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14th United European Gastroenterology Week

Berlin, Germany / October 21-25, 2006

Unlike the non-specific immunosuppressive agents traditionally used in inflammatory bowel disease (IBD), biologics target specific molecules that drive disease pathology. In IBD, currently available biologics inhibit tumour necrosis factor alpha (TNF-a), a central mediator of inflammation. Based on recent data, including those presented here at the UEGW meeting, a number of experts concluded that there is a patient population in whom TNF-a inhibitors may be considered even as a first-line option. The strongest case for early use of biologics is in patients with moderate to severe Crohn’s disease, but the principles of early intervention also have relevance for ulcerative colitis (UC) when involvement includes severe symptoms and a significant risk of resection.

Top-down Therapy Based on New Evidence

“As new evidence emerges regarding the efficacy of TNF-a inhibitors in the treatment of Crohn’s disease and UC, a newer treatment approach used in these diseases is evolving,” reported Dr. Remo Panaccione, Director, Inflammatory Bowel Disease Clinic, University of Calgary, Alberta. “New data suggest that early introduction of more optimal therapy that targets the underlying inflammation of the disease may be associated with better clinical outcomes and decreased need for long-term steroids, thus limiting their associated toxicity.”

Much of the data with biologics in IBD has been generated with infliximab, the first TNF-a inhibitor made available for the treatment of this disease. In Europe and much of the rest of the world, it is approved for use in both Crohn’s disease and UC. Although the indications for its use in many countries recommend its administration in patients who have failed other treatments, it is now accepted in the European Union for treatment of Crohn’s without prior failure of azathioprine or other medications traditionally employed first-line.

The strategy of top-down therapy was discussed by Dr. Simon Travis, John Radcliffe Hospital, Oxford, UK. He suggested that biologics should be considered even in newly diagnosed patients if the disease is sufficiently aggressive. “If the drugs are used in these selected patients directly after diagnosis of the disease, it gives rapid relief of the symptoms, avoids steroids and promotes mucosal healing. We do not yet know whether early treatment alters the need for surgery, but it has the potential to do so,” he observed, citing a variety of data that support this conclusion. He suggested that the goals in IBD overall and in Crohn’s specifically is to achieve a sustained, steroid-free remission. The GETAId (Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif) trial evaluated infliximab in combination with azathioprine (AZA) and 6-mercaptopurine (6-MP) to AZA/6-MP. The TNF-a inhibitor appeared more efficacious in those patients whose disease had previously remained active on AZA/6-MP and those naive to AZA/6-MP (Lemann et al. Gastroenterology 2006;130(4):1054-61).

Focus on Long-term Outcome

“A more aggressive, top-down strategy has been shown to be more effective than the step-up strategy for inducing and maintaining steroid-free remission. The trial of the GETAID study group demonstrated that early use of infliximab results in sustained steroid-free remission in Crohn’s disease,” stated Dr. Panaccione. He suggested that the interest in a top-down approach is based on the premise that “treatment for Crohn’s disease and UC should provide rapid and sustained control of inflammation which can maximize the patient’s long-term outcome.”

Figure 1. Steroid-dependent Crohn's disease patients off steroids at week 24

One concern about step-down therapy is that TNF-a inhibitors may lose potency over time, but new data do not support that risk. In data from the Karolinska Institute, no consistent or significant change in response was observed in patients followed on infliximab for 25 months. In this study of 49 patients, the average number of infusions was 10; the dose was increased in only one patient. Although the infusion interval was changed over time in 16 patients, it was increased in 14 and decreased in two individuals. In 60% of the patients, steroids were discontinued. The side effects were mostly confined to mild infusion reactions in 10% of patients, although one patient did experience an anaphylactic reaction.

Reported Dr. Ragnar Befrits, Department of Gastroenterology, Karolinska Institute, Stockholm, Sweden, “Maintenance treatment with infliximab in Crohn’s disease seems to be safe, efficacious and steroid-sparing in a majority of patients for at least two years. In contrast to other reports, we found loss of response to be of infrequent clinical importance.”

