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PRIORITY PRESS - 19th United European Gastroenterology Week (UEGW)

Stockholm, Sweden / October 22-26, 2011

Stockholm - At UEGW, discussions of treatment of inflammatory bowel disease (IBD) with anti-tumour necrosis factor α (TNF-α) agents focused both on long-term experience in clinical trials and on the real-life experiences of registries and observational studies. These findings should help guide future management of IBD towards the ultimate goal: deep IBD remission, i.e. clinical remission and mucosal healing. They may also help achieve goals that are clinical meaningful to patients, i.e. quick control of symptoms, sustained efficacy, avoidance of hospitalization and normalized quality of life. This may require earlier intervention, rapid optimization of conventional or first anti-TNF-α therapy and a personalized approach to treatment. The question remains of how to treat patients who have failed conventional treatment and all currently available TNF antagonists. Data presented at UEGW indicated that further options may be available to these patients. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Over the past decade, treatment of inflammatory bowel disease (IBD) has been revolutionized by the emergence of biologic therapies that target the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) in the inflammatory cascade. Three TNF antagonists—infliximab, adalimumab, certolizumab pegol—have demonstrated efficacy in the treatment of Crohn’s disease (CD). Only infliximab and adalimumab have shown efficacy in ulcerative colitis (UC).

New Findings from Clinical Trials

The first study to show that anti-TNF therapy reduces all-cause hospitalization risk in patients with moderate to severe UC was presented by Dr. Brian G. Feagan, Robarts Research Institute, University of Western Ontario, London. The study was based on a blinded review of safety reports from a combined population of patients enrolled in the ULTRA 1 (M06-826) or ULTRA 2 (M06-827) trials. These were 2 placebo-controlled trials with adalimumab in patients who had failed or were intolerant of corticosteroids and/or immunosuppressants. In the combined single data set of 939 patients, there was a significant 32% reduction in the rate of all-cause hospitalization with adalimumab treatment over placebo (P=0.015). UC-related hospitalizations were also significantly reduced by 48% (P=0.001). The colectomy rate was 22% lower in active-treatment patients compared with placebo.

A subanalysis of the UC SUCCESS trial, presented by Dr. Subrata Ghosh, University of Calgary, Alberta, showed that patients with moderate to severe UC receiving infliximab 5 mg/kg plus azathioprine 2.5 mg/kg or infliximab alone were more likely to achieve steroid-free mucosal healing at 16 weeks than patients receiving azathioprine alone. For complete mucosal healing, combination therapy was significantly more effective than either agent alone (30% vs. 12% or 13%, respectively; P<0.05), Dr. Ghosh reported. 

Long-term Efficacy of Anti-TNFs

Patients with moderate to severe UC may need higher doses of adalimumab to maintain efficacy over the long term, according to the results of a study presented by Dr. Marc Ferrante, University Hospital Leuven, Belgium. Dr. Ferrante and colleagues studied 50 patients treated at the hospital between 2005 and 2010. “This was a group of very refractory patients who had failed infliximab,” Dr. Ferrante noted. All patients received induction with 160/80 mg adalimumab followed by 40 mg every other week. 

After a median follow-up of 23 months, 26 patients (52%) were in a durable clinical response with adalimumab, 6 (12%) with no relapses. “A high proportion of patients needed dose escalation, but a majority clearly benefited from it,” Dr. Ferrante told delegates. Although 76% of patients had dose escalation, which was associated with a significant increase in adalimumab serum levels, 55% of these patients were able to have dose de-escalation after a median of 16 weeks. Twenty per cent of patients needed colectomy. Short-term clinical response and response to dose escalation were associated with colectomy-free survival (P=0.030 and P<0.001, respectively). Adalimumab serum levels did not predict long-term efficacy, Dr. Ferrante added.

The long-term benefit of infliximab as an effective rescue treatment in a moderate to severe attack of steroid-refractory UC was reported by Prof. Curt Tysk, Orebro University Hospital, Sweden. In 212 patients hospitalized between 1999 and 2010 who were unresponsive to intravenous corticosteroids and receiving infliximab 5 mg/kg as rescue therapy, colectomy-free survival was 70% at 3 months and 63% at 12 months. Six patients died during follow-up, 3 possibly related to infliximab rescue treatment, leading Prof. Tysk to describe the risk of serious complications as “low but not negligible.” 

