited option to license R-112 under a different financial agreement. IgE = Immunoglobulin E; PR = Preregistered.

However, despite their superior efÞcacy, intranasal corticosteroids are prescribed less often than oral antihistamines, primarily because most patients prefer taking oral drugs over intranasal formulations. There are several intranasal corticosteroids currently on the market for the treatment of AR. Popular agents in this class include ßuticasone propionate (GlaxoSmithKline’s Flonase/Flixonase, generics), mometasone furoate (Schering-

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Plough’s Nasonex), beclomethasone dipropionate (GlaxoSmithKline’s Beconase/ Beconase AQ, generics), budesonide (AstraZeneca’s Rhinocort/Rhinocort AQ), and triamcinolone acetonide (Aventis Nasacort/Nasacort AQ). Available intranasal corticosteroid products offer comparable clinical efÞcacy, yet agents in this class differ from one another with regard to other product attributes (e.g., systemic bioavailability, dosing frequency, and use of preservatives). (Differences between the leading intranasal corticosteroids currently on the market are discussed in greater detail in “Current Therapies.”) Because several highly effective intranasal corticosteroids are already available for AR, limited activity—as measured in terms of clinical development of new agents—is taking place within this class. In fact, only three intranasal corticosteroids—Altana/Teijin’s intranasal ciclesonide, GlaxoSmithKline’s 685698 (Avamys/Allermist), and SS Pharmaceuticals (a subsidiary of Boehringer Ingelheim)/Nippon Shinyaku’s NS-126—are in late-stage clinical development for AR. These agents are discussed in greater detail in the following sections. Viatris (formerly ASTA Medica) is conducting Phase II studies with an intranasal formulation of loteprednol etabonate, a “soft steroid” designed to be quickly inactivated upon entering the systemic circulation. (Bausch & Lomb Pharmaceuticals currently markets a 0.5% ophthalmic suspension of loteprednol etabonate as Lotemax for inßammatory eye disorders, and a 0.2% ophthalmic suspension as Alrex for allergic conjunctivitis.) A Phase I pharmacokinetic study has been conducted in healthy male volunteers (Hermann R, 2004), but no clinical efÞcacy data in AR patients have been published to date for the intranasal formulation of the drug. Mechanism of Action. Intranasal corticosteroids ameliorate the symptoms of AR by reducing edema and local inßammation and inducing vasoconstriction. Their anti-inßammatory action stems from their ability to inhibit cytokine and chemokine production and to reduce cellular inÞltration of antigen presenting cells (APCs), T cells, and eosinophils within the nasal mucosa. These agents also inhibit mediator release from basophils and prevent accumulation of mucosal mast cells (although they have little effect on mast-cell mediator release). By reducing the inßux of inßammatory cells into the nasal mucosa, intranasal corticosteroids effectively reduce nasal hyperresponsiveness to allergic stimuli. Intranasal Ciclesonide. Altana (formerly Byk Gulden) and Teijin are developing an intranasal formulation of ciclesonide (an anti-inßammatory corticosteroid) for the potential treatment of SAR and perennial AR (PAR). Altana is conducting Phase III trials in the United States and Europe, and Phase I studies are under way in Japan with Teijin. In 1998, Byk Guilden and Teijin entered into an agreement granting the latter Japanese development and marketing rights to an inhaled formulation of ciclesonide (discussed in the following paragraph). This agreement was extended in 2000 to include the intranasal formulation of the drug. Altana, Aventis (now SanoÞ-Aventis), and Teijin have also developed an inhaled formulation of ciclesonide (Alvesco) for treatment of persistent asthma.

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In January 2005, this product was launched in the United Kingdom, which serves as the reference member state for the European Mutual Recognition Procedure. In October 2004, the FDA issued an approvable letter to Altana and SanoÞ-Aventis for the inhaled formulation of ciclesonide, and in January 2004, Teijin Þled for regulatory approval in Japan. In 2001, Byk Gulden and Aventis entered into an agreement to codevelop and copromote the inhaled formulation of ciclesonide. However, it does not appear that the agreement between Altana and SanoÞ-Aventis has been extended to include the intranasal formulation. Intranasal ciclesonide, like other intranasal corticosteroids, ameliorates the symptoms of AR by reducing edema, inducing vasoconstriction, inhibiting cytokine and chemokine production, and reducing cellular inÞltration of antigenpresenting cells, T cells, and eosinophils within the nasal mucosa. Ciclesonide is not directly active, but is cleaved intracellularly to the active drug, desisobutyrylciclesonide (des-CIC), by endogenous esterases. Des-CIC has demonstrated a 100-fold greater binding afÞnity at the rat glucocorticoid receptor compared with its pro-drug, ciclesonide (Stoeck M, 2004). Additionally, the pro-drug is poorly absorbed into the systemic circulation, thus the “on-site activation” prevents systemic side effects of corticosteroid therapies, which are a concern to physicians and patients. Results from a Phase II study were announced in a March 2004 Altana company press release and were presented at the 2004 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in San Francisco (Susman E, 2004). A total of 736 patients with SAR were randomized to receive one of four doses of intranasal ciclesonide—25 µg/day, 50 µg/day, 100 µg/day, or 200 µg/day—or placebo for two weeks. At the end of 14 days, all groups treated with intranasal ciclesonide demonstrated greater improvements over baseline total nasal symptom score (TNSS) than the group treated with placebo. The improvements were −4.81 points, −4.79 points, −5.33 points, and −5.83 points for the 25 µg/day, 50 µg/day, 100 µg/day, and 200 µg/day treatment groups, respectively; placebo recipients experienced an improvement of −4.19 points. The improvements were statistically signiÞcant for the 100 µg/day and 200 µg/day intranasal ciclesonide treatment groups, but not for the groups treated with 25 µg/day and 50 µg/day. The most commonly reported adverse events were headache and pharyngitis, but the incidence of adverse events in this study was relatively low. The efÞcacy of intranasal ciclesonide was evaluated in a randomized, placebocontrolled, double-blind crossover trial involving 24 people with a history of AR who were asymptomatic at the time of the study (Schmidt BM, 1999). Study participants were treated with either 200 µg intranasal ciclesonide per nostril per day or placebo for seven days; a washout period of at least 14 days separated the treatment periods. Study participants were subjected to intranasal allergen challenge with pollen extracts for two days prior to treatment initiation and at two hours after administration of study medication on each of the treatment days. In this study, rhinal airßow was measured by anterior rhinomanometry 5 and 30

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minutes after allergen challenge; nasal obstruction, itching, and rhinorrhea were measured on a 10 cm visual analogue scale (VAS). At the conclusion of the trial, researchers found that rhinal airßow improved signiÞcantly from day 5 and nasal obstruction improved signiÞcantly from day 2 in patients treated with intranasal ciclesonide, compared with placebo recipients. A signiÞcant improvement in itching and rhinorrhea was also noted in the intranasal ciclesonide group. Intranasal ciclesonide was shown to be well tolerated both systemically and locally in this trial, and no adverse events were considered to be related to the drug. One case of each of the following adverse events was noted in this study: lumbar pain, infectious rhinitis, biliary pain, tonsillitis, and diarrhea. Use of intranasal ciclesonide did not cause irritation of the nasal mucosa in this study. The safety and tolerability of repeated intranasal ciclesonide doses were evaluated in a placebo-controlled, double-blind, modiÞed sequential-dose study involving 40 healthy volunteers and 8 asymptomatic SAR patients (Nave R, 2004). Patients were randomized to receive either 50, 100, 200, or 400 µg intranasal ciclesonide or placebo once or twice daily for a period of 14 days. During the course of the study, 41 study participants experienced a total of 134 adverse events, 74 of which were deemed to be possibly or probably related to study medication. Of the side effects experienced in this study, 97% were considered to be mild in intensity, and the remaining 3% were considered to be moderate. The most common adverse events in this study were headache, fatigue, and rhinitis. Intranasal ciclesonide was shown to have low systemic bioavailability and no effect on adrenal function. Very few detailed data pertaining to the efÞcacy or safety of intranasal ciclesonide in AR patients have appeared in peer-reviewed journals. However, less hypothalamic-pituitary-adrenal (HPA) axis suppression was observed in asthma patients treated with high-dose inhaled ciclesonide compared with highdose ßuticasone propionate (Lee DKC, 2004). This fact suggests that intranasal ciclesonide may provide a safe corticosteroid therapy for treatment of AR. However, the drug would be entering a highly competitive intranasal corticosteroid market served by established agents that allergy experts regard as highly effective with low incidences of side effects. In particular, two newer nasal steroids, ßuticasone propionate and mometasone furoate, both possess extremely low systemic bioavailability (less than 1%) (Salib RJ, 2003[b]). 685698. GlaxoSmithKline is developing a novel intranasal corticosteroid product, 685698 (Avamys/Allermist), for the treatment of AR. (GlaxoSmithKline is also developing an inhaled combination product containing 685698 and a longacting beta-2 adrenergic agonist, 159797, as a potential treatment for asthma and chronic obstructive pulmonary disease [COPD].) The intranasal formulation of 685698 is currently in Phase III development in the United States and Europe; there does not appear to be any ongoing development for 685698 in Japan. According to the GlaxoSmithKline company Web site, the company expects to Þle a new drug application (NDA) in the United States and a marketing authorization application (MAA) in Europe in 2006.

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The only information pertaining to the clinical efÞcacy and/or safety of 685698 for AR that has been released to date is a comment in a December 2003 GlaxoSmithKline company press release regarding several of the company’s pipeline projects. According to the release, intranasal 685698 has demonstrated superior efÞcacy to intranasal ßuticasone propionate in relieving nasal symptoms after allergen exposure. However, the press release did not include detailed efÞcacy and safety information for the drug, nor have such data been published in a peer-reviewed journal. NS-126. SS Pharmaceuticals (a subsidiary of Boehringer Ingelheim) and Nippon Shinyaku are codeveloping the intranasal corticosteroid NS-126. Phase III trials are under way in Japan; there does not appear to be any ongoing development with this agent in the United States and Europe. The two companies are also developing an inhaled formulation of NS-126 as a potential treatment for asthma. IgE-Mediated Signaling Inhibitors Overview. IgE is the key antibody involved in potentiating allergic reactions. Cross-linking of IgE by antigen is a key step in the initiation of the earlyphase allergic response and the subsequent development of AR symptoms. Thus, targeting IgE and intracellular signaling mediated by IgE within effector cells (e.g., mast cells, basophils) represents a potential therapeutic approach to treating AR. Currently, one agent in this class, the anti-IgE monoclonal antibody (mAb) omalizumab (also known as rhuMAb-E25; Genentech/Novartis/Sankyo/Tanox Biosystems’ Xolair), is marketed for the treatment of allergic asthma and has shown beneÞt in treating AR in clinical studies. A second agent, Rigel Pharmaceuticals’ R-112, targets the spleen tyrosine kinase (SYK), an intracellular regulator of cell IgE-mediated signaling, and is in development for AR. Both of these agents are discussed in greater detail in the following sections. Mechanism of Action. IgE plays a major role in allergic reactions by binding cell-surface IgE receptors and thereby forming receptor-IgE complexes. Crosslinking of these complexes with neighboring complexes initiates a signal transduction pathway that ultimately results in the release of histamine and other inßammatory mediators (e.g., proteases, leukotrienes [LTs], prostaglandins, cytokines) from mast cells and basophils. Agents in this class aim to block the binding of IgE to its receptor on effector cells or to disrupt the subsequent signal transduction pathway that results in the release of inßammatory mediators from mast cells and basophils. Omalizumab. Omalizumab (Genentech/Novartis/Sankyo/Tanox’s Xolair) is a recombinant, humanized anti-IgE mAb. The drug received FDA approval in June 2003 for use in patients 12 years or older with moderate-to-severe persistent asthma who have demonstrated reactivity to a perennial aeroallergen. In July 2004, Novartis Þled omalizumab for regulatory approval in Europe for treatment of allergic asthma. The drug is currently in Phase III development in Japan for bronchial asthma and AR. A U.S. Phase III trial began in May 2004 to evaluate

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omalizumab in pediatric allergic asthma patients, and a U.S. Phase II study was initiated in July 2004 to evaluate omalizumab’s potential as a therapy for peanut allergy. Omalizumab was jointly developed by Genentech, Novartis, and Tanox. In the United States, Genentech and Novartis share marketing rights for the drug, and Novartis has marketing rights in regions outside the United States. Tanox receives royalties based on worldwide sales of the product and will also share development and marketing responsibilities with Novartis in certain Asian markets (excluding Japan). In February 2003, Sankyo signed a licensing agreement with Novartis in which both companies agreed to codevelop and comarket omalizumab in Japan. The development status of omalizumab for AR is uncertain. Genentech, Novartis, and Tanox originally Þled in June 2000 for U.S. and European regulatory approval of omalizumab for asthma and AR. However, in July 2001, the FDA issued a complete response letter requesting additional preclinical, clinical, and pharmacokinetic data for omalizumab. In a December 2002 company press release, Genentech announced that the company (with Novartis) had submitted an amendment to the original biologics licensing application (BLA) for omalizumab to the FDA, and that additional data would be submitted to the European Medical Evaluations Agency (EMEA, now European Medicines Agency) as part of a resubmitted marketing application in 2004. When the December 2002 company press release was issued, Genentech and Novartis were seeking approval for omalizumab for the allergic asthma indication, not for asthma or AR independently. In July 2003, the FDA approved omalizumab for allergic asthma, and in July 2004, Novartis Þled for European approval for omalizumab for the same indication. Currently, no mention of active development of omalizumab for AR appears on the Genentech, Novartis, or Tanox company Web sites. Additionally, at the 2004 annual meeting of the AAAAI, Novartis company representatives said there were no plans to seek formal approval for omalizumab as a treatment for AR. However, according to the Sankyo company Web site, the drug is in Phase III development in Japan for bronchial asthma and AR. Omalizumab binds free IgE at the same site as the high-afÞnity IgE receptor (FcεRI) found on effector cells such as mast cells and basophils, thereby preventing IgE binding to these cells. Importantly, omalizumab is nonanaphylactogenic (i.e., it cannot cause serious allergic reactions) because it cannot bind IgE that is already bound to mast cells or basophils. The anti-IgE antibody also binds any IgE that dissociates from FcεRI or FcεR2 receptors on effector cells, a behavior that means that it essentially “mops up” unbound IgE molecules. Omalizumab also down-regulates IgE receptor expression by reducing IgE levels (MacGlashan DW, 1997). The dual action of omalizumab on IgE and its receptor contributes to the symptom improvement observed in the clinical trials. Researchers have shown that FcεRI densities on basophils from both allergic and nonallergic subjects range from 104 to 106 per cell, and hundreds of thousands of IgE receptors are usually occupied with IgE (MacGlashan DW, 1997). Additionally, only a few thousand IgE molecules are required to produce a half maximal release of histamine from basophils exposed to speciÞc allergens. IgE

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levels must therefore be nearly undetectable before anti-IgE mAb therapy will produce therapeutic effects. To achieve optimal response, dosing of the agent has to be individualized to match an AR patient’s total IgE level. Additionally, according to omalizumab’s product label, its mean serum elimination half-life in asthma patients is 26 days; IgE’s half-life is one to two days. This extended half-life allows omalizumab to be dosed once every two to four weeks, a fairly convenient dosing schedule over a six- to eight-week pollen season. A Phase II clinical trial showed that omalizumab signiÞcantly reduced serum levels of free IgE in a dose-dependent manner in AR patients (Casale TB, 1997). However, the authors were unable to demonstrate statistically signiÞcant improvement in symptoms within the dose range tested (0.15–0.50 mg/kg). A subsequent 12-week, double-blind, dose-ranging (50–300 mg), placebo-controlled trial in patients with moderate-to-severe ragweed-induced SAR provided evidence that lowering systemic free IgE levels with omalizumab provides clinical beneÞt in patients (Casale TB, 2001). A total of 536 patients were randomized to receive either 50 mg, 150 mg, or 300 mg omalizumab or placebo via subcutaneous injection. Patients with baseline IgE levels of 150–700 IU/mL were treated every three weeks; patients with baseline levels of 30–150 IU/mL were treated every four weeks. Treatment was initiated approximately two weeks prior to onset of the ragweed pollen season to assess whether blocking IgE binding before and during the pollen season could reduce SAR symptoms. During the course of the pollen season, the average daily nasal symptom severity score (DNSSS)—the primary efÞcacy end point—was 23% lower in the 300 mg omalizumab group than in the placebo group. (DNSSS was the average of patient scores for self-assessed severity and duration of nasal symptoms [sneezing, rhinorrhea, itchy nose, and stuffy nose].) This difference was statistically signiÞcant. Patients receiving 300 mg of omalizumab also experienced almost no difference in nasal symptom severity score between the Þrst treatment day and peak season. There was a signiÞcant association between the severity of nasal symptoms and free IgE levels in this study: lower free IgE levels were associated with the lowest symptom severity scores. In addition, the 300 mg omalizumab group experienced lower scores (indicating improved quality of life) on the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) than placebo recipients throughout the 12-week treatment period. (The RQLQ measures overall well-being of rhinoconjunctivitis patients on seven domains [activity limitations, sleep disturbances, non-hay fever symptoms, practical problems, nose symptoms, and emotional function] and is based on a 0 to 6 unit scale; lower scores indicate better AR-related quality of life.) The most commonly reported adverse events in this study were headache (11.6% of the 300 mg omalizumab group, 15.7% of the 150 mg omalizumab group, 15.3% of the 50 mg omalizumab group, and 16.2% of the placebo group); upper respiratory tract infection (6.2%, 8.2%, 9.5%, and 8.1%, respectively); and viral infection (5.4%, 8.2%, 6.6%, and 6.6%, respectively). A follow-up to this 12-week study in ragweed-induced SAR patients demonstrated that readministration of omalizumab is safe during a second ragweed

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pollen season (Casale TB, 2000). The rate and pattern of adverse events observed in the follow-up study were similar to those observed in the primary study. There were no serious adverse events related to omalizumab retreatment, and no patients developed anti-omalizumab antibodies. Omalizumab was shown to provide effective symptom control and to be a safe and well-tolerated therapy for patients with moderate-to-severe symptomatic PAR (Chervinsky P, 2003). In a randomized, double-blind Phase III study involving 289 patients, study participants (ages 12–70 years) were randomized to receive subcutaneous injections of either placebo or omalizumab (at least 0.016 mg/kg/IgE [IU/mL] either once or twice monthly) throughout the 16-week trial. Omalizumab doses were tailored to each patient’s baseline body weight and serum free IgE levels. Throughout the entire 16-week study period, omalizumabtreated patients demonstrated a lower average DNSSS—the primary efÞcacy end point—compared with placebo recipients. A decrease in symptom severity category (i.e., controlled, mild, moderate, and severe, depending on DNSSS) was noted in 69% of omalizumab-treated patients compared with 49% of placebo recipients. Additionally, 28% of patients in the omalizumab group and 10% of placebo-treated patients achieved a DNSSS of less than 0.75, corresponding to a severity category of “controlled.” Omalizumab was also shown to be superior to placebo on improvements in RQLQ scores and nasal congestion (stuffy nose), two of the secondary efÞcacy measures evaluated in this study. Mean RQLQ scores improved 51% and 38% for omalizumab- and placebo-treated patients, respectively, during the course of the 16-week study. Additionally, omalizumabtreated patients demonstrated a mean 31% improvement over baseline score on the measure of daily stuffy nose severity during the previous 24 hours, and a 30% improvement over baseline score on the measure of daily stuffy nose severity upon waking. Corresponding improvements for placebo-treated patients on these two measures were 14% and 11%, respectively. Omalizumab was well tolerated by PAR patients (Chervinsky P, 2003). At least one adverse event was reported by 77% of omalizumab-treated patients and 85% of placebo recipients; most adverse events were of mild to moderate intensity. The most commonly reported adverse events in this study were upper respiratory tract infections (16.7% of omalizumab recipients and 13.1% of placebo recipients); headache (15.3% and 23.4%, respectively); and nasopharyngitis (12.5% and 13.8%, respectively). Three cases of serious adverse events occurred during this trial—one in the omalizumab groups (infectious mononucleosis) and two in the placebo group (appendicitis and recurrent disk herniation)—but none of the three cases was deemed treatment-related. R-112. Rigel Pharmaceuticals is developing R-112, an intranasal SYK inhibitor, as a potential treatment for AR. Phase II studies are currently underway in the United States. According to an October 2002 company press release, an initial Phase I safety study was conducted in the United Kingdom, but no further European development has been reported. Additionally, no development has been reported in Japan.

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In 2004, Rigel Pharmaceuticals stated that it was seeking a development partner for R-112. In January 2005, Rigel entered into a research and license agreement with PÞzer; the focus of the agreement is to develop SYK inhibitors for allergic asthma and other respiratory disease. The agreement between Rigel and PÞzer currently does not cover R-112, but, following Rigel’s completion of additional Phase II studies, PÞzer will have a limited option to license R-112 under a different Þnancial agreement. SYK is an intracellular protein that is expressed in a number of leukocytes, including mast cells, macrophages, eosinophils, neutrophils, T cells, and B cells (Stenton GR, 2002). The protein induces tyrosine phosphorylation of numerous other proteins involved in the allergic inßammation signaling cascade. Studies have demonstrated that SYK-deÞcient mast cells neither degranulate nor synthesize leukotrienes and secrete cytokines following stimulation via the FcεRI receptor (Costello PS, 1996). Additionally, SYK-deÞcient variant cell lines from rat basophilic leukemia RBL-2H3 cells fail to release histamine following FcεRI receptor aggregation (Zhang J, 1996). In addition, transfection of wild-type rat SYK into these variant cells resulted in reconstitution of FcεRI receptor-mediated histamine release. These studies demonstrate the essential role that SYK plays in allergic reactions and how inhibition of SYK can preclude the synthesis and release of mediators involved in the allergic response. A Phase II, randomized, placebo-controlled, two-day study was conducted to evaluate the efÞcacy, safety, and onset of action of R-112 in 319 SAR patients (Meltzer EO, 2005). The study was conducted at two outdoor locations (one in Atlanta and one in San Diego), and patients were treated with either two sprays R-112 per nostril (for a total dose of 3 mg per nostril) or placebo twice daily at intervals four hours apart. The primary efÞcacy end point in this study was the effect of treatment on the combined Global Symptom Complex (GSC) score, which was the sum of scores for sneezing, nasal congestion, rhinorrhea, and nasal itch at three separate time points. Treatment with R-112 was associated with a mean 7.0-point reduction (38% improvement) in GSC score on day 1, compared with a mean 5.4-point reduction (29% improvement) for patients treated with placebo. The difference between the two groups was statistically signiÞcant. Similar signiÞcant results were observed on day 2; the group treated with R-112 demonstrated a mean 5.6-point reduction (35% improvement) in GSC score compared with a mean 4.3-point reduction (27% reduction) for placebo-treated patients. Additionally, treatment with R-112 was associated with signiÞcant improvements compared with placebo recipients in individual symptom scores for nasal congestion, itchy nose, sneezing, rhinorrhea, nose blows, postnasal drip/throat clearing, and cough on both days of the study. Notably, patients treated with R-112 began to demonstrate a signiÞcant improvement over placebo recipients as early as 30 minutes after dosing, and the reduction in symptoms persisted for the entire duration of the day in the outdoor park setting. The incidence of adverse events was similar for both treatment groups (21.3% of patients treated with R-112 and 20.6% of patients treated with placebo), and no serious drug-related adverse events were noted during the

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trial. The most commonly reported adverse events were somnolence (1.3% of R-112 recipients versus 0% of placebo recipients), epistaxis (bloody nose; 0.6% versus. 1.3%, respectively), and burning at the site of application (1.3% versus 0.6%, respectively). In a December 2003 company press release, Rigel announced the results from a ten-day study that evaluated the safety of three doses of R-112 compared with placebo. Each of the three R-112 dosing groups included six study participants. Although no speciÞc safety data were included in the company press release, Rigel reported that participants treated with R-112 and placebo demonstrated comparable results on a number of safety parameters. No abnormalities in blood counts, blood chemistry, electrocardiography, or spirometry (airway function tests) were noted, and patients treated with R-112 did not demonstrate local nasal irritation. Rigel announced the results of a Phase I/II study in a July 2003 company press release. This study evaluated the efÞcacy and safety of a single intranasal dose of R-112 in 20 patients with asymptomatic AR. Although the company press release did not include speciÞc efÞcacy or safety results, Rigel reported that treatment with R-112 was associated with a signiÞcant or consistently positive trend in reducing inßammatory mediator release. No signiÞcant adverse events were noted in this study. R-112 may have a signiÞcant advantage over other AR pharmacotherapies due to its novel mechanism of action and its rapid onset of action. R-112 blocks mast cell activation and subsequent release of multiple inßammatory mediators by disrupting the signal transduction pathway following binding of IgE to the FcεRI receptor. Blocking the release of multiple inßammatory mediators represents a signiÞcant improvement on the action of many other allergy medications (e.g., antihistamines, leukotriene antagonists), which target a single inßammatory mediator after it has already been released from cells. In an August 2004 company press release, Rigel acknowledged that intranasal corticosteroids—a mainstay of AR therapies—can inhibit multiple inßammatory mediators, but the company points out that intranasal corticosteroids may require multiple days of administration before a positive effect on symptoms is noted. In the Phase II study conducted at two outdoor locations, R-112’s beneÞcial effect on AR symptoms was noted as early as 30 minutes after dosing. Therefore, the company claims that R-112’s rapid onset of action may offer a signiÞcant advantage over intranasal corticosteroids for patients who want rapid relief of their AR symptoms. However, the price of R-112 may prevent the product from achieving widespread use among AR sufferers. It has been estimated that the annual cost of R-112 therapy may reach $1,800 per year, a Þgure that is much higher than the annual cost of antihistamines and intranasal corticosteroids (Carrel L, 2004). Therefore, R-112 may be relegated to third-line use behind antihistamines and intranasal corticosteroids, especially if cost-conscious third-party payers in the United States continue to remove more expensive AR therapies from their formularies as additional agents are switched to OTC status.

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Second-Generation Antihistamines Overview. Second-generation antihistamines are the most commonly prescribed class of drugs for AR because these agents are very effective at ameliorating many of the symptoms associated with AR (e.g., sneezing, nasal itching, rhinorrhea, ocular irritation). Numerous second-generation antihistamines are currently on the market. As discussed in “Current Therapies,” Þrst-generation antihistamines, which are readily available as OTC products, are associated with a number of side effects—most notably fatigue, drowsiness, and performance impairment—that ultimately make them less attractive than second-generation agents. Second-generation antihistamines, by comparison, are equally as effective as Þrst-generation agents in controlling AR symptoms, yet offer many advantages over their predecessors (i.e., they are associated with mild or no sedation, do not affect performance, have no anticholinergic effects, and have longer durations of action for reduced dosing frequency). The antihistamine market is saturated with numerous product offerings and there is very little ongoing clinical development in this class. Currently, only one second-generation antihistamine product is in late-stage clinical development: Alcon is developing an intranasal formulation of olopatadine, which is currently on the market as an ophthalmic formulation (Patanol) and as an oral formulation in Japan (Kyowa’s Allelock). The intranasal formulation of olopatadine is discussed in greater detail in the following section. Mechanism of Action. Subsequent allergen (antigen) challenge in the nasal mucosa of a sensitized AR patient results in cross-linking of IgE by antigen, which in turn causes degranulation of high-afÞnity IgE receptor (FcεRI)+ cells (e.g., mast cells, basophils). Degranulation of these cells releases a variety of inßammatory mediators involved in the acute-phase allergic response. One of the key inßammatory mediators released is histamine, the primary mediator of early AR symptoms. There are four types of histamine receptors in the human body—H1 , H2 , H3 , and H4 —and H1 is the receptor through which histamine exerts most of its effects in allergic disease. The H1 receptor demonstrates constitutive activity in the human body, even in the absence of ligand binding, as two states of the H1 receptor—the active states and the inactive state—exist in equilibrium (Simons FER, 2004). Histamine preferentially binds to the active form of the receptor, shifting the balance between the two receptor states toward the active form. The active form of the receptor then initiates a G protein-mediated signal transduction cascade that results in the degranulation of FcεRI+ cells. Antihistamines used to treat AR bind to the inactive form of the H1 receptor and stabilize this conformation, therefore shifting the equilibrium toward the inactive state. The inactive state of the receptor is unable to initiate the signal transduction cascade that ultimately results in degranulation of mast cells and basophils. Thus, the resultant effect of antihistamines is to block the release of inßammatory mediators which initiate a host of physiological changes that lead to AR’s early-phase symptoms (e.g., sneezing, itching, rhinorrhea, ocular irritation). Antihistamines

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are less effective, however, at controlling nasal congestion, because histamine is not the primary mediator of this symptom. An enhanced understanding of the molecular pharmacology of H1 antihistamines has led to their reclassiÞcation as inverse agonists; they were previously viewed as H1 receptor antagonists (Simons, FER, 2004). However, for the purpose of this section, this discussion will refer to H1 antihistamines as antihistamines. Intranasal Olopatadine. Alcon is developing Patanase, an intranasal formulation of the second-generation antihistamine olopatadine, as a potential treatment for SAR in the United States. No ongoing development has been reported in Europe and Japan. In an April 2005 company press release, Alcon announced that the FDA has accepted its new drug application for the intranasal formulation of olopatadine. Kyowa currently markets an oral formulation of olopatadine (Allelock) in Japan, and the company has licensed U.S. rights for ophthalmic and nasal formulations of the drug to Alcon. Alcon currently markets an ophthalmic formulation of olopatadine (Patanol). Olopatadine exerts its therapeutic beneÞt by blocking the effects of histamine released from mast cells during an allergic reaction. Topical administration through a nasal formulation aims to diminish the nasal symptoms characteristic of AR: rhinorrhea, sneezing, and itchy and stuffy nose. In a March 2004 company press release, Alcon announced the results of a large-scale Phase III study evaluating the efÞcacy of the nasal formulation of olopatadine. These results were also presented at the 2004 Annual Meeting of the AAAAI in San Francisco. In this randomized, double-blind, placebo-controlled study, 677 patients with SAR were randomized to receive twice-daily administrations of either 0.6% or 0.4% olopatadine nasal spray, or placebo. Patients were asked to record both an instantaneous and reßective assessment of nasal symptom severity in the morning and the evening for two weeks. At the end of the study, patients treated with 0.6% olopatadine and 0.4% olopatadine demonstrated a 30.1% and 27.6% improvement, respectively, on the primary efÞcacy end point—the change from baseline in the total nasal symptom score (TNSS), deÞned as an average of morning and evening reßective severity scores for stuffy nose, runny nose, itchy nose, and sneezing. The corresponding improvement for the placebo group was 18.7%. These differences were statistically signiÞcant for both olopatadine treatment groups. A signiÞcant difference over placebo was also noted for both olopatadine groups on the measure of TNSS for instantaneous assessments of nasal symptoms. On this secondary measure, treatment with 0.6% olopatadine and 0.4% olopatadine were associated with 26.2% and 24.3% improvements over baseline, respectively, compared with a 15.8% improvement for placebo-treated patients. Olopatadine nasal spray was shown to be safe and well tolerated in this study. Patients who participated in this Phase III study were also asked to Þll out the RQLQ. At the end of the two-week study period, the groups treated with 0.6% and 0.4% olopatadine nasal sprays both demonstrated a signiÞcant 1.1

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unit improvement on the RQLQ compared with a 0.8 unit improvement for the placebo group. Olopatadine nasal spray was shown to have a rapid onset of action in a doseranging study involving 320 SAR patients (Patel P, 2004). Three different dose concentrations of olopatadine nasal spray—0.6%, 0.4%, and 0.2%—were shown to improve nasal symptoms within 30 minutes following drug administration. Additionally, a dose response was noted in this trial, with the most pronounced improvement in nasal symptoms occurring with 0.6% olopatadine nasal spray treatment. Other intranasal antihistamine formulations are currently on the market, however. According to the available information for intranasal olopatadine, this drug does not appear to offer any clear advantages over such competing products. Chemokine Inhibitors Overview. The late-phase allergic response is characterized by recruitment of leukocytes (e.g., eosinophils, basophils, neutrophils, T cells) to the airway tissue (submucosa, epithelium, airway lumen). The accumulation of leukocytes—especially eosinophils—and their products in the airway tissues in the hours following allergen exposure is primarily responsible for the congestion and increased mucus production characteristic of the late-phase allergic response. A number of cytokines have been implicated in leukocyte recruitment activity in AR, including the chemokine family of proteins. These agents, along with their respective receptors (members of the G protein-coupled receptor (GPCR) superfamily), play a critical role in mediating chemotaxis (directional movement) of leukocytes to sites of inßammation and infection in the body. T-helper 2 (TH 2) cells, mast cells, and eosinophils—three leukocytes that play prominent roles in allergic responses—preferentially express three cysteine-cysteine chemokine receptors (CCRs): CCR3, CCR4, and CCR8 (Chantry D, 2002). Therefore, blocking these three receptors, or inhibiting the chemokines that bind to these receptors, represents potential therapeutic targets in the treatment of AR. Two chemokine inhibitors—Cambridge Antibody Technology’s bertilimumab (CAT-213) and GlaxoSmithKline’s 766994—have reached Phase II development for AR. Bertilimumab is an mAb that neutralizes eotaxin1 , a potent, highly speciÞc chemokine that attracts eosinophils from the bloodstream into the airway tissue, and is discussed in greater detail in a following section. 766994 is an oral antagonist of CCR3, a chemokine receptor found on the surface of numerous cell types, including eosinophils, TH 2 cells, mast cells, basophils, macrophages, and airway epithelial cells (Erin EM, 2002). Eotaxin1 binds to CCR3, thus, 766994 acts to prevent the interaction between CCR3 and its ligand, eotaxin1 . Inhibiting this receptor-ligand interaction is a novel approach to preventing chemotaxis of leukocytes into nasal tissue and the subsequent AR symptoms that develop during the late-phase allergic reaction. 766994 is in early Phase II development, and no data have been published to date in peer-reviewed journals demonstrating 766994’s effect on AR symptoms in human subjects.

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Mechanism of Action. Two general approaches can be employed to inhibit the effects of chemokines: neutralize the chemokine through antibody inhibition, or block the chemokine receptor. Binding of a chemokine-speciÞc antibody to a given chemokine can inhibit the latter’s ability to bind with its receptor, thus precluding subsequent physiologic effects. Alternatively, chemokine receptor inhibitors act by binding the receptor and disrupting the conformation of its extracellular domain, thereby inhibiting ligand binding to the receptor. Bertilimumab (CAT-213). Cambridge Antibody Technology (CAT) is developing bertilimumab (CAT-213), a human IgG4 mAb that targets the chemokine eotaxin1 (also known as CCL11), as a potential treatment for AR. Phase II studies are underway in the United Kingdom. CAT is also conducting trials to evaluate bertilimumab’s potential in other allergic conditions: the drug is in Phase II for allergic conjunctivitis and in preclinical development for asthma. In its 2003 annual report, CAT announced plans to seek a development partner for bertilimumab. CAT further reported in a September 2004 earnings conference call that the company is still seeking a licensing partner for the drug. Eosinophils are a type of leukocyte that plays a key role in the late-phase allergic reaction, and eotaxin1 is a potent, highly speciÞc chemokine that attracts eosinophils from the bloodstream into the airway tissue. (Eotaxin1 also plays a role in the chemotaxis and activation of other leukocytes, including basophils, mast cells, and T cells [Amerio P, 2003].) Once eosinophils (along with other leukocytes) accumulate in airway tissues, these cells release numerous inßammatory mediators—including cytokines, basic polypeptides, and leukotrienes—that can damage airway endothelial cells and the extracellular matrix. The accumulation of eosinophils (eosinophilia) in the nasal tissue is a hallmark of AR, and the accumulation of these cells and their inßammatory products is primarily responsible for the congestion and increased mucus production characteristic of the late-phase allergic response. Bertilimumab binds to and neutralizes eotaxin1 , thereby preventing this chemokine from recruiting eosinophils and other leukocytes into airway tissues. Inhibiting eosinophilia in turn leads to a reduction in AR symptoms. In a double-blind Phase II study, treatment with bertilimumab prior to allergen challenge was shown to reduce the number of inÞltrating eosinophils and mast cells in the nasal submucosa of patients with SAR (Salib R, 2003[a]). A total of 48 patients were treated with single intranasal doses of 10 mg bertilimumab or placebo, or single intravenous (IV) doses of 50 mg, 200 mg, or 500 mg bertilimumab or placebo, 30 minutes prior to being subjected to grass pollen allergen challenge. Nasal lavage (irrigation of the nasal cavity and nasal mucosa) was performed at Þve time points following allergen challenge (at 30 minutes, one hour, two hours, six hours, and eight hours); a nasal tissue sample was also obtained through biopsy six hours following allergen challenge. Compared with placebo, patients treated with 10 mg intranasal, 50 mg IV, or 500 mg IV bertilimumab demonstrated signiÞcant reductions of 42%, 40%, and 46%, respectively,

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in the number of submucosal mast cells. Patients treated with 200 mg IV bertilimumab demonstrated a 24% decrease in the number of submucosal mast cells compared with placebo, but this difference was not statistically signiÞcant. The group treated with 10 mg intranasal bertilimumab also demonstrated a signiÞcant reduction in submucosal eosinophil inÞltrate, but the corresponding reduction was not signiÞcant for any of the IV bertilimumab groups. In a second similarly designed double-blind Phase II study, pretreatment with bertilimumab was shown to attenuate nasal obstruction in patients with SAR (Pereira S, 2003). A total of 52 patients were treated with single doses of either intranasal bertilimumab or placebo, or IV bertilimumab or placebo, 30 minutes prior to grass pollen allergen challenge; doses used in this study were the same as those used in the aforementioned study conducted by R. Salib and colleagues. Treatment with 10 mg intranasal bertilimumab was associated with the greatest attenuation of nasal obstruction compared with placebo, as assessed by acoustic rhinometry measurements taken prior to allergen challenge and six hours thereafter. However, neither intranasal or IV bertilimumab was shown to signiÞcantly alter nasal symptoms or peak inspiratory ßow in this study. Three cases of adverse events were deemed to be possibly related to bertilimumab treatment in this study: one case of ßulike symptoms and fever, one case of vasovagal attack and wheezing, and one case of nosebleed. While the mechanism of action for this agent seems promising—targeting a key chemokine involved in the chemotaxis of eosinophils—it is important to note that other substances have been implicated in leukocyte recruitment activity characteristic of AR. For example, investigators have found that interleukin (IL)-5, IL-16, and leukotriene B4 have chemoattractant activity for eosinophils, and IL-4, IL-13, and tumor necrosis factor-alpha (TNF-α) increase the expression of cellular adhesion molecules (CAMs) on endothelial cells, thereby facilitating the attachment and inÞltration of leukocytes into airway tissues. Therefore, although eotaxin1 is a potent eosinophilic chemokine, numerous other cytokines and inßammatory mediators need to be targeted to completely inhibit eosinophilia that occurs in AR. Very little information is available on bertilimumab. The only clinical efÞcacy data in AR patients come from a small, early-phase, single-dose studies involving approximately 50 patients.

REFERENCES Adams JE, et al. Pharmacoeconomic beneÞts of ßuticasone propionate aqueous nasal spray 200 µg once daily in perennial allergic rhinitis. Journal of Allergy and Clinical Immunology. 1996;97:197. Adams PF, et al. Current estimates from the National Health Interview Survey, 1996. National Center for Health Statistics Vital Health Statistics. 1999;10:83–84. Allen DB. Systemic effects of intranasal steroids: an endocrinologist’s perspective. Journal of Allergy and Clinical Immunology. 2000;106:S179–S190.

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Stoeck M, et al. In vivtro and in vivo anti-inßammatory activity of the new glucocorticoid ciclesonide. Journal of Pharmacology and Experimental Therapeutics. 2004;309(1): 249–258. Strachan D. Epidemiology of hay fever: towards a community diagnosis. Clinical and Experimental Allergy. 1995;25:296–303. [a] Strachan D. Time trends in asthma and allergy: ten questions, fewer answers. Clinical and Experimental Allergy. 1995;25:791–794. [b] Strachan D, et al. Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatric Allergy and Immunology. 1997;8:161–176. Stübner P, et al. A direct comparison of the efÞcacy of antihistamines in SAR and PAR: randomized, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit-the Vienna Challenge Chamber (VCC). Current Medical Research and Opinion. 2004;20(6):891–902. Sullivan PW, et al. Transitioning the second-generation antihistamines to over-the-counter status: a cost-effectiveness analysis. Medical Care. 2003;41(12):1382–1395. Susman E, Phend C. American Academy of Allergy, Asthma, and Immunology 60th annual meeting; March 19–23, 2004; San Francisco, CA. IDDB Meeting Report. Available at www.iddb3.com. Accessed on October 19, 2004. [electronic] Togias A. Unique mechanistic features of allergic rhinitis. Journal of Allergy and Clinical Immunology. 2000;105:S599–S604. Trepka MJ, et al. The epidemiology of atopic diseases in Germany: an east-west comparison. Reviews on Environmental Health. 1996;11:119–131. van Adelsberg J, et al. Randomized controlled trial evaluating the clinical beneÞt of montelukast for treating spring seasonal allergic rhinitis. Annals of Allergy, Asthma, and Immunology. 2003;90(2):214–222. van Cauwenberge, et al. Comparison of the efÞcacy, safety, and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg, and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clinical and Experimental Allergy. 2000;30:891–899. [a] van Cauwenberge P, et al. Consensus statement on the treatment of allergic rhinitis. Allergy. 2000;55:116–134. [b] Verispan, Scott-Levin. Physician Drug & Diagnosis Audit, January 2004-December 2004. Verlato G, et al. Is the prevalence of adult asthma and allergic rhinitis still increasing? Results of an Italian study. Journal of Allergy and Clinical Immunology. 2003;111(6): 1232–1238. Viegi G, et al. Prevalence of respiratory symptoms in an unpolluted area of Northern Italy. European Respiratory Journal. 1988;1:311–318. von Mutius E, et al. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet. 1998;351:862–865. Waddell AN, et al. Intranasal steroid sprays int eh treatment of rhinitis: is one better than the other? Journal of Laryngology & Otology. 2003;117:843–845. Wang DY, et al. Effect of cetirizine, levocetirizine, and dextrocetirizine on histamineinduced nasal response in healthy adult volunteers. Allergy. 2001;56:339–343. Wiseman LR, BenÞeld P. Intranasal ßuticasone propionate: a reappraisal of its pharmacology and clinical efÞcacy in the treatment of rhinitis. Drugs. 1997;53(5):885–907.

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Asthma

ETIOLOGY AND PATHOPHYSIOLOGY Disease Definition In 1995, the Global Initiative for Asthma (GINA)—a collaborative effort by the World Health Organization (WHO), the U.S. National Institutes of Health (NIH), and the National Heart, Lung and Blood Institute (NHLBI)—published the following comprehensive deÞnition of asthma: Asthma is a chronic inßammatory disorder of the airways in which many cells and cellular elements play a role—in particular, mast cells, eosinophils, and T lymphocytes. In susceptible individuals, this inßammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or in the early morning. These symptoms are usually associated with widespread but variable airßow obstruction that is at least partly reversible either spontaneously or with treatment. The inßammation also causes an associated increase in the airway hyperresponsiveness to a variety of stimuli (Pearce N, 1998). Currently, asthma is understood to be a disease that can occur, regress, and recur at any age. Because knowledge of asthma pathophysiology and treatment approaches changes frequently (Bousquet J, 2000), diagnosis and classiÞcation practices vary (Pearce N, 1998). Etiology The etiology of asthma is widely thought to be multifactorial, being inßuenced by both environmental and genetic mechanisms. The majority of asthma cases Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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arise when a person becomes hypersensitive to allergens in the general environment, the home, or the workplace. Moreover, 66–75% of asthma patients are believed to be atopic—that is, they have a genetically predetermined sensitivity to such environmental antigens (McFadden ER, 1992). Other asthma attack triggers include exercise, drug exposure, and even lying down (in the case of nocturnal asthma). Table 1 summarizes the various types of asthma. From the 1950s through the 1990s, asthma prevalence increased throughout the world, most notably in industrialized countries. The origins of this trend remain controversial, but considerable attention has been directed toward understanding the environmental and genetic factors that contribute to the development of asthma. Environmental Risk Factors. Asthma is often classiÞed as either extrinsic or intrinsic. Extrinsic asthma—considered to be synonymous with allergic asthma—may be caused by stimuli such as airborne allergens, animal dander, speciÞc food products, and perhaps most commonly, house dust or mites. This form of asthma is much more common in children than in adults, and disease onset typically occurs before 40 years of age. Intrinsic asthma has long been thought to arise from exposure to nonspeciÞc irritants such as tobacco smoke, chemical fumes, and pollution or from other pathological conditions, such as viral infection or gastroesophageal reßux, that damage the airways. However, the possibility that intrinsic asthma is a response to undetected allergens, either environmental or autoimmune, has not been ruled out. Stimuli known to trigger asthma—whether the extrinsic or intrinsic form—can be categorized as speciÞc antigen factors, which cause inßammation, or as nonspeciÞc antigen factors, which exacerbate bronchial hyperresponsiveness (BHR). Examples of speciÞc antigens are pollen, dust mites, animal dander, fungal spores, feathers, detergents, and metals. NonspeciÞc antigens include infections, smoking, sulfur dioxide, airborne particulates, reduced ventilation, and select foods or preservatives. Two major theories have been proposed to explain the roles played by environmental factors in the development of asthma: the urbanization model and the allergic sensitization model. Urbanization Model. Some researchers have suggested that the increase in asthma prevalence, morbidity, and mortality is the result of increased exposure to allergens in the modern indoor environment. In fact, indoor allergen exposure is recognized as the most important risk factor for asthma in children. The severity of a particular asthma case is also known to reßect the degree of allergen exposure. During the past 70–80 years, the concentration of allergens found in the home has increased because the average rate of air exchange has fallen by one-third. Factors contributing to reduced air exchange include the installation of double-glazed windows, the switch from open Þres to central heating, and the blocking of chimneys.

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ASTHMA

TABLE 1. Types of Asthma Asthma Type Allergic asthma

Drug-induced asthma

Exercise-induced asthma

Near-fatal and hyperacute asthma

Nocturnal asthma

Occupational asthma

Comments Also known as extrinsic asthma, this form of the disease is thought to afflict people who are genetically predisposed to developing hypersensitivity to environmental allergens. It accounts for most childhood asthma cases and a growing proportion of adult cases. It is theorized that sensitization to specific allergens in childhood may lead to a chronic form of the disease. An estimated one in ten cases of adult-onset asthma is caused by sensitivity to aspirin or other cyclooxygenase inhibitors. No clear link between this phenomenon and immune system processes or other biochemical pathways has been established. Classic symptoms of aspirin-induced asthma are rhinitis and flushing, followed by exacerbation manifested by severe bronchoconstriction. This form of asthma occurs with exercise in asthmatics whose disease is poorly controlled. In a subset of asthmatics (particularly children), exercise is the sole cause of asthma attacks. When exercise is the initiating factor, symptoms usually become apparent after termination of the physical activity. Exacerbations brought on by exercise are similar to those of regular asthma attacks, and spontaneous recovery occurs, usually within an hour. The etiology of exercise-induced asthma is not fully understood. It appears that the principal factors behind such attacks are a greater volume of air passing through the bronchioles and the cooler temperature of this air. The effect of increased venous congestion on the airways may also contribute to this type of asthma. Some data suggest that patients with near-fatal and hyperacute asthma exhibit different histology and pathophysiology from other asthmatic patients. Near-fatal cases have a large proportion of neutrophils and few eosinophils, suggesting a different pathogenesis from other asthmatics. Furthermore, the central airways of fatal cases exhibit greater amounts of smooth muscle and submucosal glands and may be more reactive to bronchoconstrictive stimuli. Nocturnal asthma involves increased frequency of asthma symptoms at night, caused by greater bronchial hyperresponsiveness and inflammation. The heightened asthma symptoms may be partly attributable to passive venous congestion associated with lying down. Nocturnal asthma may be a continuation of daytime symptoms and an indication that daytime asthma control is inadequate. This type is caused by prolonged exposure and sensitization to chemicals used in the workplace. Symptoms typically disappear if the chemical stimulant is removed within six months of initial exposure; longer-term exposure often causes the development of persistent asthma.

Source: Based on MacKay IR, 2001; Staton GW, 2002.


439

Allergic Sensitization Model. A second theory suggests that a person’s propensity to develop asthma may be increased by exposure to speciÞc allergens at some time between birth and the Þrst two to three years of life. As a result, people develop sensitivities to the allergens typically found in the region where they lived early in life. For example, a person born in a mountainous area would more likely become sensitized to grass pollen, whereas someone living in a densely populated area would have a greater chance of developing sensitivity to dust mites and pets. On the other hand, some researchers believe that more frequent exposure to childhood infections (e.g., viruses) reduces the likelihood of developing asthma. Early exposure to a wide variety of infectious agents is thought to reduce the odds that the immune system will become sensitized to a particular allergen (Holt PG, 1999). For example, the practice of childhood immunizations reduces the exposure to infections and thus increases the likelihood of developing asthma. Conversely, the more siblings a child has, the greater the child’s exposure to viruses and the less likely that he or she will develop asthma. Moreover, a younger sibling is less likely than a Þrst-born child to develop asthma because the younger sibling has greater exposure to viruses earlier in life. Scientists hypothesize that the immune system of a newborn is skewed toward the TH2 immune response (i.e., antibody response) and therefore needs environmental stimuli (such as those just described) that enhance the TH1-cell-mediated immune response to achieve balance between TH1- and TH2-mediated immune responses (Busse WW, 2001). Therefore, practices that reduce exposure to childhood infections also reduce the TH1 immune response and create an immune system imbalance that researchers believe may promote asthma in children. The immune response is discussed further in the “Pathophysiology” section. Genetic Risk Factors. People with a family history of asthma have a slightly increased relative risk of developing the disease, and a greater concordance of asthma exists in monozygotic twins than in dizygotic twins (Clarke JR, 2000). The genetics of asthma are complex, involving different subsets of genes in different patients. Pointing to the complex pathways involved in asthma, researchers emphasize that all the genes involved in the etiology of this disease have not yet been identiÞed. Pathophysiology. Multiple pathological events occurring in the lungs produce the clinical manifestations of asthma. Whatever the type of asthma, however, the disease is always characterized by pulmonary inßammation leading to bronchial hyperreactivity (i.e., increased bronchial smooth-muscle contraction and bronchospasm) and reduced lung function. This section reviews the basic pathological mechanisms of asthma, with particular emphasis on allergic asthma, which has been the subject of most research in this Þeld. Inflammation Allergen-Induced Inflammation. The immune response begins when dendritic cells in the lungs bind, process, and present allergen, as illustrated in Figure 1.

440

ASTHMA

FIGURE 1. The allergic cascade.


441

Although the bronchial epithelium normally serves as a protective barrier against inhaled allergens, chronic inßammation renders the bronchial epithelium of asthmatics unusually permeable to certain allergens, allowing them access to the subepithelial dendritic cells. Bronchial epithelial cells in asthmatics have been shown to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which enhances the proliferation and antigen-presenting capabilities of dendritic cells. The ultimate result of these aberrations in the bronchial epithelium is increased presentation of the allergen to hypersensitivity-mediating T cells and B cells. Upon initial exposure to an allergen, a person’s CD4+ helper T cells begin to differentiate into TH1 or TH2 cells. TH1 lymphocytes predominantly secrete the cytokines interleukin-2 (IL-2), interferon-gamma (IFN-γ ), and IL-12; TH2 cells are programmed to release a different class of cytokines: IL-3, IL-4, IL-9, IL-10, IL-13, and GM-CSF. This TH2 cytokine cascade ultimately leads to the antibody-driven allergic inßammatory reaction that characterizes the asthmatic phenotype. Many researchers believe that the initiation and evolution of asthma are caused by an imbalance in the immune response that favors the development of TH2 cells. Neurogenic Inflammation. The nervous system itself can trigger an inßammatory response known as neurogenic inßammation. The neurogenic response ampliÞes ongoing inßammation and may be responsible for the chronic nature of asthma. In neurogenic inßammation, the release of growth factors stimulates sensory nerve endings. When sensitized by mediators such as bradykinin, thromboxane, prostaglandin D2 (PGD2), IL-1, tumor necrosis factor-alpha (TNF-α), and histamine, the nerve endings modulate the release of inßammatory neuropeptides. These neuropeptides may include neurokinin a, calcitonin-gene-related peptide, and substance P. Neurogenic inßammation may be caused by the reduced production of enzymes that degrade neuropeptides, which allows neuropeptide levels to increase unchecked. Early-Phase Asthmatic Reactions Immunoglobulin E. Two particularly important cytokines in the TH2 response are IL-4 and IL-13, both of which act on B cells and facilitate antibody production. Upon activation by allergen, TH2-type T cells secrete IL-4 and IL-13, which act as signals to induce the isotype switching (the mechanism by which allergenspeciÞc immunoglobulin E [IgE] antibodies are developed) and the production of allergen-speciÞc IgE by B lymphocytes (Figure 1). Once synthesized and released into the circulation, secreted IgE binds to allergen. The resulting complexes, in turn, bind to certain high-afÞnity IgE receptors (FcεRI) on mast cells in tissues or peripheral blood basophils. In addition, the allergen-IgE complexes bind to low-afÞnity receptors (FcεRII) on the surfaces of lymphocytes, eosinophils, platelets, and macrophages, but the precise effect of this interaction remains unclear.

442

ASTHMA

The Role of Mast Cells. Mast cells activated by IgE release histamine and the leukotrienes LTC4, LTD4, and LTE4, as shown in Figure 1. These potent smooth-muscle constrictors cause immediate bronchospasm and vasoconstriction of bronchial blood vessels. Leukotrienes also increase blood vessel permeability, leading to edema and hypersecretion of mucus into the airways. In addition, platelet-activating factor (PAF) released by mast cells may increase local inßammation. These effects constitute the initial early-phase asthmatic reaction, which is characterized by wheezing, coughing, difÞculty breathing, and production of sputum. Typically, the early-phase reaction resolves within one hour. Late-Phase Asthmatic Reactions. Over time, mast cells (along with macrophages and epithelial cells) release mediators (cytokines and chemokines) that attract more inßammatory cells to the lungs, leading to a late-phase reaction that occurs within four to six hours of the early-phase reaction, as depicted in Figure 1. The cells predominantly recruited during this phase include eosinophils, basophils, neutrophils, and certain lymphocytes, predominantly CD4+ TH2 cells. The Role of Eosinophils. Eosinophils have been strongly implicated in the pathology of asthma. One of the most notable cytokines secreted by activated mast cells (and TH2 cells) is IL-5, which stimulates the differentiation of eosinophils from bone marrow precursors and allows these cells to inÞltrate the lung (Figure 1). With the assistance of cell adhesion molecules (CAMs), eosinophils adhere to blood vessels in the lung and extravasate (i.e., pass between the endothelial cells lining blood vessel walls) into lung tissue. This process is enhanced by the increased level of CAMs expressed by microvascular endothelial cells. The principal CAMs expressed by endothelial cells include intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Various cytokines—but particularly IL-1 and TNF-α —induce the expression of these CAMs. VCAM-1 binds to the cell-surface receptor of verylate-activation-4 integrin (VLA-4; also known as alpha1beta2 integrin) and is thought to reduce the threshold for eosinophil activation by cytokine mediators. Eosinophil adhesion to ICAM-1 is believed to trigger transendothelial migration of the eosinophil into the lung. Once activated in the lung, the eosinophils produce mediators such as PAF, TH2 cytokines, leukotrienes, and toxic granule proteins. Together with oxygenderived radicals, these mediators cause signiÞcant deterioration of epithelial integrity and may lead to epithelial cell death. The loss of these cells is associated with reduced control of smooth-muscle relaxation, resulting in a tendency to increased bronchoconstriction and hyperreactivity. Abnormalities in automatic neural control of airway tone may also occur (discussed in the “Airway Remodeling” section). Chemokines also activate and recruit eosinophils into the airway. These molecules include a broad and diverse group of soluble proteins; the most important chemokines present in allergic inßammation during acute-stage asthma are macrophage inßammatory protein-1α (MIP-1α), RANTES (regulated upon activation, normal T cells expressed and secreted), and monocyte chemotactic protein


443

(MCP). Eotaxin is another chemokine thought to be necessary for eosinophil accumulation during the chronic stages of the asthma response. Epithelial Injury. Researchers note that asthma patients routinely show damage to the bronchial epithelium. This injury may range from a minor loss of ciliated cells to complete denudation of the epithelium. Epithelial damage contributes to increased sensitivity by allowing inhaled allergens and irritants to permeate the endothelium more rapidly. In addition to leaving subepithelial layers unprotected, epithelial breakdown eliminates various protective anti-inßammatory mediators and smooth-muscle relaxants. Moreover, the detached epithelial cells collect in bronchoalveolar ßuid. The epithelial degeneration and shedding are associated with physiological effects that aggravate and prolong asthma attacks by reducing mucociliary clearance (resulting in mucus buildup and airßow obstruction) and increasing exposure of submucosal cells and nerve endings to allergens. Disruption of the epithelium also reduces the clearance of inßammatory substances and respiratory secretions, in turn exacerbating the overproduction of mucus in the lungs. Furthermore, inßammatory mediators can trigger overproduction of mucus by submucosal glands (goblet epithelial cells), leading to the formation of potentially fatal plugs in the airways. Airway Remodeling. Persistence of the inßammatory response leads to the development of chronic inßammation, the third inßammatory phase of asthma. Over a period of several months to years, eosinophils continue to inÞltrate and release their cytoplasmic granules. Activated CD4+ T lymphocytes, macrophages, and mast cells in various states of degranulation are present as well. A prominent feature of chronic inßammation is the proliferation of Þbroblasts, with increased collagen secretion causing thickening of the airway walls. Increases in submucosal tissue, the adventitia, and smooth muscle are also apparent, followed by bronchial Þbrosis and scarring. Airway obstruction in asthma is considered reversible, but over time, chronic inßammation permanently reduces airway integrity and responsiveness. Smoothmuscle hypertrophy occurs in asthmatics who have even mild disease of long duration. In some patients, this condition results in irreversible airway obstruction and permanent reduction in baseline lung function, as demonstrated in long-term studies that followed asthmatics and age-matched, nonsmoking controls over a 15-year period (Lange P, 1998). Furthermore, observations in children with asthma suggest that preventing the progressive loss of lung function in childhood may require recognition and treatment of the disease during the Þrst Þve years of life (Martinez FD, 1995). A variety of mechanisms may contribute to the airway remodeling process, including endothelin-1 (a peptide released from inßammatory cells), growth factors, and mediators such as histamine. The roles that inßammatory cells (e.g., eosinophils, TH2 cells, mast cells) may play in causing structural airway changes are under investigation. A greater understanding of the pathophysiology and course of the remodeling process will aid researchers’ efforts to devise novel

444

ASTHMA

agents and therapeutic strategies that moderate the underlying chronic inßammatory response involved in asthma. CURRENT THERAPIES Current therapies used to manage asthma include prophylactic medications that treat the ongoing inßammation and bronchoconstriction that characterize asthma and rescue medications that relieve acute symptoms. Current treatment paradigms employ anti-inßammatory agents—most notably, inhaled corticosteroids—as Þrst-line prophylactic therapy for persistent asthma. For many patients with persistent asthma, long-acting bronchodilators are increasingly used in combination with prophylactic therapies. The treatment of asthma relies heavily on inhaled therapies that raise unique issues with regard to drug delivery and compliance for patients and prescribers. Most patients favor oral dosing over inhaled dosing. Compliance with inhaled drugs is generally low, but novel delivery devices are improving patient compliance. Combination inhalers deliver two drugs simultaneously, thereby simplifying dosing. User-friendly devices such as dry-powder inhalers and breath-operated aerosol inhalers have also improved patient compliance. Inhaler devices present unique challenges to drug developers. Countries that agreed to the terms of the Montreal Protocol on Substances that Deplete the Ozone Layer must eliminate chloroßuorocarbon (CFC) propellants from medical devices once suitable replacements become available. SigniÞcant progress has been made on this front, particularly in Europe and Japan, where CFC-free versions of most leading inhaled drugs are now available either as hydroßuoroalkane (HFA) formulations, which include an environmentally acceptable propellant, or as DPI formulations, which do not require a propellant. In the United States, the leading maintenance therapies are now available in HFA and/or DPI formulations, and rescue medications will make the transition in 2009. Table 2 summarizes the leading therapies available to treat asthma. Inhaled Corticosteroids Overview. Corticosteroids are the most effective pharmacotherapy for controlling the underlying inßammation of asthma. When administered continuously as prophylactic therapy, they improve lung function and reduce the frequency and severity of asthma exacerbations. Inhalation is the preferred and most common route of administration for these agents, although oral (systemic) formulations are sometimes required to provide more-potent effects and to control symptoms during severe exacerbations. Current treatment guidelines published by the Global Initiative for Asthma (GINA), the National Heart, Lung and Blood Institute (NHLBI), and the British Thoracic Society (BTS) recommend inhaled corticosteroids as Þrst-line therapy for the management of persistent asthma. In addition to alleviating the symptoms of the disease and the associated physiological abnormalities, regular use

TABLE 2. Current Therapies Used for Asthma Agent

Company/Brand

Inhaled corticosteroids Budesonide

AstraZeneca’s Pulmicort

Fluticasone propionate

GlaxoSmithKline’s Flovent/Flixotide

Mometasone Schering-Plough’s furoate Asmanex Long-acting beta2 agonists Salmeterol GlaxoSmithKline’s Serevent

Formoterol

Yamanouchi/Novartis’s Foradil, AstraZeneca’s Oxis

445

Corticosteroid/beta2 agonist combinations Fluticasone/ GlaxoSmithKline’s salmeterol Advair/Seretide Formoterol/ AstraZeneca’s Symbicort budesonide Leukotriene antagonists Montelukast Merck’s Singulair Anti-immunoglobulin E agents Omalizumab Genentech/Novartis/ Sankyo/Tanox Biosystems’ Xolair

[Daily] Dose DPI (Turbuhaler): 100, 200, 400 µg/inhalation; MDI: 50, 200 µg/inhalation—total 400–2400 µg, divided bid-qid. MDI: 88–880 µg, bid; highest dose is 880 µg, bid. DPI (Rotadisk): 100–1,000 µg, bid; highest dose is 1,000 µg, bid. DPI (Twisthaler):200–400 µg, qd.

Availability US, F, G, I, S, UK, J


G, UK

MDI: 42 µg (2 inhalations), bid (morning and evening); for exercise-induced asthma: 42 µg, 30–60 min. before exercise. Diskus DPI: 50 µg (1 inhalation), bid (morning and evening); for exercise-induced asthma: 50 µg (1 inhalation), 30–60 min. before exercise. MDI: 12–24 µg, bid.


DPI (Diskus): salmeterol/fluticasone: 50 µg/100 µg, 50 µg/250 µg, or 50 µg/500 µg, bid. DPI (Turbuhaler): budesonide/formoterol: 1–2 inhalations of 80 µg/4.5 µg or 160 µg/4.5 µg, bid.

US, F, G, I, S, UK

10 mg (oral tablet) qd (in the evening)


SC injection: 150 mg to 375 mg administered every 2 to 4 weeks. Dose determined by total serum IgE level measured prior to administration and body weight.

US


F, G, I, S, UK

446

TABLE 2. (continued) Agent

Company/Brand

Short-acting beta2 agonists Albuterol Schering-Plough’s Proventil, GlaxoSmithKline’s Ventolin, generics Levalbuterol Sepracor’s Xopenex Oral corticosteroids Prednisone

Methylxanthines Theophylline (extended release) Cromolyns Cromolyn sodium

Anticholinergics Ipratropium bromide Ipratropium/ albuterol

[Daily] Dose

Availability

MDI: 180 µg (2 inhalations), q4–6h, PRN. Nebulized solution: 2.5 mg, tid-qid. Higher doses not recommended.


Oral nebulization: initially 0.63 mg (1 inhalation), tid; up to 1.25 mg (1 inhalation), tid.

US

Multisource

Chronic asthma: ≤40 mg (oral tablets or liquid), every other day. Acute asthma: ≤50 mg/day for 5–14 days.


AstraZeneca’s Theo-Dur, 3M’s Theolair, generics

Extended-release oral capsules: 400–1,600 mg/day, individualized to maintain peak serum theophylline concentration in the 10–20 µg/mL range. Initially dosed bid, often switched to qd.


King Pharmaceuticals/ Sanofi-Aventis’ Intal

MDI: 1,600 µg (2 inhalations), qid. Maximum daily dose: 12.8 mg (4 inhalations), qid. For prevention, two inhalations, 10–60 minutes before exposure to inducing agent.

US, F, G, S, UK, J

Boehringer Ingelheim’s Atrovent

MDI: 36 µg (2 inhalations), qid; maximum dose: 12 inhalations. Oral nebulization: 500 µg (1 unit-dose vial), tid-qid. MDI: ipratropium 36 µg/albuterol 206 µg (two aerosol inhalations), qid; maximum dose: 12 inhalations. Oral nebulization: ipratropium 200 µg/albuterol 2.5 mg (1 unit-dose vial), tid-qid.


Boehringer Ingelheim’s Combivent, Valeas’s Breva

US, F, I, S, UK

bid = Twice daily; DPI = Dry powder inhaler; MDI = Metered-dose inhaler; PRN = Pro re nata, or use as needed; qd = Once daily; bid = Two times daily; tid = Three times daily; qid = Four times daily; q4h = every four hours; SC = Subcutaneous. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

CURRENT THERAPIES

447

of inhaled corticosteroids—even at low doses—appears to substantially reduce asthma-related hospitalizations and deaths. In an epidemiological literature survey, researchers reported that eight independent studies strongly suggested that inhaled corticosteroids, taken regularly, can reduce the number of hospitalizations for asthma by as much as 80% (Suissa S, 2001). The evidence linking corticosteroid use to reductions in asthma-related mortality is less clear, but the same researchers supported recent Þndings that demonstrated a signiÞcant reduction in fatalities with the use of these agents. The following inhaled corticosteroids are listed in order of decreasing potency, based on in vitro studies (Johnson M, 1998): • • • •

Fluticasone propionate (GlaxoSmithKline’s [GSK’s] Flovent/Flixotide). Budesonide (AstraZeneca’s Pulmicort). Beclomethasone dipropionate (GSK’s Beclovent/Beclotide, ScheringPlough’s Vanceril/Vancenase). Flunisolide (Forest Laboratories’ Aerobid/Aerobid-M) and triamcinolone acetonide (Kos’ Azmacort)—approximately equipotent.

Researchers caution, however, that in vitro potency may not accurately reproduce clinical potency. For the vast majority of patients (who have mildto-moderate asthma), the effects of increasing potency may be minimal. Although corticosteroids are by far the most effective compounds for controlling asthma, they are associated with several potentially serious side effects—particularly when used at high doses for extended periods. In adult patients, the adverse effect of greatest concern is bone mineral loss; long-term treatment with oral corticosteroids increases the risk of bone loss and osteoporotic fracture (van Staa TP, 2000). However, because inhaled corticosteroids have been available for considerably less time than oral corticosteroids, similar long-term data are not yet available on patients treated with inhaled formulations. To date, treatment guidelines created by the GINA do not recommend prophylactic treatment for osteoporosis in patients treated with inhaled corticosteroids (GINA, 2004). The medical community has raised concerns about the possibility that stunted growth in the pediatric asthma population may result from treatment with inhaled corticosteroids, but a consensus appears to be emerging that patients treated with inhaled corticosteroids as children do reach full adult height (GINA, 2004). Recent clinical studies examining this issue have consistently found a lack of long-term effect on adult height, although the Childhood Asthma Management Program (CAMP) Research Group found slightly impaired growth during the Þrst year of treatment only (Agertoft L, 2000; CAMP Research Group, 2000). DeÞning the risk-beneÞt ratio in children is particularly important because early initiation of corticosteroid therapy in these patients may prevent irreversible remodeling of bronchial tissue. As a precaution, the FDA recommends that physicians monitor the growth of corticosteroid-treated children every three to six months with a sensitive device (e.g., a stadiometer).

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Although inhaled corticosteroids cause fewer serious systemic side effects than oral formulations, systemic side effects remain a problem because only a portion of the inhaled dose reaches the lungs. The remaining medication stays in the oropharynx or reaches the gastrointestinal (GI) tract, eventually being absorbed into the systemic circulation. Inhaled corticosteroids are also associated with local adverse effects, including oral candidiasis, hoarseness, dysphonia, and throat irritation. This section focuses on the inhaled corticosteroids budesonide (AstraZeneca’s Pulmicort) and ßuticasone propionate (GSK’s Flovent/Flixotide) because they are the top-selling inhaled corticosteroids across the major markets under study. It also discusses the most recently launched inhaled corticosteroid, mometasone furoate (Schering-Plough’s Asmanex). Additional agents in this class include beclomethasone dipropionate (GSK’s Beclovent/Beclotide, Schering-Plough’s Vanceril/Vancenase); ßunisolide (Forest Laboratories’ Aerobid/Aerobid-M); and triamcinolone acetonide (Kos’s Azmacort). Mechanism of Action. All corticosteroids exert their therapeutic effect by binding to intracellular glucocorticoid receptors, which are found in all cells and are abundant in the epithelium of bronchi. In this way, corticosteroids alter intracellular activities and reduce the transcription of genes that encode proteins involved in the inßammatory response, including the cytokines IL-1, -3, -4, -5, -6, and -8; tumor necrosis factor-alpha (TNF-α); granulocyte-macrophage colony-stimulating factor (GM-CSF); and RANTES (regulated upon activation, normal T cells expressed and secreted). By lowering the levels of these inßammation mediators, corticosteroid therapy reduces the activity of lymphocytes, eosinophils, macrophages, and mast cells in mucosal ßuids. In addition, corticosteroids increase the transcription of genes responsible for producing beta2 adrenoreceptors and lipocortin 1, a protein that inhibits phospholipase A2 (a proinßammatory enzyme). Other key mechanisms by which corticosteroids help alleviate the symptoms of asthma include inhibition of T-cell activation (and subsequent cytokine release), promotion of apoptosis of eosinophils, inhibition of nitric oxide (NO) synthase, and reduction in mucus secretion by submucosal gland cells. Budesonide. Budesonide (AstraZeneca’s Pulmicort) (Figure 2) is a secondgeneration corticosteroid. The drug is marketed in a dry-powder inhaler (Pulmicort Turbuhaler), approved for once-daily use in adults and in children aged six years or older with mild-to-moderate asthma, and in nebulizer form (Pulmicort Respules), approved for the treatment of children aged 12 months to 8 years. Although this drug has been available in Europe since the early 1980s, it was not introduced in the United States until June 1997. Budesonide has been available in Japan since December 2001. Like other corticosteroids, budesonide binds to the glucocorticoid receptor and suppresses the production of proinßammatory cytokines. Although budesonide has a shorter plasma half-life than other inhaled corticosteroids, its residence in the lung is extended by the formation of lipid conjugates with esterases

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OH O HO

O

H

O

O FIGURE 2. Structure of budesonide.

in the lung. Budesonide has greater oral bioavailability than ßuticasone propionate but lower oral bioavailability than older inhaled corticosteroids such as beclomethasone. The efÞcacy and safety of budesonide delivered by dry-powder inhaler (DPI) were assessed in a 12-week, double-blind, multicenter, parallel-group study of 473 adult patients with moderate-to-severe chronic asthma (Busse WW, 1998). Patients were treated with placebo or with 200 µg, 400 µg, 800 µg, or 1,600 µg total daily budesonide. The primary end points measured in the study were mean change from baseline forced expiratory volume at one second (FEV1 ) and morning peak expiratory ßow rate (PEFR). Patients treated with budesonide showed signiÞcant increases in both measures; patients treated with placebo showed declines in both measures. The mean change in morning PEFR was 12, 22, 27, and 30 L/min in the 200 µg, 400 µg, 800 µg, and 1,600 µg dose groups, respectively, compared with −27 L/min in the placebo group. Increases in FEV1 were approximately 0.14, 0.23, 0.23, and 0.28 L in the 200 µg, 400 µg, 800 µg, and 1,600 µg dose groups, respectively, compared with a 0.22 L decline in the placebo-treated group. Similar results were obtained in a study of 309 patients with mild-to-moderate asthma that was designed to test maintenance of stable asthma with lower doses of corticosteroid (McFadden ER, 1999). In this randomized, double-blind study, patients were treated with placebo or with 200 µg or 400 µg of budesonide delivered by dry-powder inhaler (Pulmicort Turbuhaler) once daily. Patients treated with 200 µg or 400 µg of budesonide showed FEV1 increases of 0.10 and 0.11 L, respectively, after 18 weeks of treatment, while patients treated with placebo showed a 0.09 L decline in FEV1 . Greater increases in FEV1 were observed in patients not previously treated with corticosteroids. The most commonly reported adverse effects were respiratory infection, headache, and bronchospasm; several cases of oral candidiasis were also reported in both the placebo and treatment groups. Fluticasone Propionate. Launched in the early 1990s, ßuticasone propionate (GSK’s Flovent/Flixotide) (Figure 3) quickly became one of the most widely used inhaled corticosteroids. It is sold in two DPIs (the Diskus inhaler and the Rotadisk inhaler) and in a metered-dose inhaler (MDI). The Diskus and Rotadisk

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F S H3C

HO H3C

CH3

O O CH3

H F

O

H

O F

FIGURE 3. Structure of fluticasone propionate.

formulations are approved for the treatment of asthma in patients four years of age or older; the MDI formulation is approved only for patients aged 12 years or older. It is available in all seven market under study. Like all corticosteroids, ßuticasone propionate binds to the glucocorticoid receptor and reduces the transcription of genes that encode proinßammatory cytokines. Fluticasone propionate has the highest relative afÞnity for the glucocorticoid receptor of all currently marketed inhaled corticosteroids—approximately twice that of budesonide (Allen DB, 2003)—and its long half-life extends residence time in the lung. Fluticasone propionate also has low oral bioavailability, an attribute associated with reduced risk of systemic exposure and adverse effects. This agent has demonstrated better efÞcacy than budesonide in the management of severe asthma (Georgitis JW, 1999). In addition, some studies suggest that a once-daily, higher-dose ßuticasone administration is efÞcacious in the treatment of persistent asthma (Berger WE, 2002). The efÞcacy of inhaled ßuticasone propionate powder in treating moderate persistent asthma was examined in a randomized, double-blind, placebo-controlled trial involving 342 adolescent and adult patients (Pearlman DS, 1997). Patients were treated with placebo or with 50 µg, 100 µg, or 250 µg of ßuticasone propionate delivered by two inhalations daily from the Diskhaler device. Patients in all three treatment groups experienced improvements in FEV1 of 17–18% above baseline, while patients in the placebo group experienced a decline in FEV1 . Patients treated with ßuticasone also demonstrated improved PEFR, less need for rescue medication, and fewer nighttime awakenings, compared with their placebo-treated counterparts. No serious adverse events occurred; the most common adverse events considered likely to be treatment-related were dysphonia, pharyngitis, headache, and oropharyngeal candidiasis, each occurring in no more than 6% of ßuticasone-treated patients. Of these events, only headache (3%) was reported in the placebo group. Similar results were obtained in studies of patients with mild-to-moderate persistent asthma (Sheffer AL, 1996; Chervinsky P, 1994). Mometasone Furoate. Mometasone furoate (Figure 4) is the Þrst inhaled corticosteroid approved for once-daily use and has been available since 1997 in most

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markets as an aqueous nasal spray (Schering-Plough’s Asmanex) for treating allergic rhinitis. In January 2003, Schering-Plough announced that a dry-powderinhaler (DPI) formulation of mometasone, called Asmanex Twisthaler, was being launched in the United Kingdom for mild, moderate, and severe persistent asthma in patients aged 12 years or older. That February, it became available in Germany. The DPI formulation has been preregistered in the United States since 1998, but the drug did not receive FDA approval until March 2005. Like other inhaled corticosteroids, mometasone furoate binds to the glucocorticoid receptor and suppresses the production of cytokines involved in the inßammatory response. Mometasone is a potent inhibitor of anti-inßammatory cytokines but has low systemic availability (Affrime MB, 2000[a]). In a 12-week, randomized, placebo-controlled Phase III trial, 236 patients (aged 12 or older) with mild-to-moderate asthma were treated with once-daily DPI mometasone (200 or 400 µg) or with placebo (Nayak AS, 2000). Spirometric measurements indicated that patients in both the 200 µg and 400 µg mometasone-treated groups experienced a signiÞcant percentage increase in FEV 1 from baseline (14.8% and 14.2%, respectively) compared with the placebo group (2.5%). The percentage of subjects considered to be improved (based on an assessment of symptoms) by the end of the trial was higher in the 200 µg and 400 µg mometasone groups (64% and 66%, respectively) than in the placebo group (50%). Symptoms worsened in 5% of patients receiving 200 µg mometasone, in 8% receiving 400 µg mometasone, and in 21% of the patients receiving placebo. Treatment-related adverse events were distributed equally across the three groups; the most commonly reported events were oral candidiasis, headache, and pharyngitis. One patient receiving placebo, three patients receiving 200 µg mometasone, and one patient receiving 400 µg mometasone experienced severe adverse events. Mometasone may also beneÞt patients with severe persistent asthma by reducing the need for oral prednisone. A 12-week, double-blind, placebo-controlled trial compared the efÞcacy of 400 µg and 800 µg DPI mometasone administered twice daily in 132 severely ill asthmatics who required oral corticosteroid treatment (Fish JE, 2000). Results showed that treatment with 400 µg or 800 µg mometasone reduced daily oral corticosteroid requirements by 46% and 24%,

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respectively, compared with an increase of 164% in the placebo group. Furthermore, oral corticosteroids were completely eliminated in 40% and 37% of patients in the 400 µg and 800 µg treatment groups, respectively; corticosteroids were not eliminated in any patients in the placebo arm. Studies of the safety and tolerability of mometasone reveal that its systemic bioavailability is negligible. Plasma concentrations were below the limit of quantiÞcation (50 pg/mL) and were not detectable in 92% of healthy study participants, suggesting that it is extensively metabolized (Affrime MB, 2000[a]). Urinary cortisol excretion assays are often performed to determine whether a patient receiving corticosteroid therapy is adrenally suppressed, a condition commonly associated with chronic, high-dose corticosteroid therapy. Mometasone has been shown to have a minimal effect on cortisol suppression when delivered at high doses (800–1,200 µg daily total) (Affrime MB, 2000[b]). Although mometasone appears to have a favorable safety proÞle, long-term studies are needed to determine its potential for adverse effects. Long-Acting Beta2 Agonists Overview. Compared with short-acting beta2 agonists, long-acting beta2 agonists tend to have a slower onset of action and demonstrate prolonged receptor occupancy (Table 3). As a result, they are prescribed to provide partial, steadystate bronchodilation and longer-term beneÞcial effects. Formoterol (Yamanouchi/Novartis’ Foradil; AstraZeneca’s Oxis) has a relatively quick onset of action (within 5 minutes) compared with the rest of the agents in this class (salmeterol’s onset of action is between 8 and 20 minutes, for example); this agent may be prescribed for both acute and prophylactic therapy. Recent clinical studies provide support for this practice and suggest that formoterol may offer some advantages over short-acting beta2 agonists (Pauwels RA, 2003; TattersÞeld AE, 2001).

TABLE 3. Onset of Action of Short-Acting and Long-Acting Beta2 Agonists Onset of Action Source (Description)

Short-Acting Beta2 Agonist

Long-Acting Beta2 Agonist

Ullman A, 1992 (experimental model) Bensch G, 2001 (clinical trial) Anderson SD, 1991 (clinical trial of exercise-induced asthma)

Albuterol = 2 minutes

Salmeterol = 8 minutes

Albuterol = Within 5 minutes Albuterol was effective when administered within 30 minutes of exercise.

Formoterol = Within 5 minutes Salmeterol was as effective as albuterol when administered 30 minutes before exercise. It was more effective when administered 2.5, 4.5, and 6.5 hours prior to exercise.

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Ever since long-acting beta2 agonists were introduced into medical practice, some physicians have expressed concern about the potential development of tolerance to therapy. Although some publications suggest that long-term therapy is not associated with increased frequency or severity of attacks, other studies have indicated that partial tolerance to long-acting beta2 agonists develops in children when these agents are used as maintenance treatment (Bisgaard H, 2000). Mechanism of Action. Beta2 adrenergic receptors are found in smooth muscle in the airway and in the lungs, blood vessels, and other tissues throughout the body. In the airway, stimulation of these receptors by beta2 agonists relaxes bronchial smooth muscle and produces bronchodilation. Long-acting beta2 agonists provide protection against bronchoconstriction caused by allergens, exercise, histamine, and methacholine for at least 12 hours. Other effects of long-acting beta2 agonists that have been observed experimentally include the following: • • • •

Blocking of mast-cell release of leukotrienes and histamine in the lungs. Reduced microvascular permeability and mucus production. Increased mucociliary function. Possible inhibition of the activity of phospholipase A2, a key enzyme in the proinßammatory arachidonic acid pathway.

Salmeterol. Originally approved in 1994, salmeterol (GSK’s Serevent) (Figure 5) is indicated for long-term maintenance therapy for asthma and for the prevention of bronchospasm in patients older than 12 years who have demonstrably reversible obstructive airways. Salmeterol is also indicated for the prevention of exercise-induced bronchospasm in patients older than 12. The agent is marketed in both DPI and CFC-containing MDI formulations. An HFA-propelled MDI is in Phase III trials in the United States and preregistered in Europe. Several trials in asthmatics have demonstrated that salmeterol is superior to the short-acting beta2 agonist albuterol (GSK’s Ventolin; Schering-Plough’s Proventil, generics) in improving various outcomes (including asthma-speciÞc quality of life and lung function) and in reducing respiratory symptoms during the day and night. In a 12-week, randomized, double-blind, parallel-group, multicenter trial, 539 adult asthmatics were administered either salmeterol 42 µg twice daily (via MDI) or albuterol 180 µg four times daily (Wenzel SE, 1998). At 12 weeks, salmeterol resulted in signiÞcant changes from baseline quality-of-life (QOL)

OH

H N

HO

O HO

.CH3CO2H FIGURE 5. Structure of (S)-salmeterol.

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scores for asthma symptoms (1.0), emotional function (0.85), and environmental exposure (0.65), compared with albuterol (0.5, 0.4, and 0.45, respectively). Scores are based on QOL measurements over a two-week time period; each factor (including activity limitation, symptoms, and emotional function) is scored between 1 and 7, with higher scores indicating greater QOL. Average increases in PEFR over baseline for the morning and evening were signiÞcantly higher in the salmeterol group (39.3 L/min and 19.5 L/min, respectively) compared with the albuterol group (6.6 L/min and 8.4 L/min, respectively). In addition, average increases in FEV1 at weeks 4, 8, and 12 were signiÞcantly higher in the salmeterol group (0.32 L, 0.38 L, and 0.37 L, respectively) compared with the albuterol group (0.16 L, 0.21 L, and 0.20 L, respectively). Statistical significance was also observed in mean change from baseline of symptom-free day measurements (28.6% and 13.4% for salmeterol and albuterol, respectively). The frequency of adverse events between treatment groups was not signiÞcant, and the percentage of patients with a speciÞc drug-related adverse event was always below 1%. During the Þrst quarter of 2003, the Salmeterol Multicenter Asthma Research Trial (SMART), a safety study, was terminated as a result of a potential association between salmeterol and increased risk of life-threatening asthma episodes or asthma-related deaths. The study compared the effects of 28 weeks of salmeterol (42 µg twice daily) with placebo in patients with asthma. GSK added black box warnings to the package inserts of both salmeterol and the combination therapy Advair (ßuticasone/salmeterol) to alert physicians to the increase in asthma-related deaths that occurred (Pink Sheet; August 18, 2003). When the Þndings of the SMART trial were released, the FDA expressed interest in exploring the possibility of a class-based effect. However, no progress on this front has been reported to date. If investigations demonstrate that the risk is due to a class effect, similar label warnings could appear on formoterol or on formoterolcontaining products, such as Symbicort. The FDA has stated that patients should not stop taking medications containing salmeterol without consulting their physicians and that the beneÞts of treatment with salmeterol in patients with asthma (and chronic obstructive pulmonary disease [COPD]) continue to outweigh the potential risks when used according to product labeling. Formoterol. First marketed by Yamanouchi in Japan, formoterol (Yamanouchi/ Novartis’s Foradil; AstraZeneca’s Oxis) (Figure 6) was launched by Novartis in Europe and the United States in 2001. In the fourth quarter of 2002, one and one-half years after Foradil’s U.S. launch, Novartis licensed the U.S. rights to this agent to Schering-Plough for maintenance treatment of asthma and COPD and for the acute prevention of exercise-induced bronchospasm. In return, Novartis will receive royalties and milestone payments if sales exceed a certain level. Finally, AstraZeneca’s Oxis Turbuhaler has been approved in more than 60 countries and was approved for COPD in the European Union (EU) in December 2002. To evaluate the long-term efÞcacy and safety of formoterol in pediatric asthmatics, a 12-month, multicenter, randomized, double-blind study was conducted in 518 pediatric asthmatics (aged 5–12 years) who were still symptomatic despite

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OH H N

H N

OHC HO

CH3

OCH3

FIGURE 6. Structure of formoterol.

treatment with anti-inßammatory medication. Patients received placebo or formoterol 12 µg or 24 µg twice daily for 12 months (Bensch G, 2002). Morning premedication PEFR (averaged over the 12-month study) for the formoterol 12 µg and 24 µg groups increased 14.5% (+34 L/minute) and 16.3% (+40 L/minute), respectively, compared with an average increase in the placebo group of 8.6% (21 L/minute). Evening PEFR averages in patients treated with formoterol 12 µg and 24 µg increased 11.8% (+29 L/minute) and 13.7% (+35 L/minute), respectively, compared with an average increase of 7.5% (+19 L/minute) in the placebo group. The number of asthma patients who became symptomatic despite rescue treatment with albuterol during the study was not statistically different between the treatment groups, but signiÞcantly more serious asthma exacerbations (requiring hospitalization and/or discontinuation from the study) occurred in patients receiving formoterol, compared with patients receiving placebo (no serious asthma exacerbations occurred in the placebo group). The effectiveness of formoterol as relief medication is under investigation. An open-label study of 18,124 children and adults compared the safety and effectiveness of as-needed formoterol and as-needed albuterol (Pauwels RA, 2003). The primary efÞcacy variable was time to Þrst asthma exacerbation; the primary safety variables were asthma-related serious adverse events and adverse events resulting in participants’ discontinuing study participation. The frequencies of adverse events not related to asthma, asthma-related deaths, and cardiovascularrelated deaths were similar in both treatment groups. The incidence of asthma exacerbations assessed by clinical criteria was lower in the formoterol group. However, because the study evaluated exacerbations based on clinical criteria rather than spirometry and because the study design was not blinded, the possibility of investigator bias cannot be entirely ruled out. While acknowledging the study’s limitations, the investigators suggest that this study supports the prescription of formoterol to asthmatic patients on an as-needed basis. Corticosteroid/Beta2 Agonist Combinations Overview. The combination of inhaled corticosteroids and long-acting beta2 agonists produces superior outcomes compared with increased doses of singleagent inhaled corticosteroids. The combination of these classes of agents into one delivery system offers clinical beneÞts (such as increased patient compliance), as evidenced by the commercial success of marketed combination products. GSK’s Advair (Seretide in Europe) combines the long-acting beta2 agonist salmeterol and the anti-inßammatory corticosteroid ßuticasone. AstraZeneca’s Symbicort combines the beta2 agonist formoterol and the corticosteroid budesonide.

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Mechanism of Action. All corticosteroids exert their therapeutic effect by binding to glucocorticoid receptors, which are found in all cells and are abundant in the epithelium of bronchi. In this way, corticosteroids alter intracellular activities and reduce the transcription of genes that encode proteins involved in the inßammatory response, including the cytokines IL-1, -3, -4, -5, -6, and -8; TNF-α; GM-CSF; and RANTES. By lowering the levels of these inßammation mediators, corticosteroid therapy reduces levels of lymphocytes, eosinophils, macrophages, and mast cells in mucosal ßuids. In addition, corticosteroids increase the transcription of genes responsible for producing beta2 adrenoreceptors and lipocortin 1, a protein that inhibits phospholipase A2, a proinßammatory enzyme. Other key mechanisms by which corticosteroids help alleviate the symptoms of asthma include inhibition of T-cell activation (and subsequent cytokine release), promotion of apoptosis of eosinophils, inhibition of NO synthase, and reduction in mucus secretion by submucosal gland cells. Evidence also suggests these drugs help restore damaged epithelium. Long-acting beta2 agonists act on beta2 adrenergic receptors found in smooth muscle in the airway and in the lungs, blood vessels, and other tissues throughout the body. In the airway, stimulation of these receptors by beta2 agonists relaxes bronchial smooth muscle and produces bronchodilation. Long-acting beta2 agonists provide protection against bronchoconstriction caused by allergens, exercise, histamine, and methacholine for at least 12 hours. Other effects of long-acting beta2 agonists that have been observed experimentally include the following: • • • •

Blocking of mast-cell release of leukotrienes and histamine in the lungs. Reduced microvascular permeability and mucus production. Increased mucociliary function. Possible inhibition of the activity of phospholipase A2, a key enzyme in the proinßammatory arachidonic acid pathway.

In addition to the individual actions of each agent, several lines of evidence suggest interactions between corticosteroids and beta2 agonists. Salmeterol potentiates glucocorticoid receptor responsiveness by enhancing receptor translocation, binding to target sites, and phosphorylation of the receptor (Adcock IM, 2002). Corticosteroids inßuence the activity of beta2 agonists by increasing the number of beta2 adrenergic receptors. Furthermore, corticosteroids may reverse the downregulation of beta2 adrenergic receptors that occurs with long-term administration of long-acting beta2 agonists. Fluticasone/Salmeterol. Fluticasone/salmeterol (GSK’s Advair/Seretide) was launched in 1998 in the European Union and in 2001 in the United States, where it is indicated for twice-daily maintenance treatment of asthma in patients aged 4 years or older. Fluticasone/salmeterol is licensed to Almirall-Prodesfarma and Alter for sales in Spain, and in August 2000, Schwarz Pharma acquired exclusive marketing rights to ßuticasone/salmeterol in Germany. In Japan, GSK submitted a new drug application for the ßuticasone/salmeterol Diskus in April 2004.

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The individual components of ßuticasone/salmeterol provide anti-inßammatory and bronchodilating effects, respectively. Salmeterol stimulates beta2 adrenergic receptors and relaxes smooth muscle; ßuticasone suppresses the production of pro-inßammatory cytokines. Salmeterol is relatively dose-unresponsive at high concentrations; consequently, all available strengths of ßuticasone/salmeterol contain the same dose of salmeterol, but the dose of ßuticasone varies. Clinical studies were conducted to compare the efÞcacy of ßuticasone/ salmeterol in treating asthma with the efÞcacy of its constituent agents given independently. In a randomized, double-blind, placebo-controlled, parallel-group study, 349 asthmatics previously treated with medium doses of inhaled corticosteroids were given either twice-daily salmeterol 50 µg and ßuticasone 250 µg (combined in one inhaler), salmeterol 50 µg, ßuticasone 250 µg, or placebo (Shapiro G, 2000). The primary end point of mean change in FEV1 after 12 weeks was signiÞcantly greater with Advair (0.48 L) than with salmeterol (0.05 L), ßuticasone (0.25 L), or placebo (−0.11 L); these changes in volume represent percentage improvements from baseline of 23%, 4%, 13%, and 5%, respectively. Morning PEFR measurements at trial endpoint were signiÞcantly higher in participants who received combination therapy (53.5 L/min) than in those who were given salmeterol (−11.6 L/min), ßuticasone (15.2 L/min), or placebo (−14 L/min). A signiÞcantly greater number of patients remained in the study from the Advair group (84%) than from the salmeterol group (48%), ßuticasone group (73%), or placebo group (29%). The most common minor adverse events included oral candidiasis (2–4% of patients), headache (2–5%), tremors (2%), dizziness (2%), throat irritation (1–3%), and cough (1–3%). The recent addition of blackbox warnings to salmeterol package inserts, after the occurrence of asthma-related deaths in the SMART study, is likely to contribute to the shift from single inhalers to combination inhalers (Pink Sheet; February 24, 2003). Formoterol/Budesonide. The combination of formoterol and budesonide (AstraZeneca’s Symbicort), delivered by a DPI device (Turbuhaler), is marketed throughout Europe. In September 2005, AstraZeneca Þled a New Drug Application (NDA) for a formulation of formoterol/budesonide delivered by MDI in the United States. Development in Japan has not been reported. The pMDI (pressurized metered-dose inhaler) version of Symbicort is also in development in Europe. The individual components of budesonide/formoterol control inßammation by suppressing the production of proinßammatory cytokines and relax smooth muscle by stimulating beta2 adrenergic receptors. Because formoterol is doseresponsive across a wider range of doses than other long-acting beta2 agonists, physicians can increase or reduce the dose of the drug with the same inhaler by directing patients to take more or fewer puffs in response to variable symptoms. Formoterol/budesonide is approved in Europe for both Þxed-dose and adjustabledosing regimens.

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AstraZeneca is seeking regulatory approval in Europe to market budesonide/ formoterol for both maintenance and rescue therapy, allowing patients to use a single inhaler for maintenance and acute dosing. This strategy would eliminate the need for an additional inhaler containing a short-acting beta2 agonist. Because formoterol has a rapid onset of action, it may be able to provide relief of acute symptoms comparable to that of short-acting beta2 agonists. Therefore, the company is seeking to market the budesonide/formoterol combination inhaler as an agent that can also be administered in response to acute symptoms. In November 2003, AstraZeneca submitted an application to the European Medicines Agency (EMEA) for the new labeling. In November 2004, AstraZeneca withdrew the application and announced that a resubmission with additional clinical data is expected at a later date. Although corticosteroids are the most effective agent for treating moderateto-severe asthma, it is fairly common for patients to remain symptomatic and require additional treatment. To evaluate the efÞcacy of combined formoterol and budesonide, 852 asthmatics (who were being treated with glucocorticoids) were enrolled in a one-year, double-blind, placebo-controlled trial. Twice daily, patients received either 100 µg budesonide/placebo, 100 µg budesonide/12 µg formoterol, 400 µg budesonide/placebo, or 400 µg budesonide/12 µg formoterol (Pauwels RA, 1997). By the addition of formoterol to 100 µg budesonide, rates of severe and mild exacerbations were reduced by 26% and 40%, respectively; by the addition of formoterol to 400 µg budesonide, rates were reduced by 63% and 62%, respectively. The percentage of patients free of exacerbations during the study was 80.8% in the 400 µg budesonide/12 µg formoterol group and 61.4% in the group receiving budesonide alone. All treatment combinations were well tolerated, and the proportion of adverse events within each treatment group was similar. Eleven patients were hospitalized as a result of asthma exacerbation, and 29 patients withdrew because of adverse events. Seven of the withdrawals stemmed from pharmacologically predictable adverse events (headache, tremor, tachycardia, and oral candidiasis). Leukotriene Antagonists Overview. Derived from arachidonic acid, leukotrienes (LTs) are lipid mediators that are released from most of the inßammatory cells present in (or recruited to) the airways. They are logical targets for antagonism because they directly mediate bronchoconstriction and have proinßammatory effects. In addition, the leukotriene antagonists appear to lack the adverse effects on growth, bone mineralization, and the adrenal axis that have been associated with long-term corticosteroid therapy. Montelukast (Merck’s Singulair) is the class leader in the asthma market. Other available oral leukotriene antagonists include pranlukast (Ono’s Onon), zaÞrlukast (AstraZeneca’s Accolate), and zileuton (Critical Therapeutics’s Zyßo). Mechanism of Action. Leukotrienes are derivatives of arachidonic acid, an unsaturated fatty acid produced from membrane phospholipids. Mast cells and

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basophils generate a mixture of leukotrienes, which stimulate the production of airway secretions, enhance the migration of eosinophils, and cause microvascular leakage. Two modes of leukotriene inhibition have been developed: •

•

Leukotriene synthesis inhibitors. The leukotriene synthesis inhibitors include inhibitors of 5-lipoxygenase [5-LO] and 5-LO-activating protein [FLAP], which are components of the 5-LO pathway. This pathway produces several leukotrienes (e.g., leukotriene B4 (LTB4), cysteinyl leukotrienes) that can cause edema, eosinophil migration, and airway secretion—physiological processes that contribute to asthma and its associated airway remodeling (Drazen JM, 1999). Theoretically, inhibitors of this pathway might reduce inßammation due to asthma. LTD4 (leukotriene D4) receptor antagonists. The LTD4 receptor antagonists are also known as cysteinyl leukotriene-1 [cysLT1] receptor antagonists. Cysteinyl leukotrienes exert their biological effect by binding to receptors located on airway smooth muscles (Drazen JM, 1999). Therefore, blocking this interaction with LTD4 receptor antagonists might inhibit the inßammatory effects.

Montelukast. In 1998, montelukast (Merck’s Singulair) (Figure 7) became the Þrst once-daily treatment for asthma and the second LTD4 receptor antagonist (after zaÞrlukast) to win FDA approval in the United States. The agent was approved that same year in Europe; in Japan, it was approved in June 2001 and licensed to Banyu for marketing. It is the Þrst leukotriene receptor antagonist intended for use both in adults and in children as young as 12 months. Compared with inhaled antiasthma medications, montelukast enjoys a higher degree of patient acceptability thanks to its once-daily, oral administration and relative lack of side effects. Leukotriene antagonists were recently included in the GINA guidelines, but their position in current treatment algorithms is somewhat ill-deÞned. The most recent version of the guidelines cautions that discontinuing therapy with inhaled corticosteroids in favor of treatment with leukotriene antagonists could result in worsening asthma (GINA, 2004). The guidelines acknowledge that leukotriene antagonists can provide some beneÞt when used

FIGURE 7. Structure of montelukast sodium.

