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72nd Annual Scientific Meeting of the American College of Gastroenterology

Philadelphia, Pennsylvania / October 14-17, 2007

Most patients with ulcerative colitis (UC) present with mild-to- moderate disease, for which 5-aminosalicylic acid (5-ASA) is considered first-line therapy for induction and maintenance. In UC, the goal is to keep disease quiescent to prevent flares or prolonged relapses, which are associated with progressive colon involvement, increased risk of complications and the need for more aggressive and generally less well-tolerated therapies. Failure to adhere to therapy during periods of disease quiescence is considered to be a critical factor for risk of relapse and progression. In a panel discussion on strategies in inflammatory bowel disease (IBD), the release of a long-acting formulation of mesalamine was identified as a significant tool to reduce obstacles to adherence.

Fostering Adherence

According to Dr. Gary R. Lichtenstein, Director, Center for Inflammatory Bowel Diseases, Philadelphia, Pennsylvania, “Once-daily mesalamine changes the landscape for UC patients. We want to do everything we can to make sure the patient is adherent. This formulation has the highest 5-ASA content to date and the opportunity for a once-daily regimen increases the likelihood of keeping the patient controlled.”

A participant in the expert panel at the ACG meeting and a senior author of the recently completed maintenance study testing the long-term efficacy of the delayed-release mesalamine, Dr. Lichtenstein observed that while 5-ASA is the standard first-line therapy in mild-to-moderate disease, a 2006 Cochrane meta-analysis suggests that newer 5-ASA products, such as mesalamine, are better tolerated than sulfasalazine. However, he offered that the most important clinical difference between oral aminosalicylic therapies might be their relative role in fostering adherence. Once-daily therapies had been precluded by the difficulty of delivering sufficient drug to the colon. The newest agent employs a proprietary delivery system called multi-matrix (MMX) to delay release of orally ingested therapy until it reaches the colon. In the colon, release is gradual, improving coating of the length of the colon.

“The resistant film covering the tablet core delays the initial release of the 5-ASA until the tablet is exposed to a pH of 7 or higher, normally in the terminal ileum,” Dr. Lichtenstein explained. “As the tablet core and its surrounding gel mass progress through the colon, it is thought that pieces of the gel mass gradually break away from the core, releasing 5-ASA.”

Findings from New Extension Studies

In the newly completed maintenance study, an extension for patients who had achieved clinical and endoscopic remission during two previously published phase III trials of MMX mesalamine as an induction therapy (Sandborn et al. Aliment Pharmacol Ther 2007;26:205-25), 450 patients were randomized. The goal was to evaluate whether 2.4 g once daily of the 5-ASA was as effective for maintaining remission over a 12-month period as a twice-daily pill of 1.2 g. Of patients randomized in the study, 348 had left-sided disease, defined as inflammation below the splenic flexure and 102 had extensive involvement, defined as inflammation involving the transverse colon and/or pancolitis.

At the end of 12 months, the remission rate for patients with left-sided UC was 65.5% in the group receiving the once-daily regimen and 68.4% in the group receiving therapy twice daily, a non-significant difference (P=0.6). Both regimens were also similarly effective in maintaining remission in extensive UC (60.4% vs. 68.5%; P=0.4). The maintenance data build on the combined data from the induction trials in which 32% of patients receiving active agent achieved complete mucosal healing at the end of eight weeks vs. 16% of those on placebo. Remission rates were 37.2% on 2.4 g/day, 35.1% on 4.8 g/day and 17.5% on placebo (P<0.001 vs. either active regimen).

“Once-daily therapy is effective for the remission of UC, and it is effective whether patients have left-side or extensive disease,” Dr. Lichtenstein reported.

Tolerability is one of the most significant advantages of 5-ASA relative to other treatments for UC. Dr. Lichtenstein and other expert panelists in a symposium on IBD recommended strategies that favour use of these drugs in maintenance even when initial symptoms do not permit them to be used in induction. Although there was general agreement that immunosuppressive agents, such as azathioprine, and biologics, such as tumour necrosis factor alpha (TNF-a) inhibitors, should not be withheld even as first-line induction therapies in severe disease, it was agreed that a course of oral steroid therapy might induce sufficient control in patients with moderate disease to permit switching to an oral 5-ASA for maintenance.

This premise was reinforced by a second extension study of the phase III MMX mesalamine induction trials in which 304 patients who did not achieve remission in the first eight weeks were treated for an additional eight weeks with 4.8 g/day (2.4 g given twice daily). This study included those initially randomized to placebo and those patients who did not achieve remission while on active therapy. Both groups benefited with large reductions in Ulcerative Colitis Disease Activity Index (UC-DAI) scores achieved at the end of the additional eight weeks. Although the study was not controlled, Dr. Lichtenstein said that complete remissions were achieved using stringently defined criteria even in those who had received active therapy in the initial trial. These criteria were a modified UC-DAI score of £1, calculated as scores of 0 for rectal bleeding and stool frequency; a combined Physician’s Global Assessment and sigmoidoscopy score of £1; and, perhaps most significantly, no mucosal friability of any degree.

“It is possible that in some patients, therapeutic transition to steroids or other immunosuppressive agents may be avoided by continuing 5-ASA treatment beyond eight weeks,” Dr. Lichtenstein noted.

However, in patients who require immunosuppressants or biologics to induce remission, there is general consensus that the same agent should be employed for maintenance. If switching from 5-ASA to an immunosuppressant or a TNF-a inhibitor, past practice has been to discontinue 5-ASA. However, emerging data associating mesalamine with protection against colorectal cancer, including a study presented at the ACG, have led some clinicians to re-evaluate discontinuation.

“Based on the very large reductions in colorectal cancer observed in patients who received mesalamine, I am keeping many of my patients on therapy unless they have already developed dysplasia,” reported Dr. David T. Rubin, Co-Director, Inflammatory Bowel Disease Center, University of Chicago Medical Center, Illinois. Although he acknowledged that more data are needed to confirm chemoprevention, he believes the potential benefits are substantial in the absence of any measurable risks.

Chemoprevention

In the most recent study associating mesalamine with chemoprevention, cases and controls were compared at the Henry Ford Hospital, Detroit, Michigan. Led by Dr. Jeffrey Tang, the study demonstrated a 23.1% absolute reduction (P=0.23) in colorectal cancer among those who received mesalamine relative to those who did not. When conditional logistic regression analysis was performed, a total mesalamine exposure of 5068 g or greater was associated with an 89% relative reduction in risk of colorectal cancer (OR 0.11, 95% CI: 0.01-0.91). According to Dr. Rubin, this protection is now consistent across several retrospective studies and has been supported in in vitro and experimental models. In one pooled analysis, the exposure to 5-ASA was associated with a 49% reduction in the incidence of colorectal cancer (OR 0.51, 95% CI: 0.38-0.69).

Summary

At initial presentation, the majority of UC patients have mild to moderate disease. Many patients respond to an initial regimen of 5-ASA, but long-term adherence to a maintenance regimen remains a critical obstacle to preventing flares and disease progression. Simple regimens are essential for patients in remission who feel well and lose incentive to bear the burden of a complicated regimen or treatment with adverse events. The development of a once-daily mesalamine preparation has significant implications not only for patient convenience but also for long-term outcome.

Note: At the time of printing, multi-matrix mesalamine is not available in Canada.