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CME

Biologic Therapy for Inflammatory Bowel Disease

  • Authors: Uma Mahadevan, MD
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is intended for primary care physicians and physicians specializing in gastroenterology, internal medicine, and hepatology, as well as other healthcare professionals, conducting research or providing care for individuals with diseases of the gastrointestinal tract and liver.

The goal of this activity is to define current and relevant treatment strategies and clinical protocols for the prevention, diagnosis, and management of diseases of the gastrointestinal tract and liver; to enhance the care of patients with these diseases; and to support quality clinical practice of healthcare professionals involved in their care.

Upon completion of this activity, participants should be able to:

  1. Describe current and emerging strategies in biologic therapy for inflammatory bowel disease, with emphasis on anti-TNF therapies.
  2. Explore new and emerging applications of nonbiologic therapies for inflammatory bowel disease, including novel applications of 5-ASA/mesalamine.


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Author(s)

  • Uma Mahadevan, MD

    Assistant Professor, University of California, San Francisco, California; Director of Clinical Research, UCSF Inflammatory Bowel Disease Center, San Francisco, California

    Disclosures

    Disclosure: Uma Mahadevan, MD, has disclosed that she has served as an advisor or consultant for Abbott, UCB, Centocor, and Elan. Dr. Mahadevan has also disclosed that she has served as a speaker for Prometheus, Procter & Gamble, and Axcan.


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CME

Biologic Therapy for Inflammatory Bowel Disease

Authors: Uma Mahadevan, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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Introduction

Potential options for the medical management of inflammatory bowel disease (IBD), particularly Crohn's disease, are increasing at an unprecedented rate. In addition to infliximab, second-generation anti-tumor necrosis factor (TNF)-alpha agents such as adalimumab* and certolizumab* have shown efficacy in the induction and maintenance of remission in patients with Crohn's disease. Optimizing these medications with respect to timing of initiating therapy and use of concomitant immunomodulators is a topic of great debate. Other potential agents include antibodies targeting alternate mechanisms of inflammation, such as natalizumab* and visilizumab.* The excitement over these emerging agents is tempered by the potential toxicity, some of which is unique to each class of drug. This report summarizes the major data on biologic therapy as presented during Digestive Diseases Week (DDW) 2006 in the context of the clinical trial setting (which was limited to Crohn's disease), optimizing therapy, and safety.

Clinical Trials of Biologic Agents

Infliximab, a chimeric monoclonal antibody to TNF-alpha, has demonstrated efficacy in the induction[1] and maintenance[2] of remission in Crohn's disease and ulcerative colitis.[3] Adalimumab, a fully human monoclonal antibody to TNF-alpha, has demonstrated efficacy for the induction of remission[4] in anti-TNF-alpha-naive patients in the CLASSIC (CLinical assessment of Adalimumab Safety and efficacy Studied as an Induction therapy in Crohn's) I trial, and for reclaiming response in patients who have lost response or become intolerant to infliximab.[5] Patients from CLASSIC I were then followed in the CLASSIC II trial, presented at United European Gastroenterology Week in October 2005. This study demonstrated that adalimumab 40 mg weekly or every other week was effective in maintaining remission at 1 year. The CHARM (Crohn's trial of the fully human antibody adalimumab for remission maintenance) study,[6] presented during this year's DDW meeting, was a double-blind, placebo-controlled trial designed to determine the efficacy and safety of adalimumab 40 mg weekly vs every other week for maintenance of clinical remission in patients with moderate-to-severe Crohn's disease. Patients may have had prior exposure to anti-TNF-alpha agents. All 854 patients received adalimumab 80 mg at week 0, and 40 mg at week 2. At week 4, they were stratified by clinical response (defined as a decrease of >70 points [responders] on the Crohn's Disease Activity Index [CDAI]) and received adalimumab 40 mg every other week, 40 mg weekly, or placebo. The co-primary endpoints were the rate of clinical remission (CDAI < 150) at week 26 and week 56 among responders. There were 499 randomized responders, 279 randomized nonresponders, and 76 patients who discontinued the study prior to randomization. The rates of clinical remission among responders for placebo, adalimumab 40 mg every other week, and adalimumab 40 mg weekly were 17%, 40%, and 47% at week 26, respectively; and 12%, 36%, and 41% at week 56, respectively. The week 26 and 56 remission rates for both adalimumab groups were statistically higher than that achieved with placebo (P < .001). The rates of steroid-free remission and fistula healing were also significantly higher in the adalimumab group than placebo. This study demonstrated that adalimumab was effective for maintaining remission, reducing steroid use, and healing fistulas in patients with moderate-to-severe Crohn's disease, regardless of prior anti-TNF exposure.

