Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME

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1 Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME Uma Mahadevan-Velayos, MD Supported by independent educational grants from View this activity online at: medscape.org/column/crohns

2 Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME This article is a CME certified activity. To earn credit for this activity visit: medscape.org/column/crohns CME Released: 01/05/2011 Valid for credit through 01/05/2012 Target Audience This activity is intended for gastroenterologists and other healthcare professionals, including internal medicine specialists and family practitioners/primary care physicians, conducting research and/or providing care for individuals with Crohn s disease. Goal The goal of this activity is to educate physicians about the evolving role of biologic therapy in the treatment of Crohn s disease, as based on the latest/current best evidence in the literature. Learning Objectives Upon completion of this activity, participants will be able to: 1. Differentiate the heterogeneity in clinical presentation and manifestation of Crohn s disease 2. Compare the latest clinical data demonstrating the efficacy and safety of biologic agents for the induction and maintenance of clinical remission in Crohn s disease, including benefits beyond remission Credits Available Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Statements The AGA Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AGA Institute designates this educational activity for a maximum of 0.50 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Pg.2

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4 Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME Author(s) Uma Mahadevan-Velayos, MD Associate Professor of Clinical Medicine; Director of Clinical Research, University of California San Francisco Center for Colitis and Crohn s Disease, San Francisco, California Disclosure: Uma Mahadevan-Velayos, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Centocor, Inc.; Abbott Laboratories; UCB Pharma, Inc.; Elan Pharmaceuticals, Inc.; Takeda Pharmaceuticals North America, Inc. Dr. Mahadevan-Velayos does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the US Food and Drug Administration (FDA) for use in the United States. Dr. Mahadevan-Velayos does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Editor(s) Maria L. Gaiso, PhD Scientific Director, Medscape, LLC Maria L. Gaiso, PhD, has disclosed no relevant financial relationships. CONTENT: Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME Uma Mahadevan-Velayos, MD Posted: 01/05/2011 CME Released: 01/05/2011; Valid for credit through 01/05/2012 Introduction The approach to the standard of care for the management of Crohn s disease has changed dramatically over the past 10 years with the advent of biologic therapy. Although in the past therapy was predicated on control of symptoms, the goals of care have now changed to encompass sustained corticosteroid-free remission, mucosal healing, and a decrease in surgeries and hospitalizations. Biologic therapy, as of today, comprises either anti-tumor necrosis factor (TNF)-alpha agents (the chimeric IgG1 monoclonal antibody, infliximab; the fully human IgG1 monoclonal antibody, adalimumab; and the humanized antibody Fab fragment, certolizumab pegol) or anti-alpha-4 integrin agents (the humanized monoclonal antibody, natalizumab). Infliximab is approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy, and for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. [1] Adalimumab is approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn s disease who have had an inadequate response to conventional therapy, as well as for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. [2] Certolizumab pegol is approved for reducing signs and symptoms of Crohn s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. [3] Natalizumab is approved for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn s disease therapies and inhibitors of TNF-alpha. [4] With the more aggressive course of care come questions and concerns about the true benefit and safety of long-term biologic therapy. Although these questions are not fully answered at this time, what we do know about which patient will benefit from biologic therapy and how best to use these agents to increase efficacy and reduce adverse events is addressed in this clinical review. Pg.4

