Medscape Gastroenterology - Tysabri for Crohn's (from Medscape)
American College of Gastroenterology (ACG) 2008 Annual Scientific Meeting and Postgraduate Course
Ongoing Issues in Biologic Therapy for Crohn's Disease: An Expert Interview With Miguel D. Regueiro, MD
Posted 10/15/2008
Editor's Note:
For years, the control of disease-related symptoms was the primary goal of treatment with traditional nonbiologic therapy for Crohn's disease, as the use of these agents did not lead to important endpoints, such as a reduction in the need for surgery. However, the introduction of biologic agents onto the therapeutic landscape has helped evolve clinicians' approach to the medical management of patients with Crohn's disease: treatment goals now include the rapid induction of clinical remission; maintenance of steroid-free clinical remission; reduction in complications and in the need for hospitalization/surgical intervention; improvement in health-related quality of life; fistula healing; and decreased mortality rates. Currently, the approved therapeutic arsenal in biologic therapy for Crohn's disease includes agents targeting tumor necrosis factor (TNF)-alpha -- infliximab, a chimeric monoclonal antibody against TNF-alpha introduced about a decade ago; adalimumab, the fully human IgG1 anti-TNF-alpha monoclonal antibody approved in early 2007; and certolizumab pegol, a humanized anti-TNF Fab' monoclonal antibody fragment linked to polyethylene glycol approved in April 2008 -- as well as the first non-TNF-alpha inhibitor biologic compound -- natalizumab, a humanized monoclonal IgG4 antibody directed against alpha-4 integrin, which was approved in January 2008.
Against the backdrop of this evolving and complicated landscape, Medscape spoke with Miguel D. Regueiro, MD, Associate Professor of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Clinical Head and Co-Director, Inflammatory Bowel Disease Center; Associate Chief for Education and Director, Gastroenterology, Hepatology, and Nutrition Fellowship Training Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, to discuss the latest information on the use of biologic therapy for Crohn's disease, as framed by data presented at the American College of Gastroenterology (ACG) 2008 Annual Meeting and Postgraduate Course.
Medscape: Within the context of the changing and more complicated field of biologic therapy for Crohn's disease, both clinicians and patients are seeking guidance on how to optimize the efficacy of these agents, where these agents should be positioned in the current treatment paradigm, and how to address safety concerns. In your clinical experience, what are the major unmet needs currently facing the treating physician in terms of refining the role of biologics in the medical management of Crohn's disease?
Dr. Regueiro: There were several intriguing studies presented during this year's ACG meeting on the role of biologic therapy in Crohn's disease. Three important topics included: (1) the utility of concomitant immunomodulators with anti-TNF therapy; (2) the impact of top-down therapy for Crohn's disease; and (3) the efficacy of switching from one anti-TNF therapy to another due to loss of response.
Concomitant immunomodulator use with an anti-TNF agent has been a topic of great interest and confusion for the practicing gastroenterologist. Initially, it was determined that the use of concomitant immunomodulators improved the efficacy of anti-TNF-alpha therapy (specifically infliximab) by decreasing immunogenicity. Then, data emerged suggesting that the efficacy of TNF antagonists used as monotherapy was equivalent to combination therapy with TNF antagonists and immunomodulators.[1] Additionally, recent reports of very rare, but fatal, hepatosplenic T-cell lymphomas occurring in patients on combined anti-TNF/immunomodulator therapy lessened the enthusiasm for the use of concomitant immunomodulators in patients on TNF antagonists.[2] Two studies were presented during ACG 2008 that explored the role of concomitant immunomodulators in patients receiving anti-TNF-alpha therapy. The CARE (Crohn's patients treated with adalimumab: Results of a safety and Efficacy) study,[3] a multicenter, open-label European phase 3b trial, found that short-term efficacy (week 4 and sustained at week 20) was no different between patients who received adalimumab as monotherapy vs patients on concomitant corticosteroids or immunomodulators. A retrospective study from a major inflammatory bowel disease center confirmed these results, finding that concomitant immunomodulators or corticosteroids did not prolong the use of infliximab.[4] This means that the durability of response to infliximab and continued long-term efficacy were no different whether the patient was on infliximab monotherapy or in combination with immunomodulators.