In a separate study, Hinojosa and colleagues[7] assessed the safety and efficacy of adalimumab in the treatment of patients with fistulizing Crohn's disease. In this open-label multicenter study, 48 patients with prior loss of response or intolerance to infliximab received 160 mg of adalimumab at week 0, 80 mg at week 2, and then 40 mg every other week. At week 4, 41% of patients had a response (> 50% closure of their fistulas) and 23% had complete closure of fistulas. The perianal disease activity score decreased from a mean of 10.5 to 5.4. The ability to maintain response is being studied in this ongoing trial.

Certolizumab, a polyethylene-glycolated Fab' fragment of anti-TNF-alpha, is also known as CDP870. A recent phase 2 trial[8] did not demonstrate that certolizumab 400 mg monthly was more effective than placebo for induction of response in patients with moderate-to-severe Crohn's disease at the primary endpoint of week 12. This study had a very high placebo response rate. When patients with an elevated C-reactive protein (CRP) level were analyzed separately, there was a significant benefit of certolizumab vs placebo. During DDW 2006, Sandborn and colleagues[9] presented the results of the PRECiSE (Pegylated antibody fRagment Evaluation in Crohn's dIsease Safety and Efficacy) I trial, in which certolizumab demonstrated significant efficacy over placebo in patients with active Crohn's disease, regardless of CRP levels. In this phase 3, randomized, double-blind, placebo-controlled trial, patients with moderate-to-severe Crohn's disease were randomized to receive certolizumab 400 mg or placebo at weeks 0, 2, and 4 and then every 4 weeks up to week 24. Patients were stratified by CRP level (< or ≥ 10 mg/L) and immunosuppressant and corticosteroid use. Patients could have prior exposure to infliximab. The co-primary endpoints were the percentages of patients with clinical response (CDAI decrease ≥ 100) at week 6 and at weeks 6 and 26. There were 331 patients in the certolizumab group and 329 in the placebo group. At week 6, 26.8% of placebo patients and 35.2% of certolizumab-treated patients had a clinical response (P < .05). Sixteen percent of placebo and 23% of certolizumab patients (P < .05) had a clinical response at both weeks 6 and 26. This benefit of certolizumab for induction and sustained response was significant, regardless of baseline CRP levels and immunosuppressant use.

Natalizumab, a humanized monoclonal antibody to alpha-4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue. Results of 2 controlled trials evaluating natalizumab as induction and maintenance therapy in patients with active Crohn's disease were recently published.[10] For induction of response, in the ENACT (Evaluation of Natalizumab As Continuous Therapy)-1 trial, patients in the natalizumab and placebo groups had similar rates of response (CDAI decrease > 70 points) at week 10. However, natalizumab-treated patients with a high CRP level had a significantly better response than placebo patients at week 10. Patients who completed ENACT-1 and had a response at week 10 (n = 339) were randomized to natalizumab 300 mg intravenously every month or placebo. In this maintenance trial, ENACT-2, responders randomized to natalizumab maintenance had higher rates of sustained response and remission than those randomized to placebo at week 36. During DDW 2006, the 2-year results from this study were reported.[11] The 87 patients who completed ENACT-2 and who were in remission and had uninterrupted natalizumab therapy were enrolled in this open-label extension. At 1 year, 86% of these subjects remained in remission (2 years from initial enrollment in ENACT-1). There was very low immunogenicity and a low incidence of serious adverse events. Because the initial induction trial did not meet its primary endpoint, a second induction trial, ENCORE (Efficacy of Natalizumab in CrOhn's disease Response and REmission), was initiated.[12] The primary endpoint was response (CDAI decrease by 70 points) at week 8, sustained at week 12, in patients with moderate-to-severe Crohn's disease, and elevated CRP level. Patients (n = 509) were randomized to either natalizumab 300 mg monthly or placebo. At weeks 8 and 12, 48% of natalizumab-treated patients vs 32% of placebo-treated patients had a response (P < .001) and 26% of natalizumab-treated vs 16% of placebo-treated patients had clinical remission (P = .002). Among patients with severe disease (CDAI > 330), 51% of the natalizumab-treated patients vs 27% of those in the placebo group had a response at weeks 8 and 12 (P = .002). There were few serious adverse events and the rate of antibody formation was 9.5%.