5 medscape.org/column/crohns Who Should Receive Biologic Therapy? When the first biologic agent was approved for use in Crohn s disease in 1997, biologic therapy was considered a last resort, when all other conventional therapies had failed. This was known as the step-up approach, where patients may start with conventional agents such as 5-aminosalicylates, antibiotics, or corticosteroids, move up to immunomodulators such as azathioprine/6-mercaptopurine or methotrexate, and only then consider anti-tnf-alpha therapy. This is not the case today, where a top-down approach is increasingly being used. In this strategy, the biologic agent may be the first therapy introduced in the appropriate patient. Although not all patients are candidates for anti-tnf-alpha therapy, those who are, will be best served with timely and judicious use of these agents to prevent complications rather than temporize them when they occur. So who is a candidate? Any patient with moderate-to-severe Crohn s disease is a candidate for biologic therapy, regardless of how long they have had disease -- 1 month or 10 years. Patients with corticosteroid-refractory disease, corticosteroid-dependent disease, or even those who are just candidates for corticosteroid therapy should be considered. Patients with significant perianal disease and high-risk postoperative disease should also be considered. Crohn s disease has a heterogeneous presentation. In a study of 2000 patients with Crohn s disease assessing long-term disease behavior, a stricturing or penetrating complication developed in 60%. Twenty-year actuarial rates of inflammatory, stricturing, and penetrating disease were 12%, 18%, and 70%, respectively. [5] In a population-based study from Olmsted County, Minnesota, Faubion and colleagues [6] reported that only 43% of the Crohn s disease population from 1970 to 1993 had received corticosteroid therapy, suggesting that over 50% of the population has mild-to-moderate disease; these patients will never be candidates for corticosteroids, nor by extrapolation, anti-tnf-alpha therapy. However, at 1 year, of the 43% who received corticosteroids, prolonged response was seen in only 32%, corticosteroid dependence in 28%, and surgery in 38%, suggesting that those patients who receive corticosteroids or are candidates for corticosteroids are at risk for progression to more severe disease, and should be considered for anti-tnf-alpha therapy. This finding was supported by another study [7] that looked at factors on initial presentation that predicted a disabling course of Crohn s disease; 3 such factors were identified: corticosteroid use, perianal disease, and age < 40 years old. In a study that examined the natural history of fistulas in Crohn s disease, fistulizing disease was found to occur in up to 33% of patients. [7,8] Infliximab, [9] adalimumab, [10] and certolizumab pegol [11] have all shown benefit for this difficult-to-manage complication. Any patient with significant perianal Crohn s disease is a candidate for anti-tnf-alpha therapy because it is the only treatment approved by the US Food and Drug Administration for this indication (specifically, infliximab), and aside from tacrolimus,* which is off-label for Crohn s disease, infliximab is the only agent to show benefit in a randomized trial with fistula closure as the primary endpoint. [12] Another group for which anti-tnf-alpha therapy has shown benefit where other conventional agents (aside from ornidazole* and metronidazole*) have not, is among patients with an ileocolonic resection. In a small randomized trial, infliximab was found to be superior to placebo for preventing endoscopic recurrence at 1 year (9.1% for infliximab compared with 84.6% in the placebo arm; P =.0006). [13] Patients with predictors of rapid disease recurrence after surgery (perforating disease, multiple surgeries) should also be considered strongly for anti-tnf-alpha therapy. [14] How Should Biologic Therapy Be Optimized? Several studies have shown that the introduction of biologic agents earlier in the disease course (before the development of complications), leads to better response. In the CHARM (Crohn s trial of the fully Human antibody Adalimumab for Remission Maintenance) trial, [15] adalimumab given at a dose of 40 mg weekly or every other week, was found to be superior to placebo in maintaining remission for 56 weeks in patients with active Crohn s disease. However, the earlier in a patient s disease course the drug was given, the better the response. Patients with disease of less than 2 years duration had a remission rate of 51% at 56 weeks compared with 44% for those with disease of 2 to < 5 years duration and about 35% for those with disease for 5 years. [16] Data suggest that the use of biologic therapy in combination with immunomodulators is more effective than either therapy alone. Although subgroup analysis of the large clinical trials [17] did not show a benefit associated with the use of biologic therapy given in combination with immunomodulators over biologic therapy alone, 1 large prospective trial, SONIC [18] (Study of Biologic and Immunomodulator Naive Patients in Crohn s Disease), did demonstrate benefit. In this study, 508 adult patients with moderate-to-severe Crohn s disease, median disease duration of 2.3 years, and no previous exposure to immunomodulators or biologic therapy, were randomly assigned to receive azathioprine* 2.5 mg/kg; infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks; or combination therapy* with both agents. Of the 169 patients who received combination therapy, 57% were in corticosteroid-free clinical remission at week 26 (the primary study endpoint) vs 44% of those who received infliximab alone (P =.02) and 30% of those who received azathioprine alone (P <.001 vs combination therapy, and P =.006 vs infliximab). At week 50, results were similar -- with 46%, 35%, and 24% of patients, respectively, in corticosteroid-free remission. At week 26, mucosal healing had occurred in 44% of patients who received combination therapy vs 30% of those who received infliximab alone (P =.06) and 17% of those who received azathioprine alone (P <.001 for the comparison with combination therapy, and P =.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination therapy group, 4.9% of those in the infliximab monotherapy group, and in 5.6% of patients in the azathioprine group, suggesting that at 1 year, infectious complications were not increased by the use of combination therapy. Although the findings of this study are impressive, it is important to keep in mind that this does not answer the question of whether patients who fail to respond to Pg.5

