Biologics in Inflammatory Bowel Disease (Oxford American Pocket Notes)

O A P N OX F O R D A M E R I C A N P O C K E T N O T E S

Biologics in Bowel Disease

This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material, including without limitation that they make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publishers do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/ or application of any of the contents of this material. The Publisher is responsible for author selection and the Publisher and the Author(s) make all editorial decisions, including decisions regarding content. The Publisher and the Author(s) are not responsible for any product information added to this publication by companies purchasing copies of it for distribution to clinicians.

O A P N

OX F O R D A M E R I C A N P O C K E T N O T E S

Biologics in Bowel Disease Scott E. Plevy, MD Associate Professor of Medicine, Microbiology and Immunology Division of Gastroenterology and Hepatology Inflammatory Bowel Disease Center University of North Carolina School of Medicine Chapel Hill, NC

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BIOLOGICS IN IBD

TABLE OF CONTENTS

Introduction

1

Biologic Therapy in Inflammatory Bowel Disease IBD Pathogenesis in a Clinical Context

6

TNF Inhibition: Immunologic and Clinical Rationale 10 “Top-Down” Versus “Step-Up” Strategies Other Biologics and Future Directions

13

Clinical Trial Data for Biologics 15 Adalimumab (Humira®) 15 Study 1 15 Study 2 21 Study 3 21 Infl iximab (Remicade®) 24 Study 1: Crohn’s Disease

24

Study 2: Crohn’s Disease

26

Study 3: Fistulizing Crohn’s Disease

29

Study 4: Pediatric Crohn’s Disease 30 Study 5: Ulcerative Colitis ®

Natalizumab (Tysabri ) 33 Study 1 33 Study 2 35

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10

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OAPN Study 3 36 Study 4 38 Progressive Multifocal Leukoencephalopathy 39 Certolizumab Pegol (Cimzia®) 40 Study 1 40 Study 2 41 Study 3 43 Safety of Biologic Therapies for IBD 44 Serious Infection and Biologic Therapy Malignancy

46

47

Immunogenicity Among TNF Inhibitors Conclusion 49 References 50

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BIOLOGICS IN IBD

DISCLOSURES

For serving on advisory committees, Dr. Plevy has received consulting fees from: Abbott Immunology; Anaphore, Inc.; Bristol-Myers Squibb Co.; CalciMedica, Inc.; Centocor, Inc.; DeNovo Therapeutics; Elan Pharmaceuticals; Eli Lilly; Exagen; Flexion; Genentech, Inc.; GlaxoSmithKline; Implicit Bioscience; Johnson & Johnson; Novartis; Novo Nordisk; Pharmacyclics; Proctor & Gamble; Schering-Plough; Synergy Pharmaceuticals; UCB; and Unity Pharmaceuticals. He has received consulting fees and stock ownership dividends from EnGene, Inc. and Protagonist Therapeutics, Inc. As an inventor, he has received royalties from Prometheus Labs. He has received honoraria as a speaker at CME Symposia from Abbott Immunology, Centocor, Inc., and UCB.

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BIOLOGICS IN IBD

INTRODUCTION

The human chronic inflammatory bowel diseases (IBDs) Crohn’s disease (CD) and ulcerative colitis (UC) affect over 1 million North Americans. Conventional treatments (e.g., corticosteroids, immunosalicylates, antibiotics, and immunomodulators) have been available for decades and offer symptom relief for many patients; however, the majority of patients will not maintain remission with conventional agents. Four biologic therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of CD—infl iximab, adalimumab, natalizumab, and certolizumab pegol—and infl iximab has been approved by the FDA for use in UC. Illustrating unprecedented progress, two biologics (certolizumab pegol and natalizumab) entered the clinic for the treatment of moderate to severe CD in 2008. The impact of biologic therapies on the care of IBD patients has been dramatic. For the fi rst time, we are talking about intervening with these agents to alter the natural course of IBD. An expanding body of evidence from prospective, randomized controlled trials shows that biologics maintain remission, spare corticosteroids, heal fistulas, heal the intestinal mucosa, improve quality of life, and possibly prevent hospitalizations and surgeries. With this background of unprecedented efficacy, biologics are being positioned earlier in the course of disease with the intent of preventing complications. Encouragingly, this paradigm shift has now been supported by clinical trial results, published and unpublished. However, with expanding use of biologics, 1

OAPN new infectious and neoplastic safety concerns have been described. Therefore, the changing landscape of biologics in IBD presents a rapidly moving target for the clinician. We have now restated our treatment goals to include inducing and maintaining remission, healing mucosa, improving quality of life, and preventing complications. These goals may be best achieved by using biologics early in the disease process. However, efficacy and toxicity need to be balanced. The availability of four biologic agents to treat IBD ultimately provides important choices for patients and physicians and provides new options if one biologic does not work or ceases to work. The purpose of this book is to provide a background on the four FDA-approved biologic therapies in IBD. In the appropriately selected patient, the benefits of biologic agents outweigh the risks. However, with exponential growth in this field and the availability of new agents, synthesizing all of these data becomes a daunting task for the busy practitioner in gastroenterology. This book will summarize clinical indications based on the pivotal clinical trials that supported their FDA approval. There is a review of mechanism of action of the four FDA-approved biologics and discussion of major safety issues. The intent of this book is to simplify some of these controversial areas and provide “one-stop shopping” for efficacy and safety data. The material covered in this book is by no means comprehensive; it is meant to be practical and concise.