Real-life Experience

“In IBD, there is a big gap between real-life and clinical trials, so it is important to study real-life cohorts and real-life observation and registries and not only look at clinical trials,” stated Dr. Geert D’Haens, Academic Medical Centre, University of Amsterdam, The Netherlands. Prof. D’Haens presented 3-year results from the PYRAMID registry, an ongoing observational 6-year safety registry for adalimumab initiated in 2007 in 24 countries (421 sites). Of the 5080 patients originally enrolled, 52% had a history of prior anti-TNF biologic use, primarily infliximab.

By December 1, 2010, 3866 (76.1%) patients remained on study. Adalimumab continued to be well-tolerated. Rates of adverse events of interest were low and stable between years 2 and 3, with no new clinical concerns or safety signals observed. Rates of serious infections were lower in patients receiving adalimumab monotherapy (4.1%) compared with patients on concomitant immunosuppressants with (7.0%) or without corticosteroids (6.0%). “Evidence is now growing, based on this and the ENCORE registry with infliximab, that concomitant medication leads to a significantly higher risk of a serious infection,” Prof. D’Haens cautioned.

Real-life experience with adalimumab since its introduction as CD treatment in The Netherlands in 2003 was reported by Dr. Charlotte P. Peters, Academic Medical Centre, Amsterdam. Dr. Peters and colleagues examined the medical charts of a prospective cohort of 438 CD patients from 18 hospitals. Among these patients, 61.6% had failed or were intolerant to infliximab.

After 1 year, 267 patients remained in the study, of whom 83.3% had sustained benefit, with a subsequent 10% loss of response each following year. This was a higher response rate than seen in most registration trials, Dr. Peters noted. The presence of strictures before the start of adalimumab was associated with failure of remission induction (OR 2.2; 95% CI, 1.0-4.1; P=0.02). No other patient- or disease-specific factors were associated with sustained benefit. Previous treatment with infliximab did not influence the outcome of adalimumab efficacy. “This study shows that prior infliximab failure should not necessarily exclude treatment with adalimumab,” Dr. Peters concluded.

Treatment After TNF Antagonists

A human monoclonal antibody (MAb) directed against interleukin (IL)-12 and IL-23—such as ustekinumab—may be another option. It is already available for the treatment of psoriasis and is effective in patients with moderate to severe CD who previously failed or were intolerant to ≥1 TNF antagonist, according to data from the CERTIFI trial. Dr. Feagan reported that the placebo-controlled phase IIb study randomized 526 patients to intravenous ustekinumab 1, 3 or 6 mg/kg or placebo. At week 6, 35.8% of patients on all doses of ustekinumab were in clinical response (≥100-point reduction from baseline CDAI score) vs. 17.4% on placebo (P<0.001). Rates of clinical remission in individual dose groups at weeks 6 and 8 were of borderline significance vs. placebo. After re-randomization of initial responders to 90 mg or placebo, 69.4% of patients on active treatment remained in clinical response vs. 42.5% on placebo (P<0.001) at week 22. The anti-IL-12/23 is currently in a phase III program for the treatment of moderate to severe CD in patients who have failed conventional treatment or anti-TNF therapy.

Future Management Goals

An emerging concept in IBD patients is treating beyond clinical symptoms, indicated Prof. Jean-Frédéric Colombel, Centre Hospitalier Universitaire de Lille, France. He drew an analogy with other chronic diseases such as hypertension, hyperlipidemia, diabetes and rheumatoid arthritis. “There are many concepts that could be applied and translated from other chronic diseases to CD,” he told delegates. One is a “treat to target” approach to achieve “tight control” in order to block disease progression. Deep remission could be the target in CD. “In the EXTEND trial, deep remission, defined as clinical remission (CDAI <150) and complete mucosal healing, was associated with lower hospitalization and health care costs, and improved quality of life after 1 year,” Prof. Colombel noted. Clinical trials testing this concept further include the CALM study, an international trial that will determine whether tailoring therapy to more stringent measures of disease activity will improve mucosal healing in patients with moderate to severe CD. 

“Achievement of deep remission as the ultimate goal probably also applies to UC,” Prof. D’Haens noted. It may also encompass histological healing and biological remission, he concluded.