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in combination with inhaled corticosteroids, but most clinical trial data available to date indicate that long-acting beta2 agonists have superior efÞcacy as add-on therapy. Montelukast is an LTD4 receptor antagonist and exerts its biological effect by binding to receptors located on airway smooth muscles and preventing the binding of LTD4 (Drazen JM, 1999). Montelukast-treated patients show reductions in circulating eosinophils, sputum eosinophils, and exhaled nitric oxide. Montelukast is sometimes prescribed as monotherapy in patients with mild disease who might otherwise receive inhaled corticosteroids. A multicenter, randomized, double-blind, parallel-group, 24-week study compared the long-term effects of low-dose inhaled ßuticasone (88 µg; 2 puffs of 44 µg) with oral montelukast (10 mg/day) (Meltzer EO, 2002). The study involved 522 patients older than 15 years who had persistent asthma. The primary measures of efÞcacy were change from baseline (mean percentage) in morning and premedication FEV1 readings. The changes were signiÞcantly higher in the ßuticasone group (22%) than in the montelukast group (14%). Measurements of asthma symptom score and absolute change from baseline in morning and evening PEFR were significantly improved in the ßuticasone group as well: −53.7%, 63.7 L/min, and 52.7 L/min, respectively, compared with −32.9%, 37.6 L/min, and 27.2 L/min, respectively, in the montelukast group. SigniÞcantly more patients were satisÞed with ßuticasone therapy (83%) than with montelukast therapy (66%). Adverse events attributable to ßuticasone and montelukast treatment were not signiÞcantly different (7% and 8% of each group, respectively); the most common side effects reported were headache, common cold, and upper respiratory tract infection. Montelukast has been shown to attenuate LTD4-induced bronchoconstriction and exercise-induced bronchoconstriction. To compare the agent’s ability to reduce asthma exacerbations with that of salmeterol (in the presence of ßuticasone), researchers conducted a 52-week, randomized, multicenter, parallel-group, double-blind study involving 1,490 patients with chronic asthma aged 15–72 years (Bjermer L, 2003). A four-week run-in period during which all patients received ßuticasone 100 µg twice daily was followed by 48 weeks during which patients continued to receive ßuticasone 100 µg twice daily plus either montelukast (10 mg once daily) or salmeterol (50 µg twice daily). The trial’s primary end point was the percentage of patients with at least one asthma exacerbation (deÞned as worsening asthma requiring an unscheduled visit to a physician, emergency room, or hospital and/or exacerbations requiring treatment with oral, intravenous, or intramuscular corticosteroids). The difference in the number of asthma exacerbations between the treatment groups was insigniÞcant: 20.1% (150/747) of patients receiving montelukast/ßuticasone had an asthma exacerbation and 19.1% (142/743) of the patients receiving salmeterol/ßuticasone. The types of exacerbations and their distribution across each group were also insigniÞcant. The investigators reported that patients receiving salmeterol/ßuticasone experienced a signiÞcantly higher number of drug-related adverse events than patients receiving montelukast/ßuticasone during the trial—10% and 6.3%, respectively.

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The same was true for serious adverse events—7.4% and 4.6%, respectively (Bjermer L, 2003). Anti-immunoglobulin E Agents Overview. The anti-IgE monoclonal antibody omalizumab (also known as rhuMAb-E25; Genentech/Novartis/Sankyo/Tanox Biosystems’ Xolair) launched in the United States in 2003. Because IgE plays a central role in allergic respiratory diseases, the debut of omalizumab focused increased attention on the relationship between allergies and asthma. In the United States, the only country where omalizumab has received marketing approval to date, omalizumab is indicated for the treatment of moderate-to-severe persistent asthma in patients who have demonstrated reactivity to a perennial, airborne antigen and fail to respond to inhaled corticosteroids. Mechanism of Action. IgE plays a major role in allergic disease by binding cell surface IgE receptors, thereby forming receptor-IgE complexes, which (upon cross-linking with neighboring complexes) results in the release of histamine and other inßammatory mediators from mast cells and basophils. Omalizumab forms complexes with free, unbound IgE (the agent binds the same Fc portion of the IgE molecule as the high-afÞnity IgE receptor), blocking binding of IgE to mast cells and basophils and consequently inhibiting the release of inßammatory mediators (Figure 8). In addition, omalizumab does not bind to or recognize IgG molecules. Omalizumab. Omalizumab (also known as rhuMAb-E25; Genentech/Novartis/ Sankyo/Tanox Biosystems’ Xolair) is a recombinant, humanized antiimmunoglobulin E (IgE) monoclonal antibody that directly binds and neutralizes excess antibody in circulation. Omalizumab was approved in the United States Omalizumab

Anti-lgE binds free lgE and facilitates its removal through the reticuloendothelial system

lgE effector cells (mast cells and basophils) with high- (or low-) affinity lgE receptors Anti-lgE does not bind IgE that is already bound to high- (or low-) affinity lgE receptors

Result: Downregulation of lgE receptors lgE-mediated activation of effector cells is prevented lgE = Immunogloblin E.

FIGURE 8. Omalizumab’s mechanism of action.

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in June 2003 for the treatment of moderate-to-severe persistent asthma in adults and adolescents. In July 2005, the drug received marketing approval in Europe for the treatment of severe persistent allergic asthma. Omalizumab is in Phase III trials in Japan for allergic asthma and rhinitis. Tanox has marketing rights to the drug in some Asian markets, and Novartis and Genentech have marketing rights in the United States. In January 2003, Sankyo entered into an agreement with Novartis to codevelop and comarket omalizumab in Japan. Clinical data presented for omalizumab demonstrate that it has corticosteroidsparing effects. Investigators tested omalizumab in a randomized, double-blind, placebo-controlled trial involving 546 allergic asthmatics with moderate-to-severe asthma (Soler M, 2001). Ranging from 12 to 76 years of age, the subjects exhibited asthma symptoms despite inhaled corticosteroid use. Omalizumab-treated patients received subcutaneous injections (0.016 mg/kg) once every two or four weeks (depending on the weight of the patient) for seven months. During the Þrst four months, omalizumab-treated patients also received the dose of inhaled steroid at which they were stable. During the next three months (the steroid-reduction phase), the steroid dose was tapered by 25% every two weeks. Compared with placebo, omalizumab-treated patients exhibited 58% fewer exacerbations per patient during the stable phase and 52% fewer in the reduction phase. In addition, omalizumab reduced the required dose for inhaled corticosteroids; the average daily beclomethasone dose required in omalizumab-treated patients was 100 µg, compared with 300 µg in the placebo arm. Furthermore, 79% of patients treated with omalizumab, compared with 55% of patients on placebo, reduced their corticosteroid dose by 50%. By the end of the reduction phase, 43% of patients in the treatment group were able to withdraw from corticosteroids completely, compared with 19% in the placebo group. Local injection-site symptoms (bruising, redness, warmth, and mild itching), the most common adverse events that were likely drug-related, were observed in 4% (placebo-adjusted) of omalizumab-treated patients. Drug-related headaches occurred in 1% of patients, and fatigue and paresthesia occurred in 1%. No patient developed anti-omalizumab antibodies. Short-Acting Beta2 Agonists Overview. Because of their rapid onset of action and ability to relieve symptoms, short-acting beta2 agonists are used to treat acute asthma attacks. Typically, these agents are used on an as-needed basis because continuous administration is thought to reduce their effectiveness. Their effect may last for as long as eight hours (Lemanske RF, 1990), but the duration of action varies among the different agents in the class. This section discusses albuterol (the class leader in majormarket sales), also known as salbutamol (GSK’s Ventolin; Schering-Plough’s Proventil), and levalbuterol (Sepracor’s Xopenex), a recently launched isomer of racemic albuterol that offers greater potency without increased side effects. The market for short-acting beta2 agonists is currently dominated by low-cost generic agents in most countries, but environmental regulations banning the use of CFC propellants are forcing the removal of many generic agents. In the United

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States, the market for short-acting beta2 agonists is dominated by inexpensive, CFC-propelled generic albuterol, but in March 2005, the FDA announced that CFC-propelled albuterol will be withdrawn from the U.S. market as of January 1, 2009. A limited number of inhalers containing HFA are currently marketed in the United States; these agents are patent-protected, branded drugs. Therefore, the cost of rescue medication in the United States will increase considerably when CFC-MDIs are withdrawn. Mechanism of Action. Beta2 adrenergic receptors are found in smooth muscle in the airways, blood vessels, and other tissues throughout the body. In the airways, stimulation of these receptors by beta2 agonists relaxes bronchial smooth muscle and produces bronchodilation. Short-acting beta2 agonists have also been shown to have anti-inßammatory properties, including blocking the release of leukotrienes and inhibiting phospholipase A2, a key enzyme in the proinßammatory arachidonic acid pathway. Albuterol. Albuterol (GSK’s Ventolin; Schering-Plough’s Proventil, generics) (Figure 9) was approved for asthma in 1982. Known as salbutamol in Europe, this agent has more recently been recognized as effective in preventing symptoms of exercise-induced asthma when administered just before physical activities. Albuterol is also on the market as part of a combination therapy with the anticholinergic ipratropium bromide (Boehringer Ingelheim’s Combivent, Valeas’ Breva). Although albuterol has been on the market for decades, some details of the agent’s mechanism of action remain unclear. In a study designed to determine whether albuterol reverses bronchoconstriction by stabilizing mast cells, 16 mild asthmatics received 400 µg albuterol or placebo 30 minutes before being challenged with adenosine monophosphate ([AMP], which produces bronchoconstriction through the release of mediators from mast cells) or histamine (which induces direct smooth-muscle contraction). Prior to histamine challenge, albuterol and placebo inhalation increased FEV1 readings by 11% and 1.6%, respectively. Prior to AMP challenge, albuterol and placebo inhalation increased FEV1 by 16.4% and 0.3%, respectively. Albuterol provided protection against induced bronchoconstriction, as measured by the log of provocative concentrations (PC), causing a 20% or greater decline in FEV1 (PC20). The log PC20 for histamine after placebo and albuterol was -0.24 and 0.91, respectively. The log PC20 for AMP after placebo and albuterol was 0.69 and 2.22, respectively. Because these data suggest that OH HO

CH2

CH

NHR CH2

HO FIGURE 9. Structure of albuterol (R = C(CH3 )3 ).

464

ASTHMA

albuterol’s protective effect against AMP is signiÞcantly greater than the corresponding protection against histamine, the authors speculate that albuterol’s effects on lung function act through the stabilization of mast cells. Adverse events were not reported. Levalbuterol. Levalbuterol (Sepracor’s Xopenex), also known as levosalbutamol, launched in the United States in March 2002 in nebulized form for both adult and pediatric (6–11 years of age) asthmatic patients. An HFA-propelled MDI formulation of albuterol received FDA approval in March 2005. The MDI formulation launched in 2005, and became one of four HFA formulations of short-acting beta2 agonists available in the United States. Abbott Laboratories is copromoting levalbuterol in the United States with Sepracor. With the exception of levalbuterol (the [R]-isomer of albuterol), currently marketed beta2 agonists are racemic mixtures composed of both (R)- and (S)-isomers. The drive to develop levalbuterol began when the (R)-isomer of albuterol was discovered to be the active bronchodilator and the (S)-isomer was found to promote smooth-muscle contraction and oppose bronchodilation by increasing intracellular calcium levels in the airways (Yamaguchi H, 1996). A retrospective review of patients who had been hospitalized with asthma compared the efÞcacy of nebulized albuterol with that of nebulized levalbuterol. Thirty-Þve patients were nebulized with 2.5 mg albuterol every four hours, and 19 patients were nebulized with 1.25 mg levalbuterol every eight hours as medically necessary. Although FEV1 and forced vital capacity (FVC) values for patients in both groups did not differ signiÞcantly between hospital admission and discharge, the asthmatics receiving levalbuterol required 53% fewer nebulizer treatments (average of 14 treatments) than did patients in the albuterol group (average of 30 treatments). In addition, asthmatics treated with levalbuterol had a 27% shorter hospital stay (average of 3.3 days) than patients receiving albuterol (average of 4.5 days). Although fewer patients in the levalbuterol group required rescue nebulizations, the difference was not signiÞcant. This study did not Þnd a significant difference between levalbuterol and albuterol in the ability to improve lung function as measured by FEV1 , but previous studies involving outpatient analysis have reported signiÞcantly greater increases in FEV1 in asthmatics receiving levalbuterol (Milgrom H, 2001). Oral Corticosteroids Overview. Although oral corticosteroids are used less frequently than inhaled corticosteroids because of their high rate of side effects, short-term administration of oral corticosteroids is effective in patients with moderate-to-severe asthma in preventing progression of exacerbation, reversing inßammation, speeding recovery, and reducing rate of relapse. Long-term use of oral corticosteroids may prove efÞcacious for patients with severe asthma who do not respond to typical treatments. Side effects stemming from long-term use may include high blood pressure, osteoporosis, bone fractures, cataracts, muscle weakness, and slower

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growth in children. Prednisone (multisource) is the oral corticosteroid most commonly used for the treatment of asthma. Mechanism of Action. All corticosteroids exert their therapeutic effect by binding to glucocorticoid receptors, which are found in all cells and are abundant in the epithelium of bronchi. In this way, corticosteroids alter intracellular activities and reduce the transcription of genes that encode proteins involved in the inßammatory response, including the cytokines interleukin (IL)-1, -3, 4, -5, -6, and -8; TNF-α; GM-CSF; and RANTES. By lowering the levels of these inßammation mediators, corticosteroid therapy reduces levels of lymphocytes, eosinophils, macrophages, and mast cells in mucosal ßuids. In addition, corticosteroids increase the transcription of genes responsible for producing beta2 adrenoreceptors and lipocortin 1, a protein that inhibits phospholipase A2 (a proinßammatory enzyme). Other key mechanisms by which corticosteroids help alleviate the symptoms of asthma include inhibition of T-cell activation (and subsequent cytokine release), promotion of apoptosis of eosinophils, inhibition of NO synthase, and reduction in mucus secretion by submucosal gland cells. Evidence also suggests that these drugs help restore damaged epithelium. Prednisone. The oral, synthetic corticosteroid prednisone (multisource) (Figure 10)—used most often for its potent anti-inßammatory effects—has proved efÞcacious not only for asthma but also for arthritis, colitis, bronchitis, certain skin rashes, and allergic or inßammatory conditions of the nose and eyes. Prednisone is inactive in the body; to be effective, it must Þrst be converted to prednisolone by enzymes in the liver. Administering a short course of oral corticosteroids to asthmatics who are being discharged from a hospital setting is a common practice intended to reduce relapse. To compare the ability of Þve days of oral prednisone therapy (n = 261) to prevent relapse in children with acute asthma with the ability of two days of oral dexamethasone (n = 272), investigators conducted a prospective randomized trial with the primary outcome of relapse within ten days (Qureshi F, 2001). Patients were aged 2–18 years of age and had presented to a pediatric emergency room (ER) with acute asthma exacerbations. Prednisone and dexamethasone were

CH2OH C O

H3C

O OH

H3C


466

ASTHMA

found to have similar outcomes when the following were analyzed: relapse rates (6.9% and 7.4%, respectively); hospitalization rates from the ER (12% and 11%, respectively) or after relapse (17% and 20%, respectively); and symptom persistence at ten days’ post-treatment (21% and 22%, respectively). Prednisone did, however, result in signiÞcant increases in the following (compared with dexamethasone): exclusion due to vomiting in the ER (3% and 0.3%, respectively); parental noncompliance (4% and 0.4%, respectively); and missing at least two days of school (19.5% and 13.2%, respectively). This trial suggests that although efÞcacy measures are similar, dexamethasone may offer some beneÞts in compliance and side-effect parameters in children with acute asthma. Methylxanthines Overview. Methylxanthines have been used as bronchodilators for treating asthma for the past 50 years. In this class, theophylline (AstraZeneca’s TheoDur, 3M Pharmaceuticals’ Theolair, generics) is the most frequently used agent for asthma treatment. Theophylline was once a Þrst-line therapy for asthma, but with the emergence of newer, more efÞcacious agents, it has been relegated to third- or fourth-line status in patients whose disease is not adequately controlled by corticosteroids and long-acting beta2 agonists. Mechanism of Action. Methylxanthines probably have several mechanisms of action, but questions remain as to which are responsible for their bronchodilating effect. The intracellular cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) regulate bronchodilation. By inhibiting phosphodiesterase (PDE) isoenzymes, particularly PDE types 3 and 4, which degrade cAMP and cGMP, methylxanthines relax smooth muscle in the pulmonary arteries and airways. Methylxanthines are also nonselective antagonists of adenosine receptors found on the surface of some cells. Although not important in mediating bronchodilation, adenosine-receptor antagonism by methylxanthines increases ventilation during hypoxia and reduces respiratory muscle fatigue. Theophylline. Theophylline (AstraZeneca’s Theo-Dur, 3M’s Theolair, generics) (Figure 11) is one of the oldest and most widely available drugs used for the treatment of asthma, but its use has declined in the past decade, and it is no longer a preferred pharmaceutical in asthma therapy. Given the adverse events associated with theophylline use, the agent is typically reserved for patients with refractory disease (i.e., asthmatics whose symptoms are not well controlled by typical asthma agents). In a trial designed to compare the efÞcacy and safety of doxofylline with that of theophylline, 346 patients with chronic, reversible bronchial asthma received oral administration of doxofylline 200 µg or 400 µg, theophylline 250 µg, or placebo for 12 weeks (Goldstein MF, 2002). The primary efÞcacy measurements were FEV1 readings. Statistically signiÞcant mean percentage increases in FEV1 two hours post-treatment were observed in patients receiving 400 mg doxofylline and

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250 mg theophylline, compared with patients receiving placebo (mean percent increases in FEV1 ranged from 10% to 15% above increases with placebo). Beginning at week 2 of the study, both the doxofylline 400 mg and theophylline 250 mg groups experienced a signiÞcant decline (six- to eightfold) in the average number of asthmatic attacks per day. This reduction in asthma attacks was found to accompany signiÞcant declines in albuterol use, particularly in patients in the doxofylline 400 mg and theophylline 250 mg groups, where between 1 and 1.5 fewer mean puffs/day were observed. The percentage of patients dropping out because of an adverse event was signiÞcantly lower in the doxofylline 400 mg group (11.4%) than in the theophylline 250 mg group (31.4%). The lower-dose doxofylline (200 mg) group and the placebo group experienced percentage dropout rates of 3.6% and 3.4%, respectively. The most common adverse events included headache, nausea, nervousness, and insomnia. The investigators claim that for every Þve patients treated with theophylline 250 mg, one adverse event was spared by doxofylline 400 mg. Both oral and intravenous administration of methylxanthines cause systemic side effects. Therapeutic serum concentrations fall within the range of 10–20 mg/mL, but such side effects as nausea, vomiting, tremors, and mild central nervous system symptoms may occur with only slightly higher concentrations, in the range of 20–30 mg/mL. Serum concentrations greater than 30 mg/mL are associated with a small risk of seizure or myocardial infarction. Because of methylxanthines’ narrow therapeutic index, patient serum concentrations must be monitored upon initiation of therapy and at least twice yearly thereafter. Use of sustained-release theophylline formulations, the most commonly used formulations, reduces the wide variations in serum concentration that characterize the immediate-release formulations. Cromolyns Overview. Cromolyn sodium (King Pharmaceuticals/SanoÞ-Aventis’ Intal) and necrodomil sodium (King Pharmaceuticals/SanoÞ-Aventis’ Tilade) have different chemical structures, but both are inhaled, nonsteroidal anti-inßammatory drugs (NSAIDs) for the treatment of asthma. When administered on a longterm basis, given four times daily, they reduce the frequency and severity of early- and late-phase allergen-induced reactions, exercise-induced asthma, and

FIGURE 11. Structure of theophylline.

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ASTHMA

airway hyper-responsiveness. Cromolyns are often used to reduce seasonal hyperresponsiveness in asthmatics who have sensitivity to grass pollen. Because these drugs are not easily absorbed through mucous membranes, high concentrations of cromolyns are not found in the systemic circulation, and side effects are minimal. Cromolyns are extremely safe and are among the least toxic drugs used in asthma management. Therefore, these agents are more frequently prescribed for children than for adults. In recent years, however, physicians’ worries about inhaled steroids have eased somewhat, and the use of cromolyns is declining in the pediatric population as well. Mechanism of Action. Although cromolyns’ precise mechanism of action is unclear, they appear to inhibit the degranulation of sensitized and nonsensitized mast cells that occurs after exposure to speciÞc antigens. Cromolyn sodium is known to inhibit the release of histamine and SRS-A (the slow-reacting substance of anaphylaxis, a leukotriene) from the mast cell, resulting in membrane stabilization and inhibition of the early asthmatic response. Cromolyn Sodium. Cromolyn sodium (King Pharmaceuticals/SanoÞ-Aventis’ Intal) (Figure 12) is indicated by the Expert Panel II report (Second Expert Panel Report on Guidelines for the Diagnosis and Management of Asthma. NIH publication No. 97-4051; July 1997) as a component of therapy in the treatment of mild persistent and moderate persistent asthma, but it offers little beneÞt during an acute exacerbation of asthma. The agent has very few side effects and demonstrates better efÞcacy in asthmatic children than in asthmatic adults. Cromolyn administered as a dry powder can cause minor throat irritation and transient cough in some children; the following study was designed to assess the ability of a cromolyn solution, administered via nebulizer, to reduce symptoms and attacks and reduce the need for concomitant bronchodilators in children (Prenner BM, 1982). Cromolyn 20 mg was nebulized four times a day for eight weeks in two- to seven-year-old asthmatics. In addition to a physician’s overall assessment of asthma severity, symptom scores for dyspnea, tightness, wheeze, and cough were taken at baseline and in the Þnal two weeks of treatment. Scores taken near the end of the trial were signiÞcantly reduced (between threefold and sixfold) over baseline. Five of the 19 children were able to discontinue theophylline use, and 13 children had reduced theophylline use by at least 85% by the last two weeks of the trial. Fourteen children required emergency care at

O

O

O

O

OH NaOOC

O

O

FIGURE 12. Structure of cromolyn sodium.

COONa

CURRENT THERAPIES

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least once during the trial, and the incidence of these events did not change over the eight-week treatment period. Measures of the number of times the children were awakened by asthma and the number of days on which asthma interfered with normal activity did not reach signiÞcance. The investigators note that these numbers were already relatively low at baseline. This trial was not placebocontrolled, which adds to the difÞculty in interpreting these data. Anticholinergics Overview. Anticholinergics are the Þrst bronchodilators used to treat asthma. They act at cholinergic muscarinic receptors to reduce bronchial smooth-muscle tone and to block the neurogenic bronchoconstriction response triggered by inhaled irritants. Despite these favorable characteristics, marketed anticholinergics such as ipratropium bromide (Boehringer Ingelheim’s Atrovent) and oxitropium bromide (Boehringer Ingelheim’s Oxivent) are not ideal asthma agents. In addition to binding the M1 and M3 muscarinic receptors responsible for bronchoconstriction, these agents also bind to M2 receptors, thereby blocking the favorable bronchodilating effects of this receptor subtype. As discussed in “Emerging Therapies,” companies are developing novel, more-selective anticholinergics that inhibit only the M1 and M3 receptors. Mechanism of Action. Anticholinergic drugs block the effects of acetylcholine, a parasympathetic nervous system neurotransmitter that promotes bronchoconstriction. Acetylcholine, released from branches of the vagus nerve that run along the airways, binds to the M1 and M3 muscarinic receptors located in the smooth muscle and submucosal glands in the airways. Acetylcholine binding activates the receptors, stimulating both the contraction of smooth muscle (leading to bronchoconstriction) and the secretion of mucus from the submucosal glands. By binding to the M1 and M3 muscarinic receptors, anticholinergic drugs block the access of acetylcholine, thus reducing the number of activated receptors. As a result, smooth-muscle tone in the airways declines, thereby reducing bronchoconstriction and mucus secretion. Ipratropium Bromide. Ipratropium bromide (Boehringer Ingelheim’s Atrovent) (Figure 13) is the best studied of the approved anticholinergics. Boehringer Ingelheim has also developed oxytropium (Oxivent) and an ipratropium-containing combination therapy (Combivent), which is discussed in the next section. Ipratropium bromide alleviates bronchoconstriction by blocking the effects of acetylcholine. In addition, it is thought to be a useful adjunctive agent in the treatment of asthma and has shown increased efÞcacy when combined with a beta2 agonist (see “Ipratropium/Albuterol” section). Unlike adrenergic bronchodilators (such as albuterol), ipratropium’s spirometric beneÞts do not decline over time. In addition, because the agent is poorly absorbed and does not readily enter the central nervous system, high doses of ipratropium bromide can be administered to asthmatics.

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ASTHMA

In a trial designed to compare the bronchodilating effects of ipratropium bromide delivered by different inhalers, 70 patients (children and adolescents) with stable bronchial asthma were initially administered 40 µg of the agent via DPI (Ulrik CS, 1992). Twenty-one percent of the patients responded (deÞned as patients who experienced at least a 15% increase in FEV1 30 minutes after inhalation) and were then enrolled in the study’s investigational phase (a double-blind, randomized, crossover trial). Responders received 40 µg ipratropium bromide, administered by both an Ingelheim powder device system (IPI) and an MDI on two separate days less than a week apart. FEV1 measurements were taken after 15, 30, 60, 120, 180, 240, 300, and 360 minutes. Although FEV1 (% of predicted) values were lower for the agent when inhaled via MDI (5.1% and 11.2% at 15 and 30 minutes, respectively) versus IPI (12.2% and 16.2% at 15 and 30 minutes, respectively), this difference did not reach signiÞcance; both groups receiving ipratropium bromide experienced signiÞcant improvement in lung function compared with placebo. For both groups, the maximum FEV1 values (% of predicted) occurred 30 minutes post-administration, and maximal response lasted 90 minutes. No adverse events due to inhalation of ipratropium bromide were reported, and no reduction in patient FEV1 measures was observed. Anticholinergic agents can induce local and systemic side effects (e.g., blurred vision, cardiac stimulation). Uptake of anticholinergics has steadily declined since the introduction of the more speciÞc and efÞcacious beta2 agonists. Ipratropium/Albuterol. Ipratropium/albuterol (Boehringer Ingelheim’s Combivent, Valeas’ Breva) combines anticholinergic and beta2 agonist agents in a single inhaler. Anticholinergic agents promote bronchodilation primarily in the large airways, where cholinergic nerves and muscarinic receptors predominate. Beta2 agonists dilate mainly the bronchioles, where the beta-adrenergic receptors abound. Because these two drug classes act on different airways, combining an anticholinergic with a beta2 agonist should logically produce greater bronchodilation than either agent alone. Whether anticholinergics and beta2 agonists truly have additive or synergistic effects is uncertain. In general, however, lower doses of two agents are preferable to higher doses of a single agent because the risk of side effects is reduced. In particular, combination therapy may limit the dangers

FIGURE 13. Structure of ipratropium bromide.

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associated with the overuse of short-acting beta2 agonists. Combining anticholinergic and beta2 agonist agents in a single inhaler also reduces the cost of therapy and improves patient compliance. A double-blind, randomized, prospective trial involving 180 asthmatics hospitalized for exacerbation was designed to compare the combination of ipratropium and albuterol with albuterol and placebo (Rodrigo GJ, 2000). Primary outcome measures were improvement of pulmonary function (as measured by FEV1 and PEFR) and hospital admission rates. Agents were administered via MDI/spacer at ten-minute intervals for three hours (24 puffs = 2, 880 µg of albuterol and 504 µg of ipratropium). Patients receiving ipratropium/albuterol experienced signiÞcant average increases in FEV1 (48.1%) and PEFR (20.5%) compared with the control group. Post-administration, 39% of the patients in the albuterol/placebo group and 20% of the patients in the albuterol/ipratropium group were admitted, a 49% reduction in risk of admission for the ipratropium/albuterol group. Further analysis demonstrated that patients with more severe pulmonary obstruction (FEV1 ≤ 30% of predicted) were more likely to beneÞt from the addition of higher doses of ipratropium to beta2 agonist therapy than were patients with nonsevere pulmonary obstruction. With the exception of dry mouth (experienced by 50% of the ipratropium group and 22% of the control group), adverse events due to therapy did not differ signiÞcantly between treatment groups. The most common adverse events experienced by both groups were tremors and headache. EMERGING THERAPIES Current agents used to treat asthma exert their therapeutic effect by reversing bronchoconstriction, reducing inßammation, or combining these two actions. Although many emerging therapies exploit the same strategies, others are directed at novel targets or are targeted more speciÞcally than their predecessors. Table 4 summarizes the drug therapies in development for asthma. Several new agents that combine long-acting beta2 agonists and inhaled corticosteroids are in early-stage development. Noteworthy combinations now in Phase II clinical trials include Altana/SanoÞ-Aventis’s ciclesonide/formoterol combination; GlaxoSmithKline’s GSK-685698 and GSK-159797; ScheringPlough/Novartis’s mometasone (Schering-Plough’s Asmanex) and formoterol; and Skye Pharma’s combination of ßuticasone and formoterol (Flutiform). Because trial data on these new combination agents are scarce, they are not discussed in detail here. Inhaled Corticosteroids Overview. Novel corticosteroids are in various stages of development worldwide. The most commercially promising agents are those that have fewer side effects than their predecessors already on the market. The potential for side effects with long-term treatment is an ongoing concern for patients (especially children) with persistent asthma and contributes to noncompliance. Inhaled corticosteroids

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TABLE 4. Emerging Therapies in Development for Asthma Compound

Development Phase

Marketing Company

Inhaled corticosteroids Ciclesonide (Alvesco) United States Europe Japan

PR R PR

Altana/Sanofi-Aventis Altana Teijin

Long-acting beta2 agonists Arformoterol United States Europe Japan

IIIa — —

Sepracor — —

Phosphodiesterase 4 inhibitors Roflumilast United States Europe Japan

III PR II

Altana Altana Altana/Tanabe

Anticytokine agents Daclizumab (Zenapax) United States Europe Japan

II — —

Protein Design Labs/Roche — —

Mepolizumab United States Europe Japan

III — —

GlaxoSmithKline — —

Anticholinergics Tiotropium bromide United States Europe Japan

— III II

— Boehringer Ingelheim/Pfizer Boehringer Ingelheim

Cell adhesion inhibitors R-411 United States Europe Japan

II II —

Roche Roche —

IVL-745 United States Europe Japan

— II —


a Phase III development for chronic obstructive pulmonary disease.

PR = Preregistered; R = Registered.

currently in development are designed to enable less-frequent dosing with fewer adverse effects. Altana/SanoÞ-Aventis/Teijin’s ciclesonide is preregistered for the treatment of asthma in the United States; the Þrst European launch took place in the United Kingdom in January 2005. Several other corticosteroids are in earlyphase trials for asthma, including GW-685698 (GlaxoSmithKline), NCX-1020

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(NicOx), and NS-126 (SS Pharmaceutical). However, owing to the scarcity of published clinical trial data, only ciclesonide will be discussed in detail here. Mechanism of Action. All corticosteroids exert their therapeutic effect by binding to glucocorticoid receptors, which are found in the immune cells that play a role in asthma and are abundant in the epithelium of bronchi. Corticosteroids alter intracellular activities and reduce the transcription of genes that encode proteins involved in the inßammatory response, including the cytokines interleukin (IL)-1, -3, -4, -5, -6, and -8; tumor necrosis factor-alpha (TNF-α); granulocytemacrophage colony-stimulating factor (GM-CSF); and regulated upon activation, normal T cells expressed and secreted (RANTES). By lowering the levels of these inßammation mediators, corticosteroid therapy reduces the activity of lymphocytes, eosinophils, macrophages, and mast cells in mucosal ßuids. Other key mechanisms by which corticosteroids help alleviate the symptoms of asthma include inhibition of T-cell activation (and subsequent cytokine release), promotion of apoptosis of eosinophils, inhibition of nitric oxide (NO) synthase, and reduction in mucus secretion by submucosal gland cells. Evidence also suggests that these drugs help restore damaged epithelium. Ciclesonide. In an attempt to reduce systemic absorption and side effects, researchers are developing corticosteroid therapies that act locally via activated metabolites. The most advanced of these corticosteroid pro-drugs (activated in the lungs) is ciclesonide, a once-daily, metered-dose inhaler (MDI) that is being codeveloped by Altana (formerly Byk Gulden), SanoÞ-Aventis, and Teijin. In 2001, Altana entered into an agreement with Aventis for the joint development and marketing of ciclesonide in the United States, where a new drug application (NDA) was submitted to the FDA in late December 2003. In October 2004, Altana received an approvable letter from the FDA for the treatment of persistent asthma in adults and in children at least four years old. Altana stated in a press release dated October 26, 2004, that the company is working with the FDA to resolve speciÞc clinical issues outlined in the letter. Altana markets ciclesonide in Europe, where the drug recently received approval for the treatment of persistent asthma in adults through the European Mutual Recognition Procedure. In January 2005, Altana announced ciclesonide’s launch in the United Kingdom. In January 2004, Teijin, Altana’s partner in Japan, submitted an approval application in Japan for the use of inhaled ciclesonide in asthma. Altana and SanoÞ-Aventis are also developing a combination inhaler that joins ciclesonide and formoterol in SanoÞ-Aventis’ Ultrahaler device; this combination product is in Phase II clinical trials. Ciclesonide is unique among inhaled corticosteroids because it is designed to be active primarily in the lung. Inhaled ciclesonide is the inactive parent compound of the active metabolite desisobutyryl-ciclesonide (des-CIC). Ciclesonide is converted to des-CIC by esterases that are expressed predominantly in the lung but also, at much lower levels, at most other sites in the body (Reynolds NA, 2004). Therefore, the portion of ciclesonide that is not delivered to the lung but is deposited orally in the pharynx and swallowed is far less likely to be converted

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to the active form than the portion delivered to the lung. Consequently, systemic exposure to the drug is minimized. Two 12-week, placebo-controlled trials of ciclesonide were presented at the 2002 Annual Meeting of the American Thoracic Society (ATS). In one trial, 360 patients were treated once daily in the morning, either with placebo, 100 µg ciclesonide, or 400 µg ciclesonide (Engelstätter R, 2002). Primary study end points were increases over baseline in morning peak expiratory ßow (PEF) and forced expiratory volume at one second (FEV1 ). Patients treated with placebo experienced a reduction in FEV1 of 28 mL; patients treated with 100 µg and 400 µg ciclesonide experienced increases of 129 mL and 192 mL, respectively. Morning PEF increased by 2 L/min and 3 L/min in the 100 µg and 400 µg ciclesonide groups, respectively; in the placebo group, PEF fell by 18 L/min. In another trial, 329 patients were treated either with placebo or with 200 µg or 800 µg ciclesonide (Chapman KR, 2002). In this trial, patients treated with placebo experienced a signiÞcant decline in both FEV1 (144 mL) and PEF (28 L/min), while FEV1 and PEF remained stable in patients treated with either dose of ciclesonide. Head-to-head trials indicate that ciclesonide has efÞcacy comparable to that of other low-dose corticosteroids. In a 12-week, randomized trial, 554 asthmatic patients received either 80 µg or 320 µg ciclesonide (once daily in the morning) or 200 µg budesonide twice daily (Engelstätter R, 2003). Both FEV1 and forced vital capacity (FVC) were reported to be signiÞcantly increased in the three treatment groups (data not available). SigniÞcant reductions were observed in asthma symptoms and use of rescue medications in all treatment groups (data not available). Importantly, both of the once-daily doses of ciclesonide were as effective as two daily doses of budesonide in improving morning and evening PEF, reducing the use of rescue medications, and increasing FEV1 and FVC (data not available). In addition, treatment with budesonide was associated with cortisol suppression in trial participants, while treatment with ciclesonide had no signiÞcant effect on urinary cortisol excretion. (Urinary cortisol excretion assays are often performed to determine whether a patient receiving corticosteroid therapy is adrenally suppressed, a condition commonly associated with chronic, high-dose corticosteroid therapy.) Long-Acting Beta2 Agonists Overview. Long-acting beta2 agonists demonstrate prolonged receptor occupancy, compared with short-acting beta2 agonists; accordingly, they are prescribed to provide partial, steady-state bronchodilation. When prescribed in conjunction with inhaled corticosteroids, beta2 agonists may also prevent airway remodeling. For this reason, therapeutic guidelines recommend that long-acting beta2 agonists be prescribed as adjuncts to corticosteroid therapy in cases of moderate persistent and severe persistent asthma. Several long-acting beta2 agonists are in development for asthma. Of particular note is a group of compounds originally developed by Theravance. In

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January 2003, GlaxoSmithKline (GSK) and Theravance announced an agreement to develop up to eight long-acting beta2 agonists using GSK’s drug delivery technology. GSK secured worldwide marketing rights to these agents as part of the agreement; among them are several candidates in development with a goal of once-daily dosing for asthma, including GSK-159797 and GSK-597901. Clinical trial data on these agents are not yet available, so they are not discussed in detail here. Mechanism of Action. Beta2 adrenergic receptors are found in smooth muscle in the airway and in the lungs, blood vessels, and other tissues throughout the body. In the airway, stimulation of these receptors by beta2 agonists activates adenylate cyclase, increasing the production of cyclic adenosine monophosphate (cAMP) and causing bronchodilation by relaxing smooth muscle. Other effects of beta2 agonists that have been observed experimentally include the following: • • • •

Blocking of mast-cell release of leukotrienes and histamine in the lungs. Reduced microvascular permeability and mucus production. Increased mucociliary function. Possible inhibition of the activity of phospholipase A2, an enzyme in the proinßammatory arachidonic acid pathway.

Arformoterol. Arformoterol, Sepracor’s single-isomer R,R-formoterol, is in Phase III trials in the United States for asthma and chronic obstructive pulmonary disease (COPD). In a press release dated October 26, 2004, Sepracor announced completion of two pivotal Phase III studies of arformoterol in COPD and plans to discuss submission of the arformoterol NDA for the COPD indication. The development status of arformoterol for the treatment of asthma is uncertain because no clinical data have been released for some time; the company’s web site lists COPD as the only indication for which the agent is currently in development (www.sepracor.com/products/pipeline.html. Accessed February 25, 2005). Arformoterol is a single-isomer version of its parent compound, formoterol, a racemic mixture of R,R- and S,S-formoterol marketed by Yamanouchi and Novartis. Sepracor is developing arformoterol based on evidence that the R,Renantiomer is 1,000 times more potent than the S,S-enantiomer. In vitro assays indicate that the S,S enantiomer may act as a beta2 receptor antagonist and impair bronchodilation (Moore RH, 2001; Mhanna MJ, 2003). In a randomized, double-blind, single-dose, six-way crossover study, 31 patients with asthma and FEV1 readings at 40–70% of predicted value were given arformoterol (12, 24, 48, or 72 µg), salbutamol (2.5 mg), or placebo (Sepracor, media release, 2001). Peak percentage changes in FEV 1 readings for arformoterol were signiÞcantly higher than for placebo (arformoterol generated changes of 45–52%, while placebo generated a 22% increase) but not signiÞcantly different from salbutamol peak percentage changes (55.5%). Although onset of action of the two agents was similar, arformoterol doses of 24 µg and 72 µg resulted in signiÞcantly higher percentage changes in FEV1 at the 24-hour postdose time point (data not available). The number of asthma exacerbations and adverse events was

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lower in arformoterol recipients than in placebo and salbutamol recipients (data not available). In a media release dated September 20, 2001, Sepracor revealed partial data from a separate Phase II study, in which 340 patients with asthma demonstrated signiÞcant improvement in lung function when treated with a range of doses of arformoterol. The subsequent increase in FEV1 readings, relative to baseline, was in the range of 24–27%. The duration of action of the drug was up to 24 hours. Data on adverse events were not available. Phosphodiesterase 4 Inhibitors Overview. NonspeciÞc phosphodiesterase (PDE) inhibitors, such as the currently available theophylline, are often relegated to second- or third-line status owing to their relatively poor side-effect proÞles. As a result, PDE inhibition research is now focused on targeting individual PDE enzymes (each with distinct activities and tissue distributions) in hopes of improving side-effect proÞles and efÞcacy. Inhibition of PDE4 is of particular interest because of its preferential expression in inßammatory cells thought to participate in the pathogenesis of asthma. Unfortunately, Þrst-generation PDE4 inhibitors demonstrated undesirable side effects such as headache, nausea, and emesis. Because PDE4 inhibitors represent a more speciÞc therapeutic approach in the treatment of airßow limitation (compared with theophylline), companies are trying to improve the sideeffect proÞles of these compounds. Roßumilast (Altana/Tanabe’s Daxas) is the most clinically advanced PDE4 inhibitor in development. Also in development are GSK/Elbion’s 842470 (AWD-12281), Almirall-Prodesfarma’s arofylline, and Kyowa Hakko Kogyo’s KW-4490, but the lack of published trial data precludes in-depth analysis of these drugs. GSK’s cilomilast was in development for asthma, but development for this indication has been discontinued. Mechanism of Action. Inßammatory cells thought to participate in the pathogenesis of asthma (and COPD) are known to express PDE4. PDE4 breaks down cAMP in inßammatory cells, including eosinophils, and in tracheal smoothmuscle cells. PDE4 inhibition elevates cellular levels of cAMP, which in turn suppresses the inßammatory response and causes bronchodilation. Therefore, PDE4 has become a molecular target of interest in the development of novel therapies for asthma and COPD. Roflumilast. Roßumilast, the most clinically advanced PDE4 inhibitor, is being developed by Altana/Tanabe as an orally administered, once-daily treatment for asthma and COPD. Altana entered into a worldwide codevelopment and comarketing agreement with Pharmacia (now PÞzer) in April 2002. Roßumilast is in development for asthma in the United States (Phase III), Europe (Phase III), and Japan (Phase II trials under way by Tanabe). However, in July 2005 PÞzer returned all rights to the drug to Altana. The NDA Þling in the United States was expected in 2005, but in October 2004, Altana announced that because of the challenge of recruiting adequate numbers of patients for clinical trials, the Þling would be delayed until 2006.

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Several abstracts from the 99th Annual Meeting of the ATS in May 2003 (Seattle, Washington) suggest that roßumilast is an effective and well-tolerated treatment for asthma. In a 12-week, randomized, double-blind study, 499 asthmatics received either a once-daily oral dose of 500 µg roßumilast or 400 µg inhaled beclomethasone dipropionate (BDP) administered as two daily doses of 200 µg each (Bousquet J, 2003). Both agents signiÞcantly improved lung function. Mean changes compared with baseline for FEV1 were 0.30 L for roßumilast and 0.37 L for BDP; for FVC, 0.30 L and 0.36 L, respectively; and for morning PEFR, 21.59 L and 26.94 L, respectively. Both agents also signiÞcantly reduced the need for rescue medication and lowered asthma symptom scores to a similar degree. Although the abstract does not provide data on adverse events, the authors claim that 500 µg roßumilast (oral, once-daily) is comparable to inhaled, twice-daily BDP (400 µg). A randomized, double-blind, parallel-group, dose-ranging study of 690 patients examined the dose-dependent effects of roßumilast on FEV1 (Leichtl S, 2002). At baseline, the mean FEV1 was 73%. Patients were treated with 100 µg, 250 µg, or 500 µg of roßumilast once daily. FEV1 increased by 11% (260 mL) in the 100 µg treatment group, by 13% (320 mL) in the 250 µg treatment group, and by 16% (400 mL) in the 500 µg treatment group. All three treatment groups also demonstrated improvements in morning PEF (10 L/min, 12 L/min, and 20 L/min, respectively, for the 100 µg, 250 µg, and 500 µg treatment groups) and in evening PEF. For all measures examined, the improvement in patients treated with the highest dose was greater than in patients treated with the lowest dose. It should be noted that this study lacked a placebo control and that details of adverse events were not provided in the published abstract. Data from clinical trials for the COPD indication provide some insight into the likelihood and nature of adverse events observed in patients treated with roßumilast. In a randomized, placebo-controlled trial of 1,411 patients with moderate-to-severe COPD, the most frequently reported adverse events included diarrhea, nausea, and abdominal pain (Bateman ED, 2004). Most adverse events were described as being mild to moderate in intensity. Anticytokine Agents Overview. The 2003 launch of the biological therapy omalizumab (also known as rhuMAb-E25; Genentech/Novartis/Sankyo/Tanox Biosystems’ Xolair) has directed much attention toward biologics-based approaches to asthma therapy. GSK’s mepolizumab, an IL-5 antagonist, is in Phase II clinical trials. Several other anticytokine agents—including Genaera/Medimmune’s anti-IL-9 monoclonal antibody and Bayer’s IL-4 antagonist pitrakinra—are in development for asthma, but are not analyzed here because of a lack of sufÞcient published trial data. Several companies are developing anticytokine agents that disrupt multiple targets. Regeneron’s dual IL-4/IL-13 antagonist is in Phase I clinical trials, and few data on its potential efÞcacy are available. Therefore, it is not discussed in detail here.

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Mechanism of Action. To date, most anticytokine research for asthma has focused on agents that inhibit IL-4, IL-5, and more recently, IL-13 and IL-2. Although the functions of IL-4 and IL-13 appear to overlap, a distinct role is emerging for IL-13 in allergic (and parasitic) responses, with potential implications for drug development. IL-4 mediates key proinßammatory events, including induction of IgE isotype switching, increased expression of cell adhesion molecules, and increased mucus production. The cytokine IL-5 is essential for the maturation of eosinophils and their release from the bone marrow. It is well documented that IL-5 is highly expressed in the bronchial mucosa of asthmatics. An association also exists between the number of activated eosinophils in the airways and the clinical severity of asthma. Expression of both IL-2 and the IL-2 receptor are elevated in asthmatic patients, and IL-2 has been implicated in the development of corticosteroid-resistant asthma. Daclizumab. Daclizumab (Protein Design Labs/Roche’s Zenapax) is a humanized monoclonal antibody directed against the interleukin-2 (IL-2) receptor. Daclizumab is currently marketed for the prevention of kidney transplant rejection but is in development for several other indications, including the treatment of persistent asthma. In September 2004, Roche and Protein Design Labs agreed to jointly develop and market daclizumab worldwide for the treatment of persistent asthma. Daclizumab inhibits IL-2-dependent activation of T cells by blocking the alpha subunit of the human high-afÞnity IL-2 receptor. Peripheral blood lymphocyte cultures from patients with asthma have disproportionate numbers of IL-2-positive T cells and elevated levels of IL-2. Preclinical data indicate that daclizumab inhibits production of several cytokines produced by activated T cells and implicated in the pathogenesis of asthma, including interferon-gamma (IFN-γ ), tumor necrosis factor-alpha (TNF-α), IL-10, IL-5, and IL-4 (McClellan M, 2002). Preliminary results from an ongoing Phase II trial of daclizumab were presented at the American Academy of Allergy, Asthma, and Immunology meeting on March 23, 2004, in San Francisco (Busse WW, 2004). The double-blind, placebo-controlled study enrolled 116 patients with chronic persistent asthma not adequately controlled by high-dose inhaled corticosteroids. The primary end point measured in the study was the change in FEV1 from baseline to day 84 of the study. Patients received an IV infusion of daclizumab or placebo every two weeks; all patients continued treatment with inhaled triamcinolone acetonide throughout the 12-week study period. Patients treated with daclizumab showed a mean increase in FEV1 of 4.4%, compared with a decline of 1.52% in patients treated with placebo. Patients treated with daclizumab also showed prolonged time to asthma exacerbations requiring corticosteroid rescue. Mepolizumab. GSK’s anti-IL-5 MAb mepolizumab (SB-240563) is in Phase III clinical trials in the United States for the treatment of severe asthma and atopic dermatitis. GSK holds a worldwide, exclusive license for Protein Design Labs’ patents covering humanized antibodies directed against IL-5. In turn, GSK

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has agreed to pay Protein Design Labs a licensing fee, maintenance fees, and royalties on any future sales. In a Phase II, multicenter, double-blind, placebo-controlled trial, three intravenous infusions (750 mg/dose) of mepolizumab or placebo were administered to 24 patients with atopic asthma over a 20-week period (Flood-Page PT, 2003). Although mepolizumab reduced blood eosinophils to negligible levels, the effect on bone marrow and airway eosinophils compared with placebo was less pronounced, producing a median decline from baseline of 52% and 55%, respectively. Subsequent experiments demonstrated that eosinophil numbers returned to baseline values 4–20 weeks after administration of the Þnal dose of mepolizumab. Clinical measurements of lung function, such as FEV1 and morning PEFR, were not signiÞcantly different between the mepolizumab and placebo groups. Anticholinergics Overview. Anticholinergics, the Þrst bronchodilators used to treat asthma, act at cholinergic muscarinic receptors to reduce bronchial smooth-muscle tone and block the neurogenic bronchoconstriction response triggered by inhaled irritants. Although they are less potent bronchodilators than the beta2 agonists, anticholinergics are still prescribed for some asthma patients. In the most recently updated treatment guidelines of the Global Initiative on Asthma (GINA), anticholinergics are recommended as alternative rescue medications for patients who experience adverse effects (such as tachycardia, arrhythmia, and tremor) from short-acting beta2 agonists. Some physicians prescribe them as third- or fourth-line maintenance therapy for patients whose disease is not adequately controlled by inhaled corticosteroids and long-acting beta2 agonists. Tiotropium bromide (Boehringer Ingelheim/PÞzer’s Spiriva) is a reÞnement of an existing therapeutic approach that should improve lung function and provide greater symptom relief and greater convenience than existing anticholinergics. Mechanism of Action. Anticholinergic drugs block the effects of acetylcholine, a parasympathetic neurotransmitter that promotes bronchoconstriction. Released from branches of the vagus nerve that runs along the airways, acetylcholine binds to the M1 and M3 muscarinic receptors located in the smooth muscle and the submucosal glands of the airways. Acetylcholine binding activates the receptors, stimulating both the contraction of smooth muscle (leading to bronchoconstriction) and the secretion of mucus from the submucosal glands. By binding to the M1 and M3 muscarinic receptors, anticholinergic drugs block the access of acetylcholine, reduce the number of activated receptors, and as a result, reduce mucus secretion and smooth-muscle tone in the airways. However, currently marketed anticholinergics (such as ipratropium [Boehringer Ingelheim’s Atrovent]) are not ideal because they also interfere with M2 receptors, which facilitate bronchodilation. Tiotropium Bromide. Tiotropium bromide (Boehringer Ingelheim/PÞzer’s Spiriva) is marketed in the United States and Europe for COPD; in Japan, the drug is registered for COPD. Phase III trials for asthma were reported in Germany

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in 1997, and Phase II trials were reported in the United Kingdom and Japan in the same year, but the drug’s development status for asthma is not clear. Although the agent is not approved for the treatment of asthma, physician audit data indicate that physicians are prescribing the drug to asthmatic patients. Currently marketed anticholinergics bind to and block activation of M1 and M3 receptors, which promote bronchoconstriction, but they also interfere with M2 receptors, which facilitate bronchodilation. Although tiotropium bromide binds all three receptor types, the agent dissociates faster from the M2 receptor than from the M1 and M3 receptors, thereby retaining the beneÞcial bronchodilating effect—a distinct advantage in this class of agents. Tiotropium bromide is approximately ten times more potent than ipratropium and has a longer duration of action. To analyze tiotropium bromide’s duration of bronchodilation, a double-blind, placebo-controlled, single-dose crossover study was conducted in 12 atopic patients with methacholine-induced bronchoconstriction (O’Conner BJ, 1996). Patients received either placebo or tiotropium bromide at 10, 40, or 80 µg, followed by methacholine PC20 challenge. Tiotropium bromide caused bronchodilation that was sustained for 24 hours at all doses. The increase in FEV1 relative to placebo for 10, 40, and 80 µg tiotropium bromide at each time point was 6.7%, 8.2%, and 10%, respectively, at 2 hours; 10.4%, 5.5%, and 11.1% at 12 hours; and 7.3%, 7.1%, and 9.4% at 24 hours. FEV1 readings did not differ signiÞcantly from placebo at 36 and 48 hours post-drug administration. Each dose of tiotropium bromide resulted in signiÞcant protection against methacholine challenge in all patients at all time points. Peak protection occurred at the two-hour time point, when the protective effect was 5, 7.1, and 7.9 doubling doses for 10, 40, and 80 µg of drug, respectively. Tiotropium bromide was well tolerated; no adverse events occurred at any dosage. Cell Adhesion Inhibitors Overview. Reducing the inÞltration of cells into asthmatic airways by blocking cell adhesion pathways is a novel approach to asthma therapy. Monoclonal antibodies speciÞc for adhesion molecules expressed on endothelial cells, epithelial cells, and eosinophils have been successful in blocking key steps of the inßammatory response in animal models of asthma. This section analyzes two cell adhesion inhibitors, R-411 (Roche) and IVL-745 (SanoÞ-Aventis), both of which target the very-late-antigen 4 (VLA-4) integrin receptor present on inßammatory cells such as eosinophils (R-411 also targets α4β7). Additional cell adhesion inhibitors in development that are not covered here (owing to lack of data) include Encysive (formerly Texas Biotechnology)/Revotar’s bimosiamose and SanoÞ-Aventis’ 1031. In February 2005, Biogen Idec and Elan announced a voluntary marketing suspension of the VLA-4 antagonist natalizumab (Tysabri) following two reports of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients taking a combination of natalizumab and interferon beta-1a (Biogen Idec’s Avonex). In March 2005, the FDA announced that it was suspending clinical trials of other drugs in the same class, including GSK’s experimental multiple

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sclerosis drug 683–699. Roche has stated that it will continue to develop three VLA-4 antagonists, citing mechanistic differences between its compounds and those currently coming under scrutiny. Mechanism of Action. Integrin receptors promote cell adhesion and communication, leading to increases in migration, activation, and survival of inßammatory cells. The integrin receptors α4β1 (VLA-4) and α4β7 are known to be expressed on the surfaces of mast cells, eosinophils, and Th2 cells, all key players in asthma pathogenesis. In fact, VLA-4 and α4β7 have been shown to be more highly expressed in asthmatic patients, a Þnding that has made these receptors key targets for developing inhibitory drugs that would prevent inßammation by blocking the integrin-adhesion molecule connection. VLA-4 binds speciÞcally to vascularcell adhesion molecule 1 (VCAM-1), while α4β7 binds to both VCAM-1 and mucosal adressin cell adhesion molecule 1 (MAdCAM-1). R-411. Roche’s R-411 is a VLA-4 and α4β7 “dual” antagonist under investigation as a once-daily oral therapy for asthma. Phase II trials began in April 2002 in Europe; they include a dose-ranging study in patients not treated with inhaled corticosteroids, a study investigating whether R-411 can act as replacement therapy for inhaled corticosteroids, and a pediatric safety and pharmacokinetics study for chronic asthma. Roche expects its Þrst Þling for approval of R-411 to take place in 2007. R-411 interferes with the interaction between VLA-4 and VCAM-1, preventing eosinophil migration, which is observed in the late asthmatic response. VLA-4 is expressed by particular leukocytes and interacts with VCAM-1 on the endothelium to mediate leukocyte extravasation (migration of leukocytes from a vessel into surrounding tissue) to lung tissue. Early-stage trial data from a small study that assessed the pharmacokinetics and tolerability of R-411 in 50 healthy people were presented at the 2004 meeting of the ATS (Abbas R, 2004). Adverse events occurred at similar rates in people treated with R-411 and in people treated with placebo. No serious adverse events were reported. The study determined that R-411’s half-life was compatible with once-daily dosing. IVL-745. Prior to the acquisition of Aventis by SanoÞ-Synthélabo, IVL-745 was one in a series of VLA-4 antagonists held by Aventis. Aventis announced that Phase IIa trials began in February 2002, but results from these trials have not yet been released, and no news on the drug’s development status has been released by SanoÞ-Aventis. In vitro studies suggest that IVL-745 is a powerful inhibitor of eosinophil adhesion to VCAM-1 (Cairns JA, 2000). Research in ovalbumin-challenged allergic rat models demonstrated that 3 mg/kg and 10 mg/kg IVL-745 were able to reduce ovalbumin-induced lung pathology in both the epithelial and bronchiolar regions of the lung (Sargent CA, 2000). In addition, these doses signiÞcantly reduced the numbers of eosinophil and lymphocyte cell populations in the mucosal/submucosal region of the bronchioles. Duration of action analysis demonstrated that 10 mg/kg IVL-745 inhibited bronchial inßammation when

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administered 6 hours, 4 hours, and 30 minutes before and 4 hours after ovalbumin challenge. REFERENCES Abbas R, et al. Safety, tolerability, and pharmacokinetics of R-411, a dual α4β1 and α4β7 integrin antagonist after multiple ascending doses in healthy subjects. 100th Annual International Meeting of the American Thoracic Society; May 22–26, 2004; Orlando, Florida. Abstract D31/Poster C4. Adams PF, et al. Current estimates from the National Health Interview Survey, 1996. National Center for Health Statistics Vital Health Statistics. 1999;10:83–84. Adcock IM, et al. Molecular interactions between glucocorticoids and long-acting beta 2 agonists. Journal of Allergy and Clinical Immunology. 2002;110(6 Suppl):S261–8. Affrime MB, et al. Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers. Journal of Clinical Pharmacology. 2000;40(11):1227–1236. [a] Affrime MB, et al. Mometasone furoate has minimal effects on the hypothalamic-pituitaryadrenal axis when delivered at high doses. Chest. 2000;118(6):1538–1546. [b] Agertoft L, et al. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. New England Journal of Medicine. 2000;343(15):1064–1069. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics. 2002;110:315–322. Akinbami LJ, et al. U.S. childhood asthma prevalence estimates: the impact of the 1997 National Health Interview Survey Redesign. American Journal of Epidemiology. 2003;158:99–104. Akiyama K. Review of epidemiological studies on adult bronchial asthma in Japan. Nihon Kyobu Shikkan Gakkai Zasshi. 1994;32(suppl):200–210. Allen DB. Inhaled corticosteroids: past lessons and future issues. Journal of Allergy and Clinical Immunology. 2003;112(3 suppl):S1–S40. Altemeier WA, Gavin GR. How are allergic rhinitis and sinusitis connected with asthma? Pediatric Annals. 2000;29:391–398. American Lung Association (ALA). Trends in asthma morbidity and mortality. American Lung Association. Epidemiology and Statistics Unit. Best Practices and Program Services. April 2004. Available at www.lungusa.org. Accessed November 1, 2004. Anderson HR. Trends in prevalence and severity of childhood asthma. British Journal of General Practice. 1994;308:1600–1604. Anderson HR, et al. Trends in prevalence of symptoms of asthma, hay fever, and eczema in 12–14 year olds in the British Isles, 1995–2002: questionnaire survey. British Medical Journal. 2004;328:1052–1053. Anderson SD, et al. Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest. 1991;100:1254–1260. Apter AJ, Szeßer SJ. Advances in adult and pediatric asthma. Journal of Allergy and Clinical Immunology. 2004;113:407–414. Arif AA, et al. Prevalence and risk factors of asthma and wheezing among U.S. adults: an analysis of the NHANES III data. European Respiratory Journal. 2003;21:827–833. Asthma in America Survey (AIA). 2000. Available at www.asthmainamerica.com.

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Crohn’s Disease

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Crohn’s disease (CD) is a chronic, relapsing/remitting inßammatory disease of the gastrointestinal (GI) tract. The regions of the GI tract most often affected by CD are the small intestine and the large intestine, or colon, including the rectum. Unlike ulcerative colitis (UC)—a related inßammatory bowel disease (IBD) in which inßammation and ulceration are limited to the mucosal and submucosal layers of the large intestine and rectum—the inßammation and ulceration of CD can extend through all layers of the intestinal wall in both the small and large intestines. Common symptoms of CD include diarrhea, abdominal pain, rectal bleeding, and weight loss, and complications such as intestinal abscesses, Þstulas, and intestinal obstructions (discussed in the section “Local Complications”) are common in CD patients. The course of CD is intermittent, with disease exacerbations followed by periods of remission. Because of similarities in their pathogenesis and clinical manifestations, CD and UC are often collectively referred to as IBD and are frequently examined together in research studies. Whenever possible, Þndings speciÞc for CD are reported here, and comments are made on IBD results when no deÞnitive differentiation can be made between the two diseases. Currently, the etiology and pathophysiology of CD are not well understood, but three major factors have been implicated in the disease: Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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First, the intestinal damage of CD is known to be mediated by chronic inßammation. As a result, many of the therapies currently used or in development for CD are immunosuppressants. Inhibitors of tumor necrosis factor-alpha (TNFα) and other inßammatory cytokines appear to be particularly promising for the treatment of CD. Second, the aberrant immune response in CD is thought to be initiated and/or perpetuated by intestinal microbes, including the normal intestinal ßora. Therefore, antibiotics are used to treat CD, and researchers are exploring ways to enhance the innate immune response against microbes as a treatment strategy for CD. Third, several genetic factors predispose people to develop CD, and many of these factors appear to be involved in immunity—for example, the nucleotide oligomerization-binding domain 2 (NOD2) gene. Research into how these genes cause CD may reveal future drug targets.

Anatomy Figure 1 illustrates the major constituent organs of the GI tract. As mentioned previously, the small and large intestine, including the rectum, are the areas of the GI tract most often affected by CD. In a small minority of patients, the disease can affect the mouth, the tongue, the esophagus, or the stomach. Food enters the small intestine from the stomach through the pyloric sphincter. The small intestine consists of three segments—the duodenum, the jejunum, and the ileum—and is responsible for most digestion of food and absorption of nutrients. Remaining material from the small intestine then enters the large intestine through the ileocecal valve, which allows only one-way transit of material, blocking colonic bacteria from entering the small intestine. The large intestine comprises the cecum—a blind pouch that is adjacent to the ileocecal valve—and Þve other segments: the ascending colon, the transverse colon, the descending colon, the sigmoid colon, and the rectum. The colonic phase of digestion is responsible for the Þnal reabsorption of water and electrolytes. The rectum—the distal portion of the large intestine and the Þnal portion of the GI tract—begins at the sigmoid colon and ends at the anus. Peristalsis (strong wavelike contractions) of the colon forces fecal material into the sigmoid colon and rectum, and distention of the rectal walls elicits a reßex that initiates the defecation process. The walls of the small intestine and large intestine comprise four layers: the mucosa, submucosa, muscularis, and serosa, illustrated in Figure 2. The inßammation and ulceration associated with CD are transmural (they can affect all layers of the intestinal wall), and diseased segments are often ßanked by regions of normal mucosa, thus resulting in a characteristic pattern of “skip lesions” (Figure 3). Etiology The Immune Response.. The human GI tract is routinely exposed to a wide variety of antigens, including those that are ingested from food and ßuids and those produced by the natural bacterial ßora that reside in the colon and participate


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FIGURE 1. The major constituent organs of the gastrointestinal tract.

in the digestive process. In healthy people, there is continuous, clinically undetected immune stimulation in response to these antigens. In CD, scientists believe, this antigenic stimulation results in an aberrant immune response that is both prolonged and ampliÞed. Neither the precise cause of the aberrant response nor a speciÞc antigenic trigger has been identiÞed. One leading theory proposes that CD results from a genetic predisposition affecting the immune system combined with an environmental trigger, such as exposure to endogenous or exogenous intestinal antigens. Therefore, in an effort to inhibit this characteristic aberrant immune response, immunosuppressive agents are used to treat CD patients; these agents include aminosalicylates, corticosteroids, and immunosuppressants (e.g., azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine), all of which are discussed in greater detail in “Current Therapies.” Many immune cells—including neutrophils, macrophages, B and T lymphocytes, and mast cells—are present in the mucosal layer of healthy intestines.

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FIGURE 2. The four layers of the intestinal wall.

The intact epithelium lining the mucosa prevents these immune cells from being overstimulated by the large antigenic load to which the GI tract is exposed on a daily basis. According to one theory of how the disease is initiated, CD patients have increased intestinal permeability (perhaps due to a genetic predisposition) that exposes the immune cells to a multitude of antigens. In a study involving 11 CD patients, 32 healthy relatives of the patients, and 17 healthy volunteers who served as controls, researchers found that the CD patients and their relatives had a nearly twofold increase in intestinal permeability (demonstrated by enhanced absorption of polyethylene glycol-400 ingested with a meal), compared with the control participants (Hollander D, 1986). Animal studies have also demonstrated that compromises in mucosal integrity can cause CD-like lesions (Sanders DS, 2005). Thus, enhanced intestinal permeability could cause overexposure of immune cells to intestinal antigens, thereby prompting an aberrant immune response and subsequent tissue damage. Researchers believe that a cell-mediated immune response predominates in CD (Figure 4). The inßammatory response associated with CD is believed to be driven by activation of T-helper 1 (TH1) cells, as evidenced by the increased levels of interleukin (IL)-2 and interferon-gamma (IFN-γ ) in the intestinal mucosa of CD patients (Stenson WF, 1999). In contrast, UC is thought to be associated primarily with a TH2 response. The Inflammatory Cascade. CD exhibits classic characteristics of chronic inßammation: tissue inÞltration by large numbers of lymphocytes and


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FIGURE 3. Anatomical distribution patterns of Crohn’s disease.

macrophages and high levels of proinßammatory cytokines in the intestinal mucosa. During active disease, increased numbers of neutrophils and monocytes migrate from the bloodstream into the intestinal mucosa and submucosa, where they secrete large quantities of proinßammatory molecules, such as cytokines and tissue-damaging free radicals. Figure 5 illustrates key immune and inßammatory responses associated with CD. Investigation of these proinßammatory molecules has provided new therapeutic targets for CD and other immune-related diseases,

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FIGURE 4. A TH 1 response predominates in Crohn’s disease.

and many current and emerging CD pharmacotherapies target these proinßammatory molecules. Table 1 summarizes major inßammatory mediators involved in CD pathogenesis; the following sections discuss some of them. Cytokines. Specimens of inßamed mucosa taken from patients with CD have been shown to contain increased quantities of the cytokines IL-1β, IL-2, IL-6, IL8, IL-12, IL-18, TNF-α, and IFN-γ ; these molecules activate the immune system and promote tissue inßammation. Long-term overexpression of these molecules can lead to tissue damage, as occurs in CD. Conversely, blockage of cytokine overexpression may reduce inßammation and subsequent tissue damage. Furthermore, TNF-α has been shown to induce epithelial cell apoptosis, alter the expression of adhesion molecules, and affect tight junction functionality, thereby increasing intestinal permeability (Sanders DS, 2005). As mentioned previously, increased intestinal permeability is thought to be important in the initiation of CD. These cytokines, therefore, are potential drug targets in the treatment of CD. Currently, one TNF-α inhibitor, inßiximab (Centocor [a Johnson & Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade), is approved for CD and is highly efÞcacious in treatment of the disease (discussed in “Current Therapies”). Additionally, two novel TNF-α inhibitors, several IL-12 inhibitors, an IL-6 inhibitor, and an IFN-γ inhibitor are in clinical development for CD (discussed in “Emerging Therapies”). Lipid Mediators. Prostaglandins and leukotrienes, commonly referred to as eicosanoids, are lipid inßammatory mediators. Mucosal tissues of CD patients contain markedly elevated levels of prostaglandin E2 (PGE2) and leukotriene B4


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TABLE 1. Major Inflammatory Mediators in Crohn’s Disease Mediator Cytokines Interferon-gamma (IFN-γ )

Interleukin-1 beta (IL-1β)

Interleukin-2 (IL-2) Interleukin-6 (IL-6)

Interleukin-8 (IL-8) Interleukin-10 (IL-10)

Interleukin-12 (IL-12)

Interleukin-18 (IL-18)

Transforming growth factor (TGF) Tumor necrosis factor-alpha (TNF-α)

Lipid mediators Leukotriene B4 (LTB4)

Primary Sources

Biological Activities

T cells, natural killer cells

Enhances immune activation through upregulation of major histocompatability complex (MHC) class I and II molecules and Fc receptors; potentiates production of tumor necrosis factor-alpha (TNF-α) by macrophages; promotes tissue infiltration by neutrophils and monocytes by up-regulating expression of intracellular adhesion molecule-1 (ICAM-1) on endothelial cells. Macrophages, B cells, Increases production of other inflammatory dendritic cells, mediators; stimulates phagocytes and neutrophils, T cells, lymphocytes; promotes release of endothelial cells, acute-phase proteins from liver; induces epithelial cells fever. Stimulates proliferation of T cells and natural Activated T helper 1 killer cells. (TH 1) cells Macrophages, T and B Produces acute-phase proteins; promotes cells, fibroblasts, differentiation of B cells; promotes antibody endothelial cells production. T cells, monocytes Attracts neutrophils and additional T cells. Monocytes, Induces differentiation of TH cells into TH 2 cell subtype; suppresses TH 1 functions; macrophages, downregulates IFN-γ , IL-1β, IL-2, IL-6, IL-8, subsets of T and B and TNF-α production. cells Monocytes, natural Induces differentiation of TH cells into TH 1 cell subtype; suppresses TH 2 functions; induces killer cells IFN-γ , IL-1β, IL-2, IL-6, IL-8, and TNF-α production; activates natural killer cells. Macrophages, Induces IFN-γ , IL-1β, IL-8, and TNF-α dendritic cells, production; activates endothelial cells and intestinal epithelial neutrophils; upregulates expression of cell cells adhesion molecules; attracts neutrophils and T cells. Activated Inhibits proliferation of T and B cells, macrophages, T cells macrophage activation, and the production of other inflammatory mediators; stimulates growth of connective tissue. Activated Activates endothelial cells, macrophages, and macrophages, some neutrophils; upregulates expression of cell lymphocytes adhesion molecules; upregulates the synthesis of other cytokines; induces fever and cachexia. Activated neutrophils, macrophages, mast cells

Vasoconstriction; increases vascular permeability; increases leukocyte adhesion to vascular endothelium and subsequent tissue infiltration; stimulates enzyme secretion by leukocytes.

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TABLE 1. (continued) Mediator Prostacyclin (PGI2 ) Prostaglandin D2 (PGD2 ) Prostaglandin E2 (PGE2 )

Thromboxane A2 (TXA2 ) Platelet-activating factor (PAF)

Other mediators Complement fragments (e.g., C5a)

Primary Sources Vascular endothelium, macrophages Mast cells, many other tissues White blood cells, many other tissues

Platelets, leukocytes Neutrophils, macrophages, mast cells, endothelial cells Result of immune response

Biological Activities Acute inflammatory response; vasodilation; inhibits platelet aggregation. Vasodilation. Acute inflammatory response; vasodilation; increases vascular permeability; induces fever and hyperalgesia; inhibits gastric acid secretion; inhibits renal tubular reabsorption. Vasoconstriction; increases vascular permeability; stimulates platelet aggregation. Activates neutrophils; increases vascular permeability; promotes vasoconstriction and platelet aggregation.

Vasodilation; increases vascular permeability; attracts neutrophils.

(LTB4). Although both PGE2 and LTB4 induce vasodilation and increase vascular permeability (actions that enhance tissue inÞltration by leukocytes) clinical studies suggest that these molecules play distinct roles. LTB4 is also a potent chemotactic factor that can attract neutrophils to the mucosa, whereas PGE2 is involved in wound healing. PGE2 and LTB4 are metabolic products of arachidonic acid, a lipid released from cell membranes. Typically, cells contain only limited amounts of arachidonic acid, but the increased macrophage activity in CD results in the release of larger amounts. Macrophages, epithelial cells, and Þbroblasts generate PGE2 through the cyclooxygenase (COX-1 and COX-2) pathway; neutrophils, macrophages, and mast cells produce LTB4 via the 5-lipooxygenase (5-LO) pathway. Aminosalicylates and corticosteroids, both currently used in CD treatment, inhibit the production of leukotrienes and prostaglandins (discussed in “Current Therapies”). Cell Adhesion Molecules. Leukocyte migration is mediated by cell adhesion molecules (CAMs), which include selectins (P-, E-, and L-selectin), integrins (e.g., β2 integrin), and the immunoglobulin superfamily of adhesion molecules (e.g., intracellular adhesion molecule-1 [ICAM-1]). These molecules are expressed on leukocytes and on endothelial cells, which line blood vessels. CAM overexpression correlates with several inßammatory disorders, including CD. Currently, one CAM inhibitor—Elan/Biogen Idec’s natalizumab (Tysabri)—is in late-stage clinical development for CD (discussed in “Emerging Therapies”). Mitogen Activated Protein (MAP) Kinases. The MAP kinase signal transduction pathway—which comprises the p38, JNK, and ERK pathways—stimulates


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FIGURE 5. Key immune and inflammatory responses in Crohn’s disease.

the synthesis of proinßammatory cytokines. This pathway can also be activated by the binding of these cytokines to their respective receptors and thus helps to regulate cellular responses to proinßammatory cytokines. Therefore, inhibition of the MAP kinase pathway has the potential to inhibit the feedback loop common to inßammatory conditions involving proinßammatory cytokines; several MAP kinase inhibitors are in development for CD (discussed in “Emerging Therapies”). Microbial Involvement. For decades, investigators have postulated that an infectious agent is involved in CD pathogenesis, but no single agent has been consistently recovered from CD patients. One hypothesis of the etiology of CD holds that normally nonpathogenic bacteria—potentially even bacteria of the

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normal intestinal ßora—may cause CD in susceptible hosts. In fact, leukocytes present in active intestinal lesions from IBD patients do display a reduced tolerance to certain normal intestinal ßora (Duchmann R, 1995). Diversion of the fecal stream can also prevent CD relapses (Rutgeerts P, 1991). Antibodies directed against the cell-wall phosphopeptides—speciÞcally the sugar moiety of the yeast Saccharomyces cerevisiae (anti-S. cerevisiae antibodies, or ASCAs)—have been detected in as many as 79% of CD patients (Barclay GR, 1992; Sendid B, 1996), which suggests a possible association between the organism and CD. Although several diagnostic kits are available to measure ASCA levels in CD patients, the presence or absence of ASCAs cannot be used to make a deÞnitive diagnosis of CD because ASCAs have been detected in the serum of healthy people and in the serum of patients with other forms of IBD, including UC and indeterminate colitis (Walker LJ, 2004). The precise clinical importance of this serological marker remains to be determined, but ASCA antibodies have been shown to be more highly associated with gastroduodenal and ileal CD, stricturing and penetrating CD, and CD requiring surgery than with colonic disease or CD with an inßammatory phenotype (Walker LJ, 2004). Mycobacterium paratuberculosis has also been implicated as a potential causative agent of CD because it triggers Johne’s disease, an intestinal disorder of cattle and sheep that displays pathological changes similar to those associated with CD, and because it has been isolated from a small number of CD surgical specimens. However, CD patients are rarely cured by antituberculosis drugs. M. paratuberculosis does not appear to play a major role in CD, although it may cause CD-like disease in a small number of people. Paramyxovirus-like particles have been isolated from affected tissues of some CD patients, leading some researchers to suspect the measles virus as a putative cause of CD. Researchers have also speculated that people born up to three months after a measles epidemic are at higher risk for developing CD before age 30 and that maternal measles infection during pregnancy may increase the fetus’s risk of developing this disorder (Ekbom A, 1990; Ekbom A, 1991; Ekbom A, 1994). Measles vaccination has been implicated as a risk factor for developing IBD. Such a fear could dissuade parents from immunizing their children. However, a meta-analysis of studies suggests that measles vaccination is not associated with increased risk of developing CD (Ghosh S, 2001). In addition to the association of CD with particular microbes, predisposition to develop CD has been linked to mutations in genes involved in the innate immune system—the body’s Þrst line of defense against many common microorganisms—again suggesting a possible microbial connection to CD. These genes include the NOD2 gene and toll-like receptors (TLRs) (Hugot JP, 1996; Hugot JP, 2001; Ogura Y, 2001) (discussed further in the “Risk Factors, Genetics” section). Risk Factors Genetics. Results from several family-based epidemiological studies suggest that genetics may play a role in the development of CD. The disease has been


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shown to aggregate in families, and relatives of CD patients are at increased risk for developing the disease. In a study involving 964 CD patients from the Mount Sinai Hospital IBD Research Unit, 10% were shown to have a family member afßicted with IBD; of these 96 patients, 78.1% had family members who were afßicted with CD only (McLeod RS, 1997). Despite these observations, no clear pattern of Mendelian inheritance has been associated with CD. Further evidence of the role of genetics in the etiology of CD is derived from studies of twins; these studies have found concordance rates for the development of CD in identical twins that range from 42% to 58% (Bonen DK, 2003). Nevertheless, the fact that concordance rates in identical twins are less than 100% supports the theory that other factors are involved in the etiology of the disease. Evidence that CD is a multigenic disorder comes from gene expression analysis (via DNA microarray) that utilized RNA extracted from resected bowel specimens from CD, UC, and control patients. Of the 7,306 genes analyzed, 170 were differentially regulated in CD, UC, or both (Lawrance IC, 2001). Numerous genetic linkage and association studies have identiÞed potential CD- and IBD-susceptibility loci on chromosomes 1, 3, 5, 6, 7, 12, 14, 16, and 19 (Bonen DK, 2003). Researchers have identiÞed numerous genes within these loci, as well as other genetic factors, that could potentially be involved in the pathogenesis of CD; many of these genes code for molecules that are involved in the immunoregulatory and inßammatory processes. Perhaps the most important genetic discovery in understanding CD etiology was the identiÞcation of an association of the NOD2 gene on chromosome 16 with CD (Hugot JP, 1996; Hugot JP, 2001; Ogura Y, 2001). The NOD2 protein, which is predominantly expressed by monocytes and by lipopolysaccharide [LPS]-stimulated macrophages, is an intracellular receptor for muramyl dipeptide, a peptidoglycan fragment found in Gram-positive and Gram-negative bacterial cell walls (Girardin SE, 2003; Inohara N, 2003; Philpott DJ, 2004). It belongs to the Apaf-1/Ced-4 superfamily of proteins involved in apoptosis regulation and has structural homology to disease-resistant proteins found in plants (Hugot JP, 2001; Ogura Y, 2001). Researchers observed CD-associated mutations in either of two amino-terminal caspase-recruitment domains (CARD) and in a leucine-rich repeat (LRR), the region responsible for activating the transcription factor NF-κB. NF-κB, in turn, activates expression of many genes, including pro-inßammatory cytokines, such as TNF-α. People who possess nonconservative amino-acid substitutions or frame-shift mutations in the LRR were found to be at increased risk of developing CD, with a relative risk of 3 for simple heterozygous mutation and 38 for homozygous mutation (Hugot JP, 2001). Mutations in the NOD2 gene are more commonly associated with early-onset disease and CD characterized by an ileal or stricturing (Þbrostenotic) phenotype, compared with colonic disease (Abreu MT, 2002; Ahmad T, 2002; Cuthbert AP, 2002; Lesage S, 2002). The physiological function of NOD2 is not yet clearly deÞned, but the protein appears to be important in the production of antimicrobial peptides, known as defensins, that are involved in innate mucosal immunity against bacteria, fungi, and viruses. Defensins are produced in the small intestine, mainly by Paneth

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cells, which are specialized secretory epithelial cells lining the intestinal walls that also express the NOD2 protein. In one study of 45 CD patients and 12 negative controls, CD patients with involvement of the small intestine had decreased expression of ileal defensins, compared with controls or CD patients without ileal involvement; this decrease was signiÞcantly more pronounced in patients with NOD2 mutations (Wehkamp J, 2004). Interestingly, CD conÞned to the colon also seems to be associated with impaired induction of colonic defensins, but this impairment is not associated with NOD2 mutations (Wehkamp J, 2005). Further evidence for the theory that mutations in NOD2 impair the intestinal immune response against microbes comes from animal studies: NOD2-deÞcient mice were unable to express a subgroup of murine intestinal microbial peptides and were susceptible to bacterial infection introduced orally (Kobayashi KS, 2005). However, controversy still lingers over the role of NOD2 mutations in CD. Some studies have suggested that defensins are overexpressed, not decreased, in the intestinal mucosa of CD patients, thereby contradicting the observations cited in the preceding paragraph (Lawrance IC, 2001; Cunliffe RN, 2002; Wehkamp J, 2002). Furthermore, NOD2 mutations in mice corresponding to mutations found in CD patients resulted in elevated NF-κB activation and IL-1β production. Unlike the NOD2-deÞcient mice that did not exhibit intestinal inßammation, these mice showed increased susceptibility to bacterial-induced intestinal inßammation (Maeda S, 2005). Therefore, these researchers believe that the NOD2 mutations associated with CD are gain-of-function mutations that result in overactivation of the innate mucosal immune system, which in turn leads to chronic intestinal inßammation. These researchers propose IL-1β as a good therapeutic target for the treatment of CD, but no speciÞc IL-1β inhibitors are currently in active development for CD. Additional research is needed to determine precisely the role that the NOD2 gene plays in CD. Geography. Evidence suggests that the incidence of CD displays a north-south gradient. The disease occurs more commonly in northern and western Europe than in southern and central Europe (Karlinger K, 2000). It is also more common in North America than in Africa, Asia, and Australia, but whether this Þnding is attributable to geographical location or ethnicity is not known. CD also occurs more frequently in urban areas than in rural regions. Race and Ethnicity. Epidemiological studies have demonstrated that CD is more common in Caucasians than in people of other races. Additionally, CD incidence is three to eight times higher in people of Jewish descent (Stenson WF, 1999). Interestingly, the incidence of CD is higher in U.S. and European Jews than in Israeli Jews. Ethnic and regional variations also occur in CD patients who carry NOD2 mutations (Aldhous MC, 2003). For example, studies have shown that the three most common NOD2 mutations found in Caucasian CD patients occur less frequently in African-American CD patients and were not present in a sample of 350 Japanese CD patients (Bonen DK, 2002; Inoue N, 2002).


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Smoking. Cigarette smoking appears to be a risk factor for developing CD. A meta-analysis of several studies suggests that smokers are two to four times more likely to develop CD than nonsmokers (Calkins BM, 1989). Smoking also appears to affect the frequency of disease recurrence in CD patients (Sutherland LR, 1990). Researchers examined the surgery recurrence rate in 174 patients who had previously undergone surgery for CD and found that patients who smoked had recurrence rates of 36% and 70% after Þve and ten years, respectively. The Þve- and ten-year recurrence rates were only 20% and 41%, respectively, for nonsmoking CD patients. The reason for the correlation between smoking and CD is not well understood, although nicotine has been shown to have an inhibitory effect on TH2 cell function (believed to predominate in UC) but no effect on TH1 cells (believed to predominate in CD) (Madretsma S, 1996). TH1 and TH2 cells are mutually inhibitory based on the cytokines each cell type produces, and IL-10 (produced by TH2 cells) blocks activation of TH1 cells (Monteleone G, 2000). Thus, nicotine’s inhibitory effect on TH2 cells may in turn promote TH1 cell differentiation. Diet. Diet affects digestive tract physiology and may inßuence CD etiology. In general, populations that consume non-Western diets (including Africans, Chinese, East Indians, and Japanese) have a low incidence of CD. In addition, researchers have proposed a direct relationship between CD and the consumption of reÞned sugar and between CD incidence and reduced fruit and vegetable consumption (Persson PG, 1987). In studies involving CD patients, consumption of wheat, dairy, corn, and yeast products was associated with IBD recurrence (Rhodes J, 1986; Riordan AM, 1993; Workman EM, 1984). However, additional studies are required to establish a deÞnitive association between diet and CD. Pathophysiology Location and Extent of GI Tract Involvement. Based on the location and extent of their inßammation, the majority of CD patients fall into one of three categories: inßammation of the small intestine only, inßammation of the large intestine only, or inßammation of both the small and large intestines. Figure 6 illustrates the regions of the GI tract within the small and large intestines that are most commonly affected by CD. Approximately 30% of CD patients present with disease limited to their small intestine (Stenson WF, 1999). Inßammation of the ileum—the region of the small intestine most often affected by CD—is referred to as ileitis. CD limited to the large intestine is called Crohn’s colitis and is found in approximately 25% of patients (Stenson WF, 1999); in these patients, the anorectal region is often affected as well. Approximately 40% of CD patients present with inßammation of both the small and large intestines simultaneously, which is referred to as ileocolitis (Stenson WF, 1999). Identifying disease localization is important in determining the best treatment regimen because therapies have specialized formulations to target release of the active drug in different areas throughout the small and large intestines. Crohn’s colitis is often treated

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FIGURE 6. Regions of the GI tract most commonly affected by Crohn’s disease.

similarly to UC, whereas CD that affects the small intestine can be treated quite differently with alternative drug formulations. CD may also affect the mouth, the tongue, the esophagus, the stomach, and the duodenum, but these clinical presentations of the disease are seen in only a very small percentage of patients. Complications of Crohn’s Disease Local Complications. Abscesses and Þstulas, two local complications of CD, arise when ulcers or Þssures extend through the entire intestinal wall into extraintestinal tissue. An abscess forms when intestinal contents leak from a Þssure and collect as a pocket in the peritoneal cavity. Abscesses, which occur in 15–20% of CD patients (Steinberg DM, 1973), are often accompanied by fever and abdominal pain. Resection of the affected portion of the intestine is often necessary to treat an abscess effectively because simple drainage of the collected ßuid may be inadequate and result in development of a Þstula. Fistulas develop when Þssures from one loop of intestine extend through to another epithelial surface, such as another loop of intestine, the bladder, the vagina, or even the skin (Figure 7). Fistulas develop in 20–40% of patients with CD (Steinberg DM, 1973). If a Þstula is small, pharmacological treatment alone may be sufÞcient to close it. Large or multiple Þstulas may require surgery if they are associated with intractable symptoms such as fever or pain.


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FIGURE 7. Fistulas in Crohn’s disease.

Other local complications found in CD patients are intestinal obstructions (especially in the small intestine) and toxic megacolon—a potentially lifethreatening, acute dilation of the colon. Acute inßammation of the intestinal layers, scarring from previous bouts of inßammation, adhesions in the small intestine, and impaction of digested material in a narrowed portion of the intestine can all lead to development of an intestinal obstruction. Patients with intestinal obstruction develop severe cramping pain in the midabdomen that is often accompanied by vomiting and abdominal distension. Physicians initially treat obstructions caused by inßammation with pharmacotherapy, but surgery is required if the obstruction is severe, resists pharmacotherapy, or recurs frequently. Surgery may also be required to treat toxic megacolon, which, if not rapidly improved by pharmacological treatment, may result in potentially fatal colon perforation (rupture). Systemic Complications. CD patients may suffer from several systemic complications, including fever, fatigue, malnutrition, and weight loss. Patients may also suffer from arthritis, dermatological conditions, inßammation of the eyes (typically uveitis), and liver dysfunction, but these complications are more common in CD patients with Crohn’s colitis than in patients whose disease is limited to the small intestine. The cause of these extracolonic complications is not known,

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but they may be linked to the abnormal immune system responses characteristic of CD. Most patients with CD experience weight loss, in part a consequence of diminished food intake and malabsorption of nutrients. Patients who suffer from CD may eat less because of diminished appetite or to avoid the abdominal pain that may follow a meal. Also, inßammation of the small intestine compromises patients’ ability to fully digest and absorb nutrients from food. In addition to weight loss, CD patients usually have moderate anemia (stemming from iron, vitamin B12, or folate deÞciencies) and gallstones and kidney stones (caused by bile salt malabsorption). Malnutrition may also put a CD patient at risk for loss of bone mass. CD-associated arthritis typically affects joints in the hands, elbows, ankles, knees, and lower spine, but unlike rheumatoid arthritis (which is more severe), CD-associated arthritis usually does not cause destructive changes to the affected joints. Ankylosing spondylitis—a rarer form of arthritis that affects the spine—is also seen in CD patients. Dermatological conditions, such as erythema nodosum (a disorder characterized by tender, red nodules), aphthous stomatitis (canker sores), and the more severe disorder, pyoderma gangrenosum (deep, chronic skin ulcers), also occur in CD patients. Other systemic complications associated with CD include inßammation of the liver and bile ducts (including pericholangitis and primary sclerosing cholangitis [PSC]). Except for spinal arthritis, ankylosing spondylitis, and PSC, all of these conditions tend to subside in parallel with the bowel disease activity. Risk of Colon Cancer. The risk of colon cancer in CD patients is less clearly understood than the well-established risk in UC patients, but studies suggest that CD patients with extensive Crohn’s colitis have an 18-fold higher risk of developing colon cancer than the general population (Gillen CD, 1994). The incidence of colon cancer in Crohn’s colitis patients increases with the amount of time that patients have suffered from the disease (Stenson WF, 1999). Colonic malignancies usually occur in areas of active inßammation, but they may also appear in regions of the large intestine that are unaffected by CD. CURRENT THERAPIES Because the etiology and pathophysiology of Crohn’s disease (CD) are not well elucidated, pharmacological therapies used to treat the disease tend to be general immunosuppressive drugs (e.g., aminosalicylates, corticosteroids, immunosuppressants) that inhibit the inßammatory process, but currently few agents with speciÞc targets exist. The exception is the tumor necrosis factor-alpha (TNF-α) inhibitor inßiximab (Centocor [a Johnson & Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade)—the only biological agent currently approved for treatment of CD. Treatment of CD involves two main types of therapies: acute therapies designed to induce remission during ßares of disease activity and maintenance

CURRENT THERAPIES

509

therapies designed to maintain long-term remission and prevent disease ßareups. In addition, therapies are used to induce the closure and healing of Þstulas, a manifestation of CD that is notoriously difÞcult to treat. Most current CD therapies are not actually approved for the treatment of CD; many of these drugs are indicated for ulcerative colitis (UC), a related inßammatory bowel disease, and are used off label for CD. Delivery of the active metabolite of many CD drugs (e.g., aminosalicylates, corticosteroids) to speciÞc regions of the small and large intestines is important to maximize their therapeutic beneÞt and minimize systemic side effects. Therefore, these agents are available in a variety of rectal formulations for local delivery and in special oral formulations associated with carrier molecules, semipermeable membranes, or pH-sensitive resins to help target the drug. Table 2 summarizes the leading therapies available to treat CD. In 2004, the top-selling CD products were inßiximab, the ethylcellulose-coated and enteric-coated formulations of mesalamine, and the immunosuppressants 6-mercaptopurine and azathioprine. TNF-α Inhibitors Overview. The most recent advance in the treatment of CD was the introduction of inhibitors of TNF-α, a potent inßammatory cytokine. TNF-α is currently the most promising target for treatment of CD, particularly in patients with Þstulizing disease. Despite the superior efÞcacy of these agents compared with other CD therapies, TNF-α inhibitors are typically reserved for CD patients with severe, refractory, or steroid-dependent disease because of their relatively high cost, risk of immunomodulatory side effects, and inconvenient parenteral administration. Not all TNF-α inhibitors have demonstrated efÞcacy in the treatment of CD, however. Etanercept (Amgen/Wyeth/Takeda’s Enbrel) failed to meet its primary efÞcacy endpoint (induction of clinical response or remission at week 4) in a study of 43 CD patients with moderate-to-severe active disease (Sandborn WJ, 2001). This failure probably resulted from etanercept’s inability to induce the apoptosis of intestinal T cells—a capability that appears to be critical for TNF-α inhibitor effectiveness in the treatment of CD (ten Hove T, 2002; van den Brande JMH, 2003; Shen C, 2004). Mechanism of Action. Receptors for TNF-α are found on the surface of most cells, including mononuclear cells in the gastrointestinal (GI) tract. Cleavage of the membrane-bound TNF receptors yields soluble TNF receptors that retain ligand-binding ability but cannot activate cells. TNF-α inhibitors reduce free, bioactive TNF-α by emulating the physiological role played by soluble TNF receptors. This action modulates the amount of circulating, bioactive TNF-α by binding to the cytokine before it can activate cell-surface receptors on mononuclear cells (Figure 8). Some TNF-α inhibitors can also induce the apoptosis of T cells in the intestinal mucosa, a capability that appears to be critical for efÞcacy in the treatment of CD (ten Hove T, 2002; van den Brande JMH, 2003; Shen C,

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TABLE 2. Current Therapies Used for Crohn’s Disease Agent TNF-α inhibitors Infliximab

Company/Brand Centocor/Schering-Plough/Tanabe Seiyaku’s Remicade

Oral aminosalicylates EthylcelluloseShire/Ferring/Nisshin/Kyorin Seiyaku’s coated Pentasa mesalamine Enteric-coated Procter & Gamble/Giuliani’s Asacol, mesalamine GlaxoSmithKline/Faes/Merckle’s Claversal, Falk/Provalis’ Salofalk, others Sulfasalazine Pfizer’s Azulfidine, Pfizer/Mitsubishi Pharma’s Salazopyrin Balsalazide Salix’s Colazal, Menarini’s Balzide, Shire’s Colazide Olsalazine Pfizer/UCB’s Dipentum Mesalamine

Solvay’s Rowasa

Immunosuppressants 6-mercaptopurine GlaxoSmithKline/Teva’s Purinethol, generics Azathioprine GlaxoSmithKline/Prometheus Product’s Imuran/Imurel/Imurek, Tanabe Seiyaku’s Azanin, generics Methotrexate Stada/Wyeth’s Rheumatrex, Santen Seiyaku’s Metolate, generics Cyclosporine Novartis’s Sandimmune/Neoral, generics Oral corticosteroids Budesonide Prednisone

Antibiotics Ciprofloxacin

AstraZeneca’s Entocort, generics Pfizer’s Deltasone, Sanofi-Aventis’s Cortancyl, Merck’s Decortin, generics

Bayer’s Cipro/Ciflox/Ciprobay/Ciproxin, generics Metronidazole Aventis/Shionogi’s Flagyl, Sandoz’s Metrolyl, generics Topical aminosalicylates Enteric-coated Procter & Gamble/Giuliani’s Asacol, mesalamine GlaxoSmithKline/Faes/Merckle’s Claversal, Falk/Provalis’ Salofalk, others EthylcelluloseFerring/Kyorin Seiyaku/Nisshin Pharma’s coated Pentasa mesalamine Mesalamine Solvay’s Rowasa, Axcan Scandipharm’s Canasa

Daily Dosea Acute: 5 mg/kg (one infusion at wks 0, 2, 6) Mt: 5 mg/kg (starting at wk 14, infusion every 8 wks) Acute: 3 g Mt: 1.5 g Acute: 3 g Mt: 1.5 g Acute: 4 g Mt: 2 g Acute: 6 g Mt: 3 g Acute: 2 g Mt: 1 g Acute: 3 g Mt: 1.5 g Mt: 50–100 mg Mt: 175 mg

Acute: 25 mg/wk Mt: 15–25 mg/wk Acute (IV): 250–300 mg Mt (oral): 50–100 mg Acute: 9 mg Acute: 1 mg/kg for 2 wks, then tapered by 10 mg/wk for 6 wks Acute: 500–1,000 mg Acute: 0.6–2 g

Acute: 1–4 g Mt: 1–4 g, 3 times per wk Acute: 1 g Mt: 1 g, 3 times per wk Acute: 1 g Mt: 1 g, 3 times per wk

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TABLE 2. (continued) Agent IV corticosteroids Hydrocortisone

Topical corticosteroids Hydrocortisone

Budesonide

Company/Brand

Daily Dosea

Pfizer’s SoluCortef, Sanofi-Aventis’s Hydrocort, Merck’s Hydrocortone, generics

Acute: 100 mg

Paddock’s Colocort, Schwarz Pharma’s Cortifoam, GlaxoSmithKline/Ferrer’s Colifoam, generics AstraZeneca’s Entocort

Acute: 100 mg

Acute: 2 mg

a Doses listed in the table are daily amounts unless otherwise specified.

IV = Intravenous; Mt = Maintenance; wk(s) = week(s).

2004). Because TNF-α plays an important role in Þghting infections and eradicating neoplastic cells, its suppression is not without hazard, particularly as a long-term strategy. Concerns have been raised as to whether chronic immunosuppression leads to opportunistic infections, malignancies, and other complications (Brown SL, 2002; Lee JH, 2002; Nahar IK, 2003). Infliximab. Inßiximab (Centocor [a Johnson & Johnson subsidiary]/ScheringPlough/Tanabe Seiyaku’s Remicade) is the Þrst biological agent approved for CD. It was Þrst approved in the United States in 1998 and then in Europe in 1999 to induce CD remission. The drug received orphan drug status in Japan early

FIGURE 8. Blockade of inflammation by TNF-α inhibitors (infliximab): proposed mechanism.

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in 2002 and launched later that year for CD remission induction. In June 2002, the FDA approved inßiximab for maintenance therapy in patients with moderateto-severe CD, and in April 2003, it approved the product for maintaining CD Þstula closure. In May 2003, inßiximab was approved for maintenance dosing in Europe in patients with severe active CD, and in October 2003, the European Commission approved inßiximab for maintenance dosing for sustaining clinical response in patients with Þstulizing CD. Phase III trials are ongoing in Japan to evaluate the drug’s potential as a maintenance therapy. Inßiximab is also marketed in the United States and Europe for rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis, and in Japan for RA. Inßiximab received FDA approval for UC in September 2005 and is in Phase III development for UC in Europe. In July 2003, Tanabe Seiyaku Þled a new drug application (NDA) in Japan seeking approval of inßiximab for the additional indication of Behcet disease (a chronic, recurrent disease characterized by ulceration of multiple sites, including the mouth, genitalia, eyes, and veins). Inßiximab is also in Phase III development for psoriasis in the United States and Europe. Inßiximab is a chimeric monoclonal antibody (MAb) composed of 75% human and 25% mouse protein. The drug exerts its therapeutic effect by binding soluble and membrane-bound TNF-α (Figure 8). The mouse portion of the antibody contains a TNF-α binding site sufÞcient for sequestering the cytokine, and the human portion is responsible for effector function, including immunoglobulin G (IgG)stimulated elimination of TNF-α-positive cells by both antibody-dependent cellular cytotoxicity and complement-dependent mechanisms (Feldmann M, 2001). Inßiximab is capable of inducing T-cell apoptosis, probably by cross-linking TNF-α on the surface of these cells (ten Hove T, 2002; van den Brande JMH, 2003). The ability to induce apoptosis appears to be critical for efÞcacy in the treatment of CD. Inßiximab may also inhibit the expression and activation of cell adhesion molecules (CAMs) on endothelial cells and leukocytes, thereby preventing leukocyte migration into the bowel mucosa. Inßiximab is administered as an intravenous infusion by a health care professional. The recommended dosing frequency for induction of remission is three infusions, administered in weeks 0, 2, and 6 and every eight weeks thereafter for maintenance of remission. The ability of inßiximab to induce a clinical response and remission in active CD was demonstrated in a double-blind, placebo-controlled trial of 108 patients with moderate-to-severe CD (Crohn’s Disease Activity Index [CDAI] between 220 and 400). Patients were randomized to receive a single infusion of placebo or inßiximab at 5, 10, or 20 mg/kg; stable doses of concomitant CD therapies (prednisone, 6-mercaptopurine [6-MP], azathioprine, or oral aminosalicylates) were permitted. The trial met its primary end point: a signiÞcantly greater number of inßiximab-treated patients than placebo patients achieving a clinical response as measured by a 70 or greater point reduction in the CDAI score at 4 weeks. Only 17% of the placebo group achieved a clinical response at week 4, but 81% of the 5 mg/kg group, 50% of the 10 mg/kg group, and 64% of the 20 mg/kg

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group met this end point. Additionally, at week 4, 33% of inßiximab-treated patients achieved remission, deÞned as a CDAI score of less than 150; only 4% of placebo-treated patients achieved remission. SigniÞcant differences in the response rates persisted at 12 weeks (41% of inßiximab patients versus 12% of placebo patients) but not in the remission rates (30% versus 18%) (Targan SR, 1997). Inßiximab’s ability to maintain CD remission was demonstrated in ACCENT I (A Crohn’s Disease Clinical Trial Evaluating Inßiximab in a New Long-Term Treatment Regimen). In this Centocor-sponsored trial, conducted in North America, Europe, and Israel, all 573 patients enrolled received a 5 mg/kg infusion at week 0. At week 2, responses were measured, and 335 responders (58%) were randomized to one of three treatment groups: • • •

Placebo injections at weeks 2 and 6 and then every eight weeks thereafter until week 46 (group 1). Inßiximab 5 mg/kg injections at weeks 2 and 6 and then every eight weeks thereafter until week 46 (group 2). Inßiximab 5 mg/kg injections at weeks 2 and 6 followed by 10 mg/kg injections every eight weeks until week 46 (group 3).