6 Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME azathioprine monotherapy will experience a similar benefit with combination therapy as patients who were naive to both therapies. Another important question to be addressed, is how long should therapy be continued? Cost and safety are certainly factors that come into play with long-term biologic therapy. A recent systematic review assessed the efficacy of anti-tnf-alpha therapy beyond 1 year. [19] Infliximab, adalimumab, and certolizumab pegol were all effective in maintaining remission in luminal Crohn s disease, and infliximab and adalimumab for fistulizing Crohn s disease, for > 1 year, with a low-risk safety profile. A prospective French study, STORI (Stop Infliximab in Patients With Crohn s Disease) [20] looked at 115 patients with Crohn s disease who were treated with infliximab plus an immunomodulator for at least 1 year, and in stable remission for at least 6 months. Infliximab was discontinued, and 39% of patients relapsed within 1 year. Factors predictive of relapse were endoscopic disease activity, elevated C-reactive protein level, low serum hemoglobin, and infliximab trough levels < 2 µg/ml. Of course, one must keep in mind that once patients stop a biologic agent, they may not be able to resume therapy with that same agent due to the formation of antibodies. In addition, patients who have been exposed to 1 TNF antagonist and lost response or who were intolerant, can respond well to treatment with a second anti-tnf-alpha agent, but not as well as if they were anti-tnf-alpha naive. [21,22] Despite optimizing therapy, some patients with Crohn s disease may slowly lose response to anti-tnf-alpha therapy. When this occurs, a full evaluation should be conducted: Does the patient have an infection such as Clostridium difficile or bacterial overgrowth? Did a stricture or fistula develop? Did antibodies against the biologic agent develop or did the patient simply lose response to its mechanism of action? At this time, commercial assays to test for drug levels and the formation of antibodies to drug are only available for infliximab. For a patient who is losing response to infliximab, checking drug levels at either the midpoint between infusions or at trough is helpful. [23] If infliximab levels are > 12 µg/ml at the midpoint between infusions, or just detectable at trough, then there is adequate drug in the patient s serum. In this case, increasing the dose or changing to a different anti-tnf-alpha agent will not be helpful. If drug levels are low or undetectable, however, then increasing the dose of infliximab would be beneficial. If antibodies are present, then switching to a different anti-tnf-alpha agent is the best option. Low serum trough levels and the formation of antibodies against adalimumab have also been associated with poor response, [24] but unfortunately, an assay is not commercially available at this time. For those patients with Crohn s disease who do not respond to anti-tnf-alpha therapy or who have lost response to these agents, natalizumab, a biologic agent with a different mechanism of action (alpha-4 integrin inhibitor), provides a good alternative. As noted previously, this agent has been shown to be effective for the induction and maintenance of clinical response and remission in adult patients with moderate-to-severe Crohn s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn s disease therapies and inhibitors of TNF-alpha. [25] Due to concerns regarding progressive multifocal leukencephalopathy (PML), a rare demyelinating disease, which is estimated to occur in 1/1000 users, [26] natalizumab is limited to use in those patients who have failed to respond to anti-tnf-alpha therapy. Summary Points: Optimizing Biologic Therapy for Crohn s Disease Data show that introduction of biologic agents at an early stage in the disease course, before the development of strictures and need for surgery, leads to significantly improved outcomes. The use of combination therapy with a biologic agent and an immunomodulator is more effective than monotherapy for achieving sustained remission. On the basis of current best evidence, once a biologic agent is effective in a given Crohn s disease patient, it should be continued indefinitely because stopping therapy is associated with a significant risk for disease flare, and restarting or changing the agent does not result in the same level of benefit. [14] What are the Benefits of Biologic Therapy Beyond Remission? The biologics have provided clinicians the opportunity to think beyond symptomatic remission to potential disease-modifying endpoints. Infliximab, [17] adalimumab, [27] and certolizumab pegol [28] have shown benefit for the induction and maintenance of remission in patients with Crohn s disease. As noted previously, all 3 of these anti-tnf-alpha agents have demonstrated efficacy in the treatment of fistulizing Crohn s disease as well, with the strongest data available for infliximab, in a randomized controlled trial with closure of fistulas as the primary endpoint. [12] Corticosteroid withdrawal is another important benefit of biologic therapy, and has been clearly demonstrated for infliximab and adalimumab. [18,29] Natalizumab is also effective for the induction of corticosteroid-free clinical remission. [25] Mucosal healing is also emerging as an important endpoint in the treatment of Crohn s disease, and may be associated with a reduction in relapse rates, [20] need for surgical intervention, [30] and colorectal cancer. [31] The presence of deep ulcerations on colonoscopy in patients with Crohn s disease is predictive of a more aggressive disease course, with increased rates of penetrating complications and colectomy. [31] In the STORI trial, mucosal healing was one of the key predictors of maintenance of clinical remission after infliximab discontinuation. [20] Treatment with infliximab-based strategies also resulted in mucosal healing in the (SONIC) trial. [18] Mucosal healing has been demonstrated to a lesser extent with the other biologic agents as well -- certolizumab pegol, [32] adalimumab, [33] and natalizumab. [34] Finally, although subgroup analysis of the major trials suggests a reduction in hospitalizations associated with the use of anti-tnf-alpha agents, overall national trends point to an increase in hospitalizations and outpatient visits for patients with inflammatory bowel disease, suggesting that additional studies are needed over time to determine the true impact of biologic therapy on long-term outcomes in Crohn s disease. [35,36] Pg.6