Crohn’s Disease

Similar results were generated by the Danish Crohn’s Colitis Database, which now includes information on 648 patients treated with infliximab for IBD at 22 participating centres. Of these, 615 were treated for Crohn’s disease and the rest for UC or an indeterminate form of colitis. With data on 3320 infusions, the response rate was >80%, with adverse events occurring in 3.1% of infusions administrated in patients not taking another immunomodulatory agent and in 6.6% of those who were. Diminishing response over time was not reported as a significant observation in this series.

“Efficacy of infliximab has been demonstrated in placebo-controlled trials, but these data provide insight about long-term outcome,” reported Dr. Margarita Elkjaer, Department of Gastroenterology, Gentofte Hospital, University of Copenhagen, Denmark. She said these data support this therapy as “an efficacious treatment of IBD” that is well tolerated in the majority of patients.

Data with other TNF-a inhibitors has also been associated with substantial efficacy. Although there are no large direct comparisons of agents in this class, new studies suggest that patients who do not respond adequately to one may respond to another. Studies with adalimumab and certolizumab have recently demonstrated benefit regardless of whether patients have had prior exposure to a TNF-a inhibitor. In the adalimumab study presented by Dr. Paul Rutgeerts, University Hospital of Gasthuisberg, Leuven, Belgium, remission, defined as a Crohn’s Disease Activity Index (CDAI) score of <150, was achieved in 21% of patients vs. 7.2% of patients receiving placebo (P<0.001). The placebo-controlled, phase III, double-blind trial included 325 patients with moderate-to-severe Crohn’s. The TNF-a inhibitor was well tolerated.

“The objective of this study was to assess the safety and efficacy of adalimumab in the induction of clinical remission in patients with active Crohn’s disease who had secondary failure to another TNF-a inhibitor,” Dr. Rutgeerts reported. “Significant activity was observed, suggesting that failure of one drug does not predict failure of others.”

In the study with certolizumab, 322 patients with moderate-to-severe Crohn’s were naive to a TNF-a inhibitor and 103 were experienced. They were randomized separately to active treatment or placebo. In naive patients, remission was achieved in 52.8% on the active treatment and in 33.3% of controls (P<0.001). In those with prior exposure to another TNF-a inhibitor, the remission rates were 32.7% and 13.7% (P=0.008), respectively. The rate of serious side effects was slightly lower on active therapy than on placebo (4.2% vs. 5.6%), leading the authors to characterize certolizumab as “well tolerated.”

Confirmed Dr. Jean-Frédéric Colombel, Clinique des Maladies de l’Appareil Digestif et de la Nutrition, Centre Hospitalier Régional Universitaire de Lille, France, “Certolizumab demonstrated activity irrespective of whether [patients] were experienced with TNF-a inhibitor therapy.”

The efficacy of alternative TNF-a inhibitor therapies are particularly encouraging because of the concern that early use of infliximab may eliminate an important drug class in the event of failure. Rather, the expanding class of TNF-a inhibitors and the potential development of new biologicals targeting other components of the immune system indicate that these therapies can be moved from a choice reserved for advanced disease to earlier use designed to halt disease early in its progression.

Ulcerative Colitis

Although there have been fewer data evaluating the effects of TNF-a inhibitors in UC, this is changing. In UC as in Crohn’s, one of the chief advantages is the rapid onset of action, often producing healing within weeks. The rapid symptom relief has major implications for avoiding complications and improving quality of life. In new eight week data from ACT 1 and 2 (Active Ulcerative Colitis Trials), the significantly greater clinical responses in the infliximab groups vs. those receiving placebo (61% to 69% vs. 29% to 37%; P<0.001) were found to be associated with substantial reductions in hospitalizations and increases in patient well-being.

Figure 2. Ulcerative c
alizations at week 30

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Confirmed Dr. Walter Reinisch, Medical University, Vienna, Austria, “Infliximab significantly reduced the number of UC-related hospitalizations, the number of hospitalizations in which steroids were required and the average time to first hospitalization.” He noted that symptom relief in ACT 1 and 2, which was published last year, was commensurate (Rutgeerts et al. N Engl J Med 2005;353(23):2462-76). In health-related quality-of-life scores (HRQOL), all of the scales across all of the dimensions associated infliximab with a significantly greater improvement in HRQOL than placebo. Moreover, this improvement was observed at both week 8 and week 30, and the magnitude of improvement was similar regardless of the baseline disease severity.