Patients were allowed to continue stable doses of concurrent CD therapies, including azathioprine, 6-MP, corticosteroids, and aminosalicylates, during the course of the trial. At week 30, 39% of group 2 and 45% of group 3 patients were in remission, compared with 21% in group 1 (placebo). The median time to relapse throughout the 46-week trial was longer for both inßiximab-treated groups—38 weeks and 54 weeks for groups 2 and 3, respectively, compared with 19 weeks for group 1 (Hanauer SB, 2002). Because Þstulizing CD is notoriously challenging to treat and control pharmacologically, inßiximab’s efÞcacy in reducing the number of draining Þstulas is a much-needed addition to the CD armamentarium. In a randomized, doubleblind, placebo-controlled study, 94 patients with either abdominal or perianal Þstulas that existed for the three months preceding the trial were randomized to inßiximab 5 mg/kg, inßiximab 10 mg/kg, or placebo. Each group received three injections during the Þrst six weeks of the study, and patients were followed for up to 26 weeks. Closure of 50% or more of Þstulas (the primary end point) was achieved in 68% and 56% of the 5 mg/kg and 10 mg/kg inßiximab groups, respectively, compared with 26% of the placebo group. Complete Þstula closure was reported in 55% and 38% of the 5 mg/kg and 10 mg/kg inßiximab groups, respectively, compared with 13% of the placebo group (Present DH, 1999). The ACCENT II study, sponsored by Centocor in North America, Europe, and Israel, found similar, albeit diminishing, results in the treatment of Þstulizing CD over 54 weeks. Induction regimens consisting of three infusions of inßiximab were given to the 306 patients enrolled, all of whom had Þstulizing CD. Of the 282 patients remaining in the study at week 14, 69% had responded with

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a 50% or greater reduction in the number of draining Þstulas and were randomized to maintenance therapy with inßiximab (5 mg/kg every eight weeks) or placebo. Patients were allowed to continue stable doses of concurrent CD therapies (e.g., azathioprine, 6-MP, corticosteroids, aminosalicylates) during the course of the trial. The 31% of patients who did not demonstrate a response at week 14 were also randomized to either inßiximab maintenance therapy or placebo; these patients were included in the overall safety analysis at the end of the trial but not in the primary efÞcacy analysis. Of the 195 patients who demonstrated an initial response at week 14, 46% of those randomized to inßiximab maintenance therapy demonstrated a response at week 54, compared with 23% of those randomized to placebo. A complete response, deÞned by the absence of draining Þstulas, was maintained in 35% of inßiximab-treated patients, compared with 19% in the placebo group (Sands BE, 2004). Further analysis of the 282 patients completing the 54-week ACCENT II trial demonstrated that maintenance therapy with inßiximab signiÞcantly reduced hospitalizations and surgeries in patients with Þstulizing CD, compared with placebo (Lichtenstein GR, 2005[a]). Of the 139 trial participants who had at least a 50% reduction from baseline in the number of draining Þstulas at both weeks 10 and 14 and were randomized to receive 5 mg/kg inßiximab every eight weeks thereafter through week 46, only 8.6% required hospitalization, compared with 18.9% of the placebo-treated group (27/143). The mean number of all surgeries and procedures for responders in the inßiximab-treated group was 65, compared with 126 in the placebo group. Inßiximab maintenance treatment also signiÞcantly reduced the mean number of inpatient surgeries and procedures, the mean number of major surgeries per 100 patients, the mean number of hospitalization days per patient, and the mean number of CD-related hospitalizations. The reduction in the number of hospitalizations was similar in the United States and in other countries; no bias was introduced by differences in national health care systems. These results suggest that the high price of inßiximab maintenance therapy might be offset by the lower cost of CD-related hospitalizations and surgeries, but formal cost-effectiveness studies are needed to determine whether these savings make up for the expense of the agent and its associated adverse events. Adverse events associated with inßiximab are usually mild and include headache, nausea, rash, coughing, sinusitis, dyspnea, urticaria, hypotension, and upper respiratory tract infection. However, inßiximab is associated with potentially serious infusion reactions. In the clinical studies discussed in the preceding paragraphs, the overall frequency of any adverse event or serious adverse event was not statistically different in the placebo and inßiximab-treated groups. In the induction study, 60% of CD patients receiving placebo and 75% of patients receiving a single infusion of inßiximab had at least one adverse event (Targan SR, 1997). In the ACCENT I study, serious adverse events occurred in 29% of placebo-treated patients and in 28% and 22% of patients in the two inßiximabtreated groups (Hanauer SB, 2002). Similarly, of the 282 patients included in the safety analysis in ACCENT II, 14% of patients treated with inßiximab maintenance therapy and 23% of patients treated with placebo experienced serious

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adverse events. Serious infections occurred in 3% of inßiximab-treated patients and 6% of placebo-treated patients (Sands BE, 2004). However, infusion reactions did appear to occur more frequently in the inßiximab-treated groups: 23% and 19% versus 9% for placebo in the ACCENT I study (Hanauer SB, 2002). Because inßiximab is a chimeric MAb that contains murine (mouse) components, patients may develop antibodies against the drug. In the ACCENT I and ACCENT II trials, 14% and 17% of patients, respectively, tested positive for antibodies to inßiximab. An additional 46% of patients in ACCENT I and 52% of patients in ACCENT II had inconclusive antibody tests, owing to the presence of detectable inßiximab concentrations, which could compete with the detection of antibodies in the immunoassay (Hanauer SB, 2002; Sands BE, 2004). In each of these trials, the incidence of infusion reactions was higher in patients who developed antibodies to inßiximab than in patients who tested negative for such antibodies. A separate study involving 125 inßiximab-treated CD patients found that the presence of anti-inßiximab antibodies in patients correlated with a shorter duration of response (Baert F, 2003). Research has shown that continuous administration of inßiximab every eight weeks (as opposed to unscheduled, episodic treatment) lowers the incidence of anti-inßiximab antibody formation and leads to better treatment outcomes (Rutgeerts P, 2004[c]; Hanauer SB, 2004[b]). In one retrospective observational study, 37 CD patients received scheduled inßiximab maintenance therapy every eight weeks and 32 received episodic inßiximab treatment; study results demonstrated signiÞcantly lower rates of hospitalization, surgery, and permanent disability in the group receiving scheduled treatment (Williams JB, 2005). Prior to the initiation of inßiximab treatment, the rates of hospitalization (51% versus 47%) and surgery (62% versus 59%) were the same in the two groups (scheduled versus episodic, respectively). However, after inßiximab maintenance therapy for more than one year, the rate of hospitalization in the scheduled treatment group was only 14%, versus 59% for patients receiving episodic treatment, and the rate of surgery was 14% versus 53%. Furthermore, the rate of permanent disability was 3% for the scheduled treatment group and 28% for the episodic treatment group. Scheduled maintenance therapy, therefore, has signiÞcantly better treatment outcomes than episodic therapy. In fact, episodic maintenance therapy with inßiximab did not signiÞcantly improve treatment outcomes in this study, as evidenced by hospitalization and surgery rates that were the same before and after episodic treatment. These results strongly suggest that inßiximab maintenance therapy should be administered on a scheduled basis. Studies also suggest that coadministration of inßiximab with an immunosuppressant (e.g., azathioprine, 6-MP, methotrexate) lowers the incidence of antiinßiximab antibody formation, leading to better treatment outcomes (Sandborn WJ, 2002[a]; Baert F, 2003). In a May 17, 2004, press release, ScheringPlough and Centocor announced their intention to study the potential beneÞts of combination therapy with inßiximab and azathioprine in the SONIC (Study of Immunomodulatory Na¨õve Patients in Crohn’s Disease) trial. SONIC will compare the efÞcacy of this combination with the efÞcacy of either drug alone in

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patients with moderately to severely active CD who have not previously taken an immunosuppressant or biological agent for their disease. Steroid-free remission will be the trial’s primary end point. No information on the number of study participants or the length of the trial was included in the press release. A recent study that compared induction therapy with the combination of inßiximab and azathioprine to induction therapy with corticosteroids was presented at Digestive Disease Week in May 2005; results of this study suggest that the combination therapy was superior to corticosteroids in inducing remission and mucosal healing (Hommes D, 2005). The study involved 129 CD patients with active disease (CDAI >220) who had been diagnosed within the past four years and had not previously received corticosteroids, immunosuppressants, or biological agents. The primary end points were remission rates at 6 and 12 months for two treatment strategies: •

•

Group 1: Top-down strategy. Induction therapy was initiated with 5 mg/kg inßiximab at weeks 0, 2, and 6 in combination with 2–2.5 mg/kg azathioprine daily. Recurrence of disease activity was treated with inßiximab and/or methotrexate. Group 2: Step-up/bottom-up strategy. Induction therapy was initiated with 9 mg budesonide enema daily or 40 mg prednisone daily, tapered over eight weeks. Recurrence of disease activity was treated with corticosteroids; patients failing repeated corticosteroid therapy were given azathioprine. Patients failing azathioprine were permitted inßiximab therapy.

At six months, 74.5% of patients in group 1 were in steroid-free remission compared with 48.1% of patients in group 2—a statistically signiÞcant difference. In the second group, 32.7% of patients still needed corticosteroid therapy at 6 months and 18.8% at 12 months. The majority of patients in group 2 (67%) required azathioprine to achieve remission; 15% needed to resort to inßiximab for remission induction. Endoscopic evidence of mucosal healing was signiÞcantly greater in group 1 at two years, with absence of ulceration in 75% of the group 1 patients examined versus 21.4% of the group 2 patients examined. Fistulas developed in two group 2 patients and none of the group 1 patients. The occurrence of serious adverse events was similar in both groups. This study suggests that corticosteroids are not necessary in treatment of moderate-to-severe CD and that initiating induction therapy with inßiximab plus azathioprine may be a better treatment strategy than induction with corticosteroid therapy. Inßiximab’s long-term safety remains a concern for gastroenterologists. The long-term safety of inßiximab in CD is being prospectively studied using the Crohn’s Therapy, Resource, Evaluation and Assessment Tool (TREAT), a registry of CD patients from community and academic practices. Results presented at Digestive Disease Week in May 2005 for the 6,290 patients enrolled in this registry through August 2004 (3,179 receiving inßiximab and 3,111 receiving other CD therapies), with a mean follow-up of 1.7 years, demonstrate that inßiximab’s safety was similar to that of conventional immunosuppressants. Mortality

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in patients who received inßiximab was slightly lower than in patients who did not receive inßiximab: 0.41 per 100 patient-years versus 0.50 (RR = 0.83). The incidence of neoplasms and lymphomas in the two groups was very similar. The incidence of serious infections appeared to be slightly higher in patients who received inßiximab than in patients who did not receive inßiximab: 1.33 per 100 patient-years versus 0.70 (RR = 1.93). However, this increased risk was attributable to confounding factors, because inßiximab was not an independent predictor of serious infection when analyzed using logistic regression. Interestingly, prednisone was found to be an independent predictor of increased mortality and serious infection, and narcotics and moderate-to-severe CD were found to be independent predictors of serious infection (Lichtenstein GR, 2005[b]). Studies using the TREAT registry are ongoing. Despite accumulating data that inßiximab is relatively safe for long-term use, experts are still wary of the potential risks, which will limit its use as a CD maintenance therapy. Inßiximab’s package insert includes a black box warning noting an increased risk of developing tuberculosis and other opportunistic infections, and the agent has been contraindicated in patients with moderate to severe heart failure. Additionally, the product label was updated in July 2004 to include a warning about hematologic and neurological events associated with inßiximab use. The warning cautions physicians that cases of leukopenia, thrombocytopenia, pancytopenia, and central nervous system (CNS)-manifested systemic vasculitis—some of which have been fatal—have been reported in postmarketing experience. The product label for inßiximab was further updated in October 2004 to include a warning about the increased incidence of lymphoma in patients treated with TNF-α inhibitors, including inßiximab. According to the revised product label, 3 patients (1 with RA and 2 with CD) among 2,410 patients treated with inßiximab during controlled and open-label portions of RA and CD clinical trials developed lymphomas; this rate is approximately sixfold higher than the rate expected for the general population. In December 2004, an additional warning was added to inßiximab’s label about severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis, which have been reported in postmarketing data in patients receiving inßiximab. Some of these cases were fatal or necessitated liver transplantation. Inßiximab’s European patents are not expected to expire until 2014. Regulatory procedures for biosimilars (the European term for generic equivalents of biological agents) are not yet in place and will likely require at least limited indication-speciÞc clinical trials to conÞrm pharmacoequivalence, efÞcacy, and safety, thereby delaying the entry of biosimilars in Europe at least a year beyond the end of patent protection. In the United States, inßiximab is protected by method of use patents for the treatment of CD, RA, and neurological conditions; these patents will expire in 2014. However, these patents do not prevent the development of generic equivalents for inßiximab’s other approved indications (ankylosing spondylitis, psoriatic arthritis, and UC), which could then be used off label in CD and RA. However, regulatory procedures for the approval of follow-on biological agents in the United States have been slow in coming; an

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approval process is not likely to be in place for several years. Like European regulatory agencies, the FDA is likely to require additional clinical trials for follow-on biologics that will further delay the entry of generic equivalents. In Japan, the lack of regulatory guidelines and an approval procedure for biosimilars, together with low generics penetration, will make the entry of a generic equivalent of inßiximab unlikely. Oral Aminosalicylates Overview. The aminosalicylate class consists of agents that contain 5-aminosalicylic acid (5-ASA), one of the oldest anti-inßammatory compounds used in the treatment of inßammatory bowel diseases. In high doses, these drugs can induce remission in acute attacks of CD. In long-term use, lower doses of 5-ASA may be prescribed as a CD maintenance therapy, but its use in that capacity has not proved to be as effective as it is for ulcerative colitis (UC) maintenance therapy. There is mounting evidence from studies in UC patients that continuous therapy with oral or topical aminosalicylates offers some protection against development of colorectal cancer, which occurs at a higher rate in both UC and CD patients than in the general population. In fact, it is estimated that colorectal cancer accounts for 15% of all deaths related to these diseases (Munkholm P, 2003). One early study that compared 102 UC patients with colorectal cancer to 196 matched UC controls demonstrated that pharmacological therapy, especially sulfasalazine, lasting at least three months, was signiÞcantly associated with a protective effect (Pinczowski D, 1994). Another case control study in UC patients showed that continuous mesalamine therapy at doses greater than 1.2 g per day reduced the risk of colorectal cancer by 81% (Eaden J, 2000). A retrospective study of 175 UC patients found that only 3% of patients who took continuous, long-term sulfasalazine therapy developed colorectal cancer, compared with 31% of patients who were noncompliant or had their treatment stopped by a physician (Moody GA, 1996). A large epidemiological study of 18,969 patients with UC or CD demonstrated that regular 5-ASA users (based on prescriptions Þlled) had a lower risk of colorectal cancer than irregular users (van Staa TP, 2005). Furthermore, a recent meta-analysis of nine observational studies involving 1,932 UC patients concluded that 5-ASAs protect against colorectal cancer (Velayos FS, 2005). Mechanism of Action. Although 5-ASA formulations have been researched and used in CD treatment for decades, their precise mechanism of action remains unclear. Potential mechanisms that may account for the efÞcacy of 5-ASA include the following: •

Inhibition of leukotriene production. 5-ASAs inhibit cyclooxygenase (COX) enzymes and lipooxygenase (LO), thereby inhibiting the conversion of arachidonic acid to prostaglandins (PGs) and leukotrienes (LTs), respectively. PG and LT levels are elevated in the sera and mucosa of CD patients.

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519

Scavenging reactive oxygen metabolites (free radicals). In CD, these metabolites are generated by neutrophils and monocytes in the diseased mucosa. Inhibition of IL-1β and IFN-γ production. Both are proinßammatory cytokines involved in disease pathogenesis (Mahida YR, 1991).

In addition to the effects of 5-ASAs in reducing symptoms of CD, these agents may offer some protection against the development of colon cancer. The aminosalicylates are thought to confer this protection by increasing apoptosis in the intestine and inhibiting the proliferation of the colorectal mucosa (Bus PJ, 1999; Reinacher-Schick A, 2000). Formulation Because oral 5-ASA is rapidly absorbed in the stomach and jejunum (proximal small intestine), reformulation is necessary to enable the drug to reach the site of CD in the distal small intestine or colon. Therefore, mesalamine (mesalazine in Europe and Japan), the term for any 5-ASA that is not bound to another compound, is often attached to a carrier molecule, such as sulfapyridine, to deliver 5-ASA to the colon. Typically, carrier molecules are linked to 5-ASA via an azo bond, which is cleaved by the enzyme azoreductase, which is present in many intestinal bacteria species. This separation of the carrier molecule from the active 5-ASA moiety delivers the latter to the intestines, where it is absorbed and acetylated by intestinal epithelial cells. Because many side effects are associated with the sulfa moiety, second- and third-generation aminosalicylates were developed in formulations that deliver 5-ASA to the affected areas of the intestine without the use of a sulfa carrier molecule. Instead, these newer formulations of mesalamine are coated with semipermeable membranes or pH-sensitive resins that target the 5-ASA to the small intestine or colon. Although unbound, uncoated mesalamine is used occasionally in the treatment of CD, the specially formulated versions of mesalamine predominate and are therefore the agents discussed in greater detail in the following sections. Ethylcellulose-Coated Mesalamine. Ethylcellulose-coated mesalamine (Shire/Ferring/Nisshin/Kyorin Seiyaku’s Pentasa) is indicated for the induction of UC remission and for the treatment of mildly to moderately active UC. It is used off label for CD in all major-market countries except Spain. This prolonged-release formulation of mesalamine consists of 5-ASA granules coated with a semipermeable membrane that gradually dissolves in the intestines. Much of the 5-ASA is delivered to the ileum, but some active drug is delivered to the proximal colon as well. The ability of ethylcellulose-coated mesalamine to induce remission of active CD has been demonstrated in three major clinical trials. In the Þrst study, involving 67 patients, 40% of patients receiving 1.5 g Pentasa daily achieved remission at 16 weeks, compared with 30% of the placebo group (Rasmussen SN, 1987).

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The second study, involving 40 patients, had similar results: 40% of patients receiving 1.5 g Pentasa daily achieved remission at 6 weeks, compared with 35% of the placebo group (Mahida YR, 1990). The third and most rigorous study was a double-blind, multicenter trial in which 310 patients with active CD were randomized to receive placebo or Pentasa at a dose of 1, 2, or 4 g/day for 16 weeks. Only the highest dose of Pentasa proved to be more effective than placebo; 64% of patients treated with 4 g/day Pentasa achieved remission, versus 40% of the placebo group (Singleton JW, 1993). The efÞcacy of 5-ASAs in maintaining CD remission is not well documented; their use as a maintenance therapy is under debate. In two trials of 161 and 220 CD patients, Pentasa (3 g/day or 2 g/day) was unable to signiÞcantly improve remission rates over placebo at 12–24 months (Bondesen S, 1991; Gendre JP, 1993). Because it is a sulfa-free 5-ASA, ethylcellulose-coated mesalamine is a common option for the majority of patients who are intolerant of sulfasalazine. However, ethylcellulose-coated mesalamine is not without side effects, the most common being diarrhea, headache, nausea, abdominal pain, dyspepsia, vomiting, and rash. The drug is contraindicated in patients with impaired hepatic or renal function. Ethylcellulose-coated mesalamine has already lost patent protection. The product is designed to deliver mesalamine—an agent that is also off patent—to a targeted site within the GI tract using a specially formulated, semi-permeable membrane coating. This delivery mechanism gives the agent a unique pharmacokinetic proÞle. Given the agent’s unique release proÞle and targeted site of action, regulatory authorities will likely require more rigorous clinical data (e.g., dissolution, bioequivalence, and controlled comparative clinical trials) before they deem a generic oral 5-ASA equivalent to the branded version. Enteric-Coated Mesalamine. Enteric-coated mesalamine formulations (Procter & Gamble/Giuliani’s Asacol, Norgine’s Fivasa, GlaxoSmithKline/Faes/Merckle’s Claversal, Falk/Provalis’s Salofalk, Astellas’ Asamax, Chiesi’s Asalex, Norvartis’ Mesalazine Sandoz/Mesalazina San, Sofar’s Pentacol, and ScheringPlough’s Lixacol) are indicated for treatment of mildly to moderately active UC and for maintenance of UC remission. They are used off label for CD in all major-market countries except Japan. These mesalamine formulations are coated with pH-sensitive acrylic resins. Mesalamine coated with resins that dissolve at pH 7 or higher (e.g., Asacol) delivers 5-ASA to the distal ileum and colon; mesalamine coated with resins that dissolve at pH 7 or lower (e.g., Claversal and Salofalk) delivers 5-ASA to the proximal ileum. Asacol has demonstrated the ability to induce remission in patients with mildly to moderately active CD in a placebo-controlled trial involving 38 patients. After 16 weeks of treatment, 60% of patients receiving 3.2 g/day Asacol were in remission, compared with 22% of the placebo group (Tremaine WJ, 1994). The ability of 5-ASAs to maintain CD remission is under debate, but Asacol has demonstrated signiÞcantly greater remission rates than placebo at 12 weeks

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COOH

N NHSO2

OH

N

N

FIGURE 9. Structure of sulfasalazine.

in clinical trials. In one study involving 83 patients, 66% of patient receiving Asacol (2.4 g/day) achieved remission, compared with 30% of patients receiving placebo (Caprilli R, 1994). Another study involving 125 patients showed similar remission rates: 66% for Asacol (2.4 g/day) versus 45% for placebo (Prantera C, 1992). Overall, the rate of adverse events in patients treated with enteric-coated mesalamine has been similar to the placebo rate in clinical trials. Reported side effects are typically mild: headache, pain, nausea, pharyngitis, dizziness, rash, dyspepsia, vomiting, and constipation. Caution is advised when using these drugs in patients with impaired renal function. Enteric-coated mesalamine has lost patent protection in the United Kingdom and is expected to lose patent protection in the United States in 2013 and in Italy in 2007. Like the specially formulated, ethylcellulose-coated mesalamine, the enteric-coated formulations of mesalamine have unique pharmacokinetic proÞles that will be difÞcult to reproduce in generic equivalents. Sulfasalazine. The Þrst 5-ASA developed and marketed, sulfasalazine (PÞzer’s AzulÞdine/Salozopyrine/Salazpyrina, PÞzer/Mitsubishi Pharma’s Salazopyrin, generics) (Figure 9), has been used to treat CD for decades. An enteric-coated, delayed-release version of sulfasalazine (PÞzer/Santen Seiyaku’s AzulÞdineEN/Salazopyrin-EN, SanoÞ-Aventis’s Colo-Pleon, generics) is also available. Although sulfasalazine is formally indicated for UC but not CD, the drug’s utility in treating CD was established in a trial during the 1970s (Anthonisen P, 1974). Sulfasalazine is more effective in CD patients with colonic and ileocecal disease than in patients with disease conÞned to the small intestine. It is modestly effective in reducing the recurrence rates of CD following surgery (Achkar JP, 2000). Sulfasalazine consists of the sulfonamide antibiotic sulfapyridine and 5-ASA joined via an azo bond. This bond is cleaved by azoreductases to deliver the active 5-ASA moiety primarily to the colon. Because sulfasalazine has been on the market for a relatively long time, many clinical trials examining its efÞcacy are nearly 30 years old. The Anthonisen study was the Þrst double-blind trial to demonstrate sulfasalazine’s efÞcacy in inducing remission in patients with active CD. The 17-week study of 31 patients found that in the subgroup of patients who had not undergone intestinal resection, response rates were higher in the sulfasalazine-treated group (53%) than in the placebo group (6%) (Anthonisen P, 1974). In the subgroup of patients who had

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undergone earlier intestinal resection, the difference in response rates between those treated with sulfasalazine and those treated with placebo was statistically insigniÞcant. Later studies of sulfasalazine found response rates ranging from 38% to 75%; rates for placebo ranged from 8% to 55% in all trials (Malchow H, 1984; Summers RW, 1979; Van Hees PA, 1981). Despite sulfasalazine’s demonstrated efÞcacy in the treatment of active CD, clinical trial data are contradictory about its utility in maintaining remission. Most recently, several large studies have found that the risks of relapse are comparable in patients treated with sulfasalazine and patients treated with placebo (Malchow H, 1984; Summers RW, 1979; Wenckert A, 1978). Sulfasalazine has a number of common side effects. According to the product labels for AzulÞdine and AzulÞdine-EN, the most common side effects, which occur in approximately one-third of patients, include headache, nausea, dyspepsia, and anorexia. Less common side effects are fever, rash, arthralgia, hemolysis, neutropenia, exacerbation of colitis, hypersensitivity reactions, and nephrotoxicity. CD patients with acetylation polymorphisms are more likely to suffer adverse events owing to the slower metabolism of the sulfapyridine moiety (Schroder H, 1972). Male infertility is a side effect that is fully reversible within three months of discontinuing therapy. Women who are pregnant or nursing may safely use sulfasalazine, but the importance of folic acid supplementation must be stressed because sulfasalazine lowers systemic levels of this vitamin, which is critical for fetal development. Balsalazide. Balsalazide (Salix’s Colazal, Menarini’s Balzide, Shire’s Colazide) is a relative newcomer in the 5-ASA drug class, launching for the treatment of UC in 1997 in the United Kingdom and in 2001 in the United States and Italy. Although prescription data suggest that balsalazide is being used to treat patients with CD, no available clinical data demonstrate balsalazide‘s efÞcacy in treating this disorder. Balsalazide consists of 5-ASA linked to the inert, nonabsorbable molecule 4-aminobenzoyl-β-alanine via an azo bond. As described previously, this bond is cleaved by azoreductases to deliver the active 5-ASA moiety in the distal ileum and proximal colon. Balsalazide’s side effects are similar to those associated with other oral 5-ASA products; they include headache, abdominal pain, nausea, diarrhea, and vomiting. Less common adverse events include respiratory infection, fever, rash, and itching. In rare cases, hepatotoxicity has been reported in patients taking balsalazide. Balsalazide is expected to lose patent protection in the United States, Italy, and the United Kingdom in 2006. Olsalazine. Olsalazine (PÞzer/UCB’s Dipentum) consists of two 5-ASA molecules joined via an azo bond. Like sulfasalazine and balsalazide, olsalazine’s mechanism of action is dependent on bacterial azoreductase present in the intestines to cleave the azo bond and release 5-ASA to the affected areas of the GI tract. Olsalazine launched in the United States in the early 1990s for the

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maintenance of remission in UC patients who are intolerant of sulfasalazine; it is used off label for the induction and maintenance of CD remission. Few data exist to justify the use of olsalazine in the acute treatment of active CD, and the drug’s efÞcacy in the maintenance of CD remission is controversial. Although earlier studies suggested that olsalazine may be useful in maintaining remission in CD, more recent studies suggest that this drug is not superior to placebo. In a 52-week, randomized, double-blind trial, 328 patients with quiescent CD (patients who had been in remission for at least one month prior to randomization) were treated with either olsalazine (2 g/day) or placebo. No statistically signiÞcant difference in the frequency of relapse was evident between olsalazinetreated patients (48.5%) and patients receiving placebo (45%) (Mahmud N, 2001). According to the product label for olsalazine, approximately 11% of patients taking olsalazine develop profuse, nonbloody diarrhea, which can be ameliorated by reducing the dosage. Other possible side effects include headache, rash, itching, fever, and nausea—effects similar to those of other oral 5-ASAs. The patent for olsalazine expired in Italy and the United Kingdom in 2001 and 2002, respectively. The drug is expected to lose patent protection in the United States, Germany, and France in 2004, 2004, and 2007, respectively. Immunosuppressants Overview. In recent years, immunosuppressants have increasingly become Þrstline maintenance therapy for moderate and severe cases of CD. For the most part, the immunosuppressants’ delayed onset of action makes them unsuitable for acute treatment of active disease, although they are typically initiated together with acute agents to give the immunosuppressants a chance to start working before the acute therapy is halted. None of the agents in this class is approved for CD, but their off-label use for this indication began following trial results that demonstrated their utility for the following purposes: • • • •

Achieving and maintaining remission in patients with refractory CD. Healing or reducing the drainage of perianal Þstulas. Reducing dependence on corticosteroids. Reducing the need for surgical treatment.

Mechanism of Action. Immunosuppressants target key immunological processes and molecules through a variety of mechanisms. Among these agents’ effects are blocking the activation of T lymphocytes, promoting the accumulation of anti-inßammatory molecules, and reducing the formation of antibodies. 6-Mercaptopurine. 6-MP (GlaxoSmithKline/Teva’s Purinethol, generics) (Figure 10) is a purine analogue that impairs nucleic acid synthesis and inhibits both humoral and cell-mediated immunity. The drug is indicated for remission induction and maintenance therapy for acute lymphatic (lymphocytic, lymphoblastic) leukemia but is used off label for CD. In July 2003, GlaxoSmithKline granted Teva rights to Purinethol in North America as part of a settlement between

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SH H N

N R

N

N

FIGURE 10. Structure of 6-mercaptopurine (R = H).

the two companies of patent litigation over the arthritis medication nabumetone (GlaxoSmithKline’s Relafen). GlaxoSmithKline and Teva will share gross proÞts from Purinethol sales; additional details of the agreement were not disclosed. Although its precise mechanism of action is unclear, 6-MP is known to inhibit T-helper lymphocyte function. Inactive by itself, 6-MP must be metabolized in the intestinal mucosa and liver into the active metabolites that are responsible for its cytotoxicity (antitumor activity) and immunosuppressant activity. The enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) converts 6-MP into thiopurine nucleotides such as 6-thioguanine (6-TG), the active metabolite. Two other enzymes work competitively to produce inactive metabolites: xanthine oxidase converts 6-MP into 6-thiouric acid, while thiopurine methyl transferase (TPMT) converts 6-MP into 6-methylmercaptopurine (6-MMP). The efÞcacy of 6-MP versus placebo in CD was demonstrated more than two decades ago in a two-year, double-blind, crossover design trial involving 83 CD patients. Two-thirds of 6-MP-treated patients displayed a clinical response during the two years, compared with only 8% of patients on placebo. Fistula closure occurred in 31% of the 6-MP group compared with 6% of the placebo group (Present DH, 1980). Subsequent placebo-controlled and head-to-head trials have afÞrmed these results. Although it is a reasonably effective treatment for patients with refractory CD, response rates to 6-MP can vary greatly for several reasons. The drug has a slow onset of action and therefore requires several months of administration before its therapeutic effects become apparent. In the aforementioned study by D.H. Present, for instance, the mean time to response for 6-MP-treated patients was 3.1 months. Therefore, 6-MP is better suited as maintenance therapy for CD than for inducing remission in the acute setting. The efÞcacy and toxicity of 6-MP in some patients can also be inßuenced by the presence of a genetic polymorphism. Approximately 11% of the general population has low activity of the enzyme TPMT, which normally converts 6-MP into an inactive metabolite. In these patients, metabolism of 6-MP shifts toward accumulation of the active thiopurine nucleotide metabolites. Because these active metabolites are cytotoxic, increased levels put patients at higher risk of drug toxicity and leukopenia. According to the product label for Purinethol, coadministration of 6-MP with drugs that inhibit TPMT (e.g., aminosalicylates such as olsalazine, mesalazine, or sulfasalazine) may exacerbate this problem. Another 10% of the population has high TPMT activity, resulting in decreased levels of the active metabolites of 6-MP. These patients are less likely to suffer

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drug toxicities, but they are also receiving subtherapeutic doses of 6-TG (Cuffari CD, 2001; Kader HA, 2000). Approximately 15% of patients treated with 6-MP experience adverse reactions to the drug (Lamers CB, 1999). Side effects include fever, rash, nausea, and diarrhea, as well as more serious adverse events such as bone marrow toxicity (myelosuppression, leukopenia), infections, pancreatitis, and hepatitis. Therefore, patients taking 6-MP must be closely monitored, particularly in the weeks following initiation of therapy. Also, there is concern that long-term immunosuppression with 6-MP may be associated with an increased risk of malignancies; studies have yielded conßicting results thus far (Connell WR, 1994; Farrell RJ, 2000; Fraser AG, 2000). Although the patent for 6-MP expired more than three decades ago, the Þrst generic version of this drug became available in the United States only in March 2004. Azathioprine. Developed primarily to prevent tissue rejection in transplant surgery, azathioprine (GlaxoSmithKline/Prometheus Products’ Imuran/Imurel/Imurek, Tanabe Seiyaku’s Azanin, generics) (Figure 11) is a purine analogue that impairs nucleic acid synthesis and inhibits lymphocyte proliferation. It is approved for the management of severe, refractory RA and as an adjunctive therapy for the prevention of renal transplant rejection. Like 6-MP, azathioprine is used off label as a treatment for CD. Because of its long onset of action, azathioprine is better suited for maintenance therapy than for acute treatment to induce remission. Azathioprine is a pro-drug of 6-MP. After Þrst-pass metabolism, azathioprine is nonenzymatically converted into 6-MP (88%) and S-methyl-4-nitro-5thioimidazole (12%). From that point, the resulting 6-MP is metabolized via enzymatic processes described in the previous section. Azathioprine and 6-MP are used interchangeably; both agents reduce overall symptoms and steroid intake in patients with active CD. A randomized, placebo-controlled, double-blind study of azathioprine followed 63 patients with active CD. At baseline, all patients began a 12-week tapering dose of corticosteroids and were randomized to either azathioprine (2.5 mg/kg) or placebo. Remission rates at week 12 were equivalent, but after 15 months, there was a signiÞcantly greater remission rate for azathioprine (42%) than for placebo (7%) (Candy S, 1995). NO2 N S N N CH3 N

H N N

FIGURE 11. Structure of azathioprine.

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Azathioprine and 6-MP have been shown to signiÞcantly reduce the risk of relapse in CD patients for up to four years. In a long-term follow-up study, researchers followed 157 CD patients who were in clinical remission for at least six months and were treated with either azathioprine (n = 153) or 6-MP (n = 4) for more than six months (Bouhnik Y, 1996). The only concomitant CD medications allowed during the study were aminosalicylates. After one, three, and Þve years, the cumulative probability of relapse among the 157 patients was 11%, 22%, and 32%, respectively. In the study, 42 patients discontinued treatment with either azathioprine or 6-MP because of personal reasons, planned pregnancy, or side effects or because the treatment duration was deemed sufÞcient by a physician. In these patients, the cumulative risk of relapse was higher than in patients who continued azathioprine or 6-MP: 38%, 61%, and 75% at years one, three, and Þve, respectively. Results from this study also indicated that patients who continued azathioprine or 6-MP treatment were at a signiÞcantly lower risk of relapse during the Þrst four years of remission compared with patients who discontinued their study medication during this time. However, after four years of remission, there was no signiÞcant difference in relapse risk between patients continuing azathioprine or 6-MP treatment and patients who discontinued their medication. The study authors caution that because of the small number of study subjects, the lack of statistical difference after four years may result from insufÞcient statistical power. Azathioprine’s side effects are similar to those of 6-MP: fever, rash, nausea, and headache. Serious adverse events include leukopenia, pancreatitis, severe infections, and myelosuppression (bone marrow suppression). As with 6-MP, there is concern that long-term immunosuppression with azathioprine may be associated with an increased risk of malignancies, but clinical trial results are conßicting (Connell WR, 1994; Farrell RJ, 2000; Fraser AG, 2000). Methotrexate. Methotrexate (MTX; Stada/Wyeth’s Rheumatrex, Santen Seiyaku’s Metolate, generics) (Figure 12) is a folic acid analogue that interferes with DNA synthesis. The drug is indicated for several oncology indications and for severe, recalcitrant, disabling psoriasis and severe, active RA. Like other agents in this class, MTX is used off label for the treatment of CD, both in the acute and maintenance settings. Both orally administered and intramuscularly injected MTX are used in treating CD. Long-term, low-dose MTX therapy inhibits thymidylate, purine, and methionine production, resulting in accumulation of the potent anti-inßammatory

N COOH HOOCCH2CH2CHNHC O

N

N NCH2 CH3

NH2

N

NH2

FIGURE 12. Structure of methotrexate .

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molecule adenosine. MTX inhibits cellular proliferation and reduces the formation of antibodies and inßammatory mediators such as cytokines and eicosanoids. MTX has been shown to be effective in inducing remission in CD patients with chronically active, steroid-dependent disease. In a double-blind, placebocontrolled trial, 141 patients were randomized to receive MTX (25 mg/week intramuscularly) or placebo for 16 weeks. Patients received concomitant prednisone; the corticosteroid dose was tapered during the trial until the patient’s condition worsened. At the conclusion of the trial, 39% of patients in the MTX group were in clinical remission (deÞned as a Crohn’s Disease Activity Index [CDAI] score ≤ 150 points and the discontinuation of prednisone) compared with 19% of patients treated with placebo. Seventeen percent of MTX-treated patients withdrew from the study, compared with 2% in the placebo group. Side effects leading to withdrawal of MTX-treated patients included asymptomatic elevation of serum aminotransferase levels, nausea, skin rash, pneumonia, and optic neuritis (Feagan BG, 1995). MTX has also been shown to maintain remission over a period of 40 weeks in CD patients with chronically active disease. Seventy-six patients who previously entered remission following treatment with 25 mg intramuscular MTX weekly for 16–24 weeks were randomized to receive either MTX (15 mg/week intramuscularly) or placebo for 40 weeks. At the conclusion of the study, 65% of MTX recipients were in remission (CDAI score ≤ 150 points), compared with 39% of patients treated with placebo. During the course of the study, only 28% of patients treated with MTX required prednisone to treat a disease relapse (deÞned as an increase of ≥ 100 points over baseline in the CDAI), compared with 58% of placebo recipients. Of the MTX-treated patients, 40% experienced nausea and vomiting, 25% experienced symptoms of a cold, 18% experienced abdominal pain, and 18% experienced a headache. Corresponding adverse event rates for the placebo group were 25%, 28%, 25%, and 17%, respectively (Feagan BG, 2000). Although MTX is relatively well tolerated as a long-term therapy in CD, it is associated with some minor side effects, including nausea, vomiting, diarrhea, anorexia, stomatitis (inßammation of the oral mucosa), headache, skin rash, brittle nails, and alopecia. Major, less common side effects include pancytopenia, leukopenia, thrombocytopenia, irreversible and potentially lethal allergic pneumonitis, and liver Þbrosis. Product labeling, which includes a long list of black-box warnings of serious and potentially fatal side effects, recommends careful monitoring of hematology and renal and liver function every four to eight weeks in patients receiving long-term treatment. MTX is contraindicated in pregnant women. Cyclosporine. Cyclosporine (Novartis’ Sandimmune/Neoral, generics), a lipidsoluble polypeptide, is a strong immunosuppressant. Novartis reformulated the original cyclosporine product, Sandimmune, and developed Neoral, a microemulsion formulation that surpasses the original in bioavailability. Both Neoral and Sandimmune are indicated for prevention of organ rejection in patients

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receiving kidney, liver, or heart transplants; Neoral is also indicated for severe, active, methotrexate-refractory RA and for severe, recalcitrant plaque psoriasis in adult, non-immunocompromised patients. Although not approved for CD, both oral cyclosporine formulations and intravenous cyclosporine are used to treat patients with severe, steroid-refractory, and/or Þstulizing disease, typically as acute therapies to induce remission. A metabolite of the fungus Beauveria nivea, cyclosporine binds cyclophilin (an intracellular receptor) and selectively blocks the activation of T lymphocytes by inhibiting the calcium-dependent transcription of interleukin-2 (IL-2) and interferon-gamma (IFN-γ ) and, to a lesser degree, IL-3, IL-4, IL-5, TNF-α, and TNF-β. Oral and intravenous cyclosporine are generally as effective as other immunosuppressants for treating active CD, but oral cyclosporine’s long-term use in the maintenance of CD remission is not well supported by clinical trial data. Oneyear relapse rates were identical (20%) in the cyclosporine and placebo groups in one multicenter European trial involving 182 CD patients treated with concomitant corticosteroids (Stange EF, 1995). An 18-month Canadian study involving 305 patients found that CD symptoms worsened in more cyclosporine-treated patients (60%) than placebo-treated patients (52%) (Feagan BG, 1994). Like other immunosuppressant therapies, cyclosporine is associated with a number of side effects, some of them severe. The most commonly reported adverse events are paresthesias (abnormal sensations such as burning and tingling), hypertrichosis (hirsutism, or excessive hair growth), hypertension, tremor, renal insufÞciency, headache, and opportunistic infections. Both Neoral and Sandimmune’s labels contain black-box warnings cautioning physicians about the increased risk of infections and the potential risk of lymphoma. The microemulsion formulation of cyclosporine (Neoral) will lose its U.S. patent protection in 2009. Generic versions of Sandimmune are already available in the United States. Oral Corticosteroids Overview. Corticosteroids are among the most effective agents for inducing remission in acute CD attacks, but because they are associated with several signiÞcant side effects, their use as a CD maintenance therapy is typically reserved for steroid-dependent disease—severe cases in which patients cannot be weaned off steroids without resumption of disease activity. Prolonged therapy with corticosteroids can lead to adrenal atrophy, whereas abrupt cessation can cause adrenal insufÞciency, hypotension, and even death. Insomnia, night sweats, mood changes, and altered glucose metabolism may occur shortly after beginning corticosteroid use; prolonged use is associated with acne, abnormal fat deposition, and excessive hair growth. Some long-term side effects that most concern clinicians are osteoporosis, hypertension, and growth retardation, particularly in the case of pediatric CD patients. Corticosteroids can thwart healing of Þstulas and are therefore inappropriate for long-term therapy in patients with Þstulizing CD.

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Mechanism of Action. Corticosteroids exert their anti-inßammatory and immunosuppressive effects by regulating hormone-responsive gene expression. They inhibit the production of cytokines such as IL-1β, IL-2, and TNF-α, as well as leukotrienes. Corticosteroids also inhibit or reduce T-cell proliferation, monocyte and neutrophil migration into intestinal tissues, and total circulating lymphocyte levels. Formulation. Corticosteroids are available in many different formulations, so physicians can tailor corticosteroid therapy to the severity and extent of CD activity. The oral corticosteroids are the most convenient formulations and are most appropriate for CD activity located in the proximal and transverse colon. Budesonide. Budesonide (AstraZeneca’s Entocort) (Figure 13) is a secondgeneration corticosteroid that is available in an oral formulation and as an enema (discussed later in the section on topical corticosteroids). The oral formulation has a controlled-release mechanism that allows the agent to exert its effect when it reaches the ileum and ascending colon. Oral budesonide is approved for CD and is used in the acute setting to control active CD and induce remission. Because it has fewer side effects, budesonide can be used in CD patients who are intolerant of other corticosteroids. Comparative studies of budesonide and prednisolone have yielded conßicting results regarding budesonide’s comparative efÞcacy. In an eight-week study involving 176 participants, remission rates for patients treated with prednisolone and budesonide were 66% and 53%, respectively (Rutgeerts P, 1994). However, another study showed that over a 12-week period, budesonide resulted in a greater reduction in CDAI scores than prednisolone (Campieri M, 1997). Genetic studies have found that a human leukocyte antigen (HLA) gene is associated with budesonide treatment failure. Of 243 patients in one study, 17 expressed the HLA-DR8 genotype, and 13 of these 17 did not respond to budesonide therapy (Gelbmann CM, 2001). Further studies are needed to verify the link between genotype and budesonide treatment failure. Multiple trials have demonstrated that budesonide is associated with fewer adverse reactions than other corticosteroids (Campieri M, 1997; Rutgeerts P, 1994). Because budesonide is rapidly converted by the liver to inactive metabolites (primarily 16-α-hydroxyprednisolone and 6-β-hydroxybudesonide), only a OH O HO

O

H

O

O FIGURE 13. Structure of budesonide.

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low level (10–20%) of the active drug reaches the bloodstream, thus avoiding the many systemic side effects that occur when other corticosteroids circulate in high concentrations in the bloodstream. Replacement studies show that steroiddependent patients can taper prednisone and prednisolone therapy and incorporate budesonide treatment without increasing the risk of disease exacerbations (Cortot A, 2001). The patent that provided European protection for oral budesonide through 2010 was revoked in 2001 following opposition proceedings Þled by Falk and Ferring. Generic versions of the drug became available in Germany and the United Kingdom in 2004. Prednisone. Prednisone (PÞzer’s Deltasone, SanoÞ-Aventis’s Cortancyl, Merck’s Decortin, generics) (Figure 14) is one of the least expensive CD therapies and one of the most common oral corticosteroids prescribed for moderately acute CD, often for patients who do not respond to initial 5-ASA therapy. Patients typically receive two to four weeks of prednisone therapy and thereafter are tapered off the drug as quickly as possible without provoking a subsequent ßare-up. Because this class has been available for an extensive period of time, no highquality clinical studies pertaining to CD have been conducted in recent years. Therefore, this section does not cite speciÞc efÞcacy results from clinical studies for prednisone. It is well known that prolonged use of systemic corticosteroids—including prednisone—is associated with many serious side effects. (These serious side effects were discussed previously in the “Overview” section for the corticosteroid class.) Therefore, the beneÞts of prednisone must be weighed against the potential side effects when determining whether to use this agent to treat a CD patient on a long-term basis. Antibiotics Overview. Although not formally indicated for the treatment of CD, antibiotics have been used to treat CD patients for decades. Antibiotics are generally prescribed for CD with complicating abscesses or Þstulas and for postsurgical cases. Because long-term use of antibiotics can lead to development of resistance, antibiotics are typically prescribed only in the acute setting. The role of CH2OH C O

H3C

O OH

H3C


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antibiotics in CD treatment is likely to increase; mounting evidence that bacteria play a role in the initiation and pathogenesis of CD is prompting physicians to prescribe antibiotics more frequently to “sterilize the gut” and thereby remove the inßammatory stimulus. (See “Etiology and Pathophysiology” for additional information on the possible role of bacteria in CD pathogenesis.) Mechanism of Action. Broad-spectrum antibiotic agents that are highly effective against anaerobic bacteria are most effective for CD, which suggests that they may sterilize microabscesses in inßamed tissue or alter gut ßora. However, not all broad-spectrum agents are equally effective, which suggests that an additional mechanism is at work in agents that are equally effective. In a study involving a murine model of CD, animals treated with a combination of ciproßoxacin and metronidazole (two antibiotics commonly used for CD; discussed in the following sections) displayed a reduced percentage of activated gut lymphocytes and reduced production of IFN-γ and TNF-α, compared with untreated control mice (Bamias G, 2002). Ciprofloxacin. One of the principal antibiotics used in the treatment of CD is ciproßoxacin (Bayer’s Cipro/Cißox/Ciprobay/Ciproxin, generics) (Figure 15). Ciproßoxacin is a broad-spectrum ßuoroquinolone approved for treatment of infections caused by susceptible bacteria. It is used off label to induce remission of active CD and in the treatment of Þstulizing disease. Despite the paucity of placebo-controlled data on ciproßoxacin’s efÞcacy in CD, comparative studies demonstrate that it is at least as effective as other antibiotic or anti-inßammatory therapies for inducing remission. In a retrospective Italian study, the remission rates achieved with ciproßoxacin alone, metronidazole alone, and combination therapy were similar: 69%, 73%, and 71%, respectively (Prantera C, 1998). A French trial that compared the efÞcacy of ciproßoxacin with oral ethylcellulose-coated mesalamine in 40 patients suggested that these agents are equivalent for treating mildly to moderately active CD. Remission rates at six weeks were 56% in patients receiving ciproßoxacin and 55% in patients receiving mesalamine (Colombel JF, 1999). For Þstulizing disease, ciproßoxacin in combination with inßiximab was shown to be more effective than inßiximab alone in one small, double-blind, placebo-controlled study. In this study, 22 CD patients with perianal Þstulas

FIGURE 15. Structure of ciprofloxacin.

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were randomized to receive 500 mg ciproßoxacin twice daily or placebo for 12 weeks. Inßiximab (5mg/kg) was administered to all patients at weeks 6, 8, and 12. Concomitant therapy (aminosalicylates, oral corticosteroids, azathioprine, or methotrexate) at stable doses was permitted. The primary end point was clinical response, deÞned as a 50% or greater reduction in the number of draining Þstulas at 18 weeks; 73% of ciproßoxacin-treated patients achieved this primary end point, compared with only 39% of the placebo group, and logistic regression analysis indicated better response in the ciproßoxacin group (West RL, 2004). Most side effects associated with ßuoroquinolone antibiotics are minimal, usually mild GI disturbances and CNS effects. Side effects associated with ciproßoxacin use in particular include nausea, vomiting, diarrhea, restlessness, rash, urticaria, painful oral mucosa, and, infrequently, tendon rupture. Ciproßoxacin has lost patent protection in the United States, Japan, and Europe, excluding Italy, where the ciproßoxacin patent will expire in 2009. Generic versions of Cipro were available in the United States, France, Germany, Spain, the United Kingdom, and Japan in 2004. Metronidazole. Metronidazole (Aventis/Shionogi’s Flagyl, Sandoz’s Metrolyl, generics) is a synthetic antiprotozoal and antibacterial agent indicated for infections in a wide variety of body systems. These dual actions have led to its use in healing CD Þstulas (in which anaerobes are suspected to play an important role) and in inducing remission in CD ßare-ups (of which bacterial activity is likely a component). More than two decades ago, metronidazole was shown to be effective in healing Þstulas in 10 of 18 (56%) patients with active CD (Bernstein LH, 1980). In a retrospective analysis of inpatient records for 233 Italian CD patients, researchers found 73% of metronidazole-treated patients achieved complete or partial remission (Prantera C, 1998). Metronidazole has also been shown to signiÞcantly improve CDAI scores, compared with placebo, in a 16-week study involving 99 CD patients (Sutherland L, 1991). However, only 56 patients completed the trial; 43 patients withdrew because of worsening disease, adverse events, or protocol violations. The most common side effect associated with metronidazole use is nausea, accompanied occasionally by headache, anorexia, and vomiting. Parasthesias are the major side effect of long-term therapy. Metallic taste, glossitis, stomatitis, urticaria, vaginal and urethral burning, dark urine, and reversible neutropenia may also occur. Additionally, the combination of metronidazole and alcohol can cause abdominal cramps, nausea, vomiting, headaches, and ßushing. Therefore, alcohol consumption should be avoided while taking metronidazole, and for at least one day following discontinuation of therapy. Topical Aminosalicylates Overview. As stated in the discussion of oral aminosalicylates, this class consists of agents that contain 5-ASA, one of the oldest anti-inßammatory compounds used in the treatment of inßammatory bowel diseases. Topical aminosalicylates, indicated for treatment of UC, do not appear to be as efÞcacious in CD

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as in UC. However, the agents are used in some cases of CD that are conÞned to the colon, often in combination with an oral aminosalicylate or other acute therapy. Because many patients consider topical formulations inconvenient, the topical 5-ASAs are used more frequently in the acute setting than in long-term maintenance of CD remission. Few data describe the efÞcacy and safety of topical aminosalicylates in CD patients. Studies have shown that rectal mesalamine formulations are moderately effective in CD; the response rate of these formulations in treating CD affecting the rectum is relatively slower than in treating UC, and healing is incomplete in 50% of the CD patients treated (Williams CN, 1990). Rectal mesalamine formulations can cause headaches as well as anal irritation and ßatulence in 5–10% of patients. Abrupt discontinuation of rectal mesalamine can occasionally trigger a severe relapse (rebound) response: development of pancolitis requiring subsequent colectomy (surgical removal of the colon). Patients who intend to stop rectal therapy are therefore counseled to begin oral 5-ASA therapy prior to step-down discontinuation of enema or suppository. Mechanism of Action. Although the 5-ASAs have been researched and used in CD treatment for decades, their precise mechanism of action remains unclear. They are thought to have numerous anti-inßammatory mechanisms, which are discussed in greater detail in the “Oral Aminosalicylates” section. As previously mentioned, these agents may offer some protection against the development of colon cancer, which occurs at a higher rate in patients with UC or CD. The aminosalicylates are thought to confer this protection by increasing apoptosis in the intestine and inhibiting the proliferation of the colorectal mucosa (Bus PJ, 1999; Reinacher-Schick A, 2000). Formulation. Topical 5-ASAs are available in many different rectal formulations, including enemas, suppositories, and rectal foams. These agents come as unbound, uncoated mesalamine, which can reach the proximal colon directly when administered rectally, or in formulations with special coatings that help target the release of the active 5-ASA to the site of disease. Enteric-Coated Mesalamine. Enteric-coated mesalamines are available as enemas (GlaxoSmithKline/Merckle’s Claversal, Giuliani’s Asacol, Chiesi’s Asalex, Astellas’s Asamax, Provalis’s Salofalk, So Se Pharm’s Mesaßor, generics), as suppositories (Procter & Gamble/Giuliani’s Asacol, Norgine’s Fivasa, GlaxoSmithKline/Faes/Merckle’s Claversal, Falk/Provalis’s Salofalk, Astellas’s Asamax, Chiesi’s Asalex, Stada’s Enterasin, generics), and as rectal foams (Procter & Gamble/Giuliani’s Asacol, Faes/Merckle’s Claversal, Sofar’s Pentacol, Chiesi’s Asalex, Provalis’s Salofalk). Rectal formulations of the entericcoated mesalamines are indicated for treatment of UC and used off label for CD. Although the foam preparations are easier for patients to use (and many patients prefer them), enemas and suppositories provide greater proximal penetration and are thought to be more effective.

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Ethylcellulose-Coated Mesalamine. Ethylcellulose-coated mesalamine is available as an enema (Ferring/Kyorin Seiyaku/Nisshin Pharma’s Pentasa) and as a suppository (Ferring’s Pentasa). Rectal formulations of ethylcellulose-coated mesalamine are indicated for treatment of UC and used off label for CD. Mesalamine. Uncoated mesalamine is available as an enema (Solvay’s Rowasa, generics) and as a suppository (Solvay’s Rowasa, Axcan Scandipharm’s Canasa). Rowasa is indicated for treatment of active, mild-to-moderate, distal UC, proctosigmoiditis, and proctitis (inßammation of the rectum). It is used off label for treatment of CD, particularly when the disease is conÞned to the distal colon. Uncoated mesalamine enemas will lose their patent protection in the United States and Europe in 2004 and 2007, respectively. Intravenous Corticosteroids Overview. As mentioned in the “Oral Corticosteroids” section, corticosteroids are among the most effective agents for inducing remission in acute CD attacks. However, their association with several signiÞcant side effects relegates their use primarily to short-term treatment of moderate-to-severe CD. Intravenous (IV) corticosteroids are typically employed in particularly severe, refractory cases that require hospitalization and are administered as a short course, generally ten days, to bring severe disease under control. Mechanism of Action. Corticosteroids exert their anti-inßammatory and immunosuppressive effects by regulating hormone-responsive gene expression. They inhibit the production of cytokines and leukotrienes and inhibit T-cell proliferation, monocyte and neutrophil migration into intestinal tissues, and total circulating lymphocyte levels. Formulation. Corticosteroids are available in many different formulations, so physicians can tailor corticosteroid therapy to the severity and extent of CD activity. IV formulations are used in patients with severe disease as a way to bypass the impaired GI absorption that these patients may exhibit. Hydrocortisone. IV hydrocortisone (PÞzer’s SoluCortef, SanoÞ-Aventis’ Hydrocort, Merck’s Hydrocortone, generics) is one of the most commonly used IV corticosteroids for patients with severe or refractory CD. Because hydrocortisone has been available for decades, no high-quality clinical studies pertaining to CD have been conducted in recent years; thus this section does not cite speciÞc efÞcacy results from clinical studies for hydrocortisone. The side effects of hydrocortisone are similar to side effects of other corticosteroids, discussed in the “Oral Corticosteroids” section. Topical Corticosteroids Overview. In an attempt to utilize the highly effective corticosteroids for CD treatment while minimizing their systemic side effects, rectally administered topical formulations of corticosteroids have been developed. These formulations are used for treatment of CD that is conÞned to the colon.

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Mechanism of Action. Corticosteroids exert their anti-inßammatory and immunosuppressive effects by regulating hormone-responsive gene expression. They inhibit the production of cytokines and leukotrienes and inhibit T-cell proliferation, monocyte and neutrophil migration into intestinal tissues, and total circulating lymphocyte levels. Formulation. Topical corticosteroids are available as suppositories, enemas, and rectal foams, which effectively treat CD activity in the rectosigmoid area of the colon while minimizing the doses needed and the side effects of the systemic corticosteroids. Hydrocortisone. Topical hydrocortisone is available as an enema (Paddock’s Colocort, generics) and as a rectal foam (Schwarz Pharma’s Cortifoam, GlaxoSmithKline/Ferrer’s Colifoam). These formulations of hydrocortisone are typically administered in short courses to induce remission in moderately active CD proctitis. Although the foam preparations of hydrocortisone and other corticosteroids are easier for patients to use, enemas provide greater proximal penetration and are more suitable for extensive CD activity. Because hydrocortisone has been available for a long time, no high-quality clinical studies pertaining to CD have been conducted in recent years. Therefore, this section does not cite speciÞc efÞcacy results from clinical studies for hydrocortisone. Budesonide. Budesonide (AstraZeneca’s Entocort) is a second-generation corticosteroid that is available as an enema and as an oral formulation (discussed in the “Oral Corticosteroids” section). Budesonide enema is approved for UC and is used off label in the acute setting to control active CD and induce CD remission. Because it has fewer side effects, budesonide can be used in CD patients who are intolerant of other corticosteroids. Studies suggest that the efÞcacy of budesonide is similar to that of other corticosteroids and have clearly demonstrated that budesonide is associated with fewer side effects (Rutgeerts P, 1994; Campieri M, 1997). Nonpharmacological Approaches Nonpharmacological approaches for CD include probiotics, nutritional therapies, and surgical procedures. Probiotics—dietary supplements containing live microorganisms thought to restore the beneÞcial bacteria normally present in the GI tract—are gaining popularity among gastroenterologists as an adjunct CD therapy. Nutritional therapies are generally reserved for the most severe cases, such as patients suffering from poor GI absorption and malnutrition, while surgery is appropriate for patients with acute, life-threatening complications of CD and/or patients with extensive CD activity that is refractory to all available drug therapies. Probiotics are an alternative to conventional pharmacotherapy for patients with mild CD who prefer to remain drug-free, and they are increasingly used as an adjunct therapy in the treatment of CD. One theory of the etiology of

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CD proposes that bacteria in the normal intestinal ßora trigger the aberrant and ampliÞed immune response seen in CD; therefore, probiotic products aim to alter the balance of “good” and “bad” bacteria in the intestines of CD patients. Probiotic foods, such as yogurt, and food supplements, often in powder and capsule form, are now sold in stores and health food markets. However, large-scale, highquality, randomized clinical trials are needed to clarify how probiotics work and to deÞnitively demonstrate the utility of these nonpharmacological agents in the induction and maintenance of CD remission. Nutrient absorption is generally normal in mild CD cases involving the terminal ileum, except for vitamin B12, which can be replaced via monthly injections. However, if more than two or three feet of the small intestine are diseased or surgically removed, malabsorption of fats, calcium, and vitamins A, E, and D can occur. In most markets under study, hospitalized patients who are severely malnourished and pediatric or adolescent CD patients who have failed to grow normally may receive one of the following nutritional therapies to replace otherwise lacking nutrients: •

•

•

Liquid elemental diets—formulated to meet all nutritional needs of CD patients—include concentrated nitrogen in the form of amino acids and are almost completely absorbed by the upper intestinal tract. Enteral nutrition (EN) is provided via a stomach feeding tube inserted through the nose. EN is absorbed directly by the GI tract and causes few side effects. Patients can remove the tube in the morning and resume normal daily activities. Total parenteral nutrition (TPN) provides nutrition intravenously through a superior vena cava catheter that cannot be removed and reinserted by the patient. TPN is generally administered for a short course (one month) or just prior to surgery. Some patients may receive long-term TPN, but 15% will experience hyperglycemia; copper, zinc, and fatty-acid deÞciencies; or serious IV line infections.

CD patients typically undergo emergency surgery because of complications, including excessive bleeding, bowel perforation, intestinal obstruction, and abscess formation. Elective surgery may be indicated for treatment-refractory patients who are experiencing severe pain, weight loss, fever, or extreme fatigue. Surgical procedures for CD are generally aimed at removing or bypassing the diseased areas of the small intestine, leaving the healthy portions intact: • •

Bowel resection involves removal of the diseased area of the small intestine, followed by anastomosis to connect the newly severed ends. An alternative to resection is bowel bypass surgery, which creates a diverted path between the healthy portions of the small intestine and the colon. Bypass operations, which are associated with complications in leftover diseased portions of intestine, are becoming less common, thanks to improvements in bowel resection techniques.

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•

537

A third type of surgery, total abdominal colectomy with ileorectal anastomosis, is used for patients with Crohn’s colitis. The entire colon is removed and the ileum is joined to the rectum. Because this procedure leaves the rectum intact (except when the rectum is diseased and unusable for anastomosis), CD patients do not generally require subsequent use of an ostomy bag. Another surgical procedure for CD is strictureplasty. In this procedure, surgeons use a balloon catheter to Þnd areas of stricture. The intestinal wall at that point is cut and resealed in a different orientation to allow free movement of intestinal contents. A newer version of strictureplasty uses an endoscope instead of a balloon catheter.

Because CD recurs postsurgically in as much as 55% of patients at 5 years and 76% at 15 years, regardless of procedure type, surgery is usually followed by aggressive pharmacological management with mesalamine, 6-MP, or azathioprine (Achkar JP, 2000). One possible complication of surgical CD treatments (particularly those that involve small bowel resection) is short bowel syndrome (SBS). Approximately half of the small intestine can be removed without ill effects for the patient, particularly when the ileum is left intact. Removal of the jejunum, for instance, results in lactose intolerance, but the ileum can compensate and absorb most important nutrients. However, patients with a severely diseased or resected ileum can suffer from SBS, which causes malabsorption of nutrients, particularly fats, bile salts, and some critical vitamins. Diarrhea, weight loss, fatigue, abdominal bloating, and fatty stools are common symptoms of SBS and can be ameliorated by use of a parenteral diet. EMERGING THERAPIES The etiology and pathophysiology of Crohn’s disease (CD) are not well understood. Theories about the cause of CD and its progression suggest that both immunodeÞciencies, particularly in the innate immune system, and an overactive adaptive immune response may be to blame. As a result, a wide range of therapies are in development for CD treatment whose mechanisms of action appear to be mutually exclusive—for example, immune suppressants and immune stimulators, cytokine inhibitors and recombinant cytokines, antibiotics and probiotics. However, all of these therapeutic approaches have demonstrated the potential to offer beneÞt in the treatment of the disease. Current research focuses primarily on the development of biological agents that target key inßammatory components, particularly tumor necrosis factor-alpha (TNF-α) and other proinßammatory cytokines. The only biological agent currently approved for treatment of CD is the TNF-α inhibitor inßiximab (Centocor [a Johnson & Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade). Efforts are also under way to evaluate the potential of novel mechanisms of action in the treatment of CD, including immune stimulators, interleukin inhibitors, cell adhesion molecule (CAM) inhibitors, and inhibitors of the mitogen-activated protein (MAP) kinase signal transduction pathway. The most promising therapies in

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late-stage development are two TNF-α inhibitors, adalimumab (Abbott’s Humira) and CDP-870 (UCB’s Cimzia), which offer advantages over inßiximab, including decreased immunogenicity and a more convenient route of administration. These therapeutic approaches are discussed in detail in the following sections; Table 3 summarizes the drug therapies in development for CD. In addition to the therapies in development for CD discussed in the previous paragraph, Protein Design Labs (PDL) has been developing a humanized monoclonal antibody (MAb) against interferon-gamma (IFN-γ ), called fontolizumab or HuZAF. According to a PDL press release in March 2004, the drug failed to meet its primary end point of induction of a signiÞcant clinical response, compared with placebo, in two Phase II trials (HARMONY 1 and 2). In August 2005, Biogen Idec entered into collaboration with PDL to jointly develop, manufacture, and commercialize fontolizumab. It is unclear whether PDL and Biogen Idec will continue to pursue development of fontolizumab for CD after the disappointing efÞcacy results or seek instead to develop the drug for other autoimmune indications. This drug is not discussed in further detail here. TNF-α Inhibitors Overview. During active ßares of CD, neutrophils and monocytes migrate from the bloodstream into the intestinal mucosa and submucosa, where they secrete proinßammatory molecules, including cytokines and tissue-damaging free radicals. Inhibitors of TNF-α, a potent inßammatory cytokine, represent the most recent advance in the treatment of CD. Inßiximab, the Þrst anti-TNF-α agent approved for CD, was launched in 1998 in the United States, 1999 in Europe, and 2002 in Japan. Because of inßiximab’s relatively high cost, cumbersome route of delivery (IV), immunogenicity, and risk of immunomodulatory side effects, researchers have directed their attention toward the development of improved anti-TNF-α therapies for the treatment of CD. The TNF-α inhibitor etanercept (Amgen/Wyeth/Takeda’s Enbrel) has been examined in the treatment of CD but failed to meet its primary efÞcacy end point: induction of a clinical response or remission in CD patients with moderate-tosevere active disease (Sandborn WJ, 2001). This failure was probably the result of etanercept’s inability to induce the apoptosis of intestinal T cells—a capability that appears to be critical for TNF-α inhibitor effectiveness in the treatment of CD (ten Hove T, 2002; van den Brande JMH, 2003; Shen C, 2004). Phase II or Phase III trial results have been published for other TNF-α inhibitors, including Abbott’s adalimumab (Humira), UCB’s CDP-870 (Cimzia), and Serono’s onercept. Onercept is currently in Phase II development for CD in the United States and Europe. However, a randomized, placebo-controlled study of 207 patients presented at the United European Gastroenterology Week in September 2004 showed no signiÞcant beneÞt over placebo of the four onercept doses tested (Rutgeerts P, 2004[a]). Furthermore, development of onercept for psoriasis was discontinued because of two cases of sepsis, one of them fatal. The unfavorable Phase II efÞcacy results, questions about its safety, and the fact that the agent is no longer listed in the company’s pipeline make it unlikely that development

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TABLE 3. Emerging Therapies in Development for Crohn’s Disease Compound TNF-α inhibitors Adalimumab (Humira) United States Europe Japan

Development Phase

Marketing Company

III III —a

Abbott Laboratories Abbott Laboratories —

III III —

UCB UCB —

II II —

Abbott Laboratories Abbott Laboratories —

II — —

Synta Pharmaceuticals — —

Immune stimulators Sargramostim (Leukine) United States Europe Japan

III III —

Berlex Laboratories Berlex Laboratories —

Cell adhesion molecule inhibitors Natalizumab (Tysabri) United States Europe Japan

IIIb PRc —

Elan/Biogen Idec Elan/Biogen Idec —

MAP kinase inhibitors RDP-58 (delmitide) United States Europe Japan

— IId —

— Procter & Gamble —

II II —

Cytokine PharmaSciences Cytokine PharmaSciences —

CDP-870 (Cimzia) United States Europe Japan Interleukin inhibitors ABT-874 (formerly J-695) United States Europe Japan STA-5326 United States Europe Japan

Semapimod (formerly CNI-1493) United States Europe Japan

a Adalimumab is in Phase II development in Japan for the treatment of rheumatoid arthritis and psoriasis

under licensee Eisai Pharmaceuticals. b Natalizumab, which had been launched in the United States for multiple sclerosis (MS) in 2004, was

voluntarily withdrawn from U.S. markets and all clinical trials of the agent suspended by Biogen Idec and Elan in February 2005. Phase III U.S. clinical trials had been completed prior to this date. The decision to continue development of natalizumab for Crohn’s disease (CD) and to relaunch natalizumab for MS in the United States is pending. c The review of natalizumab for CD in Europe has been slowed because of the agent’s safety issues and is ongoing. d After disappointing Phase II clinical trial results for RDP-58 in CD, Procter & Gamble has decided to focus on development for ulcerative colitis; RDP-58’s continued development for CD remains uncertain. PR = Preregistered.

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of onercept for CD will continue. Therefore, only adalimumab and CDP-870 are discussed in detail in following sections. Mechanism of Action. Receptors for TNF-α are found on the surface of most cells, including mononuclear cells in the gastrointestinal (GI) tract. Cleavage of the membrane-bound TNF receptors yields soluble TNF receptors that retain ligand-binding ability but cannot activate cells. Agents in this class reduce free, bioactive TNF-α by emulating the physiological role played by soluble TNF receptors. This action modulates the amount of circulating, bioactive TNF-α by binding to the cytokine before it can activate cell-surface receptors on mononuclear cells. Some TNF-α inhibitors, such as inßiximab and adalimumab, can also induce the apoptosis of T cells in the intestinal mucosa, a capability that appears to be critical to TNF-α inhibitor effectiveness in the treatment of CD (ten Hove T, 2002; van den Brande JMH, 2003; Shen C, 2004). Adalimumab. The fully human anti-TNF-α monoclonal antibody (MAb) adalimumab (Humira) was discovered through a collaboration between Cambridge Antibody Technology (CAT) and Knoll Pharmaceuticals (acquired by Abbott Laboratories in 2001). Abbott owns exclusive worldwide rights to adalimumab and pays sales-based royalties to CAT. Abbott is developing adalimumab as a potential treatment for CD; Phase III trials are under way in the United States and Europe. Abbott launched adalimumab for the treatment of rheumatoid arthritis (RA) in the United States and Europe in 2003. Adalimumab also launched in 2005 in Europe for the treatment of psoriatic arthritis and is preregistered in the United States for this indication. In Japan, adalimumab is in Phase II development for RA and psoriasis with licensee Eisai Pharmaceuticals, but no development for CD has been reported yet. Adalimumab, whose mechanism of action is similar to that of inßiximab, blocks the activity of TNF-α and induces T-cell apoptosis (Shen C, 2004). Unlike inßiximab, which is a chimeric monoclonal antibody (MAb) composed of 75% human and 25% mouse (murine) protein, adalimumab is a fully human, antiTNF-α MAb. According to the inßiximab and adalimumab product labels, the frequency of development of neutralizing antibodies against these two agents is respectively 10% and 5%. Therefore, adalimumab is expected to be less immunogenic than inßiximab, which may result in a lower frequency of infusion reactions and fewer problems with loss of efÞcacy. Another important characteristic that differentiates adalimumab from inßiximab is the agent’s route of administration. Inßiximab must be administered by a health care professional as an IV infusion, whereas adalimumab can be self-administered by a patient as a subcutaneous (SC) injection every other week. Adalimumab’s ability to induce CD remission was demonstrated in the Phase III CLASSIC (Clinical Assessment of Adalimumab Safety and EfÞcacy Studied as an Induction Therapy in Crohn’s) trial presented at the 2004 Digestive Disease Week conference (Hanauer SB, 2004[a]). This double-blind study involved 299 patients with moderately to severely active CD (Crohn’s Disease Activity

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Index [CDAI] 220–450) who were naive to anti-TNF-α therapy. Patients were randomized to receive SC injections at weeks 0 and 2 of either placebo or one of three adalimumab regimens at the following loading and maintenance dosages: 160 mg/80 mg, 80 mg/40 mg, or 40 mg/20 mg. At week 4, 30% of patients in the two higher-dose adalimumab treatment groups achieved remission (deÞned as a CDAI score less than 150), compared with 12% of placebo recipients; this comparison, which served as the study’s primary end point, produced a statistically signiÞcant difference. The highest rate of remission induction (36%) was achieved by the 160 mg/80 mg adalimumab group. Patients in this group also achieved the highest rate of clinical response—49% achieved a 100-point or greater reduction in CDAI score and 58% achieved a 70-point or greater reduction, compared with 23% and 35%, respectively, of patients treated with placebo. These differences were statistically signiÞcant. Scant safety data were reported, but all doses of adalimumab were said to be well tolerated, and there was no difference in the incidence of adverse events between the four groups. Mild injection site reactions were the most common adverse event in this study. Only one adalimumab-treated patient tested positive for antibodies to the agent during the four weeks of the study. An uncontrolled, open-label extension of the CLASSIC trial, referred to as CLASSIC II, was presented at the 2005 Digestive Disease Week conference in Chicago, Illinois (Sandborn WJ, 2005[a]). Two hundred and twenty patients who were not in remission (deÞned as a CDAI score of less than 150) at either week 0 or 4 of the CLASSIC I study were given 40 mg adalimumab SC every other week. Dose escalation to 40 mg weekly was allowed for ßares or persistent nonresponse. After six months, 156 patients (71%) remained on adalimumab (40 mg every other week or weekly), and 63% of these patients did not require dose escalation. The rate of clinical remission at 24 weeks was 33% (73/220); clinical response rates were 78% (122/156) for achieving a 70-point or greater reduction in the CDAI score and 70% (109/156) for achieving a 100-point or greater reduction. Adverse events, not necessarily drug-related, occurred in approximately 40% of patients; 10% of patients experienced serious adverse events, and 10% withdrew from the study because of adverse events. Five infections were observed in four patients during the six-month study period. The 55 patients who were in remission (deÞned as a CDAI score of less than 150) at both week 0 and week 4 in the CLASSIC I trial are also being studied to assess adalimumab’s efÞcacy in maintenance of remission in CD (Sandborn WJ, 2005[a]). These patients were randomized to receive placebo, 40 mg adalimumab every other week, or 40 mg adalimumab weekly for up to one year. Results from this study have not yet been released. Adalimumab also appears to be efÞcacious and safe in CD patients previously treated with inßiximab who had either stopped responding or became intolerant of the drug. In a Phase III, open-label, uncontrolled study, a total of 24 patients were treated with an initial dose of 80 mg adalimumab at week 0 and then a 40 mg dose of adalimumab every other week for 12 weeks. Beginning at week 4, dosing could be increased to weekly 40 mg SC injections of adalimumab

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if necessary. At the conclusion of the 12-week treatment period, 59% of the 17 patients who had a baseline CDAI score of 220 or higher achieved a clinical response (deÞned by a 100-point or greater decline in CDAI score), while 29% achieved clinical remission (deÞned by a CDAI score of 150 points or lower). Of the nine patients who had draining Þstulas at baseline, Þve experienced a 50% or greater decline in the total number, and three patients experienced complete Þstula closure. Adalimumab was well tolerated in this study, and none of the study participants experienced hypersensitivity reactions to adalimumab, even among the 20 patients who had acute and delayed hypersensitivity reactions with inßiximab (Sandborn WJ, 2004[c]). As previously mentioned, adalimumab is marketed for RA, and its product label contains warnings similar to those in the inßiximab label. Adalimumab has a black box warning cautioning physicians and patients about the risk of tuberculosis infection. The warning recommends that patients be tested—and possibly treated—for latent tuberculosis infection prior to receiving adalimumab. The product label for adalimumab also reports that malignancies have been observed in recipients of TNF-α inhibitors, including adalimumab. According to the product label, 0.4% of the 2,468 RA patients treated with adalimumab for a median of 24 months during clinical studies developed lymphomas; this occurrence rate is higher than the rate in the general population, but not signiÞcantly higher than the rate in people with RA. In 2004, warnings were added to adalimumab’s label about hypersensitivity reactions, hematologic events, and use in patients with congestive heart failure. Adalimumab offers several potential advantages over inßiximab in the treatment of CD, including decreased immunogenicity and a more convenient subcutaneous route of administration. Currently available data suggest that the efÞcacy of adalimumab is similar to inßiximab’s efÞcacy in inducing a clinical response or remission in CD patients (see “Current Therapies” for additional information on inßiximab’s efÞcacy). This similarity bodes well for adalimumab’s potential in the CD market. However, no data have been published yet on adalimumab’s ability to maintain remission, and larger-scale, placebo-controlled trials over a longer study period are needed to verify adalimumab’s ability to treat Þstulizing disease. Adalimumab will likely be used initially in CD patients who are intolerant of or have failed inßiximab therapy, supported by the study showing adalimumab’s efÞcacy in patients who stopped responding to or were intolerant of inßiximab. Adalimumab may also challenge inßiximab as the Þrst-line TNF-α therapy for CD. CDP-870. Two Phase III trials of CDP-870 (certolizumab pegol; UCB’s Cimzia) for the induction and maintenance of a clinical response in CD have been completed in the United States and Europe. In an October 2005 press release, UCB announced its plans for regulatory submissions in both regions during the Þrst quarter of 2006. No development has been reported in Japan. This drug is also in Phase III development as a potential treatment for RA.

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CDP-870 was being developed by Celltech Group, but the company was acquired by UCB in 2004. Previously, Celltech had been codeveloping CDP-870 for RA with PÞzer. However, in December 2003, PÞzer terminated its rights to CDP-870 (prior to the completion of Phase III RA trials); PÞzer cited as its reason for termination of the agreement Celltech’s refusal to renegotiate the Þnancial terms originally established between Celltech and Pharmacia (now PÞzer) in March 2001. In May 2005, Lonza entered into an agreement with UCB to manufacture CDP-870. Using a proprietary technology, CDP-870 can be manufactured in Escherichia coli at a cost much lower than the cost of creating an antibody or receptor fusion product by using mammalian cell culture. Thus, CDP-870’s lower cost of production may translate into a price lower than inßiximab’s price. Such a cost advantage would be an important distinguishing feature for CDP-870, considering the high level of price sensitivity in the markets under study and the fact that CDP-870 will face stiff competition in the RA market, where there are already three well-established TNF-α inhibitors (etanercept, inßiximab, and adalimumab). CDP-870 is a humanized anti-TNF-α MAb fragment conjugated to two polyethylene glycol (PEG) subunits that add stability and increase the agent’s half-life. Because CDP-870 is humanized, it may be less immunogenic than the chimeric inßiximab. CDP-870 binds TNF-α with high afÞnity, thereby blocking its ability to activate the inßammatory cascade. CDP-870 lacks an Fc region, so this agent is unable to activate complement or to lyse cells through antibodydependent cell cytotoxicity, which inßiximab and adalimumab are able to do; it is not known whether those mechanisms of action are important for efÞcacy in CD. It is also not known whether CDP-870 is, like inßiximab and adalimumab, capable of inducing T-cell apoptosis, which is recognized as important in the treatment of CD. CDP-870 is formulated as a lyophilized powder for reconstitution, which can then be administered intravenously or as an SC injection using a 23-gauge needle, according to a company representative from Celltech (now UCB). Therefore, CDP-870 can be self-administered by the patient; if the patient is unwilling or unable to self-administer the SC injection, the drug can be administered intravenously by a health care professional. The ßexibility of CDP-870’s dosing and capability of being self-administered by SC injection gives it an advantage over inßiximab’s IV dosing. Furthermore, CDP-870’s monthly dosing schedule offers an advantage over the other subcutaneous TNF-α inhibitor in development for CD, adalimumab, which is administered every other week. UCB is conducting the Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and EfÞcacy (PRECiSE) program involving four studies to investigate CDP-870’s potential to treat CD. PRECiSE-1 and PRECiSE-2 are Phase III, double-blind, placebo-controlled studies in a total of 1,330 CD patients with moderately to severely active disease over a 26-week period. A July 2005 press release from UCB announced that the PRECiSE-1 trial met its primary efÞcacy end points with statistical signiÞcance, but analysis is ongoing and detailed results have yet

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to be released. Results from PRECiSE-2 demonstrating that CDP-870 met the primary end points with statistical signiÞcance were reported in an October 2005 press release from UCB and presented at the United European Gastroenterology Week in Copenhagen, Denmark (Schreiber S, 2005) (see detailed discussion of PRECiSE-2 results in the next paragraph). UCB stated that CDP-870 was well tolerated in these two studies, but the company will further assess the agent’s tolerability and long-term safety in the PRECiSE-3 and PRECiSE-4 trials. These studies are 24-month, open-label extensions of PRECiSE-1 and PRECiSE-2 and are currently ongoing. CDP-870’s ability to maintain a clinical response (100 point or more decrease in the CDAI score) in moderate-to-severe CD was demonstrated in the Phase III PRECiSE-2 trial (UCB press release, October 2005; Schreiber S, 2005). In the study, 668 patients were treated with 400 mg CDP-870 at weeks 0, 2, and 4; 428 patients (64%) achieved a clinical response after this induction regimen and were randomized to receive placebo or CDP-870 every four weeks for up to 24 weeks. At week 26, 62.8% of patients in the CDP-870 group maintained a clinical response compared with only 36.2% of the placebo group, a statistically signiÞcant difference. The percentage of patients in clinical remission at week 26 also reached statistical signiÞcance; 47.9% of CDP-870-treated patients versus 28.6% of placebo-treated patients. Based on Phase II trial results (discussed in the next two paragraphs), which found higher response rates in patients with elevated C-reactive protein (CRP; a marker for inßammation), PRECiSE-2 evaluated CDP870’s efÞcacy in patients based on CRP levels (Lorenzo A, 2004). However, the primary end points in the PRECiSE-2 trial were met regardless of the patients’ levels of CRP. Phase II trial results were reported in a Celltech company press release in February 2002 and presented at the 2003 Digestive Disease Week conference (Schreiber S, 2003). The dose-ranging, placebo-controlled study assessed the product’s efÞcacy and safety in 292 CD patients with an initial CDAI score of 220–450 points. Patients were treated with monthly SC injections of placebo or 100, 200, or 400 mg CDP-870 at weeks 0, 4, and 8. Clinical response was assessed every two weeks through week 12 using the CDAI; the primary end point was the percentage of patients achieving a 100-point or greater decline in CDAI score or a CDAI score of 150 points or lower (indicating remission) at week 12. The best response rate, 52.8%, was observed with the highest dose at week 10; this result was statistically signiÞcant compared with placebo (30.1%). However, the week 12 response rates did not reach statistical signiÞcance: 44.4% of patients receiving 400 mg CDP-870 compared with 35.6% of placebo recipients. Although it failed its primary efÞcacy end point, CDP-870 was well tolerated, and no difference in the incidence of adverse events was observed between the drugtreated and placebo groups. Additional analysis of the Phase II results revealed that signiÞcantly higher response rates to CDP-870 were found in patients who had elevated levels of CRP prior to being treated with the drug (Schreiber S, 2003). In the subset of 118 patients with a baseline CRP greater than or equal to 10 mg/L, statistically signiÞcant

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differences in response rates between placebo recipients and the 400 mg CDP-870 group were found at all time points. The highest response rates to CDP-870 were found for the highest dose at weeks 6 and 10: 67.7% and 64.5%, compared with 28.6% and 17.9% for placebo, respectively. An IV formulation of CDP-870 also demonstrated efÞcacy in CD patients (Winter TA, 2004). In a randomized, double-blind, placebo-controlled Phase II study, 92 patients with active CD were administered a single infusion of CDP870 (1.25, 5, 10, or 20 mg/kg) or placebo. The trial’s primary endpoint was the percentage of patients achieving a clinical response (deÞned as a 100-point or greater decline in CDAI score) or remission (deÞned as a CDAI score of 150 points or lower) at week 4, although efÞcacy was also measured at weeks 2, 8, and 12. Compared with placebo, treatment with CDP-870 was not associated with statistically signiÞcant differences in response rates. However, 47.1% of patients receiving 10 mg/kg CDP-870 achieved remission at week 2 compared with 16% of placebo recipients, a statistically signiÞcant difference. This difference did not persist at week 4. In total, 22 patients withdrew from the study as a result of disease progression, non-improvement, or adverse events. Adverse events, the majority of them mild to moderate in nature, were reported by 43 patients receiving CDP-870 and 15 placebo-treated patients. The most common adverse events reported in the treatment groups were headache, CD aggravation, urinary tract infection, abdominal pain, fever, and nausea. CDP-870 may offer several advantages over inßiximab, such as a more convenient formulation, decreased immunogenicity, and an anticipated lower price. Phase III results from the PRECiSE-1 and PRECiSE-2 trials, which met their primary end points, suggest that CDP-870’s efÞcacy in treating CD is similar to that of inßiximab and adalimumab. Although CDP-870 failed to meet its primary efÞcacy end points in two Phase II trials, many agents in development for CD have had difÞculty meeting primary efÞcacy endpoints because of high placebo response rates, and analysis of subgroups with high CRP levels, presumably patients with the most active disease, has demonstrated signiÞcant efÞcacy over placebo. Nonetheless, CDP-870’s effect on Þstula closure will need to be evaluated if it is going to compete with inßiximab for the treatment of Þstulizing CD. Furthermore, the agent’s uptake may be hindered by its lack of long-term safety data, compared with inßiximab (used in treatment of CD, RA, and other indications for the past seven years) and adalimumab (used in the treatment of RA for two years). Interleukin Inhibitors Overview. The identiÞcation of TNF-α as a key inßammatory mediator for CD and the subsequent launch of the TNF-α inhibitor inßiximab represented a major advance in the treatment of CD. However, numerous cytokines other than TNF-α, including interleukins, are important immune and inßammatory mediators and are also thought to be involved in the pathogenesis of CD. Companies have begun to explore interleukins as therapeutic targets; some of them appear to offer

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promising novel approaches to treatment of CD. Inhibitors of interleukin (IL)12—including Abbott’s injectable MAb ABT-874 (formerly J-695) and Synta’s oral, small-molecule inhibitor STA-5326—are currently in Phase II development for CD with at least preliminary evidence of efÞcacy in the induction of clinical response or remission. In May 2005, Centocor started enrollment for a Phase II CD clinical trial of its MAb that inhibits both IL-12 and IL-23 activity, CNTO1275. Chugai/Roche’s Actemra (tocilizumab; formerly atlizumab, MRA), an IL-6 inhibitor that launched in June 2005 in Japan for Castleman’s disease, is in Phase II development in Japan for CD, but no clinical trial data have been released on this drug’s efÞcacy in treating CD. The two IL-12 inhibitors are discussed in greater detail in following sections. Mechanism of Action. Interleukins are cytokines that have many functions in immune and inßammatory responses. They are secreted predominantly by leukocytes; their primary function is to exert immunoregulatory effects on other leukocytes, such as stimulating the differentiation and proliferation of other immune cells. Research has shown that many interleukins, such as IL-1β, IL-2, IL-6, IL-8, IL-12, and IL-18, are upregulated in the intestinal mucosa of CD patients. Drug compounds in this class inhibit the activity of a particular interleukin, thereby blocking its ability to exert its physiological role in the immune response. ABT-874. Abbott Laboratories is developing ABT-874 (formerly J-695), a fully human MAb against IL-12, as a potential treatment for CD. Phase II trials are under way in the United States and the United Kingdom. No development has been reported for this drug in Japan. ABT-874 is also in Phase II development for treatment of multiple sclerosis (MS) and RA in the United States and Europe. ABT-874 was identiÞed through a collaboration between Knoll Pharmaceuticals (acquired by Abbott in 2001) and CAT. The drug was licensed by CAT to Knoll in the same 1995 agreement that gave Abbott rights to adalimumab (discussed previously). CAT receives milestone payments from Abbott and will receive sales-based royalties if ABT-874 is brought to market. Researchers believe that a cell-mediated immune response predominates in CD. As discussed in “Etiology and Pathophysiology,” the inßammatory response associated with CD is believed to be driven by the activation of T-helper 1 (TH1) cells. IL-12 plays a key role in the differentiation of TH cells into TH1 cells, and IL-12 production appears to be increased in the intestinal tissue of CD patients (Monteleone G, 1997; Parronchi P, 1997). Thus, ABT-874, which is designed to neutralize the activity of IL-12, acts to inhibit TH1 cell differentiation and the resulting disease pathogenesis. Like some of the TNF-α inhibitors, IL-12 inhibitors can also induce apoptosis of T cells in the intestinal mucosa, and this activity may prove to be critical in achieving an effective response in the treatment of CD (Cominelli F, 2004). Although no studies have looked speciÞcally at ABT874’s ability to induce T-cell apoptosis, the fact that it is a bivalent MAb, like inßiximab and adalimumab, suggests that it may have this capability.

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Phase II clinical trial results have demonstrated signiÞcantly greater response rates in ABT-874-treated CD patients, compared with placebo (Mannon PJ, 2004). This double-blind study involved 79 patients with active CD (CDAI score of 220–450) randomized to placebo (n = 16) or to one of two cohorts treated with seven weekly subcutaneous injections of either 1 mg/kg or 3 mg/kg ABT-874 (n = 63). Patients in Cohort 1 received their Þrst and second injections four weeks apart; patients in Cohort 2 experienced no interruption between the administration of the Þrst and second injections. Concomitant CD medications, including corticosteroids, aminosalicylates, and antibiotics, were permitted. Safety was the primary end point; rates of clinical response (deÞned as a 100point or greater decline in CDAI score) and remission (deÞned as a CDAI score lower than 150 points) were secondary end points. The highest response and remission rates were in the group of patients receiving 3 mg/kg ABT-874 in Cohort 2 (n = 16). The response rate of this group was signiÞcantly higher than the response rate of the placebo group after the 7 weeks of treatment (75% versus 25%, respectively), but not at the end of the 18-week follow-up (69% versus 25%). The percentage of patients in this group who achieved remission did not differ signiÞcantly from the percentage in the placebo group, although there was a trend toward higher remission rates in the drug-treated group: 38% versus 0% at both time points. Response and remission rates for all patients in Cohort 1 and for patients in Cohort 2 who were treated with 1 mg/kg ABT-874 did not differ signiÞcantly from the rates for the placebo-treated group. ABT-874 was well tolerated in this Phase II study (Mannon PJ, 2004). Local injection site reactions, most of them mild in nature, were the most frequently reported adverse events and the only events that occurred more frequently in drug-treated patients than in the placebo group (range of 77% to 88% versus 25%, respectively). Other adverse events observed at similar frequencies in the drug-treated and placebo groups were nausea, vomiting, abdominal pain, urinary tract infections, cough, fever, headache, and fatigue. No serious infections were observed. The development of antibodies against ABT-874 was detected in three of the drug-treated patients, a frequency of approximately 5%. Although the efÞcacy results for the group treated with 3 mg/kg injections of ABT-874 for seven consecutive weeks are encouraging, further studies are needed to evaluate ABT-874’s ability to induce response and remission—likely at the 3 mg/kg dose—in a larger patient population. Abbott will likely try to position adalimumab as the Þrst-line TNF-α inhibitor in the treatment of CD, followed by ABT-874 if adalimumab should fail. The ability of ABT-874 to maintain remission and to treat Þstulizing disease would also need to be assessed if the agent is to compete with inßiximab. STA-5326. Synta Pharmaceuticals is developing STA-5326, a speciÞc, smallmolecule inhibitor of IL-12, as a potential treatment for CD. Phase II trials are under way in the United States. Based on promising results from a recently completed Phase IIa trial (see following details), Synta announced in a September 2005 press release that it has initiated a large, randomized, double-blind, placebocontrolled Phase IIb trial. No development has been reported for this drug in

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Europe or Japan. STA-5326 is also in Phase II development for treatment of psoriasis and in early development for MS and RA in the United States. As mentioned previously, IL-12 plays a key role in the differentiation of TH cells into TH1 cells that predominate in the inßammatory response in CD, and IL-12 production appears to be increased in the intestinal tissue of CD patients (Monteleone G, 1997; Parronchi P, 1997). STA-5326 works by inhibiting the transcription of IL-12 but is unlikely to have any additional effect on the induction of T-cell apoptosis in the intestinal mucosa, which may be important in the treatment of CD. In an open-label, dose-ranging Phase IIa study presented at Digestive Disease Week in May 2005, STA-5326 was shown to be generally well tolerated, with potential clinical activity in the treatment of CD (Burakoff R, 2005). This study involved 73 patients with moderate-to-severe active CD (CDAI 220–450); approximately 12 patients were assigned to each of the Þve dose groups, which ranged from 14 mg twice daily to 70 mg daily. Concomitant administration of other CD therapies was permitted. Clinical response (deÞned as a 70-point or 100-point or greater decline in CDAI score) and remission (deÞned as a CDAI score lower than 150 points) were assessed after four weeks of treatment. The group receiving 35 mg STA-5326 daily had the highest response rates (82% for a 70-point or greater decline in the CDAI score, 64% for a 100-point or greater decline in the CDAI score) and the highest remission rates (36%). The most common adverse events reported were dizziness, nausea, headache, and fatigue; seven patients discontinued treatment because of side effects. STA-5326 is the Þrst orally administered small molecule that speciÞcally inhibits IL-12 production. If this drug proves to be efÞcacious in the treatment of CD, its oral daily dosing will give it a signiÞcant advantage over the injectable cytokine inhibitors currently available or in development. Immune Stimulators Overview. One theory of the etiology of CD is that antigenic stimulation within the GI tract of CD patients triggers an aberrant immune response that is prolonged and ampliÞed. Pharmacological therapies currently used to treat CD generally aim to downregulate the production or activity of inßammatory mediators to minimize this aberrant immune response. However, predisposition to the development of CD has been linked to mutations in genes that are important in the innate immune response—for example, NOD2 and toll-like receptors (TLRs) (Ogura Y, 2001; Hugot JP, 2001). (See “Etiology and Pathophysiology” for additional information on these genes and their association with CD.) Researchers have also observed that patients with rare immunodeÞciency diseases (e.g., granulomatous disease; glycogen storage disease Ib; leukocyte adhesion deÞciency; congenital, cyclic, and autoimmune neutropenia) have GI manifestations that resemble those of CD (Couper R, 1991; Dieckgraefe BK, 2002[a]). These Þndings suggest that immune defects, particularly in innate immunity, may contribute to CD’s etiology and pathophysiology by allowing harmless antigens and the normal bacterial

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ßora to penetrate the GI membrane, triggering an aberrant immune response and development of the overactive, chronic adaptive immune response seen in the GI tract of CD patients. Therefore, immune stimulators might offer a new approach to the treatment of CD (Dieckgraefe BK, 2002[b]; Folwaczny C, 2003; Wilk JN, 2002). One immune stimulator—sargramostim (Berlex Laboratories’ Leukine)—has reached late-stage clinical trials for CD. Mechanism of Action. Agents in this class aim to counter defects in innate immunity by stimulating and strengthening a patient’s ability to mount an immune response to pathogens and disease. One way to bolster a patient’s innate immunity is the administration of the exogenous recombinant growth factors involved in hematopoiesis (the formation, differentiation, and proliferation of red and white blood cells from stem cells). Administration of such recombinant growth factors can increase the number of leukocytes (e.g., neutrophils, monocytes, macrophages), which play a vital role in immunological processes, and may help to maintain intestinal integrity by boosting mucosal defenses. Sargramostim. Berlex Laboratories, a subsidiary of Schering AG, is developing sargramostim (Leukine) as a potential therapy for moderate-to-severe CD. Phase III studies are under way in the United States and Europe. The drug has been marketed in the United States since 1991 and is used to accelerate myeloid recovery in patients undergoing autologous and allogenic bone marrow transplantation for a variety of oncology conditions. Schering AG acquired sargramostim from Immunex in July 2002, when Immunex divested the drug upon merging with Amgen. Sargramostim is a yeast-derived, recombinant form of granulocyte-macrophage colony-stimulating factor (GM-CSF), a growth factor that plays an important role in the formation of nonlymphoid blood cells (e.g., erythrocytes, monocytes, neutrophils, eosinophils, basophils, and megakaryocytes). Thus, sargramostim induces the development of cells that play a critical role in immune responses. This activity may help to maintain the GI immune barrier and minimize aberrant immune responses against harmless antigens or normal bacterial ßora, which are thought to be an underlying cause of CD. Berlex is conducting the New Opportunities to Verify Evolving Logic in Crohn’s Disease (NOVEL) program to investigate sargramostim’s potential to treat CD. The Phase II NOVEL 1 trial (discussed later) has been completed. Enrollment for the Phase II NOVEL 2 and Phase III NOVEL 4 trials have been completed; recruitment for the Phase III NOVEL 3 and 5 trials is under way. The randomized, double-blind, placebo-controlled, multicenter NOVEL 2 trial will examine the steroid-sparing properties of daily sargramostim SC injections in steroid-dependent CD patients in the United States and Canada for up to 22 weeks. The NOVEL 3 and 4 trials will be randomized, double-blind, placebocontrolled Phase III trials. NOVEL 3 will evaluate the efÞcacy of sargramostim in response and remission induction in CD patients in the United States who demonstrated a response to an initial cycle of the drug; NOVEL 4 will evaluate

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the ability of the drug to induce a response and remission in CD patients in ten countries outside the United States. NOVEL 5, an open-label trial for all patients previously treated with sargramostim, is designed to assess the drug’s long-term safety. Berlex announced the results of NOVEL 1 in an October 2003 press release; the results were presented that same month at the 68th Annual ScientiÞc Meeting of the American College of Gastroenterology and later published in a peerreviewed journal (Korzenik JR, 2005). The double-blind Phase II trial randomized 124 patients with moderate-to-severe active CD, at a ratio of 2:1, to receive 6 µg/kg of sargramostim or placebo in daily SC injections for 56 days. Concomitant use of antibiotics and aminosalicylates was allowed, but immunosuppressants and glucocorticoids were not permitted. Statistical signiÞcance was not achieved for the primary end point: a decrease of at least 70 points in CDAI at day 57 (54% for the sargramostim-treated group versus 44% for placebo). However, signiÞcantly more sargramostim-treated patients achieved the more stringent secondary endpoints: clinical remission (CDAI of 150 or less) and a decrease of 100 points or more in CDAI at day 57, compared with placebo. Remission was achieved by 40% of patients treated with sargramostim and 19% of placebo recipients; a 100-point decrease in CDAI was achieved by 48% of treated patients and 26% of placebo patients. Mucosal healing was evaluated using the Crohn’s Disease Endoscopic Index of Severity (CDEIS) score in a subset of patients from each group (19 from the sargramostim-treated group and 10 from placebo); median post-treatment CDEIS scores were found to be lower in the sargramostim-treated group than in the placebo group: 1.5 versus 5.6. Complete Þstula closure was observed in four of the eight sargramostim-treated patients who had draining Þstulas at baseline, compared with two out of Þve in the placebo group. Patients maintained clinical response, remission, and improvement in quality of life for 30 days following discontinuation of sargramostim treatment. According to a May 2004 Schering AG press release and presentation at the 2004 Digestive Disease Week conference, approximately 15% of patients maintained a clinical response to sargramostim six months after treatment was discontinued. There was no signiÞcant difference in the overall incidence of adverse events between the sargramostim-treated and placebo groups in the NOVEL 1 trial, and most of the events were mild to moderate in nature (Korzenik JR, 2005). Injection site reactions and bone pain were more common in sargramostim-treated patients than in placebo-treated patients and occurred in 90% and 37%, respectively, of treated patients. Of the 78 sargramostim-treated patients who were tested for antibodies to the agent, one patient tested positive. This patient did not experience any adverse events related to the development of neutralizing antibodies, but sargramostim-induced neutrophilia disappeared in the patient, possibly indicating a loss of drug response. According to the product label for Leukine, fever, nausea, vomiting, diarrhea, and liver abnormalities are common side effects associated with the use of sargramostim in oncology-related clinical studies.