Visilizumab is a humanized antibody to CD3, an invariant part of the T-cell receptor complex. Previous studies of visilizumab have demonstrated benefit in severe, steroid-refractory ulcerative colitis.[13] During this year's DDW meeting, a phase 1 study evaluating visilizumab in patients with Crohn's disease was presented.[14] Fourteen patients with moderate-to-severe Crohn's disease received visilizumab 10 mcg/kg intravenously on 2 consecutive days. All but 1 patient had prior infliximab exposure. Nearly 70% of patients had a response (decrease in CDAI of > 100 points) at day 59 and more than 35% of patients were in remission at day 89. Although open-label, the reduction in CRP level, steroid dose, and CDAI score seen in this study suggests that there was some activity of the agent in patients with Crohn's disease. Cytokine release syndrome was seen in the majority of patients, as expected from the experience in ulcerative colitis.

Optimizing Therapy

At this time, infliximab is the only biologic agent approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe Crohn's disease. However, debate has arisen regarding the appropriate timing of biologic therapy. Should a step-up approach be used as practiced currently, in which corticosteroids and immunomodulators are tried before infliximab, or should a top-down approach be used, in which infliximab is started prior to the initial dose of corticosteroids?

In a study presented at DDW 2006 by Hommes and colleagues,[15] patients with newly diagnosed active Crohn's disease were randomized to receive step-up therapy (n = 64) with budesonide or corticosteroids with a standardized taper schedule for 2 consecutive flares and then azathioprine or methotrexate with the third course of steroids, or to receive top-down therapy (n = 65) with infliximab at 0, 2, and 6 weeks along with azathioprine 2-2.5 mg/kg. Subsequent flares of Crohn's disease were treated with episodic infliximab dosing and with steroid therapy when this failed. Remission was defined as CDAI < 150, no surgical resection, and no corticosteroids. At week 14, 64% of top-down patients were in remission vs 33% of step-up patients (P <. 01). At 12 months, 62% of top-down patients were in remission vs 42% of step-up patients (P < .05). At 12 months, 100% of the top-down and 74% of the step-up patients were on immunosuppressants. At 24 months, 57% of the top-down and 50% of the step-up groups were in remission -- this was not statistically significant. The percentage of patients not failing therapy at 2 years was 42% for the top-down group and 14% for the step-up group (P =. 018). In this study, the top-down approach, or early use of infliximab, was superior to the step-up approach with respect to induction and maintenance of steroid-free remission, mucosal healing on colonoscopy, and reduction in corticosteroid exposure, while not having a significant increase in the rate of adverse events.

Another issue that is of great interest is the need to continue immunosuppressants once infliximab has been started. Prior studies have suggested that continuing immunosuppressants reduces the immunogenic response,[16] thereby reducing the rate of infusion reactions and loss of response. In a study by van Assche and colleagues[17] reported during DDW 2006, 80 patients received infliximab plus azathioprine/6-mercaptopurine for 6 months. At that time they were randomized to receive infliximab maintenance every 8 weeks with or without immunomodulators. The study reported no difference in the proportion of patients who required a change in dosing interval, experienced a loss of response, or experienced an adverse event based on use of immunomodulators. However, there was a significantly higher infliximab trough level in patients on immunomodulators, and an infliximab trough level of > 2 mg/L was associated with durable response. Two retrospective studies had contradictory conclusions on this point. A study from the University of Pittsburgh[18] found that 50% of Crohn's disease patients receiving long-term infliximab required an increase in dose or a decrease in dosing interval. Concomitant immunomodulators and an every-8-week dosing schedule did not prevent the need for escalated infliximab dosing. However, a retrospective chart review by Rudolph and colleagues[19] noted that concurrent immunomodulators started more than 3 months prior to initiating infliximab may increase the durability of maintenance infliximab infusions. With respect to adalimumab, the CLASSIC II study did not find that immunosuppressant use affected overall response rates[20]; however, this was a small study and further data are needed.