7 medscape.org/column/crohns Safety A meta-analysis of placebo-controlled trials evaluating the efficacy and safety of anti-tnf-alpha therapy for Crohn s disease identified 21 studies with 5356 individuals, and found that TNF antagonists did not increase the risk for death, malignancy, or serious infection. [37] Unfortunately, because most trials are 6 months to 1 year in length, this finding does not adequately address the overall safety concerns. In general, biologic therapy does pose an increased risk for complications. The rate of serious infections with anti-tnf-alpha therapy is estimated to be 4%-5% based on data for infliximab and extrapolated to the other anti-tnfalpha agents. [38] Prevention and early recognition is the key. Patients should be tested for previous exposure to tuberculosis and hepatitis B, because initiating therapy can lead to serious re-activation of these latent infections. Although bacterial infections are the most common complication, viral and fungal infections should also be considered, particularly in endemic areas. Additionally, patients should be vaccinated against preventable infections, although live virus vaccines can only be given before initiating therapy. Although general malignancies (except perhaps skin cancer) do not seem to be increased with the use of anti-tnf-alpha agents, [39] the risk for lymphoma may be increased; however, given a patient s previous exposure to thiopurines (eg, the immunomodulatory agents, azathioprine and 6-mercaptopurine), an actual independent risk rate is not known. Other potential complications associated with the use of anti-tnf-alpha agents include much rarer events such as optic neuritis, lupus-like syndrome, and aggravation of congestive heart failure, as well as the more common psoriaform rash, which can be seen in up to 20% of patients. [40] For natalizumab, an additional safety concern is the risk for PML. As of April 2010, there have been 46 cases of PML reported after exposure to natalizumab, consistent with an overall risk of 1/1000. [41] To date, all post-marketing cases have occurred after 12 months of therapy and have been in patients with multiple sclerosis. Because the efficacy of natalizumab in Crohn s disease will be known by month 6 of therapy, for the reluctant patient, treatment can be initiated and a decision made at 6 months whether to continue, with minimal risk for PML, in that timeframe, based on the timing of occurrence of the known cases of PML. Concerns about the risks associated with the use of biologic therapy for Crohn s disease must therefore be weighed against the debilitating effect of the disease itself in the patient with moderate-to-severe disease. Prevention of preventable diseases via vaccination and ensuring appropriate screening/maintenance care is important. A checklist of key health maintenance issues has been published and is an effective tool to ensure that the patient is up to date in his or her general healthcare maintenance. [42] Conclusion Crohn s disease is a complex and heterogeneous disorder. For those patients with markers predictive of a disabling disease course (corticosteroid use, perianal disease) or who have had surgery already, particularly for perforating disease, biologic therapy has shown benefit in clinical trials and epidemiologic analysis for induction and maintenance of remission. Additional benefits beyond clinical remission may include fistula closure, corticosteroid withdrawal, mucosal healing, and reduction in hospitalizations and surgeries. These potential benefits must be weighed against the safety of these agents when making treatment decisions. Biologic therapy has been associated with an increased risk for serious infections, lymphoma, and other rarer adverse events. As we consider therapy for Crohn s disease in the future, the benefits of biologic therapy, as based on current best evidence, and as outlined in this clinical review, in the appropriate candidate, appear to far outweigh the risks. Given the benefit of these agents, early intervention to achieve greater efficacy and prevent complications of disease, as well as optimizing the use of biologic therapy with concomitant immunomodulators and sustained therapy, are becoming the standard of care. *The US Food and Drug Administration has not approved this medication for this use. Supported by independent educational grants from Abbott Laboratories and Elan Pharmaceuticals, Inc. This article is a CME certified activity. To earn credit for this activity visit: medscape.org/column/crohns Pg.7

8 Trends in Biologic Therapy for Crohn s Disease: Where Are We and Where Are We Going? CME References 1. REMICADE (infliximab). Prescribing Information. Malvern, Pa: Centocor Otho Biotech Inc.; HUMIRA (adalimumab). Prescribing Information. North Chicago, Ill: Abbott Laboratories; Cimzia (certolizumab pegol). Prescribing information. Smyrna, Ga: UCB, Inc.; TYSABRI (natalizumab). Prescribing information. San Francisco, Calif: Elan Pharmaceuticals, Inc.; Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn s disease. Inflamm Bowel Dis. 2002;8: Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121: Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn s disease. Gastroenterology. 2006;130: Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. 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