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BIOLOGICS IN IBD

I hope that practitioners fi nd this book to be a useful tool to help in their decision making and beginning to address the use of biologics in conversations with their patients.

Scott E. Plevy, MD Associate Professor of Medicine, Microbiology and Immunology Division of Gastroenterology and Hepatology Inflammatory Bowel Disease Center University of North Carolina School of Medicine Chapel Hill, NC

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OAPN Biologic Therapy in Inflammatory Bowel Disease

The chronic inflammatory bowel diseases (IBDs) Crohn’s disease (CD) and ulcerative colitis (UC) affect more than 1 million Americans. The symptoms of CD can range from mild to severe, with a burden that can be bothersome to disabling. This disease results in inflammation of the ileum (the most distal part of the small intestine) and the colon; it can cause nutritional deficiencies, intestinal blockage, fistulas, and scarring and can result in the need for surgical procedures to correct complications, such as blockage or abscesses. In patients with severe CD, surgical resection is necessary. Illustrating the progressive nature of CD, over 20 years the cumulative probability of surgical intervention in CD is greater than 80%. Once surgery is necessary in an individual patient, the probability of a second and third operation becomes increasingly greater.1 For patients with CD who present with active signs and symptoms, the immediate therapeutic goal is to induce clinical remission as quickly as possible. However, once remission is induced, subsequent flares are the rule unless maintenance therapy is initiated and continued. This requires both effective induction and maintenance therapies that have appropriate risk–benefit profi les. Treatment efficacy of these therapies is measured through the Crohn’s Disease Activity Index (CDAI), which is a composite score of clinical symptoms (e.g., diarrhea, abdominal pain) and signs (e.g., abdominal mass, extraintestinal sites of inflammation, weight loss, and anemia) that has been well validated in numerous clinical trials of therapeutic interventions in CD (Table 1). 4

BIOLOGICS IN IBD

Table 1 Crohn’s Disease Activity Index (CDAI)2 Clinical or Laboratory Variable

Weighting Factor

Number of liquid or soft stools each day for 7 days

×2

Abdominal pain (graded from 0–3 on severity) each day for 7 days

×5

General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days

×7

Presence of complications*

×20

Taking Lomotil or opiates for diarrhea

×30

Presence of an abdominal mass (0 as none, 2 as questionable, 5 as defi nite)

×10

Absolute deviation of hematocrit from 47% in men and 42% in women

×6

Percentage deviation from standard weight

×1

*

One point each is added for each set of complications: • The presence of joint pains (arthralgia) or frank arthritis • Infl ammation of the iris or uveitis • Presence of erythema nodosum, pyoderma gangrenosum, or aphthous ulcers • Anal fi ssures, fi stulas, or abscesses • Other fi stulas • Fever (>100°F) during the previous week Remission of Crohn’s disease is defi ned as a CDAI < 150. Severe disease is defi ned as a value >450. Most major research studies on medications in Crohn’s disease defi ne response as a fall of the CDAI of >70 points. Adapted from Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–44.

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OAPN Inflammation in UC begins in the distal rectum and is uniform and continuous, with no intervening areas of normal mucosa (Table 2; Figs. 1 and 2). Clinically, patients with UC suffer from diarrhea, rectal bleeding, weight loss, and fever. Following a fi rst attack of UC, more than 70% of patients will experience relapses that follow a chronic intermittent or chronic continuous course. Patients with UC have an increased risk of carcinoma compared with the risk in the general population. The pharmacological management of UC is aimed at reducing colonic inflammation and controlling symptoms and consists mainly of anti-inflammatory and immunosuppressive therapies. When pharmacological management is not effective, proctocolectomy is the only alternative. Although advances in surgical therapy have provided more satisfactory outcomes for patients with UC, colectomy is associated with a variety of surgical complications (including abscess, anastomotic leaks, obstruction, chronic pouchitis, sexual dysfunction, female infertility, and poor functional results) that can result in repeated surgery, diminished quality of life, and death. Ultimately, colectomy is necessary in 25% to 40% of patients over the course of disease. IBD PATHOGENESIS IN A CLINICAL CONTEXT

Recent advances in understanding the pathogenesis of CD and UC have underpinned the development of new biologic therapies. We will briefly review advances in the understanding of the pathophysiology of IBD that forms the rationale for new biologic therapies. A simplistic paradigm for IBD pathogenesis is that in a genetically predisposed host, varied stimuli from the external environment trigger an overactive 6

