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73rd Annual Meeting of the American College of Gastroenterology

Orlando, Florida / October 3-8, 2008

The practical advantages of 5-aminosalicylic acid (5-ASA) as the first-line therapy for ulcerative colitis (UC) are recognized in several treatment guidelines. The tolerability is a major advantage over alternatives among those who respond, but adequate response is increasingly being defined as endoscopic healing because of evidence that this leads to more prolonged remissions than symptom relief alone. In two phase III trials with the controlled-released form of 5-ASA called mesalamine MMX (multi matrix system), endoscopic healing was achieved in approximately 40% of patients within eight weeks of initiating therapy using strict criteria. Although a greater rate of healing was achieved when treatment was extended, there was concern about a delay to symptom relief. The goal of a new analysis was to understand whether extension regimens are clinically acceptable.

“The extension study demonstrated that there is more healing with longer courses, but keeping patients on 5-ASA for long periods may not be clinically feasible if symptoms persist,” reported Dr. William J. Sandborn, Inflammatory Bowel Disease Clinic, Mayo Clinic, Rochester, Minnesota. “The goal of this post-hoc analysis was to examine how quickly patients in the extension study achieved complete symptom resolution on their way to healing, which is an important measure of whether we can get patients to stick with this therapy.”

The median time to symptom relief of 15 days was documented using strict UC-Disease Activity Index (UC-DAI) scores of 0 for the major symptoms of rectal bleeding and stool frequency as monitored daily. Symptom improvement occurred within days of initiating treatment. From the patient perspective, the rapid control of symptoms is likely to allow a substantial proportion of patients to circumvent the need to consider less well tolerated alternatives, such as steroids or other immunosuppressive therapies.

The two pivotal phase III studies, which evaluated mesalamine MMX over eight weeks in patients with mild to moderate active UC, have been published previously. One randomized trial included 343 patients (Kamm et al. Gastroenterology 2007;132:66-75), while the other enrolled 280 patients (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102). The results of the extension study were first presented at the 2007 meeting of the ACG (Lichtenstein et al. ACG 2007, Philadelphia).

Extension Study Findings

The extension trial included 304 patients who had not achieved mucosal healing at the end of the first eight weeks. This included patients on active treatment or on placebo. When entered into the eight-week extension study in which all patients received mesalamine MMX in a daily dose of 4.8 g, 59.5% of patients achieved mucosal healing as defined by the strict criteria in the pivotal trials (UC-DAI score of <u><</u>1 calculated as scores of 0 for rectal bleeding and stool frequency and a combined Physician’s Global Assessment and sigmoidoscopy score of <u><</u>1; no mucosal friability was permitted).

Of the 181 patients who achieved both clinical and mucosal healing in the extension study, 77 (42.5%) had received eight weeks of mesalamine MMX in one of the previous phase III studies. Most of the remaining patients had received placebo or had been randomized to an alternative 5-ASA formulation.

Figure 1. Time to initial resolution of rectal bleeding and high stool frequency in patients who achieved clinical and endoscopic remission after up to 8 weeks

While the efficacy of mesalamine MMX was expected in patients who had not been exposed previously to active therapy, the high rate of strictly defined healing in patients who had failed an initial course provides a strategy for re-trying 5-ASA before moving to immunosuppressive agents.

“We have had prior evidence that patients who are not well controlled on an initial eight-week course can still be healed if kept on therapy for a longer period, but I think these data provide some guidance about how this can be achieved in a practical approach,” Dr. Sandborn remarked. “While healing is now recognized as important in regard to long-term outcome, the immediate concern of the patient is the control of symptoms.”

Remission Strictly Defined

The evidence that healing is an important predictor of long-term disease control was the basis for requiring stringent definitions of mucosal healing in the pivotal trials of mesalamine MMX. Dr. Sandborn reported that these were the first UC efficacy trials to define endoscopic healing as the absence of mucosal friability, but this end point is supported by the importance of complete mucosal healing for reducing the risk of relapse. He expects regulatory agencies to require similarly stringent end points in future efficacy studies.

“I think it is now well accepted that symptom control is not enough. In a recurrent and chronic disease like UC, disease quiescence appears to depend on control of disease activity as it is measured in the mucosa,” Dr. Sandborn stated. He indicated that it has been reassuring that the first-line therapy of 5-ASA could provide this level of disease control in a substantial proportion of the population.

The issue of whether all 5-ASA preparations are equally effective is unresolved because of the absence of controlled trials. MMX mesalamine was the first 5-ASA approved for once-daily dosing, but other delayed-release 5-ASA treatments are available or in development. These involve a variety of technologies meant to delay drug release until the agent has reached the site of inflammation, prolong the activity of the agent to increase the dosing intervals, or both. The MMX technology includes a gastro-resistant film that delays release of the 5-ASA contents until the pH is 7 or higher, which occurs in the terminal ileum. Once the film disintegrates, hydrophilic excipients cause the tablet to swell into a viscous gel that is designed to slow diffusion as it descends the colon.

“Once-daily dosing may not be as important in patients who are symptomatic, but this has the potential for being a very big advantage once the symptoms are controlled and we try to achieve and maintain healing,” noted Dr. Gary Lichtenstein, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia. Senior author of one of the phase III studies and co-author of the extension study, Dr. Lichtenstein agreed with Dr. Sandborn that the current results provide a strategy for maximizing the proportion of patients who can be maintained on 5-ASA without having to move to less well tolerated alternatives.

Summary

In two previously published multicentre studies, the 5-ASA formulation mesalamine MMX was associated with clinical remission and endoscopic healing, defined as a complete absence of mucosal friability, in approximately 40% of patients. In an extension study that included those who were unhealed, whether on placebo or a previous course of active therapy, the overall healing rate was increased to approximately 60%. In the second round of therapy in which all patients received 4.8 g of mesalamine MMX per day, the median time to complete symptom relief was only 15 days, indicating that a second round of therapy in initial treatment failures is a viable and an acceptable strategy relative to immediately switching to less well tolerated immunosuppressive agents.