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Preliminary results from the open-label NOVEL 5 trial, designed to assess long-term safety, were presented at Digestive Disease Week in May 2005 (Valentine J, 2005). Patients with active CD who had participated in a previous sargramostim trial were given daily injections of 6 µg/kg sargramostim for up to 6 cycles of treatment over 8 weeks; 42 patients completed at least one cycle of treatment. Concomitant antibiotics, aminosalicylates, and steroids were permitted. After one cycle of sargramostim treatment, 53% of patients achieved a 100-point decrease in the CDAI score and 40% achieved remission (CDAI of 150 or less). The most commonly reported adverse events were injection site reactions, bone pain, nausea, headache, vomiting, joint pain, back pain, and fatigue. The incidence of injection site reactions and bone pain decreased over subsequent treatment cycles. No serious drug-related adverse events were reported. Sargramostim’s beneÞcial effect in CD was also demonstrated in an open-label, dose-escalation, pilot Phase I trial involving 15 patients with moderate-to-severe CD (Dieckgraefe BK, 2002[b]). After eight weeks of sargramostim treatment (4–8 µg/kg per day delivered through self-administered SC injection), 12 of 15 CD patients demonstrated a 100-point or greater decline in CDAI score, and eight of 15 patients achieved clinical remission (deÞned as a CDAI score of 150 points or lower). Health-related quality of life, as measured by improvements in the IBD Questionnaire (IBDQ) scores, signiÞcantly improved for patients during sargramostim treatment. No serious adverse events were noted in this pilot study, but 80% of patients reported localized injection site reactions (e.g., itching, erythema), and 67% of patients experienced bone pain. Sargramostim, a growth factor that promotes the production of immune cells to boost patient immunity, offers a unique therapeutic approach to treatment of CD. Phase I and II studies to date are encouraging, but results from larger Phase III studies are needed to verify the efÞcacy of this novel approach. Even if sargramostim demonstrates efÞcacy against CD in Phase III trials, its sales potential in the CD market will be relatively modest because use of the agent is expected to be limited to the acute setting, given its frequent dosing proÞle (daily SC injections). Lack of long-term efÞcacy results and safety concerns about prolonged administration of sargramostim may also limit the agent’s use to the acute setting. Its high price is likely to limit its use in the United States to treatment of severe disease that is refractory to conventional CD therapies and at least two other biological agents. Cell Adhesion Molecule Inhibitors Overview. Cell adhesion molecules (CAMs) are cell-surface receptors that mediate cell-cell interactions that are critical in many different physiological processes and disease states, including wound healing, immune responses, inßammation, infectious diseases, and cancer metastases. Biopharmaceutical companies are pursuing different approaches, including MAbs and antisense oligonucleotides, to target and block CAMs.

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SigniÞcant setbacks have occurred in the development of drugs in this class. Serious adverse events, some of them fatal, resulted in the market withdrawal of natalizumab (Elan/Biogen Idec’s Tysabri)—a MAb against the α4-integrin protein on the surface of leukocytes that had been launched in the United States for treatment of relapsing-remitting multiple sclerosis (RR-MS)—and an FDA request to suspend clinical trials for all similar CAM inhibitors. These events have brought into question the continued development of α4-integrin antagonists for CD. Millennium’s MLN-02, a MAb that targets α4β7-integrin, is in Phase II development for CD in Canada, but its development in the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan) appears to have been discontinued. Finally, Isis Pharmaceuticals discontinued development of its intracellular adhesion molecule-1 (ICAM-1) antisense inhibitor, alicaforsen (ISIS-2302), for CD in December 2004 because of poor efÞcacy data from two Phase III trials; Isis does plan to continue developing the drug for treatment of ulcerative colitis (UC). The only CAM inhibitor discussed here in greater detail is natalizumab. Mechanism of Action. CAMs include selectins (P-, E-, and L-selectin), integrins (e.g., β2 integrin), and the immunoglobulin superfamily of adhesion molecules (e.g., ICAM-1). Leukocyte migration from the bloodstream into inßamed or infected tissue is mediated by CAMs. These molecules are expressed on leukocytes and endothelial cells (the latter line blood vessels). CAM overexpression correlates with several inßammatory disorders, including CD. Blocking CAMs inhibits leukocyte migration into the intestinal mucosa and submucosa, thereby preventing the accumulation of immune cells that release proinßammatory cytokines and tissue-damaging free radicals known to be important in CD pathogenesis. Natalizumab. Elan and Biogen Idec (formerly Biogen) have been developing natalizumab (Tysabri) as a potential treatment for CD. The companies Þled a marketing authorization application (MAA) for CD with the European Medicines Agency for the Evaluation of Medicinal Products (EMEA) in September 2004. In October 2004, the FDA announced that it would require the results of ongoing Phase III induction studies before it would accept a U.S. application for CD. No development of natalizumab for CD has been reported in Japan. Natalizumab received approval for treatment of RR-MS in the United States in November 2004 after an accelerated priority review. Elan and Biogen Idec also Þled an MAA with the EMEA for MS in June 2004, and approval was expected in 2005. However, on February 28, 2005, Biogen Idec and Elan announced a voluntary withdrawal of natalizumab from the U.S. market and the suspension of all clinical trials involving the drug. These actions were based on two adverse events reported from ongoing natalizumab clinical trials in MS patients: one conÞrmed fatal case and one suspected case of progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal demyelinating disease caused by an opportunistic infection of the central nervous system by the JC virus (JCV).

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Surprisingly, the FDA also requested the suspension of clinical trials for similar agents, even though no cases of PML have been reported in patients taking any drug other than natalizumab. Phase III clinical trials for natalizumab in CD have now been completed in the United States, but no application has yet been submitted, pending a thorough safety review of the agent for further incidence of PML. Natalizumab had also been in Phase II development for RA, but few useful data could be obtained from these trials before they had to be halted in February 2005; new studies would have to be started if the development for RA were to continue. Natalizumab is a humanized MAb that targets the α4 protein, a component of the integrins α4β1 (very late activation antigen [VLA]-4) and α4β7 (mucosal adressin, MAdCAM-1). MAdCAM-1 is an adhesion molecule on mucosal epithelium; VLA-4 is an adhesion molecule expressed on activated T cells and on macrophages that are important for the migration of these cells into the GI tract during inßammation. Therefore, blocking the α4 protein may interfere with the inßux of leukocytes into the intestinal tissue in CD. Three Phase III clinical trials examining natalizumab’s efÞcacy in treating CD were completed prior to the market withdrawal and suspension of clinical trials in February 2005. The Þrst of these trials, known as Evaluation of Natalizumab in Active Crohn’s Disease Therapy-1 (ENACT-1), assessed the drug’s ability to induce a clinical response (deÞned as a 70-point or greater reduction in CDAI score) and remission (CDAI score of 150 points or lower) in moderateto-severe CD patients with active disease. This double-blind, placebo-controlled study randomized 905 patients in a 4:1 ratio to 300 mg natalizumab or placebo. Patients received three doses IV at four-week intervals and were evaluated for a period of 12 weeks. Continuation of immunosuppressants was allowed. Results of this trial, Þrst announced in a July 2003 press release by Biogen Idec and Elan, showed a high placebo-response rate, and treatment with natalizumab did not produce a statistically signiÞcant clinical response, compared with placebo, at week 10, the trial’s primary end point. However, at week 12, there was a signiÞcant difference in response and remission rates between the two groups as well as signiÞcant differences at week 10 on secondary measures of efÞcacy, such as IBDQ scores (a measure of quality of life), time to remission, and mean changes in CDAI score. A subpopulation analysis of patients with active inßammation, as indicated by elevated CRP levels—72% of all patients enrolled in the ENACT-1 trial—revealed signiÞcant differences in response and remission rates at week 10 between patients treated with natalizumab and patients treated with placebo. Endoscopic healing was also examined in a subset of ENACT-1 participants demonstrating a 50% improvement in CDEIS scores by week 10 in the natalizumab-treated group, compared with a 7% decrease in CDEIS scores in the placebo group (Rutgeerts P, 2004[b]). Additionally, 22% of the 53 natalizumabtreated patients evaluated by endoscopy who had ulcers at week 0 were ulcer free by week 10, versus 8% of the placebo-treated patients. The rate of adverse events in the ENACT-1 trial was similar in natalizumab and placebo recipients. Headache, nausea, and abdominal pain were the most

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commonly reported side effects in both treatment groups. Although few adverse events were noted, natalizumab-treated patients demonstrated a sustained increase in the number of circulating lymphocytes, a potentially serious condition known as lymphocytosis: at week 12, the mean total circulating lymphocyte count for the natalizumab-treated group was 2,857 cells/mm3 versus 1,690 cells/mm3 for the placebo-treated group (Rutgeerts P, 2004[b]). A second Phase III induction trial, entitled ENCORE, was conducted in CD patients with elevated CRP levels (greater than 2.87 mg/L), a common strategy for agents that have failed efÞcacy end points in CD trials. In this doubleblind study, 510 patients with moderate-to-severe active CD were randomized to receive 300 mg natalizumab or placebo via intravenous (IV) infusions at weeks 0, 4, and 8; efÞcacy and safety assessments were performed at weeks 4, 8, and 12. According to a June 2005 press release by Elan and Biogen Idec, the trial met its primary end point: clinical response (deÞned as a 70-point or greater reduction in CDAI score) at weeks 8 and 12. ENCORE also met all of its secondary end points, including induction of remission (CDAI score of 150 points or lower) at weeks 8 and 12. There were no signiÞcant differences between natalizumab and placebo in the overall rates of adverse events; the most common side effects were headache, nausea, abdominal pain, and nasopharyngitis. ENCORE participants are being monitored for long-term safety. Natalizumab’s third Phase III trial, known as Evaluation of Natalizumab As Continuous Therapy-2 (ENACT-2), assessed the drug’s ability to maintain clinical response in ENACT-1 participants who had achieved response and/or remission after three natalizumab infusions. The double-blind, placebo-controlled study re-randomized 339 patients to receive either placebo or 300 mg natalizumab as a monthly infusion for up to 12 months; the primary endpoint was the proportion of patients who were able to maintain a response for six consecutive months. Loss of response was deÞned as a 70-point or greater increase in CDAI, a CDAI score of 220 or greater, or the use of rescue intervention at any point. Concomitant use of immunosuppressants was permitted. After six months of additional treatment, 61% of natalizumab recipients and 29% of placebo recipients continued to demonstrate a clinical response; 44% of patients treated with natalizumab maintained clinical remission compared with 26% of patients treated with placebo (Sandborn WJ, 2004[a]). Both the response and remission Þndings were statistically signiÞcant. Natalizumab was able to maintain a clinical response and remission in patients through one year: 54% of natalizumab-treated patients maintained a clinical response and 39% maintained remission (Sandborn WJ, 2005[b]). Corresponding 12-month response and remission rates for the placebo group were 20% and 15%, respectively. Additionally, 49% of patients treated with natalizumab were able to withdraw from steroids at the end of 12 months, compared with 20% of placebo-treated patients (Colombel J, 2005). During the ENACT-2 trial, there was no noticeable difference in the rate of adverse events—either serious or nonserious—between natalizumab- and placebo-treated patients. Headache, nasopharyngitis, nausea, and abdominal pain were the most commonly reported side effects in the 12-month study.

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Natalizumab may have utility in CD patients who are intolerant of or have failed inßiximab therapy, as demonstrated in the ENACT trials that included patients who had been previously treated with inßiximab. In ENACT-1, natalizumab induced a clinical response in 54% of the 360 patients who had received prior inßiximab therapy, compared with 35% of placebo-treated patients. A trend toward increased clinical remission was observed: 33% for natalizumab and 22% for placebo (Sandborn WJ, 2004[b]). In the ENACT-2 trial, in CD patients previously treated with inßiximab and in patients who had previously failed inßiximab therapy, natalizumab also demonstrated signiÞcantly greater maintenance of clinical response and remission than placebo for an additional 12 months (Panaccione R, 2005). Results from a double-blind, placebo-controlled European Phase II trial have also demonstrated natalizumab’s ability to elicit a clinical response and clinical remission and improve quality of life in 244 patients with moderate-to-severe CD (CDAI score 220–450) (Ghosh S, 2003). Patients were randomized to one of four treatment groups: two infusions of placebo; one 3 mg/kg infusion of natalizumab and one infusion of placebo; two 3 mg/kg infusions of natalizumab; and two 6 mg/kg infusions of natalizumab. Patients received their two infusions at weeks 0 and 4 and were followed for 12 weeks from the trial’s inception. Compared with the group receiving two placebo infusions, patients treated with two 3 mg/kg infusions of natalizumab demonstrated the most consistently signiÞcant clinical responses (deÞned as a 70-point or greater decline in CDAI score) and clinical remission (deÞned as a CDAI score of 150 points or lower). At week 6, the prospectively deÞned primary end point of the study, the group treated with two 3 mg/kg infusions of natalizumab demonstrated a response rate of 71% and a remission rate of 44%, compared with rates of 38% and 27%, respectively, for the group treated with two placebo infusions. SigniÞcant Þndings for the group treated with two 3 mg/kg infusions of natalizumab persisted through week 12, at which point the response rate and remission rate were 61% and 42%, respectively; the placebo group demonstrated a response rate of 43% and a remission rate of 27% at week 12. Although the group treated with two 6 mg/kg infusions of natalizumab demonstrated a higher response rate at weeks 6 and 12 than the placebo group, the remission rate for this group was not statistically signiÞcant at these two times. Compared with the group receiving two placebo infusions, all three natalizumab-treated groups in the European Phase II study experienced signiÞcant improvements over baseline scores on the IBDQ at week 6. This improvement persisted at week 12 for the two groups receiving second infusions of natalizumab. Overall, natalizumab was well tolerated by patients in the European Phase II trial, and the number of adverse events did not differ signiÞcantly between drug-treated and placebo groups (Ghosh S, 2003). The most common adverse events experienced by patients in this study were headache (32% of both natalizumab-treated patients and placebo recipients); abdominal pain (15% of natalizumab-treated patients, 17% of placebo recipients); inßuenza syndrome (14% of natalizumab-treated patients, 8% of placebo recipients); colitis (13%

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of natalizumab-treated patients, 14% of placebo recipients); and nausea (9% of natalizumab-treated patients, 16% of placebo recipients). Serious adverse events were reported by 10% of natalizumab-treated patients and 11% of placebo-treated recipients. None of these serious adverse events were considered to be related to treatment; most were related to CD symptoms and complications. However, lymphocytosis was a common effect of natalizumab treatment, with mean lymphocyte counts increasing 1.3 to 1.9 times over baseline values. Currently available data suggest that the efÞcacy of natalizumab in maintaining remission in CD patients is similar to that of inßiximab. Encouraging results from ENACT-2 indicate that natalizumab can maintain a clinical response and remission for up to one year. However, natalizumab’s ability to induce CD remission is less clear. The ENACT-1 induction study missed its primary end point, and signiÞcant remission induction was demonstrated in the ENCORE trial only in a subset of CD patients who had high CRP levels. Many agents in development for CD have had difÞculty meeting primary efÞcacy end points because of high placebo response rates; analysis of subgroups with high CRP levels, presumably patients with the most active disease, has salvaged the efÞcacy results. Therefore, natalizumab appears able to induce remission of active CD, but its efÞcacy in so doing is likely less than that of inßiximab. In addition, inßiximab has many other advantages over natalizumab, including a demonstrated ability to treat Þstulizing disease, less frequent dosing (IV every 8 weeks versus every 4 weeks), and long-term safety data. To gain approval for treatment of CD, natalizumab must also overcome the hurdle of its association with signiÞcant life-threatening side-effects (PML). Since natalizumab’s withdrawal, the suspected PML case has been conÞrmed, and one additional conÞrmed case and two suspected cases of PML have been discovered in clinical trial participants. Of the three conÞrmed natalizumabassociated PML cases, two were in MS patients receiving 300 mg of natalizumab every four weeks in combination with Biogen Idec’s interferon beta-1a (Avonex) (Langer-Gould A, 2005; Kleinschmidt-DeMasters BK, 2005). Natalizumab’s product label for use in RR-MS patients did warn of a minor drug interaction with Avonex that resulted in decreased clearance rates but stated that this alteration in clearance rate did not necessitate reduction of natalizumab’s dose to maintain safety. The third conÞrmed case of PML was fatal, occurring in a CD patient who was taking natalizumab as monotherapy (300 mg every 4 weeks), although the patient had previously taken other immunosuppressive agents, including azathioprine and inßiximab (Van Assche G, 2005). Therefore, the cases of PML appear to be associated with natalizumab treatment, but concomitant use of Avonex or other immunosuppressants likely increases the risk of developing the disease, because of either drug interactions or cumulative immunosuppressive effects. Regulatory authorities are likely to require further safety studies or the development of screening and monitoring tests before natalizumab is relaunched for MS or gains any further approvals. It is possible to test for the presence of the JC virus to rule out natalizumab treatment in patients with latent JCV infection.

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However, the rate of seropositivity for JCV in healthy adults is high, with estimates ranging from 50% to 86% (Knowles WA, 2003; Weber T, 1997), which would severely limit the drug’s utility and market potential. Alternatively, patients taking natalizumab could be tested for increases in plasma JCV levels or monitored for PML lesions by MRI, and therapy stopped if either is detected. In one natalizumab-associated PML case, JCV was detected in the plasma two months prior to clinical onset of PML (Van Assche G, 2005). Likewise, the Þrst PML lesion was detected by MRI in an MS patient two months prior to the development of obvious neurological deÞcits (Langer-Gould A, 2005). This lesion was difÞcult to distinguish from an MS-induced lesion, but such lesions in a CD patient would be highly unusual and indicative of PML onset. While it is possible to monitor for early signs of PML before the onset of clinical disease, natalizumab’s immunosuppressive effects appear to persist for approximately three months after cessation of treatment, and it is not known whether stopping therapy after detection of JCV or PML lesions would prevent full-blown PML (Langer-Gould A, 2005). Biogen Idec and Elan Þnished a thorough review of natalizumab’s safety data in MS trials in August 2005 and in CD and RA trials in October 2005 and found no additional cases of PML. According to a press release in April 2005, the companies are taking preliminary steps to restart MS trials. In September 2005, the companies submitted an application to resume marketing of natalizumab for MS in the United States; an FDA decision is expected within six months. MAP Kinase Inhibitors Overview. The MAP kinase signal transduction pathway is central to the normal physiological functioning of cells, including cell growth, division, and survival. The MAP kinase pathway is also important in cytokine production, including TNF-α production. Overactivation of this pathway is involved in many disease states, such as immune and inßammatory disorders, central nervous system disorders, cardiovascular disease, and cancer. Therefore, drugs that inhibit this signaling pathway have potential applications across several therapeutic areas. MAP kinase inhibitors have the potential to address several unmet needs in inßammatory conditions like CD, including control of aberrant inßammatory cytokine production via an orally available, small-molecule formulation. Small-molecule MAP kinase inhibitors would be more convenient and potentially less expensive than parenteral agents such as the biological TNF-α inhibitors. However, an incomplete understanding of signal transduction biology has hampered the development of safe and effective agents that modulate this pathway because drug discovery has relied on imprecise, high-throughput screens that result in molecules with cross-reactivity to other kinases. Consequently, agents within this drug class have had a high discontinuation rate; the development of many agents within this class has been terminated because of cross-reactivity with unknown, related proteins that results in unanticipated side effects or a lack of efÞcacy. This section focuses on the two MAP kinase inhibitors currently in Phase II development for CD: Procter & Gamble’s RDP-58

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and Cytokine PharmaSciences’ semapimod. Boehringer Ingelheim’s MAP kinase inhibitor, doramapimod, which was in Phase II development in the United States for CD, has had no development reported since March 2003, so it is not discussed in further detail here. Mechanism of Action. The MAP kinase signal transduction pathway—which comprises the p38, JNK, and ERK pathways—is involved in the synthesis of proinßammatory cytokines. This pathway can also be activated by the binding of these cytokines to their respective receptors and thus helps to regulate cellular responses to proinßammatory cytokines. Therefore, drugs that inhibit the MAP kinase pathway have the potential to inhibit the feedback loop common to inßammatory conditions that involve proinßammatory cytokines. Specimens of inßamed mucosa taken from CD patients contain increased quantities of several proinßammatory cytokines (e.g., TNF-α, IL-1β, IL-2, IL-6, IL-8, IL-12, IL-18, and IFN-γ ), and long-term overexpression of these proinßammatory cytokines can result in tissue damage, as occurs in CD. Furthermore, colonic biopsies of patients with severe CD have demonstrated enhanced p38 and JNK activation (Hommes D, 2002). Therefore, MAP kinase inhibitors may represent a promising novel approach for treating CD. Targeting the MAP kinase pathway requires caution, however. Agents in this class must be carefully designed because of the potential for toxicity. An overly robust inhibitor of the MAP kinase pathway may cause side effects (such as blocking normal levels of signal transduction required for cellular homeostasis), whereas a nonspeciÞc MAP kinase inhibitor may not demonstrate any efÞcacy and may provoke unwanted responses. RDP-58. Procter & Gamble (P&G) is developing RDP-58 (delmitide) as a potential treatment for inßammatory bowel disease (IBD; a general term that encompasses CD and the related disease UC). The drug was discovered by the Institut de Transplantation et de Recherche en Transplantation (ITERT) and SangStat Medical in collaboration with Synt:em, using the latter’s computer-aided rational design technology, Acti:map. SangStat had completed Phase II European trials with RDP-58 when the company was acquired by Genzyme in September 2003. In April 2004, Genzyme announced an agreement whereby the company licensed worldwide development, manufacturing, and commercialization rights for RDP-58 to P&G in exchange for up-front and milestone payments, as well as royalties based on sales. (Genzyme retained the rights to RDP-58 for pulmonary conditions and other indications not covered in this agreement and the rights to copromote RDP-58 with P&G for oncology-related disorders.) Clinical studies have been conducted to evaluate RDP-58 as a potential treatment for CD, but according to an April 2004 press release issued by P&G and Genzyme, the former will initially focus on UC as the primary indication for RDP-58. RDP-58 is an orally administered decapeptide composed of nine D-amino acids and glycine. The agent’s D-amino acid composition makes it resistant to degradation by proteases (Sorbera LA, 2004). Although administered orally, RDP-58

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does not appear to be systemically bioavailable and is believed to exert its therapeutic effect locally in the intestines. According to a May 2003 SangStat press release, RDP-58 inhibits the intracellular protein complex TRAF6/MyD88/IRAK (TRAFYK), thereby preventing the activation of p38 MAP kinase and JNK 1 and 2 kinases in the MAP kinase signaling pathway. The TRAFYK complex is also believed to play an important role in the NFκB signaling pathway, important in inßammatory responses. RDP-58’s interference with multiple signaling pathways through its interaction with TRAFYK results in the inhibition of the synthesis of several proinßammatory cytokines, including TNF-α, IFN-γ , IL-2, and IL-12. SangStat announced disappointing efÞcacy results from two European Phase II trials in an April 2003 company press release and a subsequent peer-reviewed journal article (Sorbera LA, 2004). A total of 104 patients with mild-to-moderate CD participated in the blinded, placebo-controlled studies. Patients were randomized to receive an oral solution containing placebo or 100, 200, or 300 mg/day of RDP-58 for 28 days; patients were subsequently followed for an additional month. Using a 70-point or greater decline in the CDAI as a measure of response and a CDAI score of 150 points or lower as a measure of remission, treatment with 200 mg/day RDP-58 was associated with the highest response rate (66%) and highest remission rate (48%), compared with response and remission rates of 43% and 20%, respectively, for the placebo group. However, these Þndings were not statistically signiÞcant. RDP-58 was generally well tolerated; all serious adverse events were related to either disease progression or leukopenia (which occurred in one patient). Nausea and headache were the most commonly reported side effects; the incidence of headache was statistically signiÞcant and was more prominent in the placebo and 100 mg/day groups. At the time the Phase II trial results were released, SangStat believed that increased or longer dosing of RDP-58 might be necessary to produce statistically signiÞcant results in CD patients because of the transmural nature of CD-related inßammation. However, P&G is apparently pursuing UC as the lead indication for RDP-58; the drug’s future development for CD is uncertain. Semapimod. Semapimod (formerly CNI-1493), a synthetic guanylhydrazone MAP kinase inhibitor, is under development by Cytokine PharmaSciences (formed in 1999 by the merger of Cytokine Networks and PharmaSciences). Phase II trials are being conducted for CD in the United States and Europe. The drug is also in Phase II development in the United States for pancreatitis and psoriasis, and studies are under way to examine its potential to treat cancer, congestive heart failure, and pain. No development has been reported in Japan. The company has announced on its Web site that it is seeking licensing partners for semapimod in various indications and regions. Semapimod has been shown to inhibit p38 MAP kinase and JNK phosphorylation (Hommes D, 2002). It has also been shown to inhibit the production of nitric oxide, the proinßammatory cytokines TNF-α, IL-1, and IL-6, and the macrophage inßammatory proteins (MIP)-1α and MIP-1β in both murine models and in vitro studies (Bianchi M, 1995; Bianchi M, 1996).

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The results of an open, randomized, double-blind study that showed a dose response for semapimod in 33 CD patients were presented at the 2004 Digestive Disease Week conference (Buchman AL, 2004). The study randomized patients with moderate-to-severe CD to receive daily IV infusions of placebo or one of two doses of semapimod (30 mg or 60 mg) for Þve days. On day 29, 20%, 31%, and 60% of patients treated with placebo, 30 mg semapimod, and 60 mg semapimod, respectively, demonstrated a response (deÞned as a 70-point or greater reduction in CDAI score). On day 57, response rates were 10%, 46%, and 50% respectively for the three treatment groups. No signiÞcant toxicities associated with the drug were reported in this open study, but there was a signiÞcant increase in infusion site irritation and/or phlebitis in the groups treated with semapimod, compared with placebo-treated patients. The rate of infusion site irritation and/or phlebitis was 69% and 80% in patients treated with 30 mg and 60 mg semapimod, respectively, compared with only 20% in patients treated with placebo. The study was terminated early because of poor accrual on account of the infusion discomfort and dosing schedule. Alternative formulations and shorter durations of treatment are now being evaluated (Gotham S, 2004). In a Phase I pilot study involving 12 patients with severe CD, semapimod was shown to be safe and effective in reducing CDAI scores (Hommes D, 2002). Study participants were randomized to receive 8 mg/m2 or 25 mg/m2 of semapimod once daily via IV infusion; study medication was administered for 12 days and patients were followed for 4 months. Safety was the trial’s primary end point, and patients were allowed to continue stable doses of other CD therapies (e.g., corticosteroids, aminosalicylates, antibiotics, immunosuppressants) during the course of the study. Eight of the 12 patients completed the full 12 days of the study. Four patients discontinued the study because of elevated liver enzymes (alanine aminotransferase levels in two patients), catheter-related infection (one patient), or worsening CD (one patient). The most common side effects associated with semapimod treatment in this study were digestive/hepatic, cardiovascular, or hematologic in nature. Hommes and colleagues also evaluated semapimod in a small, uncontrolled study of 12 CD patients, with measures of efÞcacy as secondary end points. The highest response rate (deÞned as a 25% or greater reduction in CDAI score and 70-point or greater reduction in CDAI occurring at least once after the start of the trial) was 67% and occurred 15 and 29 days after the start of the study. The highest remission rate (deÞned as a CDAI score of 150 points or lower at least once after the start of the trial) was 50% and occurred at day 112 in the study. At week 4, all but one of the study participants experienced rapid endoscopic healing, and 4 of the 5 patients with Þstulizing CD experienced Þstula closure during the course of the study. If future clinical studies conÞrm the Þndings of this pilot study, then semapimod could become an important therapy in CD treatment. However, there is currently no statistically signiÞcant evidence for the efÞcacy of the drug in inducing a clinical response or remission in CD patients compared with placebo.

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Furthermore, the current formulation of the drug, which requires daily IV dosing, would limit its use to hospitalized patients with severe acute exacerbations of CD and thereby hinder its market penetration. Therefore, the drug would likely have to be reformulated for oral delivery, like other agents in this class, to achieve signiÞcant uptake. REFERENCES Abreu MT, et al. Mutations in NOD2 are associated with Þbrostenosing disease in patients with Crohn’s disease. Gastroenterology. 2002;123(3):679–688. AcciufÞ S, et al. Strengths and limitations of the Crohn’s disease activity index, revealed by an objective gut lavage test of gastrointestinal protein loss. Alimentary Pharmacology and Therapeutics. 1996;10:321–326. Achkar JP, et al. Medical therapy to reduce postoperative Crohn’s disease recurrence. American Journal of Gastroenterology. 2000;95:1139–1146. Ahmad T, et al. The molecular classiÞcation of the clinical manifestations of Crohn’s disease. Gastroenterology. 2002;122(4):854–866. Aldhous MC, et al. NOD2/CARD15 and the Paneth cell: another piece in the genetic jigsaw of inßammatory bowel disease. Gut. 2003;52(11):1533–1535. Andres PG, et al. Epidemiology and the natural course of inßammatory bowel disease. Gastroenterology Clinics of North America. 1999;28:255–281. Anthonisen P, et al. The clinical effect of salazosulphapyridine (Salazopyrin) in Crohn’s disease. A controlled double-blind study. Scandinavian Journal of Gastroenterology. 1974;9(6):549–554. Arias E. United States Life Tables, 2000 . National Vital Statistics Reports; Vol. 51 No. 3. Hyattsville, MD: National Center for Health Statistics; 2002. Arias E. United States Life Tables, 2002. National Center for Health Statistics. National Vital Health Statistics. 2004;53(6). Armitage E, et al. Increasing incidence of both juvenile-onset Crohn’s disease and ulcerative colitis in Scotland. European Journal of Gastroenterology and Hepatology. 2001; 13:1439–1447. Aronchick C, et al. Medroxyprogesterone acetate (MPA) is effective for the induction of remission in patients with Crohn’s disease (CD). Gastroenterology. 2001; 120:5(suppl 1). Abstract 2314. Baert F, et al. Inßuence of immunogenicity on the long-term efÞcacy of inßiximab in Crohn’s disease. New England Journal of Medicine. 2003;348(7):601–608. Bamias G, et al. Down-regulation of intestinal lymphocyte activation and Th1 cytokine production by antibiotic therapy in a murine model of Crohn’s disease. Journal of Immunology. 2002;169:5308–5314. Barclay GR, et al. The effect of dietary yeast on the activity of stable chronic Crohn’s disease. Scandinavian Journal of Gastroenterology. 1992;27(suppl):196–200. Bernstein CN, et al. The relationship between inßammatory bowel disease and socioeconomic variables. American Journal of Gastroenterology. 2001;96(7):2117–2124. Bernstein LH, et al. Healing of perianal Crohn’s disease with metronidazole. Gastroenterology. 1980;79:357–365.

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Schering-Plough news release, September 28, 2004. Data from registry of nearly 6,000 patients conÞrm long-term safety of remicade in Crohn’s disease. Schreiber S, et al. CDP870, a humanized anti-TNF antibody fragment, induces clinical response with remission in patients with active Crohn’s disease (CD). Digestive Disease Week. May 17–22, 2003; Orlando, FL. Schreiber S, et al. Certolizumab pegol, a humanized anti-TNF pegylated Fab’ fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn’s disease: a Phase III study (PRECiSE). United European Gastroenterology Week. October 15–19, 2005; Copenhagen, Denmark. Schroder H. Acetylator phenotype and adverse effects of sulphasalazine in healthy subjects. Gut. 1972;13:278–284. Seagroatt V, Goldacre MJ. Crohn’s disease, ulcerative colitis, and measles vaccine in an English population, 1979–1998. Journal of Epidemiology and Community Health. 2003;57:883–887. Sendid B, et al. SpeciÞc antibody response to oligomannosidic epitopes in Crohn’s disease. Clinical and Diagnostic Laboratory Immunology. 1996;3:219–226. Shen C, et al. A fully human anti-TNF mAb adalimumab (D2E7) induces caspasedependent apoptosis of human peripheral blood monocytes and T cells. Gastroenterology. 2004;126(suppl 2):A-153. Shivananda S, et al. Incidence of inßammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inßammatory Bowel Disease. Gut. 1996;39:690–697. Shoda R, et al. Epidemiologic analysis of Crohn’s disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn’s disease in Japan. American Journal of Clinical Nutrition. 1996;63: 741–745. Singleton JW, et al. Mesalamine capsules for the treatment of active Crohn’s disease: results of a 16-week trial. Pentasa Crohn’s Disease Study Group. Gastroenterology. 1993;104(5):1293–1301. Singleton JW, et al. Quality-of-life results of double-blind, placebo-controlled trial of mesalamine in patients with Crohn’s disease. Digestive Diseases and Sciences. 1995; 40(5):931–935. Sorbera LA. RDP-58. Drugs of the Future. 2004;29(2):121–126. Sostegni R, et al. Review article: Crohn’s disease: monitoring disease activity. Alimentary Pharmacology and Therapeutics. 2003;17(suppl 2):11–17. Spanish Epidemiological and Economic Study Group on Crohn’s Disease. Epidemiological and clinical features of Spanish patients with Crohn’s disease. European Journal of Gastroenterology and Hepatology. 1999;11:1121–1127. Stange EF, et al. European trial of cyclosporine in chronic active Crohn’s disease: a 12-month study. Gastroenterology. 1995;109(3):774–782. Steinberg DM, et al. Abscess and Þstulae in Crohn’s disease. Gut. 1973;14:865. Stenson WF. Inßammatory bowel disease. In: Yamada T, ed. Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins Publishers; 1999. Stone MA, et al. Prevalence and management of inßammatory bowel disease: a crosssectional study from central England. European Journal of Gastroenterology & Hepatology. 2003;15:1275–1280.

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Summers RW, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology. 1979;77(4 Pt 2):847–869. Sutherland L, et al. Double-blind, placebo-controlled trial of metronidazole in Crohn’s disease. Gut. 1991;32(9):1071–1075. Sutherland LR, et al. Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology. 1990;98(5):1123–1128. Targan SR, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor-alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. New England Journal of Medicine. 1997;337(15):1029–1035. Ten Hove T, et al. Inßiximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut. 2002;50:206–211. Thompson NP, et al. Patients consulting with Crohn’s disease in primary care in England and Wales. European Journal of Gastroenterology and Hepatology. 1998;10: 1007–1012. Timmer A, et al. Time trends in the incidence and disease location of Crohn’s disease, 1980–1995: a prospective analysis in an urban population in Germany. Inßammatory Bowel Diseases. 1999;5:79–84. Timmer A. Environmental inßuences on inßammatory bowel disease manifestations. Digestive Diseases. 2003;21:91–104. Tourtelier Y, et al. Incidence des maladies inßammatoires du tube digestif chez l’enfant en Bretagne (1994–1997). Archives de Pédiatrie. 2000;7:377–384. Tragnone A, et al. Incidence of inßammatory bowel disease in Italy: a nation-wide population-based study. International Journal of Epidemiology. 1996;25:1044–1051. Trallori G, et al. A population-based study of inßammatory bowel disease in Florence over 15 years (1978–92). Scandinavian Journal of Gastroenterology. 1996;31:892–899. Tremaine WJ, et al. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn’s colitis and ileocolitis. Journal of Clinical Gastroenterology. 1994;19(4):278–282. Tsironi E, et al. Incidence of inßammatory bowel disease is rising and abdominal tuberculosis is falling in Bangladeshis in East London, United Kingdom. American Journal of Gastroenterology. 2004;99:1749–1755. Valentine J, et al. Repeated cycles of sargramostim for active Crohn’s disease: update from an open-label trial (N.O.V.E.L. 5). Digestive Disease Week. May 14–19, 2005; Chicago, IL. Van Assche G, et al. Progressive multifocal encephalopathy after natalizumab therapy for Crohn’s disease. New England Journal of Medicine. 2005;353(4):362–368. Van den Brande JMH, et al. Inßiximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology. 2003;124:1774–1785. Van Gossum A, et al. Epidemiology of inßammatory bowel disease in Brussels’ area (1992–1993). Acta Gastro-Enterologica Belgica. 1996;59:7–9. Van Hees PA, et al. Effect of sulphasalazine in patients with active Crohn’s disease: a controlled double-blind study. Gut. 1981;22(5):404–409. Van Staa TP, et al. 5-aminosalicylate use and colorectal cancer risk in inßammatory bowel disease: a large epidemiological study. Gut. 2005. In press.

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Psoriasis

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Psoriasis, derived from the Greek word psora, meaning “itch,” was Þrst classiÞed as a unique skin disorder in the late 18th century. It is a chronic disease that encompasses a wide range of severities. This dermatologic disease causes tremendous morbidity and may be associated with increased mortality. Skin involvement ranges from mild to very severe, and skin disease is sometimes accompanied by the debilitating joint disease psoriatic arthritis (PsA). Psoriasis is now understood to be an inßammatory disease, and current research is largely directed to understanding the roles of T cells and inßammatory cytokines in the pathology of psoriasis. Pathophysiology Psoriasis may affect the skin and nails; psoriatic arthritis may also develop in a subset of these patients and can become debilitating. Clinical presentation varies greatly among affected patients and may even vary markedly in an individual patient during the course of the disease. Psoriasis presentation may be as innocuous as a single pit in a Þngernail or as serious as generalized, disÞguring skin lesions and disabling PsA. Psoriasis is thought to arise from a combination of factors, including genetics, environmental triggers (e.g., climate, trauma), associated diseases (particularly infection), immunological status, and concurrent medications. The hallmark psoriatic skin lesions are sharply demarcated, thick, erythematous (red) patches that are covered by silvery scales. These lesions are often Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

577

578

PSORIASIS

Scalp Ears

Chest Elbows

Trunk

Umbilicus Gluteal cleft

Nails

Genitalia Knees

Toenails FIGURE 1. Typical locations of psoriasis lesions.

pruritic (itchy), may be painful, and typically bleed slightly upon removal of the scale (a phenomenon known as the Auspitz sign). Psoriasis lesions may occur anywhere on the body; Figure 1 depicts typical sites. The vast majority of patients have chronic plaque psoriasis. The disease course is quite variable, regardless of severity. Some patients experience periods of remission followed by exacerbation, both of which can vary widely in duration; in others, lesions are always present. Table 1 describes the classiÞcation of the clinical forms of psoriasis, which are based principally on the patterns and shapes of skin lesions. Pathophysiological characteristics of psoriatic skin include increased keratinocyte activity and lymphocyte inÞltration. The result is hyperproliferation and accelerated maturation of the epidermis; inßammation involving T cells, T-cell products (e.g., tumor necrosis factor alpha [TNF-α]), other cells (e.g., neutrophils), and cell products of inßammation; and vascular alterations. In clinical trials, a wide variety of measures are used to evaluate the severity of psoriasis and response to therapy. They include individual scores for signs such as erythema, plaque thickness, or scaling, as well as pooled indices of signs of psoriasis. The most commonly used pooled index in clinical trials is the Psoriasis Area and Severity Index (PASI). The Overall Lesional Assessment (OLA) is a measure of a physician’s judgment of a patient’s overall lesional severity, with emphasis on plaque elevation, and is used in some clinical trials. The Physicians Global Assessment (PGA), a more general evaluation tool, is also sometimes employed. However, in everyday medical practice such measures are seldom used and no single deÞnition of disease severity is uniformly accepted. Table 2


579

TABLE 1. Clinical Forms of Psoriasis Percentage of Psoriasis Patients Affected

Type

Cutaneous manifestations Plaque-type 75–85 psoriasis (Psoriasis vulgaris, chronic stationary psoriasis)

Guttate psoriasis (eruptive psoriasis)

15–20

Pustular psoriasis

2

Erythrodermic 1–2 psoriasis (exfoliative dermatitis, psoriatic erythroderma)

Description of Lesions • First appears as small papules, then grows to form red-violet round or oval plaques overlaid with silvery scales. • May be hyperpigmented with brown or black coloration in darkly pigmented patients. • Comprises droplet-shaped (dotlike) lesions ranging in diameter from 0.1 to 1.0 cm. • Lacks the scaliness and induration that is common to plaque psoriasis. • Found predominantly on the trunk and proximal areas of extremities and likely to involve the face. • Sterile pustules are frequently localized to the palms and soles (Pustulosis palmaris et plantaris) but may be generalized (von Zumbusch variant). • Localized form may develop from vesicles to vesicopustules to frank pustules to dried brown maculopapules. • Generalized form has irregular red patches over which thousands of 1–2 mm superficial pustules develop and coalesce to form large collections of pus. • Inflammatory lesions may cause extreme reddening (erythema) of all or most of the body surface. • Large areas of skin may slough off during the exfoliative phase.

Comments • Most commonly affected areas: knees, elbows, scalp, behind the ears, sacrum (gluteal cleft), umbilicus, intergluteal cleft, genitalia.

• May be the initial manifestation or a flare of chronic plaque psoriasis. • May be precipitated by Streptococcus groups A, C, and G, by viral infection, or by immune system compromise. • The most common form in children; characteristic of earlyonset psoriasis. • May present de novo or as a flare of plaque psoriasis. • Average age of onset is 50 years. • Localized form occurs more frequently in females, is difficult to treat, and frequently recurs. • Generalized pustular psoriasis is very severe, is difficult to treat, may require inpatient care, and may cause death. • Usually occurs in people with chronic plaque psoriasis but may occur de novo. • Average age of onset is 50 years. • Occurs more frequently in males.

580

PSORIASIS

TABLE 1. (continued)

Type

Percentage of Psoriasis Patients Affected

Description of Lesions • Pustules may develop, leading to generalized pustular psoriasis.

Scalp psoriasis Approximately 50

Inverse psoriasis

—

• Plaque-type psoriasis lesions on the scalp.

• Usually smooth and erythematous, not scaly. • Occurs on flexural sides of the extremities, in contrast to the distribution of plaque psoriasis.

Extracutaneous manifestations • Nail psoriasis Up to 50 (80 in patients with • psoriatic arthritis)

Psoriatic arthritisApproximately 20

Large, deep, random pits of the nail plate are the most common manifestation. Nail thickening, ridging, crumbling, and splinter hemorrhaging are common. • Loss of the nail plate may occur in severe lesions. • Fingernails are more commonly affected than toenails. • Similar pathology to rheumatoid arthritis (may progress to severe joint destruction and deformity).

Comments • Precipitating factors include excessive use of potent topical or systemic corticosteroids, systemic illness, psychological stress, and alcoholism. • Very difficult to treat because topical formulations generally do not penetrate well. • Typically appears in the armpit or groin, under pendulous breasts, or in the skin folds of obese patients.

• Nail psoriasis may closely resemble onychomycosis (fungal infection of the nail), which must be ruled out first.

• Arthropathy that typically affects asymmetrical joints (unlike rheumatoid arthritis).

provides some commonly used deÞnitions of psoriasis severity and estimated percentages of psoriasis patients with each severity. Keratinocyte Hyperproliferation. The epidermal cell cycle is dramatically shortened from the 26–28 days normally required to form the epidermis to 4–6 days in people with psoriasis. Cell division in the basal layer occurs every 1.5 days, and migration of keratinocytes to the stratum corneum (the outer layers of the epidermis) occurs within approximately 4 days. This much-shortened cycle of cell division is further exacerbated by the proportion of germinal center cells entering the growth fraction—essentially 100% in patients with psoriasis, compared with 60–70% in normal skin. This high proportion results in a net increase


581

TABLE 2. Psoriasis Severity Definitions in Clinical Practice Percentage of Psoriasis Patients Affectedb

Body Surface Area Covered (%)

Mild

65–80

10

Severitya

Description Generally, isolated patches of psoriasis appear on the knees, elbows, hands, feet, and scalp. Topical therapies, including over-the-counter and prescription creams, ointments, and shampoos, are usually effective. Psoriatic skin lesions may occur on arms, legs, torso, scalp, and other areas. Topical agents, phototherapy, and/or oral drug therapy may be used, depending on the location and extent of the lesions, and on individual factors. Extensive areas of skin may be covered with psoriatic plaques or pustules. Alternatively, widespread erythrodermic lesions may cause severe peeling of the skin. Concomitant psoriatic arthritis often occurs. Therapeutic options intensify to include powerful oral agents with significant risk of side effects.

a In clinical trials, measures including the Psoriasis Area and Severity Index (PASI), the Physicians Global

Assessment (PGA), and the Overall Lesional Assessment (OLA) are used to assess disease severity and quantify response to treatment. b The National Psoriasis Foundation estimates a 20–35% share for moderate and severe psoriasis. Note: Percentages add up to 95–110%, underscoring the overlap between severities. Source: Modified from National Psoriasis Foundation estimates.

in the number of cells produced per day per square millimeter of skin surface. The rapid arrival of newly formed keratinocytes at the skin surface precludes proper differentiation and maturation of these cells, resulting in deÞcient keratinization of the stratum corneum and a three- to Þvefold increase in thickness of the psoriatic epidermis, which is full of scaly cells. Blood vessel dilation in the papillary layer of the dermis occurs, along with inÞltration of inßammatory cells (e.g., T cells, neutrophils). It has been suggested that an intrinsic regulatory defect that is critical to psoriatic lesion development is present in the epidermis itself, including nonlesioned skin. Indeed, one study found that uninvolved (i.e., nonlesioned) skin of psoriatics demonstrates altered epidermal kinetics when grafted onto athymic mice (Fraki JE, 1982). Koebner’s phenomenon—a hallmark of the disease—is the development of psoriatic plaques following mechanical trauma to nonlesioned skin and occurs in approximately 20% of patients with psoriasis. This phenomenon provides additional support for this theory. Keratinocytes participate in immunomodulation through the production of proinßammatory and inhibitory cytokines (e.g., interleukin-1 [IL-1], -6, and -8

582

PSORIASIS

and TNF-α). Cytokine production by hyperproliferating keratinocytes appears out of balance in psoriasis; TNF-α and IL-8 levels are increased. Keratinocytes also produce angiogenic factors that may account for capillary proliferation observed in psoriatic lesions (addressed later in this section). T Cells. Psoriasis is now thought to be principally a T-cell-mediated disease, and many theories regarding the role(s) of T cells in the pathophysiology of psoriasis have been proposed. One theory holds that cytokines released by keratinocytes (which may have been activated by Koebner’s phenomenon) activate T cells, which then produce more cytokines, amplifying the inßammatory, T-cell, and keratinocyte responses. Another theory holds that epidermal Langerhans cells interact with helper T cells, which activate keratinocytes and the ampliÞcation loop just described. A further theory of T-cell involvement proposes an autoimmune mechanism whereby killer (CD8+ ) T cells attack and activate keratinocytes. The Þrst evidence of a major role for T-cell dysregulation in psoriasis was the serendipitous discovery that inhibiting T-cell activation with cyclosporine (an immunosuppressant) was effective for treating the disease. Further support was provided by a study in which the destruction of activated T cells with a speciÞc toxin (consisting of the receptor-binding domain of IL-2 coupled with diphtheria toxin) caused remission of psoriatic symptoms and a reduction in epidermal CD8+ T cells (Gottlieb SL, 1995). CD4+ and CD8+ T cells have both been implicated in psoriasis disease progression. It is thought that inÞltrating CD4+ T cells localize in the epidermis during plaque development and send a signal that activates dormant CD8+ T cells already present in the epidermis. The observation of an increase in circulating CD8+ T cells in psoriatic patients provides further evidence. T cells positive for cutaneous lymphocyte antigen (CLA), indicating they are primed for cutaneous accumulation, are found in high concentrations in psoriatic lesions. Psoriasis appears to be mainly a TH 1-mediated disorder because both circulating and lesional CD8+ and CD4+ T cells produce type I cytokines including IL-2 and interferon-gamma (IFN-γ ), with an associated increase in TNF-α, IL-6, and IL-8; only a small proportion of cells produce the TH 2 cytokines IL-4 and IL-10. CD4+ T cells appear to be involved in plaque initiation (by preparing the microenvironment), while CD8+ T cells produce the TH 1 cytokines (e.g., IFN-γ ) that are involved in plaque persistence. The lack of structural uniformity in psoriatic lesions has led some researchers to speculate that different subsets of T-cell products may play different roles in lesion pathogenesis at different stages of lesion progression. T cells release lymphokines in the relatively quiescent center of plaques that can initiate a positive feedback loop with keratinocytes (described previously), which respond to these T-cell molecules and produce T-cell-activating cytokines. This T-cell loop is important for maintaining chronic lesions. However, chemokines (such as IL-8) and complement factors (such as C5a/C5a des Arg) are released by keratinocytes at the highly inßamed edges of lesions and are powerful attractants for neutrophils. Neutrophils express the human leukocyte antigen HLA-DR and subsequently induce the growth and differentiation of the surrounding keratinocytes


583

Keratinocytes

HLA Cytokines Other Activated mediators

Activation of T cells and Keratinocytes

Production of chemoattractants (e.g., IL-8, C5a) Neutrophil

T cells

Leukocyte recruitment

Hyperproliferation

Blood vessel

T-cell adhesion

HLA = Human leukocyte antigen. IL = Interleukin.

FIGURE 2. Inflammation in psoriasis.

and activation of T cells. The activated T cells then induce the transendothelial migration of more neutrophils and set up a positive feedback loop that leads to excessive cytokine release and inßammation. Thus, the addition of the T-cell/neutrophil loop creates a unique environment at the border of plaques that can perpetuate acute inßammation (Figure 2). Cellular inÞltrates in skin lesions and PsA joints contain aberrantly active T-cell populations, supporting the hypothesis that psoriasis and its related pathology, PsA, are immunologic in origin. Indeed, impaired T-cell suppressor function; overexpression of the IL-2 receptor, HLA-DR, and various cell-adhesion molecules (CAMs); and proinßammatory cytokine (particularly IL-6) secretion are associated with psoriasis. Researchers theorize that these cytokines (secreted by activated T cells and other mononuclear inßammatory cells) induce hyperproliferation of epidermal and synovial Þbroblasts that, in turn, secrete IL-1β, IL-2, IL-6, and platelet-derived growth factor (PDGF), contributing to disease pathology. As in psoriatic skin lesions, various cytokines found in affected joints of people with PsA exhibit conßicting activities (e.g., IL-2 is pro-inßammatory, and IL-13 is anti-inßammatory). TNF-α. TNF-α is present in elevated levels in psoriatic skin plaques (along with the TH 1 cytokines IL-2, IFN-γ , IL-6, and IL-8). This overexpression of TNF-α is implicated as a key factor in keratinocyte activation and proliferation, as well as stimulating the overexpression of endothelial adhesion molecules. However, the pathogenic role TNF-α plays is not entirely clear. Research during the past decade has implicated T cells in the etiology and pathogenesis of psoriasis. In psoriatic skin plaques, mononuclear cells (principally T cells) inÞltrate the dermis and produce cytokines that cause keratinocyte hyperproliferation and plaque formation. Infection may trigger both skin lesions, and some researchers believe

584

PSORIASIS

that TNF-α produced by monocytes and macrophages during infection plays a major role in the T-cell response, causing activation and proliferation of T cells and serving as a link between etiology and pathogenesis. Although clinical studies have demonstrated the effectiveness of TNF inhibitors against psoriatic skin, their mechanisms of action are not clear. Experimental models have demonstrated a connection between TNF-α and infection in psoriatic skin. In one of the most convincing experiments, streptococcal and staphylococcal superantigens induced an inßammatory response in uninvolved skin from patients with psoriasis (but not other skin disorders), and TNF-α was dramatically upregulated in the epidermis, indicating that it plays a role in driving the inßammatory response (Travers JB, 1999). The precise role is not clear, however, and in one study, TNF-α had no effect on proliferation or differentiation of healthy and psoriatic keratinocytes (Fransson J, 2000). According to some researchers, this Þnding provides further evidence that TNF-α may act in psoriasis principally through its effects on T cells (among other inßammatory effects) and that T cells, rather than abnormal keratinocytes, cause the skin changes of psoriasis. Other inßammatory effects of TNF-α that may contribute to skin lesions and damage cartilage and bone in articular lesions include the following: increased adherence of T cells to postcapillary venules; activation and proliferation of polymorphonuclear leukocytes (PMNs, or neutrophils); expression of human leukocyte antigens (HLAs); and B-cell differentiation and antibody formation in joints. Aberrant Angiogenesis. Dermal capillary proliferation is a pathological characteristic of psoriatic lesions and explains why bleeding occurs easily when lesions are removed. Keratinocytes produce angiogenic factors—endothelial-cellstimulating angiogenesis factor (ESAF) and vascular endothelial growth factor (VEGF)—both of which have been reported to be elevated in patients with psoriasis, compared with controls; increases in these levels correlate with disease severity (Bhushan M, 1999). For example, according to results presented by Regeneron Pharmaceuticals at the 2002 Society for Investigative Dermatology in Los Angeles (Xia AY, 2002), VEGF-transgenic mice that chronically express VEGF in the skin developed a skin condition resembling psoriasis. Single-nucleotide polymorphisms in the VEGF gene were recently identiÞed in patients with early onset chronic plaque psoriasis, which also correlated with elevated plasma levels of VEGF (Young HS, 2004). One of the therapeutic mechanisms of retinoids in psoriasis may be the inhibition of angiogenesis; studies have demonstrated that retinoids inhibit the action of VEGF at the transcriptional level (Diaz BV, 2000). Researchers have worked extensively on elucidating the role of angiogenesis in cancer. Further study of a potential role of anti-angiogenesis is warranted because some of the many anti-angiogenic drugs in development as cancer therapeutics may prove useful in psoriasis, particularly if topical delivery is feasible. Table 3 lists mechanisms thought to be involved in the pathogenesis of psoriasis that serve as targets for drug development. These mechanisms are addressed in more detail in “Emerging Therapies.”


585

TABLE 3. Select Potential Therapeutic Targets in Psoriasis and Psoriatic Arthritis Targets of Developmental Agents TNF-α IL-1β IL-6 IL-8 IL-10 IL-11 Pyrimidine synthesis T-cell vaccines Complement components

Suspected Mechanisms of Action Inhibits T-cell activation and proliferationa Inhibits T-cell activation and proliferation Inhibits T-cell activation and proliferation Reduces recruitment of T cells, chemoattraction of T cells and neutrophils, angiogenesis, and keratinocyte proliferation Suppresses synthesis of pro-inflammatory cytokines Suppresses synthesis of pro-inflammatory cytokines Inhibits DNA and RNA synthesis Suppresses T-cell response Inhibits complement activation and reduces the overproduction of C5a observed in psoriasis

a See ‘‘TNF-α ’’ section for more details. IFN = Interferon. IL = Interleukin. TNF = Tumor necrosis factor.

Etiology The precise causes of psoriasis are not known. Genetic defects that cause aberrant inßammatory and immune-mediated responses are thought to be the basis of the abnormally rapid keratinocyte proliferation and inßammation that lead to the development of psoriatic lesions. Risk factors associated with psoriasis include compromised immunity, the presence of bacterial antigens, age, and environmental factors (e.g., climate, trauma, infection, diseases, psychological stress, concurrent medications). Genetic Factors. Substantial data derived from studies of familial inheritance and genetic association patterns with psoriasis suggest that genetics play a role in the development of this disease. Studies of family history have found that in approximately 35% of people afßicted with psoriasis, one or more family members also have the disorder. A study of the lifetime risk for developing psoriasis estimated the risks at 4% for a person with no family history, 28% when one parent is affected, and 68% when both parents are affected (Swanbeck G, 1997). Studies of twins similarly demonstrate increased risk; a concordance rate of 65% for monozygotic twins and 30% for dizygotic twins was observed in one study; other studies have derived different Þgures, but none have shown a rate of 100% concordance (Krueger GG, 1994; Henseler T, 1997). The lack of 100% concordance between monozygotic twins and other genetic Þndings demonstrate that additional factors play a role in the risk of developing psoriasis. Genetic factors are thought to increase an individual’s susceptibility to environmental risk factors such as psychological stressors, climate, and infections. Most researchers believe psoriasis to be a polygenic disorder, although the precise gene locus or loci associated with increased susceptibility or initiation of

586

PSORIASIS

psoriasis are not known. A potential role for the human leukocyte antigen (HLA) region on chromosome 6 was reported almost 30 years ago. More-recent studies have suggested roles for regions on chromosomes 1, 2, 3, 4, 8, 10, 16, 17, and 20. Some of these putative susceptibility loci have been named psoriasis susceptibility loci 1 through 8, or PSORS1-8. Most research, however, has focused on the major histocompatibility (MHC) class I region (coded for by genes on chromosome 6) and, in particular, the HLA-Cw6 allele (Nickoloff BJ, 1999; Guedjonsson JE, 2002). Other genes associated with psoriasis pathophysiology include the gene encoding the CD1d molecule, which is located near other implicated genes on chromosome 1, and genes that encode nonclassical MHC antigens, including MICA, PERB 11, and the S gene, which are located on chromosome 6. The importance of the MHC class I region was underscored by the International Psoriasis Genetics Study (The International Psoriasis Genetics Consortium, 2003). To conÞrm previously reported linkages to psoriasis, 942 affected sibling pairs from 710 family pedigrees were analyzed for polymorphic satellites spanning 14 psoriasis candidate regions. The alleles that appeared to be shared by affected siblings at the most statistically meaningful frequencies were located within the MHC class I region. Two other loci on chromosomes 10q (D10S2327 ) and 16q (D16S3032 ) were also identiÞed in the same study as potentially promising candidates for more detailed examination. Genotypic analysis of 644 subjects (from 195 Swedish families with a history of psoriasis) revealed an association of SCL12A8 (a gene that encodes a member of the solute carrier family 12 proteins) with psoriasis. This analysis used a single-nucleotide polymorphism (SNP) map spanning 900–1,200 kb of chromosome 3q21, which maps to the psoriasis susceptibility locus PSORS5. SCL12A8 belongs to a class of genes that was previously unrecognized as playing a role in psoriasis pathogenesis (Hewett D, 2002). Age. The onset of psoriasis symptoms can occur at any age, but two peaks in onset have been observed. The initial peak occurs during the teen years: approximately 40% of patients Þrst experience the disease before the age of 20, and initial onset before age 10 occurs in approximately 10% of cases. A second peak has been reported in patients who are in their mid 50s. Onset at an earlier age (before age 40) predicts a more severe disease course. An association between HLA haplotype and age of onset for psoriasis has been reported (Table 4). Climate. Cold, dry weather is known to provoke ßare-ups of psoriasis, whereas sunny, hot, and humid weather helps relieve symptoms in most patients. In the case of photosensitive psoriasis, however, the reverse is true: the sunlight of summer may exacerbate the condition, and symptoms may improve during winter. Trauma. Cuts, burns, injections, and even very mild abrasions and other trauma to the skin may cause psoriatic skin plaques to erupt. Koebner’s phenomenon—a hallmark of the disease—is the development of psoriatic plaques following mechanical trauma to nonlesioned skin and occurs in approximately 20% of


587

TABLE 4. Select Genetic Factors in Psoriasis Genes

Comment

HLA-Cw6, HLA-B13, HLA-B17 HLA-B27, HLA-Cw2, HLA-B44, HLA-Cw5 Chromosome 3q21 (SCL12A8) Chromosome 10q22-q23 (D10S2327)

Associated with earlyonset psoriasis Associated with late-onset psoriasis Associated with psoriasis

Chromosome 16q (D16S3032)

Associated with psoriasis

Associated with psoriasis

Reference Szczerkowska-Dobosz A, 1996 Szczerkowska-Dobosz A, 1996 Hewett D, 2002 Nair RP, 1997; The International Psoriasis Genetics Consortium, 2003 Nair RP, 1997; The International Genetics Consortium, 2003

HLA = Human leukocyte antigen.

patients with psoriasis. Koebner’s phenomenon may explain the increased frequency of lesions on the elbows and knees. Psychological Stressors. A strong association between psoriasis and emotional disorders (including anxiety and depression), repressed anger, and psychological stress has been reported. Nearly 40% of patients in one study could recall a speciÞc stressor that occurred within one month of a psoriatic ßareup. Researchers are beginning to investigate potentially aberrant biochemical responses to stress in these patients. Infections. Both viruses and bacteria have been implicated as potential etiologic agents in the development of psoriasis. SpeciÞcally, streptococcal infections of the upper respiratory tract (e.g., “strep” throat, tonsillitis, sinusitis) are known to trigger the disease, particularly guttate (eruptive) psoriasis in individuals who express the MHC molecule HLA B-13. HIV infection has been linked to psoriasis; compromised immunity (i.e., T-cell suppression) is the suspected mechanism. Bacterial Superantigens. Bacterial superantigens (SAs) are bacterial products that nonspeciÞcally activate subsets of T cells by binding directly to MHC class II molecules and Vβ -chains of T-cell receptors outside of the antigen recognition domains of these molecules. This interaction of superantigens with T cells results in the nonspeciÞc activation of as much as 20% of all T cells—a percentage exponentially higher than that activated by an antigen that speciÞcally interacts with MHC or T-cell receptor molecules. SAs have been implicated in inßammatory skin disorders, such as atopic dermatitis. Researchers speculate that these SAs may contribute to the development of psoriasis through T-cell mechanisms. SigniÞcant levels of the gram-positive Staphylococcus aureus bacteria, which produces a potent SA, have been detected on the skin of more than 50% of patients with plaque psoriasis compared with 5–10% of the nonpsoriatic population. However, Þndings regarding the importance of bacterial SAs in exacerbating psoriasis do not conÞrm the role of SAs in the development of psoriasis. Despite increased humoral and cellular immunity against the gram-positive bacteria found in psoriatic plaques, a cause-and-effect relationship is not clear

588

PSORIASIS

(i.e., plaques may be colonized or secondarily infected, rather than caused by these organisms). Furthermore, the T-cell response to streptococcal antigens is similar in both PsA and rheumatoid arthritis (RA) patients, indicating that it may be a generalized response regardless of the etiology. Results from an in vivo study of the humoral (immunoglobulin G [IgG] antibody) response to Streptococcus pyogenes antigens (speciÞc recombinant proteins) suggest that streptococcal infection may be an etiologic agent in the development of PsA (Muto M, 1996[a]). Thus, T cells recognizing streptococcal antigens may cross-react with auto-antigens found in the skin, such as on keratinocytes. This phenomenon is perhaps most classically recognized in the case of the streptococcal M protein and proteins present on the heart. Here, cross-reactive T cells targeting the bacteria also target the heart, causing permanent heart damage. Concurrent Medications. Drugs that can exacerbate psoriasis include β-adrenergic blockers, angiotensin-converting enzyme (ACE) inhibitors, progesterone, lithium, systemic (or high-potency topical) corticosteroid withdrawal, and chloroquine. Nonsteroidal anti-inßammatory agents (NSAIDs) can also trigger psoriasis or exacerbate symptoms in some patients, although some NSAIDs (e.g., meclofenamate) improve the condition in certain patients. Drugs that cause skin rashes can also trigger psoriasis via Koebner’s phenomenon because of trauma induced by scratching the rash. CURRENT THERAPIES Psoriasis is a chronic disease for which there is no cure. Drug therapies and phototherapies may clear lesions and relieve uncomfortable symptoms, but remission is usually short-lived. Most patients experience one or more exacerbations or relapses per year. Exacerbations occur when drug therapy is discontinued (because of side effects and/or patient noncompliance) or tolerance to therapy develops, necessitating a change in therapies. Table 5 lists treatments in their typical order of application in the management of psoriasis, based on disease severity and response to therapy. Table 6 lists selected current therapies for psoriasis. Table 7 lists topical corticosteroids used in the treatment of psoriasis. Although many of the agents prescribed for psoriasis are used as monotherapies, the potential for adverse effects and tachyphylaxis, as well as the need to maximize efÞcacy, have often prompted physicians to resort to combination therapy. Recent clinical trials involving long-established drug classes have focused on identifying combinations of drugs that minimize adverse effects while maximizing clearance of plaques. Guidelines for using combination therapies are summarized in Table 8, and selected combinations are described in detail later in this section. Many of the topical treatments described in this section are used in combination with emollient and keratolytic agents that supply moisture and help remove scales. Because these agents are predominantly used as adjunct therapy, they are not described in detail here. Other agents that are prescribed only for limited subtypes of psoriasis, such as antibiotics prescribed for pustular psoriasis, are not discussed here.

CURRENT THERAPIES

589

TABLE 5. Treatments for Psoriasis Treatment

Common Members in Class

Frequency of Use

Topical therapies

Vitamin D3 analogues (calcipotriene, High: nearly all patients are treated others); topical corticosteroids; with topical agents retinoids (tazarotene); anthralin Phototherapies Ultraviolet B (UVB) light; UVB Moderate: prescribed only when monochromatic light (311 nm); UVB disease is moderate to severe or light + coal tar (Goeckerman when topical therapy fails regimen); UVB light + anthralin + coal tar (Ingram regimen) Psoralen + UVA light; psoralen Systemic Moderate: prescribed only when therapies + UVA light + UVB light; oral disease is moderate to severe or retinoids-acitretin (may be combined when topical therapy fails with UVB light or psoralen + UVA light); methotrexate; cyclosporine; alefacept; efalizumab

Corticosteroids Overview. Topical corticosteroids are Þrst-line treatments for psoriasis, particularly mild and mild-to-moderate psoriasis. They may also be used to supplement systemic therapies for patients with moderate-to-severe psoriasis. Patients readily accept topical corticosteroids because these agents—formulated into ointments, creams, lotions, and gels—cause no irritation, have no odor, and are frequently effective (especially in mild cases). Also, side effects at low doses are often minimal. Corticosteroids are available in a range of potencies and concentrations that permit physicians to optimize efÞcacy and minimize side effects. A comprehensive list of topical corticosteroids according to potency is provided in Table 7. The potency of a corticosteroid is assessed by its ability to induce vasoconstriction, with class I (superpotent) corticosteroids being the most potent and class VII (low potency) being the least potent. The corticosteroids prescribed for psoriasis are usually class I to class IV (medium potency) corticosteroids. The topical corticosteroids prescribed most frequently for psoriasis in the major markets are clobetasol propionate (Oclassen Pharmaceuticals’ Cormax, GlaxoSmithKline’s Temovate, Connetics’ Olux), optimized betamethasone propionate (Schering-Plough’s Diprolene), dißorasone diacetate (Dermik’s Psorcon), halobetasol (Bristol Myers Squibb’s Ultravate), and mometasone furoate (Schering-Plough’s Elocon). Because many of these agents have very similar properties, only betamethasone dipropionate and mometasone furoate, two of the most frequently prescribed topical corticosteroids, are discussed in detail here as representative examples of corticosteroids commonly used to treat psoriasis. Most of the topical corticosteroids used to treat psoriasis are available as generic drugs, particularly in the United States. The exceptions are mometasone furoate, halobetasol propionate, and the augmented form of betamethasone dipropionate, each of which will lose market exclusivity in the next ten years. Side effects associated with topical corticosteroid use include allergic contact dermatitis, skin atrophy (thinning), striae (stretch marks), telangiectasias (spider

590

PSORIASIS

TABLE 6. Current Therapies Used for Psoriasis Agent

Company/Brand

Topical corticosteroids Betamethasone Schering-Plough’s dipropionate Diprolene, generics

Mometasone Schering-Plough’s furoate Elocon Vitamin D3 analogues Calcipotriene Leo Pharmaceuticals/ Bristol-Myers Squibb’s Dovonex

Retinoids Acitretin

Tazarotene

Roche’s Soriatane/Neotigason

Allergen’s Tazorac

Antimetabolites Methotrexate Wyeth’s Rheumatrex; generics Anthralin

Bioglan Pharma’s Micanol, generics

Daily Dose

Availability

For all topical corticosteroids, US, F, G, I, S, twice-daily application to start; UK, J empirical observations for optimal interval between dosing; use formulation from lowest-potency class that clears skin. US, G, S, UK, J

0.005% cream or ointment; topical application twice daily; not more than 5 mg per week (equal to 100 g of vehicle base); can use for up to eight weeks; not to be used directly after salicylic acid treatment; apply after UV treatment for combination therapy.


Oral administration of US, F, G, I, S, 0.3–0.5 mg/kg/day initially; UK increased in 3–4 week intervals to 0.75 mg/kg/day; pustular psoriasis requires initial dose of 1 mg/kg/day tapered to 0.5 mg/kg/day for maintenance. 0.05–1.0% applied topically once US, F, G, I, S, daily at bedtime; can be used UK, J for up to 12 weeks. 10–25 mg once weekly in three US, F, G, I, S, doses every 12 hours for 36 UK, J hours 0.05–0.1% ointment used US, F, G, I, S, initially; increased in UK, J increments to 5% until plaques resolve

Immunosuppressants Cyclosporine Novartis’s Oral administration of 2.5–3.0 US, F, G, I, S, Neoral/Sandimmune, mg/kg/day in two divided UK, J SangStat’s SangCya doses, ≤5 mg/kg/day; dosage tapered once clinical effect is seen. T-cell modulators Alefacept Biogen Idec’s Amevive 7.5 mg once-weekly bolus IV or US 15 mg once-weekly IM Efalizumab Genentech/Xoma’s 1 mg/kg once-weekly SC US Raptiva

CURRENT THERAPIES

591

TABLE 6. (continued) Agent TNF-α inhibitors Etanercept

Company/Brand Amgen/Immunex/ Wyeth’s Enbrel

Photosensitizers 8-methoxypsoralen ICN Pharmaceuticals’ (8-mop) Oxsoralen

Coal tar

Various

Daily Dose 50 mg/kg once-weekly SC

Availability US

Topical: applied 20 minutes F, G, I, S, UK, J prior to UVA treatment. Oral: 0.6–0.8 mg/kg taken 2 hours prior to UV treatment. Available in many US, F, G, I, S, concentrations; 5% works UK, J best.

IM = Intramuscular; IV = Intravenous; SC = Subcutaneous; UV = Ultraviolet. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

veins), hypopigmentation, rosacea, acne, perioral dermatitis, and increased Þne hair growth. The side effects of a topical corticosteroid are directly proportional to its potency, though some evidence suggests that newer formulations may provide enhanced beneÞt-to-risk ratios. Topical corticosteroids must be used carefully near the eyes because of an increased risk of cataracts and glaucoma. Physicians must also be aware of the potential for systemic absorption, which may lead to adrenal suppression, a serious side effect that is often incorrectly associated only with systemic corticosteroids. The risk of systemic side effects increases as the surface area of skin treated (i.e., a larger quantity of drug) and potency of the corticosteroid used increases. Other factors that affect the risk of side effects from topical corticosteroids include the drug vehicle (which affects the quantity of corticosteroid available to the skin), the concomitant use of occlusion therapy, the integrity of the skin, and the area being treated (e.g., absorption is greater in skin folds). Oral corticosteroids used at doses considered effective for treating psoriasis are associated with adverse side effects. Therefore, they are very seldom prescribed for psoriasis and are not discussed here. Mechanism of Action. The beneÞcial actions of topical corticosteroids in psoriasis include vasoconstriction, immunosuppression, and antiproliferative and anti-inßammatory effects. The potency of topical corticosteroids is determined by their ability to induce blood vessel constriction, with more-potent corticosteroids inducing greater vasoconstriction. Vasoconstriction results in decreased vascular permeability of dermal capillaries. It decreases edema and erythema and reduces leukocyte migration into affected skin. Topical glucocorticoids prevent cellular proliferation by inhibiting DNA synthesis and subsequently blocking mitosis. The anti-inßammatory and immunosuppressive actions of corticosteroids result largely from the inhibition of particular functions of leukocytes. Corticosteroids enter cells, bind to glucocorticoid receptors, and are transported to the nucleus as a corticosteroid-receptor complex. The corticosteroid-receptor

592

PSORIASIS

TABLE 7. Select Topical Corticosteroid Preparations Corticosteroida

Concentration (%)

Clobetasol propionate Betamethasone dipropionate (optimized) Diflorasone diacetate Halobetasol propionate

0.05 0.05

Temovate (c/o) Diprolene (c/o)

0.05 0.05

Psorcon (o) Ultravate (c/o)

II. High potency

Amcinonide Betamethasone dipropionate Fluocinonide Desoxymetasone Mometasone fuorate Diflorasone diacetate Halcinonide

0.1 0.05 0.05 0.25 0.1 0.05 0.1

Cyclocort (o) Diprosone (o) Lidex (g/c/o) Topicort (c/g/o) Elocon (o) Florone (o), Maxiflor (o) Halog (c)

III. Potent

Triamcinolone acetonide Fluticasone propionate Amcinonide Betamethasone dipropionate Diflorasone diacetate Halcinonide Fluocinonide Betamethasone valerate

0.1 0.005 0.1 0.05 0.05 0.1 0.05 0.1

Aristocort A (o) Cutivate (o) Cyclocort (c/l) Diprosone (c) Florone (c), Maxiflor (c) Halog (o) Lidex E (c) Valisone (o)

IV. Medium potency

Flurandrenolide Mometasone fuorate Triamcinolone acetonide Fluocinolone acetonide Hydrocortisone valerate

0.05 0.1 0.1 0.025 0.2

Cordran (o) Elocon (c) Kenalog (c) Synalar (o) Westcort (o)

V. Midstrength

Flurandrenolide Fluticasone propionate Betamethasone dipropionate Triamcinolone acetonide Hydrocortisone butyrate Fluocinolone acetonide Betamethasone valerate Hydrocortisone valerate

0.05 0.05 0.05 0.1 0.1 0.025 0.1 0.2

Cordran (c) Cutivate (c) Diprosone (l) Kenalog (l) Locoid (l) Synalar (c) Valisone (c) Westcort (c)

VI. Mild

Aclometasone dipropionate Triamcinolone acetonide Desonide Fluocinolone acetonide Hydrocortisone

0.05 0.1 0.05 0.01

Aclovate (c/o) Aristocort (c) DesOwen (o), Tridesilon (c) Synalar (c)

2.5, 1

Hytone (c/o) (generics)

Class I. Superpotent

VII. Low potency Hydrocortisone, dexamethasone, flumethasone, prednisolone, and methylprednisolone

Brand Name

a Different preparations of the same corticosteroid (ointment, cream, lotion, gel) can be members of different

potency classes. c = Cream; g = Gel; l = Lotion; o = Ointment.

CURRENT THERAPIES

593

TABLE 8. Combination Therapies for Psoriasis

Therapy

Weeks Required for Full Efficacy of Monotherapy Efficacy of to (1) Clear Lesions and Monotherapy (2) Maintain Clearance

Anthralin

3–16

(1) Moderate to excellent (2) Moderate

Anthralin + acitretin Anthralin + calcipotriol Anthralin + cyclosporine Anthralin + methotrexate Anthralin + coal tar

Acitretin

Recommended Recommended Recommended Recommended Recommended to strongly recommended 8–12

(1) Poor (2) Excellent

Acitretin + cyclosporine Acitretin + coal tar Acitretin + methotrexate Acitretin + calcipotriol Acitretin + PUVAa Acitretin + UVB Calcipotriol

Contraindicated Recommended Recommended Strongly recommended Strongly recommended Strongly recommended 8

(1) Moderate to excellent (2) Moderate

Calcipotriol + coal tar Calcipotriol + methotrexate Calcipotriol + topical corticosteroids

Recommended Recommended Recommended to strongly recommended Strongly recommended Strongly recommended Recommended

Calcipotriol + cyclosporine Calcipotriol + PUVAa Calcipotriol + UVB Coal tar

Variable

(1) Moderate (2) Poor

Coal tar + methotrexate Coal tar + topical corticosteroids Coal tar + PUVAa Coal tar + UVB

Cyclosporine Cyclosporine + coal tar Cyclosporine + topical corticosteroids Cyclosporine + methotrexate Cyclosporine + PUVAa Cyclosporine + UVB

Guidelines for Using Combination

Recommended Recommended Contraindicated Recommended to strongly recommended 4–8

(1) Excellent (2) Not recommended Recommended Recommended Contraindicated Contraindicated Contraindicated

594

PSORIASIS

TABLE 8. (continued)

Therapy Topical corticosteroids

Weeks Required for Full Efficacy of Monotherapy Efficacy of to (1) Clear Lesions and Monotherapy (2) Maintain Clearance 2–4

(1) Good (2) Excellent

Topical corticosteroids + acitretin Topical corticosteroids + methotrexate Topical corticosteroids + PUVAa Topical corticosteroids + anthralin Topical corticosteroids + UVB PUVAa

Recommended Recommended Recommended Recommended Not recommended 4–8

(1) Excellent (2) Not recommended

PUVA + anthralin PUVA + methotrexate UVB

Recommended Contraindicated 3–8

(1) Good (2) Good

UVB + methotrexate UVB + anthralin Methotrexate

Guidelines for Using Combination

Recommended Not recommended 8–16

(1) Excellent (2) Excellent

a The most common form of UVA phototherapy includes pretreatment with the photosensitizing agent pso-

ralen and is known by the acronym PUVA. Source: Adapted from Van de Kerkhorf PC. Combinations and comparisons. Clinical Dermatology. 1997;15:831–834; and Lebwohl M, et al. Combination therapy to treat moderate to severe psoriasis. Journal of the American Academy of Dermatology. 2004;50:416–430.

complex modulates transcription of corticosteroid responsive genes. Inhibited genes include those encoding the inßammatory cytokines IL-1, IL-2, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ , and TNFα, which are produced by T cells (TH 1 and TH 2), B cells, monocytes, and macrophages. Corticosteroids also inhibit the expression of AP-1 and nuclear factor-kappa B (NF-κB), transcription factors that regulate expression of several inßammatory cytokines. Formulation. Topical corticosteroids are available as ointments, creams, lotions, and foams. Solutions for the treatment of scalp lesions are also available. Various vehicles are used in topical corticosteroid medications. Neutral vehicles, such as petrolatum, are popular. Some physicians avoid propylene glycol, which enhances penetration of the active drug, because it can irritate the skin. Halogenated corticosteroids (ßuorinated or chlorinated) are seldom prescribed. Although a halogen increases potency, it also increases systemic absorption and the potential for

CURRENT THERAPIES

595

systemic side effects. Newer, highly lipophilic formulations (e.g., ßuticasone propionate and mometasone furoate) have been developed to promote absorption through the skin and increase potency while promoting rapid metabolism to inactive metabolites in the circulatory system and limiting systemic effects. Betamethasone Dipropionate. Betamethasone dipropionate (Schering Plough’s Diprolene/Diprosone, generics) is among the most popular topical corticosteroids. Betamethasone dipropionate is available in a variety of formulations and vehicles that range in potency from class I to class IV. Augmented betamethasone dipropionate ointment is a class I corticosteroid known for its rapid onset of action. The formulation differs from other formulations of the drug because it contains propylene glycol, which enhances skin penetration. Like other topical corticosteroids, betamethasone dipropionate has antiinßammatory and antiproliferative properties. Betamethasone dipropionate suppresses the production of inßammatory cytokines and reduces leukocyte migration into psoriatic skin. Dosage of class I corticosteroids must be managed carefully to minimize adverse effects. The FDA-approved labeling for augmented betamethasone dipropionate and for the class I corticosteroids clobetasol propionate and halobetasol propionate recommends limiting the duration of treatment with these agents. Pulse therapy, a limited, long-term dosing strategy, involves an initial period of daily application of a class I corticosteroid until the plaque being treated is ßattened (Katz HI, 1991). In a randomized double-blind, placebo-controlled study, an intermittent dosing regimen was tested for augmented betamethasone dipropionate (Katz HI, 1991). The initial phase of the study was an open-label screening phase during which psoriasis patients with ≤10% skin involvement applied augmented betamethasone dipropionate to their lesions twice a day for three to four weeks. After this initial phase, study participants were qualiÞed to proceed to the maintenance phase of the trial if their overall disease status was cleared or slight. Ninety of the original 123 patients enrolled in the trials were evaluated for efÞcacy during the maintenance phase of treatment. Of these, 46 were treated with augmented betamethasone and 44 were treated with placebo. Patients applied betamethasone or placebo three times per week at 12-hour intervals for a maximum treatment period of six months. Evaluation of clinical beneÞt was based on the length of time until treatment failure occurred, an end point assessed by changes in weighted scores of disease signs, overall disease status, and the patients’ evaluation of treatment effectiveness. Sixty-Þve percent of the patients treated with augmented betamethasone remained in remission for the duration of the sixmonth treatment period, while 20% of the latter group remained in remission. None of the patients in either treatment group exhibited any signs of cutaneous atrophy at the end of treatment. No trends suggestive of HPA axis suppression were evident during the course of the six-month treatment period. Therefore, intermittent therapy with high-potency topical corticosteroids appears to provide an extended period of disease remission while minimizing adverse effects.

596

PSORIASIS


Betamethasone dipropionate is frequently combined with other topical medications, including vitamin D3 analogues and topical retinoids, to reduce the effective dose of each agent, improve overall efÞcacy, and extend the period of remission following treatment. Topical corticosteroids can also alleviate skin irritation induced by vitamin D3 analogues or topical retinoids. Like all topical corticosteroids, betamethasone dipropionate can cause hypothalmic-pituitary-adrenal (HPA) axis suppression when applied under occlusive dressings or when used daily for extended periods of time. As with other topical corticosteroids, skin atrophy, thinning, and striae are possible, particularly at high doses or when used for extended periods. Tachyphylaxis is a concern with betamethasone dipropionate, as it is with other topical corticosteroids. Mometasone Furoate. Mometasone furoate (Schering-Plough’s Elocon) (Figure 3) is a class II corticosteroid formulated as an ointment and a class IV corticosteroid formulated as a cream. Mometasone furoate has a relatively low potential for producing local and systemic side effects, including adrenal suppression. Like other topical corticosteroids, mometasone furoate enters cells and binds to the corticosteroid receptor. The corticosteroid-receptor complex modulates transcription of corticosteroid responsive genes, including inßammatory cytokines, AP-1, and NF-κB. Mometasone furoate is believed to penetrate human skin slowly, allowing for less frequent applications of the agent. Because mometasone furoate has been on the market for some time, few randomized clinical trials using contemporary methodology and end points are available to detail the safety and efÞcacy of the drug. However, a comparison with well-established agents indicated that mometasone furoate can induce similar clearing of psoriatic lesions with less frequent application than triamcinolone acetonide or ßuocinolone acetonide. The combined results of four randomized, single-blind, parallel-group studies compared the efÞcacy of mometasone furoate ointment and cream with the ointment and cream formulations of ßuocinolone acetonide and triamcinolone acetonide (Medansky RS, 1988). A total of 823 patients with chronic moderate to severe psoriasis were enrolled in the study and followed for 21 days of treatment. Mometasone ointment applied once daily was found to have a more rapid onset of action and produced a greater improvement in

CURRENT THERAPIES

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disease than triamcinolone ointment applied twice daily or ßuocinolone ointment applied three times daily. Mometasone cream applied once daily demonstrated a similarly rapid onset of action, was more effective in reducing signs of disease than ßuocinolone cream applied three times daily, and showed comparable efÞcacy with triamcinolone cream applied twice daily. Therefore, mometasone furoate produced comparable or superior results with a more favorable dosing schedule. A limited number of side effects were judged to be related to treatment with mometasone furoate. The most commonly observed were burning, itching, and dryness, which occurred at similar or lower frequency compared with triamcinolone or ßuocinolone (Medansky RS, 1988). Mild to moderate instances of skin atrophy were observed in less than 1% of patients treated with mometasone, in 2.5% of the patients treated with triamcinolone, and in no patients treated with ßuocinolone. Clinical laboratory tests revealed few values outside of the normal range, and these were deemed to be of no clinical signiÞcance or were judged by investigators to be unrelated to treatment. Therefore, once-daily application of mometasone furoate was judged to be safe. Like all topical corticosteroids, mometasone furoate should not be used at very high doses. The FDA-approved labeling for mometasone furoate cautions that treatment of greater than 30% of body surface area can result in HPA axis suppression. Also, tachyphylaxis, skin thinning, skin atrophy, and striae are potential side effects of treatment with mometasone furoate. Vitamin D3 Analogues Overview. Topical preparations of vitamin D3 analogues are Þrst-line treatments for mild psoriasis, particularly in children, because they do not present the risk of HPA axis suppression. Few adverse effects are observed. The most common adverse effect observed with topical vitamin D3 analogues is contact irritation (for this reason, topical use is contraindicated in sensitive areas such as the face and groin), but combining a vitamin D3 analogue and a topical corticosteroid can ameliorate the irritation. Oral vitamin D3 supplements cause adverse hypercalcemic effects and are therefore seldom prescribed. Calcipotriene (Leo Pharmaceuticals/Bristol-Myers Squibb’s Dovonex) is the most widely used vitamin D3 analogue, but two other agents, tacalcitol and calcitriol, are available outside the United States. Tacalcitol (Teijin’s Bonalfa), a topical vitamin D3 analogue, is frequently prescribed in Japan and in some European countries, but is not as widely available as calcipotriene. Calcitriol is available in both topical (Savient/Galderma’s Silkis) and oral (Roche’s Rocaltrol) formulations. Orally administered calcitriol has been largely displaced by calcipotriene because of the hypercalcemic effects associated with systemic administration of the former. In an effort to counter these negative effects, calcitriol has been reformulated as an ointment; nonetheless, calcipotriene is likely to remain the most widely used vitamin D3 analogue and is thus the agent discussed in detail in this section.

598

PSORIASIS

FIGURE 4. Structure of calcipotriene.

Mechanism of Action. Vitamin D3 and vitamin D3 analogues suppress growth and stimulate the terminal differentiation of keratinocytes. The high-afÞnity vitamin D receptor (VDR), a mediator of transcription, is expressed in a number of cell types, including all epidermal layers of skin, T lymphocytes, macrophages, and Langerhans’ cells. Several genes involved in cell proliferation and differentiation and in inßammation show altered expression levels when exposed to vitamin D3 analogues. Expression of involucrin, a marker protein of keratinocyte differentiation, increases, as does expression of the anti-inßammatory cytokine IL-10, while expression of the proinßammatory cytokine IL-8 decreases. Calcipotriene. Calcipotriene (Figure 4) is a vitamin D3 analogue that blocks proliferation of skin cells, enhances keratinocyte maturation, and exhibits antiinßammatory effects. It is available formulated as an ointment or a cream and is also available in a premixed combination with the topical corticosteroid betamethasone dipropionate (Leo Pharmaceuticals’ Dovobet). Calcipotriene is currently marketed exclusively as a branded drug, but will lose market exclusivity in the United States in 2007; in France in 2009; in Germany, Italy, and Spain in 2006; and in Japan in 2010. The efÞcacy and safety of calcipotriene were examined in a randomized, double-blind, right/left comparison of calcipotriene ointment (50 µg/g) on one side of the body and a placebo (vehicle) ointment on the other side (Dubertret L, 1992). Sixty-Þve patients were evaluated using a modiÞed Psoriasis Area and Severity Index (PASI) score, a measure used to evaluate the severity of psoriasis and response to therapy. Participants were seen at two-week intervals for a period of four weeks. While the average PASI score decreased on both sides of the body, a signiÞcantly greater improvement was observed with calcipotriene. The most frequent adverse events were lesional irritation, and one patient treated with calcipotriene became marginally hypercalcemic. Vitamin D3 analogues are often combined with topical corticosteroids. Leo Pharmaceuticals has developed a topical preparation combining the corticosteroid betamethasone dipropionate (0.5 mg/g) with calcipotriol (50 µg/g)

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(Dovobet/Daivobet). Clinical trial data support the effectiveness of this combination therapy. A randomized, double-blind trial enrolling 1,103 patients presented at the 60th Annual American Academy of Dermatology in New Orleans conÞrmed that this combination was superior to either agent alone. The average improvement in PASI score at the end of the four-week trial with the combination ointment was superior to that observed with either agent alone: 74.4% improvement for the combination, 55.3% improvement for calcipotriol, and 61.3% improvement for the steroid (p < 0.001) (Gollnick H, 2002). This combination appears to provide efÞcacy similar to that of individually applied corticosteroids and vitamin D3 analogues but with only a single application per day—an improvement over current dosing regimens (Kragballe K, 2002). Combining topical corticosteroids and vitamin D3 analogues can also improve the duration of remission observed with topical corticosteroids. In a doubleblind, placebo-controlled, parallel group study, 44 patients with mild to moderate psoriasis were treated with a two-week combination regimen of calcipotriene ointment in the morning and halobetasol ointment (a class I steroid) in the evening (Lebwohl M, 1998). From that group, 40 patients demonstrated at least a 50% improvement on a 0 to 8 scale used to score disease severity, and those 40 patients were rerandomized to two groups: 20 treated with halobetasol twice daily on weekends and calcipotriene twice daily on weekdays, and 20 that received halobetasol ointment only. Of the patients treated with the combination regimen, 76% remained in remission for six months, compared with 40% treated with halobetasol. Calcipotriene causes local skin irritation and is therefore not suitable for use on the face, groin, or other sensitive areas of the body. At very high doses, as seen in patients using more than 200 grams of ointment (50 µg/g of ointment) per week, patients may become hypercalcemic. Elevated calcium levels return to normal with cessation of treatment. Retinoids Overview. The topical and oral retinoids used to treat psoriasis are synthetic vitamin A derivatives. The oral retinoid etretinate (Roche’s Tegison/Tigason) has largely been replaced by the newer oral retinoid acitretin (Roche’s Soriatane/Neotigason), but it is the only oral retinoid available in Japan. The primary difference between acitretin and etretinate is the period of time the drug is retained by the body after treatment is discontinued. Etretinate is still detectable for three years after therapy is discontinued, while acitretin drops to undetectable levels within a few weeks. Because etretinate is no longer available in most of the markets under study, it will not be discussed in detail here. Mechanism of Action. Retinoids bind to speciÞc receptors called retinoid receptors (RARs and RXRs) in the cell nucleus, affecting the transcription of genes involved in keratinocyte differentiation, cell proliferation, and inßammation. Clinical evidence and in vitro studies demonstrate that retinoids downregulate transcription of proinßammatory cytokines, halt proliferation of cultured cells, and alter expression of indicators of keratinocyte differentiation.

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Acitretin. Acitretin (Roche’s Soriatane/Neotigason) is marketed in the United States and Europe for severe psoriasis and is often prescribed for patients who do not respond to other treatments. Acitretin is effective in severe psoriasis, particularly pustular and erythrodermic psoriasis. This agent is often used in combination with other psoriasis therapies, including topicals and UVB light or PUVA. However, combining acitretin and cyclosporine requires close monitoring because both agents can raise triglyceride and serum cholesterol levels. While acitretin is currently marketed as a branded drug, patent protection and market exclusivity have expired in all markets under study. No generics manufacturer has announced plans to market a generic version of acitretin to date. Acitretin, a second-generation oral retinoid, is the principal metabolite of etretinate, the Þrst retinoid that was developed to treat psoriasis. Acitretin activates the retinoid receptors RAR-α, RAR-β, and RAR-γ , but does not activate the retinoid receptors RXR-α, RXR-β, and RXR-γ (Duvic M, 2004). Activation of RAR-α is associated with adverse effects, including elevated serum lipid and triglyceride levels (Duvic M, 2004). It is not yet known whether metabolites of acitretin activate the RXR receptors, which are also associated with adverse effects. Acitretin downregulates transcription of proinßammatory cytokines, halts proliferation of cultured cells, and alters expression of indicators of keratinocyte differentiation. The efÞcacy of acitretin was compared with that of its predecessor, etretinate, in a randomized, double-blind study in Germany (Gollnick H, 1988). A total of 175 patients with severe psoriasis of different types were treated with 10 mg, 25 mg, or 50 mg of acitretin and compared with patients receiving 50 mg etretinate over a period of eight weeks. Complete remission occurred among patients receiving 50 mg of acitretin or etretinate, and an average improvement in PASI score of 53.8% was seen with acitretin, compared with 61.1% with etretinate. However, enlargement of psoriatic lesions was observed in some patients with both agents despite overall improvements in PASI scores. Like all systemic retinoids, acitretin has potentially serious side effects similar to those observed with megadoses of vitamin A. Common, less serious side effects include dry eyes, nose, and lips; peeling skin of the palms and soles; thinning hair; bruising and nose bleeds; bone and joint pain; and headache. Vision-related symptoms may include decreased night vision, blurred vision, and cataracts. Adverse musculoskeletal effects include bone overgrowth in the knee and ankle joints and the pelvic area. Cholesterol levels may also rise. More rarely, patients experience nausea, vomiting, and buildup in intracranial pressure. Acitretin is teratogenic and should not be used by women who may become pregnant. Concomitant ingestion of alcohol with acitretin therapy results in its conversion to etretinate, a form retained by the body for several years; thus, alcohol use is contraindicated for women of childbearing age taking acitretin. Although acitretin is cleared more rapidly than etretinate, it is nevertheless recommended that women taking acitretin avoid becoming pregnant for three years after therapy is discontinued. Because teratogenicity is a serious concern, acitretin is seldom prescribed to women of childbearing age.

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Tazarotene. Tazarotene (Allergan’s Tazorac), the Þrst topical retinoid found to be effective for moderate psoriasis, is used either as a single agent or in combination with UV light or anthralin. Tazarotene acts rapidly; improvement often occurs within one week of use and is generally seen within 10–12 weeks, and success rates of up to 70% of treated patients have been reported. Used either alone or in combination with topical corticosteroids, tazarotene can induce longer periods of remission compared with topical steroid monotherapy (Lebwohl M, 1998). Local skin irritation, pruritus, and erythema may occur, but topical retinoids are considered safe and are not prone to the serious side effects that corticosteroids may cause. Topical tazarotene is currently marketed only as a branded drug; market exclusivity will expire in all markets discussed here during the next ten years. Tazarotene is a third-generation retinoid that selectively binds to retinoic acid receptor (RAR)-β and RAR-γ for the treatment of moderate to severe psoriasis. Binding to tazarotene’s cognate RARs downregulates transcription of proinßammatory cytokines and suppresses keratinocyte proliferation. Because it does not activate RAR-alpha and retinoid X receptors (RXRs), oral tazarotene is not associated with some side effects—such as hypertriglyceridemia, hypothyroidism, and hepatoxicity—that occur with other oral retinoids (Duvic M, 2004). Two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efÞcacy of tazarotene cream evaluated a total of 892 patients with mild to moderate plaque psoriasis, deÞned as involving at least 2% of the total body surface area and lesions of at least moderate severity (Weinstein GG, 2003). Clinical success was evaluated using the Overall Lesional Assessment (OLA), a measure that scores a patient’s psoriasis with respect to plaque elevation, scaling, and erythema. An OLA score of none, minimal, or mild was the primary efÞcacy variable. Patients were treated with 0.1% or 0.05% tazarotene cream or with vehicle for a period of 12 weeks and were followed for an additional 12 weeks after completing treatment. More patients treated with tazarotene achieved clinical success than did patients treated with placebo at both concentrations of tazarotene and in both studies, with success rates ranging from 39.4% to 50.7%, versus values of 24.5% and 26.2% for vehicle. The therapeutic effect of tazarotene continued to be statistically signiÞcant throughout the post-treatment period. Topical tazarotene can cause local skin irritation and therefore cannot be used in sensitive areas such as the face or groin. Topical tazarotene should not be used by pregnant women because of the risk of teratogenicity, and it can increase sensitivity to sunlight, requiring that patients avoid excessive sun exposure. Antimetabolites Overview. Antimetabolites interfere with the rapid proliferation of cells and decrease inßammation associated with psoriasis. Antimetabolites exert their effects largely by interrupting cellular metabolism, particularly nucleic acid synthesis. Methotrexate (Wyeth’s Rheumatrex, generics), a systemic antimetabolite, and anthralin, a topical agent, are the antimetabolites most commonly used to treat psoriasis.

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PSORIASIS

H2N

N

N CH3

N

N N H N

NH2 O

COOH COOH


Systemic antimetabolites can be extremely successful at improving severe cases of psoriasis, but toxicity limits their use. Methotrexate is the most extensively used agent in this class, but it requires careful monitoring of liver function in patients who receive long-term therapy. Other systemic antimetabolites, such as 6-thioguanine and hydroxyurea, are prescribed in rare instances where other therapies have failed, but high toxicity and signiÞcant adverse effects limit their use. Because they are used very infrequently, 6-thioguanine and hydroxyurea are not discussed here. Mechanisms of Action. The most commonly used antimetabolites halt division of proliferating cells by interfering with nucleic acid metabolism and blocking DNA synthesis. Methotrexate. Methotrexate (Wyeth’s Rheumatrex, generics) (Figure 5) is a synthetic analogue of folate, a vitamin that is essential for production of purine DNA bases. Methotrexate is an antimetabolite and chemotherapy drug that interferes with cell proliferation by blocking purine nucleotide synthesis and exerts anti-inßammatory actions. It is effective in, and usually reserved for, patients with severe disease that is resistant to topical therapy and phototherapy. Methotrexate therapy decreases the epidermal cell proliferation rate, monocyte and neutrophil chemotaxis, Langerhans’ cell activity, and leukotriene B4 production by neutrophils. Methotrexate has been approved for the treatment of psoriasis since 1972, and few randomized clinical trials measuring its efÞcacy using contemporary study end points are available from that era. However, it is widely regarded by clinicians as a very effective treatment for severe psoriasis. In a retrospective case-report study, researchers found that among 113 psoriatic patients treated over a 20-year period in one clinic with 15 mg/week of methotrexate, 82% of patients had “prolonged clearance or near clearance” (Van Dooren-Greebe RJ, 1994). Methotrexate is frequently prescribed for patients who fail topical therapy and UV therapy and is often part of combination or rotational regimens. Methotrexate is usually well tolerated in low doses, but it can cause many side effects and has the long-term potential of damaging the liver. Nausea and vomiting, skin rash, itching, and stomatitis (mouth sores) are the most common side effects. Gastrointestinal (GI) side effects are minimized by the use of H2 histamine antagonists, and stomatitis can be minimized by concomitant folic acid administration.

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FIGURE 6. Structure of anthralin.