BIOLOGICS IN IBD

Fig. 1 Clinical image: Crohn’s disease. (Reprinted with permission from Feldman M, Jain R. Braunwald E, ed. Atlas of internal medicine. Current Medicine, Inc. © 2000.)3

mucosal immune response, leading to chronic inflammatory changes in the intestine. Of the environmental factors that initiate and perpetuate mucosal inflammation in IBD, the one that has attracted the most recent attention is the role of the normal enteric microbial flora. The normal intestine is colonized with 10 to 100 microbes for every mammalian cell in the human body. The microbial flora is separated by a single layer of intestinal epithelial cells from the largest immune organ in the body—the mucosal (or intestinal) immune system. In most cases, this enormous and diverse biomass of microbes lives in peace with the mucosal immune system, but in IBD there is inappropriate activation of mucosal immune responses against the enteric microbial flora, initiating and perpetuating inflammation in the gut.6 7

OAPN

Fig. 2 Clinical image: ulcerative colitis. (Reprinted with permission from Friedman LS, Graeme-Cook F, Schapiro RH, et al., eds. Gastroenterology and hepatology: colon, rectum, and anus. Current Medicine, Inc. © 2000.) 4

Several defi ned immunologic abnormalities have been targeted for therapeutic intervention in human IBD. Intestinal inflammation in IBD is characterized by (1) secretion of cytokines and other inflammatory products from activated immune cells, which in turn leads to injury of the intestine and abnormal healing response; (2) activation of inflammatory T-cell populations, resulting in perpetuation of the inflammatory state; and (3) increased trafficking to the intestine of inflammatory leukocytes. For example, the cytokine tumor necrosis factor (TNF) is a pivotal inflammatory protein that is overproduced in IBD and contributes to 8

BIOLOGICS IN IBD

Table 2 Clinical Features in Crohn’s Disease and Ulcerative Colitis5 Ulcerative Colitis

Crohn’s Disease

Limited to the large intestine

Affects small and large intestines in 80% of cases

Rectal bleeding present in all cases

Rectal bleeding present in 75% to 85% of cases

No significant perianal sores

Significant perianal sores present in 25% to 35% of cases

Fistulas do not occur

Fistulas are common

Continuous, uniform infl ammation of intestinal mucosa

Intestinal lining appears patchy, with spots of ulceration and normal tissue (called “skips”)

Rectum involved

Rectum often spared

Loss of vascular markings

Aphthous ulcers

Diff use erythema

“Cobblestoning” from submucosal edema

Mucosal granularity (“wet sandpaper”)

Linear or serpiginous ulcers

Fistulas not seen

Fistulas

Normal-appearing terminal ileum

Ulceration of the terminal ileum

Adapted from Lee SD. The role of endoscopy in infl ammatory bowel disease. Medscape General Medicine 2001;3(4). © 2001 Medscape.

many aspects of the unregulated immune responses in the gut.7 As will be discussed, antibodies directed against TNF represent the prototypic biologic therapy in IBD and other chronic inflammatory disorders. 9

OAPN TNF Inhibition: Immunologic and Clinical Rationale Despite longstanding experience with conventional agents in IBD, numerous unmet medical needs remain. The majority of patients will not maintain remission with any conventional agent, and there is no clear evidence that even immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate fundamentally alter the natural course of the disease. Hence, there remains considerable interest in developing new biologic therapies that target inflammatory pathways critical to the pathogenesis of IBD. The prototypic biologic therapies are the anti-TNF agents. TNF is a potent, multifunctional mediator of inflammation and a number of inflammatory diseases, including CD, UC, rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. Overproduction of TNF plays an important role in the initiation and maintenance of a cascade of inflammatory events that affect multiple cell and tissue types, which in IBD leads to increased inflammation of the intestinal mucosa and tissue destruction. Since anti-TNF therapy with infl iximab was approved for the treatment of CD, there has been an expanding clinical data set regarding the safety and efficacy of various antiTNF strategies, including the use of chimeric (infl iximab) and fully human (adalimumab) monoclonal antibodies, and a pegylated Fab fragment (certolizumab pegol) (Fig. 3). “Top-Down” Versus “Step-Up” Strategies The prevailing therapeutic strategy in CD has been called a “step-up” approach; that is, treatment progresses from 5-aminosalicylic acid (5-ASA), antibiotics, and topical and/or 10

BIOLOGICS IN IBD

Cell membrane

TNFRI

TNFRII

Infliximab or adalimumab

sTNF TACE inhibitor

Etanercept

TACE

sTNF

proTNF

TACE

Fig. 3 Mechanism of action of anti-TNF agents. Etanercept, a fusion protein of TNFRII and the Fc region of IgG1, and the anti-TNF antibodies infl iximab and adalimumab, bind to TNF and prevent the molecule from interacting with its two receptors, TNFRI and TNFRII, thereby stopping signaling events. These large inhibitor molecules prevent binding of either sTNF or proTNF to their membrane receptor targets. TACE processes proTNF from the cell membrane to yield sTNF. Inhibitors of TACE block signaling by the soluble, but not membrane-bound, form of TNF. Abbreviations: proTNF, precursor TNF; sTNF, soluble TNF; TACE, TNF-converting enzyme; TNF, tumor necrosis factor; TNFRI, TNF receptor I; TNFRII, TNF receptor II. (Reprinted with permission from Macmillan Publishers, Ltd: Nature Clinical Practice Rheumatology. Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol 2008 Jun;4(6):300–9, © 2008.) 8