Safety

The dominant theme emerging from DDW 2006 was the issue of safety with the use of immunomodulators and biologic therapy. Women with IBD on immunomodulators[21] and infliximab[22] had higher rates of abnormal Pap smears and cervical dysplasia compared with normal controls and women with IBD not on these medications, suggesting that these patients should have more frequent surveillance. The rate of skin warts and genital herpes simplex was also significantly higher among patients on azathioprine vs patients not on these agents.[23]

A case-control study[24] from the Mayo Clinic, Rochester, Minnesota, found that patients with IBD had higher rates of opportunistic infections than did normal controls. Although this study did not control for disease severity, risk factors for opportunistic infections included the use of immunomodulators, biologic therapy, corticosteroids, and combination therapy with these agents. A decision analysis model[25] found that the use of infliximab was associated with a substantial clinical benefit with respect to remission rates, reduction in need for surgery, and quality-adjusted life-years. However, there was an associated increase in the risk of lymphoma and death. The TREAT (the Crohn's disease Therapy, Resource, Evaluation, and Assessment Tool) registry, a prospective registry[26] of 6273 patients (3272 on infliximab and 3001 not on infliximab) did not find an increase in mortality or lymphoma among patients on infliximab therapy compared with those not exposed to infliximab. Infliximab-treated patients had an increased risk for serious infection (odds ratio = 1.90, confidence interval 1.34-2.70), but a Cox proportional hazards analysis suggested that this might be associated with corticosteroid and narcotic use.

With respect to other biologic therapies, the trials involving adalimumab and certolizumab did not show an increase in adverse events over what is expected for this class of drugs. Visilizumab is associated with cytokine release syndrome with infusion, but this is usually readily treatable with hydration and meperidine. Natalizumab had an excellent safety profile in its clinical trials, but 3 patients developed progressive multifocal leukoencephalopathy (PML), a debilitating and often fatal demyelinating disease of the brain.[27] After analyzing 3826 patients exposed to the drug (all patients from clinical trials and a few multiple sclerosis patients receiving the drug after FDA approval), no further cases were found, providing an estimated risk of PML of 1/1000 (95% confidence intervals 0.2-2.8 per 1000).

Concluding Remarks

Large controlled trials have demonstrated that adalimumab, certolizumab, and natalizumab are effective for induction and maintenance of response and remission in patients with moderate-to-severe Crohn's disease. Infliximab remains effective for long-term maintenance therapy, and concomitant immunomodulators may not be necessary long-term to maintain response. Visilizumab, still in the early stages of development, may have an effect in Crohn's disease as well.

Patients with IBD have received tremendous benefit from the recent advances in medical therapy. The value of reduced steroid use, avoidance of hospitalizations and surgeries, and prolonged symptom-free intervals on quality of life is immeasurable. However, these benefits from advances in therapy must be weighed against the potential risks of immunomodulation. Patients should be vigilantly monitored for the development of infection, dysplasia, and lymphoma. The potential benefit to maintaining response to biologic therapy has to be weighed against the risk of combined immunosuppression for infection and malignancy. Strategies to reduce overall immunosuppression, such as stopping azathioprine/6-mercaptopurine in patients on maintenance infliximab after 6 months, will need to be seriously considered. We look forward to future studies and registry data that will help guide management of these complex patients.

Supported by an independent educational grant from Abbott, Novartis, and Shire.

*The US Food and Drug Administration has not approved this medication for this use.

References

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