Potential hepatotoxicity is of great concern, and the total dose must be carefully monitored. Liver enzymes may become elevated, necessitating (usually monthly) monitoring. The American Dermatology Society recommends that a liver biopsy be performed after administration of the Þrst 2.5 g of methotrexate and then at every 1.5 g thereafter. Very rarely, frank liver Þbrosis and cirrhosis may develop, necessitating liver biopsy. Liver damage is most likely to occur in the subset of patients who have received a cumulative dose of more than 1.5 g and demonstrate other risk factors. These factors include taking NSAIDs or other medications that are contraindicated during methotrexate therapy; alcoholism or substance abuse; existing liver or kidney problems; diabetes mellitus; obesity; or old age. Anthralin. Anthralin (Figure 6), or dithranol (Bioglan Pharma’s Micanol, generics), a topical antimetabolite, is a synthetic derivative of chrysarobin (obtained from the Brazilian tree Andira araroba) and has been used to treat psoriasis since the mid 1800s. Anthralin is very effective for mild to moderate psoriasis. As a photosensitizer, it is sometimes used in combination with UV light monotherapy (without psoralen). Although the mechanism of action of anthralin is not well understood, it exerts an anti-inßammatory action, promotes cellular differentiation, and reduces cellular proliferation (as demonstrated by changes in markers of psoriasis, T-cell activation, and chemotaxis). In recent years, conventional applications of anthralin have been replaced by short-contact anthralin therapy, in which a high concentration of anthralin (1% or greater) is applied for several minutes to one hour. However, comparisons with corticosteroids and vitamin D3 analogues have revealed few efÞcacy advantages, and patients favor other agents that are less irritating and are less likely to stain skin or clothing. In a multicenter, randomized, open study, 306 patients of either gender with stable chronic plaque psoriasis covering at least 100 cm2 of surface area applied calcipotriol (50 µg/mg) twice daily or shortcontact anthralin (0.1–2%) for up to three months. The number of patients who were assessed by physicians as being “cleared” or showing “marked improvement” at the end of treatment was greater in the calcipotriene group than in the anthralin group (60.1% versus 51.1%), but both groups showed improved quality of life as assessed by the Psoriasis Disability Index (PDI) and the Sickness Impact ProÞle (SIP) (Wall AR, 1998). However, calcipotriene provoked less contact irritation, and patients found it more appealing to use. Anthralin can cause nonpsoriatic skin to become irritated and inßamed. While anthralin is not known to cause any serious adverse effects, it does not offer

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efÞcacy advantages over other topical treatments, and other agents that are less prone to staining clothing are preferred by patients. Immunosuppressants Overview. Immunosuppressants may be very effective in psoriasis, but their use is limited to severe cases because of potentially serious side effects. Cyclosporine (Novartis’s Sandimmune/Neoral, SangStat’s SangCya, generics) is the immunosuppressant most widely used to treat severe cases of psoriasis. More toxic drugs, such as mycophenylate mofteil and azathioprine, are used infrequently because of high toxicity and only moderate efÞcacy. Mechanisms of Action. Cyclosporine and similar immunosuppressants bind to cytoplasmic receptors, which are isomerases known as immunophilins. The drug-immunophilin complex exerts its primary immunosuppressive activity by binding to and inhibiting calcineurin, a protein that plays an essential role in calcium-dependent signal transduction in T cells. This signal transduction pathway activates expression of cytokine genes, among others. Decreased cytokine production concomitantly decreases T-cell (TH 1 and TH 2) activation, including IL-2 production, growth, migration, and cytotoxic T-cell degranulation. Reduced cytokine secretion also affects the functions of keratinocytes, antigen-presenting cells, and neutrophils. Calcineurin is involved in T-cell-derived IL-2, IL-4, GMCSF, TNF-α, and IFN-γ production. Therapy with cyclosporine or tacrolimus reduces the synthesis of all of these cytokines. See “Pathophysiology” for more information on the role of cytokines in psoriasis. Cyclosporine. Cyclosporine (Novartis’s Sandimmune [an oil-in-water emulsion] and Neoral [a microemulsion], SangStat’s SangCya [a microemulsion], generics) plays an important role in the treatment of psoriasis. The effectiveness of cyclosporine for psoriasis was discovered serendipitously and was a pivotal Þnding with regard to the development of T-cell hypotheses of the pathogenesis of psoriasis (see “Pathophysiology”). Cyclosporine binds to an intracellular receptor, the immunophilin cyclophilin. The immunophilin-cyclosporine complex inhibits the phosphatase, calcineurin, and cytokines activated by calcineurin. Decreased cytokine production leads in turn to decreased T-cell activation and migration. Cyclosporine is often effective for refractory psoriasis and must be administered systemically (orally). Efforts to develop a topical formulation have failed, principally because cyclosporine is a large (>1,200 KDa) molecule, limiting its absorption. Because of potentially serious side effects, cyclosporine therapy is titrated upward until remission is induced and then downward to the lowest effective maintenance dose. Therapy is initiated at 3 mg/kg/day; if no response is obtained in one month, the dose may be titrated upward to 4 mg/kg/day; 5 mg/kg/day is the maximum dose. Following the induction of remission, the dose is adjusted downward by 0.5 mg/kg/day every two weeks to reach the lowest effective maintenance dose. Topical agents may be used to help maintain remission. Relapse

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occurs two to four months after cyclosporine discontinuation in virtually all patients. A 16-week trial involving 181 patients with severe psoriasis evaluated the ability of cyclosporine to induce and maintain disease remission (Shupack J, 1997). After 16 weeks of treatment with an initial dose of 5 mg/kg/day, 86% of patients achieved 70% or greater reduction in body surface area involvement. Responders were randomized to receive cyclosporine or placebo daily for six months; 42% of patients who received 3 mg/kg cyclosporine, compared with 84% in the placebo group, relapsed at the end of the six-month maintenance period. Disease relapse was marked by a 50% or greater return in skin surface involvement relative to baseline. The median time to relapse was six weeks in both the placebo and 1.5 mg/kg groups and was delayed in the 3.0 mg/kg group; 58% of patients that received the 3.0 mg/kg dose of cyclosporine remained relapse-free at end of this six-month maintenance period, compared with 16% of patients who received placebo. The efÞcacy of cyclosporine and methotrexate were compared in a randomized, controlled trial involving 88 patients with moderate to severe psoriasis (Heydendael MD, 2003). Patients were treated for 16 weeks and followed for an additional 36 weeks after treatment was discontinued. PASI scores were determined at baseline and monthly thereafter by trained assessors unaware of the treatment assignments. After 16 weeks of treatment, the reduction in PASI scores from baseline was 64% in the methotrexate group and 72% in the cyclosporine group. Almost complete remission (deÞned as a reduction in baseline score for the PASI index of more than 90%) was achieved in 40% of the patients in the methotrexate group and 33% of patients in the cyclosporine group. Partial remission (deÞned as a reduction in baseline score for the PASI index of more than 75%) was achieved in 60% of patients in the methotrexate group and 71% of patients in the cyclosporine group. The time to reach these degrees of remission was not signiÞcantly different in either group, with maximum degrees of clearance reached at weeks 12–16. Methotrexate and cyclosporine therefore appear to have comparable efÞcacy for treating moderate to severe psoriasis. Alterations in renal function occur in approximately 25% of cyclosporinetreated patients, necessitating blood monitoring for kidney dysfunction. Liver toxicity is also a potential side effect, and cyclosporine therapy is therefore contraindicated in patients with liver disease. GI side effects may include nausea, vomiting, anorexia, and diarrhea. Headache, sensory disturbances in the extremities, musculoskeletal pain, ßu-like symptoms, and upper-respiratory-tract infections are common side effects. The hematologic and metabolic disturbances associated with cyclosporine treatment, including alterations in blood coagulation and lipid levels, are more relevant to transplant patients than to psoriatics. Blood pressure may increase by up to 13 mm Hg systolic and 5 mm Hg diastolic. Study authors have reported that the risk of developing skin cancer may be elevated with cyclosporine treatment, but increased risk caused by concomitant UVA light treatments may have been a confounding variable. Dermatologic side effects of cyclosporine include hypertrichosis, acne eruptions, keratosis pilaris,

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and sebaceous hyperplasia. Adverse effects occur with the same frequency in all available cyclosporine preparations. T-Cell Modulating Agents Overview. T-cell modulating agents represent the Þrst generation of biological agents available to treat psoriasis. The systemic agents alefacept (Biogen Idec’s Amevive) and efalizumab (Xoma/Genentech’s Raptiva, previously known as Xanelim) received FDA approval in 2003, and efalizumab was recommended for approval in the European Union in June 2004. T-cell modulators are a signiÞcant addition to the arsenal of agents available to treat moderate to severe psoriasis, particularly in patients who have failed other therapies. Mechanism of Action. Cell-adhesion molecules (CAMs) play integral roles in all phases of inßammatory and immune responses, including recruiting inßammatory and immune cells from the circulation, retaining these cells within tissues, and, by regulating downstream signaling events, activating them to become effector cells and causing their subsequent proliferation. Selectins, integrins, and immunoglobulin (Ig) superfamily proteins mediate these activities through well-characterized cell-cell and cell-matrix interactions. Because psoriasis pathophysiology is thought to be largely a T-cell-mediated disease, several drugs in development attempt to interfere with CAM and accessory molecule interactions involved in T-cell activation. Targets include LFA-3, LFA-1 (CD11a), ICAM-1, and ICAM-3. Alefacept. Alefacept (Biogen Idec’s Amevive, formerly known as LFA3TIP) was introduced in the United States in 2003, but its launch in Europe will be delayed for some time because of a European Medicines Agency (EMEA) request for additional study data. Amevive is currently available only as a branded drug, and it is expected to retain market exclusivity for the next decade. Alefacept is a soluble fusion protein composed of the Þrst extracellular receptor-binding domain of the LFA-3 protein linked to the hinge domain of human IgG1. LFA-3 is present on a wide variety of cells, including antigenpresenting cells (APCs). Its ligand, the CD2 molecule, is expressed by T cells, thymocytes, and natural killer (NK) cells. The LFA-3/CD2 interaction facilitates adhesion of T-helper cells to APCs, activating a signal transduction cascade important for T-cell activation and proliferation. It was initially theorized that alefacept would block T-cell/APC interactions by binding to the CD2 molecule on T cells, thereby inhibiting T-cell activation. However, studies have revealed that the in vivo effects of alefacept appear to result from a bridge formed between CD2+ T cells and accessory cells bearing Fc receptors (such as macrophages and NK cells). The LFA-3 domain of alefacept binds to CD2 on T cells, whereas the CH2 domain (an Fc fragment) binds to Fc receptors on accessory cells. The formation of this intercellular bridge is believed to induce lysis of peripheral CD2+ T cells by directing NK-cell-mediated

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cytolysis (Majeau GR, 1994). Clinical evidence indicates that memory-effector T cells, believed to play a critical role in the development of psoriasis, decline in number in patients who are responsive to therapy with alefacept (Lowe N, 2002[a]). A Phase III trial of alefacept compared the efÞcacy of a single 12-week course of alefacept or two consecutive 12-week courses of alefacept with placebo. A total of 553 patients with moderate to severe psoriasis were randomized to receive alefacept (7.5 mg once weekly by 30-second IV bolus) for both courses of therapy (course 1), alefacept for the Þrst course and placebo for the second course (course 2), or placebo for the Þrst course and alefacept for the second course (course 3) (Krueger GG, 2002[b]; Krueger GG, 2003). Among patients who received course 1, 40% achieved 75% or greater improvement in PASI score (an improvement from 14% at week 14, compared with 4% among placebo-treated patients), and 71% achieved 50% or greater improvement in PASI score at any point during the study (Krueger GG, 2002[b]; Lebwohl M, 2002[a]). A “clear” or “almost clear” PGA status occurred more frequently among patients who received course 1 (32%) than course 2 or 3 (23% combined). These results suggest that two consecutive courses of alefacept prior to a disease ßare-up may provide greater beneÞt than re-treatment following a disease ßare-up (compare response rates of this trial with the open-label trial just described [Lowe N, 2002(a)]). Although the effect of continuous courses of alefacept is unknown, these data suggest that this agent may have a role as a maintenance therapy. Alefacept administered by intramuscular (IM) injection is also approved for the treatment of psoriasis. A multicenter and multinational dose-ranging Phase III trial evaluated the effect of IM administration of alefacept in 507 patients with chronic plaque psoriasis (Lebwohl M, 2003[a]). Patients received onceweekly IM injections of placebo or alefacept (10 mg or 15 mg) for 12 weeks; researchers Þrst measured efÞcacy at 14 weeks. Consistent with the Phase III trial of IV alefacept, maximum improvements in PASI score following one course of therapy were observed at week 18. Patients who received a 15 mg dose responded the most: 21% and 42% of these patients achieved 75% and 50% improvements in PASI scores, respectively, compared with 5% and 18%, respectively, among the placebo-treated patients. In the 15 mg group, 74% of patients who experienced a 75% or greater decline in PASI score maintained at least a 50% reduction in PASI during the 12-week follow up period after treatment was discontinued. Of those patients who experienced a 50–74% decline in PASI score, 79% maintained at least a 25% decline over the same follow-up period. Because the IM formulation permits self-administration by patients, it is likely to be favored over the IV formulation, which requires an ofÞce visit. Alefacept has been remarkably well tolerated, and none of the trials showed any evidence of increased cytokine release, capillary leak syndrome, disease rebounding, or rapid ßaring-up of disease following termination of therapy. Adverse events were mild and generally occurred at a similar rate in both the drug-treated and placebo-treated patients, as did patient withdrawal rates. In addition, alefacept was not found to elicit a signiÞcant antidrug antibody response

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in either the IV- or IM-dosing Phase III trials. A total of 22 patients developed anti-alefacept antibodies: 8 of the 553 patients in the IV dosing study and 14 of the 339 in the IM dosing study (Krueger GG, 2002[c]). These antibodies were transient in 14 of 22 cases; titers were generally low and did not increase with increasing exposure to alefacept. Additional studies are required to determine if the difference between the IV- and IM-dosing trial is signiÞcant. Limitations of alefacept include a likely high price, and, as with all psoriasis therapies, the eventual recurrence of psoriatic lesions at some point after discontinuation of treatment. Efalizumab. Efalizumab (Xoma/Genentech’s Raptiva, previously known as Xanelim) launched in the United States in 2003 and received marketing approval in Europe in 2004. It is currently marketed as a branded drug and is expected to retain market exclusivity for the next ten years. Efalizumab is a humanized monoclonal antibody (MAb) that targets CD11a (LFA-1). CD11a (the β chain) associates with CD18 (the α chain) to form the heterodimeric integrin LFA-1, which is expressed on the surfaces of T-helper cells and can interact with ICAM-1, -2, and -3. LFA-1/ICAM interactions are critical for T-cell proliferation and migration, and their disruption is hypothesized to inhibit T-cell function, providing clinical beneÞt in psoriasis. Results from an in vitro study suggest that efalizumab is effective in inhibiting transendothelial migration of T cells and suggest that it may decrease the accumulation of T cells in the skin (Lowe NJ, 2002[b]). A randomized, double-blind, placebo-controlled study of 556 patients with moderate to severe psoriasis explored efÞcacy and improvements in quality of life for patients treated with efalizumab (Gordon KB, 2003). Study participants received a 12-week course of subcutaneous efalizamab or placebo equivalent. The primary study end point was a 75% improvement as measured by the PASI index; secondary end points were improvement on the overall Dermatology Quality of Life Index (DLQI), Itching Visual Analogue Scale (VAS), and Psoriasis Symptom Assessment (PSA) at 12 weeks compared to baseline. An improvement of 75% or better on the PASI index was seen in 27% of the efalizumab-treated group versus 4% in the placebo group. Efalizumab-treated patients also showed greater mean percentages of improvement than placebo-treated patients on all secondary end points. Efalizumab was well tolerated, with adverse events including headache, chills, fever, myalgia, and pain. A Phase III, randomized, placebo-controlled, double-blind study of 597 patients in the United States explored increased doses of efalizumab and longer courses of treatment (Lebwohl M, 2003[b]). Patients received once-weekly subcutaneous (SC) injections of placebo or efalizumab (0.7 mg/kg for the Þrst week followed by 1 mg/kg or 2 mg/kg of efalizumab for the remaining 11 weeks). The primary end point was a 75% or greater improvement in PASI score, which was measured at various time points in a 12- or 24-week course of treatment and during a 12-week period after discontinuing treatment. SigniÞcant improvements in PASI were observed in both treatment groups relative to placebo after

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two to four doses (Lebwohl M, 2003[b]). After 12 weeks of therapy, 28% of patients who received 2 mg/kg of efalizumab and 22% of patients who received 1 mg/kg of efalizumab achieved 75% or greater improvements in PASI, compared with 5% of patients who received placebo. A subset of 434 subjects with varied responses to initial treatment with efalizumab underwent re-randomization and were followed for another 12-week course of treatment. Patients who initially achieved 75% or greater improvements in PASI maintained high rates of PASI improvement during the second 12-week period. Similar results were observed in the CLEAR (Clinical Experience Acquired with Raptiva) trial, an international, Phase III, randomized, double-blind, placebocontrolled study involving 793 patients (Sterry W, 2004). Patients with moderate to severe chronic plaque psoriasis received subcutaneous injections of 1mg/kg efalizumab or placebo once weekly for 12 weeks. The primary end point of the study was the percentage of patients achieving a PASI 75 improvement. At week 12 of the study, 31% of patients treated with efalizumab and 4% of patients treated with placebo had achieved a PASI 75 improvement. The mean percentage of PASI improvement in the efalizumab group was 48%, compared with an average 9% improvement in the placebo group. Adverse events included headache and inßuenza-like illness. No severe adverse events were reported. The drug generally has been well tolerated, and clinical trials have revealed no signiÞcant safety concerns. The most common side effects were mild headache and low-grade fever. Acute adverse events (AEs), occurring within two days of efalizumab injection, happened more frequently than in the placebo-only group with the Þrst two doses, and serious AEs were rare (2.4% among efalizumabtreated patients and 1% among placebo-treated patients). However, a recent hematologic analysis revealed that efalizumab-treated patients developed elevated lymphocyte counts when compared with placebo-treated patients; additional studies are required to determine the signiÞcance of this observation (Koo JY, 2002; Gordon KB, 2003). In an FDA brieÞng document on Raptiva released on September 9, 2003, concern was aired that some patients treated with efalizumab experience serious disease relapses, or “rebound,” upon withdrawal of the drug. Rebound is deÞned as reaching 125% of baseline PASI score within 12 weeks of discontinuation. In the clinical trials submitted to the FDA for review, 13.8% of patients treated with efalizumab experienced rebound ßares, compared with 11.1% of placebo. Some of these ßares may reßect a short washout period during clinical trials. TNF-α Inhibitors Overview. The central role of inßammation and TH 1 cytokines in the development of psoriasis is underscored by the emergence of agents targeting tumor necrosis factor alpha (TNF-α). Amgen/Wyeth’s etanercept (Enbrel) is the only TNF-α inhibitor currently approved for the treatment of psoriasis, though other agents targeting the same mechanism are currently in development (see “Emerging Therapies”).

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Mechanism of Action. TNF-α is a primary mediator of inßammation. In normal immune responses, TNF-α is produced in response to microbial infection and tissue injury. Increased expression of TNF-α provokes the recruitment of leukocytes from the circulation into tissue and increased production of chemokines and other proinßammatory cytokines. In patients with psoriasis, higher levels of TNF-α are observed in psoriatic lesions than in clinically normal skin. Levels of TNF-α produced by peripheral blood mononuclear cells in patients with active psoriasis correlate with disease severity, and elevated levels of TNF-α in psoriatic skin blister ßuids are signiÞcantly correlated with higher PASI scores. TNF-α inhibitors bind to both soluble and membrane-bound forms of TNF-α and inhibit their reaction with cell surface TNF-α receptors, preventing TNF-α from exerting effects on immune cells and keratinocytes. Etanercept. Amgen/Wyeth’s etanercept (Enbrel) is marketed for the treatment of RA and PsA in the United States and Europe and is preregistered for RA in Japan. Etanercept is marketed outside North America by Wyeth. A portion of global sales of etanercept must be paid as royalties to Genentech and Serono International because of their intellectual property rights to TNF-related technologies. Etanercept received FDA approval for the treatment of moderate to severe chronic plaque psoriasis in April 2004, and in August 2004 it received a recommendation for approval in Europe for the treatment of moderate to severe psoriasis in patients who have failed to respond to other therapies. Etanercept is currently marketed as a branded drug and is expected to retain market exclusivity during the next ten years. Etanercept is a soluble TNF-α receptor fusion protein consisting of part of the soluble p75 TNF-α receptor fused with the Fc fragment of human IgG1 . The TNF-α receptor component of etanercept binds both soluble and membranebound TNF-α with higher afÞnity than does the natural TNF-α receptor. A randomized, double-blind Phase III study of 672 patients examined the efÞcacy and safety of etanercept over a 24-week study period (Leonardi CL, 2003). Patients received placebo, low-dose etanercept (25 mg once weekly), mediumdose etanercept (25 mg twice weekly), or high-dose etanercept (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary endpoint in the study was the percentage of patients achieving PASI 75. The mean improvement in PASI score and patient quality of life as assessed by the Dermatology Life Quality Index (DLQI) were also assessed. In the three treatment groups, 14% of patients treated with low-dose etanercept, 34% of patients treated with mediumdose, and 49% of patients treated with high-dose met the primary endpoint of a 75% or greater improvement in PASI scores, compared with 4% of patients in the placebo group. The mean improvement in PASI scores were 40.9 ± 2.4, 52.6 ± 2.4, and 64.2 ± 2.4, for the low-dose, medium-dose, and high-dose treatment groups, respectively, compared to an average improvement of 14.0 ± 2.6 with placebo. Etanercept was well tolerated in this study, with the most common adverse events being injection site reaction, headache, and upper-respiratory

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infection. Activation of latent tuberculosis infection is a concern with the TNF-α inhibitors inßiximab and adalimumab, but no cases of tuberculosis or opportunistic infections were reported during the study, and all laboratory abnormalities were of mild to moderate intensity. Because etanercept was approved for the treatment of psoriatic arthritis (PsA) in the United States and Europe in 2002, patients with both PsA and psoriasis were treated with etanercept prior to FDA approval for psoriasis. Also, many patients received off-label prescriptions for psoriasis even when they had no joint involvement, particularly in the United States. Therefore, etanercept was rapidly adopted by many physicians prior to regulatory approval for psoriasis. Etanercept has been prescribed for multiple indications, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, for Þve years, and longterm safety data indicate that it is well tolerated by patients who require ongoing treatment for chronic conditions. Patients treated with etanercept do not develop neutralizing antibodies to the molecule, and the therapeutic effect is therefore not expected to wane with chronic administration. As a biological agent, etanercept is among the most expensive agents available for the treatment of psoriasis. While Þve-year data have provided some reassurance regarding long-term, chronic administration of etanercept, many physicians remain concerned about the potential for malignancies arising in patients whose immune systems have been suppressed for extended periods. Infections will also remain a concern for any agent that causes long-term immunosuppression. Phototherapy and Photosensitizers Overview. Ultraviolet (UV) light phototherapy is used to treat localized lesions that do not respond to topical treatment and to treat widespread moderate to severe psoriasis. UV light is often combined with topical or systemic agents to reduce the dose of phototherapy. UV light exerts anti-inßammatory and immunosuppressive actions and induces apoptosis in proliferating cells. Two types of UV light are used: UVA and UVB. UVB is approximately 1,000 times more powerful than UVA, does not require the use of adjunct compounds, and is supplanting UVA as the Þrst choice of phototherapy. While UVB does not require the use of a photosensitizer, it is often used in combination with systemic and topical agents, including methotrexate, acitretin, calcipotriene, and coal tar. Mechanisms of Action. UVB and UVA phototherapies have similar mechanisms of action. However, because UVB radiation is more superÞcially absorbed, its effects are restricted to superÞcial keratinocytes and Langerhans’ cells. UVA radiation, which penetrates more deeply, affects superÞcial keratinocytes, Langerhans’ cells, dermal Þbroblasts, and dendritic and endothelial cells. Both phototherapies induce the expression of naturally anti-inßammatory mediators (e.g., IL-10 and the neuropeptide alpha-melanocyte-stimulating hormone [α-MSH]) and inhibit the expression of the TH 1 cytokine, IFN-γ . Both UVB and UVA radiation decrease the expression of receptors for the inßammatory cytokines IL-1 and TNF-α and of the intercellular adhesion molecule (ICAM)-1 on epidermal

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keratinocytes—the target for lymphocyte functional antigen (LFA)-expressing T cells in psoriasis. Recent data suggest that narrow-band UVB therapy may also induce T-cell apoptosis. UVB Radiation. UVB radiation may be used as monotherapy or in combination with anthralin or coal tar (the Goekerman regimen), both anthralin and coal tar (the Ingram regimen), retinoids, or other agents. Most research indicates that, unlike UVA, UVB radiation does not increase the risk of skin cancer, including melanoma. When used alone, both broadband (290–320 nanometer [nm]) and narrow-band (311–312 nm) UVB phototherapies have been shown to be effective for psoriasis. However, narrow-band UVB phototherapy has been shown to be superior to broadband for clearing psoriatic plaques, and it causes fewer side effects. Patients usually require 20–40 UVB radiation treatments at an average of three per week to obtain a full response (usually for three or more weeks). The initial treatment is followed by maintenance therapy twice weekly for at least one month and by once-weekly therapy for four months to prevent recurrence. The cumulative dose of UVB can be reduced by combining UVB therapy with systemic agents. The combination of UVB with methotrexate, for example, appears to be synergistic (Paul BS, 1982). One of the most clinically effective applications of UVB in psoriasis involves a combination of UVB and an oral retinoid (reUVB). In a randomized, doubleblind comparison of UVB therapy alone and UVB therapy with acitretin, 34 patients were assigned to two treatment groups (Lowe NJ, 1991). One group received UVB and placebo; the other received UVB and 50 mg per day acitretin. A third group of 16 severity-matched patients was treated in parallel with 50 mg per day of acitretin. Each group was treated for 12 weeks and evaluated every 4 weeks. The psoriasis grade scores used in the study decreased most significantly in the combination-treated group, an average of a 75% decline, versus a 35% decline in the UVB-only group and a 42% decline in the acitretin-only group. Although UVB phototherapy is believed to be largely free of cancer risk (except for applying it to the male genitalia), one case of melanoma in human tissue caused by UVB radiation has been reported. However, many physicians believe that UVB light may in fact be protective because the low doses used thicken but do not burn the skin. The primary limitation of phototherapy treatment is the requirement for multiple weekly visits to a treatment center, a requirement many patients are not able to reconcile with work schedules or family life. UVA Radiation with a Photosensitizer (PUVA). UVA treatment does require the concomitant use of a photosensitizing agent. UV lamps used for UVA phototherapy typically emit light at either 352 nm or 370 nm. The most common form of UVA phototherapy includes pretreatment with the photosensitizing agent psoralen and is known by the acronym PUVA. The most widely used psoralen formulation is 8-methoxypsoralen (8-MOP/methoxsalen/xanthotoxin; ICN Pharmaceuticals’ Oxsoralen), which is a naturally occurring plant product. Newer

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psoralen formulations with fewer side effects include 4, 5, 8-trimethoxypsoralen (ICN Pharmaceuticals’ Trisoralen) and 5-MOP (bergapten). Several mechanisms of action may underlie the effectiveness of PUVA therapy in psoriasis. Psoralens intercalate between DNA base pairs and, upon activation by photons in the UV spectrum, react with the pyrimidine bases to crosslink the DNA strands and inhibit DNA replication. This mechanism is thought to explain at least some of PUVA’s effectiveness in reducing the epidermal hyperproliferation of psoriasis. Psoralens also affect RNA and proteins—either directly or through free-radical generation—and this activity may in part explain their therapeutic effects in psoriasis and other dermatologic disorders. PUVA therapy decreases the concentration of several cell types in the skin, including CD4+ and CD8+ T cells as well as cutaneous antigen-presenting Langerhans’ cells, and decreases the production and release of IL-1β, IL-6, IL-8, and TNF-α. Psoralen formulations are administered before treatment with UVA light therapy as an oral formulation (two hours prior to light treatment), topical cream formulation, or placed in a bath preparation. When large areas of skin are treated, systemic levels of topical psoralens (as a 0.15% emulsion or solution) approach those present after oral administration. Psoralens applied by bath are readily absorbed into the skin yet result in low systemic concentrations. ICN Pharmaceuticals’ Trisoralen is frequently used in Scandinavia for bath PUVA. Delayed phototoxic erythema (skin reddening) occurs to varying degrees after PUVA therapy. Because a strong dose-response relationship exists between erythema and the dosage of psoralen and UVA energy, it is a major criterion for adjusting the dosage for future treatments. Treatments require eight hours and are administered no more than two to three times per week. Patients usually require a total of 30 PUVA treatments. Sunburn, blistering, and itching are the obvious potential side effects of PUVA, but they can be avoided with careful administration. Oral 8-MOP causes malaise and nausea in 20–30% of treated patients and vomiting in 10%. Overdoses of PUVA can cause swelling, intense pruritus, and a stinging sensation. PUVA therapy can also damage skin and accelerate aging of the skin. Psoralens can induce mutations in DNA, and PUVA signiÞcantly increases the risk for squamouscell carcinoma and slightly increases the risk for basal-cell skin malignancies (both of which are nearly always curable). A higher risk is associated with receiving more than 200 PUVA treatments, a history of skin cancer, radiation therapy or immunosuppressant drug therapy, and light skin tone. The risk of melanoma is also elevated in patients treated with PUVA, and it is cited as the main reason why physicians are decreasing use of PUVA and increasing use of UVB. Oral retinoids are sometimes used in conjunction with PUVA phototherapy to signiÞcantly lower the doses of radiation and of the oral retinoid. The mechanism of synergy between retinoids and UV radiation is not understood, but relatively low does of acitretin (10–25 mg daily, compared to 50 mg when given as monotherapy) accelerate the response to UV monotherapy, reducing

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the number and duration of sessions need to achieve clearance. A randomized, double-blind study of 60 patients compared PUVA plus placebo with PUVA plus acitretin (Tanew A, 1991). Marked or complete clearing occurred in 80% of the patients treated with PUVA plus placebo and in 96% of the patients treated with PUVA plus acitretin. In this study and a similar comparison, the addition of retinoids reduced the dose of PUVA needed for clearance by more than 40% (Tanew A, 1991; Saurat JH, 1988). Other agents that are combined with UVA phototherapy include glucocorticoids, anthralin, calcipotriene, and coal tar. PUVA cannot, however, be combined with cyclosporine due to increased risk of squamous cell cancers. The combination of methotrexate and PUVA may also increase the risk of squamous cell carcinomas, but it is an effective combination therapy in patients whose psoriasis is refractory to other treatments. Coal Tar. Coal tar is obtained by heating crude bituminous coal in the absence of oxygen. Although coal tar preparations have been used for the treatment of psoriasis for hundreds of years, they contain many organic products and it is not known which particular compound(s) are active or how they work in treating psoriasis. Coal tar is anti-inßammatory, decreases epidermal cell mitosis/development of scales, and reduces the production of sebum by sebaceous glands. Various preparations are available in different vehicles. OTC and prescription strengths are used clinically as monotherapy or in combination regimens. They are particularly useful in treating mild to moderate psoriasis when itching is severe and in guttate psoriasis. Coal tar is a photosensitizer and is sometimes used in conjunction with UV light monotherapy (without psoralen). It is also used with other topical therapies (usually corticosteroids). Coal tar is not recommended for pustular or erythrodermic pustular psoriasis because it may cause irritation, inducing Koebner’s phenomenon. Potential side effects of this therapy include folliculitis, contact dermatitis, and phototoxicity. Patient acceptance is a major problem because coal tar preparations are often greasy and messy, have an unpleasant odor, and stain clothing. EMERGING THERAPIES Psoriasis has attracted signiÞcant development over the past several years as biological agents, particularly the TNF-α inhibitors, emerge as therapeutic options for patients with severe disease. New immunosuppressants and fumaric acid esters also represent potential treatment options for patients with moderate or even mild disease. However, in recent years development has been discontinued for several drugs that reached Phase II or Phase III trials for this indication, including the therapeutic vaccine PVAC, oprelevkin, and ilodecakin, because of concerns about safety or failure to demonstrate adequate efÞcacy. Table 9 summarizes emerging therapies in late-stage development for psoriasis. The discussion of emerging therapies here is organized according to their mechanism of action.

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TABLE 9. Emerging Therapies in Development for Psoriasis Compound

Development Phase

Marketing Company

TNF-α inhibitors Infliximab United States Europe Japan

III III II

Johnson & Johnson/Centocor/Tanabe Johnson & Johnson/Centocor Tanabe

Adalimumab United States Europe Japan

III PC —

Abbott Laboratories Cambridge Antibody Technology —

Immunosuppressants Topical pimecrolimus United States Europe Japan

— IIa —

— Novartis —

Oral pimecrolimus United States Europe Japan

II II —

Novartis Novartis —

Topical tacrolimus United States Europe Japan

III II PC

Fujisawa Fujisawa Fujisawa

Retinoids Oral tazarotene United States Europe Japan

PR III —

Allergan Allergan —

Fumaric acid esters BG-12 United States Europe Japan

II IIIa —

Biogen-Idec Biogen-Idec —

PPAR-gamma agonists Rosiglitazone United States Europe Japan

III — —

GlaxoSmithKline — —

a European clinical trials conducted in Switzerland.

D = Discontinued; PC = Preclinical (including discovery); PR = Preregistered; R = Registered; S = Suspended.

TNF-α Inhibitors Overview. Tumor necrosis factor-alpha (TNF-α) inhibitors are the most prominent class of drugs in development for the treatment of psoriasis. Within the next Þve years, as many as four TNF-α inhibitors will be competing for a share of the psoriasis market. Two TNF-α inhibitors are in Phase III development

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for the treatment of psoriasis. Inßiximab (Johnson & Johnson/Centocor/Tanabe’s Remicade) and adalimumab (Abbott Laboratories/Cambridge Antibody Technology’s Humira) are approved for other indications, including rheumatoid arthritis and Crohn’s disease. Two TNF-α inhibitors that are not yet approved for any indication are also in development for psoriasis. CDP-870 (from Celltech) is in preclinical development for psoriasis, but will not be discussed in detail here because of the scarcity of clinical data speciÞc to psoriasis. The fourth, etanercept, is approved for the treatment of psoriasis in the United States and Europe. A Þfth TNF-α inhibitor, Serono’s onercept, was in Phase III trials for psoriasis, but development was discontinued when two patients treated with the drug developed sepsis. Mechanism of Action. TNF-α is a primary mediator of inßammation. In normal immune responses, TNF-α is produced in response to microbial infection and tissue injury. Increased expression of TNF-α provokes the recruitment of leukocytes from the circulation into tissue and increased production of chemokines and other proinßammatory cytokines. In patients with psoriasis, higher levels of TNFα are observed in psoriatic lesions than in clinically normal skin. Levels of TNF-α produced by peripheral blood mononuclear cells in patients with active psoriasis correlate with disease severity, and levels of TNF-α in psoriatic skin blister ßuids are signiÞcantly correlated with Psoriasis Area and Severity Index (PASI) scores. TNF-α inhibitors bind to both soluble and membrane-bound forms of TNF-α and inhibit their reaction with cell surface TNF-α receptors, preventing TNF-α from exerting effects on immune cells and keratinocytes. Infliximab. Inßiximab (Centocor/Johnson & Johnson’s Remicade) is a mousehuman chimeric monoclonal antibody (MAb) targeting TNF-α. It has been available in the United States since August 1998 for the treatment of Crohn’s disease and since November 1999 for rheumatoid arthritis (RA). In 2000, ScheringPlough launched inßiximab in Europe for Crohn’s disease and RA. In Japan, where it has been licensed to Tanabe Seiyaku, it is marketed for Crohn’s disease and RA. Inßiximab is currently in Phase III trials for psoriasis in the United States and Europe and in Phase II in Japan. Inßiximab consists of 75% human protein, comprising effector functions (elimination of TNF-α-positive cells and inhibition of upregulation of adhesion molecules), and 25% mouse protein, which contains the TNF-α binding sites. Inßiximab binds both soluble and membrane-bound TNF-α. Human antichimeric antibodies—reportedly as high as 30% (twice the rate of antibody production induced by etanercept)—have been observed, but with no clinically signiÞcant effects. Inßiximab is administered by IV infusion (over a two-hour period, in a physician’s ofÞce) every six to eight weeks. Inßiximab is already used off-label for psoriasis and psoriatic arthritis (PsA). Several small studies of its effectiveness for treating PsA and psoriasis are ongoing. Indeed, retrospective analysis of 31 patients with PsA and skin lesions who were treated with inßiximab at zero, two, and six weeks and every eight weeks

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thereafter revealed that 30 out of 31 patients experienced signiÞcant improvements in both skin lesions and affected joints, and only 1 patient failed to respond to therapy (Fleishmann RM, 2002). A small, randomized, controlled trial involving 33 patients with moderate to severe plaque psoriasis suggests that inßiximab may be efÞcacious for psoriasis as a monotherapy. Patients received placebo or inßiximab (5 or 10 mg/kg) at weeks 0, 2, and 6 and were evaluated at week 10. Inßiximab-treated patients achieved a median of 90% improvement in PASI score, compared with 11% among the placebo-treated group. All responders in the 5 mg/kg group and 64% of the 10 mg/kg group were rated either excellent (75–99% clearing with marked improvement) or clear on the Physician’s Global Assessment (PGA). In addition, markers of keratinocyte activation and inßammation declined relative to week 0 (Gottlieb AB, 2002[c]). Inßiximab was well tolerated; three patients, one from each treatment group, withdrew from the trial and were considered to be nonresponders. In an open-label follow-up study of these patients, the responders (19/22 patients) remained relapse-free for as long as ten months; however, one of two placebo-treated “responders” also remained relapse-free for nine months (Gottlieb AB, 2002[d]). Data from a larger Phase II study were presented at the annual meeting of the American Academy of Dermatology in February 2004 and at the annual meeting of the Society of Investigative Dermatology in April 2004 (Gottlieb AB, 2003; Gottlieb AB, 2004). In this randomized, placebo-controlled trial, 249 patients with moderate to severe psoriasis were treated with placebo or with infusions of 3 mg/kg or 5 mg/kg of inßiximab at weeks 0, 2, and 6. Patients were evaluated at week 10, and the primary end point of the study was a 75% improvement in PASI score (PASI 75). At week 10, 72% of patients receiving the lower dose of inßiximab and 88% of patients receiving the higher dose achieved PASI 75, compared with 6% of patients receiving placebo. Patients were followed through week 26 of the study to evaluate adverse events. Infusion reactions, a commonly noted adverse event, were observed in 4.1–10.7% of patients at various points in the study, versus 0–2% for placebo. The most common adverse events included upper respiratory infections, headaches, pruritus, sinusitis, pain, and arthralgia (Gottlieb AB, 2003; Gottlieb AB, 2004). Four potentially related serious adverse events occurred through week 40 of the study. In the lower-dose group, one patient developed squamous cell carcinoma and one developed cholecystitis and cholelithiasis. In the higher-dose group, one patient developed diverticulitis and one developed sepsis and pyelonephritis. These adverse events raised concerns about infections and malignancies arising from inßiximab-induced immunosuppression. Blood was drawn from participants through week 46 of the study to assess the development of antibodies against inßiximab as well as antinuclear antibodies (Gottlieb AB, 2004). The overall incidence of antibodies was 23.3%, comparable to similar patient populations in other clinical trials of inßiximab. Of participants who received inßiximab, 24% were newly positive for antinuclear antibodies during the study, with 13.5% positive at the Þnal visit.

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Overall, the Phase II data presented to date indicate that inßiximab effectively clears plaques in most patients, but the data fail to lay to rest concerns about inßiximab’s safety. Waning efÞcacy over time also remains a concern due to the development of anti-inßiximab antibodies. The package insert for inßiximab includes a boxed warning about tuberculosis and other opportunistic infections. The warning also states that patients should be evaluated for latent tuberculosis infection prior to treatment with inßiximab; latent tuberculosis infections have become active in a small number of patients treated with inßiximab. In a presentation at the Society of Investigative Dermatology in April 2004, the speaker noted that patients develop neutralizing antibodies against the murine sequences of inßiximab unless they receive a concomitant course of methotrexate when treatment with inßiximab is initiated (Gottlieb AB, 2004). Patients can be weaned from methotrexate at a later date. Inßiximab is delivered by a four-hour intravenous infusion requiring ofÞce space and staff that are not commonly found in dermatology practices. It is not clear from clinical trial data presented to date that inßiximab offers signiÞcant advantages in efÞcacy over the TNF-α inhibitor adalimumab (Abbott/Cambridge Antibody Technology’s Humira). Furthermore, dosage creep and waning efÞcacy are signiÞcant concerns for long-term administration. Adalimumab. The fully human monoclonal anti-TNF-α antibody adalimumab (D2E7, Humira) was developed by Abbott (formerly Knoll) in collaboration with Cambridge Antibody Technology. As a human monoclonal antibody, adalimumab is unique among monoclonal antibodies in this class. Adalimumab is currently marketed in the United States and in Europe for RA. Adalimumab is in Phase III clinical trials for psoriasis in the United States and in the discovery phase for psoriasis in Europe. Development of adalimumab for this indication has not commenced in Japan. Adalimumab’s mode of action is unique in the class of TNF-α inhibitors. While the monoclonal antibody comprises a TNF-α-binding site like other members of its class, its effector region promotes the lysis of TNF-expressing cells in the presence of complement. Adalimumab has a longer half-life than etanercept and therefore can be administered less frequently. Because it is derived from human sequences, it is likely to be minimally immunogenic. Promising preliminary results of the Phase II U.S. trial were presented at the annual meeting of the American Academy of Dermatology in February 2004 and at the Society of Investigative Dermatology Meeting in April 2004 (Gordon KB, 2004; Gottlieb AB, 2004; Peterson L, 2004). A total of 142 patients with moderate to severe chronic plaque psoriasis and no history of treatment with TNF-α antagonists were enrolled for a 12-week, double-blind study comparing two dosage regimens of adalimumab with placebo. In one treatment group, patients received 80 mg adalimumab at week 1, followed by 40 mg every other week from week 1 onward. The second group received 80 mg at weeks 0 and 1, and 40 mg weekly beginning at week 2. Placebo was administered weekly

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619

to patients in the placebo group. The primary end point of the study was the percentage of patients achieving PASI 75 at week 12 of the study. In the weekly treatment group, 80% of patients achieved PASI 75, compared with 53% of patients treated every other week and 4% of patients receiving placebo. The response to adalimumab was rapid, with a signiÞcantly greater mean percentage change in PASI score becoming evident as early as one week after the initial dose. According to adalimumab’s product label, the most frequently observed side effects of adalimumab in placebo-controlled clinical trials were mild injection-site reaction, hypertension, headache, pruritus, and rashes. The incidence of serious infections was 0.04 per patient-year in adalimumab-treated patients compared with 0.02 per patient-year with placebo; serious infections included pneumonia, septic arthritis, and erysipelas. The product label for adalimumab acknowledges that malignancies have been observed in recipients of TNF inhibitors, including adalimumab. Among 2,468 patients treated with adalimumab for a median of 24 months during clinical studies for RA, 0.4% of patients developed lymphomas. This occurrence is higher than that of the general population, but the rate of lymphoma may be higher in patients with highly active RA. Adalimumab’s label also includes a boxed warning cautioning physicians and patients about the risk of tuberculosis infection. The warning recommends that patients should be tested—and possibly treated—for latent tuberculosis infection prior to receiving adalimumab. Immunosuppressants Overview. Immunosuppressants are among the most effective agents for treating psoriasis, but those that are currently available are linked to renal toxicity and other serious adverse effects. Several new immunosuppressants that have demonstrated efÞcacy in other indications, such as renal and liver transplantation and graft-versus-host disease, are in development for psoriasis. These include tacrolimus (Fujisawa’s Prograf) and ISA-247 (Isotechnika/Roche). Isotechnika has completed Phase II trials of ISA-247 in Canada, and the drug is in Phase II trials in the United States for transplant rejection. Safety data for this agent derived from clinical trials of renal transplantation patients appear promising, but it will not be discussed here because of the scarcity of available data speciÞc to the psoriasis indication. Novartis’s pimecrolimus is in clinical trials for the psoriasis indication in topical formulation, but no new development has been announced for the indication since 1999. Pimecrolimus also reached late-phase clinical trials in an oral formulation, but Novartis announced in November 2005 that clinical trials of the drug had been suspended. Mechanism of Action. Immunosuppressants such as cyclosporine, tacrolimus, and pimecrolimus bind to cytoplasmic receptors, which are isomerases known as immunophilins. The drug/immunophilin complex exerts its primary immunosuppressive activity by binding to and inhibiting calcineurin, a protein that

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plays an essential role in calcium-dependent signal transduction in T cells. This signal transduction pathway activates cytokine gene expression, among others. Decreased cytokine production concomitantly decreases T-cell (TH 1 and TH 2) activation, including IL-2 production, growth, migration, and cytotoxic T-cell degranulation. Reduced cytokine secretion also affects the functions of keratinocytes, antigen-presenting cells, and neutrophils. Calcineurin is involved in T-cell-derived IL-2, IL-4, GM-CSF, TNF-α, and IFN-γ production. Therapy with cyclosporine or tacrolimus reduces the synthesis of all of these cytokines. See “Pathophysiology” for more information on the role of cytokines in psoriasis. Formulation. Topical and oral immunosuppressants are in development for psoriasis. Existing immunosuppressants, most notably cyclosporine, have not successfully been developed as topical agents. Cyclosporine is a high molecular weight compound that exhibits poor skin penetration, and it is therefore unsuitable for treating psoriatic plaques. Pimecrolimus is currently marketed in topical form only. Tacrolimus is marketed in both topical and oral forms for indications other than psoriasis. Pimecrolimus. The topical formulation of Novartis’ pimecrolimus (Elidel) is currently indicated for atopic dermatitis in the United States and Europe and is also in Phase II trials in Europe for psoriasis. The European trials have progressed slowly; no new development has been reported since 1999. Like other ascomycin derivatives, pimecrolimus is an immunophilin ligand. Its cognate receptor is the cytosolic immunophilin macrophilin-12. The pimecrolimus/macrophilin-12 complex prevents the synthesis of inßammatory cytokines by inhibiting calcineurin, much like other ascomycin derivatives (Gupta AK, 2003). In a ten-patient, double-blind trial reported in 1998, both 0.3% and 1% topical pimecrolimus, used under occlusion (e.g., occlusive tape), were effective in treating psoriasis. After two weeks of therapy, patients treated with 0.3% and 1% pimecrolimus exhibited 60% and 80% reductions, respectively, in microplaque score, compared with 18% for patients treated with the vehicle alone (i.e., placebo). Drug-treated patients exhibited a greater than 90% reduction in microplaque score—results comparable to those obtained with 0.05% clobetasol propionate, a high-potency corticosteroid. A galenic formulation of pimecrolimus has also been developed, and preliminary results suggest that it is effective at a 1% concentration for psoriasis. These results suggest that topical pimecrolimus is as effective as topical corticosteroids (Mrowietz U, 1998). Tacrolimus. Another immunosuppressant, tacrolimus (Fujisawa’s Prograf) (Figure 7), is indicated for atopic dermatitis. The topical formulation is currently in Phase III clinical trials in the United States and in Phase II trials in Europe. The oral formulation, however, is not presently in active development for psoriasis. A pilot study of 70 psoriasis patients comparing topical tacrolimus ointment with calcipotriene and with placebo found no statistically signiÞcant difference between the efÞcacy of tacrolimus and placebo ointment (Zonneveld IM, 1998).

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HO

H3CO

CH3 H3C HO

O

O N O O

O

H3C

HO H3C

H3C O

OCH3 OCH3 FIGURE 7. Structure of tacrolimus.

However, the authors of that study noted that the high molecular weight of tacrolimus might prevent penetration into psoriatic skin. This theory is bolstered by evidence that systemic tacrolimus is effective for treating psoriasis (European FK506 Multicentre Psoriasis Study Group, 1996). Therefore, additional studies were undertaken exploring the potential of tacrolimus for treating the face and intertriginous areas (e.g., the groin and other skin folds) and combining tacrolimus with salicylic acid to promote penetration of psoriatic skin. An open-label clinical trial of 21 patients with psoriasis examined the efÞcacy of tacrolimus for treatment of the face and intertriginous areas, as assessed by the investigator’s evaluation of signs and symptoms of disease (Freeman AK, 2003). Assessments of adverse events were also made throughout the study to evaluate the safety of tacrolimus ointment. Few adverse events were noted, and no signs of skin atrophy, telangiectasia (an abnormal dilatation of capillary vessels and arterioles), or striae (stripes or lines in the skin)—complications associated with topical corticosteroids—were noted during the study. Most patients showed signiÞcant improvement compared with baseline. The authors acknowledged the limitations of the study design and noted that more extensive randomized, controlled trials were needed to conÞrm the observations. A right-left comparison study of 30 subjects compared 6% salicylic acid gel plus vehicle with 6% salicylic gel plus 0.1% tacrolimus ointment (Carroll CM, 2004). The primary outcome measure was the difference in change from baseline to end of treatment in a sum score of erythema, scale, and thickness scores. Lesions treated with tacrolimus on one side of the body were compared with lesions treated with placebo on the other side of the body. Twenty-four subjects completed the eight-week study. Adverse events were limited and included a stinging sensation on the side of the body treated with tacrolimus reported by four subjects. Greater improvement was observed with tacrolimus plus salicylic acid in the target plaque at weeks 1, 2, and 8 of treatment, but not at week 4.

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While topical tacrolimus causes relatively few adverse effects, it is more expensive than many topical agents, particularly generic topical corticosteroids. Topical corticosteroids are currently the most prescribed agents for psoriasis of the face and intertriginous areas, the most likely sites of application for topical tacrolimus. Nevertheless, topical tacrolimus is likely to be viewed as safer for treating sensitive and/or visible areas than topical corticosteroids, particularly given that it does not appear to cause the same side effects as topical steroids, such as atrophy, striae, and telangiectasia. Tacrolimus offers an improved treatment option for patients with facial lesions, who currently rely on topical corticosteroids. Topical immunosuppressants appear to promote clearance with fewer side effects than corticosteroids and are likely to be used for this purpose. Relatively few patients develop facial plaques, however, so only a small number of patients are likely to beneÞt. Retinoids Overview. Oral retinoids have been a mainstay of treatment for psoriasis for the past two decades. New retinoids, however, face substantial hurdles to approval due to increased concerns about fetal exposure to these teratogenic agents. Retinoids with improved selectivity for particular receptor classes and with shorter retention times in the body are being developed for psoriasis. At least two oral retinoids, tazarotene (Allergan’s Tazoral) and bexarotene (Ligand’s Targretin), are in development for this indication. Because of the limited availability of clinical trial data speciÞc to psoriasis, bexarotene will not be discussed in detail here. Mechanism of Action. Retinoids bind to speciÞc receptors called retinoic acid receptors (RARs) in the cell nucleus, affecting the transcription of genes involved in keratinocyte differentiation, cell proliferation, and inßammation. Clinical evidence and in vitro studies demonstrate that retinoids downregulate transcription of proinßammatory cytokines, halt proliferation of cultured cells, and alter expression of indicators of keratinocyte differentiation. Oral Tazarotene. Allergan recently submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for oral tazarotene (Tazoral). Phase III trials of oral tazarotene are also under way in Europe. Tazarotene is a third-generation retinoid that selectively binds to retinoic acid receptors (RARs)-beta and -gamma for the treatment of moderate to severe psoriasis. Binding to its cognate RARs downregulates transcription of proinßammatory cytokines and suppresses keratinocyte proliferation. Because it activates neither RAR-α nor retinoid X receptors (RXRs), oral tazarotene is not associated with some of the side effects that occur with other oral retinoids, such as hypertriglyceridemia, hypothyroidism, and hepatoxicity (Duvic M, 2004). The efÞcacy and safety of oral tazarotene were examined in two multicenter, double-blind, randomized, placebo-controlled Phase III studies (Koo JY, 2004). In these studies, a total of 706 patients with moderate to severe psoriasis were enrolled and evaluated (Kang S, 2004). Greater than 50% global improvement and changes in Overall Lesional Assessment (OLA) scores were used as end points to

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measure the effects of tazarotene. After a three-month period, 54% of the patients treated with oral tazarotene achieved at least 50% global improvement (compared with 15% of the patients treated with placebo). Of those who experienced at least 50% global improvement, 80% maintained their condition for at least one additional three-month period without treatment. Among tazarotene-treated patients, 28% experienced a two-grade improvement in OLA (on a six-grade scale), compared with 6% of the patients treated with placebo; 81% of these tazarotene-treated patients were able to maintain an improved OLA score for at least three months post-treatment. Results also showed a measurable reduction in lesional elevation, scaling, and erythema on all parts of the body but especially on difÞcult-to-treat lesions on the knees and elbows (Koo JY, 2004; Kang S, 2004). The safety of oral tazarotene has been examined in Þve studies involving a total of 1,100 patients. The combined results of the Þve studies were presented at the annual meeting of the American Academy of Dermatology in February 2004 (Walker PS, 2004). Adverse events that occurred at higher frequency among tazarotene-treated patients than among placebo-treated patients were dry lips (66% versus 17%), dry skin (24% versus 15%), headache (19% versus 12%), and several other adverse events that occurred at lower frequency. None was serious in nature. Other adverse effects typically observed among patients treated with oral retinoids occurred at levels comparable to placebo. These included elevated serum triglyceride and cholesterol levels, abnormal liver function tests, eye dryness, shedding of skin (desquamation), and alopecia. Oral tazarotene has the potential to replace the current oral retinoid therapy, acitretin (Roche’s Soriatane). Because pivotal clinical trials for tazarotene and acitretin used different end points, however, it is difÞcult to compare their efÞcacy. Tazarotene has a more selective mechanism of action and causes less elevated lipid levels and liver toxicity than acitretin. Furthermore, investigation of the pharmacokinetic proÞle of tazarotene demonstrated that the drug has a half-life of 7 to 12 hours and is completely eliminated within 11 days. In contrast, acitretin elimination can take up to four weeks, and consumption of even small amounts of alcohol can extend retention considerably (Yu D, 2004). Therefore, women of reproductive age must avoid pregnancy for three years after discontinuing therapy with acitretin. No such long-term restriction is necessary for tazarotene, but fetal exposure must nevertheless be avoided while taking the drug and for one month after discontinuing therapy. The launch of oral tazarotene suffered a substantial setback in July 2004 when the FDA panel evaluating the drug voted against approving oral tazarotene for the treatment of moderate to severe psoriasis. In a joint meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on July 12, 2004, the joint panel focused heavily on the program proposed by Allergan to prevent fetal exposure to tazarotene. However, the panel also mentioned concerns about efÞcacy, particularly among patients with very severe disease, and several members felt that more data were needed (particularly longer studies) to assess the drug’s efÞcacy. Furthermore,

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several members of the panel expressed limited conÞdence regarding the instruments used to assess efÞcacy. In a conference call broadcast on July 12, 2004, Allergan indicated that it will continue to pursue approval for this indication and will work with the FDA to resolve the issues identiÞed by the committee. Fumaric Acid Esters Overview. Fumaric acid esters have been prescribed in Germany for several decades, but they have only recently attracted attention in other markets. However, fumaric acid esters are not currently approved for the treatment of psoriasis in markets outside of Germany. Agents currently available in Germany are mixtures of dimethylfumarate and monoethylfumarate salts. A single agent belonging to this class, Biogen-Idec/Fumapharm’s BG-12, is in Phase II clinical trials in the United States and Phase III clinical trials in Europe. Mechanism of Action. Fumaric acid esters, and dimethylfumarate in particular, appear to downregulate TH 1 cytokines and modulate cytokine expression toward a TH 2 proÞle (Loewe R, 2002). Dimethylfumarate and its hydrolysis product methylhydrogen fumarate both appear to inhibit keratinocyte proliferation and monocyte differentiation into dendritic cells. Dimethylfumarate also induces apoptosis in activated human T cells (Treumer F, 2003). BG-12. Biogen Idec acquired the rights to develop and market a secondgeneration fumaric acid derivative from Fumapharm AG in October 2003. Phase II trials have been completed for this indication and were presented at the 2004 annual meeting of the European Academy of Dermatology and Venereology (Langner A, 2004). A double-blind, placebo-controlled, dose-Þnding study of 144 patients measured improvements in PASI score, the Physician’s Clinical Global Impression, Patient’s Global Assessment, and quality of life (using the Skindex-29 instrument) over a 12-week period. Patients received placebo or 120 mg, 360 mg, or 720 mg of fumaric acid ester. At week 12, the median percentage reductions from baseline PASI score were 6% for the placebo group and 31%, 52%, and 71% for the 120 mg, 360 mg, and 720 mg doses, respectively. PASI 75 reductions were observed in 11%, 8%, 25%, and 42% of the placebo, 120 mg, 360 mg, and 720 mg groups, respectively. PASI 50 reductions were observed in 14%, 39%, 50%, and 64% of the placebo, 120 mg, 360 mg, and 720 mg groups. The response to BG-12 was rapid, with evidence of clearing appearing two weeks after beginning therapy. Gastrointestinal side effects, the most commonly noted adverse effect in patients receiving mixed fumaric acid esters, were observed in less than 5% of patients in each group. Adverse events included ßushing, minor elevations of liver enzymes, and respiratory infections (Langner A, 2004). PPAR Agonists Overview. Peroxisome proliferator-activated receptor (PPAR) agonists are wellestablished and widely marketed drugs for diabetes, but their potential value

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FIGURE 8. Structure of rosiglitazone.

for treating psoriasis has only recently been noted. The initial motivation for exploring the utility of PPAR agonists in the treatment of psoriasis was the serendipitous observation that patients affected with both diabetes and psoriasis noticed improvements in their skin condition upon initiating treatment with PPAR agonists for diabetes. While preclinical studies exist exploring the effect of various PPAR agonists on proliferating keratinocytes and on inßammation, only rosiglitazone (GlaxoSmithKline’s Avandia) is known to be in clinical development for psoriasis. Mechanism of Action. PPARs are members of the nuclear hormone receptor superfamily. The family comprises ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR subfamily of ligand-activated transcription factors includes three isotypes (PPAR-α, PPAR-β/γ , and PPAR-γ ), which are all expressed in keratinocytes. PPAR-β/γ is expressed at the highest levels of the three subtypes in human epidermis, though PPAR-α and PPAR-γ increase upon differentiation. In psoriatic epidermis, all three subtypes show altered patterns of expression compared with normal epidermis. Rosiglitazone. Rosiglitazone (GlaxoSmithKline’s Avandia) (Figure 8), a PPAR-γ agonist currently approved for the treatment of type II diabetes, is in Phase III clinical trials for psoriasis in the United States. Preclinical data indicate that rosiglitazone inhibits keratinocyte proliferation and motility in cell culture (Bhagavathula N, 2004). Rosiglitazone also reduces acute inßammation in animal models (Cuzzocrea S, 2004). While the theoretical basis for treating psoriasis with PPAR-γ agonists is well documented, no Phase II or Phase III clinical trials have been published in peer-reviewed journals or presented at scientiÞc conferences to date. Clinical data in the public domain are limited to the results of a small pilot study of eight patients followed for 30 days, in which no clinically signiÞcant improvement was seen in patients taking rosiglitazone compared with patients treated with placebo (Kuenzli S, 2003). In the diabetes market, rosiglitazone is generally regarded as safe, with notable adverse effects being weight gain and ßuid retention. REFERENCES Abel EA. Psoriasis. In: Dale DC, Federman DG, eds. ScientiÞc American Medicine. New York: ScientiÞc American Inc.; 1994.

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Amblard P. Psoriasis: diagnostic, evolution, prognostic, treatment. La Révue du Praticien (Paris). 1993;43:229–231. Antoni C, et al. Successful treatment of psoriatic arthritis with inßiximab. Presented at the American College of Rheumatology 63rd Annual ScientiÞc Meeting; November 16, 1999; Boston. Abstract 1801. Antoni C, et al. Long-term open label treatment of psoriatic arthritis with inßiximab. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P538. Baron SE, et al. The use of complimentary medicine within a population of dermatological outpatients in Leeds, UK. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P271. Bell LM, et al. Incidence of psoriasis in Rochester, Minn., 1980–1983. Archives of Dermatology. 1991;127:1184–1187. Bhagavathula, N. Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes. Journal of Investigative Dermatology. 2004;122: 130–139. Bhushan M, et al. Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis. British Journal of Dermatology. 1999;141:1054–1060. Camisa C. Psoriasis: a clinical update diagnosis and new therapies. Cleveland Clinical Journal of Medicine. 2000;67:105–119. Carroll CM, et al. Topical tacrolimus ointment in combination with 6% salicylic acid gel for the treatment of psoriasis: results of a randomized, double-blind, right to left clinical trial. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P579. Christophers E. Psoriasis—epidemiology and clinical spectrum. Clinical and Experimental Dermatology. 2001;26:314–320. Cohen MR, et al. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Journal of Rheumatology. 1999;26: 1752–1755. Cuzzocrea S, et al. Rosiglitazone, a ligand of the peroxisome proliferators-activated receptor-gamma, reduces acute inßammation. European Journal of Pharmacology. 2004;483:79–93. de Jong EMGJ. The course of psoriasis. Clinics in Dermatology. 1997;15:687–692. Diaz BV, et al. Regulation of vascular endothelial growth factor expression in human keratinocytes by retinoids. Journal of Biological Chemistry. 2000;275:642–650. Dubertret L, et al. EfÞcacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris. Journal of the American Academy of Dermatology. 1992;27:983–988. Dummer W, et al. Pharmacodynamic effects of subcutaneous (SC) administration of efalizumab (anti-CD11a). 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P547. Duvic M, et al. Oral retinoids in the treatment of psoriasis. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P599. Elder JT, et al. Epidemiology and the genetics of psoriasis. Journal of Investigative Dermatology. 1994;102:24S–27S.

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The European FK 506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. Archives of Dermatology. 1996;132:419–423. Farber EM, Nall L. Epidemiology: natural history and genetics. In: Roenigk HH, ed. Psoriasis. 2nd ed. New York: Marcel Dekker, Inc.; 1990:2009–2058. Farber EM, Nall L. Epidemiology: natural history and genetics. In: Roenigk HH, Maibach HI, eds. Psoriasis. 3rd ed. New York: Marcel Dekker, Inc.; 1998:107–157. Ferrándiz C, et al. Prevalence of psoriasis in Spain (Epiderma Project: Phase I). Journal of the European Academy of Dermatology and Venereology. 2001;15:20–23. Finzi AF, Benelli C. A clinical survey of psoriasis in Italy: 1st AISP report. Journal of the European Academy of Dermatology and Venereology. 1998;10:125–129. Fleischer AB, et al. Disease severity measures in a population of psoriasis patients: the symptoms of psoriasis correlate with self-administered psoriasis area severity index scores. Journal of Investigative Dermatology. 1996;107:26–29. Fleischer AB, et al. Introduction. The magnitude of skin disease in the United States. Dermatologic Clinics. 2000;18(2):xv–xxi. Fleishmann RM, et al. Inßiximab in the treatment of psoriasis and psoriatic arthritis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P566. Fraki JE, et al. Uninvolved skin from psoriatic patients develops signs of involved psoriatic skin after being grafted onto nude mice. Science. 1982;215:685–687. Fransson J. Tumour necrosis factor-alpha does not inßuence proliferation and differentiation of healthy and psoriatic keratinocytes in a skin-equivalent model. Acta DermatoVenereologica. 2000;80:416–420. Freedberg I, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York: McGraw-Hill; 1999;I:495. Freeman AK et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. Journal of the American Academy of Dermatology. 2003;48:564–568. Gaspari A, et al. Enbrel improves the clinical and pathologic features of psoriasis. 63rd Annual Meeting of the Society for Investigative Dermatology; May 15–18, 2002; Los Angeles. Abstract 172. Gladman DD. Psoriatic arthritis. Rheumatic Disease Clinics of North America. 1998;24: 829–844. Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opinion on Investigational Drugs. 2000;9:1151–1522. Gollnick H, et al. Acitretin versus etretinate for psoriasis. Clinical and pharmacokinetic results of a German multicenter study. Journal of the American Academy of Dermatology. 1988;19:458–468. Gollnick H, et al. A new calcipotriol/betamethasone formulation with rapid onset of action is superior to betamethasone dipropionate ointment and calcipotriol ointment in psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P543. Gordon KB, Continuous treatment improves outcomes in patients with moderate to severe plaque psoriasis treated with efalizumab. 60th Annual Meeting of the Society for Investigative Dermatology; February 22–27, 2002; New Orleans. Abstract P585.

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Gordon KB, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. Journal of the American Medical Association. 2003;290: 3073–3080. Gottlieb A, et al. Subcutaneous efalizumab (anti-CD11a) is effective in the treatment of moderate to severe plaque psoriasis pooled results of two Phase III clinical trials. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P576. [a] Gottlieb AB, et al. EfÞcacy of Enbrel in patients with psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract 159. [b] Gottlieb AB, et al. Inßiximab monotherapy normalizes keratinocyte differentiation and decreases inßammation in skin biopsies from patients with moderate to severe plaque psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P539. [c] Gottlieb AB, et al. Inßiximab prevents relapse of moderate to severe psoriasis in responding patients. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P540. [d] Gottlieb AB, et al. The efÞcacy and safety of inßiximab induction treatment in subjects with severe plaque-type psoriasis. 9th International Psoriasis Symposium; June 17–22, 2003; Poster. Gottlieb AB, et al. Evaluating therapeutic strategies for psoriatic disease and the use of biologics. 65th Annual Meeting of the Society for Investigative Dermatology; April 28-May 3, 2004; Providence, RI. Seminar. Gottlieb SL, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nature Medicine. 1995;1:442–447. Greaves MW, Weinstein GD. Treatment of psoriasis. New England Journal of Medicine. 1995;332:581–588. GrifÞths C, et al. Treatment with oral pimecrolimus signiÞcant improves psoriasis with a clear dose-response effect. Joint Meeting of the European Society for Dermatological Research, Japanese Society for Investigative Dermatology, and Society for Investigative Dermatology; April 30-May 4, 2003; Miami Beach, FL. Abstract 0391. Guedjonsson JE, et al. HLA-Cw6-positive and HLA-Cw6-negative patients with psoriasis vulgaris have distinct clinical features. Journal of Investigative Dermatology. 2002;118:362–365. Gulliver W, et al. The effect of intramuscular alefacept on the individual components of the psoriasis area and severity index. 63rd Annual Meeting of the Society for Investigative Dermatology; May 15–18, 2002; Los Angeles. Abstract P822. Gupta AK, et al. Pimecrolimus: a review. Journal of the European Academy of Dermatology and Venereology. 2003;17:493–503. Henseler T. The genetics of psoriasis. Journal of the American Academy of Dermatology. 1997;37(2 Pt. 3):S1–S11. Hewett D, et al. IdentiÞcation of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics. 2002;79:305–314. Heydendael et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. New England Journal of Medicine. 2003;349:658–665.

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The International Psoriasis Genetics Consortium. The International Psoriasis Genetics Study: assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs. American Journal of Human Genetics. 2003;73:430–437. Johnson MT, Roberts J. Prevalence, disability, and health care for psoriasis among persons 1–74 years: United States. Advance data from vital and health statistics; no. 47. Hyattsville, MD: National Center for Health Statistics; 1979. Kang S, et al. Oral tazarotene and difÞcult-to-treat psoriatic lesions. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P597. Katz, HI, et al. Intermittent corticosteroid maintenance of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica. 1991;183:269–274. Kehren JC, et al. Genomic analysis of blood cells from psoriatic patients following treatment with oral pimecrolimus (SZD ASM 981). 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P101. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatologic Clinics. 1996;14:485–496. Koo JY, et al. Efalizumab (anti-CD11a) is safe and well tolerated in the treatment of moderate to severe plaque psoriasis: pooled results of two Phase III clinical trials. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P548. Koo JY et al. Duration of clinical improvement with oral tazarotene in plaque psoriasis. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P598. Kragballe K, et al. A new combination of calcipotriol and betamethasone dipropionate is effective used once daily in psoriasis vulgaris. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P536. Krueger GG, Duvic M. Epidemiology of psoriasis: clinical issues. Journal of Investigative Dermatology. 1994;102:14S–18S. Krueger GG, et al. Duration of response to alefacept therapy in patients with chronic plaque psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P584. [a] Krueger GG, et al. EfÞcacy of two courses of intravenous alefacept in patients with chronic plaque psoriasis. 63rd Annual Meeting of the Society for Investigative Dermatology; May 15–18, 2002; Los Angeles. Abstract 819. [b] Krueger GG, et al. Alefacept (human LFA-3/IgG1) is well tolerated and non-immunogenic: results of two randomized, placebo-controlled Phase III trials. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P583. [c] Krueger GG, et al. Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis. Journal of the European Academy of Dermatology and Venereology. 2003;17 Suppl 2:17–24. Kuenzli S. et al. Effect of topical PPAR beta/delta and PPAR gamma antagonists on plaque psoriasis. A pilot study. Dermatology. 2003;206:252–256. Langner A. et al. Oral fumarate for the treatment of severe forms of psoriasis: results of a phase II clinical study. 2nd Spring Symposium of the European Academy of

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Dermatology and Venereology. April 29-May 1, 2004; Budapest, Hungary. Abstract PS296. Lebwohl M. et al. Tazarotene in combination with topical corticosteroids. Journal of the American Academy of Dermatology. 1998;39S:139–143. Lebwohl M, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of treatment. Journal of the American Academy of Dermatology. 1998;39:447–450. Lebwohl M, et al. Results of a multiple-course, randomized, Phase III study of alefacept (human LFA-3/IgG1) in patients with chronic plaque psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P580. [a] Lebwohl M, et al. Etanercept improved psoriasis activity in patients with psoriatic arthritis: results of a Phase 3 multicenter clinical trial. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P561. [b] Lebwohl M, et al. An international, randomized, double-blind, placebo-controlled Phase III trial of intramuscular alefacept in patients with chronic plaque psoriasis. Archives of Dermatology. 2003;139:719–727. [a] Lebwohl M, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. New England Journal of Medicine. 2003;349:2004–2013. [b] Lebwohl M, et al. Combination therapy to treat moderate to severe psoriasis. Journal of the American Academy of Dermatology. 2004:50;416–430. Leonardi C, et al. Pilot study of topical ISIS 2302, an antisense oligodeoxynucleotide, in patients with plaque tope psoriasis vulgaris. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P28. Leonardi CL, et al. Etanercept as monotherapy in patients with psoriasis. New England Journal of Medicine. 2003;349:2014–2022. Leonardi CL, et al. The safety of efalizumab in patients with moderate to severe plaque psoriasis: summary of clinical trial experience. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P613. Loewe R, et al. Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. Journal of Immunology. 2002;168:4781–4787. Lowe N, et al. Results of repeat courses of alefacept therapy for the treatment of chronic plaque psoriasis. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P578. [a] Lowe NJ, et al. Acitretin plus UVB therapy for psoriasis. Comparisons with placebo plus UVB and acitretin alone. Journal of the American Academy of Dermatology. 1991;24:591–594. Lowe NJ, et al. Efalizumab (anti-CD11a) inhibits trans-endothelial migration of T cells. 63rd Annual Meeting of the Society for Investigative Dermatology; May 15–18, 2002; Los Angeles. Abstract 710. [b] Majeau GR, et al. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. Journal of Immunology. 1994;152:2753–2767. Mease PJ, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet. 2000;356:385–390.

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Rea JN, et al. Skin disease in Lambeth. British Journal of Preventive and Social Medicine. 1976;30:107–114. Rees JL, Farr PM. Dermatology. Journal of the Royal College of Physicians of London. 1997;31(3):238–240. Ritchlin C. Patterns of cytokine production in psoriatic synovium. Journal of Rheumatology. 1998;25:1544–1552. Saurat JH, et al. Randomized double-blind multi-center study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica. 1988;177:218–224. Shbeeb M, et al. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982–1991. Journal of Rheumatology. 2000;27:1247–1250. Shupack J, et al. Cyclosporine as maintenance therapy in patients with severe psoriasis. Journal of the American Academy of Dermatology. 1997;36(3 pt 1):423–432. Siragusa M, et al. Skin pathology Þndings in a cohort of 1,500 adult and elderly subjects. International Journal of Dermatology. 1999;38:361–366. Soto P, et al. Systemic safety evaluation of calcitriol 3µg/g ointment in patients with plaque psoriasis involving varying body surface areas. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P526. Sterry W, et al. Efalizumab for patients with moderate to severe chronic plaque psoriasis: results of the international, randomized, controlled phase III clinical experience acquired with Raptiva (clear) trial. 34th Annual Meeting of the European Society for Dermatological Research. September 9–11, 2004; Vienna, Austria. Abstract 386. Swanbeck G, et al. Genetic counselling in psoriasis: empirical data on psoriasis among Þrst-degree relatives of 3,095 psoriatic probands. British Journal of Dermatology. 1997; 137:939–942. Szczerkowska-Dobosz A, et al. Psoriasis vulgaris with the early and late onset—HLA phenotype correlations. Archivum Immunologiae et Therapiae Experimentalis. 1996; 44(4):265–269. Tanew A, et al. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. Journal of the American Academy of Dermatology. 1991;25:682–684. Thaci D, et al. Individual pharmacodynamics in psoriasis patients treated with calcipotriol or/and betamethasone 17 valerate. 60th Annual Meeting of the American Academy of Dermatology; February 22–27, 2002; New Orleans. Abstract P554. Travers JB, et al. Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. Journal of Clinical Investigation. 1999;104: 1181–1189. Treumer F, et al. Dimethylfumarate is a potent inducer of apoptosis in human T cells. Journal of Investigative Dermatology. 2003;121:1383–1388. Walker PS, et al. Safety of oral tazarotene in moderate to severe plaque psoriasis. 62nd Annual Meeting of the American Academy of Dermatology; February 6–11, 2004; Washington, D.C. Abstract P595. Wall AR, et al. A comparison of treatment with dithranol and calcipotriol on the clinical severity and quality of life in patients with psoriasis vulgaris. Lancet. 1998;337: 193–196.

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Rheumatoid Arthritis

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Rheumatoid arthritis (RA) (International ClassiÞcation of Diseases, Ninth Revision [ICD-9], code 714, and Tenth Revision [ICD-10], code M06.9) is characterized by chronic joint inßammation that typically leads to debilitating tissue damage, further compounded by joint deformation. Although the precise etiology remains elusive, experts view RA as a disease of autoimmune origin, spurred by environmental triggers acting on a genetically predetermined host. However, few genetic, and no environmental, factors have yet been identiÞed deÞnitively. This section reviews the disease course and complications of RA as well as the potential role of select genetic and environmental risk factors in the initiation and evolution of RA pathophysiology. Pathophysiology Immune Response. RA is widely considered an autoimmune disease. The prominence of the T-cell inÞltrate in the synovium (the inner lining of synovial joints) suggests that these cells are key participants. A 1998 study reported that a subset of CD4+ (helper) T cells in RA patients, but not human leukocyte antigen (HLA)-DR-matched controls, displayed increased expression of the cell survival protein bcl-2, which blocks apoptosis (Schirmer M, 1998). The researchers speculated that this increase may favor the clonal expansion of autoreactive T cells in RA patients. Several additional studies have focused on the expression of the Fas (a member of the TNF receptor family) and its ligand in RA. Fas regulates apoptosis (cell death) in the immune system through interaction with Fas ligand. Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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In addition, synovial cells express elevated levels of bcl-2, likely induced by pro-inßammatory cytokines and contributing to pannus (an inßammatory exudate overlying the layer of synovial cells lining the inside of a joint) formation. Infusion of Fas ligand by gene transfer techniques or by injection of cross-linking Fas antibodies is being explored in animal models of arthritis. In a recently reported study in a murine model, upon treatment with anti-Fas in vitro, cell death of Þbroblasts was reduced and the expression of pro-inßammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) increased, pointing to a role of Fas in joint destruction (Hoang TR, 2004). Disease Course. RA typically displays an insidious onset spanning weeks or months. Symptoms may begin with general fatigue, morning stiffness, and pain. They may progress to localized, symmetrical joint inßammation, most commonly in the hands, wrists, and feet. Systemic effects of RA may appear later in the disease (as discussed in the section “Extra-articular and Systemic Manifestations”). Importantly, no clinical markers currently exist that can deÞnitively diagnose RA in all patients. RA progression is classiÞed into four stages. Stage I marks the onset of the earliest clinical manifestation—synovial inßammation (synovitis), which is characterized by an increase in synovial ßuid volume containing abnormally elevated quantities of Þbrin, immune complexes, complement components, proteases, impaired protease inhibitors, and the pro-inßammatory cytokines interleukin-1beta (IL-1β), IL-6, and TNF-α. Inßammation of the synovial microvasculature and increased capillary permeability result in an inßux of B cells, T cells, macrophages, and neutrophils. In addition, cyclooxygenase and lipoxygenase gene expression increases, resulting in greater prostaglandin and leukotriene production. All these events result in the induction and maintenance of an inßammatory state in the joint. Stage II of RA is marked by synovial hypertrophy and cellular proliferation, resulting in invasion of the joint cavity. Erosion of the articular cartilage ensues because the avascular, cartilage-producing chondrocyte layer is denied access to the nutrient-rich synovial ßuid, resulting in chondrocyte death. The synovium becomes further inundated with activated Þbroblasts and immune cells, exacerbating the inßammatory state of the joint. Endothelial cells also may be observed in the synovium because of ongoing neovascularization. Stage III of RA is characterized by pannus formation. Consisting of numerous Þbroblasts, small blood vessels, and mononuclear cells, this vascular granulation tissue spreads to cover the articular cartilage. In response to this chronic inßammatory state, large amounts of tissue- and cartilage-degrading enzymes, including collagenases and stromelysins, are produced. Eventually, subchondral bone is exposed and demineralized by osteoclasts, which are activated by the high levels of IL-1β, TNF-α, and prostaglandin E2 . Signs of articular deformity may be observed at this stage. The inßammatory process begins to diminish by stage IV, when erosion of articular cartilage and bone is extremely advanced, and Þbrous or bony ankylosis severely limits the function of affected joints. Nodulosis (the formation of

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subcutaneous rheumatoid nodules) occurs in 20–30% of patients, particularly in those strongly seropositive for rheumatoid factor (RF; see the later section “Pathogenesis of Joint Damage”). These nodules, which are seldom symptomatic, may be caused by focal vasculitis and consist of a central necrotic core, a middle zone of palisading macrophages, and an outer ring of granulation tissue. RA patients can also be classiÞed into four categories according to the Steinbrocker Functional Class system, which enables a determination of the percentage of patients presenting by severity of disease (Beckman JC, 1992; Sany J, 1998): • • • •

Class I (early) consists of patients with no restriction of ability to perform normal activities (approximately 24% of prevalent RA cases). Class II (moderate) encompasses patients who have moderate physical restriction but are nevertheless able to perform normal activities (50%). Class III (severe) comprises patients with marked restriction; they are unable to perform most tasks related to occupation or self-care (25%). Class IV (terminal) consists of RA patients incapacitated by the disease and, in some cases, conÞned to bed or a wheelchair (1%).

Extra-articular and Systemic Manifestations. Research suggests that the term rheumatoid disease more properly deÞnes RA, particularly because of systemic involvement. Rheumatoid nodules may develop in the posterior portion of the brain, pleura, or meninges, with potentially serious complications. Cardiopulmonary manifestations include pleuritis and pericarditis with effusions resembling synovial ßuid. These events are difÞcult to diagnose, but asymptomatic pericarditis is observed in 40–50% of autopsied RA patients. Lung parenchymal involvement may present as either interstitial pneumonitis or pulmonary Þbrosis. Renal abnormalities such as proteinuria may occur in RA patients, often as a complication of drug therapy. Rheumatoid vasculitis can affect any organ system and is typically observed in patients who have aggressive disease and are strongly RF-positive. Approximately 15–20% of RA patients develop Sjögren’s syndrome, which is characterized by kerato-conjunctivitis sicca (typical signs being hyperemia of the conjunctiva, lacrimal deÞciency, thickening of the corneal epithelium, itching and burning of the eye, and often reduced vision). Other ocular manifestations affecting less than 1% of patients include scleritis, episcleritis (an inßammatory condition of the connective tissue between the conjunctiva and sclera), and ocular nodules. Osteoporosis is a common and often underdiagnosed complication of RA. Felty’s syndrome may occur late in the disease course, involving neutropenia, thrombocytopenia, and splenomegaly. Pathogenesis of Joint Damage. Although the cause of RA remains elusive, the destructive features of the disease have been extensively documented and described. The following sections review each key element of disease pathogenesis. They include the inÞltration of lymphocytes and macrophages into synovial tissue, hyperplasia of synovial cells, and the enhanced expression of multiple inßammatory mediators, such as cytokines and degradative enzymes.


637

FIGURE 1. Pathological changes in the joints of patients with rheumatoid arthritis.

Leukocyte Infiltration in the Joints. As depicted in the left side of (Figure 1), the healthy joint consists of cartilage layered upon bone that is encased by the synovial membrane, or synovium. By contrast, in the joint of an RA patient (Figure 1, right side), the tissue beneath the synovial lining becomes vascularized and inÞltrated with T cells, B cells, and macrophages. Leukocytes also accumulate in the synovial ßuid, leading to cartilage destruction and bone damage. B cells present in the synovial ßuid characteristically produce large quantities of immunoglobulin G (IgG) or IgM autoantibodies directed against the constant region of other IgG antibodies. These autoreactive antibodies are termed rheumatoid factors (RFs) and form immune complexes that activate the complement cascade and phagocytic activity of macrophages. Both CD4+ and CD8+ (cytotoxic) T cells are present in the synovial ßuid. Researchers note that the CD4+ subset appears to exist in an activated state, presumably owing to the abundance of IL-2 present in the synovial ßuid, which also promotes the initiation of an immune response involving major histocompatibility complex (MHC) class II molecules.

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Synovial Cell Hyperplasia and Tissue Destruction. Researchers believe that synovial tissue macrophages and proliferating Þbroblasts are major contributors to cartilage and bone destruction because both cell populations produce degradative enzymes, such as matrix metalloproteinases (MMPs). Synovial Þbroblasts produce collagenase and cathepsins as well, and they demonstrate proliferative and invasive properties similar to those of transformed tumor cells. Monocytes and macrophages may produce large quantities of pro-inßammatory cytokines, including TNF-α and IL-1β; IL-8, a potent stimulator of angiogenesis; and monocyte chemoattractant protein-1 (MCP-1). This overabundance of proinßammatory cytokines results in persistent inßammation. The clinical success of the TNF-α inhibitor etanercept (Amgen/Wyeth/Takeda’s Enbrel) has resulted in an increased interest in the role of cytokines in RA. Table 1 lists some commonly detected cytokines in the synovial tissue and ßuid of RA patients; Table 2 describes the pathophysiological effects of key cytokines. “Current Therapies” discusses the role of TNF-α in RA pathology. Cytokines in Rheumatoid Arthritis. The RA synovium contains increased levels of cytokines, prominent among which are TNF-α and IL-1. Many other pro-inßammatory cytokines, including IL-6 and IL-18, are also present, as well as anti-inßammatory cytokines such as IL-10, IL-13, and transforming growth factor-beta (TGF-β), suggesting that an imbalance in favor of pro-inßammatory mediators may be a central pathogenic mechanism in RA. An array of cytokines with pro-inßammatory activity in RA synovitis have been described that offer therapeutic potential, including IL-6, IL-12, IL-15, and IL-18. Research has demonstrated that the macrophage-produced cytokine IL-1β plays a dominant role in cartilage degradation and joint invasion by synoviocytes. IL-1 receptor antagonist (IL-1ra) expression correlates with the induction of IL-1β. SpeciÞcally, IL-1ra neutralizes the ability of IL-1β to induce inßammation by binding to IL-1β receptors and inhibiting cellular activation. IL-10, a T helper (Th)2-type cytokine, also has anti-inßammatory properties; it suppresses synthesis of the pro-inßammatory Th1 cytokines IL-1β and TNF-α. Elevated levels of IL-10 are detected in the synovial ßuid of active RA patients, and two laboratories have reported that adenoviral transfer of the vIL-10 gene prevents arthritis development in animal models (Whalen JD, 1999, Lechman ER, 1999). The results of these studies suggest that IL-1ra and IL-10 buffer the pro-inßammatory effects of TNF-α and IL-1β. IL-6, a pleiotropic cytokine, has a wide range of effects, including stimulating B cells to differentiate into plasma cells in order to produce immunoglobulin and stimulating T lymphocytes to differentiate into cytotoxic T cells. Serum IL-6 concentrations have been shown to correlate with disease activity in active RA (Dasgupta B, 1992). IL-12, and the more recently discovered IL-23 and IL-27, comprise a family of structurally related cytokines that regulate cell-mediated immune responses and Th1-type inßammatory reactions. Inhibition of IL-15 and IL-18 represent additional attractive approaches that could block Th1 differentiation, inßammatory mediator production, or TNF-α expression. IL-15 is produced


639

TABLE 1. Select Cytokines Detected in the Synovial Tissue of Patients with Rheumatoid Arthritis

Cytokine TNF-α IL-1β IL-2 IL-6

IL-8 IL-10

IL-12 IL-15 IL-17 IL-18

Primary Sources

Targets Activated

Monocytes, macrophages Monocytes, macrophages T lymphocytes Monocytes, macrophages, fibroblasts Monocytes, macrophages Monocytes, macrophages, T lymphocytes Monocytes, macrophages Fibroblasts, monocytes, macrophages T lymphocytes T lymphocytes

Macrophages, fibroblasts Fibroblasts, macrophages T lymphocytes, NK cells Lymphocytes

Degree of Degree of Effect Abundance in on Inflammation Synovial Tissue or Tissue or Fluid Damage High

High

High

High

Medium Medium

Medium Medium

Neutrophils

Medium

Medium

Lymphocytes

Medium

None

Lymphocytes

Low

Medium

Lymphocytes

Low

Medium

Low Medium

Medium Medium

Low Medium

Medium None

Medium

Medium

Fibroblasts Monocytes, macrophages, T lymphocytes, NK cells IFN-γ T lymphocytes NK cells TGF-β Fibroblasts, monocytes, Lymphocytes, fibroblasts macrophages, T lymphocytes GM-CSF Monocytes, Neutrophils, macrophages, macrophages T lymphocytes

GM-CSF = Granulocyte-macrophage colony-stimulating factor; IFN = Interferon; IL = Interleukin; NK cell = Natural killer cell; TGF = Transforming growth factor; TNF = Tumor necrosis factor.

by endothelial cells and is a potent T-cell chemoattractant. It also activates cell adhesion molecule expression on T cells. IL-17, produced by activated CD4+ T cells, is highly expressed in the diseased joint and stimulates formation of bone-resorbing osteoclasts. The pleiotropic cytokine IL-18 acts as a proinßammatory cytokine by inducing TNF-α, interferon-gamma (IFN-γ ), IL-8, IL-2, and prostaglandin production by macrophages and/or T cells, and elevated levels have been detected within the joints of RA patients. Angiogenesis and Rheumatoid Arthritis. Angiogenesis occurs within the synovium early in the pathogenesis of RA. These new vessels support the growing synovial tissue, express chemokines that attract additional cells (including

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TABLE 2. Select Cytokines Involved in the Pathogenesis of Rheumatoid Arthritis Mechanism Synovial tissue inflammation

Cytokines IFN-γ , IL-1β, TNF-α IL-8 IL-1β, IL-2, IL-6, TNF-α IFN-γ , IL-1β, IL-2, IL-6, TNF-α

Synovial fluid inflammation

Synovial proliferation Cartilage and bone damage Systemic manifestations

GM-CSF, IFN-γ , TNF-α GM-CSF, IFN-γ , IL-2 IFN-γ , IL-1β, TNF-α IL-8, TNF-α GM-CSF, IL-8 TNF-α IL-1β, TGF-β TNF-α, TGF-β IL-1β, TNF-α

Role of Cytokine Increased adherence of postcapillary venules Chemotaxis of T cells T-cell activation and proliferation B-cell differentiation and antibody formation Increased expression of HLA antigens Macrophage activation Increased adherence of postcapillary venules Chemotactic for PMN Activation of PMN Fibroblast growth

IL-1β, TNF-α

Neovascularization Activation of chondrocytes, fibroblasts, and osteoblasts/osteoclasts Fever, constitutional symptoms

IL-1β, IL-6, TNF-α

Acute-phase reactants

GM-CSF = Granulocyte-macrophage colony-stimulating factor. HLA = Human leukocyte antigen. IFN = Interferon. IL = Interleukin. PMN = Polymorphonuclear leukocyte. TGF = Transforming growth factor. TNF = Tumor necrosis factor.

leukocytes), and provide an additional source of inßammatory mediators to the synovium. In 1998, researchers proposed that the rheumatoid synovium can be viewed as a rapidly dividing tumorlike structure (Fassbender HG, 1998), a view later endorsed by other researchers. Thus, inhibiting angiogenesis in RA may limit the inßux of inßammatory cytokines and inhibit synovial proliferation. Prognosis. The clinical prognosis of RA varies signiÞcantly. Although a small number of patients display complete remission, and as many as 20–30% experience periods of partial remission, the vast majority suffer chronically. RA patients who are RF positive are more likely to experience a worse disease course. The susceptibility epitope might also inßuence the severity of disease. Patients with HLA-DR1 or HLA-DR4 molecules (see the following section “Genetic Risk Factors”) are at greater risk of developing extra-articular and erosive disease, while individuals who inherit two shared-epitope-containing HLA-DR molecules suffer particularly aggressive disease (Weyand CM,1992). Most patients eventually develop some form of chronic disability, associated with severe pain and progressive functional decline.


641

Etiology Genetic Risk Factors. RA occurs in patients’ relatives 2.3 times more frequently than in the general population, suggesting that genetics plays a role in disease development. This suggestion is supported by comparisons of monozygotic twins (derived from one ovum) and dizygotic twins. Studies suggest that the concordance of RA in monozygotic twins is 15.4% versus only 3.6% for dizygotic twins. This concordance extrapolates to an incidence of 12.0 cases per 1,000 per year for monozygotic and 2.2 for dizygotic twins (Silman AJ, 1993; Jawaheer D, 1994). Numerous studies have found a correlation between RA susceptibility and the expression of speciÞc alleles encoding components of the MHC. The MHC is located on the short arm of chromosome 6 and is the only genetic region that has been consistently associated with RA. Much of the MHC comprises the human leukocyte antigen (HLA) genes, which encode an individual’s tissue type and participate in antigen presentation. Two different classes (I and II) of MHC may be expressed on the cell surface for the purposes of antigen presentation. The strongest link to RA within the MHC is the class II HLA region, in particular the HLA-DR locus, and precisely the third hypervariable region of DRβ chains, known as the susceptibility epitope. This epitope is found in multiple HLA-DR genes, including DR1, DR4, and DR14 . Expression of the HLA-DR4 allele has been found in as many as 70% of white and Japanese RA patients, compared with 28% of unaffected individuals. Expression of the HLA-DR1 variant has been associated with RA in Israeli Jews and Asian Indians, and expression of the HLA-Dw16 variant has been associated with RA in the Yakima (Native American) population. Additional HLA-DR alleles—including HLA-Dw4, HLA-Dw14, and HLA-Dw15 —have also been correlated with RA incidence in speciÞc populations (Jaraquemada D, 1986; Ronningen KS, 1992; Lai NS, 1995). (See the earlier “Immune Response” section.) Although HLA-DR alleles show a consistent correlation with RA susceptibility, many researchers believe that RA is polygenic in origin and that subtle differences in the quantitative and qualitative expression of many genes result in a cumulative effect on RA susceptibility. Indeed, the concordance among monozygotic twins with RA is higher than that among siblings bearing identical copies of MHC risk alleles, suggesting a role for additional genes. The North American Rheumatoid Arthritis Consortium (NARAC) was established in 1997 to identify additional genes associated with RA susceptibility using genomic analysis of 1,000 sibling pairs. In a recent analysis, researchers pooled data from 512 families. While conÞrming the association between RA and HLA genes, the study found that genetic regions on chromosomes 1 and 18 are likely to contain genes involved in RA (Jawaheer D, 2003). Another study suggests a role for a single nucleotide polymorphism (SNP) in a gene (PTPN22 ) that encodes for an enzyme known to be a negative regulator involved in controlling T-cell activation. Where the SNP is present, regulation by the enzyme appears inefÞcient such that T cells and other immune cells are hyperresponsive, leading to increased inßammation and tissue damage. The variation is present in approximately 28%

642


of individuals with RA compared with 17% of the general population (Begovich AB, 2004). SNP mapping exercises are planned while further studies will determine the actual contribution of such genes to RA susceptibility and their utility as therapeutic targets. Environmental Risk Factors. Despite compelling evidence linking genetic risk factors to the occurrence of RA, long-term concordance rates among monozygotic twins do not exceed 20%, suggesting a role for nongenetic risk factors. Indeed, typically, only one member of an identical twin pair is afßicted with RA. However, while environmental factors appear to interact with, and trigger, RA in genetically predisposed individuals, none has been identiÞed deÞnitively as causative agents. Infectious agents present clear candidates, because many are associated with arthritic disorders. For example, HIV may precipitate an arthritic illness, while infection with Mycobacteria or one of several other pathogens can produce a transient synovitis similar to that characteristic of RA. Persistent Epstein-Barr virus (EBV) has been implicated in a number of studies as having a role in the development of RA, either acting alone or in concert with other viruses such as cytomegalovirus (CMV) or parvovirus B19 (Mehraein Y, 2004). However, no single pathogen or pathogen type is routinely detected in RA patients, and the disease does not occur in clusters or demonstrate seasonal variation. Although some RA cases may develop as a result of infection, the theory that such infection deÞnes the etiology of RA has become less accepted. Some researchers have proposed that RA and other autoimmune diseases result from cross-reactivity of a pathogenic epitope with self-antigens, also known as molecular mimicry. Attention has focused recently on the role of heat-shock proteins such as Mycobacterium tuberculosis hsp65. This protein is highly homologous to the human form, and an immune response against the former could trigger an autoimmune response against the latter (Durai M, 2004). The identiÞcation of such implicated disease-regulating determinants offers the prospect of a potential novel approach for immunotherapy in RA. However, no speciÞc autoantigen (or cross-reactive “self-protein”) has been identiÞed consistently in RA patients. Hormonal Risk Factors. RA is two to three times more common in women than men, with incidence in women steadily increasing with age until menopause. Although RA incidence is rare among younger men compared with younger women, it rises sharply among elderly males, eventually approaching incidence rates in women. Indeed, male RA patients frequently present with decreased testosterone levels, which may suppress normal immunity. Both male and female RA patients exhibit low levels of the female androgen dehydroepiandrosterone (DHEA), and reductions in levels of the steroid appear to precede RA onset. However, DHEA supplementation does not appear to affect RA progression (Giltay EJ, 1998). In the female RA population, disease onset and ßare-ups are most frequent at menopause and in the postpartum period, when estrogen and/or progesterone

CURRENT THERAPIES

643

levels fall. In contrast, RA usually remits during pregnancy, likely as a result of the increased production of corticosteroids, estrogens, and progesterones (a deÞciency of these hormones promotes cellular immunity, which is characteristic of RA). Exposure to oral contraceptives—but not estrogen replacement therapy—has been shown to reduce the risk of development of RA (Doran MF, 2004), and the former has been attributed to the decline in RA incidence in women during recent decades. Breast-feeding for more than 12 months has also been shown to lower RA risk (Karlson EW, 2004). Despite these observations, the idea that sex hormones are etiological factors in RA remains contentious, and there are no consistent data on the long-term effects of pregnancy or any protective role for oral contraceptives (Merlino LA, 2003). CURRENT THERAPIES Table 3 lists the current therapies used for the treatment of rheumatoid arthritis (RA). Patients diagnosed with RA typically receive two major forms of therapy. Disease-modifying antirheumatic drugs (DMARDs) are started with a view to halting the destructive course of RA, while anti-inßammatory drugs are prescribed to provide symptomatic relief. This section is organized from the perspective of rheumatologists, who consider the mainstay of treatment to be disease modiÞcation, supported by symptomatic treatment. It Þrst discusses DMARDs, including conventional agents and the more recently introduced biologics. It then discusses symptomatic treatments for RA, including traditional nonsteroidal anti-inßammatory drugs (NSAIDs; including the preferential cyclooxygenase [COX]-2 inhibitors), selective COX-2 inhibitors, and corticosteroids. It also reviews key clinical trials of these agents. In many such trials, researchers measured patient outcomes using the 1987 American College of Rheumatology (ACR) 20, 50, or 70 response criteria, which refer to the percentage of reduction in the signs and symptoms of RA. For example, an ACR 20 response is deÞned as a 20% or greater improvement in the tender and swollen joint count and three of the following Þve outcome measures: physician’s global assessment of disease activity; patient’s global assessment of disease activity; patient’s pain assessment; patient’s disability assessment, typically determined using the health assessment questionnaire (HAQ); and acute-phase reactant levels as measured by C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). Conventional Disease-Modifying Antirheumatic Drugs Overview. The conventional DMARD class includes a wide range of agents as diverse as antimalarials, cytotoxics, and immunosuppressants. Unlike antiinßammatories, which provide symptomatic relief without altering the natural course of the disease, DMARDs lack a direct analgesic effect but have the potential to slow or prevent joint damage in RA patients (ACR, 2002). It may take months of treatment for the clinical beneÞts of conventional DMARDs to become apparent, and some clinicians and researchers use the term slow-acting antirheumatic drugs (SAARDs) to indicate that these agents take longer than

644


TABLE 3. Current Therapies Used for Rheumatoid Arthritis Agent

Company/Brand

Dose

Conventional DMARDs Methotrexate Stada’s Rheumatrex, 7.5–25 mg in a single generics weekly dose Leflunomide Sanofi-Aventis’s Arava 10–20 mg daily Sulfasalazine

Hydroxychloroquine/ chloroquine Biological agents Etanercept

Infliximab

Adalimumab

Anakinra Traditional NSAIDs Diclofenac

Pfizer’s Azulfidine/ Salozopyridine, generics Sanofi-Aventis’s Plaquenil, generics

2,000 mg daily

400 mg daily

Amgen/Wyeth/ Takeda’s Enbrel

Either 25 mg twice weekly or 50 mg once weekly (SC injection, self-administered) Centocor/Schering300 mg every 6-8 weeks Plough/Tanabe (IV perfusion, Seiyaku’s Remicade administered by a health care professional) Abbott/Eisai’s Humira 40 mg every other week (SC injection, self-administered) Amgen’s Kineret 100 mg daily (SC injection, self-administered)

Novartis’s Voltaren/ Voltarol, generics Naproxen Roche’s Naprosyn/ Anaprox/Proxen, Bayer’s Aleve, generics Meloxicam Boehringer Ingelheim/ Abbott/Daiichi’s Mobic Selective COX-2 inhibitors Celecoxib Pfizer/Astellas’s Celebrex Valdecoxib Pfizer/Astellas’s Bextra Etoricoxib Merck’s Arcoxia Corticosteroids Prednisone Pfizer’s Deltasone, generics Methylprednisolone Pfizer’s Depo-Medrol, acetate generics

150 mg daily 1,000 mg daily

Availability US, F, G, I, S, UK, J US, F, G, I, S, UK, J US, F, G, I, S, UK, J US, F, G, I, S, UK US, F, G, I, S, UK


US, F, G, I, S, UK US, F, G, I, S, UK US, F, G, I, S, UK, J US, F, G, I, S, UK, J

10–15 mg daily


400 mg daily

US, F, G, I, S, UK US, G, I, UK I, S, UK

10–20 mg daily 60-120 mg daily 5-25 mg daily (oral)

US, F, G, I, S, UK 40 mg per injection (prn no US, F, G, I, S, more than 3–4 times per UK, J year)

COX-2 = Cyclooxygenase-2; DMARDs = Disease-modifying antirheumatic drugs; IV = Intravenous; NSAIDs = Nonsteroidal anti-inflammatory drugs; prn = As needed; SC = Subcutaneous. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

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anti-inßammatories to achieve an effect. However, DMARDs is the more widely used terminology. In 2002, the ACR published revised guidelines for the treatment of RA. These revised guidelines advocate more aggressive use of DMARDs earlier in the RA treatment regimen in an effort to limit joint damage and minimize loss of joint function and disability. As a result, the use of DMARDs, which were once reserved for treating severe or late-stage RA, has become widespread and is now the cornerstone of RA treatment. Numerous conventional DMARDs are employed in the treatment of RA. The discussion here is limited to the agents that are most commonly employed in current practice. Older DMARDs such as cyclosporine (Novartis’s Neoral, generics), penicillamine (Merck’s Cuprimine, generics), and azathioprine (AZA) (GlaxoSmithKline’s Imuran, generics) are now only infrequently employed in RA. Thus, these drugs are not discussed individually here. Bucillamine (Santen’s Rimatil, generics), actarit (Nippon Shinyaku’s Orcl, Mitsubishi Pharma’s Mover), and lobenzarit (Chugai’s Carfenil) are three conventional DMARDs used in Japan, but these agents are not available in any other region under study and hold only a small fraction of patient share in the RA market, so these agents are not discussed in detail. Mechanism of Action. Conventional DMARDs include a wide range of agents, such as antimalarials, cytotoxics, and immunosuppressants, each with a distinct mechanism of action. In general, agents in this class are anti-inßammatory and/or antiproliferative, inhibiting various molecules and cell types that play a role in the inßammatory cascade. Most have demonstrated the ability to slow the rate of progression of joint erosion and disability to varying degrees. Methotrexate. Originally developed as a treatment for cancer, methotrexate (Stada’s Rheumatrex, generics) (Figure 2) was not widely used in RA therapy until the 1980s. It has since become the leading DMARD in most countries because it offers relatively rapid onset of action (within three to eight weeks), low cost, and arguably the best balance between efÞcacy and tolerability among conventional DMARDs. Although methotrexate’s precise pharmacology is unclear, it is known to inhibit the action of several regulatory enzymes in the folic acid metabolic pathway and to alter leukocyte trafÞcking (Cronstein BN, 1997). Methotrexate is a H2N

N

N CH3

N

N N H N

NH2 O

COOH COOH


646


folic acid analogue that interferes with DNA synthesis. Long-term use of this drug at low doses inhibits thymidylate, purine, and methionine production, resulting in the accumulation of a potent anti-inßammatory molecule, adenosine. Methotrexate inhibits cellular proliferation and decreases the formation of antibodies and inßammatory mediators such as cytokines and eicosanoids. Most patients treated with methotrexate exhibit improvement in both subjective and objective measures of disease activity. In a Þve-year study evaluating methotrexate’s long-term efÞcacy among 123 patients, 64% continued taking this agent (Weinblatt ME, 1994). Only 7% discontinued treatment because of lack of efÞcacy, while another 7% withdrew because of adverse effects. Patients who continued therapy exhibited a 70% improvement in the joint pain/tenderness and the joint swelling indices. A ten-year study that enrolled 256 patients who were refractory to treatment with other DMARDs demonstrated that patients who failed to beneÞt from methotrexate therapy were generally those with a poor prognosis (Krause D, 2000). Methotrexate is also the most popular DMARD for use in combination therapy with other conventional DMARDs or with biologics. Recent clinical trials have shown that methotrexate used in combination with a biological agent increases efÞcacy without signiÞcantly increasing adverse effects. In the one-year Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO), 682 patients with active RA were randomly allocated to treatment with etanercept (Amgen/Wyeth/Takeda’s Enbrel) 25 mg (subcutaneously twice a week), oral methotrexate (>20 mg weekly), or the combination. The primary efÞcacy end point was the numeric index of the ACR response (ACR-N) over the Þrst 24 weeks. ACR-N area under the curve (AUC) at 24 weeks was greater for the combination group compared with etanercept or methotrexate alone (18.3% versus 14.7% and 12.2%, respectively) (Klareskog L, 2004). Similarly, in a oneyear study in combination with inßiximab (Centocor [a subsidiary of Johnson & Johnson]/Schering-Plough/Tanabe Seiyaku’s Remicade), 1,049 RA patients were randomly assigned in a ratio of 4:5:5 to three treatment groups: methotrexate with placebo, methotrexate with 3 mg/kg inßiximab, and methotrexate with 6 mg/kg inßiximab. Methotrexate dosages were rapidly escalated to 20 mg/week, and inßiximab or placebo infusions were given at weeks 0, 2, and 6, and every eight weeks thereafter. At week 54, the median percentage of ACR-N improvement was higher for the methotrexate plus 3 mg/kg inßiximab and methotrexate plus 6 mg/kg inßiximab groups than for the methotrexate plus placebo group (38.9% and 46.7% versus 26.4%, respectively) (St Clair EW, 2004). The maintenance dose of oral methotrexate ranges from 7.5 mg (generally 10 mg) to 20.0 mg (25 mg in some practices) in a single, weekly dose. Intramuscular injections are sometimes used to improve bioavailability and to achieve higher dosages. A 2004 study demonstrated that methotrexate given intramuscularly showed improved clinical efÞcacy with fewer side effects than when given orally (Wegrzyn J, 2004). Methotrexate is, however, teratogenic and can cause severe toxicities, including myelosuppression, pneumonitis, nephrotoxicity,

CURRENT THERAPIES

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CF3

O N N O

H CH3

FIGURE 3. Structure of leflunomide.

and hepatotoxicity (Ostensen M, 1998; van Ede AE, 1998). As a result, regular liver function tests, full blood counts, and monitoring of renal function are recommended. Leflunomide. Launched in the United States in 1998, leßunomide (SanoÞAventis’s Arava) (Figure 3) was the Þrst drug to be approved by the FDA for reducing the signs and symptoms of active, adult RA and for retarding structural joint damage—a decision based on the strength of Phase III trial X-ray evidence. In June 2003, the FDA approved additional labeling for leßunomide for improvement in physical function in RA patients. After a lengthy approval process, the agent was launched for use in adults with RA in Europe in 1999 and in Japan in 2003. Patents expire in Europe in 2004 and in 2006 in the United States; the Japanese patent for leßunomide has already expired. Leßunomide is an orally administered isoxazole pro-drug with antiproliferative and anti-inßammatory properties, the latter attributable to direct inhibition of COX-2. The drug’s active metabolite (A77-1726) is believed to block immune-cell proliferation by inhibiting dihydroorotate dehydrogenase, a ratelimiting enzyme involved in de novo pyrimidine synthesis, which is required for lymphocyte turnover. It may also inhibit lymphocyte tyrosine kinases and reduce responsiveness to interleukin (IL)-2 (Fox RI, 1998). Onset of action is as little as four weeks, giving it a signiÞcant advantage over many conventional DMARDs. Its recommended dosage is 100 mg once daily for three days and 10–20 mg once daily thereafter. The relative efÞcacy of leßunomide and methotrexate is controversial, but leßunomide is generally considered to have efÞcacy comparable to that of methotrexate. A double-blind, parallel-group Phase III trial of 999 RA patients, randomized to receive either 10–15 mg weekly methotrexate or 20 mg daily leßunomide (following a 100 mg daily loading dose for three days), found a signiÞcant difference in efÞcacy in favor of methotrexate at one year—50.5% of patients in the leßunomide group were ACR 20 responders compared with 64.8% in the methotrexate group. In fact, the ACR response rate and improvements in all efÞcacy variables with methotrexate were signiÞcantly greater than with leßunomide. However, radiographically assessed disease progression was not statistically different between the two treatments. After two years in 612 patients continuing this trial, ACR 20 response rates were similar with both leßunomide and methotrexate (64.3% and 71.7%). Furthermore, a second, two-year Phase

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III comparative study found that leßunomide efÞcacy and safety were superior to methotrexate (Cohen S, 2001). In this double-blind trial, 235 patients were randomized to receive leßunomide (20 mg daily, loading dose 100 mg for three days) or methotrexate (8–17 mg) weekly. At the end of the study period, 79%, 56%, and 26% of the leßunomide-treated patients achieved ACR 20, ACR 50, and ACR 70 responses, respectively, compared with 67%, 43%, and 20% for methotrexate. Leßunomide was also signiÞcantly superior to methotrexate in improving physical function over the 24 months of treatment in this study. Leßunomide is considered to have a similar or slightly better safety proÞle as compared with methotrexate. Serious adverse events were reported in 1.6% of the leßunomide-treated patients and 3.7% of the methotrexate-treated patients in the 2001 (Cohen) study. In addition to being teratogenic, the most common drugrelated adverse events associated with leßunomide in these clinical trials were diarrhea, liver enzyme abnormalities, rash, reversible alopecia, and hypertension. In an open-label extension study in 96 patients, diarrhea and nausea were less frequent in patients who did not receive a loading dose, with no apparent decrease in efÞcacy (Kremer J, 2004). In a mandatory post-marketing surveillance program in all leßunomide-treated RA patients in Japan (n = 3, 658), interstitial lung disease (ILD) was reported in 0.8%. Twenty-nine cases of interstitial pneumonitis were reported, 11 of which proved fatal. However, the causality link between leßunomide use and the reported ILD was frequently confounded by pre-existing pulmonary disease and previous or concomitant use of other DMARDs. These events are being evaluated by SanoÞ-Aventis, which has recommended that pulmonary status be assessed prior to the initiation of leßunomide, together with close monitoring of patients during treatment. Leßunomide is frequently employed in combination with other DMARDs. According to the opinion obtained at an International Expert Panel Meeting held in Paris in May 2003, 61% of the Expert Panel would use leßunomide with methotrexate, 71% with sulfasalazine (PÞzer’s AzulÞdine/Salozopyridine, generics), 43% with inßiximab, 38% with anakinra (Amgen’s Kineret), 33% with adalimumab (Abbott/Eisai’s Humira), and 19% with etanercept (Kalden JR, 2004). Sulfasalazine. Sulfasalazine (PÞzer’s AzulÞdine/Salozopyridine, generics) (Figure 4) is available in all the markets under study, including Japan, where it is called “salazosulfapyridine.” It is a conjugate of salicylic acid, belonging to the sulfonamide drug class. The drug is metabolized to two key components: sulfapyridine, which has antibacterial activity, and 5-aminosalicylic acid, which is an anti-inßammatory (Rains CP, 1995). Although sulfasalazine suppresses disease activity in RA, its mode of action as a disease modiÞer remains unknown. Sulfasalazine was shown to have superior efÞcacy compared with placebo in a 48-week, double-blind, prospective study (Hannonen P, 1993). The study enrolled 80 patients with early RA, and study participants were randomized to receive either 2 g sulfasalazine daily or placebo; patients were also allowed concomitant NSAID and corticosteroid therapy. At the end of the 48-week study,

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COOH

N NHSO2

OH

N

N

FIGURE 4. Structure of sulfasalazine.

patients treated with sulfasalazine were shown to have statistically signiÞcant improvements compared with placebo on three of the four measures of efÞcacy: joint tenderness (measured by a modiÞed Ritchie articular index; score range 0–90), number of swollen joints, and patient’s global assessment of disease activity (measured by a 5-point scale); the difference in improvement between the two treatment groups for the physician’s global assessment of disease activity was not signiÞcant. Improvements on these efÞcacy measures were greater for rheumatoid factor seronegative (RF-) early RA patients compared with seropositive (RF+) early RA patients. RF− and RF+ patients taking sulfasalazine had mean improvements of 5.46 and 1.68 points, respectively, on the Ritchie articular index. Corresponding mean changes for the placebo group were a 1.69-point improvement for RF- patients and a 0.24-point worsening for RF+ patients. The mean number of swollen joints improved by 4.39 and 1.77 for RF- and RF+ patients taking sulfasalazine, respectively, while RF- and RF+ patients taking placebo had a 0.23 improvement and a 0.76 worsening, respectively, in the number of swollen joints. Lastly, mean improvements in the global assessment of disease activity were 0.92 and 0.23 for RF- and RF+ patients taking sulfasalazine, respectively. RF- and RF+ patients taking placebo had corresponding improvements of 0.08 and 0.04, respectively. Sulfasalazine is used alone for mild disease and in combination with other conventional DMARDs, principally methotrexate, in moderate RA when the latter has proven inadequate as monotherapy. Once highly popular in Europe, sulfasalazine has been displaced as the Þrst-choice DMARD by methotrexate, primarily because the latter is seen as a more effective agent. The dosage of sulfasalazine is 500 mg twice daily taken orally, with increases of up to 2–3 g per day in divided doses. Onset of action requires three to eight weeks, with approximately 70% of patients demonstrating a satisfactory clinical response within one year (Rains CP, 1995). The agent’s use is constrained by its sideeffect proÞle. Gastrointestinal symptoms, the most common side effect, are often resolved with dose attenuation, but some rare but serious hematological reactions necessitate regular blood tests. Occasionally, hepatotoxicity, pneumonitis, and myelosuppression occur (Scott DL, 1988). Hydroxychloroquine/Chloroquine. Originally developed as antimalarials, these agents are employed principally in treating mild RA. Because of its superior side-effect proÞle, hydroxychloroquine (SanoÞ-Aventis’ Plaquenil, generics) (Figure 5) is more popular than chloroquine (generics), its parent compound.