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OAPN systemic corticosteroids through immunomodulators and culminates with anti-TNF therapy. The premise is that conventional agents should be used to treat patients who have mild disease, whereas those who do not respond should be switched to more potent agents, which may be more effective but involve an increased need for monitoring, cost, and toxicity concerns. Despite conventional treatment, the course of CD often progresses to the development of complications (fibrosis, stricture, fistula, perforation) and the need for surgery. Accordingly, an alternative strategy, called “topdown” therapy, has been proposed. In this case, more potent agents are introduced early in the course of the disease to arrest inflammation, promote mucosal healing, and prevent complications that may over the long term result in structural damage and disability. A randomized controlled study compared top-down therapy with classic step-up therapy in 133 patients with CD with relatively early (40 weeks vs. 14 weeks; P = 0.001).21 The effect of infl iximab maintenance on hospitalizations, surgeries, and Crohn’s-related procedures was retrospectively evaluated in ACCENT II. The rate of hospitalization per 100 patients was significantly lower in those who received infl iximab maintenance than in those who received placebo (14% vs. 31%; P < 0.05). The mean number of inpatient surgeries and procedures per 100 patients in the infliximab maintenance group was reduced by >70% compared to placebo maintenance (P < 0.001).22 Study 4: Pediatric Crohn’s Disease

REACH was a multicenter, randomized, open-label study designed to evaluate the efficacy and safety of maintenance with infl iximab in children with moderately to severely active CD, defi ned as a pediatric CDAI of >30 points. A total of 112 patients underwent induction therapy with infl iximab 5 mg/ kg at weeks 0, 2, and 6. Patients responding at week 10 were randomized to receive maintenance with infl iximab 5 mg/kg 30

BIOLOGICS IN IBD

every 8 weeks or every 12 weeks through week 46 and were followed through week 54. At week 54, the rates of clinical response and remission were significantly higher in patients who received infliximab every 8 weeks (63.5% and 55.8%, respectively) than in patients who received infl iximab 5mg/kg every 12 weeks (33% and 23.5%, respectively; P ≤ 0.002 for each comparison). At week 10, 88.4% of patients responded to infl iximab, and 58.9% achieved clinical remission.23 Study 5: Ulcerative Colitis

The FDA based its approval for the treatment of UC on the results of two large-scale, randomized, double-blind, placebo-controlled, multicenter clinical studies, the 54-week ACT1 and the 30-week ACT2 trials (Table 13).20 The ACT trials were conducted and published simultaneously and investigated infl iximab in patients with active UC who had

Table 13 ACT1 and ACT2 Treatment

Response (week 8) (ACT1/ACT2)*

Remission (week 8) (ACT1/ACT2)

(Decrease in Mayo score 3 points and ≥30%)

(Mayo score ≤ 2)

Infl iximab 5 mg/kg

69%/64%

39%/34%

10 mg/kg

62%/69%

32%/28%

Placebo

37%/29%

15%/6%

* Primary endpoint. Response at week 8 in ACT1 and ACT2, infl iximab versus placebo: P < .001 for both comparisons. In both studies, patients who received infl iximab were more likely to have a clinical response at week 30 (P < .002 for all comparisons).

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OAPN failed to respond to steroids or other conventional treatments. The inclusion criteria in the studies were the same, except that in ACT2 25% of patients who had failed to respond to 5-ASA alone were enrolled. Otherwise, in both ACT1 and ACT2, inclusion criteria were active UC (defi ned as a Mayo Clinical Disease Activity [MCAI] score of 6 to 12) despite the use of steroids alone or in combination with 6-mercaptopurine or azathioprine. Endoscopic evidence of moderate or severe UC had to be demonstrated (Mayo endoscopic sub-score 2). Of the 728 patients enrolled in the two studies, 72% were treated with concomitant 5-ASA, 56% with corticosteroids, and 46% with 6-mercaptopurine–azathioprine. Doses of concomitant medications remained constant except for corticosteroids, which were tapered by 5 mg weekly after week 8 until a dose of 20 mg/day was reached. Thereafter, the dose was reduced by 2.5 mg weekly until discontinuation. The primary endpoint was clinical response at week 8, defi ned as a decrease in the Mayo score of at least 30% and at least 3 points, plus a decrease in the rectal bleeding score of at least 1 or a rectal bleeding score of 0 or 1. Secondary endpoints were remission at week 8, defi ned as a Mayo score of 2 or less with no individual sub-scores above 1, mucosal healing at week 8, endoscopic sub-score 0 or 1, and response, remission, and mucosal healing at weeks 30 and 54. In each study, 364 patients with moderate to severe active UC received either placebo or infl iximab 5 mg/kg intravenously at weeks 0, 2, and 6, and then every 8 weeks through week 46 in ACT1 or week 22 in ACT2. In ACT1, 69% of 32

