COMMENTARY

Certolizumab Pegol for the Treatment of Patients With Moderate-to-Severe Crohn's Disease

David A. Johnson, MD, FACG, FACP

Disclosures

September 07, 2007

Certolizumab Pegol for the Treatment of Crohn's Disease

Sandborn WJ, Feagan BG, Stoinov S, et al
N Engl J Med. 2007;357:228-238

Abstract

Maintenance Therapy With Certolizumab Pegol for Crohn's Disease

Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al
N Engl J Med. 2007;357:239-250

Abstract

Editor's Note: Dr. Johnson's summary and commentary collaboratively address these 2 reports on the role of certolizumab pegol in Crohn's disease.

Crohn's disease is a chronic, relapsing inflammatory bowel disease (IBD) with a spectrum of disease locations and involvement. This disease can be progressive and is associated with a significant increased risk for morbidity as well as increased mortality. Current treatment guidelines recommend therapy that is based on disease severity. Treatment is aimed at inducing and maintaining remission of clinical disease. It is well known that the risks for complicated disease increase over the duration of the disease, and the cumulative risk for surgical resection approaches 80%.[1] Unfortunately, conventional therapy with corticosteroids has not been effective in altering the long-term natural history of Crohn's disease. Treatment with other immunosuppressants, such as azathioprine or 6-mercaptopurine, has been shown to decrease steroid dependency, but not the long-term complications associated with disease or the need for surgery.[2]

The development of the tumor necrosis factor (TNF)-alpha antagonists has revolutionized the treatment approach to Crohn's disease. The use of these biologic agents has shown effectiveness both in inducing and maintaining remission in patients with Crohn's disease. Infliximab (a human-murine chimeric monoclonal antibody against TNF-alpha) and adalizumab (a fully human immunoglobulin [Ig]G1 anti-TNF-alpha monoclonal antibody) have been approved by the US Food and Drug Administration (FDA) for reducing signs and symptoms and inducing and maintaining clinical remission in moderately to severely active Crohn's disease. The investigational agent certolizumab pegol, a humanized anti-TNF Fab' monoclonal antibody fragment linked to polyethylene glycol, represents the most recent addition to the anti-TNF arsenal. To date, there have been limited clinical trial data reported on this agent. Unlike other monoclonal antibodies, certolizumab does not contain an Fc fragment and therefore does not induce in vitro complement activation, antibody-dependent cellular toxicity, or apoptosis.

These 2 large phase 3 clinical trials evaluated the efficacy of certolizumab in the induction and maintenance of remission in adults with moderate-to-severe Crohn's disease. These studies, known as PRECISE 1 and 2 (Pegylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy), enrolled adult patients with moderate-to-severe Crohn's disease and involved more than 140 clinical sites in multiple countries. The Crohn's Disease Activity Index (CDAI) was used to assess disease activity and response to therapy during the 26 weeks of these studies. Patients were stratified according to baseline levels of C-reactive protein (ie, above or below the threshold C-reactive protein level of 10 mg/L) and randomized to treatment with certolizumab vs placebo. The clinical characteristics of patients involved in both studies was nearly identical and the dose of certolizumab (400 mg administered subcutaneously) used was the same. The main difference was that in the first trial (PRECISE 1), patients were randomly assigned to receive certolizumab or placebo at the onset of the study. In contrast, for PRECISE 2, all patients received 3 doses of certolizumab at weeks 0, 2, and 4; patients with a clinical response (defined as a reduction in the CDAI by at least 100 points from baseline at week 6) were then stratified by C-reactive protein level and assigned to receive 400 mg of certolizumab or placebo. Clinical remission was defined as a CDAI score of ≤ 150.

In both trials, there was consistency in the proportion of patients who had a response to certolizumab at week 6 and still had a response at week 26 (65% and 63%, respectively). For both trials, there was no significant difference in fistula closure between the treatment and placebo groups. Data from the PRECISE 1 trial showed that induction and maintenance therapy with certolizumab was associated with a modest improvement in response rates (8% over placebo), although there was no significant improvement in remission rates. In PRECISE 2, however, for those patients who responded to induction therapy, certolizumab was effective in preventing relapse; this effectiveness was independent of the C-reactive protein level threshold at randomization. Overall, the magnitude of response for active treatment in both studies was not affected by the concomitant use of other immunosuppressants, previous treatment with infliximab, or smoking status. Additionally, the incidence of adverse effects was comparable between all treatment and placebo groups.

Data from these trials should not be used to make direct comparisons with other anti-TNF-alpha therapies, as they were designed to show efficacy over placebo and not other active therapies. However, certolizumab appears to offer yet another therapeutic alternative in the ever-growing list of biologic agents for the treatment of Crohn's disease. The results from PRECISE 1 suggested a modest improvement in response, but no improvement in remission rate. Data from PRECISE 2, however, suggested that patients who respond to induction therapy with certolizumab are more likely to maintain a response and be in remission at 26 weeks. These studies provided the basis for the recent American Gastroenterological Association (AGA) Institute consensus panel recommendations on the use of biologic therapy for the treatment of IBD.[3] This consensus panel suggested that the indications for certolizumab therapy in Crohn's disease include: (1) induction of response and induction of remission in outpatient adults with moderate-to-severe Crohn's disease; (2) maintenance of response to certolizumab and maintenance of remission after certolizumab treatment; and (3) loss of response to infliximab.

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