650


FIGURE 5. Structure of hydroxychloroquine.

Researchers believe that hydroxychloroquine and chloroquine inhibit antigen presentation and block receptor-mediated endocytosis, granulocyte migration, the action of phospholipase A2 , and the release of cytokine IL-1β (Fox RI, 1993). The efÞcacy of hydroxychloroquine was compared with that of placebo in a six-week double-blind, randomized trial involving 126 patients with early RA (Clark P, 1993). Patients were randomized to receive either 400 mg daily hydroxychloroquine or placebo. Treatment with hydroxychloroquine was associated with clinically and statistically signiÞcant improvements over placebo on four efÞcacy measures used in the study: joint score (sum of scores for joint swelling [58 joints graded on a 0–3 point scale] and joint tenderness [60 joints graded on a 0–3 point scale])—the primary end point of the trial; patients’ assessment of joint pain (using a 10-cm visual analogue scale [VAS]); grip strength (measured by a mercury-column sphygmomanometer in mm Hg); and ESR (measured in mm/hr). Mean improvements for joint score, patient’s assessment of pain, grip strength, and ESR were 18.5 points, 25.8 mm, 31.9 mm HG, and 5.6 mm/hr, respectively, for the group treated with hydroxychloroquine; the corresponding improvements for the placebo group were 11.9 points, 6.5 mm, 10.7 mm Hg, and 4.3 mm/hr. Hydroxychloroquine was well tolerated in this study with no difference in the overall incidence of adverse events between the active and placebo groups, although the incidence of headache was signiÞcantly higher in the treated group. Prescribed in oral daily dosages of 200 mg to 400 mg, antimalarials are employed as an alternative to sulfasalazine in early disease. Support for the use of hydroxychloroquine in the treatment of early RA came in a recent study that demonstrated that, after two years, a majority of early RA patients (56/94) were controlled on hydroxychloroquine or were in remission (Matteson EL, 2004). Much of current prescribing of antimalarials is, however, in dual or triple combinations with other conventional DMARDs, particularly methotrexate and sulfasalazine (Jobanputra P, 2004). Nausea or dizziness may accompany use, although the most serious side effect is irreversible macular damage (Jones SK, 1999), so regular ophthalmologic exams are recommended. Biological Agents Overview. Biological DMARDs for the treatment of RA include the tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, inßiximab, and adalimumab,

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FIGURE 6. Role of select cytokines in rheumatoid arthritis pathogenesis.

as well as the IL-1β receptor antagonist anakinra. TNF-α is a potent proinßammatory cytokine. Its role in RA has been demonstrated in transgenic mouse models in which TNF-α overexpression has led to joint destruction and aggressive synovitis (Figure 6). Among RA patients, the degree of synovial TNF-α expression correlates with the degree of synovitis and bone erosion. In addition to TNF-α, many other proinßammatory cytokines—including IL-1β —are involved in the pathogenesis of RA. Current biological agents antagonize the destructive role of such cytokines in the disease. Mechanism of Action. Receptors for TNF-α are found on the surface of most cells, including mononuclear cells and cells in the synovium. Two distinct types of TNF-α receptors have been identiÞed: type I (p55) and type II (p75). Cleavage of membrane-bound TNF-α receptors yields soluble receptors that retain ligandbinding ability but cannot activate cells. TNF-α inhibitors reduce free, bioactive TNF-α by emulating the physiological role played by soluble TNF-α receptors, which modulate the amount of circulating, bioactive TNF-α by binding

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to the cytokine before it can activate cell-surface receptors on mononuclear cells. Because TNF-α plays an important role in the eradication of neoplastic cells, its suppression is not without hazards—particularly as a long-term strategy. Concerns have been raised as to whether chronic immunosuppression leads to opportunistic infection, malignancies, or other complications (Alldred A, 2001; Lee JH, 2002). In October 2004, the FDA recommended a warning concerning malignancy be added to the labeling for all TNF-α inhibitors stating that in controlled studies, more cases of lymphoma have been observed among patients receiving TNF-α inhibitors than among control group patients. In practice, rheumatologists trade the beneÞts of anti-TNF-α therapy in treating this serious disease with persistent worry over possible long-term effects. Such concerns remain particularly pronounced when initiating lifelong treatment in young patients. Inßammation induces IL-1 production in macrophages, in turn mediating various inßammatory and immunological responses including cartilage degeneration, stimulation of bone resorption, and joint invasion by synoviocytes. Anakinra, the Þrst interleukin-modulating therapy indicated for RA, competitively inhibits the activity of IL-1β, thus limiting the degrading effects of the cytokine. Etanercept. Launched in 1998 in the United States, etanercept (Amgen/ Wyeth/Takeda’s Enbrel) was the Þrst TNF-α inhibitor approved for the treatment of RA. It was initially indicated for moderate to severe RA patients unresponsive to one or more conventional DMARDs or for use in combination with methotrexate for patients unresponsive to methotrexate alone. It has since been granted orphan drug approval for use in juvenile RA patients. In June 2000, the FDA expanded the agent’s label to include reducing symptoms and delaying structural damage in patients with moderate to severe, active RA at an early stage. In July 2003, the FDA approved a further indication extension for use in improving physical function in patients with moderate to severe, active RA, while in October 2003, approval was also gained for a 50 mg once-weekly dosage for adults (compared with the then-standard dosage of 25 mg twice weekly). This development was followed by the approval in September 2004 of a 50 mg preÞlled syringe formulation in the United States. In the same month, etanercept became the only FDA-approved biologic to induce a major clinical response in RA patients, deÞned as achieving an ACR 70 response for six consecutive months. This agent is marketed by Amgen (formerly Immunex) in conjunction with Wyeth in the United States and by the latter in Europe. It was approved by the European Agency for the Evaluation of Medicinal Products (EMEA) for use in adult and juvenile RA patients in the 15 European Union countries in February 2000 and was launched later that year. Japanese approval was granted to copromoters Wyeth and Takeda in January 2005, and the drug launched in March 2005. Patents expire in 2010 in Japan, in 2014 in the United States, and in 2015 in Europe. Etanercept is a soluble TNF-α receptor fusion protein, consisting of a portion of the soluble p75 TNF-α receptor fused to the Fc fragment of human

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653

immunoglobulin G (IgG)1. The TNF-α receptor component binds free TNF-α protein, and the antibody component can mediate effector functions such as initiation of the complement system and phagocytosis. Etanercept was bioengineered to have a higher binding afÞnity for TNF-α than the natural receptor. Moreover, the presence of an Fc fragment extends the agent’s half-life approximately Þvefold to eightfold in vivo. TNF-α inhibitors tend to have a faster onset of action than conventional DMARDs, and etanercept’s effects become apparent within two to three weeks. A two-year, double-blind trial designed to compare clinical and radiographic outcomes in early, aggressive RA showed that etanercept is superior to methotrexate in reducing disease activity, arresting structural damage, and decreasing disability (Genovese MC, 2002[a]). The trial enrolled 632 patients who had suffered from RA for up to three years. Patients were randomized to receive etanercept (10 or 25 mg) twice weekly or methotrexate (mean dose 19 mg) weekly. The primary end points were ACR 20 response and X-ray progression as measured according to the Sharp score. (The Sharp score is the sum of a measure of joint space narrowing and a measure of bone erosion; increases in Sharp scores indicate a worsening of disease.) Although all three treatments effectively reduced the signs and symptoms of RA, signiÞcantly more patients in the etanercept 25 mg group achieved an ACR 20 response (72% versus 59% with methotrexate). Patients receiving etanercept 25 mg also experienced the most dramatic reduction in radiographic progression. The mean increase in Sharp score was 1.3 units in the etanercept 25 mg group compared with 3.2 units in the methotrexate group. Approximately 15% of patients in the etanercept groups withdrew because of adverse events versus 21% in the methotrexate group. Injection site reactions were the most common adverse event in the etanercept-treated group. Etanercept has also been investigated in combination with methotrexate in the ongoing, two-year TEMPO study of 686 patients with RA. As assessed by the Disease Activity Score (DAS) at 52 weeks, signiÞcantly more patients (35%) receiving the combination of etanercept and methotrexate achieved clinical remission, compared with 16% on etanercept alone and 13% on methotrexate alone (Klareskog L, 2004). No radiographic progression of joint damage, as assessed by Sharp score, was seen at two years in 74.2% of patients taking the combination therapy, compared with 65.5% and 59.2% of etanercept and methotrexate alone, respectively. Patients treated with the combination experienced a 56% mean improvement in HAQ scores from baseline, compared with 39% with etanercept alone and 36% with methotrexate alone (Amgen, press release, October 18, 2004). In August 2001, Immunex (acquired by Amgen in 2002) and Wyeth announced the initiation of the largest clinical trial to date to evaluate the impact of etanercept in U.S. RA patients. The trial, known as the Rheumatoid Arthritis DMARD Intervention and Utilization Study (RADIUS), will compare the safety, efÞcacy, and treatment patterns of 5,000 RA patients treated with etanercept in the second phase of the study with those of 5,000 patients treated with a variety of other DMARDs in the Þrst phase of the study. In July 2003, Amgen announced the

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completion of enrollment of 5,000 patients at more than 400 study sites for the second phase of the study. Data will be collected for at least Þve years. Studies have shown that etanercept may cause hematological reactions and demyelinating disorders, the latter in patients with preexisting central nervous system demyelinating disease (Alldred A, 2001; Mohan N, 2001). In addition, several patients developed serious infections during postmarketing surveillance, resulting in the inclusion of a warning on etanercept’s label advising caution in patients with a history of recurring infections or predisposition to infection. Observed event rates among 2,054 clinical trial participants eligible to enroll in extension studies with a combined etanercept exposure of 7,382 patient-years were presented at the 2004 ACR Annual Congress. Rates of serious adverse events, serious infections, opportunistic infections, and deaths did not increase with more than seven years of treatment. However, the incidence of lymphoma was higher than that expected in the general population (67 versus 61 cases), and the authors called for additional studies to determine whether this Þnding reßects inherent risk in RA or is related to etanercept treatment (Moreland LW, 2004[b]). Infliximab. Inßiximab (Centocor [a subsidiary of Johnson&Johnson]/ScheringPlough/Tanabe Seiyaku’s Remicade) was the second TNF-α inhibitor to make a major impact on the treatment of RA. It is marketed in the United States by the originator, Centocor; by licensee Schering-Plough in Europe; and by Tanabe Seiyaku in Japan, where it has been the only TNF-α inhibitor available until the 2005 launch of etanercept. Initially launched in the United States in 1998 for the short-term treatment of Crohn’s disease, inßiximab received FDA approval in 1999 for use in combination with methotrexate to treat adult RA patients refractory to methotrexate alone. In December 2000, labeling was expanded for use of the same regimen in inhibiting the progression of structural damage. In February 2002, supplemental FDA approval was gained for improving physical function in patients with moderate to severe, active RA. In September 2004, the FDA approved expanded labeling for inßiximab in combination with methotrexate as a Þrst-line regimen for moderate to severe RA, eliminating the requirement that patients must Þrst fail to respond to methotrexate alone. Inßiximab received centralized marketing authorization from the EMEA in June 2000 for use in combination with methotrexate for the reduction of signs and symptoms in RA patients with active disease showing inadequate response to previous DMARDs, including methotrexate. In June 2004, approval was granted in Europe as Þrst-line therapy for the treatment of early RA. Additional labeling was approved in Europe in July 2004 for ankylosing spondylitis, while in September 2004, the EMEA approved further labeling for inßiximab in combination with methotrexate for the treatment of active and progressive psoriatic arthritis in patients responding inadequately to DMARDs. In December 2004, approval was gained in the United States for the treatment of psoriatic arthritis in patients with active disease. Inßiximab was launched in Japan for Crohn’s

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disease in May 2002 and for RA in July 2003. Patents expire in 2012 in Europe and Japan and in 2016 in the United States. Inßiximab is a chimeric monoclonal antibody composed of 75% human and 25% mouse protein. The drug exerts its therapeutic effect by binding soluble and membrane-bound TNF-α, thereby blocking its ability to activate the inßammatory cascade. The mouse portion of the antibody contains the TNF-α binding sites, and the human portion is responsible for effector function, including IgGstimulated elimination of TNF-α positive cells by both antibody-dependent cellular cytotoxicity and complement-dependent mechanisms (Feldmann M, 2001). Inßiximab may also inhibit the upregulation of cell-surface adhesion proteins—a process that plays an important role in mediating inßammation. The development of human antichimeric antibodies has been reported in as many as 50% of patients across various clinical studies, or more than twice the rate associated with etanercept use (Moreland LW, 2001). No clinically signiÞcant effects have been observed as a result of these antibodies, although debate regarding their importance is ongoing. Inßiximab must always be used in conjunction with methotrexate because doing so appears to help reduce antibody production. The inclusion of the murine component leads some physicians to prefer other anti-TNF-α agents, as they are perceived to carry less of an immunological risk. The approval of inßiximab for improving physical function was based on data from a Phase III trial, the Anti-TNF-α Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) (Wong JB, 2002). Study participants had active RA for an average of 8.4 years, had failed to respond to a median of three DMARDs, and had previously experienced an insufÞcient response to methotrexate alone. In this multicenter trial conducted at 34 centers in the United States and Europe, 428 patients were randomized to receive inßiximab (3 mg/kg or 10 mg/kg) or placebo for one year. All received concomitant methotrexate (10–15 mg weekly). Inßiximab was administered at zero, two, and six weeks, and additional doses were given every four or eight weeks thereafter. ACR 50 response criteria were achieved in 29, 27, 26, and 31% of patients receiving 3 mg/kg every four or eight weeks or 10 mg/kg every four or eight weeks, respectively, compared with 5% of patients receiving placebo plus methotrexate. In a second Phase III study, the ASPIRE trial (Active Controlled Study of Patients Receiving Inßiximab for Treatment of Rheumatoid Arthritis of Early Onset), a total of 1,004 patients with early RA were assigned to receive infusions of placebo or inßiximab at weeks 0, 2, and 6, and then every eight weeks thereafter to week 46. All patients received concomitant methotrexate. At the 2004 ACR Annual ScientiÞc Meeting, Centocor presented new Þndings from this study which formed the basis for the expanded indication as Þrst-line therapy in patients with moderate to severe, active RA. An erosion-free state was observed in 79% of patients who began the study with no joint erosions that were treated with inßiximab plus methotrexate for one year, compared to 58% of patients treated with methotrexate alone (Centocor, press release, October 18, 2004).

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Adverse events associated with inßiximab are generally mild. They include headache, nausea, rash, coughing, sinusitis, dyspnea, urticaria, hypotension, and upper respiratory tract infection. Although the incidence of malignancies in clinical trials is not greater than with placebo, experts remain concerned about the agent’s long-term safety, particularly with regard to chronic immunosuppression. Inßiximab’s packaging has long included a disclaimer stating that patients should discontinue therapy if they develop a serious infection or sepsis. Following an FDA recommendation, Centocor also included a boxed warning on the package insert noting an increased risk of developing tuberculosis and other opportunistic infections. The warning was based on the occurrence of more than 80 cases of tuberculosis in inßiximab-treated patients worldwide. In August 2001, following the completion of clinical trials in congestive heart failure, Centocor/ScheringPlough/Tanabe Seiyaku issued a warning stating that inßiximab therapy should not be initiated in patients with concomitant congestive heart failure. The companies have discontinued trials in this indication because of adverse events. By August 2004, worldwide postmarketing experience revealed hematological events in patients receiving inßiximab, including leukopenia, neutropenia, thrombocytopenia, and pancytopenia—some with fatal outcomes. Accordingly, a warning statement was added to inßiximab labeling. Inßiximab is administered in 3 mg/kg doses given as a two-hour infusion every eight weeks, following a standard induction regimen requiring treatment at weeks 0, 2, and 6. The regimen requires administration directly by caregivers in the clinic or ofÞce setting. Most patients who respond do so within two to three weeks. Adalimumab. Like other TNF-α inhibitors, adalimumab (Abbott/Eisai’s Humira) blocks the activity of TNF-α by binding to this cytokine. Discovered by Cambridge Antibody Technology and developed by Abbott Laboratories, adalimumab is the Þrst fully human monoclonal anti-TNF-α antibody to be marketed. Abbott and GTC Biotherapeutics have established a strategic partnership in which the latter will produce adalimumab in transgenic goats. Adalimumab was launched in the United States for RA in January 2003. It is approved for reducing the signs and symptoms of RA and inhibiting the progression of structural damage in adults with moderate to severe, active RA who have had insufÞcient response to one or more DMARDs. In August 2004, the labeling was expanded to include improvement in physical function for adult patients with moderate to severe, active RA. The product was launched in September 2003 in Germany and the United Kingdom, followed by other European countries in subsequent months. In Europe, adalimumab is approved for the treatment of moderate to severe, active adult RA following inadequate response to DMARDs, including methotrexate. In May 2004, Abbott announced that the EMEA had granted a “positive opinion” for an RA label extension for reducing the rate of progression of joint damage as measured by X ray and improving physical function in adults when given in combination with methotrexate. In Japan, adalimumab is licensed to Eisai and is in Phase II development for RA. Patents expire in 2014 in the United States and in 2017 in Europe and Japan.

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Patients with chronic RA treated with adalimumab in combination with methotrexate demonstrated signiÞcant clinical improvements in Phase II and III clinical trials. In a 52-week, double-blind study, 619 patients with active RA were randomized to receive adalimumab (20 mg weekly or 40 mg every other week) plus methotrexate or placebo. A total of 467 patients (75.4%) completed the full course of treatment. At week 52, there was statistically signiÞcantly less radiographic progression, as measured by the change in Sharp score, in the patients receiving adalimumab either 40 mg (mean change 0.1) or 20 mg weekly (0.8) compared with placebo (2.7). ACR 20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg and 20 mg, respectively, versus 24% of patients taking placebo. Physical function, as measured by HAQ scores, demonstrated signiÞcant improvement with adalimumab 40 mg (mean change in HAQ score −0.59) and 20 mg (−0.61) compared with placebo (−0.25) (Keystone EC, 2004[b]). To evaluate adalimumab immunotherapy in RA where previous DMARD treatment had failed, 544 patients were randomized to monotherapy versus placebo. After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had a statistically significantly better ACR 20 response rates than those treated with placebo (35.8%, 39.3%, 46.0%, and 53.4%, respectively, versus 19.1%) (van de Putte LB, 2004). The most frequently observed adverse events in clinical trials of adalimumab were injection site reactions, upper respiratory infection, injection site pain, headache, hypertension, rash, and sinusitis. In November 2004, Abbott issued revised warnings including serious infections with the combined use of adalimumab and anakinra, hypersensitivity reactions including anaphylaxis, hematologic events including pancytopenia, and aplastic anemia. The product label also acknowledges that malignancies have been observed in patients treated with adalimumab and that there may be an increased risk of lymphoma with TNF-α inhibitor therapy. To ensure maximum efÞcacy, adalimumab is typically given in combination with methotrexate. Adalimumab can also be given as monotherapy in cases of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Because it is a fully human antibody, this agent is expected to cause less immunogenicity than the chimeric monoclonal antibody inßiximab, and adalimumab may eventually replace inßiximab for this reason. Adalimumab, given as twice-monthly 40 mg subcutaneous injections, is also more convenient than either inßiximab or etanercept. However, adalimumab may have greater difÞculty displacing etanercept, a drug already favored by many rheumatologists. Adalimumab’s reduced immunogenicity is unlikely to confer a signiÞcant advantage over etanercept because this problem occurs only infrequently following long-term etanercept use. The most signiÞcant barrier to adalimumab displacing etanercept is physician comfort and experience with etanercept. Therefore, adalimumab will likely be used as a second-line TNF-α inhibitor, following treatment failure with etanercept.

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In an attempt to tip the scale in favor of the use of adalimumab over etanercept in the U.S. RA market, Abbott announced the start of the Humira Medicare Assistance Program in January 2003. This drug access program will provide adalimumab to Medicare-eligible senior citizens in the United States. Only inßiximab is currently reimbursed by Medicare, given that self-administered therapies, like etanercept and adalimumab, are not covered. Starting in 2006, however, the Centers for Medicare and Medicaid Services—a federal agency within the U.S. Department of Health and Human Services—is providing access to selfadministered prescription medicines through the Medicare replacement drug demonstration program. Adalimumab will already be well established in the elderly U.S. population when the restrictions on the reimbursement of self-administered drugs by Medicare recipients are relaxed, giving it a potential advantage over etanercept. Anakinra. Anakinra (Amgen’s Kineret) is an IL-1β receptor antagonist that competitively inhibits the activity of IL-1β, a macrophage-produced cytokine that plays a dominant role in cartilage degeneration and joint invasion by synoviocytes. The drug was launched in the United States in December 2001 for the treatment of RA in patients with moderate to severe disease failing to respond to one or more DMARDs. In March 2002, anakinra was approved in Europe for the treatment of RA in combination with methotrexate in patients with an inadequate response to methotrexate alone. By June 2002, the agent was launched in Germany, the United Kingdom, and a number of smaller European markets. Amgen and the University of Colorado Foundation have been granted a U.S. patent for the IL-1β inhibitor sequences and the methods for producing them, thereby securing rights to this and future IL-1β inhibitory molecules. Patents expire in 2009 in France, Germany, and Japan; in 2014 elsewhere in Europe; and in 2017 in the United States. A 24-week, multicenter study designed to evaluate the safety and efÞcacy of the agent in 506 patients with moderate to severe active RA showed that anakinra combined with methotrexate is superior to methotrexate alone (Cohen SB, 2004). Patients received subcutaneous injections of anakinra 100 mg/day or placebo in a single daily subcutaneous injection. All patients received concomitant methotrexate (10–25 mg weekly), and the primary end point was an ACR 20 response at 24 weeks. SigniÞcantly greater proportions of patients treated with anakinra compared with placebo achieved ACR 20 (38% versus 22%), ACR 50 (17% versus 8%), and ACR 70 (6% versus 2%) responses. Data presented at the 66th annual ACR meeting in 2002 demonstrated that anakinra inhibits bone and joint damage in RA patients (Shergy W, 2002). In the study, 906 patients were randomized to receive anakinra (100 mg) or placebo for 52 weeks. All patients received concomitant methotrexate (10–25 mg weekly), and the primary end point was X-ray progression as measured according to the Sharp score. At the end of the study period, 50% of the anakinra-treated patients showed no disease progression compared with 42% for placebo. Adverse events, events leading to withdrawal, and infectious events were similar in the two treatment groups. Based on the results of this study, Amgen gained additional

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labeling for slowing the progression of structural damage in moderate to severe, active RA. In a study to examine the safety of anakinra when added to background DMARD therapy, patients with RA were randomly assigned in a 4:1 allocation ratio to treatment with anakinra 100 mg or placebo administered daily by injection. Anakinra patients (n = 1, 116) showed no difference in the incidence of upper respiratory infections or overall serious adverse events compared with placebo patients (n = 283). The anakinra group had more injection site reactions (72.6% versus 32.9%), and a small increase in serious infections (2.1% versus 0.4%) was observed (Tesser J, 2004). An increased incidence of adverse events such as infections were reported with anti-TNF-α and IL-1 receptor antagonist combination therapy trials in RA patients, prompting the FDA’s Arthritis Advisory Committee to release a statement in August 2001 (at the time of anakinra’s approval) advising against such therapy. Anakinra requires daily administration by 100 mg subcutaneous injection because of its rapid clearance, which is seen as a drawback in comparison with the TNF-α inhibitors. This agent has assumed a niche role in patients refractory to conventional DMARDs and the TNF-α inhibitors. Traditional Nonsteroidal Anti-Inflammatory Drugs Overview. Generally, the Þrst course of therapy for RA initiated by primary care physicians has been nonsteroidal anti-inßammatory drugs (NSAIDs), which are mainly administered to help relieve pain and inßammation. Their analgesic effect is felt quickly and lasts just a few hours, whereas their anti-inßammatory properties become apparent only after several days of repeated administration. However, NSAIDs are unable to halt the progression of RA or prevent joint damage caused by the disease. This symptomatic treatment approach covers the use of both older NSAIDs and the more recently introduced selective (COX-2) inhibitors. The older NSAIDs are often referred to as nonselective relative to the highly selective COX-2 inhibitors, but these agents actually demonstrate a spectrum of selectivity for the COX enzymes, ranging from preferential COX-1 inhibition to preferential COX-2 inhibition. In line with industry convention, the discussion here groups the older, less selective agents (including the preferential COX-2 inhibitors) together under the heading of traditional NSAIDs and considers them separately from the selective COX-2 inhibitors. Numerous traditional NSAIDs—many of which are available as inexpensive over-the-counter (OTC) preparations—are available to relieve the pain and inßammation associated with RA. However, treatment of moderate to severe pain generally requires dosing that is available only by prescription. Because of the large number of traditional NSAIDs available on the market, this section discusses only three of the most popular agents used in the treatment of RA—diclofenac (Novartis’ Voltaren/Voltarol, generics), naproxen (Roche’s Naprosyn/Anaprox/Proxen, Bayer’s Aleve, generics), and meloxicam (Boehringer Ingelheim/Abbott/Daiichi’s Mobic)—as representatives of this class.

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Mechanism of Action. Although the mechanism of NSAID action is not fully understood, these drugs are known to block the arachidonic acid pathway at an early stage. Arachidonic acid is the major fatty acid incorporated into cell membranes, and its metabolites serve as precursors to the synthesis of prostaglandins. These inßammatory mediators, especially prostaglandin E2 (PGE2 ), cause inßammation by increasing the vascular permeability of blood vessels. Elevated expression of prostaglandins has been detected in the synovium of arthritic joints. The COX-1 and COX-2 enzymes initially convert arachidonic acid into intermediary cyclic endoperoxides, which, in turn, are converted into prostaglandins. Traditional NSAIDs inhibit the activity of one or both of the COX enzymes, thereby preventing the production of prostaglandins (see Figure 7). Although NSAIDs are highly effective at relieving symptoms of pain and inßammation, their use is complicated by serious side effects. Researchers now recognize that both the desired therapeutic effects and the main side effects of NSAIDs are attributable largely to the suppression of PGE2 . In addition to mediating inßammation, PGE2 , as well as other prostaglandins, has a protective role in the gastrointestinal (GI) tract and kidneys. The most common and disturbing adverse events associated with traditional NSAIDs are impaired renal function and GI complications, including GI hemorrhage, ulcers, perforations, and obstructions. In a large study evaluating treatment outcomes of RA patients receiving NSAID therapy for an average of 2.5 years, 15% of patients experienced

FIGURE 7. The role of tumor necrosis factor-alpha in the pathogenesis of rheumatoid arthritis.

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an NSAID-induced GI side effect (Singh G, 1996). To mitigate the suppression of PGE2 , some physicians prescribe proton pump inhibitors or misoprostol (PÞzer’s Cytotec) along with NSAID therapy. Proton pump inhibitors block the production of acid in the GI tract, minimizing the formation of ulcers, and misoprostol is a synthetic PGE1 analogue that protects the lining of the stomach by mimicking the action of naturally occurring prostaglandins. To facilitate dosing convenience, combination products combining a traditional NSAID with either a proton pump inhibitor or misoprostol are now available. For example, TAP Pharmaceutical Products (a joint venture between Abbott and Takeda) markets Prevacid Naprapac, a combination of the proton pump inhibitor lansoprazole (TAP’s Prevacid) and naproxen, while PÞzer markets Arthrotec, a combination of misoprostol with diclofenac. Diclofenac. Diclofenac (Novartis’s Voltaren/Voltarol, generics) (Figure 8) is a phenylacetic acid derivative. In addition to inhibiting the COX enzymes, diclofenac decreases the availability of arachidonic acid and inhibits production of leukotrienes. It is a rapidly metabolized NSAID with a plasma half-life of less than two hours, requiring multiple daily doses. The efÞcacy of diclofenac was compared with that of placebo in a two-week double-blind trial of 44 RA patients (Doreen MS, 1978). Patients were given either placebo or 75 mg diclofenac daily during the Þrst week; diclofenac doses were increased to 75–150 mg daily during the second week of the study. Patients were also allowed to take acetaminophen as a rescue analgesic. After the Þrst week of the study, 50% of patients treated with diclofenac reported an improvement in their pain, compared with 24% of placebo recipients; this difference was statistically signiÞcant. After the second week of treatment, 60% and 33% of diclofenac- and placebo-treated patients, respectively, reported improvement in pain; this difference was not statistically signiÞcant. However, acetaminophen consumption was signiÞcantly lower for patients treated with diclofenac compared with those receiving placebo. At the end of the 14-day treatment period, improvements in grip strength (measured by the sum of three readings for each hand using a grip bag inßated to 30 mm Hg) and articular index of joint tenderness (measured using the Ritchie scale with a maximum score of 69) were signiÞcantly superior to those of the placebo group. The diclofenac group demonstrated

COOH NH Cl

Cl 3' 4'

FIGURE 8. Structure of diclofenac.

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a 15 mm Hg increase in grip strength and an improvement of 3.5 on the articular index, compared with a 40 mm Hg worsening on grip strength and an improvement of 0.8 on the articular index for the placebo-treated group. Duration of morning stiffness decreased by 20 minutes for patients treated with diclofenac and increased 18 minutes for placebo recipients at the end of the study period. Six patients in the diclofenac group reported minor GI side effects and/or headaches and dizziness, compared with ten patients treated with placebo. Like other NSAIDs, diclofenac’s side effects are predominantly GI-related, including dyspepsia, epigastric pain, vomiting, and diarrhea (Singh G, 1996). Hepatotoxicity is also a concern. According to 180 cases reviewed by the FDA between 1988 and 1991, diclofenac poses a risk of liver damage to all patients, particularly women (Banks AT, 1995). Naproxen. Naproxen (Roche’s Naprosyn/Anaprox/Proxen, Bayer’s Aleve, generics) (Figure 9), a naphthaleneacetic acid derivative, is a long-acting traditional NSAID available OTC and by prescription. The OTC preparations of this drug are all sodium salts (naproxen sodium), but prescription formulations are either naproxen (Naprosyn) or naproxen sodium (Anaprox). The sodium salt was developed to enable faster drug dissolution, thus speeding absorption and onset of action. A controlled-release formulation of naproxen sodium (Wyeth/Elan’s Naprelan, generics) is also available. Like other traditional NSAIDs, naproxen inhibits the activity of the COX enzymes, thereby preventing the production of prostaglandins. By inhibiting prostaglandin production, naproxen is able to reduce pain and inßammation. In a placebo-controlled, double-blind study, 1,149 RA patients were randomized to receive 500 mg naproxen twice daily, 100 mg, 200 mg, or 400 mg celecoxib (PÞzer/Astellas’s Celebrex, a selective COX-2 inhibitor, discussed later in this section) twice daily, or placebo for 12 weeks (Simon LS, 1999). Patients were allowed to maintain stable doses of oral corticosteroids or DMARDs during the course of the trial. EfÞcacy measures included the percentage of patients achieving an ACR 20 response, a reduction of two or more grades from baseline on the Þve-point patient’s and physician’s global assessment scales, and mean improvements over baseline on the patients’ assessment of arthritis pain (100 mm VAS). Results for these four efÞcacy measures for the Þve treatment groups are reported in the following order: placebo, 500 mg naproxen twice daily, 100 mg celecoxib twice daily, 200 mg celecoxib twice daily, and 400 mg celecoxib twice

CO2H O FIGURE 9. Structure of naproxen.

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daily. Response rates using the ACR 20 criteria were 29%, 36%, 40%, 44%, and 39%, respectively. The percentage of patients demonstrating an improvement on the patient’s global assessment were 16%, 19%, 22%, 30%, and 25%, respectively. The percentage of patients demonstrating an improvement on the physician’s global assessment were 15%, 20%, 21%, 30%, and 25%, respectively. Lastly, the various treatment groups demonstrated improvements of 9.3 mm, 16.9 mm, 16.9 mm, 20.7 mm, and 18.1 mm, respectively, on the patient’s assessment of arthritis pain. The naproxen group’s ACR 20 response rate and improvement in arthritis pain were signiÞcantly superior to those of the placebo group. However, the naproxen group’s improvement on the patient’s and physician’s global assessments over placebo was not statistically signiÞcant. In this trial, adverse events were reported by 65% of patients treated with naproxen and 55% of placebo recipients. The most commonly reported adverse events for the naproxen group were GI tract disturbances (31% of patients), headache (16%), and upper respiratory tract infections (11%), compared with 19%, 23%, and 9% of placebo-treated patients, respectively. One of naproxen’s advantages over other traditional NSAIDs is its 12- to 15-hour plasma half-life, which allows for fewer daily doses. Naproxen is contraindicated in patients taking anticoagulants such as warfarin because naproxen prevents these anticoagulants from binding to plasma proteins, resulting in toxic blood levels of these agents. Recent controversy over the cardiovascular safety of naproxen was spurred by the suspension of the Alzheimer’s Disease Antiinßammatory Prevention Trial (ADAPT) due to concerns over the safety of celecoxib and preliminary Þndings that naproxen increased the risk of cardiovascular and cerebrovascular adverse events. However, the vast majority of data show that there is no relationship between the use of naproxen and an increased risk of myocardial infarction or stroke, although recent data suggest that naproxen may not have the cardioprotective effect it was previously thought to have (Graham DJ, 2005). Meloxicam. Meloxicam (Boehringer Ingelheim/Abbott/Daiichi’s Mobic) has been available in Europe since 1996. It was approved and launched in mid 2000 in the United States for osteoarthritis (OA), where it is co-promoted by Boehringer Ingelheim and Abbott. In July 2004, the FDA expanded meloxicam’s label by approving the drug to treat signs and symptoms of RA. The drug launched in Japan in February 2001, and was comarketed by Nippon Boehringer Ingelheim and Daiichi Pharmaceutical. However, Daiichi took over full Japanese marketing rights for meloxicam in May 2004. Meloxicam lost European patent protection at the end of 2003 and U.S. patent protection in 2005; the Japanese patent for meloxicam has already expired. Meloxicam has the strongest preference for inhibition of COX-2 of the traditional NSAIDs. The drug preferentially inhibits COX-2 over COX-1, so the inhibition of COX-2-stimulated proinßammatory prostaglandin production is greater than the inhibition of the production of COX-1-stimulated prostaglandins, which regulate renal function, blood ßow, platelet activity, and the protection of the

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mucous membrane along the GI tract. As a result, meloxicam was the Þrst NSAID to be marketed speciÞcally as a COX-2 inhibitor. Since then, debate has ensued over whether meloxicam is, in fact, a selective COX-2 inhibitor. The development of truly selective COX-2 agents (discussed later in “Selective COX2 Inhibitors”) has squelched that claim for meloxicam, and it is now referred to as a preferential COX-2 inhibitor. The efÞcacy of meloxicam (7.5 mg or 15 mg daily) has been demonstrated in double-blind trials of more than 5,000 RA and OA patients to be signiÞcantly greater than placebo and comparable to other traditional NSAIDs, such as diclofenac (100 mg daily slow release) and naproxen (750–1000 mg daily) (Barner A, 1996). One double-blind, randomized, placebo-controlled trial of 468 RA patients found that 15 mg meloxicam administered for 21 days was signiÞcantly superior to placebo in three of the four primary end points: patient’s and physician’s assessments of disease activity and reduction in the number of tender joints (Lemmel EM, 1997). A lower dose of meloxicam (7.5 mg) used in this study was also signiÞcantly better than placebo in the patient’s assessment of disease activity and reduction in the number of tender joints. In a 12-week, randomized, double-blind, double-dummy, parallel-group study of 894 RA patients, meloxicam (7.5 mg and 22.5 mg) was signiÞcantly superior to placebo in all Þve primary efÞcacy end points (patient’s and physician’s global assessments, patient’s assessment of pain, tender joint count, and swollen joint count) (Furst DE, 2002). In the same trial, 75 mg diclofenac administered twice daily signiÞcantly improved four of the primary end points over placebo, excluding swollen joint count. A six-month, double-blind, parallel-group study of 700 RA patients that compared 7.5 mg meloxicam with 750 mg naproxen showed no signiÞcant difference between the two treatment groups in the four primary efÞcacy end points (patient’s and physician’s global assessments, tender joint count, and swollen joint count) and in eight of the ten secondary end points (Wojtulewski JA, 1996). There is also evidence that meloxicam produces signiÞcantly fewer GI side effects than other traditional NSAIDs (Barner A, 1996). Meloxicam had fewer GI adverse events than naproxen (30.3% versus 44.7%) in the six-month, doubleblind study of 700 RA patients discussed previously (Wojtulewski JA, 1996). Furthermore, signiÞcantly more patients discontinued treatment because of GI adverse events in the naproxen group as compared with the meloxicam group. However, the 12-week, placebo-controlled, dose-response study of 894 RA patients comparing meloxicam (7.5–22.5 mg daily) and diclofenac (75 mg twice daily) found that the rate of GI events for all of the treatment groups did not differ signiÞcantly from each other or from placebo (Furst DE, 2002). Researchers and physicians were hopeful that these results validated the theory that preferential COX-2 inhibitors were safer than other traditional NSAIDs. However, GI disturbances, including dyspepsia, nausea and vomiting, abdominal pain, and diarrhea, remain common side effects of meloxicam treatment (Hawkey C, 1998; Dequeker J, 1998). In addition, the U.K. Medicines Control Agency and the Committee on Safety of Medicines received 733 reports of 1,339 suspected

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adverse drug reactions during postmarketing surveillance of meloxicam’s Þrst two years on the market in the United Kingdom. Gastric perforation, ulcers, or bleeding accounted for 18% of the reports, and Þve patients died as a result of GI side effects. In response to these adverse drug reactions, packaging for meloxicam was updated to include warnings about potentially serious GI and dermatologic side effects. Still, current concerns regarding the cardiovascular safety of selective COX-2 inhibitors (discussed in the next section) have boosted meloxicam’s popularity as physicians seek safer therapies to replace selective COX-2 agents. Selective Cyclooxgenase-2 Inhibitors Overview. As a result of the GI side effects that occur with traditional NSAIDs, considerable effort has been expended in developing new agents with less GI toxicity. In 1991, researchers achieved a major breakthrough when they discovered that two distinct isoforms of COX exist. COX-1, or constitutive cyclooxygenase, is present in cells under normal physiological conditions and stimulates the synthesis of prostaglandins that help regulate renal function, blood ßow, and platelet activity and help protect the mucous membrane along the GI tract. COX-2, or inducible cyclooxygenase, is expressed only under pathological conditions. Its production is induced by proinßammatory cytokines, mitogens, or endotoxins, and it stimulates the production of prostaglandins that drive the inßammatory process. Researchers believe that inhibition of COX-2 by NSAIDs is responsible for their analgesic and anti-inßammatory properties, while inhibition of COX-1 causes GI side effects by decreasing the production of gastroprotective prostaglandins. Unlike traditional NSAIDs, agents in this class inhibit COX-2 while only minimally affecting COX-1’s beneÞcial effects. Figure 10 illustrates the structural differences between COX-1 and COX-2 and how nonspeciÞc and speciÞc inhibition of these enzymes occurs. Drugs targeting COX-2, such as meloxicam and etodolac (Wyeth’s Lodine, generics), have been available since the mid 1990s. However, these agents are no longer considered to be true COX-2 inhibitors because they are only modestly selective for the inducible COX isoform. Thus, such agents are now considered to be preferential COX-2 inhibitors. The Þrst two agents to be considered truly selective COX-2 inhibitors, celecoxib (PÞzer/Astellas’s Celebrex) and rofecoxib (Merck’s Vioxx), were launched in 1999. These Þrst-generation selective COX-2 inhibitors demonstrated their ability to reduce GI side effects compared with traditional NSAIDs, but still cause some degree of GI upset. Thus, research and development efforts have focused on developing second-generation COX-2 inhibitors with even higher degrees of selectivity for COX-2. In 2002, two second-generation selective COX-2 inhibitors, valdecoxib (PÞzer/Astellas’s Bextra) and etoricoxib (Merck’s Arcoxia), entered the market. All these agents are indicated for treatment of RA pain. Selective COX-2 inhibitors boast a GI side-effect proÞle that is safer than that of traditional NSAIDs, but some experts have expressed concern over an

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FIGURE 10. Effect of nonsteroidal anti-inflammatory drugs and corticosteroids on the arachidonic acid pathway.

increased risk of cardiovascular and cerebrovascular adverse events associated with the selective agents. This concern stems from their potential to diminish vascular prostacyclin (PGI2 ) production; PGI2 acts as a vasodilator and inhibits aggregation of platelets (Mukherjee D, 2001). It was argued that by inhibiting the production of PGI2 , selective COX-2 inhibitors may alter the natural balance between prothrombotic thromboxane A2 and antithrombotic PGI2 . This altered balance could lead to an increase in thrombotic vascular events (Mukherjee D, 2001).

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Data showing that rofecoxib increases the risk of cardiovascular and cerebrovascular adverse events led to Merck’s voluntary worldwide withdrawal of this agent in September 2004. Upon rofecoxib’s launch in the United States in 1999, drug safety data did not demonstrate an increased risk of heart attack or stroke, although data from six-week studies suggested that thromboembolic events may be more frequent in patients receiving rofecoxib as compared with placebo (Villalba ML, 1998). Concerns over the cardiovascular safety of rofecoxib heightened with the results of the Vioxx GI Outcomes Research (VIGOR) clinical trial of 8,076 RA patients, which was designed to examine whether rofecoxib (50 mg daily) had fewer GI events than naproxen (500 mg twice daily), a traditional NSAID. Both drugs showed similar efÞcacy in this study, but rofecoxib had signiÞcantly fewer GI events and signiÞcantly more myocardial infarctions than naproxen (Bombardier C, 2000). The issue came to a head in August 2001, when a meta-analysis of more than 18,000 patients in four clinical trials, including VIGOR, concluded that the risk of cardiovascular events in patients treated with rofecoxib was signiÞcantly higher than placebo-treated patients (Mukherjee D, 2001). Merck responded later that year with its own meta-analysis of more than 28,000 patients from 23 rofecoxib clinical trials ranging from Phase IIb to Phase V showing that the relative risk of cardiovascular events is similar with rofecoxib and placebo (Konstam MA, 2001). As a result of these studies, the FDA revised the rofecoxib label in April 2002 to include language cautioning that the agent poses higher cardiovascular risks than a traditional NSAID but no greater risk than placebo. Most recently, interim data demonstrated a doubling in the risk of myocardial infarction and cerebrovascular accident for rofecoxib versus placebo at 18 months, leading to the suspension of the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and prompting Merck to withdraw the drug (Merck, press release, September 30, 2004; Bresalier RS, 2005). The withdrawal of rofecoxib has focused attention on the cardiovascular and cerebrovascular safety associated with the remaining selective COX-2 inhibitors. The FDA issued a public health advisory in December 2004 recommending limited use of COX-2 inhibitors pending further review of the accumulating data suggesting an increased cardiovascular risk with selective COX-2 inhibitor use. The participants in an FDA joint committee meeting on COX-2 inhibitor safety in February 2005 suggested that the increased risk of cardiovascular and cerebrovascular events associated with rofecoxib is a class-wide effect. However, current data suggest that the level of risk differs for each agent and that rofecoxib has the highest risk of all selective COX-2 inhibitors (Graham DJ, 2005). In the FDA meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee in February 2005, all committee members agreed that available data support the conclusion that rofecoxib, celecoxib, and valdecoxib signiÞcantly increase the risk of cardiovascular events. However, a majority of the committee members concluded that the overall risk versus beneÞt proÞles for all three agents supports their marketing in the United States. Celecoxib received the most votes for a favorable risk-beneÞt assessment supporting continued U.S. marketing, 31 to 1, as compared with 17 to 13 for

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valdecoxib (2 members abstained) and 17 to 15 for rofecoxib. The FDA committee also suggested a black box warning be added to selective COX-2 inhibitor package inserts and that DTC advertising should be curtailed. The EMEA issued a contraindication in February 2005 for the use of selective COX-2 inhibitors in patients with ischemic heart disease or risk of stroke. Shortly after the FDA’s advisory committees ruled in favor of valdecoxib remaining on the market, the FDA took action itself in April 2005 by asking PÞzer to withdraw the agent from the market because of its unfavorable cost/beneÞt proÞle; the FDA’s decision reßects valdecoxib’s association with an increased risk of serious skin reactions in addition to CV and cerebrovascular events. The EMEA followed suit and also asked PÞzer to remove the drug from all European markets. As a result, PÞzer withdrew valdecoxib from the worldwide market. Celecoxib is currently the only selective COX-2 inhibitor on the U.S. market. Although Merck might decide to revive rofecoxib, the company is more likely to keep it off the market because of the drug’s negative image. Instead, Merck will likely focus its attention on its newer selective COX-2 agent, etoricoxib. Although the future of individual COX-2 therapies is somewhat murky, what is clear is that prescriptions for all agents in this class, regardless of the Þnal FDA decision, will be severely restricted to patients who cannot tolerate the GI side effects associated with traditional NSAID use and who are not at risk for cardiovascular problems. Mechanism of Action. Selective COX-2 inhibitors predominantly inhibit COX-2 while minimizing inhibition of COX-1 (see Figures 7 and 10). These agents block the activity of COX-2, which produces prostaglandins that drive the inßammatory process, without disrupting the beneÞcial effects of COX-1 prostaglandins in the GI tract. Celecoxib. Celecoxib (PÞzer/Astellas’s Celebrex) (Figure 11) received FDA approval for the treatment of OA and RA in December 1998 and was launched in Europe in 2000. PÞzer markets this agent in all the countries under study except Japan, where Astellas Pharma (formerly Yamanouchi Pharmaceuticals, which merged with Fujisawa Pharmaceuticals on April 1, 2005, to form Astellas Pharma) is guiding it through clinical development. A new drug application (NDA) for pain and other symptoms of RA and OA was submitted in Japan in December 2002, with approval expected in 2004, but the application was still under consideration at the time of the writing of this report. Celecoxib gained FDA approval for the management of acute pain and primary dysmenorrhea in October 2001, and it is approved in the United States and Europe as an adjunct treatment for familial adenomatous polyposis (FAP). These additions give celecoxib the broadest range of approved indications of any selective COX-2 inhibitor. The agent is also in development for a range of further indications such as pancreatic and prostate cancers. Patent coverage extends to the end of 2013 in the United States and to the end of 2014 in other countries under study. Celecoxib works by the same mechanism of action as all selective COX-2 inhibitors, as discussed in the “Mechanism of Action” section for the drug class.

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FIGURE 11. Structure of celecoxib (R1 = NH2 , R2 = CH3 ).

The numerous trials of celecoxib have been designed primarily to show that its efÞcacy in OA and RA is comparable to that of other NSAIDs and to highlight its improved GI safety. In three large clinical trials that cumulatively involved more than 2,000 patients, celecoxib at doses of 100, 200, and 400 mg twice daily was found to have signiÞcantly better efÞcacy than placebo and similar efÞcacy to traditional NSAIDs—namely, naproxen 500 mg twice daily or diclofenac slow release 75 mg twice daily (Emery P, 1999; Goldstein JL, 2001; Simon LS, 1999). These studies also showed a lower incidence of upper GI events as compared with traditional NSAIDs, suggesting that celecoxib has decreased GI toxicity. PÞzer designed the Celecoxib Long-Term Arthritis Safety Study (CLASS) in hopes of providing statistically signiÞcant evidence that celecoxib results in fewer GI adverse events than traditional NSAIDs, much as the VIGOR trial did for rofecoxib. The double-blind, randomized, one-year CLASS trial assigned 8,059 OA and RA patients to receive celecoxib 800 mg, ibuprofen 2,400 mg, or diclofenac 150 mg daily. The celecoxib dose used was four times that recommended for OA and twice the recommended highest RA dose. Patients were allowed to take concomitant aspirin for cardiovascular prophylaxis. The main outcome measures were the incidence of symptomatic upper GI ulcers and ulcer complications. Preliminary analysis at six months suggested that the celecoxib-treated group had signiÞcantly fewer upper GI incidents than the NSAID-treated groups (Silverstein FE, 2000). Based on these results, PÞzer petitioned the FDA for a revision of celecoxib’s labeling. However, the full data at one year showed that celecoxib did not differ from traditional NSAIDs in its effect on the predeÞned GI end points, although there may have been fewer GI events in celecoxib-treated patients who were not taking aspirin (Fitzgerald GA, 2003). The FDA concluded that CLASS did not show a safety advantage in upper GI events for celecoxib as compared with traditional NSAIDs and that the celecoxib label should continue to have the standard warning associated with all NSAIDs, including risks of GI ulceration, bleeding, and perforation. As mentioned in the overview of selective COX-2 inhibitors, there are concerns that celecoxib may be associated with an increased risk of cardiovascular adverse events. A meta-analysis of more than 18,000 patients in four clinical trials, including CLASS, concluded that the risk of cardiovascular events in patients treated with celecoxib was signiÞcantly higher than placebo-treated

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patients (Mukherjee D, 2001). In December 2004, the Data Safety Monitoring Board for the Prevention of Sporadic Colorectal Adenomas with Celecoxib (APC) trial recommended suspension of the trial based on interim data at 33 months indicating an increased risk of serious cardiovascular events, including myocardial infarction, stroke, and death, in patients treated with celecoxib (200 or 400 mg twice daily) as compared with placebo-treated patients. The frequency of adverse cardiovascular events in this trial was as follows: 7 of 679 patients in the placebo group, 16 of 685 patients in the 200 mg celecoxib group, and 23 of 671 patients in the 400 mg celecoxib group (corresponding to hazard ratios of 1.0, 2.3, and 3.4, respectively), suggesting that celecoxib use was associated with a dose-related increase in cardiovascular risk (Solomon SD, 2005). In response to the APC data, the Prevention of Colorectal Sporadic Adenomatous Polyps Trial (PreSAP) and ADAPT were also suspended despite the lack of an increased cardiovascular risk for celecoxib-treated patients over placebo in these trials. However, most epidemiological studies and clinical trials with up to one-year duration show no increased cardiovascular risk for celecoxib over placebo or traditional NSAIDs. Although celecoxib may increase the risk of adverse cardiovascular events, this risk is signiÞcantly lower than that of rofecoxib (Graham DJ, 2005). Pending further analysis of the trial data and the dosages employed, the FDA has advised physicians to evaluate the risk-beneÞt ratio of celecoxib in individual patients and, if continued use is considered appropriate, advises the use of the lowest effective dose for the shortest possible time (FDA Alert, December 2004). Elsewhere, regulatory authorities have recommended that celecoxib be reserved for patients at risk for GI complications and that it not be used in patients with established heart disease or those at high risk of cardiovascular or cerebrovascular events. Valdecoxib. In April 2002, PÞzer launched the Þrst second-generation selective COX-2 inhibitor, valdecoxib (Bextra) (Figure 12), in the United States for the treatment of OA, RA, and dysmenorrhea. In May 2003, valdecoxib received approval in Europe for treatment of the pain and inßammation associated with OA, RA, and primary dysmenorrhea and has since launched in the United Kingdom, Germany, and Italy. As of this writing, sales of valdecoxib remain suspended. In vitro studies by PÞzer showed valdecoxib to be the most potent and selective of the marketed COX-2 inhibitors, providing a basis for the observed potent

FIGURE 12. Structure of valdecoxib.

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analgesic and anti-inßammatory activity of the agent in humans (Gierse JK, 2004). Valdecoxib works by the same mechanism of action as all selective COX-2 inhibitors, as discussed in the “Mechanism of Action” section for the drug class. Valdecoxib has demonstrated efÞcacy similar to that of traditional NSAIDs and signiÞcantly superior to that of placebo in numerous clinical trials. In a 12-week double-blind study of 1,090 RA patients, study participants were randomized to receive 10, 20, or 40 mg valdecoxib once daily, naproxen 500 mg twice daily, or placebo. All three doses of valdecoxib provided similar relief of the signs and symptoms of RA superior to placebo and similar to naproxen as assessed by ACR 20 response (Bensen W, 2002). In another study of 726 adult-onset RA patients, valdecoxib (20 and 40 mg daily) was compared with diclofenac (75 mg slow release twice daily) at 26 weeks (Pavelka K, 2003). EfÞcacy was measured by the patient’s assessment of arthritis pain and the modiÞed HAQ. Both doses of valdecoxib were comparable to diclofenac in efÞcacy, with no signiÞcant differences observed between treatment groups. Further evidence of the efÞcacy of valdecoxib came from the results of a meta-analysis of nine studies involving a total of 5,726 RA and OA patients. Valdecoxib (10 or 20 mg) was found to have efÞcacy superior to placebo and equivalent to the maximum daily doses of traditional NSAIDs (Edwards JE, 2004). Like celecoxib, valdecoxib has some data supporting a lower incidence of GI adverse events, but deÞnitive evidence from a large-scale clinical trial is lacking. In the 12-week study of 1,090 RA patients discussed previously, the incidence of gastroduodenal ulcers was 6% in patients receiving valdecoxib 20 mg and 4% for valdecoxib 40 mg, which were both signiÞcantly lower than diclofenac-treated patients (16%) (Pavelka K, 2003). There were also signiÞcantly fewer discontinuations due to gastrointestinal adverse events (4% versus 8%) or endoscopic ulcers of 3 mm or more (5% versus 13%) with valdecoxib compared with traditional NSAIDs in the meta-analysis of 5,726 RA and OA patients (Edwards JE, 2004). However, the study authors cautioned that convincing evidence of reduced major gastrointestinal adverse events could not be addressed by the trials. In November 2002, valdecoxib’s label was updated with new warnings following postmarketing reports of serious adverse events, including toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, and anaphylactoid reactions. In December 2004, the previous warnings about the risk of lifethreatening skin reactions were strengthened with a boxed warning added to the product label advising that treatment be stopped at the Þrst appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Like celecoxib, valdecoxib is contraindicated in patients with an allergy to sulfa-containing products. In Europe, the EMEA has issued a public statement warning that treatment with valdecoxib may result in serious skin reactions. In November 2004, following lay press criticism of the cardiovascular safety of valdecoxib, PÞzer responded by citing a peer-reviewed meta-analysis of data from 7,934 patients. In this study, the incidence of cardiovascular thrombotic events was determined by analyzing pooled valdecoxib (10–80 mg daily), nonselective NSAID (diclofenac 75 mg twice daily, ibuprofen 800 mg three times daily, or

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naproxen 500 mg twice daily), and placebo data from ten randomized OA and RA trials of 6–52 weeks duration. Short- and intermediate-term treatment with valdecoxib doses was not associated with an increased incidence of thrombotic events relative to nonselective NSAIDs or placebo in OA and RA patients in controlled clinical trials (White WB, 2004). However, two clinical trials that examined the potential use of valdecoxib for pain immediately following coronary artery bypass graft (CABG) surgery demonstrated an increased risk of adverse cardiovascular events in this high-risk population (Ott E, 2003; Nussmeier NA, 2005). The second of these studies involved 1,671 patients randomly assigned to receive intravenous parecoxib (PÞzer’s Dynastat) for at least three days followed by oral valdecoxib (20 mg every 12 hours) through day 10, intravenous placebo followed by oral valdecoxib, or placebo for ten days. (Parecoxib, approved for the treatment of acute pain in Europe, is the injectable, water-soluble pro-drug that is metabolically converted to valdecoxib in vivo.) Cardiovascular events, including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism, were signiÞcantly more frequent in the group treated with parecoxib and valdecoxib as compared with placebo (2.0% versus 0.5%). The group treated with intravenous placebo followed by valdecoxib had more cardiovascular events than placebo (1.1%), but was not statistically different from the other two groups (Nussmeier NA, 2005). As a result of these studies, labeling in the United States and Europe was revised in December 2004 contraindicating valdecoxib in patients undergoing CABG surgery, and the EMEA issued a public statement regarding the drug’s cardiovascular risks. Although some studies suggest that valdecoxib increases the likelihood of cardiovascular events by as much as two- to threefold (Furberg CD, 2005), there are limited published data, and further studies are needed to evaluate the cardiovascular risk. Etoricoxib. Merck’s second-generation COX-2 inhibitor, etoricoxib (Arcoxia) (Figure 13), was approved in the United Kingdom in April 2002 for the treatment of symptomatic pain relief in OA, RA, acute gouty arthritis, chronic musculoskeletal pain, acute pain associated with dental surgery, and primary dysmenorrhea. By October 2002, etoricoxib had been approved in Europe under the Mutual Recognition Procedure, and it has since launched in Italy and Spain. The U.K. launch came on the heels of the company’s withdrawal of its initial NDA for approval in the United States, following the FDA’s request for additional data on etoricoxib’s cardiovascular safety. In December 2003, Merck submitted an expanded NDA, seeking indications for the treatment of OA, RA, chronic low back pain, acute pain, dysmenorrhea, acute gouty arthritis, and ankylosing spondylitis. In October 2004, the FDA issued an approvable letter. However, it informed Merck that before approval could be issued, additional safety and efÞcacy data for the drug are required. Patent coverage in all the markets under review extends to 2017. Etoricoxib works by the same mechanism of action as all selective COX-2 inhibitors, as discussed in the “Mechanism of Action” section for the drug class.

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FIGURE 13. Structure of etoricoxib.

Etoricoxib has demonstrated efÞcacy signiÞcantly superior to that of placebo and at least comparable to that of naproxen in reducing the signs and symptoms of RA. In a double-blind study involving 816 RA patients, the efÞcacy of etoricoxib was shown to be signiÞcantly better than that of either placebo or naproxen (Matsumoto AK, 2002). Participants were randomized to receive either 90 mg etoricoxib once daily, 500 mg naproxen twice daily, or placebo for 12 weeks. Patients were allowed to take concomitant oral corticosteroids or DMARDs during the trial. Primary efÞcacy measures in this study included improvements over baseline on the 100 mm patient global assessments of disease activity VAS, a four-point investigator global assessment of disease activity scale, the total number of tender joints, and the total number of swollen joints. The etoricoxib group demonstrated a mean 17 mm improvement on the patient’s global assessment of disease activity VAS, a mean 0.63 point improvement on the investigator global assessment of disease activity scale, a mean 6.3 joint reduction in the number of tender joints, and a mean 3.3 joint reduction in the number of swollen joints. Each of these improvements for the etoricoxib group was statistically signiÞcant compared with the placebo and naproxen groups. The percentage of patients who completed the trial and met the ACR 20 response criteria was 21%, 39%, and 53% for the placebo, naproxen, and etoricoxib groups, respectively. An identically designed study using the same primary and secondary end points in 891 RA patients found similar significant improvements over baseline scores for the etoricoxib group compared with placebo recipients (Collantes E, 2002). However, there was no significant difference in improvements between the etoricoxib and naproxen treatment groups. Etoricoxib has a low risk of GI adverse events owing to its higher selectivity for COX-2 than the Þrst-generation COX-2 inhibitors or traditional NSAIDs. In the study discussed in the previous paragraph, the incidence of drug-related adverse events did not differ signiÞcantly between treatment groups, though the incidence of GI-related adverse events (i.e., dyspepsia, heartburn, nausea) was slightly higher for the naproxen group compared with the placebo and etoricoxib groups (Matsumoto AK, 2002). A combined analysis of ten endoscopy

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trials of patients with OA, RA, or ankylosing spondylitis presented at the Annual European Congress of Rheumatology in June 2004 showed that treatment with etoricoxib was associated with 52% fewer conÞrmed upper GI perforations, ulcers, and bleeds compared with treatment with nonselective, traditional NSAIDs (Ramey DR, 2004). Further support for the improved GI tolerability of etoricoxib was supplied by the Etoricoxib Diclofenac Gastrointestinal Evaluation (EDGE) study, a double-blind trial in 7,111 OA patients treated for up to 16.5 months (Baraf HSB, 2004). Patients were randomized to receive etoricoxib 90 mg daily (n = 3, 593) or diclofenac 50 mg three times daily (n = 3, 518). At study baseline in both treatment groups, 4% of patients had a history of an upper GI event and 28% were taking low-dose aspirin. The discontinuation rate due to GI adverse events, the primary end point of this study, was signiÞcantly lower with etoricoxib than diclofenac, at 9.4 versus 19.2 events per 100 patient years, respectively, or a risk reduction of 50%. Although etoricoxib appears to be associated with fewer GI adverse events than traditional NSAIDs, other studies have shown that the GI safety proÞle is still signiÞcantly worse than placebo. For example, a 12-week, double-blind, randomized study in 680 patients found that the incidence of endoscopy-detected ulcers was 17% for ibuprofen (800 mg three times daily), 8% for etoricoxib (120 mg daily), and 2% for placebo, all of which were signiÞcantly different from each other (Hunt RH, 2003). Despite an improved GI safety proÞle, consideration of etoricoxib’s safety has been dominated by debate over potential cardiovascular complications that appear to affect the selective COX-2 inhibitors as a class. There has been little research on the cardiovascular safety of etoricoxib, but available data show no evidence for increased cardiovascular risk. There was no signiÞcant difference between etoricoxib and diclofenac in the incidence of overall, drug-related, serious adverse events in the EDGE trial (Baraf HSB, 2004). Furthermore, cardiovascular data from the study demonstrated that the rates of conÞrmed thrombotic cardiovascular events were similar for both etoricoxib and diclofenac. The relative risk of etoricoxib compared with diclofenac was 1.07 for events that occurred within 14 days of discontinuing study treatment and 1.02 for events that occurred within 28 days of discontinuing study treatment (a relative risk of 1.00 means equivalence between the two treatment groups). Fewer patients discontinued etoricoxib for any adverse event as compared with diclofenac, although signiÞcantly fewer patients taking diclofenac (0.7%) discontinued the study because of hypertensionrelated adverse events compared with patients taking etoricoxib (2.3%) (Merck, press release, October 2004). Two ongoing clinical trials may shed light on the debate over etoricoxib’s cardiovascular safety. The EDGE II trial is examining the GI tolerability of etoricoxib (90 mg daily) as compared with diclofenac (50 mg three times daily) in approximately 4,000 RA patients. The Multinational Etoricoxib Diclofenac Arthritis Long-Term (MEDAL) study was designed with cardiovascular safety as a primary end point, comparing diclofenac (50 mg three times daily) with etoricoxib (60 or 90 mg) in more than 23,000 RA and OA patients. Results from

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both trials are expected to become available in 2006. Until then, the EMEA advises limited use of all selective COX-2 inhibitors in patients with a risk of GI complications and without ischemic heart disease or a history of stroke. Corticosteroids Overview. Corticosteroids have long been employed in the treatment of RA and remain a key component of symptom management. They produce potent, rapid suppression of inßammation with consequent improvements in joint pain and swelling. Studies showing that corticosteroids can reduce the rate of joint damage in RA patients led to their initial classiÞcation as disease-modifying agents (Kirwan RJ, 1995; van Everdingen AA, 2002). However, rheumatologists caution that the disease-modifying properties of corticosteroids are limited, and they should not be administered as a monotherapy to RA patients with active disease. Instead, true DMARDs, either conventional or biological, should be initiated, and corticosteroids used as supplemental therapy to control symptoms as needed. Corticosteroids are associated with many side effects. Insomnia, night sweats, mood changes, and altered glucose metabolism may occur shortly after beginning corticosteroids. Prolonged corticosteroid therapy can lead to adrenal atrophy, and abrupt cessation can cause adrenal insufÞciency, hypotension, and even death (Caldwell JR, 1991; Hunter JA, 1999). Long-term use of systemic corticosteroids is associated with osteoporosis, hypertension, cataracts, acne, abnormal fat deposition, and excessive hair growth. These side effects generally occur less often with corticosteroid injections, but injection site infections, post-injection ßares, and crystal-induced synovitis can occur with parenteral delivery. A wide variety of generic corticosteroids, salts, and formulations are available in the markets under study. This section assesses two of the most commonly prescribed agents, orally administered prednisone (PÞzer’s Deltasone, generics) and intra-articular (IA) methylprednisolone acetate (PÞzer’s Depo-Medrol, generics). Mechanism of Action. Corticosteroids act as anti-inßammatory and immunosuppressive agents through multiple effects: inhibiting synthesis of proinßammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Corticosteroids can also inhibit the expression of COX-2 and the activity of collagenase and other cartilage-damaging enzymes. Figure 7 illustrates how corticosteroids suppress prostaglandin and leukotriene synthesis by blocking the arachidonic acid pathway. Formulation. Rheumatologists employ a wide variety of corticosteroid formulations and doses to relieve RA symptoms. Oral corticosteroids are often used as bridge therapy, meaning they are initiated by primary care physicians or rheumatologists upon diagnosis, but then discontinued when the slower-acting, conventional DMARD therapy takes effect. Intravenous corticosteroids are occasionally used as bridge therapy, as well. In addition, oral and intravenous corticosteroids

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are used during periodic ßare-ups to control symptoms during times of high disease activity. For alleviating severe RA symptoms, high doses of intravenous corticosteroids can be used on a short-term basis (up to 1 g per day for three days). The intravenous treatment can be repeated after four to six weeks if necessary. Alternatively, oral corticosteroids can be initiated at a high dose (e.g., 30–40 mg prednisone daily) and then gradually tapered down in 5 mg steps to a continuous dosage of 5–10 mg per day. For milder symptoms, a low dose of oral corticosteroids can be used as short-term or long-term therapy. Because of the serious side effects associated with corticosteroids, rheumatologists prefer to discontinue these drugs as soon as possible. However, abrupt cessation of corticosteroids can cause adrenal insufÞciency, hypotension, and even death, so doses must be carefully tapered to a level where these drugs may be safely discontinued. To minimize side effects and to prevent problems with abrupt discontinuation of systemic therapy, intramuscular or IA injections are used for relief of localized, aggressive joint ßare-ups. A single intramuscular dose of a depot corticosteroid, such as methylprednisolone acetate or triamcinilone acetonide (both 40 mg/mL), is preferred by rheumatologists when rapid control is required. Furthermore, physicians and researchers have expressed concern that repeated corticosteroid injections into joints can actually exacerbate progressive cartilage damage. As a result, many rheumatologists consider this strategy a last resort and will not use it in more than one joint at a time. The ACR also recommends that intra-articular injections not be administered in the same joint more than once within three months (ACR, 2002). Prednisone. Oral prednisone (PÞzer’s Deltasone, generics) (Figure 14) is commonly prescribed in low doses (less than 10 mg daily) to treat the signs and symptoms of RA. Oral corticosteroids—including prednisone—can be used as a short-term therapy during periods of high disease activity or as a bridge therapy and can be administered for long-term use in combination with DMARDs. Corticosteroids act as anti-inßammatory and immunosuppressive agents through multiple effects: inhibiting synthesis of proinßammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Corticosteroids can CH2OH C O

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H3C


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also inhibit the expression of COX-2 and block the activity of collagenase and other cartilage-damaging enzymes. Low-dose oral prednisone (7.5 mg) has been shown to provide a rapid and signiÞcant decrease in RA symptoms between two and eight weeks after treatment initiation, an effect that was maintained for three months and that was not associatedwith rebound in symptoms after treatment cessation (Kirwan JR, 2004). In a prior study, the efÞcacy, disease-modifying properties, and safety of lowdose oral prednisone were compared with those of placebo (van Everdingen AA, 2002). This two-year, randomized, double-blind study involved 81 patients with early active RA who had not been treated previously with DMARDs. Trial participants received either 10 mg daily oral prednisone or placebo, and both treatment groups were given 500 mg daily of elementary calcium. Patients were allowed to take acetaminophen or NSAIDs for pain, if necessary, and sulfasalazine (2 g daily) could be added as a rescue medication after six months if the activity of RA warranted the addition of a DMARD. At the conclusion of the two-year trial, treatment with prednisone was associated with a greater mean improvement over baseline scores for most efÞcacy measures, including early-morning stiffness, morning pain, general well-being, and 28-joint score for swelling. There were signiÞcant differences between the improvements for the two groups on two efÞcacy measures: grip strength (measured by a vigorimeter) and the 28-joint score for tenderness. A clinically relevant improvement (deÞned as 20% or greater improvement in the 28-joint scores for swelling and tenderness, and 20% or greater improvement in two of the following four variables: pain, general well-being, HAQ, and CRP level) was demonstrated by 33% and 30% of patients receiving prednisone at 12 and 24 months and by 24% and 22% of placebo recipients at these two time periods, respectively. Treatment with prednisone was associated with signiÞcant increases in mean body weight and mean serum glucose level compared with placebo. Additionally, the incidence of new vertebral fractures was higher in the prednisone group compared with the group treated with placebo. Perhaps the most interesting Þnding from the study is the ability of prednisone to reduce progression of radiologically detected joint damage over the course of two years (van Everdingen AA, 2002). At the start of the trial, radiologic evidence demonstrated that 40% of patients randomized to prednisone and 37% of patients randomized to placebo had erosive disease. After 24 months, the percentage of patients with erosive disease was 70% for the prednisone group and 78% for the placebo group. Total radiologic scores (sum of erosion and joint-space narrowing scores using the van der Heijde modiÞcation of the Sharp method for scoring radiographs) were signiÞcantly lower for the prednisone group compared with placebo at 12, 18, and 24 months. The prednisone group demonstrated a mean 8-point and 16-point increase from baseline in total radiologic score at 12 and 24 months, respectively, compared with mean 15-point and 29-point increases from baseline for the placebo group at these two time periods, respectively. However, corticosteroids are not considered true DMARDs because their disease-modifying properties are far inferior to those of conventional and biological DMARDs. For

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OR O HO

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O

FIGURE 15. Structure of methylprednisolone acetate (R = COCH3 ).

example, the combination of etanercept with methotrexate has achieved a 69% ACR 50 response in reducing the signs and symptoms of RA and a negative Sharp score, indicating no progression of joint damage at 52 weeks (Klareskog L, 2004). Methylprednisolone Acetate. Methylprednisolone acetate (PÞzer’s DepoMedrol, generics) (Figure 15) is the 6-methyl derivative of the corticosteroid prednisolone. Methylprednisolone acetate is indicated for a number of arthritic disorders as well as other inßammatory conditions such as asthma. Similar to other corticosteroids, methylprednisolone acetate inhibits the synthesis of proinßammatory mediators (prostaglandins, leukotrienes, and cytokines), the expression of COX-2, and the activity of collagenase and other cartilagedamaging enzymes. Because of the lack of large-scale, placebo-controlled trials comparing methylprednisolone acetate with placebo in RA patients, this section presents the Þndings of a blinded study involving 18 knees of 16 patients with RA or other arthritic conditions (e.g., psoriatic arthritis, juvenile rheumatoid arthritis) (Ostergaard M, 1996). In this study, patients underwent arthrocentesis to remove excess ßuid from their knee(s), after which 30 mg lidocaine hydrochloride and 80 mg methylprednisolone acetate were injected into these knees. Gadolinium-DTPA (diethylenetriamine penta-acetic acid) enhanced magnetic resonance imaging (MRI) was performed on each patient prior to arthrocentesis (day 0) and after treatment on days 1, 7, 30, 180, and until clinical relapse (deÞned by the presence of joint swelling and/or tenderness) to measure synovial membrane volume and joint effusion volume. On day 0, the mean synovial membrane volume and joint effusion volume of patients was 58 mL and 35 mL, respectively. There was no signiÞcant difference between the knees of patients with RA and other arthritic conditions. Compared with baseline measurements, mean synovial membrane volume decreased by 43%, 50%, and 64% on days 1, 7, and 30, while joint effusion volumes decreased 57%, 63%, and nearly 69% at the same time points. Each of these improvements was statistically signiÞcant compared with baseline measurements. On day 180, only 5 knees of the original 18 remained in clinical remission. Safety data were not reported in the study conducted by Ostergaard and colleagues. Risk of infection is associated with the use of IA corticosteroids, but this

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complication is rare if proper aseptic techniques are followed (Gifford RH, 1973). Additionally, IA corticosteroids can cause crystal-induced synovitis, which can cause a temporary increase in joint swelling and pain following administration of the drug. Concern that repeated corticosteroid injections into joints can actually exacerbate progressive cartilage damage has made this strategy a last resort in the treatment of RA symptoms. It is recommended that intra-articular corticosteroid injections not be used in more than one joint at a time and not more than every three months in the same joint (ACR, 2002). Nonpharmacological Therapies Prosorba Column. Developed by Cypress Bioscience as a novel blood-Þltering device, the Prosorba column was licensed for comarketing in the United States, Europe, and Japan to Fresenius Hemotechnology. The column received FDA approval in 1999 for patients unresponsive to or intolerant of DMARD therapy, and it was launched in the United States and Europe in 2000. This device uses approximately 200 mg of protein A (a component of the Staphylococcus bacterium that selectively binds IgG and IgG-bound antigens) covalently bound to an inert silica matrix. In a process similar to kidney dialysis, a patient’s blood is removed from a vein in one arm and passed through a machine that separates the blood cells from the plasma. The plasma is then passed through the Prosorba column, where circulating immune complexes are removed, recombined with the blood cells, and returned to the patient through the other arm. The standard course of therapy involves 12 weekly, two-hour outpatient sessions. A 99-patient, double-blind trial resulted in a 41.7% ACR 20 improvement in Prosorba-treated patients versus 15.6% with placebo (Furst D, 2000). Surgery. Surgical treatment for RA takes three main forms: carpal tunnel relief and metatarsal head resections, synovectomies (partial removal of the diseased joint lining), and arthroplasty (total joint replacement). Carpal tunnel and metatarsal head procedures are rarely performed, but they are useful when corticosteroid injections have failed or the maximum dose provides no further improvement. Synovectomies are perhaps even rarer because the long-term beneÞts are outweighed by the procedure’s cost. Arthroplasty of the knee and hip are the most common type of surgery for RA. Approximately 15–25% of all RA patients eventually undergo this procedure for one or more joints. Most of these patients have end-stage disease, and many have secondary OA. EMERGING THERAPIES The launch of highly effective biological therapies in the late 1990s—in particular, the tumor necrosis factor-alpha (TNF-α) inhibitors—has dramatically improved the therapeutic options available for the treatment of rheumatoid arthritis (RA). The availability of these effective, albeit expensive, agents has signiÞcantly raised the bar for emerging therapies in the RA market. Despite the steep

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competition in developing therapies for this market, a vast number of agents, many of them biologics, are under development for the treatment of RA. This discussion focuses on emerging therapies that have mLed comparatively late-stage development for RA (i.e., Phase II or later trials, for which clinical results are available). Table 4 summarizes emerging therapies in late-stage development for RA. The discussion of emerging therapies is organized in this section according to their mechanisms of action. Tumor Necrosis Factor-α Inhibitors Overview. Inhibitors of TNF-α represent the most recent and signiÞcant advance in the treatment of RA. The Þrst anti-TNF-α agent approved for RA, etanercept (Amgen/Wyeth/Takeda’s Enbrel), was launched in the United States in 1998. Since then, two other agents have entered the market—inßiximab (Centocor [a Johnson&Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade) and adalimumab (Abbott/Eisai’s Humira). Because of the relatively high cost and risk of immunomodulatory side effects associated with these agents, researchers have directed their attention toward the development of improved anti-TNF-α therapies for the treatment of RA. Different approaches to targeting and blocking TNF-α include monoclonal antibodies, TNF-α receptors, TNFbinding proteins, and antisense technology. Two new TNF-α inhibitors that have progressed into Phase II clinical trials or beyond are discussed here. Currently available products are administered parenterally, and various companies have sought to develop orally active agents as a means of reducing cost and broadening the market scope for anti-TNF-α therapy. Oral delivery of TNF-α inhibition is seen as a particularly desirable goal by many rheumatologists. In practice, however, the development of orally active agents has proven difÞcult. Work on a number of apparently promising oral agents, such as AtheroGenics’ AGIX-4207, Bristol-Myers Squibb’s BMS-561392, and Isis’s ISIS-104838, has been discontinued. The most promising oral TNF-α inhibitor remaining in the pipeline is apratastat (Wyeth’s TMI-005). This agent, however, is in early Phase II development and is not discussed because of a lack of clinical trial data. Mechanism of Action. The role of TNF-α in RA has been demonstrated in transgenic mouse models in which TNF-α overexpression led to joint destruction and aggressive synovitis (Figure 6). Among RA patients, the degree of synovial TNF-α expression correlates with the degree of synovitis and bone erosion. Further investigations have shown increased expression of TNF-α receptors in synovial tissues of patients with RA but not in some other forms of arthritis. Receptors for TNF-α are found on the surface of most cells, including mononuclear cells and cells in the synovium. Cleavage of membrane-bound TNF-α receptors yields soluble TNF-α receptors that retain ligand-binding ability but cannot activate cells. Two distinct types of TNF-α receptors have been identiÞed: type I (p55) and type II (p75). TNF-α inhibitors reduce free, bioactive TNF-α by emulating the physiological role played by soluble TNF-α receptors.

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TABLE 4. Emerging Therapies in Development for Rheumatoid Arthritis Compound

Development Phase

Marketing Company

TNF-α inhibitors CDP-870 United States Europe Japan

III III —

UCB UCB —

Pegsunercept United States Europe Japan

II — —

Amgen — —

III III III

Chugai/Roche Chugai/Roche Chugai/Roche

II — —

Amgen — —

PR — —

Bristol-Myers Squibb — —

III III —

Roche/Biogen Idec/Genentech Roche/Biogen Idec/Genentech —

Conventional DMARDs Iguratimod United States Europe Japan

IIa IIa PR

Toyoma Chemical/Eisai Toyoma Chemical/Eisai Toyoma Chemical/Eisai/Taisho

Selective COX-2 inhibitors Lumiracoxib United States Europe Japan

III PR II

Novartis Novartis Novartis

Immunosuppressants Tacrolimus United States Europe Japan

III II PR

Astellas Astellas Astellas

Interleukin-based therapies Atlizumab United States Europe Japan AMG-714 United States Europe Japan Lymphocyte modulators Abatacept United States Europe Japan Rituximab United States Europe Japan

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TABLE 4. (continued) Compound MAP kinase inhibitors SCIO-469 United States Europe Japan Doramapimod United States Europe Japan

Development Phase

Marketing Company

II II —

Scios Scios —

II II —

Boehringer Ingelheim Boehringer Ingelheim —

COX-2 = Cyclooxygenase-2; DMARDs = Disease-modifying antirheumatic drugs; IL = Interleukin; MAP = Mitogen-activated protein; PR = Preregistered; TNF-α = Tumor necrosis factor-alpha.

This action modulates the amount of circulating, bioactive TNF-α by binding to the cytokine before it can activate cell-surface receptors on mononuclear cells. Because TNF-α plays an important role in the eradication of neoplastic cells, its suppression is not without hazard—particularly as a long-term therapeutic strategy. Concerns have been raised as to whether chronic immunosuppression leads to opportunistic infection, malignancies, or other complications (Alldred A, 2001; Lee JH, 2002). CDP-870. UCB is developing CDP-870, a pegylated anti-TNF-α antibody fragment, for the treatment of RA and other inßammatory disorders such as Crohn’s disease in the United States and Europe. The agent was originally under development with Celltech, which was acquired by UCB in mid 2004, and is currently in Phase III trials. Celltech had previously been developing the agent in collaboration with PÞzer under an agreement terminated in December 2003. Regulatory Þlings are expected in 2006. No development has been reported in Japan. CDP-870 binds TNF-α with high afÞnity, thereby blocking its ability to activate the inßammatory cascade. Unlike inßiximab, which is a chimeric monoclonal antibody (mAb) composed of 75% human and 25% mouse protein, CDP-870 is a humanized anti-TNF-α mAb fragment conjugated to two polyethylene glycol (PEG) subunits. The agent is being developed as an injectable formulation with a once-monthly subcutaneous (SC) dosing regimen. UCB can manufacture CDP-870 in Escherichia coli at very low cost using proprietary technology. The production cost may be as little as 10% of that for creating an antibody or receptor fusion product using mammalian cell culture. In a Phase II, double-blind, placebo-controlled study involving 203 patients, CDP-870 signiÞcantly reduced the signs and symptoms of RA (Keystone E, 2001). In the study, patients were randomized to receive CDP-870 (50, 100, 200, or 400 mg) once monthly as an SC injection or placebo for 12 weeks. Clinical response was assessed using American College of Rheumatology (ACR) criteria. The percentages of patients achieving an ACR 20, ACR 50, or ACR 70 response

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at week 12 after treatment with the most-effective dose (400 mg) of CDP-870 were 72%, 48%, and 32%, respectively, compared with 15%, 0%, and 0% for placebo. The most common adverse events reported in this trial were headache, nausea, and upper respiratory tract infection. In October 2002, Celltech presented data from a Phase II clinical trial involving approximately 600 RA patients. Of the patients receiving CDP-870 (400 mg once monthly), 75% achieved an ACR 20 response seven days after initial administration. The company reported no signiÞcant differences in adverse events between CDP-870 (400 mg or 800 mg once monthly) and placebo, and no signiÞcant occurrences of injection-site reaction or urinary tract infection. In 2004 press releases, Celltech announced preliminary results from two Phase III studies in RA, in which CDP-870 was used both in combination with methotrexate (Stada’s Rheumatrex, generics) and as monotherapy. Again, the agent met the primary end point: a signiÞcant ACR 20 response at 24 weeks. A further trial required for registration, designed to assess the impact of CDP-870 on disease progression, was scheduled to commence in the second half of 2004. Additional information on the drug’s safety or efÞcacy were not announced in the press releases, but UCB stated that full results will be released after conclusion of the entire Phase III program in RA. CDP-870 treatment was considered to be well tolerated in a Phase II study in 36 RA patients (Choi EH, 2002). The most common adverse event reported was headache, and there was a higher incidence of mild or moderate lower respiratory tract infections and urinary tract infections in the treatment group as compared with placebo. Overall, CDP-870 appears to have a similar safety proÞle to the other TNF-α inhibitors, with the most common side effects being headache, nausea, and respiratory and urinary tract infections. Pegsunercept. Amgen has been evaluating the pegylated monomeric soluble TNF receptor type I inhibitor pegsunercept (PEG-sTNF-RI) in Phase II clinical trials in the United States. Although the product remains in the corporate portfolio, no clinical development has been reported since 2003, and Amgen appears to be pursuing other opportunities in RA. Despite the lack of recent development, pegsunercept is cited here as an emerging therapy because Amgen may decide to revive the product for use in combination regimens or as a defensive posture against market encroachment by CDP-870. Pegsunercept is a second-generation TNF-binding protein (TNF-bp) that comprises a soluble TNF-receptor type I (TNF-RI) subunit joined by a pegylated (PEG) linker. Like other TNF-α inhibitors, pegsunercept binds TNF-α with high afÞnity, thereby blocking its ability to activate the inßammatory cascade. As with CDP-870, pegsunercept is manufactured in Escherichia coli at a very low cost. At the 67th annual ACR meeting in October 2003, researchers presented results of a Phase II trial in which 309 patients with active RA were randomized to receive an SC injection of pegsunercept (400, 800, or 1,100 µg/kg) twice weekly or placebo for 24 weeks (Piercarlo S, 2003). All patients received concomitant methotrexate, and the primary end point was improvement in ACR response.

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At the end of the study period, all doses of pegsunercept signiÞcantly improved ACR 20, ACR 50, and ACR 70 responses, but the most signiÞcant response was seen for pegsunercept at 800 µg/kg. The ACR 20, 50, and 70 responses for pegsunercept 800 µg/kg in combination with methotrexate were 68%, 35%, and 25%, respectively, compared with 26%, 10%, and 3% for placebo. The results indicate that pegsunercept may reduce disease activity when administered concomitantly with methotrexate. The overall incidence of adverse events was similar between treatment groups, but injection site reactions were more frequent in patients receiving pegsunercept (38%, 36%, and 50% for 400, 800, and 1,100 µg/kg) than in those given placebo (30%). Pegsunercept has been evaluated in combination with other agents in clinical trials, suggesting that its efÞcacy as a monotherapy cannot compete with that of currently available drugs. Additionally, the ACR 20, 50, and 70 response rates for pegsunercept in combination with methotrexate are lower than those demonstrated by etanercept in combination with methotrexate in the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) study: 85%, 69%, and 43%, respectively (Klareskog L, 2004). Interleukin-Based Therapies Overview. Despite the relatively low efÞcacy of the interleukin (IL)-1β antagonist anakinra and the relative lack of success of this agent in the RA market, companies continue to study IL-1 and other interleukins in the hope of Þnding a novel drug for RA. Three interleukin-based therapies that have advanced to comparatively late-stage development are discussed here, including Chugai/Roche’s atlizumab (Actemra, MRA) and Amgen’s AMG-714 (HuMax IL-15), which target IL-6 and IL-15 respectively. Abbott’s ABT-874, an anti-IL-12 mAb currently in Phase II studies, is not discussed owing to a lack of clinical data in RA. Regeneron’s IL-1 inhibitor RGN 303 was also in clinical trials for RA, but development was discontinued in September 2005. Mechanism of Action. The inßammatory cascade involves many proinßammatory cytokines in addition to TNF-α —notably, IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, and IL-23. Dysregulated expression of these cytokines has been observed in RA patients and likely contributes to progressive joint degradation. Therefore, suppressing other inßammatory pathways may be an effective way to control RA, and blocking multiple pathways in the inßammatory cascade may act synergistically to block disease progression. Atlizumab. Chugai and its parent company Roche are developing atlizumab (Actemra, MRA), a humanized anti-IL-6 receptor mAb for the treatment of RA, Crohn’s disease, multiple myeloma, and Castleman’s disease (giant lymph node hyperplasia). In February 2003, the companies announced their intention to copromote the drug in the United Kingdom, France, and Germany. Roche will codevelop and promote atlizumab worldwide, except in Japan, South Korea, and Taiwan. Chugai also retained copromotion rights in the United States, Italy, and Spain. Phase III

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trials are ongoing in Japan and a Phase III preparation program is under way in Europe and the United States. Atlizumab inhibits the proinßammatory cytokine IL-6, which has a wide range of effects, including stimulating B cells to differentiate into plasma cells to produce immunoglobulin and stimulating T lymphocytes to differentiate into cytotoxic T cells. IL-6 is implicated in the pathogenesis of RA and stimulates chondrocytes, synoviocytes, and osteoblasts to secrete prostaglandins, plasminogen activator, collagenases, and other proteases. These substances promote the breakdown of extracellular matrix and cause extensive tissue destruction. Unlike the situation with the other cytokines, increased serum levels of IL-6 appear to correlate with increased levels of acute-phase reactant proteins (such as C-reactive protein and Þbrinogen) in arthritic patients. Results presented at the 66th annual ACR meeting in October 2002 demonstrate atlizumab’s efÞcacy and tolerability (Nishimoto N, 2002). In a multicenter, double-blind, placebo-controlled Phase II study, 164 patients with active RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were randomized to receive a monthly infusion of atlizumab (4 or 8 mg/kg) or placebo for three months. Patients were permitted to take prednisolone (10 mg/day or less). The primary end point was the ACR 20 response at week 12, at which point both doses of atlizumab demonstrated successful outcomes. ACR 20 responses for atlizumab 4 mg/kg and 8 mg/kg were 57.42% and 78.2%, respectively, compared with 11.3% for placebo; ACR 50 responses were 25.9%, 40.0%, and 1.9% and ACR 70 responses were 20.4%, 16.4%, and 0% of patients taking atlizumab 4 mg/kg, 8 mg/kg, and placebo, respectively. Patients receiving the 8 mg/kg dose also displayed 63.1% and 63.4% reductions, respectively, in the number of tender and swollen joints, compared with 7.7% and 2.6% reductions for placebo. Open-label extension study data were presented at the ACR 2003 meeting that conÞrmed the long-term safety of atlizumab. Subsequent to the original study, 142 patients were treated with 8 mg/kg of atlizumab intravenously every four weeks. Blood cholesterol increase was frequently observed, but stabilized at 3 months (185 mg/dL at base line; 224 mg/dL at 3 months; 225 mg/dL at 12 months). No cardiovascular events were observed (Nishimoto N, 2003). AMG-714. Amgen is developing AMG-714 (HuMax IL-15) under an agreement with Genmab of Denmark for the treatment of inßammatory conditions. The lead indication is RA, in which AMG-714 is currently being evaluated in U.S. Phase II trials. In July 2003, Genmab announced that Amgen had exercised its commercial option to AMG-714 and would be responsible for all further development costs for the product. In addition to the ongoing studies in the United States, Amgen is expected to initiate clinical studies for AMG-714 in Europe. AMG-714 is a fully human monoclonal IgG1 antibody that binds to human IL-15, a pro-inßammatory cytokine present in RA synovium, and inhibits IL-15induced effector functions. Data from an interim analysis of a Phase II study were presented at the ACR Annual ScientiÞc Meeting in October 2004 (McInnes I, 2004). In this study, 110

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patients naive to therapy with biologics and with active disease despite treatment with at least one conventional DMARD were randomized to receive one of four doses of AMG-714 (40, 80, 160, or 280 mg injected subcutaneously) or placebo every two weeks for 12 weeks. Stable background methotrexate, NSAIDs, and low-dose corticosteroids were continued. Clinical and safety assessments were performed at 2-week intervals for 16 weeks and monthly over the subsequent 8 weeks. The primary efÞcacy outcome measured was ACR 20 response at 12 weeks. At this time point, those patients receiving the highest dose (280 mg) demonstrated a 62% ACR 20 response compared with 26% for placebo. The other active treatment groups demonstrated higher ACR responses compared with placebo, but the differences were not statistically signiÞcant. The total incidence of adverse events in all four AMG-714 groups (60.9%) was similar to placebo (56.5%). The incidence of infectious adverse events was also similar between the 280 mg AMG-714 group (33.3%) and placebo (34.8%). RGN-303. Regeneron’s RGN-303 (IL-1 Trap) is in Phase IIb development in the United States for the treatment of RA. In March 2003, Regeneron signed an agreement with Novartis concerning its development and commercialization. However, in February 2004, after reviewing Phase II trial results, Novartis informed Regeneron that it would no longer continue development of the agent unless the terms of the collaboration were revised. Regeneron rejected Novartis’s proposed revisions and proceeded with clinical development alone. In September 2005, Regeneron discontinued development for the RA indication. RGN-303 is a fully human IL-1 inhibitor consisting of the Fc portion of IgG1 fused to the extracellular domains of both IL-1 receptor components, thereby mimicking the cell surface receptor for IL-1. RGN-303 binds to both IL-1α and IL-1β with high afÞnity, trapping the cytokine to block its activity. Results of a 12-week, placebo-controlled Phase II study in 201 patients with moderate to severe RA who had failed at least one prior DMARD were presented at the ACR Annual ScientiÞc Meeting in October 2004 (Bingham CO, 2004). Patients were randomized to receive weekly SC injections of placebo or 25, 50, or 100 mg of RGN-303. Stable doses of background conventional DMARDs, but not other biologics, were permitted. The primary end point was improvement in ACR 20 response at 12 weeks. At the end of the study period, 46.0% of the patients receiving 100 mg RGN-303 achieved an ACR 20 response compared with 30.9% in the placebo group; these results were not statistically signiÞcant. However, signiÞcant improvements in the Disease Activity Score (DAS28) of the 100 mg RGN-303 group over placebo were apparent by one week (−0.55 versus −0.29) and continued through the end of the study (−1.121 versus −0.702). The percentage of RA patients with a moderate or good response to treatment with 100 mg RGN-303 as assessed by the DAS28 was also signiÞcantly greater than placebo (46% versus 26%). The authors of this study concluded that further evaluation of the efÞcacy of the drug at higher doses is warranted. No signiÞcant infectious complications were seen, with the most common adverse event being injection site reactions.