BIOLOGICS IN IBD

patients who received 5 mg/kg infl iximab and 61% of those who received 10 mg/kg infl iximab had a clinical response at week 8, compared with 37% in the placebo group (P < .001 for both comparisons). In ACT2, 64% of patients receiving 5 mg/kg and 69% of those receiving 10 mg/kg had a clinical response at week 8, compared with 29% in the placebo group (P < .001 for both comparisons). In both studies, patients who received infl iximab were more likely to have a clinical response at week 30 (P < .002 for all comparisons). At 8, 30, and 54 weeks there were statistically significant differences in clinical remission in patients treated with infl iximab 5 or 10 mg/kg every 8 weeks compared with placebo. Overall, there was a remission rate in the infl iximab maintenance groups of 2 to 2.5 times that seen with placebo (P < .003 for all comparisons). Infl iximab maintenance allowed reductions in the median daily steroid dose. A higher percentage of patients demonstrated mucosal healing in the infl iximab maintenance group compared with placebo (P < .001 for all comparisons; at weeks 30 and 54, P ≤ .009 for all comparisons).20 Natalizumab (Tysabri ®) Table 14 gives details about natalizumab. Study 1

The phase II/III study by the Natalizumab Pan-European Study Group was a double-blind, placebo-controlled trial of natalizumab in 248 patients with moderate to severe CD (CDAI 220–450) (Table 15). Patients were randomly assigned to receive one of four treatments: two infusions 33

OAPN Table 14 Natalizumab Chemical properties

Recombinant humanized IgG4 κ monoclonal antibody. Natalizumab contains human framework regions and the complementarity determining regions of the murine antibody that binds the α4 integrin. Molecular weight 149 kDa.

Manufacture

Produced in murine myeloma cells

Stability

Lyophilized single-use vials are stable when stored refrigerated at 2–8°C. Once reconstituted, natalizumab must be used within 8 hours.

Pharmacokinetics

Following repeat intravenous administration of a 300-mg dose of natalizumab to patients with multiple sclerosis, the mean maximum observed curate serum concentration was 110 ± 52 mcg/ mL. The observed time to steady state was approximately 24 weeks after every 4 weeks of dosing. The mean half-life is 11 ± 4 days.

Drug interactions

The presence of persistent anti-natalizumab antibodies increases natalizumab clearance by approximately 3-fold. Given the side-effect profi le, natalizumab is recommended for use only as monotherapy.

of placebo, one infusion of 3 mg/kg natalizumab followed by placebo, two infusions of 3 mg/kg natalizumab, or two infusions of 6 mg/kg natalizumab given 4 weeks apart. The primary efficacy endpoint was clinical remission, defi ned by a CDAI < 150 at week 6, and clinical response, defi ned as a decrease in the CDAI of at least 70 points at the highest dose of natalizumab used. All other efficacy analyses were prespecified as secondary endpoints. The study did not attain its primary endpoint in that the group given two infusions of 6 mg/kg natalizumab did not have a 34

BIOLOGICS IN IBD

Table 15 Natalizumab Pan-European Study Treatment

Response (week 6)

Remission (week 6)*

(Decrease in CDAI by at least 70 points)

(CDAI < 150)

3 mg/kg

59%

29%

3 mg/kg q4 weeks (×2)

71%

44%

6 mg/kg q4 weeks (×2)

57%

31%

Placebo

38%

27%

Natalizumab

* Primary endpoint; P not significant at primary endpoint. However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple other time points.

significantly higher rate of clinical remission than the placebo group at week 6. However, both groups that had received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced significant improvement in response rates.21 Study 2

ENACT 1 was a phase III, international, randomized, doubleblind, placebo-controlled trial to assess induction of response in remission compared with placebo in patients with active CD treated with natalizumab (Table 16).22 The study population consisted of patients with moderately to severely active CD (CDAI 220–450). Patients (n = 905) were randomized 4:1 to natalizumab 300 mg or placebo, with one infusion every 4 weeks. The primary endpoints were clinical response at week 10, defi ned as a 70-point decrease from 35

OAPN Table 16 ENACT 1 Treatment

Response (10 weeks)*

Remission (10 weeks)

(Decrease in CDAI by at least 70 points)

(CDAI < 150)

300 mg q4 weeks

56%

37%

Placebo

49%

30%

Natalizumab

*Primary endpoint; P < .051 for response, P 7 mg/L showed significant improvement in the 400-mg group versus placebo).

4, and 8 (Table 20).26 Although patients treated with certolizumab pegol tended toward a clinical response, there were no significant differences between the treatment and placebo groups at the primary endpoint at week 12. In a post hoc analysis, it was observed that patients with high baseline CRP levels were more likely to respond. Specifically, among patients with a baseline CRP level above 10 mg/L, 53% of patients who received certolizumab 400 mg had a clinical response, compared with 18% of patients who received placebo.26 Study 2

PRECiSE 1 was a placebo-controlled phase III trial to evaluate the efficacy and tolerability of subcutaneous certolizumab pegol 400 mg for the induction and maintenance of clinical response and remission in patients 41

OAPN Table 21 PRECiSE 1: Phase III Treatment

Response (decrease in CDAI by at least 100 points) Week 6

Week 26

Weeks 6 and 26*

0, 2, 4, and q4 weeks

35%

37%

23%

Placebo

27%

27%

16%

Certolizumab pegol 400 mg on weeks

* Primary endpoint. In the overall population, response rates at week 6 were 35% in the certolizumab group and 27% in the placebo group (P < .02). At both weeks 6 and 26, the response rates were 23% and 16%, respectively (P < .02). At weeks 6 and 26, the rates of remission in the two groups did not differ significantly (P < .17).