Data from the pivotal SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease) trial, which compared efficacy outcomes in patients with Crohn's disease who were treated with azathioprine, infliximab, or combination azathioprine/infliximab as first-line therapy, were also presented during this year's ACG meeting.[5] This study addressed the role of the top-down strategy (earlier use of more aggressive therapy) as well as the utility of concomitant immunomodulators and biologic therapy. Patients eligible for the study included those who had not been on prior immunomodulators or biologic therapy and had only received previous treatment with corticosteroids and/or 5-aminosalicylates (conventional step-up strategy). Due to the nature of the inclusion criteria, patients had a short duration of Crohn's disease -- approximately 2 years -- before study entry. Week 26 steroid-free remission (Crohn's Disease Activity Index [CDAI] < 150) was the primary endpoint, with week 54 endoscopic remission as a second important endpoint. At week 26, patients receiving azathioprine in combination with infliximab had the highest rate of remission (57%) compared with infliximab alone (44%) or azathioprine alone (30%). Endoscopic remission rates paralleled clinical remission rates in that patients on combination therapy fared the best, while those receiving infliximab alone fared second best, and those on azathioprine alone fared the worst. Mucosal healing at week 26 was shown in 43.9% of the patients treated with infliximab + azathioprine, 30.1% of those treated with infliximab alone, and 16.5% of those treated with azathioprine alone. Important subgroup analysis included stratification of results by C-reactive protein level and evidence of ulcers on endoscopy at baseline. The most significant remission rates were observed in patients with baseline elevated C-reactive protein levels and baseline evidence of mucosal ulcerations on colonoscopy. The striking remission rate in this subgroup makes intuitive sense due to the fact that patients with the greatest inflammatory burden are most likely to respond to aggressive therapy.
Putting the SONIC data into the context of clinical practice is important. These data suggest that patients with Crohn's disease, especially those with elevated C-reactive protein levels and/or active inflammatory disease on colonoscopy/endoscopy, benefit most from primary treatment with infliximab. The rates of remission are even higher when they receive combined treatment with azathioprine. I think it is clear from these data that the role of azathioprine monotherapy for severe inflammatory or penetrating Crohn's disease is limited. The main question will be whether to use infliximab as monotherapy or in combination with an immunomodulator. These data show a statistically significant benefit for combination therapy over infliximab monotherapy, but one must take into account the risk-benefit ratio. It is my opinion that patients with especially aggressive disease who have not previously received immunomodulators or biologics -- that is, those with multiple fistulas and/or recurrent surgery with recurrent inflammatory disease -- may be a subgroup to target for the use of combination therapy, at least for the first 6 months, and to then decide whether to use infliximab monotherapy thereafter.
Finally, 3 studies presented during ACG 2008 evaluated the utility of using a second anti-TNF agent after loss of response or primary nonresponse to the first. Data from the CARE study showed that at week 20, 36% of primary nonresponders and 40% of patients who had lost response to infliximab had a response to adalimumab.[6] A systematic review and meta-analysis confirmed these findings.[7] Similarly, in the WELCOME (26-Week Open-Label Trial Evaluating the Clinical Benefit and Tolerability of Certolizumab Pegol Induction and Maintenance in Patients Suffering From Crohn's Disease With Prior Loss of Response or Intolerance to Infliximab) study,[8] certolizumab pegol was found to be effective in regaining response lost to infliximab; whether patients were on concomitant immunomodulators or corticosteroids did not have an impact on outcome.
Medscape: The availability of biologic agents has, in a way, "reset the bar" for what may be considered an acceptable symptomatic response to treatment in Crohn's disease. This may allow for the possibility of altering the natural history of the disease. In this setting, can you discuss some of the key data presented at this year's ACG meeting that looked beyond maintenance of remission and to the more aggressive endpoints that may potentially be achieved with these biologic agents, such as steroid-free remission, healing of fistulas, reduction in hospitalizations/surgery, or improvement in health-related quality of life?