Clinical vs. Biologic Remission

The increasing interest in top-down strategies for IBD, whether Crohn’s or UC, is partly driven by the potential for TNF-a inhibitors to slow disease progression. Steroids are effective in both diseases in rapidly controlling symptoms, but these therapies are far less effective for healing and the risks from prolonged steroid use are substantial. TNF-a inhibitors are being moved forward in treatment algorithms because of their specific activity at the site of disease.

“Clinical remission as defined by absence of symptoms can be achieved by most non-biologic therapies, such as steroids. However, clinicians need to reach beyond achieving an absence of symptoms and strive for biologic remission, defined as mucosal healing,” observed Dr. Panaccione. “Mucosal healing can be achieved with biologic therapy, such as TNF-a inhibitors. Patients treated with steroids may achieve clinical remission but will not achieve mucosal healing or biologic remission.”

One of the most important potential advantages of TNF-a inhibitors is reducing the risk of resection. While large studies are needed to evaluate the effect of early vs. late use of TNF-a inhibitors for reducing the risk of surgery, the protective effect may extend to UC as well as Crohn’s. In a case series of 11 patients with UC presented by Dr. Reddy Yogananda, Stepping Hill Hospital, Manchester, UK, all patients had been treated with various combinations of 5-ASA, azathioprine and steroids prior to infliximab, which was introduced to reduce the risk of colectomy. Although three patients did fail infliximab and went on to colectomy, eight patients achieved complete or partial remission after one or more infusions. According to Dr. Yogananda, “Eight of 11 patients avoided colectomy, which was inevitable without infliximab.”

Reducing Risk of Surgery

Expanding clinical experience suggests that even patients with complex IBD who were once considered to be contraindicated for TNF-a inhibitor therapy may be candidates when the goal is to reduce the need for resection.

Senior author Dr. Jean-Claude Soulé, Hôpital Bichat-Claude Bernard, Paris, France, reported on a series of 18 Crohn’s patients with symptomatic stenosis, of which four had complete occlusion. Infliximab treatment was characterized as fostering complete success in five, partial success in 10 and failure in three. Although the best results were achieved in patients who received concomitant steroids, the results suggest that the TNF-a inhibitor may have a role even in the presence of strictures. “Based on these results, we believe that infliximab should be attempted in Crohn’s disease patients with symptomatic strictures before resorting to surgery,” investigators concluded.

Summary

The specificity of action of TNF-a inhibitors in IBD is credited with rapid mucosal healing and rapid relief of symptoms. While these biologics were initially reserved for patients with advanced Crohn’s disease or UC that was not responding to conventional immunosuppressant treatment, the potential for improved long-term outcome has been a powerful impetus to move TNF-a inhibitors further up in treatment algorithms. For patients with moderate-to-severe IBD, a top-down approach in which TNF-a inhibitors are used early, even as first-line therapy, has important implications for rapid symptom relief and slowing or preventing progression toward resection.

Questions and Answers

The following question-and-answer session was conducted with Dr. Paul Rutgeerts, University Hospital of Gasthuisberg, Leuven, Belgium, during the scientific sessions.

Q: Why is interest in top-down therapies for IBD increasing, particularly if the less expensive traditional therapies are effective in at least some patients for managing symptoms?

A: It is recognized that in addition to managing symptoms, therapeutic goals must also include the rapid control of symptoms and mucosal healing, maintenance of remission off steroids and reduction of surgeries and hospitalizations. Achieving these goals is critical to the success of therapy and the resulting improvement of patients’ lives.

Q: Does a top-down strategy have relevance for UC?

A: Use [of TNF-a inhibitors] in UC has been protracted for many years, as it has been thought that these might play less of a role in UC than in Crohn’s disease. However, two positive phase III studies have demonstrated that in UC, as in Crohn’s disease, the use of the TNF-a inhibitor infliximab results in a meaningful clinical benefit with regard to induction and maintenance of remission over 54 weeks.

Q: Does the development of biologics like TNF-a inhibitors change the goals of therapy?

A: The hope is that by achieving rapid healing, improving remission rates and reducing surgeries with these therapies, we can change the natural history of the inflammatory bowel disorders in a way that will favourably affect long-term outcome.