with moderately and severely active CD (CDAI 220–450) (Table 21).27 Patients were initially randomized to receive placebo (n = 328) or certolizumab pegol (n = 331) at week 0 and continued receiving treatment for 26 weeks. Unlike the large maintenance studies of infl iximab or adalimumab, this was a placebo-controlled trial without an open-label induction phase. Patients were stratified according to baseline levels of CRP and were randomly assigned to receive either 400 mg certolizumab pegol or placebo subcutaneously at weeks 0, 2, and 4, and then every 4 weeks. Primary endpoints were induction of a response at week 6 (100-point decrease in CDAI) and response at both weeks 6 and 26. Results in the intention-to-treat population were similar to those observed in patients with raised CRP levels. A significant difference in response rate was observed as early as week 4 (29% versus 22%, certolizumab pegol versus 42

BIOLOGICS IN IBD

placebo; P < .05), and the difference in response between the two treatment arms was maintained at week 26 (35% versus 27%, respectively; P < .05). The primary endpoint of sustained clinical response at both weeks 6 and 26 was seen in 23% of certolizumab-treated patients and 16% of those in the placebo group (P < .05).27 Study 3

Akin to the pivotal maintenance studies of infl iximab and adalimumab in CD, PRECiSE 2 evaluated the efficacy and tolerability of certolizumab pegol for maintenance of clinical response following successful open-label induction in patients with active CD (CDAI 220–450) (Table 22).28 A total of 668 patients underwent open-label induction with certolizumab pegol 400 mg by subcutaneous injection at weeks 0, 2, and 4.

Table 22 PRECiSE 2: Phase III Treatment

Response (week 26)

Remission (week 26)

(Decrease in CDAI by at least 100 points)*

(CDAI < 150)

400 mg q4 weeks

63%

48%

Placebo

36%

29%

Certolizumab pegol

* Primary endpoint. Among patients with a response to open-label induction at week 6 (64%), response was maintained through week 26 in 63% of patients in the intention-to-treat population who were receiving certolizumab pegol (versus 36% receiving placebo, P < .001). Remission at week 26 was achieved in 48% of patients in the certolizumab group and in 29% in the placebo group (P < .001).

43

OAPN A total of 428 patients (64%) responded to induction (decrease in CDAI of at least 100 points from baseline) at week 6 and were randomized to placebo (n = 212) or certolizumab pegol 400 mg every 4 weeks (n = 216) for an additional 20 weeks. Efficacy was evaluated at week 26 using the same criteria for clinical response (decrease of 100 points or more from baseline CDAI). Clinical response was seen in 63% of patients in the certolizumab pegol group compared with 36% in the placebo group at week 26 (P < .001), and remission (CDAI < 150) was achieved by 48% of patients in the certolizumab pegol group compared with 29% in the placebo group (P < .001). In PRECiSE 2, efficacy was demonstrated in patients who were concomitantly taking and/or had previously been exposed to immunomodulators and TNF inhibitors.28 SAFETY OF BIOLOGIC THERAPIES FOR IBD

Biologic therapy with TNF inhibitors has radically changed the treatment of refractory IBD. The use of infl iximab for luminal and fistulizing CD has become an integral part in the management of these conditions.17,20,21,35,36 The more recent approval of infl iximab for UC has provided an alternative to surgery and hospitalization in patients with disease refractory to conventional therapies. Short- and long-term therapy courses with TNF inhibitors are well tolerated; however, the increased risk of infrequent but serious complications such as opportunistic infection, autoimmunity, infusion reactions, and lymphoma warrants sustained vigilance on the part of

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BIOLOGICS IN IBD

physicians and patients alike. The decision to initiate and continue therapy must be based on weighing the risk of complications versus benefit to the patient and is paramount in the ability of the gastroenterologist to use biologic therapies to their fullest potential (Table 23).37,38

Table 23 Summary of Adverse Events Associated with Biologic Therapy for IBD Common

Uncommon

Rare

TNF antagonists (infl iximab, adalimumab, certolizumab pegol)

Upper respiratory tract infection, headache, cough, arthralgias

Infusion reactions,* serious infections, injection site reactions, antibodies to infl iximab (~30%;† ~10% for infl iximab + immunomodulator), antibodies to certolizumab pegol (12%), antibodies to adalimumab (~1-3%; 0% for adalimumab + immunomodulator)

Reactivation of tuberculosis, opportunistic infections, lymphoma, demyelinating disorders, exacerbation of congestive heart failure

Natalizumab

Headache, nausea, nasopharyngitis

Antibodies to natalizumab (8-9%)

Progressive multifocal leukoencephalopathy

* Infl iximab only. † For infl iximab monotherapy without premedication with corticosteroids.