Dr. Regueiro: There were several studies presented during this year's meeting that evaluated the impact of biologic therapy on the natural course of Crohn's disease. Indeed, a definitive study on postoperative Crohn's disease treatment was presented at ACG 2008. This study evaluated the efficacy of infliximab in preventing postoperative endoscopic recurrence 1 year after surgery. The results of this study showed a highly statistically significant benefit in the infliximab (compared with placebo)-treated patients in terms of prevention of endoscopic, histologic, and clinical recurrence 1 year after resective surgery for Crohn's disease.[9] Although additional investigation is required, anti-TNF prophylaxis after surgery should be considered for Crohn's disease patients with a high risk for postoperative recurrence (eg, those with penetrating disease or recurrent resective surgery).
Several other important studies also explored the role of biologic agents in decreasing surgical rates in Crohn's disease and in achieving mucosal healing, as well as their efficacy in treating Crohn's disease of the pouch. A study evaluating the effects of adalimumab maintenance therapy on major Crohn's disease-related surgery in patients who participated in the CHARM (Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) trial revealed that subjects who received adalimumab every other week or weekly vs placebo had a significantly decreased risk for Crohn's disease-related surgery and surgical hospitalization.[10] The MUSIC (Endoscopic Mucosal Improvement in Patients With Active Crohn's Disease Treated With Certolizumab Pegol) clinical trial demonstrated the efficacy of certolizumab pegol in reducing endoscopic and histologic lesions in severe Crohn's disease.[11] Finally, a small open-label study on Crohn's disease of the ileal pouch found that adalimumab was able to effectively treat active disease in the majority of these patients.[12]
Medscape: Let's turn our attention to the benefit-risk profile of these agents. Given the accumulating clinical experience with the biologics, what can you tell us about the overall safety of these agents in Crohn's disease, and how do data presented at ACG 2008 help us address/contextualize safety concerns?
Dr. Regueiro: Generally, the use of biologic therapy for the treatment of Crohn's disease has been well tolerated and safe. Nonetheless, there are rare but serious side effects associated with the use of biologic response modifiers. These safety concerns include opportunistic infections (eg, histoplasmosis and tuberculosis); malignancy, specifically lymphoma; and neurologic complications, including demyelinating diseases and progressive multifocal leukoencephalopathy (PML). The use of biologics in pregnancy has also been evaluated. In general, data from this year's ACG meeting support prior reports, and results are consistent with previously published information.
An update[13] from the TREAT (Crohn's Therapy Resource, Evaluation and Assessment Tool) registry, which was established to evaluate the long-term safety of infliximab and other therapies in Crohn's disease, was presented. The registry has enrolled over 5000 patients with Crohn's disease, approximately half of whom have received infliximab and half of whom have received other non-TNF-alpha treatments only. After 24,575 patient-years of follow-up, the rates of mortality, lymphoma, and opportunistic infection remain quite low and consistent with prior reports. Similarly, integrated safety data collected from the certolizumab pegol Crohn's disease development program, including a total exposure to certolizumab of over 2160 patient-years, revealed no cases of lymphoma and very rare opportunistic infections, consistent with data from previous reports.[14] Another study presented during ACG 2008 examined the safety of natalizumab in pregnancy[15]; to date, no significant adverse outcomes have been reported in patients exposed to natalizumab during pregnancy. Additionally, there was a study reported on pregnancy outcomes in women with rheumatoid arthritis exposed to adalimumab.[16] There were no concerns raised regarding increased risks for adverse pregnancy outcomes associated with early pregnancy exposure to adalimumab in the treatment of rheumatoid arthritis. Although this study did not evaluate Crohn's disease patients, the results will likely hold true for the pregnant patient with inflammatory bowel disease on adalimumab as well.
Medscape: In the last 1-2 years, we've had 3 new biologic agents approved for the treatment of Crohn's disease: adalimumab, certolizumab pegol, and natalizumab. Can you briefly discuss what you consider to be the most clinically relevant data presented on each of these agents at this year's meeting?