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Although the agent failed to meet its primary end points in this study, Regeneron considered it possible that the optimal dose level for RGN-303 had not yet been achieved (Regeneron, press release, June 10, 2003). In April 2004, the company announced its intention of initiating a Phase IIb trial with RGN-303 in the second half of 2004, following the recommendation of an independent advisory panel of medical experts. The panel recommended that the new Phase IIb trial examine higher doses of RGN-303 in a larger patient population for a longer period of time compared with previous Phase II trial protocols (Regeneron, press release, February 27, 2004). Lymphocyte Modulators Overview. A new class of biological agents has emerged that speciÞcally target T and B lymphocytes, the main cells involved in an adaptive immune response. Most currently available biological agents target the products of activated macrophages, cytokines. However, T cells help activate macrophages, and both types of lymphocytes have been implicated in the inßammation and joint destruction found in RA. The rheumatoid synovium contains activated T and B cells, and immunoglobulin produced by B cells, such as rheumatoid factor and antinuclear or anticytoplasmic autoantibodies, serve as diagnostic markers for RA that may also be involved in the disease process. This section discusses one emerging therapy that targets T cells and one that targets B cells. Excluded from this analysis are lymphocyte modulators in Phase II clinical trials for which large-scale trial data are currently lacking, such as Human Genome Sciences/Cambridge Antibody Technology’s belimumab. Mechanism of Action. Lymphocyte modulators target T and B cells, which are immune cells known to be involved in the RA disease process. Agents in this class can act in a variety of ways, but the main mechanisms of action for therapies in late-stage development are interfering with lymphocyte activation or the actual depletion of the speciÞc cell population. Either way, the lymphocytes cannot carry out their effector functions, which contribute to the inßammatory state and the production of autoantibodies. Abatacept. Bristol-Myers Squibb is developing the CD28 antagonist abatacept (CTLA4-Ig BMS-188667) for the treatment of RA, multiple sclerosis, systemic lupus erythematosus (SLE), and other autoimmune disorders. Abatacept will be the Þrst of a new class of agents termed T-cell costimulation modulators. The FDA has granted fast-track status for RA in the United States, and a rolling biologics license application (BLA) submission was initiated in November 2004.The drug received FDA approval in December 2005, and a launch is expected in the Þrst half of 2006. No development has been reported elsewhere, but BMS is likely to submit further new product applications in European markets. Abatacept is a genetically engineered fusion protein that consists of the extracellular domain of human CTLA-4 and a fragment of the Fc portion of human IgG1. Abatacept binds to CD80 and CD86 molecules on antigen-presenting cells,

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blocking their engagement with CD28 on T cells. The blockade of this costimulatory signal prevents T-cell activation and the consequent proinßammatory cytokine release and acquisition of effector functions that contribute to the RA disease process. Published clinical trial results demonstrate that abatacept improves physical function in patients with active RA (Kremer JM, 2003). In this Phase IIb study, 339 patients refractory to methotrexate were randomized to receive intravenous administrations of abatacept (2 mg/kg or 10 mg/kg) or placebo on days 1, 15 and 30, and monthly thereafter for six months. All patients received concomitant methotrexate. At the end of the study period, the most signiÞcant ACR responses were seen with abatacept 10 mg/kg. The percentages of patients in the 10 mg group who achieved ACR 20, ACR 50, and ACR 70 responses were 60%, 37%, and 17%, respectively, compared with 35%, 12%, and 2% for placebo. The incidence of adverse events was similar for abatacept and placebo. The most frequent adverse events were headache, upper respiratory tract infection, musculoskeletal pain, and nausea. Further clinical response results over two years incorporating a one-year open-label extension study were presented at the 2004 ACR scientiÞc meeting. Of those patients randomized to the abatacept treatment arm, 75 (89%) completed two years of treatment. At two years, ACR 20, 50, and 70 responses were 77.3%, 54.7%, and 29.3%, respectively. Furthermore, 15% of patients demonstrated a 90% improvement in ACR criteria at two years (Kremer JM, 2004). The company is also pursuing development of abatacept in patients refractory to TNF-α inhibitors. Data from the Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) were presented at the ACR 68th Annual ScientiÞc Meeting in October 2004 (Genovese MC, 2004). In this placebo-controlled study, 391 patients with active RA were treated with at least one conventional DMARD and abatacept at a Þxed dose of 10 mg/kg (258 patients) or placebo (133 patients). All patients had discontinued TNF-α therapy. After six months of treatment, signiÞcant differences were observed in the ACR response rates: 50.4% of abatacept-treated patients achieved an ACR 20 response compared with 19.5% on placebo; 20.3% of abatacept-treated patients achieved an ACR 50 response versus 3.8% on placebo; and 10.2% of abatacept-treated patients achieved an ACR 70 response versus 1.5% on placebo. The incidence of adverse events was similar between abatacept and placebo, with the most common side effects being headache and nasopharyngitis. The incidence of serious infections was the same in each group (2.3%). Rituximab. Rituximab is being developed by Roche as MabThera and codeveloped by Biogen Idec and Genentech as Rituxan as a potential treatment for RA. Both compounds have already launched their respective products worldwide for the treatment of relapsed or refractory, low-grade, CD20-positive, Bcell non-Hodgkin’s lymphoma. Rituximab is being evaluated across a range of immunological indications, including multiple sclerosis, vasculitis, SLE, and RA. It is in Phase III clinical trials for anti-TNF-α refractory RA and Phase IIb clinical trials for moderate to severe RA in the United States and Europe. No development

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has been reported in Japan for RA, but rituximab is marketed there for B-cell lymphoma by Zenyaku Kogyo. This mouse/human chimeric mAb targets CD20 on the surface of B lymphocytes and recruits the body’s natural defenses to attack and kill the marked B cells. The labeling for rituximab indicates that the drug is associated with serious adverse events, including fatal infusion reactions, tumor lysis syndrome, mucocutaneous reactions, hypersensitivity reactions, cardiac arrhythmias and angina, and renal failure. The product label includes black box warnings for the Þrst three of these adverse events. Rituximab demonstrated efÞcacy for the treatment of RA in a Phase II trial of 161 partial methotrexate responders with long-standing disease (Edwards JCW, 2004). Study participants were randomized to receive methotrexate alone (≥10 mg per week), rituximab alone (1 g administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. All groups also received a 17-day course of corticosteroids (100 mg intravenous methlyprednisolone on days 1, 3, 15, and 17; 30 mg oral methlyprednisolone on days 2 and 4 through 7; and 60 mg oral methlyprednisolone on days 8 to 14). Rituximab treatment resulted in nearly complete depletion of peripheral B cells, but peripheral blood immunoglobulin concentrations remained within normal ranges throughout the study period. At week 24, 43% of patients taking rituximab plus methotrexate achieved an ACR 50 response compared with 41% of patients taking rituximab plus cyclophosphamide, 33% of patients taking rituximab alone, and 13% of patients taking methotrexate alone. All ACR 50 responses for the patients treated with a combination of rituximab and methotrexate were maintained at 48 weeks. The majority of adverse events occurred with the Þrst rituximab infusion. At 24 weeks, serious infections occurred in 2.5% of the control group and in 3.3% of the rituximab groups. Subsequent data from the study were presented at the 68th annual ACR meeting in October 2004. Results demonstrated that a single course of rituximab in combination with methotrexate produced a substantial duration of response over two years. At week 104, ACR 20 and 50 responses were achieved by 34% and 21% of the rituximab plus methotrexate group compared with 14% and 11% on methotrexate alone, while 13% of the former group achieved a major clinical response (ACR 70 maintained for ≥6 months). The authors concluded that all three rituximab treatment arms were well tolerated with no signiÞcant differences observed in rates of infection (Emery P, 2004[a]). Many rheumatologists have employed rituximab off-label on a compassionate basis for patients refractory to currently available therapies. This agent is considered a highly exciting development in the Þeld of RA because it has the potential to induce long-term remission—up to two years, in some patients. Initially, rituximab is likely to be reserved for RA patients who are refractory to other DMARDs, conventional and biologic, although it is unclear what dosing strategy would be used. In clinical trials, rituximab has been administered intravenously weekly or every two weeks, but if the agent can truly induce

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long-term remission, dosing could be much less frequent. Excitement for the potential of the drug is tempered with serious concerns over the adverse events associated with rituximab. Administration of rituximab is linked to a high rate of infusion reactions, with up to 77% incidence for the Þrst infusion. Some of these infusion reactions have proved fatal, prompting the black box warnings discussed previously. Conventional Disease-Modifying Antirheumatic Drugs Overview. The conventional DMARD class includes a wide range of agents as diverse as antimalarials, cytotoxics, and immunosuppressants. Unlike antiinßammatories, which provide symptomatic relief without altering the natural course of the disease, DMARDs typically lack a direct analgesic effect but have the potential to slow or prevent joint damage in RA patients. In 2002, the ACR published revised guidelines for the treatment of RA advocating more aggressive use of conventional DMARDs earlier in the RA treatment regimen in an effort to limit joint damage and minimize loss of joint function and disability (ACR, 2002). As a result, the use of conventional DMARDs, which were once reserved for treating severe or late-stage RA, has become widespread and is now the cornerstone of RA treatment. The development of new DMARDs for the treatment of RA has focused primarily on biological agents. Biological agents, particularly the TNF-α inhibitors, have the best efÞcacy of all drugs used for the treatment of RA, but their high cost limits their widespread use. The production costs of synthetic compounds are much lower than those of biological agents, allowing them to be priced competitively and therefore used as Þrst-line DMARD therapy. Synthetic agents are also usually available in oral formulations that offer an additional advantage over the parenteral biological agents. Emerging conventional DMARDs, however, must contend with methotrexate, which is Þrmly established as the favored DMARD because it offers the best balance of efÞcacy, cost, and safety. Mechanism of Action. Conventional DMARDs include a wide range of agents, such as antimalarials, cytotoxics, and immunosuppressants, each with a distinct mechanism of action. In general, agents in this class are anti-inßammatory and/or antiproliferative, inhibiting various molecules and cell types that play a role in the inßammatory cascade. Most have demonstrated the ability to slow the rate of progression of joint erosion and disability to varying degrees. Iguratimod. Toyama Chemical is developing a chromone derivative, iguratimod (T-614), as a potential therapy for RA. As of November 2004, iguratimod was preregistered in Japan, while a Phase IIa program had been completed in the United States and Europe. Toyama has a codevelopment and comarketing agreement with Eisai, and Toyoma licensed Japanese marketing rights to Taisho Pharmaceuticals in 2003. We anticipate iguratimod will launch in Japan in 2006. Iguratimod was discovered in a program to develop novel anti-inßammatory compounds that preferentially inhibit cyclooxygenase (COX)-2 activity. The drug

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is now recognized as a DMARD, reßecting its ability to block the synthesis of proinßammatory cytokines and immunoglobulin production in addition to inhibiting COX-2 enzyme activity and COX-2 mRNA induction (Tanaka K, 2004). Unlike most other conventional DMARDs, iguratimod has direct analgesic properties that should help the drug provide symptomatic relief in addition to its disease-modifying ability. Iguratimod has demonstrated efÞcacy at least comparable to that of sulfasalazine. In a Japanese multicenter, double-blind trial presented at the 2004 European League Against Rheumatism (EULAR) meeting, 375 patients with active RA were randomly allocated to receive either iguratimod 50 mg/day (n = 146), sulfasalazine 1,000 mg/day (n = 156), or placebo (n = 73). The efÞcacy end point was ACR 20 response at 28 weeks. The ACR 20 response of the iguratimod group was 62.5%, which was comparable to the sulfasalazine group (58.1%). The presenters also stated that iguratimod was signiÞcantly superior to placebo, although the percentage of ACR 20 respondents in the placebo group was not shown. Elevated plasma enzyme levels (e.g., aspartate aminotransferase and alanine aminotransferase) were relatively frequent in the iguratimod group but were transient and improved after discontinuation (Hara M, 2004). The failure to provide placebo data in the study results hinders determination of the true efÞcacy of this agent. If it proves to have efÞcacy comparable to that of sulfasalazine, an agent widely considered to be a comparatively ineffective DMARD, iguratimod’s use will be limited. Furthermore, concerns over the cardiovascular safety of selective COX-2 inhibitors may limit uptake of this agent, since it does preferentially inhibit COX-2 in addition to its immunosuppression. Therefore, iguratimod is likely to be used in milder forms of RA or in combination with other DMARDs in European and U.S. markets, although the agent may become an alternative to salazosulfapyridine (sulfasalazine) in Japan. Selective Cyclooxgenase-2 Inhibitors Overview. The Þrst generation of selective COX-2 inhibitors, such as rofecoxib (Merck’s Vioxx) and celecoxib (PÞzer’s Celebrex), demonstrated their ability to reduce gastrointestinal (GI) side effects in comparison with traditional nonsteroidal anti-inßammatory drugs (NSAIDs), which suppress the isoforms of COX, COX-1 and COX-2, less discriminately. These agents still cause some degree of GI upset, however, so R&D efforts have been focused on developing a second generation of inhibitors that have an even higher degree of selectivity for COX-2. Valdecoxib (PÞzer’s Bextra) and etoricoxib (Merck’s Arcoxia) were the Þrst of this second generation of selective COX-2 inhibitors to be launched; they are reviewed in “Current Therapies.” Concerns regarding the cardiovascular safety of COX-2 inhibitors have drastically lowered expectations for new selective COX-2 agents. It remains unclear whether current selective COX-2 inhibitors will remain on the market and whether agents in the pipeline will launch. Although development of earlier-stage drugs in this class may be abandoned as a consequence of their signiÞcantly lowered sales potential, development for etoricoxib in new markets and for lumiracoxib

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(Novartis’s Prexige) will likely continue. Therefore, the discussion of emerging therapies in this drug class is limited to lumiracoxib. Mechanism of Action. COX-1 (also called constitutive cyclooxygenase) is present in cells under normal physiological conditions and stimulates the synthesis of prostaglandins that help regulate renal function, blood ßow, platelet activity, and protection of the mucous membrane along the GI tract. COX-2 (also known as inducible cyclooxygenase) occurs only under pathological conditions. Its production is induced by proinßammatory cytokines, mitogens, or endotoxins, and it stimulates the production of prostaglandins that drive the inßammatory process. Selective COX-2 inhibitors predominantly inhibit COX-2 while minimizing inhibition of COX-1. As a result, COX-2 inhibitors act speciÞcally to reduce pathological inßammation caused by prostaglandins, without disrupting their beneÞcial effects. Lumiracoxib. Lumiracoxib (Novartis’ Prexige, COX-189), at a dose of 100–200 mg daily, was approved by the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) in September 2003 for the treatment of osteoarthritis (OA). In addition, lumiracoxib at a dose of 400 mg daily was approved for the short-term relief of moderate to severe acute pain associated with primary dysmenorrhea and dental and orthopedic surgery. With these approvals, the United Kingdom was acting as the reference member state for the European mutual recognition procedure. However, Novartis temporarily withdrew its European Union mutual recognition procedure application in November 2004 pending European Agency for the Evaluation of Medicinal Products (EMEA) review of the selective COX-2 inhibitor class in 2005. The U.K. approval of lumiracoxib came on the heels of news that the FDA had requested additional clinical data on lumiracoxib for OA and acute pain. The FDA also denied the registrational Þling for RA. By January 2003, Novartis had initiated an additional clinical trial for RA. In October 2004, the company revised its anticipated U.S. resubmission date for all indications to 2007. Similar to other agents in its class, lumiracoxib predominantly inhibits COX-2 while minimizing inhibition of COX-1. As a result, lumiracoxib acts speciÞcally to reduce pathological inßammation caused by prostaglandins without disrupting their beneÞcial effects. Data from a Phase III study demonstrated that the efÞcacy of lumiracoxib is signiÞcantly better than placebo and similar to naproxen in the reduction of RA symptoms (Geusens P, 2004). In the study, 1,124 patients with symptomatic RA were randomized to receive lumiracoxib 200 mg once daily, lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or placebo for 26 weeks. The primary end point was ACR 20 response at week 13, and secondary end points included ACR 20 response at weeks 4, 20, and 26. After 13 weeks of treatment, an ACR 20 response was achieved by 41.1% and 42.7% for lumiracoxib 200 and 400 mg, respectively, compared with 39.1% and 32.4% for naproxen and placebo. Similar response levels were observed after 26 weeks of treatment. The rate of discontinuation due to adverse events was similar in all treatment

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groups. However, incidence of GI events was 15.7% and 16.4%, respectively, for lumiracoxib 200 mg and 400 mg, compared with 19.7% and 10.9% for naproxen and placebo. A meta-analysis presented at the annual meeting of the American Society for Gastrointestinal Endoscopy in May 2003 suggests that lumiracoxib’s GI safety proÞle is superior to that of traditional NSAIDs and comparable to that of celecoxib and rofecoxib. This analysis, which included 6,295 patients and data from nine OA studies, showed that the overall incidence of GI events was 22% for lumiracoxib (200 and 400 mg daily), 22% for celecoxib (200 mg daily), 29% for rofecoxib (25 mg daily), and 47% for ibuprofen (2,400 mg daily) (Hawkey CJ, 2003). Further evidence of an improved GI safety proÞle for lumiracoxib as compared with traditional NSAIDs came from the large-scale Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET). In this study, 18,325 OA patients were randomized to receive lumiracoxib 400 mg once daily (n = 9, 156), naproxen 500 mg twice daily (n = 4, 754), or ibuprofen 800 mg three times daily (n = 4, 415) for 52 weeks in two substudies of identical design. The primary gastrointestinal end point was the one-year incidence of upper GI ulcer complications: bleeding, perforation, or obstruction. Lumiracoxib demonstrated a signiÞcantly lower incidence of ulcers than the traditional NSAIDs in the overall population and in patients not taking aspirin, but the difference was not signiÞcant for the group taking aspirin (Schnitzer TJ, 2004). Thus, lumiracoxib demonstrated a three- to fourfold decrease in ulcer complications compared to traditional NSAIDs, although concomitant aspirin appears to negate lumiracoxib’s improved GI safety proÞle. The critical question of lumiracoxib’s cardiovascular safety was also addressed in TARGET. The primary cardiovascular end point in that study was deÞned as the incidence of major adverse cardiovascular events—nonfatal and silent myocardial infarction, stroke, or cardiovascular death. At one year, incidence of the primary end point was low with both lumiracoxib (59 events [0.65%]) and the NSAIDs (50 events [0.55%]). No signiÞcant differences were observed between lumiracoxib and the comparator NSAIDs in the overall population or in the subpopulations investigated separately (patients taking or not taking low-dose aspirin). Furthermore, no signiÞcant differences were observed in the incidence of myocardial infarctions, congestive heart failure, and other thrombotic events in the overall population groups studied (Farkouh ME, 2004). The fate of this agent is inextricably linked with that of the other members of this class, currently under review by regulatory agencies in the United States and Europe. While the results of the TARGET study provide some encouragement, increased cardiovascular risk associated with rofecoxib therapy did not become apparent until 18 months. Immunosuppressants Overview. Even though immunosuppressive agents such as azathioprine (GlaxoSmithKline’s Imuran, generics) and cyclosporine (Novartis’ Sandimmune/

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Neoral, generics) have been used for decades to treat the signs and symptoms of RA, development of novel agents in this class for RA has been sluggish because of efÞcacy and safety concerns that have arisen in clinical trials of agents under development. Nonetheless, companies are pursuing development of immunosuppressive therapies. Excluded from this analysis are immunomodulators currently in Phase II trial programs but for which large-scale trial data are currently lacking, including Androclus Therapeutics’ AT-001 and Wyeth’s temsirolimus. Mechanism of Action. Immunosuppressants function through a variety of mechanisms, but they generally target key immunologic processes and molecules. In general, these agents exert their effects by blocking the activation of T-helper and cytotoxic T lymphocytes, promoting the accumulation of anti-inßammatory molecules, and decreasing the formation of antibodies. Tacrolimus. Tacrolimus, or FK-506 (Astellas’s Prograf) (Figure 16), has been launched for atopic dermatitis and for the prophylaxis of liver and kidney allograft rejection. A supplementary new drug application (NDA) was Þled in Japan for RA in November 2002, and in April 2005 the drug was approved for the treatment of RA in patients who responded insufÞciently to conventional treatments. The drug will be marketed in Japan by Astellas, formed from the merger of Fujisawa and Yamanouchi. The agent is in Phase III trials in the United States and in Phase II in Europe. Tacrolimus is a microbial product isolated from the bacterium Streptomyces tsukubaensis. The drug binds to a T-cell-speciÞc FK-binding protein, preventing T-cell activation, proliferation, and survival. As an immunosuppressant, tacrolimus is 50–100 times more potent than cyclosporine, as measured by inhibition of lymphocyte activation in vitro. HO

H3CO

CH3 H3C HO

O

O N O O

O

H3C

HO H3C

H3C O

OCH3 OCH3 FIGURE 16. Structure of tacrolimus.

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The safety and efÞcacy proÞles of tacrolimus appear to be favorable both as monotherapy and in combination with methotrexate. A six-month, randomized, double-blind, placebo-controlled Phase III trial that enrolled 464 patients with active RA who were intolerant of or refractory to one or more DMARDs, including methotrexate, found that 18.8% and 26.8% of patients receiving 2 mg and 3 mg, respectively, of tacrolimus daily achieved an ACR 20 response compared with 10.2% of patients receiving placebo (Yocum D, 2003). Of the patients receiving 2 mg and 3 mg of tacrolimus, 11.7% and 11.8%, respectively, achieved ACR 50 responses compared with 4.5% of patients in the placebo group. A 12-month, open-label extension of this trial, which enrolled 896 patients, sought to establish the long-term safety of tacrolimus (Yocum D, 2004). This study involved patients who chose to enroll in the extension trial, together with an additional 685 patients who either had never received tacrolimus or had not received it in 11 months or more. All patients received 3 mg of tacrolimus daily; 38.4% achieved ACR 20, 18.6% achieved ACR 50, and 9.0% achieved ACR 70. The drug was found to be generally well tolerated in this study; minor side effects included diarrhea (14.6%), nausea (10.3%), tremor (9.0%), and headache (8.7%). Tacrolimus is occasionally used off-label in RA patients who are refractory to methotrexate and other marketed DMARDs, a practice that may be indicative of the limited patient population to whom this agent will be prescribed when it is approved for RA. MAP Kinase Inhibitors Overview. Biotechnology companies such as Scios (a subsidiary of Johnson&Johnson), Vertex, Celgene, and Cephalon dominate the Þeld of mitogenactivated protein (MAP) kinase-based therapeutics. These companies are developing oral small-molecule inhibitors of MAP kinase for the treatment of inßammatory disorders such as RA and Crohn’s disease as well as oncology indications. This section discusses those agents that have advanced to Phase II trials, the most advanced stage of development for members of this class. Mechanism of Action. The enzyme p38 MAP kinase is part of an intracellular signal transduction cascade involved in regulating the expression of several proinßammatory cytokines, including IL-1β and TNF-α. Patients with active RA exhibit increased activation of p38 MAP kinase (Pargellis C, 2003). Researchers believe that p38 MAP kinase plays an important role in the induction of inßammation, and that agents targeting this pathway may provide a more effective and complete blockade of inßammatory cytokines than biological cytokine inhibitors. The potential therapeutic beneÞt of targeting the MAP kinase pathway in RA is also suggested by preclinical studies with selective inhibitors of p38 MAP kinase. In one study, SmithKline Beecham’s (now GlaxoSmithKline’s) research compounds SB-203580 and SB-202190 arrested disease progression in a rat adjuvant-induced arthritis model (Liverton NJ, 1999). In a later study, these same agents blocked the expression of the matrix metalloproteinases MMP-1 and MMP-13 (Ieda Y, 2001). MMP-1 and MMP-13 play a role in cartilage destruction and inßammation in RA.

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SCIO-469. Scios is developing SCIO-469, an oral p38 MAP kinase inhibitor, for the treatment of RA and Crohn’s disease. The agent is in Phase II development in the United States and Europe. No development in Japan has been reported. SCIO-469 blocks the activity of MAP kinase, which in turn inhibits the production of proinßammatory factors such as TNF-α, IL-1β, and COX-2 mRNA. Thus, the agent can be thought of as an indirect TNF-α inhibitor with additional anti-inßammatory effects. By July 2004, Johnson&Johnson reported that two Phase IIa studies of SCIO469 for RA had been successfully completed and a Phase IIb efÞcacy and tolerability trial was under way. The main objective of the Þrst of these studies was to evaluate six escalating doses of SCIO-469 compared with placebo in 120 patients with active RA receiving concomitant methotrexate. The second study was a 24-week, placebo-controlled trial to determine the efÞcacy of SCIO-469 in RA patients not receiving DMARDs other than hydroxychloroquine. Results from the studies have not yet been reported. In April 2001, Scios reported data from a randomized, double-blind, placebocontrolled Phase Ib trial conducted in the United Kingdom that evaluated safety, tolerability, and pharmacokinetics in 30 healthy volunteers over a wide range of doses (Scios, press release, October 20, 2000). According to the company, the drug demonstrated excellent bioavailability and pharmacokinetics and was well tolerated. In October 2002, at the 66th annual ACR meeting, the company presented preclinical data on SCIO-469. In a 28-day study involving rats with preexisting RA, administration of SCIO-469 (10 mg/kg or 40 mg/kg) once daily resulted in a signiÞcant dose-related reduction in the severity of arthritis (joint swelling and erythema). By day 28, the clinical severity score (a measure of disease severity with higher scores indicating greater disease severity) was 5.10 in the control group compared with 4.25 for SCIO-469 10 mg/kg group and 2.16 for SCIO469 40 mg/kg group. In addition, the mean radiographic score for the control group was 3.30 compared with 2.62 for SCIO-469 10 mg/kg group and 0.16 for SCIO-469 40 mg/kg group (Brahn E, 2002). Doramapimod. Boehringer Ingelheim’s doramapimod (BIRB-796) is in Phase II trials in the United States and Europe for RA, psoriasis, and Crohn’s disease. No development has been reported in Japan. Doramapimod, a pyrazole phenyl urea derivative, is a reversible, competitive inhibitor of p38 MAP kinase that acts by interfering with adenosine triphosphate (ATP) binding of p38. Like SCIO-469, this agent blocks TNF-α and IL-1β synthesis. Multiple Phase I trials have demonstrated the agent’s tolerability and lack of signiÞcant adverse events. The Þrst human study conducted with this drug was a randomized, double-blind, placebo-controlled, 64-patient trial presented at the 2002 annual meeting of the American Academy of Asthma, Allergy, and Immunology. In this study, doramapimod administered as an oral solution with PEG400 exhibited safety in doses ranging from 1 mg to 600 mg (Gupta A, 2002).

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Diabetic Retinopathy

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Diabetic retinopathy—described by ICD-10 code H36.0+—is the leading cause of new blindness among adults aged 20–74 (Fong DS, 2003). This condition is characterized by abnormal blood vessel growth in the retina, the light-sensitive tissue at the back of the eye that communicates light signals to the brain. Diabetic retinopathy can be classiÞed by severity into a Þrst stage of nonproliferative retinopathy and a later, progressive stage of proliferative retinopathy. Uncontrolled proliferative retinopathy can progress to the point where complications can eventually lead to severe visual acuity loss and/or blindness. Anatomy Figure 1 illustrates the anatomy of the eye. Hyperglycemia-mediated damage to the eye occurs primarily in the retina, the nerve-dense, light-sensitive tissue that lines the interior of the eye. The macula is the avascular center portion of the retina responsible for central vision. At the center of the macula is the fovea, a further specialized retinal section that is responsible for Þne, sharp vision. Retinal tissue (also detailed in Figure 1) consists of three primary cell types: neurons, glial cells, and blood vessels. Inputs from four types of retinal neurons (photoreceptors and amacrine, bipolar, and horizontal cells) are transmitted to the cells of the ganglia, which then convey electrical output to the nerve Þber layer and optic nerve. Retinal neurons are highly redundant; approximately half of neural cells can be damaged or destroyed before signiÞcant functional impairment or visual acuity loss will occur. Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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4

DIABETIC RETINOPATHY

FIGURE 1. Anatomy of the eye.

Müller cells and astrocytes are the two key glial cell types found in the retina, and they function as the metabolic modulators for neural and vascular components of the retina (Abbott NJ, 1992). Both cell types regulate ion concentrations, neurotransmitters, and nutrients for neural cells. Astrocytes also play an important role in the development and differentiation of vascular endothelial cells, particularly during fetal development (Zhang Y, 1997). Capillaries, arterioles, and venules constitute the important components of the retinal vascular network. Arterioles are the main “valves” through which blood ßows into the retina. Smooth muscle present in arterioles allows them to regulate the resistance they pose to blood ßow. Venules are largely passive vessels that drain blood out of the retina. Although passive, venules do possess a large number of receptors for vasoactive agents. All retinal blood vessels contain two types of cells: endothelial cells and pericytes. Pericytes act like modiÞed smooth muscle cells to control capillary tone in the retina. The endothelial cells in the retina are like other vascular cells in the body except that they have tight junctions that prevent leakage. These tight junctions are the functional component of the blood-retina barrier that allows the retina to self-regulate metabolism and homeostasis and to protect retinal neurons from circulating cytotoxic agents. A number of proteins, including occludin and claudins, are responsible for maintaining the tight junctions and limiting ßuid ßow between endothelial cells (Gardner TW, 2002).


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FIGURE 2. Pathological features of diabetic retinopathy.

Pathophysiology In many cases, the early stages of diabetic retinopathy do not manifest any obvious symptoms (e.g., visual acuity loss). Therefore, the pathophysiology of the disease is described primarily by clinical signs of retinal abnormalities. Figure 2 illustrates the common clinical signs of diabetic retinopathy. Vascular changes are the hallmark of diabetic retinopathy, but recent research also points to cellularlevel deÞcits in neural function that may be an equally important component of the disease. Microvascular Abnormalities. With the onset of diabetic retinopathy, two important changes occur in capillary cells. The tight junctions between endothelial cells loosen and the capillaries become permeable, allowing the inÞltration of glial cells, leukocytes, and other materials. This inßux of cellular material—which adheres to vessel walls—eventually causes capillary occlusion. Second, pericytes die and leave behind “pericyte ghosts.” Without the smooth-muscle activity of the pericytes, the capillaries dilate beyond normal levels, allowing the formation of microaneurysms and other early intraretinal microvascular abnormalities (IRMAs). Capillary microaneurysms appear as small red dots distributed sporadically throughout the retina. As this condition worsens, arteriovenous shunts occur, and bleeding into the nerve Þber layer causes ßame-shaped, blot-shaped, or linear lesions.

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Neovascularization (growth of new blood vessels) reßects the eye’s attempt to restore retinal blood ßow to areas rendered hypoxic by ischemia and signiÞcant vascular occlusion. New blood vessels grow perpendicularly from the surface plane of the retina into the vitreous space. These new vessels are typically hyperpermeable (allowing the inßux of materials) and more prone to hemorrhage than the normal retinal microvasculature. Consistent with wound healing in other tissues, the vessels are eventually subjected to a process of remodeling that includes Þbrosis and replacement with collagen (Gardner TW, 2000). The Þbro-vascular tissue can hemorrhage and/or scar, causing preretinal hemorrhage, vitreous hemorrhage, and/or retinal detachment (described later in the section “Complications”). Retinal Neurodegeneration. Research suggests that defects in retinal glial cell and neuron function precede the development of microvascular abnormalities in diabetic retinopathy and may be an important step in disease pathogenesis. Indicators of glial cells’ metabolic dysfunction include decreased production of glial Þbrillary acidic protein (GFAP; a marker of astrocyte function), decreased conversion of glutamate to glutamine by Müller cells, and increased production of cytokines that are known to increase vascular permeability (Gardner TW, 2002). Subtle defects in vision also suggest that retinal neurons incur damage from hyperglycemia. Using electroretinogram (ERG) measurements of retinal neuron electrical activity, researchers demonstrated that the amplitude of oscillatory potentials was reduced in type 1 diabetics within the Þrst Þve years after disease onset but before the development of clinical signs of retinopathy (FrostLarsen K, 1980). Disease Severity. Diabetic retinopathy is graded in two severity stages: nonproliferative and proliferative. The gold standard for measurement of severity is the criteria developed more than a decade ago in the Early Treatment Diabetic Retinopathy Study (ETDRS). This staging system relies on clinical signs that are evident with fundus photography using seven standard stereoscopic Þelds, and the combined number and position of microvascular abnormalities dictates the severity level (ETDRS Research Group, 1991). Although widely used in clinical trials, the ETDRS staging system is fairly complex and not commonly used for severity grading in practice. In an attempt to simplify the ETDRS criteria, the International Council on Ophthalmology recently proposed new severity scales for diabetic retinopathy (Ciulla TA, 2003; International Council on Ophthalmology, 2002). The International Diabetic Retinopathy Severity Scale is essentially a simpliÞcation of the ETDRS classiÞcations but is intended for use with dilated ophthalmoscopy investigation. Table 1 summarizes the international scale. Nonproliferative retinopathy (previously called background retinopathy) is the slowly progressing, less severe stage of the disease that is characterized by nonneovascular changes in the retina. The severity of nonproliferative retinopathy is determined by the location and quantity of retinal microvascular abnormalities, including microaneurysms, intraretinal hemorrhages, venous beading, and other vascular lesions. Proliferative retinopathy is characterized by neovascularization


7

TABLE 1. Proposed International Clinical Diabetic Retinopathy Disease Severity Scale Severity Level No apparent retinopathy Nonproliferative diabetic retinopathy Mild Moderate

Severe

Proliferative diabetic retinopathy

Dilated Ophthalmoscopy Findings

Comparable ETDRS Stage(s)

No retinal abnormalities

No retinopathy: Level 10

Microaneurysms present, no other clinical signs Microaneurysms and other signs (intraretinal hemorrhages, venous beading, and/or IRMA) present, but less than severe nonproliferative diabetic retinopathy No signs of proliferative diabetic retinopathy, with any of the following: >20 intraretinal hemorrhages in each of four quadrants, definite venous beading in ≥2 quadrants, prominent IRMA in ≥1 quadrant Neovascularization and/or vitreous or preretinal hemorrhage

Very mild nonproliferative diabetic retinopathy: Level 20 Moderate nonproliferative diabetic retinopathy: Levels 35–47

Severe and very severe nonproliferative diabetic retinopathy: Level 53

All stages (high-risk, very severe, and/or advanced proliferative diabetic retinopathy): Levels 61 and higher

ETDRS = Early Treatment Diabetic Retinopathy Study. IRMA = Intraretinal microvascular anomalies.

on the retina, disc, and/or iris and is a quickly progressing, vision-threatening stage of disease. Research has demonstrated that in the preclinical stage of diabetic retinopathy, changes in retinal function (as measured by ERG) can cause perceptive resolution deÞcits, including impaired contrast sensitivity (particularly blue-yellow contrast) and impaired night vision (Bangstad HJ, 1994; Barber AJ, 2003; Della Sala S, 1985; Sokol S, 1985). However, because it precludes the development of classic vascular abnormalities, preclinical diabetic retinopathy is not a widely accepted disease severity stage. Complications. Macular edema and retinal traction detachment are signiÞcant complications of diabetic retinopathy that can, if left untreated, lead to blindness. Macular edema is a thickening/swelling of the center portion of the retina caused by deterioration of the blood-retina barrier that allows leakage from retinal capillaries into normally nonperfused tissues. Clinically signiÞcant macular edema (CSME) is deÞned as thickening of the macula or the area within 500 µm of the macula, hard exudates within 500 µm of the macula, and/or any thickening of the retina one disk area or more in diameter that is within one disk diameter of the center of the retina (ETDRS Research Group, 1985).

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Retinal detachment generally describes the separation of the retina from the underlying retinal pigment epithelium (RPE). There are three main types of retinal detachment: rhegmatogenous, where a tear in the retain causes detachment; exudative, where ßuid accumulation in the subretina causes detachment; and tractional, where scar tissue on the retinal surface contracts and pulls the retina off the RPE. The tractional type is most often associated with diabetic retinopathy. The Þbro-vascular tissue produced in the proliferative stage of disease eventually scars, causing retinal contraction and traction detachment. If the area of detachment includes the macula, signiÞcant vision impairment can arise. Etiology The Growth Factor Hypothesis. In 1948, I.C. Michaelson published what has been termed the “growth factor hypothesis” (Aiello LP, 2000; Michaelson IC, 1948). His hypothesis was that retinal ischemia (like that found in diabetic retinopathy) promotes production of angiogenic growth factors that would be responsible for proliferative neovascularization. Researchers have since focused on a number of likely candidates, including basic Þbroblast growth factor (bFGF), growth hormone (GH), and hepatocyte growth factor (HGF). However, a large body of in vitro and in vivo evidence has narrowed the focus of this search to one highly probable etiological factor: vascular endothelial growth factor (VEGF). VEGF is a potent angiogenic agent whose production is upregulated by hypoxia in RPE cells and retinal pericytes (Adamis AP, 1993; Plouet J, 1993). A study of ocular ßuid taken from the eyes of patients with diabetic retinopathy and other neovascularizing eye disorders conÞrmed VEGF’s association with neovascular retinal disorders (Aiello LP, 1994). In the ocular ßuid of diabetics, VEGF was detectable in 83% of samples from patients with active proliferative diabetic retinopathy, 22% of samples from patients with quiescent proliferative diabetic retinopathy, and only 8% of samples from patients with nonproliferative diabetic retinopathy. Not only does VEGF promote retinal neovascularization, but it is also a highly effective inducer of vascular permeability. Research with bovine retinal endothelial cell cultures demonstrated that the administration of VEGF causes a 46–54% reduction in occludin concentrations (Antonetti DA, 1998). Occludin is the “glue” between retinal endothelial cells that helps maintain the blood-retina barrier, so this research suggests that VEGF-mediated loss of occludin may be a key process underlying the retinal vascular “leakiness” and hemorrhage that occur in diabetic retinopathy. The Role of Hyperglycemia. The metabolic abnormalities of diabetes contribute to the destruction of blood vessels in the eye, just as these abnormalities affect blood vessels in many other organs. The etiological link between hyperglycemia and diabetic retinopathy has not been conclusively established, but several metabolic mechanisms have been proposed to explain how chronic hyperglycemia leads to retinal damage (Figure 3):


9

FIGURE 3. Pathways of hyperglycemia-induced damage.

• • •

The activation of the enzyme protein kinase C. The accumulation of advanced glycation end-products (AGEs). The overactivation of the polyol pathway.

Protein Kinase C. The protein kinase C isozymes are a family of 12 related serine/threonine enzymes found in nearly every tissue and cell type in the body (Aiello LP, 2000; Koya D, 1998). These enzymes have many responsibilities, including cell proliferation, differentiation, and apoptosis. One member of this family, protein-kinase-C beta (PKCβ), has been the target of diabetes research since researchers linked it to hyperglycemia-induced processes. The predominant hypothesis holds that AGEs and oxidants produced in nonenzymatic glycation and the polyol pathway, respectively, are converted to diacylglycerol (DAG). In turn, DAG synthesis promotes the activation of PKCβ (Xia P, 1994). Diabetic

10


animal models have shown high levels of the enzyme in the retina, heart tissues, and renal glomeruli. PKCβ activation in the retina is believed to promote the overgrowth of blood vessels characterizing diabetic retinopathy, primarily through its relationship to VEGF activity. The β isozyme primarily causes cell proliferation, and both animal and human models have shown that blockade of PKCβ stops hypertrophy of the retinal vasculature. PKCβ promotes the expression of VEGF and is a critical mediator of the proliferative and permeability effects of VEGF (Aiello LP, 1997; Xia P, 1996). Furthermore, PKCβ can mediate signal transduction initiated by hormones such as vasopression and angiotensin II, possibly leading to renin-angiotensin-aldosterone system (RAAS) dysfunction. The RAAS is a critical factor in the regulation of the vasculature in the retina and in other body tissues. Advanced Glycation End Products. Advanced glycation end products (AGEs) are formed through a process called nonenzymatic glycosylation. AGEs make up a heterogeneous group of proteins, nucleic acids, and lipids that have been exposed and irreversibly bound to reducing sugars. They are believed to form when blood and tissue glucose levels increase, thereby chemically modifying various extracellular and intracellular macromolecules. One such AGE is glycosylated hemoglobin A1c (HbA1c ), the overproduction of which is a key clinical marker of diabetes-related hyperglycemia. AGEs can alter the structural and functional properties of proteins. Much of this damage is believed to originate intracellularly, particularly in vasculature endothelial cells. It is believed that AGEs damage endothelial cells by intensifying oxidative stress and possibly by upregulating gene transcription, both of which may contribute to vascular disease. The AGE-mediated overproduction of superoxide anion (O-2) creates oxidative stress, which can promote abnormal regulation of apoptosis (cell death). Hyperglycemia also affects the primary enzyme that detoxiÞes O-2, superoxide dismutase 1 (SOD1), which is deactivated by glycosylation, leaving no counterbalance to the damage caused by AGEs. AGEs accumulate in the retinal capillaries, leading to capillary basement membrane thickening, decreased elasticity, and increased leakiness. The Polyol Pathway. A large body of research has studied the role of the enzyme aldose reductase in diabetic complications. Excessive activity of aldose reductase, which reduces glucose to sorbitol via the polyol pathway, causes sorbitol to overaccumulate in cells, producing osmotic stress and creating structural and functional abnormalities in sensitive tissues such as the eye. Because aldose reductase has a low afÞnity for glucose, the polyol pathway has only minimal importance in people with normal glucose levels. In people with hyperglycemia, however, the excessive availability of glucose pushes this reaction in favor of aldose reductase activity. The polyol pathway can account for as much as 30% of glucose metabolism in diabetics with hyperglycemia. Excessive aldose reductase activity may be responsible for overactivation of the GLUT-1 transport mechanism, allowing excessive amounts of glucose to enter


11

endothelial cells. Myoinositol competes with glucose for transport into cells. If aldose reductase enables glucose uptake to increase signiÞcantly, myoinositol will be unable to enter the cell. Abnormal sorbitol and myoinositol levels have also been implicated in increased vascular permeability in the blood/retinal barrier, as well as glomerular hyperÞltration (a kidney abnormality that is an early symptom of diabetes) and nerve cell dysfunction. Risk Factors Duration of Diabetes. The strongest predictor for both development and progression of diabetic retinopathy is the duration of diabetes. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) found that the prevalence of diabetic retinopathy (any stage) was 8% at 3 years after type 1 diabetes diagnosis, increasing to fully 80% at 15 years (Klein R, 1984[a]). The prevalence of PDR was 0% at 3 years and 25% at 15 years. Glycemic Control. Observational data from the WESDR showed a signiÞcant correlation between HbA1c at baseline at the development or progression of diabetic retinopathy among type 1 diabetics, type 2 diabetics who used insulin, and type 2 diabetics who did not use insulin. Depending upon type of diabetes and HbA1c level, the relative risk of developing diabetic retinopathy was 1.1–2.7 compared with the quartile of patients with the lowest average HbA1c . The risk of any disease progression was 1.1–4.3, and the risk of progression to proliferative diabetic retinopathy was 1.2–13.8 (Klein R, 1988; Klein R, 1994; Klein R, 2000). The 1993 publication of the landmark Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that interventional strict glycemic control prevents the development and slows the progression of microvascular complications (including diabetic retinopathy) in type 1 diabetics. The United Kingdom Prospective Diabetes Study (UKPDS) and the Steno Type 2 Randomized Trial found similar results in type 2 diabetics. Table 2 highlights key points from these trials. Hypertension. Hypertension is assumed to be a risk factor for diabetic retinopathy, although it has not been proved to play a role in the progression from the nonproliferative stage to the proliferative one. Researchers believe hyperglycemia causes an increase in retinal blood pressure that causes capillary damage. The role of systemic hypertension in diabetic retinopathy is less clear; studies investigating a possible link have produced conßicting results. Observational studies have examined the role of hypertension in development and/or progression of diabetic retinopathy. The UKPDS compared retinal photographs from 1,919 newly diagnosed type 2 diabetics at diagnosis and six years later. The study found that systolic blood pressure at baseline was signiÞcantly associated with the incident of diabetic retinopathy, and patients in the highest blood pressure tertile were 2.8 times more likely to develop diabetic retinopathy than patients in the lowest tertile (Stratton IM, 2001). However, baseline blood pressure was not signiÞcantly associated with progression of existing retinopathy.

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TABLE 2. Hyperglycemia and Diabetic Retinopathy: Select Results from Clinical Trials Trial

Details of Study

Selected Results

Diabetes Control and Complications Trial (DCCT)

In patients with no initial The DCCT was conducted from retinopathy, IIT reduced the risk 1983 to 1993 and followed 1,441 of sustained disease by 76%. type 1 diabetics. Intensive insulin In patients with mild initial therapy (IIT) was employed to retinopathy, IIT reduced the risk maintain strict glycemic control, of sustained retinopathy by defined as serum HbA1c levels no higher than 7%. 54%, the risk of developing severe proliferative retinopathy by 47%, and the need for laser treatment by 56% (The DCCT Group, 1993). The U.K. The UKPDS randomized 3,867 A modest decrease in HbA1c Prospective type 2 diabetics to receive (11%) reduced the risks for Diabetes Study conventional dietary advice progression to retinopathy by (UKPDS) (fasting glucose levels at 15 21%. mmol/L) or dietary advice in This reduction in HbA1c lowered the risk of microvascular combination with either intensive complications by as much as sulphonylurea or intensive insulin 25%. treatment (fasting glucose levels The median complication-free at less than 6 mmol/L). interval was 1.3 years longer for the intensive treatment group (UKPDS Group, 1998[a]). Progression of retinopathy—either The Steno Type 2 One hundred and sixty type 2 a worsening of existing Randomized Trial diabetics with microalbuminuria retinopathy or development of (albumin excretion rate of new retinopathy—occurred in 19 30–300 mg/day) were followed intensively treated and 33 for four years. Patients were conventionally treated patients randomized to receive either (Gaede P, 1999). standard treatment according to Danish guidelines (n = 80) or intensive treatment that maintained HbA1c levels at 6.5% (n = 80). Full source citations appear in ‘‘References.’’

The WESDR also found that the risk of proliferative retinopathy after 14 years of follow-up was positively correlated with diastolic blood pressure at baseline among type 1 diabetics. However, neither systolic nor diastolic blood pressure was associated with incidence or progression of diabetic retinopathy among type 2 diabetics (Klein R, 1998, Klein R, 2002). The Þrst interventional trial to catch the attention of physicians and other experts was the EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes (EUCLID). For two years, 530 type 1 diabetics in European centers were randomized to either placebo or lisinopril (10 or 20 mg, depending on severity of hypertension). At baseline, 65% of the placebo group and 59% of the lisinopril group had some evidence of retinopathy. The control of blood

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pressure with lisinopril resulted in a 50% reduction in the number of patients whose retinopathy progressed one or more stages compared with the placebo group, after controlling for glycemic control (Chaturvedi N, 1997). It should be noted, however, that the results of this trial are a matter of some debate. The lisinopril-treated group had a signiÞcantly lower average HbA1c at baseline, and some researchers have postulated that its positive effect was due to lowering of undetected baseline hypertension (Fong DS, 2003). In a UKPDS interventional study, 1,148 hypertensive type 2 diabetics were randomized to tight blood pressure control (goal of 150/85 mm Hg or lower) with an ACE inhibitor or a beta blocker or to less tight control (goal of 180/105 mm Hg or lower). Tight blood pressure control was associated with a 35% lower risk of progression of diabetic retinopathy (two or more steps on the modiÞed ETDRS scale) during the median 7.5-year follow-up, and a 47% lower risk of visual acuity loss (three or more lines on the ETDRS chart). There was no signiÞcant difference in these effects between the two antihypertensive agents (UKPDS Group, 1998[b]). A similar study—the Appropriate Blood Pressure Control in Diabetes (ABCD) trial—randomized 470 hypertensive type 2 diabetics to intensive (goal of 75 mm Hg diastolic pressure) or moderate (goal of 80–89 mm Hg diastolic pressure) blood pressure control. At the end of the Þve-year follow-up, the data showed no signiÞcant difference between the groups in the progression of diabetic retinopathy (Estacio RO, 2000). Taken together, the available data (both observational and interventional) do not paint an entirely conclusive picture of the association between hypertension and diabetic retinopathy. However, most physicians and researchers believe that the link is highly plausible and that well-designed studies in the future will provide evidence of a clear causal relationship. Diabetic Nephropathy. Epidemiological data have shown that the incidence and progression of diabetic retinopathy is highly correlated with diabetic nephropathy, as measured by micro- and/or macroalbuminuria (Cruickshanks KJ, 1993; Klein R, 1993; West KM, 1980). In fact, some researchers believe microalbuminuria alone is a predictor of increased diabetic retinopathy risk. It is unlikely that diabetic nephropathy itself inßuences the development of retinopathy, but researchers believe hyperglycemia inßicts similar damage to kidneys and the retina. One hypothesis proposes that increased VEGF in both retinal and renal tissues is to blame, given that diabetics with retinopathy display increased VEGF levels in the eye, and elevated VEGF levels are often found in the urine of diabetics with proteinuria. CURRENT THERAPIES The only proven pharmacological therapy for diabetic retinopathy is the prophylactic achievement of near-normal glucose control. As described in “Etiology and Pathophysiology,” studies have found that rigorous glycemic control can prevent the development of nonproliferative retinopathy and delay progression to proliferative disease (DCCT Group, 1993; Gaede P, 1999; UKPDS Group, 1998[a]).

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TABLE 3. Current Therapies Used for Diabetic Retinopathy Agent

Company/Brand

ACE inhibitors Lisinopril AstraZeneca’s Zestril/Acerbon, Bristol-Myers Squibb’s Carace/Coric, Merck’s Prinivil, generics Captopril Bristol-Myers Squibb’s Lopirin/Capoten, ´ Sanofi-Synthelabo’s Alopresin, generics

Daily Dose

Availability

5–10 mg qd or bid


25–50 mg qd or bid


ACE = Angiotension-converting enzyme; bid = Twice daily; qd = Once daily. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

Most physicians and other experts have consequently tightened glycemic control in retinopathy patients, particularly since the publication of the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) results. Besides antidiabetic agents, only antihypertensive drugs have been shown to have a positive effect on the development and progression of diabetic retinopathy. Nevertheless, physicians do not routinely prescribe antihypertensives speciÞcally for the treatment of diabetic retinopathy. Many diabetics already take one or more antihypertensive agents, either for cardiovascular disease or renal dysfunction, at the time of retinopathy diagnosis. Most physicians are unwilling to prescribe antihypertensives to diabetics who are normotensive and have no discernible renal dysfunction. When antihypertensives are used in these patients, they are, almost without exception, angiotensin-converting enzyme (ACE) inhibitors; they are described here and in Table 3. ACE Inhibitors Overview. Since the 1997 publication of the EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID, described later in the section “Lisinopril”), many physicians and researchers contend that strong evidence proves the beneÞcial effect of ACE inhibitors on the progression of diabetic retinopathy. This section highlights the agents in the class for which there are signiÞcant Þndings from high-quality clinical trials. Other ACE inhibitors that are also prescribed for diabetic retinopathy (and diabetics in general) include ramipril (Aventis’ Altace/Triatec, AstraZeneca’s Vesdil/Unipril), enalapril (Boehringer Ingelheim’s Pres, Merck’s Vasotec, generics), fosinopril (BristolMyers Squibb’s Monopril/Fosinorm, Merck’s Fozitec), and quinapril (PÞzer’s Accupril/Accupro, SanoÞ-Synthélabo’s Korec). Mechanism of Action. ACE inhibitors lower blood pressure by inhibiting the vasoconstrictive action of the renin-angiotensin-aldosterone system (RAAS). Additionally, ACE inhibitors are known to have some action in preventing cell

CURRENT THERAPIES

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NH2 H2C H2C

CH2 H2C CH

HOOC

CH2

CH NH

CH2

N C O

COOH

FIGURE 4. Structure of lisinopril.

proliferation, reducing platelet aggregation, and enhancing Þbrinolysis (Lonn EM, 1998). Pharmacologically, ACE inhibitors act to prevent the ACE-mediated conversion of angiotensin I into angiotensin II (AII)—a potent vasoconstrictive agent that also promotes cardiovascular tissue growth and water and sodium retention. AII is also known to stimulate contraction of the vascular smooth-muscle cells lining the vascular wall, an action ultimately leading to hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number). This action manifests as a thickening of the arterial wall and a narrowing of the lumen, developments that generate an increase in the peripheral resistance of the vasculature. AII also increases production of excess reactive oxygen species, which in turn increase vasoconstriction and damage the endothelial wall (Sowers JR, 2002). Lisinopril. Lisinopril (Merck’s Prinivil, AstraZeneca’s Zestril, generics) (Figure 4) was approved in the United States in December 1987 for use as an antihypertensive agent. The agent is now available in all seven markets under study. The EUCLID study enrolled 530 type 1 diabetics who were both normotensive and either normoalbuminuric (85%) or microalbuminuric (15%) from 15 European centers. At baseline, 65% of the placebo group and 59% of the lisinopril group had some evidence of retinopathy. Patients were randomized to either placebo or lisinopril (10 mg or 20 mg). After two years, treatment with lisinopril resulted in a 50% reduction in the number of patients whose retinopathy progressed one or more stages compared with the placebo group, after controlling for glycemic control (Chaturvedi N, 1997). It should be noted, however, that the results of this trial are a matter of some debate. The lisinopril-treated group had a signiÞcantly lower average HbA1c at baseline, and some researchers have postulated that the drug’s positive effect was due to lowering of undetected baseline hypertension (Fong DS, 2003). Lisinopril’s adverse events proÞle is similar to that of other ACE inhibitors. A common side effect of agents in this class is a dry, nonproductive cough, which can occur in 5–20% of patients. Independently of their action on the RAAS, ACE inhibitors reduce breakdown of the vasodilator bradykinin, accounting for the cough frequently associated with ACE inhibitor prescription. ACE inhibitors are

16


CH3 HSCH2CHC O

N COOH

FIGURE 5. Structure of captopril.

contraindicated in pregnancy (the FDA has rated this class of drugs as Pregnancy Category C [risk cannot be ruled out] in the Þrst trimester and Category D [published documentation of risk exists] for the second and third trimesters). ACE inhibitors are also contraindicated for patients with serious renal stenosis or widespread vascular lesions in the kidney due to potentially decreased renal perfusion. A further concern is angioedema (swelling and accumulation of ßuid in the deep layer of the skin and the connective tissue that underlies mucous membranes); angioedema occurs in approximately 0.1% of patients taking ACE inhibitors. Captopril. Captopril (Bristol-Myers Squibb’s Capoten, generics) (Figure 5) is available in all seven markets under study. In a UKPDS study, 1,148 hypertensive type 2 diabetics were randomized to tight blood pressure control (goal of blood pressure lower than 150/85 mm Hg) with either captopril or a beta blocker (atenolol; AstraZeneca’s Tenormin, generics) or to less tight control (goal of blood pressure lower than 180/105 mm Hg). Tight blood pressure control was associated with a 35% lower risk of progression of diabetic retinopathy (an increase of two or more steps on the modiÞed Early Treatment Diabetic Retinopathy Study [ETDRS] scale) during the median 7.5-year follow-up, and a 47% lower risk of visual acuity loss (an increase of three or more lines on the ETDRS chart). There was no signiÞcant difference in these effects between the two antihypertensive agents (UKPDS Group, 1998[b]). Like lisinopril, captopril is associated with a dry, unproductive cough. It is also known to cause rashes in 2–7% of treated patients, generally within the Þrst few weeks of treatment. Captopril is contraindicated in patients with renal insufÞciency or angioedema. Nonpharmacological Approaches Although tight control of hyperglycemia and hypertension are effective in slowing the progression of diabetic retinopathy, the modest beneÞts conferred by pharmacological agents are not sufÞcient to completely prevent neovascularization. For this reason, nonpharmacological approaches such as laser photocoagulation and surgery are the only effective means to prevent vision loss. Laser Photocoagulation. Photocoagulation destroys large sections of the hypoxic retina, thereby reducing the stimulus for abnormal vascular proliferation. Generally, photocoagulation involves placing a contact lens on a patient’s

CURRENT THERAPIES

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eye after dilation and then focusing a laser beam (argon or krypton) on the retina using a slit lamp. Two techniques are commonly used to treat diabetic eye disease: panretinal photocoagulation (also called scatter photocoagulation) and focal photocoagulation. Panretinal photocoagulation treats a large section of the retina, excluding the macular and foveal areas. Using a blue-green laser, physicians apply moderately intense burns for 0.1 second. Panretinal treatment usually consists of 1,200 to 1,500 of these burns, spaced a half-burn diameter apart from one another. Most patients undergo multiple sessions of 600 to 800 burns each. Panretinal treatment is indicated for proliferative retinopathy but may also be used in patients with severe preproliferative retinopathy, depending on the physician’s assessment of the need for aggressive treatment. In the Diabetic Retinopathy Study (DRS), in which 1,742 patients were randomly assigned to either argon or xenon laser treatment, panretinal photocoagulation reduced severe vision loss by 60% after three years. The same trial also showed a 90% reduction in blindness at Þve years after photocoagulation (Diabetic Retinopathy Study Research Group, 1978). Focal photocoagulation is often used for macular edema, a common complication of diabetic retinopathy, as well as for speciÞc discrete vascular abnormalities elsewhere on the retina of diabetic retinopathy patients. This technique employs the same laser used in panretinal photocoagulation but at a lower energy level (commonly an argon green-only laser). The laser is applied either in a grid pattern or directly to leaking microaneurysms to destroy the blood vessels. In the Early Treatment Diabetic Retinopathy Study (ETDRS), focal/grid photocoagulation reduced by approximately 50% the risk of moderate visual acuity loss (deÞned as doubling of visual angle) in patients with clinically signiÞcant macular edema (ETDRS Research Group, 1985; ETDRS Research Group, 1987). Photocoagulation therapy is generally safe, but it can produce serious side effects and complications in a minority of patients. For example, some patients lose their peripheral vision—in the DRS, 5% of argon-treated eyes and 25% of xenon-treated eyes experienced a constriction of visual Þeld to less than 45◦ but greater than 30◦ (DRS Research Group, 1981[b]). Patients may also develop night vision problems. Potentially more serious is the risk that the laser might burn the wrong part of the retina, causing further deterioration and/or loss of vision. Among argon-treated eyes in the DRS, 11% had a treatment-related persistent decrease in visual acuity of one line, while 3% had a persistent decrease of two or more lines. Xenon-treated eyes had a higher rate of treatment-related side effects—19% had a persistent decrease in visual acuity of one line, and another 11% had a persistent decrease of two or more lines (DRS Research Group, 1981[b]). Vitrectomy. Vitrectomy is indicated for media opacities (primarily vitreous hemorrhage), retinal traction detachment, and, rarely, traction-induced macular edema. A more substantial surgical undertaking than photocoagulation, vitrectomy usually requires hospitalization and general anesthesia. The goal of

18


vitrectomy is removal of the posterior vitreous surface, which provides the “scaffolding” upon which neovascular tissue grows in diabetic retinopathy. The procedure involves making three incisions into the pars plana of the eye, the region behind the iris and in front of the retina. Three instruments are inserted into the incisions: a small light pipe to provide illumination; an infusion port to maintain proper ßuid balance during the procedure; and the vitrector, or cutting device. Once the instruments are positioned inside the eye, subhyaloid blood is extracted and the posterior two-thirds of the vitreous gel and posterior vitreous surface are excised. Fibrovascular tissue causing retinal traction detachment may also be excised by this method. Photocoagulation may be applied thereafter in a panretinal pattern. The Diabetic Retinopathy Vitrectomy Study (DRVS) conducted two randomized trials to assess the efÞcacy of early vitrectomy in type 1 and 2 diabetics and conducted an observational study of a third group of diabetics. One interventional arm of the trial enrolled 616 diabetic patients with severe vision loss from a recent vitreous hemorrhage (5/200 or less for one month or longer). Patients were randomized to either early vitrectomy or deferral of vitrectomy for one year (conventional therapy). The results showed that 25% of the early vitrectomy group recovered good vision (10/20 or better) at two years, compared with 15% of those who received the conventional therapy (DRVS Research Group, 1985). The second interventional arm randomized 381 patients with proliferative retinopathy who still had useful vision (10/200 or better) in at least one eye to either early vitrectomy or conventional therapy. In this arm, the early vitrectomy group had a 36% recovery rate at two years, versus 12% of the conventional group (DRVS Research Group, 1988). Although the Þndings of the DRVS and other studies show that vitrectomy can produce positive results, the procedure’s complicated nature has relegated its use only to cases of severe diabetic retinopathy when photocoagulation has failed or proved technically impossible. The operation puts patients at much higher risk for complications than photocoagulation does; the complications include the buildup of silicon ßuid in the eye, recurrent vitreous hemorrhage, retinal detachment, and anterior hyaloidal Þbrovascular proliferation (vessel proliferation at the front of the eye, behind the lens capsule). EMERGING THERAPIES Of all the agents in development for the treatment of the diabetic microvascular complications, the agents outlined in this section are potentially the most exciting. No current pharmacotherapy, with the possible exception of antihypertensives, can halt the progression of retinopathy. While effective, the current retinopathy treatments (photocoagulation or surgery) are appropriate only for patients who have progressed to the more severe, proliferative stage of disease, leaving few options other than tightened glycemic control for the treatment of patients with nonproliferative disease. Most pharmacotherapies in development target the aberrant angiogenesis that characterizes proliferative diabetic retinopathy, while some

EMERGING THERAPIES

19

are also being tested for related diabetic macular edema. The most interesting therapies in development for diabetic retinopathy are outlined in Table 4. Protein Kinase Cβ Inhibitors Overview. Protein kinase C (PKC) inhibitors are potential treatments for diabetic retinopathy. Eli Lilly’s PKCβ inhibitor, ruboxistaurin, was the Þrst potential oral drug therapy for the indication to reach late-stage development. However, recent clinical trial data have cast some doubt on the potential of this class of drugs. Mechanism of Action. The protein kinase C family consists of several structurally related enzyme isoforms that are present throughout the body. Experimental evidence has shown that the beta isoform (PKCβ) is a key mediator of diabetes-induced retinal abnormalities. When activated by diacylglycerol—cellular levels of which are increased by a chronic hyperglycemic state—PKCβ promotes the synthesis of vascular endothelial growth factor (VEGF), a potent promoter of angiogenesis known to play a role in inducing proliferative diabetic retinopathy (Frank RN, 2002). Agents that inhibit the activation and/or activity of PKCβ could therefore block the effects of VEGF, including promotion of vascular angiogenesis and hyperpermeability. Ruboxistaurin. Eli Lilly’s PKCβ inhibitor ruboxistaurin (LY-333531), an orally available agent, has been discontinued. For purely historical purposes, it is of interest to note that it was highly selective for the β isozyme from the PKC family, and did reach Phase III development in the United States and Europe. In early 2004, Takeda and Eli Lilly agreed to codevelop and comarket ruboxistaurin in Japan, where it was in Phase II. Ruboxistaurin was also in Phase III development for the treatment of diabetic peripheral neuropathy. The Þrst data published from Phase III trials of ruboxistaurin in diabetic retinopathy were not as promising as physicians and researchers had expected. The Protein Kinase C Diabetic Retinopathy Study (PKC-DRS) was a Phase II/III, multicenter, double-blind, placebo-controlled, randomized trial. Two hundred Þfty-two patients with either type 1 (19%) or type 2 (81%) diabetes were randomized to one of three ruboxistaurin doses (8, 16, or 32 mg daily) or placebo for a minimum of 36 months. At baseline, patients had either moderate to severe nonproliferative diabetic retinopathy: as judged by the severity of disease in the worst affected eye, 45% had retinopathy of Early Treatment Diabetic Retinopathy Study (ETDRS) severity level 47, and 55% were at level 53. The primary outcomes measured were progression of retinopathy by three or more steps on the ETDRS scale or application of photocoagulation. At 42 months, ruboxistaurin did not have any signiÞcant effect on those primary end points: event-rate estimates were 57%, 72%, and 52% in the 8, 16, and 32 mg groups, respectively, compared with 55% in the placebo group. However, the highest-dose ruboxistaurin group did show a trend toward a positive effect on some outcome measure. The rates of moderate visual loss (loss of 15 or more letters on the Snellen chart) were

20


TABLE 4. Emerging Therapies in Development for Diabetic Retinopathy Compound

Development Phase

Protein kinase Cβ inhibitors Ruboxistaurin United States Europe Japan Ocular corticosteroid implants Fluocinolone acetonide (Retisert) United States Europe Japan Dexamethasone (Posurdex) United States Europe Japan

Marketing Company

III III I

Eli Lilly Eli Lilly Eli Lilly

III — —

Bausch & Lomb/Control Delivery Systems — —

IIIa — —

Allergan/Oculex Pharmaceuticals — —

Somatostatin analogues Octreotide (Sandostatin LAR) United States Europe Japan BIM-23190 United States Europe Japan

— IIIb —

— Novartis —

— PC PC

— Ipsen Teijin

Angiotensin II receptor antagonists Candesartan (Atacand) United States Europe Japan

III III III

AstraZeneca/Takeda AstraZeneca/Takeda AstraZeneca/Takeda

VEGF antagonists Pegaptanib (Macugen)c United States Europe Japan

II II —

Eyetech Pharmaceuticals/Pfizer Eyetech Pharmaceuticals/Pfizer —

Hyaluronidase modulators Hyaluronidase (Vitrase)d United States Europe Japan

PR III PC

Ista/Allergan Ista/Allergan Otsuka

a Phase III trials are being conducted in diabetic macular edema patients. b Phase III trials are being conducted in Switzerland. c Phase II trials are being conducted in diabetic macular edema patients. Pfizer and Eyetech have publicly

discussed the potential for additional diabetic retinopathy trials, but to date no such formal development program has been announced. d Vitrase is preregistered in the United States for the treatment of vitreous hemorrhage and as a dispersion agent for other ophthalmic drugs. It is in Phase III development in Europe and preclinical development in Japan for vitreous hemorrhage, and Phase II trials for diabetic retinopathy have been conducted in Mexico. PC = Preclinical (including discovery). PR = Preregistered.

EMERGING THERAPIES

21

lower in the 32 mg group than in the placebo group at 12 months (12% versus 20%), 24 months (8% versus 29%), and 36 months (19% versus 28%), with an average risk reduction of 35% (Milton R, 2003). The second Phase III trial of ruboxistaurin—the Protein Kinase C Diabetic Macular Edema Study (PKC-DMES)—measured the drug’s effect on diabetic macular edema (DME) and found similar results. Ruboxistaurin had no signiÞcant effect on either the progression of DME or the application of photocoagulation, but data revealed a trend, with a 32 mg daily dose, toward a positive effect on the development of DME that involves or imminently threatens the center of the macula (Eli Lilly, press release, August 25, 2003). One possible explanation for the largely disappointing results from these two Phase III trials (which used partially overlapping patient populations) was the lower-than-expected event rates in the placebo groups (Davis MD, 2003). The trials were designed based upon event-rate data from the ETDRS, where the rates of both diabetic retinopathy and DME events were notably higher than those found in the PKC-DRS or PKC-DMES. Thus, the PKC-DRS and PKCDMES were perhaps not powered sufÞciently to show a treatment effect, if any existed. Eli Lilly stated already in December 2002 that these results would delay the EU and U.S. regulatory Þlings for ruboxistaurin for diabetic retinopathy, but that additional Phase III studies were to be conducted that would, the company had hoped, address the methodological issues of the PKC-DRS. These hopes did not come to fruition. Ocular Corticosteroid Implants Overview. Corticosteroids have been utilized in eyedrop formulations for a number of ophthalmic indications. However, these products are unable to penetrate the vitreous and retinal areas and therefore have little effect on retinal vasculature and inßammation. Corticosteroid implants currently in development for diabetic macular edema and retinopathy may allow site-speciÞc delivery of these compounds, which have potent anti-inßammatory and antiangiogenic qualities. Mechanism of Action. Corticosteroids act as anti-inßammatory, immunosuppressive, and antiangiogenic agents through multiple effects: inhibiting synthesis of proinßammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Although systemic corticosteroids are effective against many inßammatory and immune-mediated disorders, their prolonged use is associated with a high risk of side effects. Insomnia, night sweats, mood changes, and altered glucose metabolism may occur shortly after beginning corticosteroid use, while long-term use of systemic corticosteroids is associated with adrenal atrophy, osteoporosis, hypertension, cataracts, acne, abnormal fat deposition, and excessive hair growth. Local corticosteroid delivery in the form of ocular drops, injections, or sustained-release implants has been postulated as a therapeutic option that would target inßammation and neovascular processes in numerous

22


retinal disorders—including diabetic retinopathy—in the hopes of minimizing the risk of systemic side effects. Fluocinolone Acetonide. Fluocinolone Intraocular implant has been discontinued. Originally, Bausch&Lomb and Control Delivery Systems were developing a sustained-release intravitreal ßuocinolone implant (Retisert) using Control Delivery Systems’ Envision TD delivery technology. The agent did reach Phase III development in the United States for diabetic macular edema and diabetic retinopathy, as well as Phase III trials for uveitis and Phase II trials for age-related macular degeneration (AMD). Twelve-month data from the Þrst Phase III trial demonstrating the ßuocinolone implants’ efÞcacy were presented at the 2003 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). Eighty patients with diabetic macular edema were randomized to ßuocinolone implant (0.5 mg or 2 mg) or standard of care (observation or laser photocoagulation). The 2 mg implant was discontinued early in the trial when investigators determined it conferred no additional treatment beneÞt compared with the 0.5 mg implant. After 12 months, the ßuocinolone implant had a signiÞcant effect on retinal thickness (macular edema)—49% of patients receiving the 0.5 mg implant had complete response, compared with 25% of the control group (Bausch & Lomb, press release, May 7, 2003). This trial was not powered to demonstrate signiÞcant effects on diabetic retinopathy or overall visual acuity, but those data were presented and suggested a trend toward an effect. Fewer ßuocinolone-treated patients demonstrated a worsening of diabetic retinopathy (5%) than did patients in the control group (30%). Although the results for visual acuity changes were not statistically signiÞcant, patients receiving the ßuocinolone implant did demonstrate a trend toward a treatment effect. More ßuocinolone-treated patients had stable (70%) or improved (19.5%; 15 or more letters) visual acuity than did control patients (50% and 7.1%, respectively). Although the 12-month data from the Phase III trial looked promising—particularly for the treatment of diabetic macular edema—ßuocinolone treatment was also associated with a number of side effects. Nearly 20% of ßuocinolone-treated patients had a serious increase in intraocular pressure (≥30 mm Hg), whereas no control-group patients did. Cataract progression at six months was evident in 55% of patients in the ßuocinolone-treated group, compared with no patients in the control group. After discussions concerning the adverse event rates from this trial, the FDA had requested additional 12-month safety data from additional ßuocinolone-implanted diabetic eyes. Eventually, these effects resulted in the discontinuation of the ßuocinolone intraocular implant. Dexamethasone. Oculex has developed a biodegradable, sustained-release dexamethasone implant (Posurdex) for the treatment of macular edema. In October 2003, Allergan purchased Oculex and began to design and plan Phase III

EMERGING THERAPIES

23

trials in the United States for diabetic macular edema and nondiabetic edemas (Allergan eyes Posurdex . . ., 2003). Preliminary data from a Phase II, randomized, dose-ranging trial of intravitreal dexamethasone were presented at the 2003 annual meeting of ARVO. The study enrolled patients with persistent macular edema associated with diabetes (n = 171), uveitis or Irvine-Gass syndrome (n = 40), or central or branch retinal vein occlusion (n = 103), all with visual acuity of 20/40 or worse. Patients were randomized to intravitreal dexamethasone (350 µg or 700 µg) or standard of care/observation (Haller JA, 2003; Kuppermann BD, 2003; Williams GA, 2003). EfÞcacy data were reported for a combined study population of 306 patients three months after treatment initiation. Patients who received the 700 µg demonstrated signiÞcant improvements in visual acuity (two or more lines) compared with the control group. Both the 350 µg and 700 µg intravitreal dexamethasone groups showed signiÞcant decreases in retinal thickness and ßuorescein leakage compared with control (Oculex, press release, May 8, 2003). Like the ßuocinolone implant, intravitreal dexamethasone was associated with an increased risk of glaucoma—4% of treated patients had developed elevated intraocular pressure in the three-month assessment. Although this rate is lower than reported in the previously described trial of the ßuocinolone implant, it is premature to assume that intravitreal dexamethasone will have a more favorable adverse event proÞle. Preliminary data regarding the ßuocinolone implant also demonstrated a low occurrence of serious side effects, and not until longerterm data were available did the serious adverse event rate become substantial (approximately 40–50%). According to Allergan, the intended Phase III development program for intravitreal dexamethasone will include approximately 700 patients (diabetic and nondiabetic), with treatment periods of at least six months and follow-up periods of a year or more. Somatostatin Analogues Overview. The normal process of retinal vascular growth and apoptosis involves both proangiogenic and antiangiogenic elements. In an attempt to capitalize on the body’s naturally antiangiogenic compounds, researchers are developing analogues of somatostatin, a naturally occurring hormone with strong inhibitory effects on the endocrine system and possibly on the retinal vasculature speciÞcally. Mechanism of Action. Somatostatin is an endogenous hormone that is secreted in a number of body tissues, including the hypothalamus, intestines, and pancreas. It has a potent and multifaceted inhibitory effect on the endocrine system—endogenous somatostatin release inhibits the secretion of growth factors such as insulin, thyroid-stimulating hormone (TSH), human growth hormone (GH), and insulin-like growth factor 1 (IGF-1). Case studies and other experimental evidence have demonstrated that GH and IGF-1, in particular, are angiogenic factors that contribute to retinal neovascularization in diabetics. Some diabetics

24


f C F W K T C T–ol FIGURE 6. Structure of octreotide.

who have undergone hypophysectomy (removal of the pituitary gland) experienced reversals of proliferative retinopathy that correlated with the degree of GH deÞciency postsurgery (Patterson JH, 1974; Poulsen JE, 1953; Sharp PS, 1987). Serum and vitreal concentrations of IGF-1 correlate positively with the presence of proliferative retinopathy in diabetics (Burgos R, 2000; Merimee TJ, 1983). Thus, by mimicking the inhibitory effects of endogenous somatostatin and blocking the secretion of GH, IGF-1, and other growth factors, somatostatin analogues may be effective against neovascularization in the diabetic retina. Octreotide. Novartis’s octreotide (Figure 6) is a somatostatin analogue marketed as Sandostatin and as Sandostatin LAR, a long-acting release formulation, worldwide for the treatment of acromegaly and diarrhea. The long-acting formulation is in Phase III trials in Switzerland for diabetic retinopathy. A 15-month pilot study of 23 patients with type 1 or type 2 diabetes and severe nonproliferative diabetic retinopathy was conducted in the United States. Octreotide-treated patients received four daily subcutaneous injections of shortacting octreotide at the maximum tolerable dose for each individual (total daily doses ranged from 200 µg to 5,000 µg). The number of patients requiring panretinal photocoagulation (PRP) during the study period was signiÞcantly reduced in the octreotide-treated group: 1 of 22 eyes required PRP compared with 9 of 24 eyes in the control group. In addition, the incidence of progression to require PRP (ETDRS score 71 or 75) was 42% in the control group compared with 9% in the octreotide group, although those results were not statistically signiÞcant (Grant MB, 2000). In a small U.K. trial, 18 patients (type 1 or type 2 diabetics) with persistent proliferative retinopathy after laser photocoagulation were randomized to either octreotide treatment (n = 9) or a control group (no placebo; n = 9). Octreotidetreated patients received three times daily subcutaneous 100 µg injections of short-acting octreotide. After three years of treatment, octreotide reduced the risk of vitreous hemorrhage and vitreoretinal surgery signiÞcantly compared with control. Average visual acuity remained stable in the octreotide-treated patients but decreased in the control group (Boehm BO, 2001). The currently marketed short-acting product is an intramuscular injection that requires physician administration, and trials using this formulation of octreotide in retinopathy have used thrice-daily injections. The ongoing Phase III diabetic retinopathy trial is utilizing the sustained-release octreotide LAR, and the dosing protocol in the study will use monthly injections. However, octreotide LAR is an intramuscular injection that requires in-ofÞce administration by a physician, so it may not offer a large convenience beneÞt over daily but self-administered injections of the short-acting octreotide product.

EMERGING THERAPIES

25

BIM-23190. Ipsen’s BIM-23190 is a somatostatin analogue that is highly selective for the human somatostatin analogue receptor subtype 2 (Morgan JP, 1996). In July 2003, Teijin signed an exclusive codevelopment and comarketing agreement with Ipsen for BIM-23190 in Japan for the treatment of diabetic retinopathy. No human trial data are yet published that would allow for direct comparison of BIM-23190’s efÞcacy and safety with those of octreotide, but it appears that BIM-23190 will also be administered parenterally. Angiotension II Receptor Antagonists Overview. Since the 1997 publication of the EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID, described in the “Current Therapies” section), antihypertensives (speciÞcally, ACE inhibitors) have been posited to have a strong effect on the progression of diabetic retinopathy. However, EUCLID was not designed with incidence or progression of diabetic retinopathy as primary outcomes, leaving some uncertainty about antihypertensives’ effects on the disease (Sjolie AK, 2002). Another question remains as well: Will agents that produce the same antihypertensive effect as ACE inhibitors via different mechanisms be comparable or superior to those agents in the treatment of diabetic retinopathy? To that end, angiotensin II receptor antagonists (AIIRAs) are under investigation as potential therapies for this indication. Mechanism of Action. Angiotensin II (AII) is a potent vasoconstrictive agent that also promotes cardiovascular tissue growth and water and sodium retention. AII is also known to stimulate contraction of the vascular smooth-muscle cells lining the vascular wall, an action ultimately leading to hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number). This action manifests as a thickening of the arterial wall and a narrowing of the lumen, developments that generate an increase in the peripheral resistance of the vasculature. AII also increases production of excess reactive oxygen species, which in turn increase vasoconstriction and damage the endothelial wall (Sowers J, 2002). AIIRAs, like ACE inhibitors, act on the renin-angiotensin-aldosterone system (RAAS) to block the activity of AII; however, AIIRAs selectively antagonize the angiotensin II receptor subtype 1 (AT1), whereas ACE inhibitors function by blocking AII generation. Data from animal models have shown that AII can stimulate retinal neovascularization in vitro (Otani A, 1998) and that AIIRA treatment can inhibit retinal VEGF expression and angiogenesis in vivo (Moravski CJ, 2000; Nagisa Y, 2001). Candesartan. Candesartan (AstraZeneca’s Atacand/Ratacand/Amias, Takeda’s Kenzen/Blopress) (Figure 7) is marketed in all regions under study for the treatment of hypertension and is currently in Phase III trials for diabetic retinopathy. A large-scale Phase III diabetic retinopathy trial of candesartan was initiated in early 2003. The Diabetic Retinopathy Candesartan Trial (DIRECT) is a multicenter, placebo-controlled, double-blind, randomized clinical trial consisting of

26


Me

N O N O

OH HN N

N N

FIGURE 7. Structure of candesartan.

three study arms. The three arms of the DIRECT study are a primary prevention trial in type 1 diabetics with no retinopathy, a secondary prevention trial in type 1 diabetics with nonproliferative retinopathy, and a secondary prevention trial in type 2 diabetics with nonproliferative retinopathy. Study investigators plan to enroll approximately 4,500 participants from 20 countries who will be randomized to either candesartan (up to 32 mg/day) or placebo for at least three years. The primary endpoints to be measured in DIRECT are incidence of retinopathy in those with no retinopathy at baseline (a two-step increase in ETDRS severity grade) and progression of existing retinopathy (a three-step or greater increase in ETDRS severity grade) (Chaturvedi N, 2002). According to AstraZeneca and Takeda, full results of the DIRECT study are expected by 2006. VEGF Antagonists Overview. Although many agents in development inhibit the production of vascular endothelial growth factor (VEGF), research has also focused on agents that can antagonize circulating ocular VEGF. The majority of VEGF antagonists are in active development for retinal neovascularization disorders such as AMD. However, by virtue of the common VEGF-mediated pathways that result in diabetic retinopathy and/or diabetic macular edema, these indications may be logical additional targets for those same anti-VEGF agents. Mechanism of Action. Unlike antiangiogenesis agents, which inhibit the production of VEGF through enzymatic or other processes, VEGF antagonists are a heterogeneous group of drugs in development that bind to free VEGF and render it unable to activate receptors in the retinal vasculature (or theoretically in any body tissue). Agents that can be classiÞed into this group include receptor fusion proteins, anti-VEGF aptamers, and monoclonal antibodies. Though different in composition and structure, all VEGF antagonists share the ability to mimic endogenous VEGF receptors and thus “capture” the molecule and render it inactive. Pegaptanib. PÞzer and Eyetech are jointly developing pegaptanib (EYE-001; Macugen), an intravitreal injection in Phase III trials for the treatment of

EMERGING THERAPIES

27

AMD and Phase II trials for diabetic macular edema. Pegaptanib is an antiVEGF aptamer, a synthetic oligonucleotide with high afÞnity and selectivity for VEGF165. Eyetech originally licensed pegaptanib from Gilead in 2000, and in December 2002, PÞzer and Eyetech entered a codevelopment and comarketing agreement for the molecule. Under this agreement, PÞzer will fund most of the remaining development, and the companies will copromote pegaptanib in the United States. PÞzer has exclusive marketing rights outside the United States. Pegaptanib has not been tested in diabetic retinopathy patients, but Phase IIa data in AMD patients were presented in May 2002 at the TIDES meeting, a joint event that included the Sixth International Oligonucleotide Technology Conference and the Fifth International Peptide Technology Conference. Patients received three monthly intravitreal injections (0.1 mL) of pegaptanib either alone or in conjunction with photodynamic therapy (PDT). At three months, 86% of pegaptanib-treated patients demonstrated stabilization of AMD progression, compared with 51% of patients receiving PDT alone. Three-line improvements in visual acuity were evident in 26% of pegaptanib-treated patients, compared with 2% of PDT-treated patients. The combined effect of pegaptanib and PDT was even more beneÞcial: 60% of patients receiving combination therapy achieved a three-line or better improvement in visual acuity (Scypinski S, 2002). These Phase II AMD data suggest that after just three months, pegaptanib can inhibit the progression of retinal neovascularization. These results are promising for the use of this anti-VEGF aptamer to halt or possibly reverse retinal neovascularization associated with other conditions, including diabetic retinopathy. The general transferability of pegaptanib’s AMD trial results to diabetic retinopathy remains to be proven, however, because of key differences in the pathology and pathogenesis of each disease. The pathology of AMD neovascularization is distinct (the former occurs in the choroid, a normally avascular portion of the eye posterior to the retina), and the natural history of AMD progression follows a more rapid, progressively degenerative course than does the metabolic-dependent progression of diabetic retinopathy. Hyaluronidase Modulators Overview. Vitreous hemorrhage (leakage of the vitreous humor into the retina) is a complication of retinopathy that is difÞcult to treat and can occlude the imaging of the retina for screening or laser photocoagulation. The current treatment method, surgical vitrectomy, is generally effective but highly invasive. Hyaluronidase modulators, which are preparations of a naturally occurring enzyme, offer promise as treatment for vitreous hemorrhage secondary to proliferative diabetic retinopathy and may also be effective for preventing progression of nonproliferative disease. Mechanism of Action. Hyaluronidase is a naturally occurring enzyme that digests proteoglycans. This group of molecules, which are largely present in connective tissues, includes hyaluronan, hyaluronic acid, and chondroitin sulfate. When introduced into a medium containing proteoglycans, hyaluronidase digests

28


the molecules and decreases the viscosity of the medium. Research has shown that intraocular injections of hyaluronidase can induce posterior vitreous detachment (PVD; a loosening or separation of the vitreous humor from the retina), which allows for the clearing of vitreous hemorrhage. Researchers postulate that liquefaction or detachment of the vitreous humor will remove the “scaffolding” upon which retinal neovascular tissue forms and therefore may prevent or delay progression to proliferative retinopathy. Hyaluronidase. Ista Pharmaceuticals is developing an intravitreal injection of highly puriÞed ovine hyaluronidase (Vitrase) for the treatment of vitreous hemorrhage and diabetic retinopathy and as a spreading agent to facilitate the dispersion and absorption of other ophthalmic agents. Ista partnered with Allergan in March 2000 to comarket hyaluronidase in the United States and all international markets except Mexico and Japan. In late 2001, Ista gave exclusive development and marketing rights for hyaluronidase in Japan to Otsuka. Hyaluronidase is currently in preregistration in the United States and Japan and in Phase III development in Europe for the treatment of vitreous hemorrhage. The FDA gave hyaluronidase fast-track designation in 1998 for this indication. Ista submitted hylauronidase for FDA approval in December 2002 for the treatment of vitreous hemorrhage but received an approvable letter in April 2003 citing insufÞcient statistical evidence to support its approval. In August 2003, Ista Þled a second NDA for hylauronidase for approval as a dispersion enhancer for other ophthalmic agents. The FDA has accepted this second NDA. In addition to these development programs, Phase II trials for diabetic retinopathy have been conducted in Mexico. Initial results from a randomized, placebo-controlled, Phase IIa trial of hyaluronidase showed it was effective at inducing PVD. The study enrolled approximately 60 diabetics with nonproliferative retinopathy from Mexico City. Patients were randomized to receive one of four treatments: an injection of hyaluronidase, a placebo (saline) injection, a single treatment with sulfurhexaßuoride gas (SF6; a surgical adjunct for retinal detachment treatment), or a single, combination treatment with SF6 and a hyaluronidase injection. Interim results showed that 16 weeks following treatment, 60% of patients who received hyaluronidase injections demonstrated complete PVD, as measured via ultrasound. Complete PVD rates were 53% in the SF6-treated group, 50% in the SF6/hyaluronidase combination group, and 6% in the placebo group (Ista, press release, October 19, 2000). The full one-year data measured the effect of hyaluronidase on ETDRS diabetic retinopathy levels and found that the agent prevented worsening of diabetic retinopathy. At 12 months, 67% of hyaluronidase-treated patients had stable ETDRS scores, compared with 40%, 43%, and 38% of the SF6-treated group, the SF6/hyaluronidase combination group, and the placebo group, respectively. Fewer hyaluronidase-treated patients (13%) had a worsening of ETDRS severity, compared with 20% of the SF6-treated group, 21% of the SF6/hyaluronidase combination group, and 38% of the placebo group (Ista, press release, January 8, 2002).

REFERENCES

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Chuang LM, et al. The status of diabetes control in Asia—a cross-sectional survey of 24,317 patients with diabetes mellitus in 1998. Diabetic Medicine. 2002;19:978–985. Ciulla TA, et al. Diabetic retinopathy and diabetic macular edema. Diabetes Care. 2003; 26(9):2653–2664. Cruickshanks KJ, et al. The association of microalbuminuria with diabetic retinopathy: the Wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology. 1993;100(6): 862–867. Davis MD, et al. Diabetic retinopathy and macular edema progression rates in recent placebo-controlled clinical trials. Diabetes. 2003;52(suppl 6). Abstract 858-P. Deckert T, et al. Prognosis of proliferative retinopathy in juvenile diabetics. Diabetes. 1967;16:728–733. DECODA Study Group. Age- and sex-speciÞc prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care. 2003;26:1770–1780. DECODE Study Group. Age- and sex-speciÞc prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care. 2003;26:61–69. Delcourt C, et al. Low prevalence of long-term complications in non-insulin-dependent diabetes mellitus in France: a multi-center study. CODIAB-INSERM-ZENECA Pharma Study Group. Journal of Diabetes and Its Complications. 1998;12:88–95. Della Sala S, et al. Impaired contrast sensitivity in diabetic patients with and without retinopathy: a new technique for rapid assessment. British Journal of Ophthalmology. 1985;69:136–142. The Diabetes Control and Complications Trial (DCCT) Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine. 1993;329:977–986. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. New England Journal of Medicine. 2000;382:381–389. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. American Journal of Ophthalmology. 1976;81:383–396. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study Þndings. Ophthalmology. 1978;85(1):82–106. The Diabetic Retinopathy Study Research Group. A modiÞcation of the Airlie House classiÞcation of diabetic retinopathy. DRS Report No. 7. Investigative Ophthalmology and Visual Science. 1981;21:210–226. [a] The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) Þndings: DRS Report No. 8. Ophthalmology. 1981;88:583–600. [b] The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: Relationship of adverse treatment effects to retinopathy severity. Diabetic Retinopathy Study (DRS) Report No. 5. Developments in Ophthalmology. 1981;2:248–261. [c] The Diabetic Retinopathy Vitrectomy Study (DRVS) Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: two-year results of a randomized

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Garancini P, et al. Prevalence of retinopathy in diabetic subjects from out-patient clinics in Lombardy (Italy) and associated risk factors. Diabetes Research and Clinical Practice. 1989;6:129–138. Gardner TW, Aiello LP. Pathogenesis of diabetic retinopathy. In: Flynn HW, Smiddy WE, eds. Diabetes and Ocular Disease: Past, Present, and Future Therapies. San Francisco: The Foundation of the American Academy of Ophthalmology; 2000. Gardner TW, et al. Diabetic retinopathy: more than meets the eye. Survey of Ophthalmology. 2002;47(suppl 2):S253–S262. Grant MB, et al. The efÞcacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy. Diabetes Care. 2000;23(4):504–509. Grusser M, et al. [Preventive care for early detection of diabetes mellitus complications: a model project in Wolfsburg.] Zeitschrift für Arztliche Fortbildung und Qualitätssicherung. 2000;94:411–416. Haller JA, et al. Treatment of persistent macular edema associated with central and branch retinal vein occlusion with extended delivery of intravitreal dexamethasone. Presented at the 2003 annual meeting of the Association for Research in Vision and Ophthalmology. May 4–9, 2003; Fort Lauderdale, FL. Harris MI, et al. Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A U.S. population study. Diabetes Care. 1998;21:1230–1235. [a] Harris MI, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care. 1998;21:518–524. [b] Henricsson M, et al. Mortality in diabetic patients participating in an ophthalmological control and screening programme. Diabetic Medicine. 1997;14(7):576–583. Hesse L, et al. Population-based study of diabetic retinopathy in Wolfsburg. Opthalmologie. 2001;98:1065–1068. Hoogeveen EK, et al. Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study. Archives of Internal Medicine. 2000;160:2984–2990. International Council on Ophthalmology. International clinical diabetic retinopathy disease severity scale. October 2002. www.icoph.org/standards/pdrdetail.html. Accessed September 25, 2003. Joner G, et al. A nationwide cross-sectional study of retinopathy and microalbuminuria in young Norwegian type 1 (insulin-dependent) diabetic patients. Diabetologia. 1992;34:1049–1054. Kato S; Retinopathy in older patients with diabetes mellitus. Diabetes Research and Clinical Practice. 2002; 58:187–192. Keeffe JE, et al. Impact of vision impairment on functioning. Australian and New Zealand Journal of Ophthalmology. 1998;26(suppl 1):S16–S18. Khaleeli AA, et al. Diabetic retinopathy: outcome at Þve-year follow-up of 203 people with diabetes. Practical Diabetes International . 1999:16(3):68–70. Klein R, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, part II: prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology. 1984;102:520–526. [a]

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Dyslipidemia

ETIOLOGY AND PATHOPHYSIOLOGY Introduction The term dyslipidemia refers to any abnormality in circulating lipid levels. This abnormality can include an elevation in any one of the lipid subfractions of lowdensity lipoprotein (LDL), very-low-density lipoprotein (VLDL), or triglycerides (TG). The term additionally encompasses any reduction in the circulating levels of high-density lipoprotein (HDL). The manifestation of dyslipidemia is generally deÞned according to the cholesterol levels set forth by the U.S. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), published in 2001. According to ATP III guidelines, a total serum cholesterol (TSC) level of 200–239 mg/dL is considered “borderline high,” and a TSC level greater than or equal to 240 mg/dL is considered “high.” Such lipid abnormalities are known risk factors for atherogenesis, coronary heart disease (CHD), and cardiovascular disease (CVD), and can result from accelerated synthesis or from retarded degradation of lipoproteins. (Note that CHD is a subcategory of CVD, which encompasses all diseases that affect the heart and blood vessels, including ischemic stroke and peripheral arterial disease.) Lipid Pathways and Mechanisms Overview. To fully understand the development of dyslipidemia, familiarity with lipid pathways and mechanisms is essential. Cholesterol and TGs are the Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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38

DYSLIPIDEMIA

FIGURE 1. Cholesterol biosynthesis.

two key lipids transported by blood plasma. Cholesterol, which is used by adrenal glands and sex organs to manufacture steroid hormones, is present in all cell membranes. The majority of cholesterol synthesis in adults occurs in the liver, gut, and central nervous system. Cholesterol derives from acetyl-coenzyme A (CoA); the pivotal, nonreversible step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). Figure 1 depicts the cholesterol biosynthesis sequence. The enzyme responsible for this step, HMG-CoA reductase, can be inhibited by a variety of physiological factors, the most inßuential being the intracellular level of cholesterol. The enzyme is also the target for the most popular class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors, also known as statins. The major breakdown products of cholesterol are bile acids, which are highly effective detergents that are involved in the solubilization of dietary lipids. Bile acid action increases the surface area of lipids, promoting hydrolysis by lipases and facilitating absorption in the intestine. Because of their role in lipid solubilization, bile acids are the target site for bile acid sequestrants, another class of antidyslipidemic therapeutics (see “Current Therapies”). Plasma TGs are derived from dietary fat or synthesized in the body from other energy sources, such as carbohydrates. Stored in adipose (fat) cells until needed, TGs consist of glycerol combined with three fatty acids.


39

FIGURE 2. Lipoprotein structure.

Types of Lipoprotein and Lipoprotein Components. In plasma, proteinlipid particles called lipoproteins carry cholesterol, TGs, phospholipids (lipids that have been phosphorylated), and apolipoproteins (proteins that combine with lipids to form lipid-protein complexes). More than half of the coronary heart disease (CHD) in the United States is attributable to abnormalities in the levels and metabolism of plasma lipids and lipoproteins (Ginsberg HN, 2001). Figure 2 illustrates the structure of lipoprotein. The lipid content of lipoproteins, mainly cholesteryl esters and phospholipids, increases with age in all healthy arteries. At birth, cholesterol levels average 1.5 mmol/L (60 mg/dL); by the Þrst year, they rise to 4.5 mmol/L (175 mg/dL). A second rise begins after age 20 and continues to age 50–60. Six classes of lipoproteins have been identiÞed: chylomicrons, chylomicron remnants, VLDL, intermediate-density lipoprotein (IDL), LDL, and HDL. These various types differ from one another in terms of size, density, and the amount of cholesterol, TG, phospholipid, and apolipoprotein they contain. Figure 3 illustrates the composition of the four lipoproteins most often associated with dyslipidemia (chylomicron, VLDL, LDL, and HDL). Each lipoprotein, discussed in the following sections, performs a speciÞc function in terms of the type of lipid it transports and where it is transported to. TGs, also discussed in more detail, are

40

DYSLIPIDEMIA

FIGURE 3. Composition of lipoproteins.

another lipoprotein component that plays a signiÞcant role in lipid metabolism and dyslipidemia. Chylomicrons. Chylomicrons transport exogenous TGs (TGs absorbed from the gut). They typically appear only transiently in the blood after a fatty meal, but defects in lipid metabolism, usually genetic in origin, may lead to chylomicrons and chylomicron remnants being present in plasma in the fasting state. Chylomicron remnants—a by-product of chylomicron lipolysis in the liver—transport exogenous cholesterol. They are considered to have only some atherogenic potential because they do not appear in the absence of other underlying lipid abnormalities, such as high serum TG levels. Very-Low-Density Lipoprotein Cholesterol. VLDLs are small, cholesteroland TG-rich lipoproteins synthesized by the liver that account for 10–15% of TSC. VLDLs are responsible for the transport of endogenous TGs (newly synthesized TGs). A large body of evidence suggests that VLDL and VLDL remnants play an important role in atherogenesis (Sacks FM, 2000; Thompson GR, 1998). Serum levels of VLDL are usually combined with LDL to give a measure of nonHDL cholesterol and are therefore treated alongside LDL abnormalities. ATP III identiÞes elevated VLDL levels as the surrogate for elevated atherogenic remnants in people with TGs ≥200 mg/dL.