45

OAPN Serious Infection and Biologic Therapy TNF plays an important role in cellular immunity, especially granuloma formation in infectious diseases caused by intracellular microorganisms such as Mycobacterium tuberculosis.39 Large controlled trials of infliximab for patients with CD have reported rates of serious infections of up to 4.6%. Open-label trials and retrospective studies have revealed increased rates of opportunistic infections such as tuberculosis, listeriosis, and histoplasmosis.25 Infections, particularly those presenting atypically or subtly, are a serious adverse effect of anti-TNF biologics. Tuberculosis stands out in this respect. In vitro and animal models have shown a putative protective effect of TNF against tuberculosis. The unpredictable course of tuberculosis in patients on anti-TNF agents might represent a variable degree of immunosuppression. Current recommendations by the British Thoracic Society warrant a thorough clinical examination, history, a tuberculin skin test, and if indicated a chest x-ray to evaluate for tuberculosis exposure before initiating anti-TNF therapy. Even with such stringent screening, monitoring for tuberculosis during treatment is paramount. For high-risk patients, prophylactic treatment with isoniazid (INH) is recommended.40–42 It is important to establish a close liaison between the gastroenterologist and tuberculosis specialist when dealing with patients with latent infections or reactivation during the course of anti-TNF therapy.43 Reactivation of other intracellular infections such as histoplasmosis, coccidioidomycosis, and blastomycosis has also been described as a complication of all TNF inhibitors. As exposure to these fungal pathogens is ubiquitous in endemic areas, screening is not useful as it is for tuberculosis. Therefore, 46

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clinical vigilance is important when initiating a TNF inhibitor in patients who come from endemic regions. Malignancy In contrast to the established risk of colorectal cancer in CD and UC, the risk of hematologic malignancies is marginally increased if at all.44,45 An increased association of hematologic malignancies with anti-TNF agents has emerged as a cause for concern over the past few years.46,47 Although the results from hospital- and population-based studies have confl icted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk approximately 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against TNF are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Hepatosplenic T-cell lymphoma (HSTCL) is an extremely rare form of non-Hodgkin’s lymphoma reported most commonly in adolescent and young adult males. The background incidence of HSTCL is unknown: only approximately 150 documented cases have been published in the medical literature since it was fi rst recognized as a distinct lymphoma subtype in the early 1990s. The clinical course of the disease is extremely aggressive, with a fatal outcome in most patients. Eight post-marketing cases of HSTCL have been reported in adolescent and young adult patients with CD who were treated with infl iximab.46,48 The patients were all in the United States, ranged in age from 12 to 31 years, 47

OAPN and had received azathioprine or 6-mercaptopurine concomitantly with infl iximab. In patients for whom the duration of infl iximab use was reported, exposure ranged from one or two infusions to approximately 4 years of maintenance therapy. A causative role for infl iximab versus combination immunosuppression in the development of HSTCL in these eight patients has not been established. Immunogenicity Among TNF Inhibitors Infl iximab, a chimeric antibody, and certolizumab pegol, a humanized construct, contain mouse protein sequences (approximately 25% and 5%, respectively). Adalimumab is a fully human IgG1 antibody that does not contain mouse protein sequences. In a recent study, 61% of patients with CD who received infl iximab on an episodic basis developed antibodies to infl iximab (ATIs), contributing to a higher risk for infusion reactions and to a loss of response to treatment.49 However, data from the ACCENT trials suggest that ATIs did not affect clinical responses and that either scheduled maintenance or concomitant immunomodulators reduce the incidence of ATIs.18,21 Clinical trials in rheumatoid arthritis demonstrated that approximately 5% of patients receiving adalimumab developed low-titer anti-adalimumab antibodies (AAA) at least once during treatment.14,50 Thus, adalimumab, like other TNF antagonists, may be immunogenic and can result in the development of AAAs. However, there was no apparent correlation between the development of AAA and the occurrence of adverse events. In a phase 2 study, the cumulative incidence of antibodies to certolizumab pegol was 12.3% at 12 weeks in a cohort of 73 patients who 48

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had received three subcutaneous injections of certolizumab pegol 400 mg at 1-month intervals.30 Although concentrations of certolizumab pegol were lower in patients who were positive for certolizumab antibodies, efficacy did not appear to be affected by antibody status: 44% of antibody-negative patients responded to treatment by week 12, as did 44% of antibody-positive patients. The issue of immunogenicity with natalizumab has engendered much discussion, as it is approved for use only as a monotherapy. Eight percent and 9% of patients in ENACT-1 and ENACT-2, respectively, developed anti-natalizumab antibodies. Maintenance therapy with natalizumab does not appear to require concomitant administration of immunosuppressants for sustained efficacy in CD. Conclusion The concern about developing serious adverse effects to antiTNFα agents such as tuberculosis, lymphoma, congestive heart failure, and demyelination is fully warranted. However, we must realize that patients with chronic inflammatory disease are already at an increased risk for these complications as a sequela of their underlying chronic inflammatory state and/or concomitant use of immunosuppressive medications. Therefore, interpretations of the data on adverse events in patients on anti-TNF agents must correct for such baseline risk factors. Many clinical trials that evaluate the safety of a new biologic are in themselves subject to fault. Limited sample size, different patient populations, the varying natural course of the disease, and the duration of study might over- or underestimate the true toxicity associated with the agent.51 49