Dr. Regueiro: As mentioned, many abstracts focusing on biologic therapy for Crohn's disease were presented during this year's meeting, and a number of them specifically addressed these "newer agents" (ie, adalimumab, certolizumab pegol, and natalizumab). Additional data were presented from previous large studies involving these agents as well as findings from new clinical trials.
The role of adalimumab in the treatment of fistulas in patients with Crohn's disease was further discussed during ACG 2008. Indeed, 2 studies reported that adalimumab was effective in the healing of fistulas in patients with Crohn's disease. In the CHOICE (Clinical Study of the Human Antibody Adalimumab in Crohn's Patients Who Failed Prior Infliximab: Collection of Safety and Efficacy) trial, adalimumab was shown to be effective in healing fistulas in patients who were primary nonresponders to infliximab.[17] And a long-term follow-up of patients from CHARM (an additional 2 years of treatment in an open-label extension study) found that the rates of fistula healing were sustained after 3 years of adalimumab therapy.[18]
Long-term extension data from the PRECiSE (Pegylated Antibody Fragment Evaluation in Crohn's Disease Safety and Efficacy) studies demonstrated that there was sustainable efficacy (defined as remission) out to 2.5 years in patients who received 400 mg certolizumab pegol every 4 weeks.[19] In addition to showing prolonged and sustained efficacy, there were no additional safety signals identified. These data support a long-term maintenance benefit for certolizumab pegol without apparent attenuation of response.
Interesting data were also presented comparing the cost-effectiveness of natalizumab with other anti-TNF agents in patients with Crohn's disease who had failed to respond to previous treatment with TNF antagonists.[20] This study used mathematical modeling to determine a cost-effectiveness analysis in the treatment of patients with moderate-to-severe Crohn's disease. The model projected that natalizumab had the best cost-efficacy ratio (lowest cost to highest efficacy) among comparator biologics for patients who had failed to respond to prior anti-TNF-alpha therapy.
Medscape: What, in your clinical experience, are the major factors to consider in guiding patient selection in order to optimize the use of biologics in Crohn's disease?
Dr. Regueiro: Positioning biologic therapy in the treatment of Crohn's disease is still a bit of a challenge. On the basis of data presented at this year's ACG meeting and reported over the past few years, it appears that most patients with Crohn's disease will develop complications of their disease (ie, strictures and fistulas) that ultimately require surgery. Whether immunomodulators alone will have an impact on the inevitable worsening course of disease is not entirely clear. It is my opinion that patients who present with new-onset Crohn's disease complicated by internal or external fistulas should be considered for anti-TNF-alpha therapy.
Similarly, given that 70% to 80% of patients[21] ultimately require surgery, and many require more than one surgery, defining the most appropriate postoperative strategy has been debated. Emerging data suggest that patients with a high risk (eg, penetrating disease, multiple surgeries, smokers) for postoperative Crohn's disease recurrence have a very high rate of recurrence. As mentioned previously, data presented during this year's ACG meeting revealed the efficacy of infliximab (compared with placebo) in preventing postoperative endoscopic recurrence 1 year after surgery.[9] Although it is too early to make any definitive statement, there may be a role for biologic therapy as a "top-down postoperative" strategy for these high-risk patients.
Currently, the "first-line biologic therapy" is one that blocks TNF-alpha. Patients who are primary nonresponders to a TNF antagonist or who are secondary nonresponders have limited options. Data presented over the last several years have demonstrated efficacy with natalizumab in this setting. The rate of response and remission for patients who had been previously treated with anti-TNF-alpha therapy and then received natalizumab is on the order of 40% to 60%.[22,23]
The rare reports of PML have tainted clinicians' enthusiasm in regard to natalizumab. However, when considering the low relative risk of PML (5 cases reported to date) and the lack of other safety signals, it is my opinion that natalizumab should be considered in primary or secondary nonresponders to anti-TNF therapy.
This activity is supported by an independent educational grant from Abbott.