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Low-Density Lipoprotein Cholesterol. LDLs transport cholesterol to tissues and typically make up 60–70% of TSC. A strong and graded positive association exists between LDL cholesterol and risk of CVD events over a wide range of cholesterol concentrations, as identiÞed in the ATP III guidelines. The association applies to patients without CVD as well as to patients with established CVD, and other factors modify the risk considerably. Even with moderately elevated LDL levels (130–159 mg/dL), factors such as low HDL and nonlipid risk factors can increase the potential for CVD events. (See the “Secondary Dyslipidemia” section for more on nonlipid risk factors.) The results of epidemiological studies and of trials with angiographic or clinical end points conÞrm the importance of LDL as a cause of atherosclerosis. Reduction of LDL must therefore be a primary concern in both primary and secondary prevention of CVD. High-Density Lipoprotein Cholesterol. Researchers have found an inverse association between plasma HDL and the risk of CVD (Assman G, 1992). This phenomenon has been documented for both men and women and for both asymptomatic people and patients with conÞrmed CVD. Low HDL is considered an independent risk factor for CVD; the 2004 update of the ATP III guidelines places increased emphasis on treating low HDL levels (1,000 patients). The mechanism of resistance to daptomycin remains unknown and no study has determined whether resistance is transferable. Nitroimidazoles Overview. Nitroimidazoles are potent, bactericidal, anti-anaerobic, and antiprotozoal agents. The most commonly used agent in this drug class is metronidazole, which has been available worldwide since the late 1970s. Formulations of metronidazole contain an inactive pro-drug that aerobic and anaerobic organisms convert to cytotoxic intermediates. Patients with cSSTIs caused by anaerobic pathogens typically receive nitroimidazoles to treat perianal abscesses, diabetic ulcer infections, and gangrene. Mechanism of Action. Although researchers have yet to document the exact mechanism of action of the nitroimidazole class, it appears that these agents require anaerobic conditions for optimal efÞcacy. The key component of the

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COMPLICATED SKIN AND SOFT TISSUE INFECTIONS

antimicrobial effect of nitroimidazoles may be the formation of toxic intermediates and free radicals, which have subsequent cytotoxic effects on susceptible organisms. Metronidazole. Metronidazole (SanoÞ-Aventis/SCS/Shionogi’s Flagyl/Flagyl IV/Metro IV, generics) is indicated to treat intra-abdominal wound infections and other serious nosocomial infections caused by susceptible anaerobic bacteria. In mixed aerobic and anaerobic infections (e.g., abscesses), physicians often combine metronidazole with another aerobic-spectrum antibiotic to provide a regimen with broad coverage. Because this agent has been available since the late 1970s, there are no recent, rigorous clinical studies of metronidazole pertaining to SSTIs. Rather, evidence of its efÞcacy is apparent from its widespread successful clinical use against anaerobic pathogens. Because metronidazole does not target aerobic bacteria or mammalian cells, the drug has few side effects, except when it interacts with alcohol or other contraindicated drugs. According to the Flagyl package insert, two serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures and peripheral neuropathy (numbness, tingling sensation), but these effects are rare. More common, but mild, adverse reactions include nausea, headache, anorexia, and occasionally vomiting, diarrhea, epigastric distress, abdominal cramping, and constipation. Reports of a sharp, unpleasant metallic taste are not unusual, and overgrowth of Candida in the mouth or vagina may also occur. Oxazolidinones Overview. The oxazolidinones (which include only one approved agent, linezolid [PÞzer’s Zyvox/Zyvoxid]), are an antimicrobial class with a unique mechanism of action. The oxazolidinones are available both orally and parenterally and have a bioavailability of 100%. The development of oxazolidinones helped address the need for antibiotics effective against resistant gram-positive bacteria, speciÞcally MRSA. The oxazolidinones provide yet another option for treating gram-positive hospital infections, as they address concerns about the toxicity and resistance patterns of glycopeptides. Furthermore, by switching patients to the oral formulation of oxazolidinones, physicians are able to discharge patients earlier in the treatment cycle, which helps to reduce health care costs. Oxazolidinones have signiÞcant activity against all gram-positive cocci, including strains resistant to methicillin, vancomycin, macrolides, tetracyclines, aminoglycosides, ßuoroquinolones, and sulfonamides. Of particular importance, they are active against MRSA, methicillin-resistant Staph. epidermidis, Strep. pyogenes, and vancomycin-resistant enterococci (VRE). They are bactericidal in a concentration-dependent manner against streptococci and are bacteriostatic against staphylococci and enterococci. The oxazolidinones are also active against anaerobes and have limited activity against some fastidious gram-negative pathogens, but not gram-negative enterobacteriaceae.

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O O

N

N

O

O HN

F

CH3

FIGURE 21. Structure of linezolid.

Because of potential adverse events, physicians must monitor patients during oxazolidinone treatment (Gerson SL, 2002). In particular, physicians must monitor blood chemistries and platelets in patients who have received more than two weeks of oxazolidinone therapy. In vitro studies with linezolid demonstrate a complete lack of cross-resistance with existing antimicrobial agents. Isolated cases of linezolid resistance among treated patients have appeared in the major markets, but the agent remains the only antibiotic capable of treating multidrugresistant organisms without cross-resistance. Mechanism of Action. Oxazolidinones bind to a site on the bacterial 23S ribosomal RNA of the 50S subunit, preventing the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. Existing studies have not demonstrated any direct action on DNA or RNA synthesis. Linezolid. Linezolid (PÞzer’s Zyvox/Zyvoxid) (Figure 21) has been available in the United States and the United Kingdom since 2000 and 2001, respectively, and is indicated for cSSTIs, VRE, and nosocomial infections. In June 2001, PÞzer launched linezolid in Japan for the treatment of VRE infections, and it is currently in Phase III trials there for MRSA infections. Available in intravenous, injection, tablet, and oral suspension formulations, linezolid is active against infections caused by a variety of gram-positive bacteria. One clinical study compared the IV-to-oral treatment regimens of linezolid with IV oxacillin and oral dicloxacillin in 826 patients with suspected grampositive deep soft-tissue infections that may have required surgical intervention. This multicenter, international trial randomly assigned patients to treatment with linezolid 600 mg IV every 12 hours followed by 600 mg orally every 12 hours, or treatment with oxacillin 2 g IV four times daily followed by dicloxacillin 500 mg orally four times daily, for a total of 10 to 21 days. Eligible patients had suspected gram-positive cSSTIs for which microbiologists could conduct Gram’s stains. Among clinically evaluable patients, the clinical cure rate for the linezolid-treated patient population was 88.6%, compared with 85.3% in the oxacillin/dicloxacillin-treated patient population. The microbiological success rate was 88.1% for the linezolid group and 86.1% for the oxacillin/dicloxacillin group. The study demonstrated that linezolid is as effective as an oxacillin/dicloxacillin regimen in eradicating Staph. aureus, Staph. epidermidis, Strep. pyogenes, and Staph. agalactiae (Stevens DL, 2000).

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Another study evaluated the efÞcacy of linezolid and vancomycin in the treatment of MRSA SSTIs. One group of 240 patients received 600 mg of linezolid twice daily (Þrst intravenously, then orally) while another group of 220 patients received 1 g of vancomycin twice daily. Among clinically evaluable patients with proven MRSA, 73.2% of the linezolid-treated group and 73.1% of the vancomycin-treated patients achieved clinical cure (Stevens DL, 2002). Clinical studies have revealed some hematological abnormalities (e.g., thrombocytopenia, anemia) that are consistent with mild, reversible, duration-dependent myelosuppression in patients receiving linezolid. This suppression of bone marrow activity limits prolonged use of linezolid. According to the Zyvox package insert, other adverse reactions to linezolid include diarrhea (8.3%), headache (6.5%), and nausea (6.2%). Physicians must monitor patients who have recurrent nausea or vomiting for lactic acidosis. Other side effects of linezolid are relatively benign and are similar to those reported for other antibiotics.

Streptogramin Combinations Overview. The fungi streptomycetes produces streptogramins, which are classiÞed as streptogramin A (dalfopristin) or streptogramin B (quinupristin). These compounds are bacteriostatic when used separately, but in combination they can act in synergy to become bactericidal, mainly against gram-positive bacteria (Allington DR, 2001). Physicians primarily use this streptogramin combination to treat serious nosocomial infections caused by antibiotic-resistant gram-positive bacteria. As with the oxazolidinones, the development of streptogramin combinations helped Þll the need for antibiotics that are effective against MRSA and other resistant bacteria. Despite a favorable spectrum of activity, the need to administer streptogramins through a central line has limited their use and popularity among physicians. The more recent launch of linezolid with its more convenient formulations has almost entirely replaced the use of streptogramin combinations in the treatment of cSSTIs. Mechanism of Action. Streptogramins enter bacterial cells by diffusion and bind to different sites on the 50S ribosomal subunit to form a stable quinupristinribosome-dalfopristin ternary complex, resulting in an irreversible inhibition of protein synthesis. The two compounds serve different roles: quinupristin (streptogramin B) inhibits peptide chain elongation, while dalfopristin (streptogramin A) blocks the peptidyl transferase reaction. The synergistic bactericidal effect of the combination appears to result from conformational changes brought about in the peptidyl transferase center. Streptogramin combinations are bactericidal (concentration-independent) against streptococci and staphylococci and are bacteriostatic against enterococci, but the presence of the constitutive macrolide-lincosamide-streptogramin B (MLSB ) erm resistance phenotype (often found in Enterococcus faecium and MRSA) can limit their bactericidal effect.

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Quinupristin/Dalfopristin. The streptogramin combination of quinupristin and dalfopristin (Q/D) (King Pharmaceuticals/SanoÞ-Aventis/Fujisawa’s Synercid) is a parenteral antibiotic that was approved for use in the United States and the United Kingdom in 1999. In July 2001, the product also became available in France, Germany, Italy, and Spain. Fujisawa began marketing the agent in Japan in 2003. Because Q/D is intended for use as a second-line therapy for resistant organisms, clinical trials of Q/D enrolled patients in need of second-line antibiotics. One trial evaluated the efÞcacy of Q/D in 396 patients infected with vancomycinresistant Ent. faecium (VREF). Most patients (84%) received 7.5 mg/kg intravenously every 8 hours, while 16% received the same dosage every 12 hours, based on the physician’s assessment at day 2 of therapy. The average duration of therapy was 14.5 +/− 11 days. The study reported clinical success in 74% of patients, and there was bacterial eradication in 71% of patients. Arthralgias and myalgias were the most common systemic adverse events (9.1% and 6.6%, respectively) (Moellering RC, 1999). Two randomized, open-label, controlled clinical trials compared Q/D with cefazolin or oxacillin (however, patients received vancomycin in place of the comparator if the clinician believed that resistant pathogens were responsible for the infection). One study was based in the United States while the other was conducted internationally. The studies enrolled a total of 893 patients; 450 received Q/D and 443 received one of the comparator drugs. While Q/D was equivalent to these comparators in clinical success, it fell short in bacteriological clearance in both trials (66% and 67% clearance for Q/D versus 73% and 78% in the comparator groups, respectively). The studies speculated that this lower rate was the result of a higher degree of polymicrobial infections in the Q/D test group; clinical data showed that bacteriological eradication rates for polymicrobial infections were 63% for Q/D and 83% in the comparator group (Nichols RL, 1999). Q/D produces considerable myalgias and arthralgias and has the potential to interact with other drugs. Patients taking Q/D in clinical trials suffered from a much greater rate of venous adverse events (66%) compared with the comparator group (28%). These adverse reactions were responsible for a signiÞcant percentage of patients who discontinued Q/D in these trials (19.1%), while discontinuation of comparator drugs was primarily due to treatment failure (11.5%) (Nichols RL, 1999). Nonpharmacological Approaches Because of their depth and severity, many cSSTIs require immediate surgical attention as well as antibiotic therapy. In numerous cases, cSSTIs encompass a large amount of necrotic tissue that serves as an entry point for further infection. Therefore, it is standard clinical practice to surgically debride (cut away) dead and infected tissue in coordination with an immediate course of antibiotic therapy in the more severe cSSTI cases. Surgical debridement is especially common in abscesses, in which physicians incise the wound and drain the purulent contents (a

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mixture of bacteria and host immune cells). Almost all cases of necrotizing fasciitis and gangrene require surgical debridement because of their life-threatening nature, but physicians attempt to limit debridement in diabetic ulcers, except in cases where the underlying diabetes has damaged the tissue (i.e., the foot) to the point that it is likely to be a continual source of infection. Most surgeons pack these cSSTI incisions, leaving them open for inspection and irrigation in the days following surgery. EMERGING THERAPIES Complicated skin and soft-tissue infections (cSSTIs) represent an area of relatively high unmet need compared with other bacterial infections. A new agent to treat cSSTIs must have high activity against gram-positive organisms and speciÞc activity against methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) to be considered for this market. In addition, it must be available in an oral formulation for step-down therapy from intravenous (IV) treatment to allow continuous therapy as patients are discharged from the hospital. Even if emerging therapies achieve some or all of these characteristics, they are unlikely to replace current therapies that are less expensive or more familiar to physicians in treating life-threatening conditions. Most emerging therapies will be held in second- or third-line reserve for patients who fail Þrst-line therapy with already established, less expensive antibiotics. The majority of antibacterial agents in late-stage development for the treatment of cSSTIs simply expand the range of choices already available to physicians in conventional drug classes. These drugs aim to provide more effective treatment against resistant pathogens and have some advantages in formulation or dosing. Some drugs in development are effective against a broad spectrum of gram-positive and gram-negative bacteria and will be effective treatments for empirical therapy. Other, narrower-spectrum drugs are being developed to treat gram-positive infections only and will likely be used to treat infections caused by resistant strains (e.g., MRSA) when current Þrst-line agents have failed or in deÞned at-risk patient populations. Table 7 lists emerging therapies in development for cSSTIs. As already discussed, bacterial resistance is a major issue in this market. Unfortunately, bacteria are able to efÞciently transfer genetic material, so resistance is easily propagated among different organisms. Moreover, because many antibiotic agents act via similar mechanisms of action, resistance against one drug often crosses over to include resistance against the entire drug class. Therefore, signiÞcant effort has gone into developing novel classes of antibiotics that will not be susceptible to current mechanisms of resistance. These agents will likely Þnd an increasing role over the next 10 to 20 years as bacterial resistance to current drug classes builds. MRSA rates are very high in many hospitals, and, even more concerning, MRSA rates are rising dramatically in the community. Vancomycin was previously regarded as the most effective agent against all gram-positive pathogens

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TABLE 7. Emerging Therapies in Development for Complicated Skin and Soft Tissue Infections, 2004 Compound

Development Phase

Marketing Company

Glycopeptides Dalbavancin United States Europe Japan

PR PR —

Pfizer Pfizer —

Oritavancin (LY-333328) United States Europe Japan

III — —

Targanta — —

Telavancin United States Europe Japan

III — —

Theravance — —

Cephalosporins BAL-5788 United States Europe Japan

III III —

Johnson & Johnson/Basilea Pharmaceutica Johnson & Johnson/Basilea Pharmaceutica —

RWJ-442831 United States Europe Japan

I — —

Johnson & Johnson — —

DHFR Inhibitors Iclaprim United States Europe Japan

— II —

— Arpida —

Topoisomerase Inhibitors AVE-6971 United States Europe Japan

— I/II —


until VRE emerged in 1988, followed by glycopeptide intermediate-resistant Staphylococcus aureus (GISA) in 1999. In response, biopharmaceutical companies have focused their efforts since the mid 1990s on new antibiotics (e.g., streptogramins, novel peptides) to be used primarily for infections most often associated with resistant gram-positive bacteria, for which there are few therapeutic alternatives. Emerging narrow-spectrum agents with potent in vitro activity against resistant gram-positive pathogens include Johnson & Johnson’s RWJ442831 (a cephalosporin) and the peptide antibiotic dalbavancin (PÞzer). Table 8 summarizes both the reported minimum inhibitory concentration required to inhibit 90% of the isolates (MIC90 ) of these emerging agents against key grampositive pathogens and the MIC90 of available agents. Most of the emerging

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TABLE 8. In Vitro Activity of Narrow-Spectrum Antibiotics Against Key Nosocomial Gram-Positive Bacteria Antibiotic Vancomycin Teicoplanin Linezolid Quinupristin/Dalfopristin RWJ-54428 Daptomycin Oritavancin Dalbavancin

Pathogen MIC90 (mg/L) MSSE MRSE PSSP

MSSA

MRSA

0.5–1 0.5–1 2–4 0.25–1 0.5 0.12–0.5 2 0.25

1–2 0.5–4 2–4 0.5–2 2 0.12–1 2–4 0.02–0.5

1–2 2–8 1–4 0.12–0.5 0.5–1 0.5 2–4 N/A

VRE >64 >16 2 16–32 0.125–1 1–4 2 32

VSEF VREF 2–4 >64 0.5–2 >16 1–2 1–2 0.25–8 1–2 8 8 2–4 2–4 0.25–0.5 1–4 0.02–4 32

Antibiotic VSE Vancomycin 2–4 Teicoplanin 0.25–1 Linezolid 2 Quinupristin/Dalfopristin 4–32 RWJ-54428 0.25–1 Daptomycin 1–2 Oritavancin 1–2 Dalbavancin 0.02–4

1–2 2–16 1–4 0.25–2 0.5–4 0.25–0.5 2–8 N/A

0.25–0.5 0.12 1 0.5 0.06–0.03 0.25 0.015 0.02–0.06

PRSP 0.25–0.5 0.12 1 0.5–1.0 0.25–0.5 0.25 0.06 0.02–0.5

Other Streptococci 0.25–5 0.5 1–2 0.25–0.5 0.06–2 0.06–2 0.25–1 0.03

MIC90 = Minimum inhibitory concentration required to inhibit 90% of the isolates; MRSA = Methicillin-resistant Staphylococcus aureus; MRSE = Methicillin-resistant Staphylococcus epidermidis; MSSA = Methicillin-susceptible Staph. aureus; MSSE = Methicillin-susceptible Staph. epidermidis; PSSP = Penicillin-susceptible Streptococcus pneumoniae; PRSP = Penicillin-resistant Strep. pneumoniae; Strep = Streptococci serogroups A, B, C, and G; VRE = Vancomycin-resistant enterococci; VREF = Vancomycin-resistant Enterococcus faecium; VSE = Vancomycin-susceptible enterococci; VSEF = Vancomycin-susceptible Ent. faecium. Note: MIC90 data are compiled from several studies that evaluated the in vitro antibacterial activity of emerging agents, which was determined using broth microdilution procedures according to the recommendations of the National Committee for Clinical Laboratory Standards.

narrow-spectrum therapies are as good as or better than current narrow-spectrum agents against common resistant pathogens. However, several of the new agents are signiÞcantly better than current therapies against VRE. These and other emerging agents are proÞled in the following sections. Glycopeptides Overview. Current glycopeptides, such as vancomycin, are used for the treatment of severe or life-threatening infections that are caused by gram-positive organisms, such as streptococci and staphylococci. These agents have potent narrow-spectrum activity against methicillin-resistant Staph.aureus (MRSA) and are generally reserved for patients who have nosocomial infections, or they may be used as second-line agents in patients who have failed to respond to Þrst-line therapy. MRSA is most commonly associated with cellulitis and abscess, but it can be found in other cSSTIs as well. Because of the rising rates of MRSA in hospital and community settings, glycopeptides have become a very important antibiotic class in cSSTI treatment. New glycopeptides need to demonstrate

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TABLE 9. Comparative Activities of Tigecycline Against Key Nosocomial Pathogens Type of Pathogen Gram-positives

Gram-negatives

Anaerobes/intracellullar pathogens

Tigecycline’s Spectrum of Activity Has potent activity against most gram-positive bacteria, including staphylococci, streptococci, enterococci, and Listeria species. Against gram-positive bacteria, its in vitro activity is comparable to that of daptomycin (slightly better than vancomycin). Is effective against isolates resistant to currently available agents, such as MRSA, GISA, PRSP, and VRE. Has good in vitro activity against a wide variety of gram-negative pathogens, including Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumonia, Acinetobacter spp., Stenotrophomonas (Pseudomonas) maltophilia, Enterobacter spp., and Citrobacter spp., including ESBL-producing strains. Against most gram-negative bacteria, generally less active than ciprofloxacin, imipenem, and ceftazidime. Like other tetracyclines, tigecycline is also active against a range of intracellular pathogens (e.g., Mycoplasma) and anaerobic bacteria (e.g., Clostridium difficile). Is generally more active than cefepime but less active than imipenem against clinically important anaerobes.

ESBL = Extended-spectrum β -lactamase; GISA = Glycopeptide-intermediate susceptible Staphylococcus aureus; MRSA = Methicillin-resistant Staphylococcus aureus; PRSP = Penicillin-resistant Streptococcus pneumoniae; VRE = Vancomycin-resistant enterococci.

increased activity against MRSA and vancomycin-resistant enterococci (VRE) for uptake in cSSTIs, and they will ideally have better dosing and side-effect proÞles than vancomycin, which is the leading antibiotic against resistant infections. To compete effectively with linezolid, new glycopeptides must be available not just in parenteral formulations, but in oral formulations as well. Mechanism of Action. Glycopeptides inhibit biosynthesis of the bacterial cell wall by blocking glycopeptide polymerization. This effect produces immediate inhibition of cell-wall synthesis and secondary damage to the cytoplasmic membrane of the bacterial cell. Glycopeptides also alter the permeability of the cytoplasmic membrane and directly inhibit RNA synthesis. However, the impact of these effects on bacterial viability is largely unknown. Glycopeptides have a concentration-independent bactericidal action resulting primarily from inhibition of cell-wall synthesis. They are considered slowly bactericidal against staphylococci. Dalbavancin. PÞzer (formerly Vicuron) is developing dalbavancin*, a secondgeneration injectable glycopeptide for clinically important gram-positive infections. Dalbavancin’s mechanism of action is the same as that for the glycopeptide class, inhibiting bacterial cell-wall synthesis. However, dalbavancin is a chemically modiÞed version of a naturally occurring glycopeptide that is speciÞcally

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designed to have better activity than vancomycin and teicoplanin against staphylococci, including MRSA. Dalbavancin’s primary advantage over current antibiotics is that it has a long half-life, allowing it to be given just once per week. In vitro studies have shown that dalbavancin is more potent than vancomycin and teicoplanin against clinically important gram-positive bacteria, including MRSA, methicillin-resistant Staph. epidermidis (MRSE), and penicillin-resistant Strep. pneumoniae (PRSP) (Malabarba A, 1998; Jones RN, 2001). Dalbavancin is also more potent than Q/D against most gram-positive bacteria; it is equivalent to Q/D against methicillin-susceptible Staph. aureus (MSSA). Dalbavancin’s activity against VRE is variable: it is effective against VanB-encoded resistance but not against VanA-encoded resistance. Like other glycopeptides, dalbavancin is not effective against gram-negative bacteria. In animal models of infection, a single dose of dalbavancin is reported to be as effective as six doses of linezolid or four doses of vancomycin for the treatment of PRSP and MRSA, respectively (Candiani GP, 2001; Jabes D, 2001). Also, dalbavancin was more potent than teicoplanin or vancomycin in murine models of staphylococcal, streptococcal, and enterococcal septicemia and staphylococcal endocarditis (Malabarba A, 1998). Vicuron began two randomized, double-blind, Phase III clinical trials in December 2002. Vicuron announced results of these trials in August 2004. In a double-blind trial, 854 cSSTI patients were randomly assigned to receive dalbavancin (1 g IV on day 1 and 500 mg IV on day 8) or standard dosing of linezolid for 14 days; 88.9% of dalbavancin patients showed a clinical response at followup visit, versus 91.2% of patients taking linezolid. Dalbavancin was reportedly well tolerated. The second trial was an open-label study that enrolled 156 patients with SSTIs suspected or conÞrmed to be due to MRSA. Patients receiving dalbavancin had an 89.9% rate of clinical response, compared with 86.7% of patients receiving vancomycin. Dalbavancin fared even better in the intent-to-treat group, with 86% of patients receiving dalbavancin showing a clinical response, compared with only 65.3% of patients receiving vancomycin (Versicor press release, August 12, 2004). In September 2002, Vicuron announced positive Phase II clinical trial results for dalbavancin in the treatment of SSTIs (Versicor, press release, September 5, 2002). The randomized clinical trial enrolled 62 patients with infections that involved deep skin structures or required surgical intervention, such as abscesses, infected ulcers, burns, and cellulitis. Dalbavancin administered once weekly for two weeks had higher clinical and microbiological response rates than other standard care regimens, including vancomycin, given for a mean duration of 15 days (Selzer E, 2003). Table 10 shows clinical trial results for dalbavancin in the treatment of skin and soft-tissue infections. In Phase I clinical trials involving 12 patients, dalbavancin administered as a once-daily, 30-minute IV infusion demonstrated linear kinetics with low interindividual variability and good tolerability (Leighton A, 2001[a]; White RJ, 2000). The drug has a serum half-life of 6.6 to 7.8 days; signiÞcant drug accumulation was observed following multiple doses. Patients who received 360 mg of

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TABLE 10. Clinical Trial Results for Dalbavancin in the Treatment of Skin and Soft-Tissue Infections Success of Therapy Evaluable Populations

Dalbavancina

Dalbavancinb

Standard Carec

Clinically evaluabled Microbiological success

16/17 (94.1%) 8/11 (72.7%)

8/13 (61.5%) 3/11 (27.3%)

16/21 (76.2%) 9/14 (64.3%)

a Patients received two doses of dalbavancin given one week apart (day 1 and day 8). b Patients received one dose of dalbavancin given on day 1. c Standard care was any antibiotic (physician’s choice) given daily for 7–21 days. d Cure or improvement observed at first follow-up. Source: Based on Seltzer E, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections.Clinical Infectious Diseases. 2003;37(10):1298–1303.

dalbavancin exhibited bactericidal activity even when their serum was diluted 8fold 24 hours after dosing. Indeed, seven days after a single dose, plasma levels remained above the minimum bactericidal concentration required for eradication of 90% of the MRSA and MRSE isolates (MBC90 ). These data support the use of dalbavancin in a wide range of dosing regimens, including once-weekly therapy (Versicor press release, November 28, 2001). In all clinical studies to date, dalbavancin has proved well tolerated, whether dosed daily or weekly. No adverse events were considered to be clinically signiÞcant, although pyrexia and headache were reported most frequently. Notably, no ototoxicity (either auditory or vestibular) has been detected for any dose of dalbavancin (Leighton A, 2001[b]). If it is approved, dalbavancin will be the Þrst once-weekly, injectable antibiotic on the market and could become the standard of care for cSSTIs caused by grampositive bacteria, especially staphylococci and streptococci. This possibility is strengthened by dalbavancin’s superiority in potency and tissue penetration, as well as its longer serum half-life, compared with vancomycin. The availability of a once-weekly antibiotic will not only enable more ßexible and convenient dosing regimens; it will encourage shorter hospital stays and may reduce the incidence of local and systemic infections associated with prolonged use of IV lines. Oritavancin. Targanta Therapeutics is developing oritavancin*, a parenteral, Nsubstituted derivative of a semisynthetic glycopeptide antibiotic, LY-264826, for the treatment of gram-positive bacterial infections, including infections resistant to current antibiotics. Oritavancin’s mechanism of action is the same as that described in the “Mechanism of Action” section for the glycopeptide class. In vitro studies have demonstrated that oritavancin has rapid bactericidal activity against all strains of staphylococci, streptococci, and enterococci, including MRSA, multidrug-resistant Strep. pneumoniae, and VRE (Coyle EA, 2001; Jones RN, 1997; Noviello S, 2001; Zeckel ML, 2000). Its potency against these organisms was comparable to or superior to that of vancomycin, teicoplanin, moxißoxacin, ciproßoxacin, imipenem, linezolid, and Q/D (Fasola E, 1996; Rubio MC, 1999; Schwalbe RS, 1996). The drug is also active against a wide range of anaerobic gram-positive bacteria, including some that are not susceptible

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to vancomycin or teicoplanin (Biavasco F, 1997). Activity against anaerobic gram-positive bacteria is similar to or better than that of clindamycin and cefoxitin (Sillerström E, 1998). Like other glycopeptides, oritavancin is not effective against gram-negative bacteria. In animal infection models, N-substituted derivatives of LY-264826 were effective against lethal Strep. pneumoniae and Strep. pyogenes infections at doses two to six times lower than effective vancomycin doses. These compounds were effective against lethal Staph. aureus infections at doses 1.5 to 3 times lower than effective vancomycin doses (Nicas TI, 1996). Other animal studies show that oritavancin is effective in the treatment of various Staph. aureus and enterococcal infections, including lethal VRE infection and endocarditis due to MRSA (Boylan CJ, 1998; Kaatz GW, 1998; Saleh-Mghir A, 1997; Schwalbe RS, 1997). Resistant variants have not been observed after prolonged exposure to the drug, but development of moderate resistance in some VREs has occurred in vitro˜(Arthur M, 1999). Table 11 depicts the results of a double-blind, randomized Phase III clinical trial involving 517 patients with cSSTIs, which demonstrate that oritavancin therapy can halve treatment time—from 11.5 days to approximately 5.5 days—compared with the current standard combination of vancomycin plus cephalexin follow-up treatment (Wasilewski MM, 2001[b]). This decrease in treatment time stems from the elimination of the oral cephalexin stepdown therapy. However, because step-down therapy is inexpensive and convenient, the impact of this reduced treatment time could be negligible. In a small Phase II clinical trial involving 27 patients with gram-positive bacteremia, oritavancin demonstrated clinical success. Bacterial eradication was conÞrmed in four of Þve patients with vancomycin-resistant Enterococcus faecium infections, in the three patients infected with vancomycin-sensitive Enterococcus faecalis infections, in the only patient infected with Strep. pneumoniae, TABLE 11. Clinical Trial Results for Oritavancin in the Treatment of Complicated Skin and Soft-Tissue Infections Caused by Gram-Positive Bacteria

Evaluable Populations

1.5 mg/kg Oritavancina

Intent to treat (n = 480) Clinically evaluabled (n = 384) Microbiological success (n = 256) Clinically evaluable with MRSA (n = 33) Relapse rate at late follow-up (day 60) Average length of therapy

63% (n = 163) 76% 74% 74% 10% 5.3

Success of Therapy 3.0 mg/kg 30 mg/kg Oritavancinb Vancomycinc 63% (n = 153) 76% 74% 74% 4% 5.7

65% (n = 164) 80% 76% 80% 5% 11.5

a Administered IV once daily, followed by oral placebo. b Administered IV once daily, followed by oral placebo. c Administered IV in two divided doses daily, followed by oral cephalexin (500–1,000 mg, twice daily). d Cure or improvement observed at first follow-up (day 28).

Source: Based on Wasilewski M, et al. Equivalence of shorter course therapy with oritavancin compared to vancomycin/cephalexin in complicated skin/skin structure infections (CSSI). Clinical Microbiology and Infection. December 2001; Chicago, IL. Abstract UL-18.

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and in the only patient infected with methicillin-resistant Staph. epidermidis (MRSE) (Wasilewski MW, 2001[a]). Phase I clinical trials have demonstrated that oritavancin (once daily IV infusion over 30 minutes) has favorable pharmacokinetics, with a serum half-life of approximately 10.5 days and low inter-individual variability (Chien J, 1998; Thomasson HR, 1999). The bacteria-killing kinetics of oritavancin are significantly affected by inoculum size and the presence of serum, which result in higher MICs, longer killing time, and shorter post-antibiotic effect; this problem is easily solved by increasing the concentrations of administered doses (Mercier RC, 1997; Zhanel GG, 1998). Safety data for oritavancin are limited, but preliminary data from clinical trials suggest that the drug is generally well tolerated. However, additional data relating to phlebitis, edema, anemia, tremor, elevated liver enzyme, and renal function abnormalities are needed to better evaluate the compound’s safety and tolerability. Telavancin. Theravance (formerly Advanced Medicine) is developing its oncedaily injectable glycopeptide telavancin * for gram-positive infections. Telavancin has an extended mechanism of action, inhibiting both peptidoglycan synthesis and phospholipids synthesis in cell-wall production, which Theravance hopes will lower the level of spontaneous resistance against the drug. Telavancin is expected to be effective against MRSA and methicillin-resistant Ent. faecalis. Theravance initiated Phase III trials for telavancin in cSSTIs in late 2004. Researchers reported results of a Phase II study of telavancin in September 2004. A total of 167 patients with suspected or conÞrmed gram-positive cSSTIs were randomized and given either telavancin or standard therapy (a penicillin or vancomycin). For the 102 patients with Staph. aureus, telavancin cured 80% of patients while standard therapy cured 77%. Patients with MRSA (44 total) who received telavancin were cured 82% of the time, compared with only 69% of MRSA patients receiving standard therapy. It is not clear from available data whether standard therapy for these patients was solely vancomycin, or if some patients received only standard penicillin that would normally be ineffective against MRSA. Approximately 5% of patients withdrew from each arm because of adverse events, though fewer serious adverse events were reported for patients taking telavancin than for those on standard therapy, 4 versus 9, respectively (Stryjewski M, 2004). Phase I studies in 119 healthy volunteers who received a 7.5 mg/ kg or 15 mg/kg dose of telavancin as a 60-minute infusion over three days demonstrated linear pharmacokinetics, which were equal in men and women. This study also showed that at the higher dose, 33% of patients had nausea, 21% had headache, 15% had vomiting, dizziness, and rash, and 10% had abdominal pain/cramps. These adverse effects were classiÞed as mild. More detrimental, at the higher dose, 10% of patients discontinued administration because of infusionrelated “red man syndrome,” which is a serious allergic response (Barriere S, 2003). This response is one of the chief complaints about vancomycin, and it will severely limit the uptake of telavancin.

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Cephalosporins Overview. The cephalosporin class is currently very competitive, with many branded and generic drugs available. Drugs in this class are widely used for a variety of infections; thus, doctors are comfortable prescribing new members of the class. However, this high physician acceptance is tempered by formulary restrictions that are placed on new cephalosporins that are not perceived to offer a signiÞcant advantage over less expensive or generic drugs in the same class. Novel cephalosporins with greater potency than those that currently exist, especially against MRSA, may Þnd Þrst-line use in cSSTIs, but they must prove especially effective to compete with the other members of this large class. Mechanism of Action. Cephalosporins, like all β-lactams, bind to PBPs in bacteria and prevent bacterial cell-wall formation. PBPs are involved in numerous roles within the bacterial cell, including maintenance of structural integrity, determination of cell shape, cell division, induction of capsule synthesis, and regulation of autolysis. Cephalosporins inhibit these bacterial processes, leading to bacterial cell death. BAL-5788. Basilea Pharmaceutica is developing a novel cephalosporin, BAL5788 (ceftobiprole, a pro-drug of BAL-9141), that has broad-spectrum activity and additional potency against MRSA and penicillin-resistant Strep. pneumoniae (PRSP). The FDA has granted BAL-5788 two fast-track designations, one in March 2003 for the treatment of cSSTIs due to MRSA and one in June 2004 for hospital-acquired pneumonia due to MRSA. Roche had an option to license BAL-5788 but turned it down in May 2004, leaving Basilea with the global development, marketing, and manufacturing rights. BAL-5788 recently completed additional Phase II clinical trials for cSSTIs, though results are not yet available. Basilea initiated Phase III trials in November 2004. BAL-5788 is an intravenous fourth-generation cephalosporin with coverage against both gram-positive (including Ent. faecalis) and gram-negative pathogens. Like other β-lactams, BAL-5788 binds to bacterial PBPs to inhibit cell-wall production. Unlike many other β-lactams, though, BAL-5788 provides very good potency against MRSA. MRSA is resistant to most β-lactams using two mechanisms. The Þrst is the expression of β-lactamases that cleave antibiotics such as methicillin and other β-lactams. The second resistance mechanism is that MRSA acquires a new PBP from the chromosomal determinant mecA. This protein, dubbed PBP2a, has a much lower binding afÞnity for methicillin and similar compounds, and these drugs are therefore very inefÞcient at blocking the protein’s activity. BAL-5788 is effective against MRSA because it is 10,000 times more resistant to hydrolysis by β-lactamases than penicillin G and it has a more than 100 times greater afÞnity for PBP2a than methicillin. Basilea announced in November 2004 that it was initiating Phase III trials that will compare BAL-5788 with vancomycin in 700 MRSA patients worldwide (company press release, November 10, 2004). In June 2004, Basilea reported positive results from a Phase II trial of BAL-5788 (company press release, March 4, 2004). Forty hospitalized patients with cSSTIs requiring surgical intervention

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were enrolled in the trial. Most had deep infections caused by streptococci or staphylococci, and some patients were infected with MRSA. Of the 35 patients who were clinically evaluable, Basilea reported that all were cured. No major organ toxicity was reported, and the most frequent side effect was mild to moderate nausea. Further details were not disclosed. In a Phase I trial in 40 healthy male volunteers, 30-minute infusions of BAL-5788 equivalent to 150, 250, 500, 750, and 1,000 mg of the active compound BAL-9141 were evaluated (SchmittHoffmann A, 2002). No adverse effects were reported, and analysis of the data suggested that the 750 mg dose infused twice a day would be effective against MRSA. A second Phase I trial was conducted in 5 healthy volunteers and 15 patients with varying degrees of renal impairment (Roos B, 2003). Each patient was given a single 250 mg dose by IV and monitored for Cmax (peak concentration, usually taken at end of infusion) and the steady-state distribution of the drug. All groups were reportedly equivalent in both parameters. RWJ-442831. RWJ-442831 is a pro-drug that is converted metabolically into the active cephalosporin, RWJ-54428. RWJ-54428 entered Phase I clinical trials in the United States in November 1999, but observations of injection-site irritation resulted in the development of RWJ-442831 (Essential Therapeutics, press release, June 10, 2002). In July 2002, Essential Therapeutics announced that RWJ-442831 had entered Phase I clinical trials after preliminary studies in animals had demonstrated reduced venous irritation at the injection site than RWJ-54428. Essential developed this parenteral cephalosporin in collaboration with Johnson & Johnson Pharmaceutical Research & Development (formerly R.W. Johnson) for the treatment of antibiotic-resistant gram-positive infections. However, Essential Þled for bankruptcy in May 2003, and Johnson & Johnson has since taken over development. The pro-drug RWJ-442831 is expected to have in vitro antibacterial potency comparable to that of RWJ-54428. Studies have shown that the activity of RWJ54428 is equivalent to, or better than, the activity of vancomycin, imipenem, linezolid, ceftriaxone, and cefotaxime against most gram-positive bacteria, including VRE, MRSA, MRSE, GISA (glycopeptide intermediate-resistant Staph. aureus), and PRSP (penicillin-resistant Strep. pneumoniae) (Chamberland S, 2001; Johnson AP, 2002; Swenson JM, 2002). Against mecA-positive Staph. aureus and ampicillin-resistant Ent. faecium, RWJ-54428 is less potent than Q/D. Although only marginally effective against most gram-negative bacteria, RWJ-54428 has also demonstrated signiÞcant in vitro activity against the common respiratory pathogens Haemophilus inßuenzae and Moraxella catarrhalis. Other Þndings about RWJ-54428 may also apply to RWJ-442831. For example, in vitro studies indicate that coadministration of RWJ-54428 with antibiotics that are effective against gram-negative bacteria, although not synergistic, is not antagonistic (Foleno B, 2000). In animal models of infection (e.g., septicemia, pyelonephritis, endocarditis, pneumonia), RWJ-54428 also has proved highly effective in clearing infection caused by gram-positive bacteria, including MSSA and MRSA (Frosco MB, 1997; GrifÞth D, 1997; Liu C, 1999). Singledose pharmacokinetic data on RWJ-54428 in animal studies suggest a serum

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half-life of 1 to 2.3 hours for humans, which is similar to that of other marketed cephalosporins (Harford L, 1998). As a result, RWJ-442831 is likely to be administered twice daily. RWJ-442831 is a promising new parenteral cephalosporin for the treatment of infections caused by gram-positive bacteria, particularly those resistant to available drugs. However, the success of this agent, should it proceed in development, will depend on clinical trials demonstrating safety and efÞcacy. Also, because several antibiotics with good activity against resistant gram-positive bacteria have recently been launched (e.g., Q/D, linezolid), the extent to which RWJ-442831 is used for cSSTI treatment will depend on the success of competing antibiotics. Dihydrofolate Reductase Inhibitors Overview. Dihydrofolate reductase (DHFR) inhibitors are a drug class in development that researchers believe will be less susceptible to resistance. Members of this drug class are currently used to treat cancer (e.g., methotrexate) or some bacterial infections. Trimethoprim/sulfamethoxazole is currently used for urinary tract infections and some respiratory tract infections, but it is subject to high levels of resistance. If this resistance does not cross over to new DHFR inhibitors, then these may be effective drugs to treat cSSTIs while limiting resistance because the drug class is relatively novel. Mechanism of Action. Members of this drug class are effective against bacteria by blocking the action of the bacterial DHFR enzyme. DHFR plays an essential role in the synthesis of thymine nucleotides. By inhibiting synthesis of thymine, DHFR inhibitors target DNA and RNA synthesis, thereby causing bacterial cell death. More speciÞcally, folate donates a methyl group to uracil to make thymine. In the process, the folate molecule is oxidized and must be reduced by DHFR to allow another cycle of synthesis. If DHFR is inhibited, the absence of reduced folate causes a precipitous drop in the levels of thymine nucleotides, causing uracil to be erroneously incorporated in its place in growing DNA strands. Replication is eventually disrupted by this process, killing the bacteria (Goodsell 1999). Bacterial DHFR is distinct enough from human DHFR that drugs targeting the bacterial DHFR protein are generally not toxic to human cells. Iclaprim. Arpida has licensed all commercialization rights of the DHFR inhibitor iclaprim (AR-100) from Roche; the drug has completed Phase II trials in Europe for cSSTIs. Previous clinical trials have evaluated an IV formulation of iclaprim, but Arpida is working to develop an oral formulation as well. Iclaprim works by the mechanism of action described previously, and because there is only one other antibiotic in the DHFR inhibitor class, Arpida hopes that existing bacterial pathogens, including MRSA and VRSA, will prove sensitive to it. Arpida also reports that iclaprim has good tissue penetration, a critical asset for treating deep cSSTIs. In January 2004, Arpida announced results from a Phase II trial in which iclaprim was tested for efÞcacy and tolerability in hospitalized cSSTI patients (including those with infected burns, diabetic foot ulcers, cellulitis, and abscesses)

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(Arpida press release, January 9, 2004). Arpida enrolled 92 patients in this double-blind trial and compared 1 or 2 mg/kg of iclaprim to a standard dose of vancomycin. Both drugs were given intravenously twice a day for 10 days. Twenty-six of 28 patients (92.9%) taking 1 mg/kg iclaprim were clinically cured, compared with 29 of 31 patients (93.5%) taking 2 mg/kg iclaprim and 26 of 28 patients (92.9%) taking vancomycin. Microbiological success rates were similar for 1 mg/kg iclaprim and vancomycin (57.1% and 50%, respectively) and were superior for 2 mg/kg iclaprim (76.7%). Iclaprim was well tolerated, and adverse events were similar for all three groups. Topoisomerase IV Inhibitors Overview. The topoisomerase IV inhibitors—which target bacterial replication—are a new class of antibiotics that addresses the problem of drug resistance. This class is related to the ßuoroquinolones in their mechanism of action, though it is too early to determine the extent of similarity between the two classes. Drugs in this class will likely have efÞcacy against both gram-positive and gramnegative bacteria and will compete with other broad-spectrum agents in Þrst-line treatment of cSSTIs. Like the new DHFR inhibitors, these drugs will be aimed primarily at treating resistant bacteria such MRSA and VRSA. Mechanism of Action. Along with DNA gyrase (topoisomerase II), topoisomerase IV is a protein involved in bacterial DNA replication. Both of these proteins are the target of ßuoroquinolones, although individual drugs vary in their afÞnity for either one. It is unclear how individual topoisomerase IV inhibitors will differ from current ßuoroquinolones in their mechanism of action, if at all. Topoisomerase IV is responsible for decatenation and segregation of the bacterial chromosomes after replication. Inhibition of this activity stops the replication process and ultimately kills the bacteria. AVE-6971. SanoÞ-Aventis is developing AVE-6971 * as a broad-spectrum antibiotic with the potential to treat pathogens that are resistant to currently available drugs. AVE-6971 is currently in Phase I/II trials in Europe, but SanoÞ-Aventis has not released any details about the study or the indication. AVE-6971 has the same mechanism of action as previously described for this class, but it is said to be distinct from the mechanisms of ßuoroquinolones and linezolid. In preclinical studies using a mouse thigh abscess model, oral AVE-6971 was found to be ten times more potent than subcutaneous vancomycin; the 50% effective dose (ED50 ) against MRSA was found to be 10 mg/kg for oral AVE-6971 compared with an ED50 of 100 mg/kg for subcutaneous vancomycin (Aventis company presentation, R&D Day 2002, June 18, 2002). REFERENCES Allington DR, Rivey MP. Quinupristin/dalfopristin: a therapeutic review. Clinical Therapeutics. 2001;23(1):24–44.

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Hepatitis C

ETIOLOGY AND PATHOPHYSIOLOGY Introduction Hepatitis is a disease of the liver that is characterized by hepatic inßammation and hepatocellular necrosis (destruction of liver cells). The disease may be acute or chronic and can be caused by various agents, including alcohol, drugs, and viruses. Acute hepatitis is usually a self-limiting course of liver inßammation. Chronic hepatitis denotes ongoing inßammation of the liver, which leads to progressive hepatic Þbrosis, cirrhosis, end-stage liver disease, and an increased risk of hepatocellular carcinoma (HCC). The Þve major viral hepatitides are hepatitis A through E; diagnosis depends on serologic assays speciÞc to each of the different viruses. Etiology Viral hepatitis was historically separated into two types of infection based on epidemiological characteristics: “infectious” hepatitis (associated with oral-fecal transmission) and “serum” hepatitis (associated with the percutaneous transfer of material containing human serum). With the advent of serological testing, it became evident that most cases of infectious hepatitis were due to hepatitis A virus (HAV) and that many cases of serum hepatitis were associated with hepatitis B virus (HBV) (note that HBV is also associated with sexual transmission). Still, clinicians recognized that not all cases of serum hepatitis were due to HBV, and the term non-A, non-B (NANB) hepatitis was used in these cases (Feinstone SM, 1975). In 1989, scientists conclusively identiÞed hepatitis C virus (HCV) as the organism responsible for most cases of NANB hepatitis, an achievement that Wiley Handbook of Current and Emerging Drug Therapies, Volumes 1–4 Copyright © 2007 Decision Resources, Inc. Published by John Wiley & Sons, Inc.

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resulted from a joint effort involving Chiron and the Centers for Disease Control and Prevention (CDC) (Choo QL, 1989; Kubo Y, 1989). A major obstacle to HCV drug development has been the fact that HCV is exceedingly difÞcult to grow in cell culture; indeed, it was the Þrst infectious agent to be discovered entirely through analysis of cloned nucleic acid sequences. The lack of reliable cell culture systems and animal infection models has hampered studies of the viral life cycle, as well as the development of new antivirals or vaccines. These issues have been somewhat overcome with the development of a viral replicon system (Lohmann V, 1999). The replicon model for HCV replaced genetic sequences encoding HCV structural proteins with drug-resistance genes, enabling selection of cells in culture that maintained infection with the clone. This system allows for viral replication in cell culture and the study of individual viral proteins but does not allow for the study of viral assembly, propagation, and infection in vitro or in vivo. Use of the HCV replicon system as the model for characterization of drug-induced inhibition of HCV-encoded proteins has driven the current expansion of therapeutics against viral targets like the polymerase and protease proteins. More recently, scientists studying a genotype 2a HCV isolate (genotypes are discussed in greater detail later in this chapter) have established a full-length replicating model of HCV genotype 2 virus, which can produce infectious particles in cell culture (Lindenbach BD, 2005; Wakita T, 2005; Zhong J, 2005). This new experimental model system may enable further development in drug discovery because researchers will be able to broaden the focus of their search for potential antiviral targets or targets of host cell proteins involved in viral propagation. However, although experts widely consider this genotype 2a HCV isolate to be a major development in the creation of tools to study this important virus, many thought leaders state that the key will be development of similar replicating HCV genomic models for the more-difÞcult-to-treat HCV genotype 1 virus. Key Viral Proteins and Drug Targets. HCV is a small, enveloped, positivestrand RNA virus of the Flaviviridae family and the only member of the genus Hepaciviridae. It is genetically unrelated to the hepatitis B virus. Despite the lack of culture systems available to efÞciently replicate the virus, the genome has been studied extensively and is now well characterized. The hepatitis C viral genome is approximately 9.4 kb in length and encodes a polyprotein of approximately 3,000 amino acids. This polyprotein is processed by host signal peptidase (localized in the endoplasmic reticulum [ER]) and by two viral proteases to generate three major structural proteins and several nonstructural (NS) proteins necessary for viral replication (Figure 1). In the following sections, HCV genomic sites and their translation products are described. Experts are enthusiastic about the prospects of drugs targeting HCV proteases and polymerases. HCV RNA polymerase and proteases play important roles in the HCV life cycle and thus persistence of infection: protease activity is required to enable activity of HCV-encoded proteins, and the RNA polymerase is essential for viral replication. Drugs targeting these important functions are likely to be launched within the ten-year forecast period. Other long-term targets include entry inhibitors and

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Open reading frame (ORF)

Nonstructural protein precursor

Gene 5'

UTR

Protein function

C

E1

E2

HVR1

RNAHyper5' untrans- binding Envelope variable glycocore region lated region, protein proteins IRES

NS2

NS3

NS4A NS4B NS5A

Serine protease/ helicase

Protein translation and transport inhibitor

Antiapoptotic factor and forms protease NS2-NS3 with NS3

NS3 protease cofactor

NS5B

UTR

Untranslated region 3'

RNA polymerase

Interferon sensitivitydetermining region

Regulation of RNA transcription and stability

FIGURE 1. Hepatitis C viral genome.

therapeutic vaccines. Table 1 lists emerging HCV drug targets and the potential advantages and disadvantages of drugs modulating these targets. NS2 and NS2/3 Protease. Cleavage of the HCV polyprotein between the NS2-NS3 junction is mediated by the NS2/3 protease, an autocatalytic protease encoded within NS2 and the N-terminus of NS3 (Wu Z, 1998). Host proteins located on the endoplasmic reticulum are required to sustain efÞcient cleavage of the NS2-NS3 junction (Santolini E, 1995). The largely hydrophobic HCV NS2/3 protease is essential for the normal infectious cycle of HCV and is a major focus for development of HCV-speciÞc therapies. Once processed by the NS2/3 protease, the NS2 protein is targeted to the endoplasmic reticulum, forming an integral transmembrane protein (Santolini E, 1995; Yamaga AK, 2002). Research has suggested that NS2 may inhibit gene expression and interact with the liver-speciÞc proapoptotic protein CIDE-B by inhibiting its ability to induce cell death of infected hepatocytes (Dumoulin FL, 2003; Erdtmann L, 2003). In this manner, NS2 may be essential for promoting viral persistence and may be a key factor in disease progression to HCC. NS3 Protease. The N-terminal region of the NS3 protein encodes a 180-aminoacid serine protease required for processing Þve of the six HCV nonstructural proteins (Tomei L, 1993). It cleaves four sites within the polyprotein, yielding the NS3, 4A, 4B, 5A, and 5B proteins. NS3 is an induced-Þt protease, requiring both the NS4A cofactor protein and the substrate to fully activate its catalytic machinery (LaPlante SR, 1999; Pizzi E, 1994; Yan Y, 1998). Also, the NS3 protease contains a tetrahedral zinc-binding site, which guides folding of the NS3 protease, maintains protein activity, and provides structural stability (De FR, 1998). The NS3 protease is essential for HCV replication and is a primary target for novel antiviral therapies. Many investigational inhibitors of the NS3 protease have taken advantage of the susceptibility of that protease’s active site to inhibition


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by its cleavage products (corresponding to the NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B N-terminal cleavage sites). NS3 Helicase. The NS3 protein also contains a helicase domain at its Cterminus. Helicase is an ATP-dependent enzyme that catalyzes the unwinding of duplex RNA prior to its replication by RNA-dependent RNA polymerase (RdRp; encoded by NS5B). The strand-separating activity is associated with hydrolysis TABLE 1. Advantages and Disadvantages of Emerging Drug Classes with Specific HCV-Life-Cycle-Regulating Targets Emerging Drug Class Polymerase inhibitors

HCV-Specific Targets NS3 helicase, NS5B (RNA polymerase), NS5A (transcription activator)

Protease inhibitors

NS2, NS2/3, NS3, proteases

Replication cofactors

NS4A

HCV-encoded immunomodulators

NS2, NS4A, NS4B, NS5A

Advantages/Disadvantages of Drugs Modulating Activity of These HCV-Specific Targets + HCV-specific, no immunomodulating properties, potentially reducing side effects.

+ Can potentially block propagation of virus. − High susceptibility for development of antiviral drug resistance, forcing a requirement for a drug with high bioavailability and long-term persistence. − Less likely to be available as a monotherapy as it may require combination therapy to boost clearance of the nonpropagating virus. + HCV-specific, no immunomodulating properties, potentially reducing side effects. + Can potentially block propagation of virus. − High susceptibility for development of antiviral drug resistance, forcing a requirement for a drug with high bioavailability and long-term persistence. − Less likely to be available as a monotherapy as it may require combination therapy to boost clearance of the nonpropagating virus. − Difficult to disable owing to structural chemistry surrounding the active site of the target. + HCV-specific; no immunomodulating properties, potentially reducing side effects. − Possibly not as efficient in therapeutic use, leading to potential as an enhancer to existing or emerging therapies. + HCV-specific. + Potentially increase efficacy of existing combination therapies by reducing or blocking interferon resistance or by blocking antiapoptotic properties of some targets. − Host-pathways affected by these proteins are poorly defined, thus efficacy may be unimpressive.

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of nucleoside triphosphate (NTP), which disrupts the hydrogen bonds that keep the two strands together. The RNA helicase activity of HCV NS3 is enhanced in the presence of NS4A and, unlike the majority of NTPase/helicases, the HCV NS3 helicase is capable of unwinding DNA/DNA, RNA/RNA, and DNA/RNA duplexes. In addition, the NS3 helicase is thought to confer the speciÞcity of NS5B for HCV viral RNA (Piccininni S, 2002). Because the HCV NS3 helicase structure has been well characterized, it is regarded as a promising target for antiviral therapy, though drugs in development against this target are still early in preclinical development. NS4A. NS4A is an essential cofactor for the NS3-dependent processing of the NS3-NS4A, NS4A-4B, and NS4B-NS5A junctions. In addition, although its presence is not required, NS4A increases the efÞciency of cleavage at the NS5A-5B site. This membrane-associated protein is believed to enhance the stability of the NS3 N-terminal structure and may have several molecular functions: • • • • •

Modulating NS3 serine protease activity through binding and cleavage of NS3 (Yang SH, 2000). Increasing NS3 stability by targeting it to the membrane of the ER. Enhancing RNA synthesis by tethering the replication complex to ERassociated NS3. Promoting phosphorylation of NS5A. Mediating inhibition of protein synthesis, an important process for regulating viral replication.

NS4B. NS4B is a hydrophobic, transmembrane protein with possible roles in HCV replication and inhibition of protein translation and transport. Using electron microscopy, researchers found that NS4B induces morphological changes in the ER (Gretton SN, 2005), which may play a role in HCV replication. Researchers have also observed NS4B-mediated inhibition of protein translation (Florese RH, 2002; Piccininni S, 2002) and have demonstrated inhibition of ER-to-Golgi protein transport in the presence of unprocessed NS4A/B (Konan KV, 2003). The authors of these studies suggest that inhibition of protein translation and transport may downregulate a cell’s ability to secrete cytokines and express MHC molecules, allowing HCV to circumvent the host immune response. Furthermore, NS4A and NS4B have been shown to induce expression of interleukin-8 (IL-8) (Kadoya H, 2005), which has previously been shown to play an important role in angiogenesis, tumor growth, and metastasis. NS4B also plays a critical role in HCV RNA replication through binding and hydrolysis of GTP (Einav S, 2004; Elazar M, 2004). In other ßaviviruses, such as dengue, West Nile, and yellow fever virus, NS4B has been shown to block activation of interferon- (IFN-) alpha and beta responsive transcription factors such as STAT1, and IFN-stimulated response elements (Munoz-Jordan JL, 2005). Although similar activity has not yet been described for the HCV NS4B, if the HCV NS4B functions similarly to its counterpart in related ßaviviruses, it is possible that NS4B plays a role in IFN resistance.


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NS5A. Although associated with other HCV proteins as part of the viral replication complex, NS5A’s role in viral replication has not yet been deÞned. It is thought that differential phosphorylation of NS5A may affect its role in RNA replication (Appel N, 2005). Proper phosphorylation of NS5A requires the expression of the protein in its polyprotein context (Koch JO, 1999). NS5A is known to be associated with membranes and to act as a transcriptional activator. It displays a multitude of activities that are believed to trigger crucial steps in the pathophysiology of HCV infection. For example, NS5A has been shown to interact with growth factor receptor-binding protein 2, p53, p21, interleukin (IL)-8, NF-κB, and the signal-transduction pathway for tumor necrosis factor-alpha (TNF-α) (Qadri I, 2002; Reyes GR, 2002; Waris G, 2002). Many of these interactions block the cellular response to persistent HCV infection by inhibiting apoptotic processes. NS5A has distinct homology to the antiapoptotic protein Bcl-2, and NS5A was able to interact with the proapoptotic protein Bax to inhibit apoptosis in p53negative HCC cells (Chung YL, 2003). Clearly, the activity of NS5A and NS2 in preventing apoptosis may explain the chronic persistence of HCV in the liver and, with the activity of NS4A and NS4B, its progression to HCC. Drug therapies that are unable to kill infected cells (i.e., antibodies that only clear extracellular virus) may be ineffective at preventing HCV disease progression. NS5A has generated considerable interest because it has been implicated in causing HCV tolerance to IFN treatment (He Y, 2002). Although the idea is controversial, the molecular mechanism of this IFN tolerance is thought to involve inhibition of the IFN-induced, double-stranded, RNA-activated protein kinase (PKR) by NS5A. PKR is a major mediator of the IFN-induced biological response. NS5B. NS5B encodes the RNA-dependent RNA polymerase (RdRp) activity of HCV and is the central catalytic enzyme responsible for HCV replication. As such, this protein represents a promising and popular target for antiviral drug discovery (Leveque VJ, 2002). Alone, NS5B lacks speciÞcity for HCV RNA; it requires additional viral factors, such as the NS3 helicase and NS4A, to recognize and initiate viral replication. Indeed, the NS3 helicase is believed to dramatically modulate template recognition by NS5B (Piccininni S, 2002). Advances in understanding the structure-function of NS5B, such as the identiÞcation of features important for binding the RNA template, have provided a framework for structure-based drug design. Nucleoside and non-nucleoside inhibitors of NS5B have been identiÞed, and both are the subject of ongoing research efforts. Untranslated Regions. Within the 5 and 3 ends of the HCV genome, two untranslated regions (UTRs) are critical for viral transcription and translation. The 5 UTR contains an internal ribosomal entry site (IRES) that is involved in the initiation of translation. This highly conserved region of the HCV genome is the subject of much research because IRES-mediated translation occurs via a unique prokaryotic-like mechanism that makes it an attractive antiviral target (Gallego J, 2002).

644

HEPATITIS C

The 3 UTR consists of a poorly conserved short segment (approximately 28–42 bases), followed by a polyU(C) region of variable length and a highly conserved 98-base sequence that is essential for viral replication (Blight KJ, 1997). This highly structured region of the HCV genome is thought to promote HCV RNA genome stability and may serve as a replicase recognition site during the initiation of minus-strand RNA synthesis. Core Protein. The core protein (or nucleocapsid protein) is immunogenic, and antibodies directed against the core protein are typically present in infected persons. A number of biological activities have been associated with the core protein; these biological activities include its role in alterations in cell-cycle regulation, transcription of cellular proto-oncogenes, induction or suppression of apoptosis, and suppression of the host immune response (Ray RB, 2001; Soo HM, 2002). The signiÞcance of these biological activities in the pathophysiology and persistence of HCV infection is not clear. However, research indicates that the core protein’s most important role is encapsidation of the viral RNA prior to viral budding. Aspartic acid 111 has been mapped as a critical residue for virus assembly and budding, and may represent a novel site for drug development (Blanchard E, 2003). E1 and E2. E1 and E2 are envelope proteins that play pivotal roles in viral assembly, budding, and HCV entry of host cells; for these reasons, they are important targets in HCV vaccine development. The mechanism by which HCV penetrates hepatocytes remains loosely deÞned. Strong evidence indicates that the human CD81 receptor, which is expressed on various cell types, is involved in the attachment of HCV via the hypervariable regions (HVR1) of envelope protein E2 (Drummer HE, 2004; Drummer HE, 2005; Hughes MG, Jr., 2005; McKeating JA, 2004; Meyer K, 2004). Additional host-cell surface components have been implicated to play a role in cellular tropism of HCV entry, including scavenger receptors and lectins (Bartosch B, 2003; Cormier EG, 2004b; Cormier EG, 2004a). E2-speciÞc antisera can block binding and entry of HCV to host cells, conÞrming the important role of E2 in HCV host cell invasion (Keck ZY, 2004). In addition to facilitating entry, these proteins may have other roles. E1 and E2 form a stable heterodimeric complex that anchors viral particles to the ER during replication of the virus (Op De BA, 2001). Furthermore, E2 has been implicated as a potential inhibitor of protein kinase R (PKR), which may contribute to the resistance of HCV to IFN (Pavio N, 2002). Hypervariable Regions. Analysis of the HCV genome has revealed the presence of three hypervariable regions (HVRs) located within the E1, E2, and NS5A regions. Hypervariable region-1 (HVR-1), near the amino terminus of E2, is approximately 30 amino acid residues in length and is thought to exist as a polypeptide loop on the surface of the virion. Functional analysis of E2 suggests that HVR-1 is involved in modulating CD81 receptor binding, perhaps through SR-B1 binding (Bartosch B, 2003; Roccasecca R, 2003).


645

Infected people frequently possess neutralizing antibodies (antibodies that block viral replication) to the HVR-1 sequences of the virus with which they are infected. Researchers believe that the appearance of such antibodies results in the selection of variant viruses with HVR-1 sequences that are less reactive; this important pathogenic mechanism leads to evasion of the host immune response and persistent infection (Mondelli MU, 2001). Genetic Variability. Genetic variability is a key feature of HCV genomes and one that they share with many other RNA viruses, such as HIV and dengue virus. Viral heterogeneity appears to result primarily from the high transcription error rate associated with the RdRp, as well as from the absence of any proofreading mechanisms. The resulting genetic hypervariability poses a challenge to drug and vaccine development. New drugs targeting HCV proteins (polymerases and proteases) may be susceptible to drug resistance, and vaccines designed to target a speciÞc viral epitope may be rendered ineffective with shifts in the peptide sequence of the antigen. HCV exhibits genetic heterogeneity on three levels: genotypes, subtypes, and quasi species. Within each subclassiÞcation, the percentage nucleotide difference in the RNA sequences declines: 31–35% of viral RNA differs between genotypes; 20–23% of RNA differs between subtypes; and in quasi species, only 1–9% of the nucleotides differ (Bukh J, 1995). Genotypes. Genotypes represent the accumulation of mutations that have occurred over the long-term evolution of the virus. Phylogenetic analyses of the NS5 and E1 sequences from HCV samples taken from around the world have identiÞed six major genotypes. These genotypes have been further divided into closely related subtypes. The nomenclature designates the genotype with an Arabic numeral; the subtype is denoted by a lowercase letter. Table 2 illustrates the distribution of HCV genotypes in the major pharmaceutical markets. Genotypes 1, 2, and 3a are broadly distributed in patients around the world, whereas the other types are more geographically restricted. Most people are infected by a single genotype. Blood transfusion is responsible for the worldwide spread of genotype 1b; in contrast, needle sharing among drug users is associated with the transmission of genotypes 1a and 3a in most industrialized countries. Genotype 3b is found mainly in the Indian subcontinent; genotype 4 is found mainly in the Middle East and Africa; genotype 5 is found mainly in South Africa; and genotype 6 is found mainly in Hong Kong. The clinical consequences of infection by the various genotypes remain unclear. Although investigations have shown that liver steatosis is particularly frequent in patients with HCV genotype 3 infection (Rubbia-Brandt L, 2004), an association between severity of disease (over a natural course of infection) and HCV genotype has not been found (Freeman AJ, 2003; Reid AE, 1999). The inßuence of genotype on the expected response to therapy is somewhat clearer. Indeed, HCV genotype has emerged as an important factor in predicting a sustained response to antiviral therapy and determining the duration of such treatment. Genotypes 2, 3, and 5 respond better to pegylated interferon alpha (pegIFNα)/ribavirin combination therapy (the current gold-standard therapy) than do

646

HEPATITIS C

TABLE 2. Geographic Distribution of HCV Genotypes in the Major Pharmaceutical Markets, 2004 Country

1a

1b

2a

2b

United States France Germany Italy Spain United Kingdom Japan

x x x x x x x

x x x x x x x

x x

x

2c

2 nsp

x x x x

x x x

x x

3a x x x x x x x

3b

4a

4 nsp

5

x x x

6 x

x x

x x

x x x

nsp = Not specified. Note: The distribution of HCV genotypes is constantly changing, and an accurate assessment of the actual distribution of prevalence of HCV genotypes has not recently been determined. Data in this table reflect data collected from published reports or cases describing HCV genotype prior to 2005.

genotypes 1 and 4. Patients with genotypes 1, 4, 5, and 6 respond better to 48 weeks of combination therapy than to 24 weeks, whereas responses in patients with genotypes 2 or 3 infection are similar after 24 and 48 weeks of therapy. Furthermore, patients infected with HCV genotype 1 require 1,000–1,200 mg of ribavirin daily to achieve optimal response rates, whereas only 800 mg daily is needed for patients infected with genotype 2 or 3. The molecular etiology behind the differential treatment outcomes for genotype 1 versus genotype 2- or 3-infected patients remains unclear. Quasi Species. The term quasi species describes the heterogeneous mixture of genetically related but sequence-distinct variants that circulates within each HCV-infected person’s bloodstream. A quasi species is generated simply by random mutations that occur as virus is replicated in a patient’s cells. This random mutation generates a mixed pool of heterogeneous viral variants, with certain genetic variants constituting the bulk of virions. The genetic variant that is in the majority is termed the quasi species. At any time, one quasi species predominates within an infected host, although this dominant form may change or be replaced over time. Changes in the dominant quasi species, through selection and expansion of less common genetic variants, can result from spontaneous changes in the host environment (e.g., immune responses) or be triggered by factors such as concurrent infections or drug intake. The ability of HCV to survive for decades in the host is a direct result of its genomic plasticity and the evolution of quasi species within an infected person. This evolution enables the virus to continually evade the host immune response. HCV’s ability to avoid detection until it has become well entrenched permits the development of persistent HCV infection in 60–85% of all people who have contracted the virus. The genetic ßuidity that is so characteristic of HCV also presents a signiÞcant barrier to the development of vaccines against this infection. HCV Transmission. Before the identiÞcation of HCV, the majority of non-A, non-B hepatitis cases were transmitted and acquired through blood transfusions.


647

Since the isolation of the virus and the institution of antibody screening measures and nucleic-acid testing to exclude blood from infectious donors, the risk of transfusion-related HCV infection has been virtually eliminated. Indeed, most newly acquired cases of hepatitis C in the major markets are related to intravenous drug use. Other risk factors include occupational exposure to contaminated blood (primarily via needle sticks), hemodialysis, sexual transmission, vertical transmission (transmission from mother to child), and nonintravenous drug use (e.g., intranasal cocaine). In addition, percutaneous exposure through body piercing and tattooing are possible (but unconÞrmed) means of transmission. Accumulated evidence indicates that sexual transmission of HCV does occur, but the efÞciency of transmission is much lower than that of other sexually transmitted viruses, such as HBV and HIV. The transmission rate from mother to infant is also low—4% to 7%—and is correlated with high levels of maternal viremia (i.e., high viral load in the maternal blood) and HIV coinfection. Indeed, coinfection with HIV increases the rate of vertical transmission four- to Þvefold (Roberts EA, 2002). Despite the plethora of risk factors, most studies have been unable to identify a speciÞc risk factor in approximately 10% of all patients examined (Alter MJ, 1998).

Pathophysiology HCV Disease Progression. The natural course of HCV infection and disease varies widely. Although HCV-related liver disease is a leading cause of mortality in adults and is the primary reason for liver transplantation in the major markets (Kim AI, 2005; Kim WR, 2001; World Health Organization Initiative for Vaccine Research, 2005), experts tell us that the vast majority of carriers die with rather than from this infection. Disease manifestations are absent or minimal in the majority of cases. HCV RNA can be detected in the blood within one to three weeks after initial exposure; however, a signiÞcant proportion of infected individuals will experience few or no symptoms of infection and therefore will remain unaware of their disease. Chronic HCV infection is diagnosed by the repeated detection of virus in the blood over a period of at least six months. Patients with persistent viremia are at risk of Þbrosis and cirrhosis (extensive Þbrosis that distorts the structure and degrades the function of the liver), but the extent of liver damage and the time course of disease progression vary among individuals. Because acute infection is often clinically silent, it has proved difÞcult to establish the true incidence and time course of progression to disease. Retrospective studies have found that approximately 20% of all infected people will eventually develop cirrhosis, typically after a “silent period” of 20–40 years. Nevertheless, a meta-analysis of community-based cohorts whose populations most closely represent the current HCV-infected populations in the major markets indicates that the risk of progression to cirrhosis within 20 years of infection is less than 10% (Freeman AJ, 2001). Few natural history studies have gone

648

HEPATITIS C

Infection (often asymptomatic)

Typical time to progression

Weeks or months

Natural resolution of infection 5-25%

Progression to chronic infection 75-95%

10 years Infection persists but disease does not develop, or progresses only to mild or moderate disease 80% (usually asymptomatic; serum ALT concentrations may be normal or persistently or intermittently elevated)

20 years

Progression to cirrhosis 20%

30 years

Cirrhosis progresses slowly and patient dies from other causes 50-70%

Progression to decompensated cirrhosis and liver failure 20-30%

Progression to hepatocellular carcinoma 10-25% of cirrhotic patients

ALT = Alanine aminotransferase.

FIGURE 2. The natural history fo hepatitis C infection.

beyond the Þrst 20 years of infection, so the true outcome of HCV infection beyond this time period is not known. Cirrhosis can remain asymptomatic for several years as healthy tissue compensates for diseased tissue. However, once it is established, complications such as jaundice, ascites, variceal hemorrhage, and encephalopathy may ensue. The development of these complications deÞnes decompensated cirrhosis, or end-stage liver disease. In patients with decompensated cirrhosis, the Þve-year survival rate declines to 50%. In addition, approximately 10–25% of patients who develop cirrhosis go on to develop HCC. The course of infection and disease varies in individual patients on three levels: at the level of the viremia, at the level of histology, and at the level of symptoms. In the following sections, the course of events that may ensue from HCV infection are discussed (Figure 2). Spontaneous Resolution of HCV Infection. With regard to viremia, infection may follow two main courses:


•

•

649

Approximately 5–25% of people who contract HCV recover spontaneously within 2–12 weeks (although antibodies persist, the virus has been eradicated from the blood). The remaining 60–85% of infected people fail to eradicate the virus and develop a chronic infection.

Numerous studies have attempted to identify factors associated with the spontaneous resolution of infection. Accumulated evidence indicates that incubation period, degree of elevation of liver enzymes, and viral load during the acute phase are not predictive of whether the infection will resolve or become chronic. It has been noted, however, that children and young women are more likely to undergo a spontaneous resolution of infection than are adults, whereas AfricanAmerican men are among those with the highest risk of HCC (Fleckenstein J, 2004). Patients who experience symptomatic hepatitis (e.g., jaundice) during the acute phase of infection are also less likely to develop chronic hepatitis C than those who are asymptomatic in the acute phase. Most patients who spontaneously clear the virus after acute hepatitis C infection demonstrate a strong TH 1 immune response to infection (secreting type-1 cytokines, such as IL-2, IFNγ , and TNF-α), with little or no TH 2 response (secreting type-2 cytokines, such as IL-4, IL-5, and IL-10), whereas those who develop chronic hepatitis C show the reverse. Other host-dependent genetic factors—speciÞcally human leukocyte antigen (HLA) class—have been shown to be related to viral clearance or disease progression (Jinushi M, 2003; Mangia A, 1999; Wang Y, 2003). Studies in the chimpanzee model of HCV infection have revealed that a strong intrahepatic T-cell response (rather than a peripheral T-cell response) to HCV correlates with viral clearance (Su AI, 2002; Thimme R, 2002). Moreover, it is suggested that some mechanism other than the destruction of infected hepatocytes is responsible for the virus’s clearance. Chimpanzees that transiently and permanently cleared the infection were observed to initiate a vigorous, multispeciÞc, IFNγ -producing, intrahepatic T-cell response. These chimpanzees were also observed to upregulate genes involved in antigen presentation and the adaptive immune response. In contrast, a strong type 1 IFN (IFNα/IFNβ) response was observed in all chimpanzees, regardless of the outcome of infection, suggesting that HCV is relatively resistant to the antiviral effects of type 1 IFNs. Histology of HCV Infection. At the histological level, patients with chronic HCV have historically been classiÞed as having chronic active or chronic persistent hepatitis; that is, more or less progressive disease as evaluated by the extent and nature of liver injury. This nomenclature captures an important feature of HCV; the disease progresses more quickly in some patients than in others. One patient who has been infected for 30 years may have mild disease, whereas another who has been infected for only 10 years may have severe disease. Under this system, the future rate at which the disease will progress is indicated by how fast it progressed between the date of infection and the date of diagnosis.

650

HEPATITIS C

TABLE 3. Histological Activity Index (Knodell Score) for Assessment of the Extent of Liver Disease Histological Feature Periportala necrosis, including piecemeal necrosisb (PN) and/or bridging necrosisc (BN)

Severity None

Mild PN Moderate PN Marked PN Moderate PN + BN Marked PN + BN Multilobular necrosis Intralobular degeneration and focal necrosis

Score 0

1 3 4 5 6 10

None

0

Mild Moderate Marked

1 3 4

Portal inflammation

None Mild Moderate Marked

0 1 3 4

Fibrosis

None Fibrous portal expansion Bridging fibrosis Cirrhosis

0 1 3 4

Maximum score

22

a Surrounding the portal vein. b Disruption of the periportal hepatocytes by inflammatory cells.

In reality, people infected with HCV may Þnd themselves anywhere on a continuum of severity of liver disease. For this reason, most specialists have rejected the terms chronic active and chronic persistent in favor of newer grading systems that describe the virus’s histological activity in the liver (grade) and degree of progression (stage). Grade is based on the degree of necrosis (death of an area of tissue), inßammation, and Þbrosis (formation of Þbrous tissue). The most popular grading system used in clinical trials is the Histologic Activity Index, or Knodell score, shown in Table 3 (Knodell RG, 1981). This score is formulated by scoring based on evaluation of four parameters with regard to function/dysfunction of the liver, with a lower score indicating fewer histological anomalies: periportal and/or bridging necrosis (scored 0 through 10), intralobular degeneration and focal necrosis (scored 0 through 4), portal inßammation (scored 0 through 4), and Þbrosis (scored 0 through 4). The scores from the Þrst three categories are then summed to provide a quantitative value for the severity of inßammation: • •

0 = No inßammation. 1–4 = Minimal inßammation.


• • •

651

5–8 = Mild inßammation. 9–12 = Moderate inßammation. 13–18 = Marked inßammation.

The Þbrosis portion of the Knodell score comprises the fourth category and is scored from 0 to 4, although no value is set for a score of 2 in this scale: • • • •

0 = No Þbrosis. 1 = Fibrous portal expansion. 3 = Bridging Þbrosis (portal-portal or portal-central linkage). 4 = Cirrhosis.

This scaling is similar to the Metavir scoring system, which aims to evaluate liver function and histology on two scales: grade and stage. In the Metavir system, grade denotes the activity or amount of inßammation and is scored 0 through 4 with 0 being no activity and 3 or 4 indicating severe activity. The stage scoring indicates the amount of Þbrosis and is also scored 0 through 4: • • • • •

0 = No scarring. 1 = Minimal scarring. 2 = Scarring present and extends outside of areas of the liver that are peripheral to blood vessels. 3 = Bridging Þbrosis, spreading and connecting areas of Þbrotic tissue. 4 = Cirrhosis or advanced scarring of the liver.

Because of the similarities between the Þbrosis portion of the Knodell score and the Metavir scoring system, clinical trials will often report the effect of a drug on changes in Þbrosis status as quantiÞed using the Metavir scale or by using only the Þbrosis portion of the Knodell scoring. Outside the context of clinical trials, hepatitis may be graded simply as mild, moderate, or severe. The Child-Pugh score is a grading/evaluation system for cirrhosis, based on analysis of various liver function tests (Table 4). It involves summation of score values assigned to results from Þve different liver function/status tests, and the summation of these scores is divided into three classes (A, B, and C, with A being more mild cirrhosis and C indicating end-stage liver disease). Although this scoring system is not typically used in describing the effects of a drug in clinical trials, it is often referred to concerning medical practice and treatment options in cirrhotic patients. Symptoms of HCV Infection. Although the majority of patients do not develop symptoms during the acute phase of infection, 20–30% of them experience malaise, fatigue, weakness, anorexia, or right upper quadrant pain, followed by the appearance of jaundice. Patients who go on to develop chronic infection generally have few symptoms during the Þrst 20–40 years after infection. A subset of chronic HCV patients (approximately 20%) will develop nonspeciÞc symptoms, including mild fatigue and malaise, nausea, and right upper quadrant

652

HEPATITIS C

TABLE 4. Child-Pugh Grading System for Evaluation of Cirrhosis Score

Albumin (g/dL)

Bilirubin (mg/dL)

PT (sec. prolonged)

Hepatic Encephalopathies

Ascites (grade)

1 2 3

>3.5 2.8–3.5 6

None 1–2 3–4

None Mild Severe

After summation of scores for each category, the Child-Pugh class is defined in the following manner: A = 5–6. B = 7–9. C = 10+ (end-stage liver disease). PT = Prothrombin time.

pain. Many patients with chronic hepatitis C Þrst exhibit symptoms when cirrhosis develops, although patients can continue with cirrhosis without symptoms for several years. Risk Factors for Progression. In 1999, L. Pagliaro and colleagues published a meta-analysis of variables predicting the probability of progression to cirrhosis. Their study showed that the stage of disease at diagnosis was indeed a key indicator of the risk of progression, particularly if the patient had been infected for at least ten years. Each of nine longitudinal studies that Pagliaro assessed found that higher necroinßammatory grading or staging of Þbrosis at diagnosis was associated with more frequent and accelerated progression to cirrhosis (Pagliaro L, 1999). Other factors consistently associated with a higher risk of progression to severe liver disease include excessive alcohol consumption, smoking, advanced age at the time of infection, gender, the presence of competing etiologies for liver disease (e.g., superinfection with HAV or HBV), and coinfection with HIV (Hezode C, 2003; Poynard T, 1997; Seeff LB, 1999). Disease progression is not associated with the level of viremia; however, disagreement about the role of HCV genotype in disease progression is evident in the literature. Persistent elevation of serum aminotransferase (ALT) levels (10–20 times above normal) is often indicative of progression to chronic hepatitis, but the magnitude and frequency of elevation of serum ALT levels correspond poorly with the extent of Þbrosis (Shiffman ML, 2000). Furthermore, whereas serum HCV RNA levels remain fairly constant once persistent viremia is established, serum ALT levels may ßuctuate independent of symptoms or disease progression. Approximately 30% of patients with chronic hepatitis C have serum ALT levels that are normal, and another 40% have serum ALT levels that are less than two times the upper normal limit (Bacon BR, 2002). Of patients with normal/nearnormal ALT levels, up to 35% may show signiÞcant inßammation and Þbrosis upon liver biopsy. Disease Mechanisms. The Host Immune Response. HCV is thought to principally exert its pathological effects indirectly, via the host’s immune response, rather than through its


653

own cytopathic properties. In most infected patients, a wide array of antibodies are generated to structural and nonstructural regions of the virus, but the clinical signiÞcance of this humoral (B-cell-mediated) response with respect to controlling infection and disease remains poorly understood. Unfortunately, infection persists in most patients despite the development of HCV-directed antibodies. Furthermore, in studies of chimpanzees, animals that were previously infected could later be reinfected, despite the development of a humoral response (Farci P, 1992). Specialists believe that the neutralizing immune responses are strainspeciÞc and that the quasi-species nature of the virus allows other strains to emerge when the dominant strain comes under immune pressure. The cellular arm of the immune system appears to play the major role in both controlling infection and damaging the HCV-infected liver. The mechanisms by which CD4+ helper T cells (TH ) and CD8+ cytotoxic T cells (TC ) eradicate infection in some patients and contribute to liver damage in others are unclear, but evidence suggests that an imbalance between the TH 1 and TH 2 response results in the inability to clear infection and the progression of liver disease (Sobue S, 2001). An early TH 1 response indirectly promotes TC activity and establishes the antiviral cellular responses. Conversely, researchers hypothesize that in chronic hepatitis C, the T-cell response is polarized early to a TH 2 response, which allows viral persistence rather than viral clearance (Jacobson Brown PM, 2001). The persistence of HCV in infected hepatocytes causes continuous hepatic inßammation and injury. Cytokine-Induced Hepatocellular Damage and Fibrosis. After years of HCV infection, Þbrosis may develop. Fibrosis is characterized by the accumulation of collagen and other insoluble extracellular matrix proteins that ultimately destroy the liver architecture. During this process, proinßammatory cytokines (e.g., TNFα, IL-1, IL-6) are released by Kupffer cells in the liver or by inÞltrating neutrophils and macrophages. These cytokines stimulate normally quiescent stellate cells, which grow adjacent to hepatocytes, to secrete collagen and other proteins that impair the ability of liver cells to process materials. If Þbrosis progresses, cirrhosis can result; cirrhosis is characterized by bands of Þbrosis that enclose nodules of regenerating hepatocytes. Researchers are investigating ways to disrupt the process by which stellate cells become stimulated as a means of preventing disease. One such target is transforming growth factor-beta (TGF-β), a potent Þbrogenic cytokine produced by Kupffer and stellate cells. Note, however, that the liver can continue to function for many years despite the presence of cirrhosis. HCV Cytopathic Effects. Some evidence also suggests that HCV can, like other members of the Flaviviridae family, induce tissue damage directly. Histopathologists sometimes Þnd damaged hepatocytes in the absence of adjacent inßammation. Several liver transplant centers have also reported that immunocompromised transplant recipients with high levels of hepatic RNA expression develop rapidly progressing graft dysfunction; their biopsies reveal only mild inßammation (e.g., presence of lymphocytes). The relative scarcity of intrahepatic lymphocytes in

654

HEPATITIS C

these immunosuppressed people and the increased expression of HCV suggest that HCV itself causes liver damage. Nevertheless, biopsy studies have failed to correlate hepatic viral load with biochemical or histological markers of disease activity—possibly because virus-mediated damage occurs only beyond a certain level of intracellular antigen accumulation, which most infected cells may not have reached. CURRENT THERAPIES Current therapies for chronic hepatitis C virus (HCV) aim to reduce or halt progression of liver Þbrosis. Most experts agree that the best method for achieving this goal is through eradication of HCV. Thus, the primary end point for all current therapies for HCV is achieving a sustained virological response (SVR), deÞned as the absence of detectable HCV RNA in polymerase chain reaction (PCR) screens of serum 24 weeks after the conclusion of antiviral therapy. The secondary end points for current HCV therapies are the normalization of serum alanine aminotransferase (ALT) levels and improvements in liver histology, both of which can occur in the absence of an SVR. Studies of the long-term efÞcacy of HCV therapy conÞrm that an SVR is associated with the normalization of serum ALT levels, resolution of liver damage (regression or slowing of Þbrosis), and a low likelihood of relapse of HCV infection (Coverdale SA, 2004). Recent studies suggest that the achievement of SVR signiÞcantly increases survival among chronic HCV-infected individuals (Brok J, 2005; Kasahara A, 2004). Another recent study has shown that the eradication of HCV virus (with peg-IFN-α and ribavirin therapy) reduces the incidence of hepatocellular carcinoma (HCC) in patients who have HCV-related cirrhosis, corroborating the value of SVR as a surrogate end point for efÞcacy and clinical outcome (Hung CH, 2004). The interferon (IFN) family of glycoproteins includes four naturally occurring cytokines that exhibit antiviral, antiproliferative, and immunomodulatory activities: IFN-alpha (α), IFN-beta (β), IFN-gamma (γ ), and IFN-omega (ω). Interferons are produced predominantly by leukocytes in response to viral infection and other biological stimulants. Recombinant or natural IFN-α is the mainstay of HCV treatment in the seven major pharmaceutical markets under study (United States, France, Germany, Italy, Spain, United Kingdom, and Japan), but it has many shortcomings, including limited efÞcacy, signiÞcant side effects, and the need for an extended course of therapy. ModiÞcations to recombinant IFN-α, through covalent attachment of a polyethylene glycol (peg) molecule, substantially changes the drug’s pharmacokinetics, reducing its rate of degradation in the bloodstream and allowing for less frequent administration. Ribavirin is a nucleoside analogue that was approved for hepatitis C in the United States in 1998, in Europe in 1999, and in Japan in 2001. Acting by mechanisms that are not completely understood, the combination of ribavirin and peg-IFN-α elicits an SVR in more than 50% of treated patients (Hadziyannis SJ, 2004). This therapeutic advantage has made once-weekly peg-IFN-α in combination with daily ribavirin the current gold standard for the treatment of HCV.

CURRENT THERAPIES

655

Table 5 lists the regimens used to treat chronic hepatitis C; Table 6 describes the mechanism of action for each molecule used to treat HCV; and Table 7 lists current HCV therapies’ key patent expiries. Pegylated-Interferon-Alpha/Ribavirin Regimen Overview. The gold standard for treatment of chronic HCV infection is a combination therapy comprising peg-IFN-α and ribavirin. This regimen has produced the highest efÞcacy of all current therapies, eradicating the virus in nearly 80% of HCV genotype 2- or 3-infected patients and in 40% of patients infected with genotype 1 and 4. Because genotype 1 accounts for nearly 70% of all HCV infections in the United States and Europe, the average efÞcacy of the peg-IFN/ribavirin regimen is estimated at 50–55% (Hadziyannis SJ, 2004). Two forms of peg-IFN-α are available in all seven of the major pharmaceutical markets covered here: • •

Peg-IFN-α-2b (Schering-Plough/Enzon’s PEG-Intron). Peg-IFN-α-2a (Roche/Chugai’s Pegasys).

In mid 2000, Schering-Plough launched peg-IFN-α-2b for the treatment of HCV in the European Union, with the U.S. launch coming shortly afterward in early 2001. Roche launched peg-IFN-α-2a for the treatment of HCV in the European Union in mid 2002 and in the United States in early 2003. Chugai Pharmaceuticals (a member of the Roche group) received approval for peg-IFN-α-2a in Japan in mid 2003, and the molecule was launched soon after. Schering-Plough received approval for peg-IFN-α-2b in Japan in late 2004 and the molecule was launched before the end of that year. Roche and Schering-Plough have been battling for market share, and each company has made signiÞcant attempts to market its peg-IFN-α product as superior among different patient populations and treatment groups. Table 6 describes the mechanism of action of the peg-IFN-α agents. In an effort to boost therapeutic efÞcacy, researchers explored combination therapy of peg-IFN-α with other antiviral or immunomodulatory compounds, and they found success with the addition of ribavirin (Schering-Plough’s Rebetol, Roche’s Copegus). Ribavirin (Figure 3) is a synthetic guanosine nucleoside analogue with a broad spectrum of activity against several RNA and DNA viruses. ICN Pharmaceuticals (now Valeant Pharmaceuticals) developed ribavirin in the early 1970s for aerosol administration in children with respiratory syncytial virus. The company also developed an oral form of ribavirin as an HCV therapy, and the product was initially licensed to Schering-Plough in 1998. Since 2002, Roche has marketed a ribavirin product (Copegus) under license from Valeant, and in 2004 generic ribavirin products entered the market in the U.S. and some European markets. The combination of peg-IFN-α with ribavirin for the treatment of chronic hepatitis C is associated with signiÞcant adverse effects. Peg-IFN-α’s side effects include fatigue, inßuenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms (Table 8). Indeed, premature withdrawal from therapy

656 TABLE 5. Current Regimens/Classes Used for Chronic Hepatitis C, 2005 Regimen Components Regimen or

Class

Interferon alphas

Pegylated interferon alphas

Agent

Availability

Dose

Common Toxicities

Interferon-alpha-2b (Schering-Plough’s Intron A)


3 MU tiw for 24–48 weeks

Flulike symptoms Fatigue Anorexia Alopecia Neutropenia Thrombocytopenia Apathy Cognitive changes Irritability Depression

Interferon-alpha-2a (Roche’s Roferon A) Interferon-alpha-con1 (Yamanouchi/Amgen’s Advaferon; Valeant’s Infergen) Pegylated interferonalpha-2b (ScheringPlough’s PEG-Intron)


3 MU tiw for 24–48 weeks 9 µg tiw for 24–48 weeks

US, F, G, I, J


1.5 µg/kg/qw for 24–48 weeks

Flulike symptoms Fatigue Anorexia Alopecia Neutropenia Thrombocytopenia Apathy Cognitive changes Irritability Depression

TABLE 5. (continued) Regimen Components Regimen or

Class

Ribavirin

Agent

Availability

Dose

Pegylated interferonalpha-2a (Roche’s Pegasys) Ribavirin (Schering- Plough’s Rebetol, Roche’s Copegus, generics)


180 µg qw for 24–48 weeks 400–600 mg bid for 24–48 weeks


Interferon- beta

Interferon-beta (Mochida’s IFN-beta; Toray-Daiichi’s Feron)

Ja

3–6 MU qd for 6–12 weeks, then tiw for 6–18 weeks

Ursodeoxy- cholic acid

Ursodeoxycholic acid (Mitsubishi Pharma’s Urso/Ursosan) Glycyrrhizic acid (Minophagen Pharmaceutical’s Stronger Neo-Minophagen C [SNMC])

Jb

600 mg qd for 24 weeks

J

5–20 mL qd for 24 weeks

Glycyrrhizic acid

Common Toxicities

Anemia Anorexia Dyspnea Insomnia Nausea Pharyngitis Pruritis Rash Flulike symptoms Fatigue Anorexia Alopecia Neutropenia Thrombocytopenia Apathy Cognitive changes Irritability Depression Unknown

Unknown

657

a Recombinant IFN-beta is marketed in the United States and Europe for multiple sclerosis. It is not approved for the treatment of hepatitis C. b Ursodeoxycholic acid is marketed in the United States and Europe for cholestatic liver disease and for cholesterol gallstone dissolution. It is not approved for the treatment

of hepatitis C. bid = Twice daily; IFN = Interferon; kg = Kilogram; mcg = Microgram; mg = Milligram; MU = Million units; qd = Once daily; qw = Once weekly; tiw = Three times weekly. US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom; J = Japan.

658

HEPATITIS C

FIGURE 3. Structure of ribavirin.

owing to adverse events has been reported in 7–12% of participants in randomized controlled trials, and dose reductions of 50% were required in up to 42% of participants because of adverse events (Table 9) (Fried MW, 2002; Hadziyannis SJ, 2004). The most common reasons for dose modiÞcations are peg-IFN-induced neutropenia and ribavirin-induced anemia. Patients taking peg-IFN-α and ribavirin sometimes require administration of growth factors to counter these adverse effects. Approximately 50% of patients who discontinue therapy do so because of severe depression or other adverse psychiatric events. Dose-reduction and discontinuation-of-therapy rates are often higher with combination therapy than with peg-IFN-α alone. Ribavirin’s side effects include anemia, anorexia, dyspnea, insomnia, nausea, pharyngitis, pruritis, and rash (Khakoo S, 1998). SigniÞcantly, ribavirin causes an acute dose-dependent drop in hemoglobin levels in approximately one-third of patients; this drop in hemoglobin typically occurs within two weeks of initiation of therapy. In approximately 10% of patients, ribavirin causes hemoglobin levels to fall to below 10 g/dL; for this reason, hemoglobin levels of all drug recipients should be monitored closely. Because of ribavirin-induced anemia, patients with cardiovascular disease warrant cautious management and may be contraindicated for combination therapy. Patients with hemoglobinopathies (e.g., thalassemia, sickle-cell anemia) are similarly contraindicated for ribavirin. Ribavirin-induced anemia often mandates dose reductions, which experts believe reduces the efÞcacy of therapy. Animal studies have revealed that ribavirin causes signiÞcant teratogenic and embryocidal effects (Fried MW, 2002); therefore, this agent is contraindicated in pregnant women and in men whose partners are pregnant. For patients and partners of patients taking ribavirin, extreme care must be taken to avoid pregnancy for the duration of therapy and for six months beyond the end of treatment; ribavirin’s product label includes a recommendation that couples employ two forms of contraception. Formulation. The IFN-α products are self-administered subcutaneously, and ribavirin has an oral formulation. A major drawback of natural or recombinant IFN-α is its very short half-life; its serum half-life is only a few hours. As a result,

CURRENT THERAPIES

659

TABLE 6. Mechanism of Action by Molecule for Chronic Hepatitis C Virus Molecule Interferon-α

Ribavirin

Ursodeoxycholic acid (UDCA)

Mechanism of Action Experts attribute the antiviral effects of the IFNs to the induction of intracellular enzymes, such as 2 5 oligoadenylate synthetase and protein kinase R, which ultimately cause degradation of viral RNA and inhibit protein synthesis. IFNs also enhance the expression of human leukocyte antigens on the surface of infected cells, resulting in increased recognition of the infected cells by cytotoxic T cells and natural killer cells. IFNα, IFNβ, and IFNω have predominantly antiviral and antiproliferative effects, whereas IFNγ acts as an immunomodulatory mediator. Broad-spectrum antivirals are drugs that work to inhibit the replication of a virus, but do not act directly on the virus itself. Ribavirin is one such drug, and although it was developed more than 30 years ago, the drug’s precise mechanism of action remains unclear and is somewhat controversial. Furthermore, it is not clear which of ribavirin’s reported effects is most important to its efficacy in treating HCV infection. Researchers have proposed that ribavirin’s antiviral activity is exerted by inducing mutations in viral genomes forcing RNA viruses into ‘‘error catastrophe.’’ Other proposed antiviral effects of ribavirin include the following: • Inhibition of host inosine monophosphate dehydrogenase (IMPDH) that leads to depletion of the intracellular supply of guanosine triphosphate (GTP) and ultimately results in the suppression of viral nucleic acid synthesis. • Direct inhibition of the virus-encoded RNA-dependent RNA polymerases, leading to inefficient translation of viral messenger RNA. Scientists also believe that ribavirin can improve the host’s ability to clear viral infection by modulating the CD4+ T-helper-cell response. Research suggests that ribavirin enhances the expression of TH1 cytokines (e.g., IL-2, TNF-α, IFNγ ) and suppresses the expression of TH2 cytokines (e.g., IL-10, IL-4) in cultured T cells (Tam RC, 1999). These immunomodulatory activities may, in part, account for ribavirin’s ability to enhance the antiviral and antifibrotic activities of IFNα. Researchers have shown that the greater efficacy of IFNα/ribavirin combination therapy is associated with ribavirin’s repression of IL-10 production (Cramp ME, 2000). UDCA is a naturally occurring hydrophilic bile acid that is present in small amounts in human bile. It is also an immunomodulator that suppresses the production of IL-1, IL-6, and TNF-α, all of which are potent mediators of inflammation.

660

HEPATITIS C

TABLE 6. (continued) Molecule

Mechanism of Action

Glycyrrhizic acid

Glycyrrhizic acid is an aqueous extract from licorice with anti-inflammatory and antiallergic properties. It has been shown to induce interferon to indirectly inhibit virus production and to directly inhibit several viruses in cell culture, including vaccinia, herpes simplex virus, Newcastle disease, and vesicular stomatitis viruses (Abe N, 1982; Pompei R, 1980). Glycyrrhizic acid also inhibits the immunosuppressive effects of cortisone. The necessary activity of glycyrrhizic acid to inhibit HCV-induced liver damage has not yet been elucidated.

TABLE 7. Key Patent and Exclusivity Expiries of Drugs Used to Treat HCV Drug Interferon alpha-2a Interferon alpha-2b Interferon con-1 Interferon alpha-n1 Pegylated interferon alpha-2a Pegylated interferon alpha-2b Interferon beta

United States 21 Dec 2013 21 Dec 2013 13 Dec 2011 21 Dec 2013 Post2014 Post2014 Post2014

France Germany 20 Dec 2013 20 Dec 2013 14 Apr 2013 20 Dec 2013 Post2014 Post2014 28 Jan 2014

20 Dec 2013 20 Dec 2013 14 Apr 2013 20 Dec 2013 Post2014 Post2014 28 Jan 2014

Italy

Spain



United Kingdom 20 Dec 2013 20 Dec 2013 14 Apr 2013 20 Dec 2013 Post2014 Post2014 28 Jan 2014

Japan 20 Dec 2013 Post2014 14 Apr 2013 20 Dec 2013 Post2014 Post2014 30 Jul 2012

Note: Our patent and exclusivity expiration dates are based on the latest information from the following sources: FDA Orange Book, IMS Patent Focus, and a review of ongoing news and litigation found in a variety of proprietary sources.

even with daily dosing, troughs occur in the IFN-α serum concentration, making it difÞcult to effectively eradicate HCV infection. Pegylation of IFN-α reduces IFN-α’s accessibility and susceptibility to degradative proteolytic enzymes, which allows for a more sustained concentration of peg-IFN-α in the blood (Bailon P, 2001). As a result, the duration of the drug’s clinical efÞcacy is increased as it provides constant viral suppression, and less frequent administration of the drug is needed. Many factors inßuence the serum half-life of the pegylated protein, but the size of the attached peg molecule plays some role. Peg-IFN-α-2b (Schering-Plough’s PEG-Intron) consists of a 12-kDa linear peg molecule attached to IFN-α-2b. Peg-IFN-α-2b has a large volume of distribution, and dosing is therefore based

CURRENT THERAPIES

661

TABLE 8. Summary and Frequency of Treatment-Related Adverse Events Reported in Clinical Trials for Chronic Hepatitis C Trial 1 (Manns MP, 2001)

Trial 2 (Fried MW, 2002)

PEG-Intron plus Ribavirin (%)a

Intron A plus Ribavirin (%)b

Pegasys plus Ribavirin (%)c

Blood disorders Thrombocytopenia Neutropenia Leukopenia Anemia

5 26 6 12

2 14 5 17

5 27 14 11

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