OAPN Given the tremendous efficacy that anti-TNF agents have had on the disease activity in IBD, they should continue to be safely used in the management of short- and long-term CD. However, close monitoring and efficient reporting of adverse effects should be encouraged. Developing an efficient multidisciplinary team composed of the surgeon, infectious disease specialist, and gastroenterologist will help reduce the risks associated with these agents while maximizing the benefit to the patient. REFERENCES 1. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 2003;18(Suppl 2):1–5. 2. Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–44. 3. Feldman M, Jain R, Braunwald E, eds. Atlas of internal medicine. Current Medicine, Inc., 2000. 4. Friedman LS, Graeme-Cook F, Schapiro RH, et al., eds. Gastroenterology and hepatology: colon, rectum, and anus. Current Medicine, Inc., 2001. 5. Lee SD. The role of endoscopy in inflammatory bowel disease. Medscape General Medicine 2001;3(4). 6. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol 2002;20:495–549. 7. Judge TA, Lichstenstein GR. Inflammatory bowel disease. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current diagnosis and treatment in gastroenterology, ed 2. New York: Lange Medical Books/McGraw Hill, 2003:108–30. 8. Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol 2008;4:300–9. 50

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9. Hommes D, et al. Digestive Disease Week 2006 (Abstract 749). 10. Haens GR, et al. Digestive Disease Week 2006 (Abstract 764). 11. Sandborn WJ, Colombel JF, Enns R, et al., International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–25. 12. Targan SR, et al. Digestive Disease Week 2006 (Abstract 747). 13. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924–33. 14. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–33. 15. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52–65. 16. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infl iximab: a randomized trial. Ann Intern Med 2007;146:829–38. 17. Targan SR, Hanauer SB, van Deventer SJ, 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. N Engl J Med 1997;337:1029–35. 18. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infl iximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. 19. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infl iximab in Crohn’s disease. Gastroenterology 2004;126:402–13. 51

OAPN 20. Present DH, Rutgeerts P, Targan S, et al. Infl iximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405. 21. Sands BE, Anderson FH, Bernstein CN, et al. Infl iximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350:876–85. 22. Lichtenstein GR, Yan S, Bala M, et al. Infl iximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology 2005;128:862–9. 23. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infl iximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007;132:863–73. 24. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infl iximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. 25. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30. 26. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32. 27. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–25. 28. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 2007;132:1672–83. 29. DeMasters, 2005 #23; Langer-Gould, 2005 #24; Van Assche, 2005 #22. PML is caused by reactivation of the JC polyoma 5, 2006 #21 30. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 2005;129: 807–18. 52

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31. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228–38. 32. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239–50. 33. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infl iximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–9. 34. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232–9. 35. McCabe RP, Woody JN, van Deventer SJ, et al. A multicenter trial of cA2 anti-TNF chimeric monoclonal antibody in patients with active Crohn’s disease [abstract]. Gastroenterology 1996;110(Suppl 4):A962. 36. Wolfe F, Michaud K. The risk of lymphoma among persons with rheumatoid arthritis in the United States: no association with anti-TNF therapy. European League Against Rheumatism [abstract]. JAMA 2006;296. 37. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50(6):1740–51. 38. Sandborn WJ. New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease. Rev Gastroenterol Disord 2005;5(1):10–8. 39. Amano K. Pulmonary infections in patients with rheumatoid arthritis who have received anti-TNF therapy. Intern Med 2006;45(17):991–2. 40. Cunnane G, Doran M, Bresnihan B. Infections and biological therapy in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2003;17(2):345–63. 53

OAPN 41. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005;60(10):800–5. 42. Stas P, D’Hoore A, Van Assche G, et al. Miliary tuberculosis following infl iximab therapy for Crohn disease: a case report and review of the literature. Acta Gastroenterol Belg 2006;69(2):217–20. 43. Ledingham J, Wilkinson C, Deighton C. British Thoracic Society (BTS) recommendations for assessing risk and managing tuberculosis in patients due to start anti-TNF-α treatments. Rheumatology (Oxford) 2005;44(10):1205–6. 44. Askling J, Brandt L, Lapidus A, et al. Risk of haematopoietic cancer in patients with inflammatory bowel disease. Gut 2005;54(5):617–22. 45. Friedman S. Cancer in Crohn’s disease. Gastroenterol Clin North Am 2006;35(3):621–39. 46. Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005;40(2):220–2. 47. Losco A, Gianelli U, Cassani B, et al. Epstein-Barr virusassociated lymphoma in Crohn’s disease. Inflamm Bowel Dis 2004;10(4):425–9. 48. Centocor Inc. Press release, May 22, 2006. 49. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infl iximab in Crohn’s disease. N Engl J Med 2003;348:601–8. 50. Adalimumab package insert. Abbott Laboratories, Chicago, IL, 2006. 51. Hyrich KL. Assessing the safety of biologic therapies in rheumatoid arthritis: the challenges of study design. J Rheumatol Suppl 2005;72:48–50. 54