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PRIORITY PRESS Canadian Digestive Diseases Week (CDDW) 2009

Banff, Alberta / February 27-March 2, 2009

The substantial proportion of ulcerative colitis (UC) patients who can achieve strictly defined mucosal healing on a controlled-release formulation of mesalamine has been previously published. In a combined analysis of two phase III studies with the Multi Matrix (MMX) system mesalamine formulation, nearly 40% were healed on an eight-week course. In an extension study that recruited patients who did not achieve mucosal healing within the first eight weeks of therapy, 59.9% were healed in a subsequent eight-week course on 4.8 g daily of the same controlled-release formulation. In a new evaluation of that extension data, the median time to symptom resolution on the second course of treatment was 15 days.

A Second Chance to Heal

As reported by Dr. Remo Panaccione, Division of Gastroenterology, University of Calgary, Alberta, senior author in a panel review of the new findings, “Most physicians agreed that this is exciting data and in fact may change treatment paradigms.” Although the previous data provided a proof of concept regarding the ability of a treatment extension to increase rates of healing, the new findings put the data into a clinical context. These data permit clinicians and patients to weigh the risks and benefits of extending the MMX treatment course to avoid steroids.

According to Dr. Panaccione’s interpretation of these data, an additional eight weeks of this treatment would make sense within an effort to avoid more aggressive therapy, “as long as patients are not worsening and progressively improving,” he cautioned. Based on the new evidence that the average patient with mild-to-moderate UC can anticipate symptom control within about two weeks of starting a second eight-week course of mesalamine, clinicians have an evidence basis on which to counsel patients.

“This decision would be one made by the physician and patients after discussing the pros and cons of escalating to prednisone or holding the course with MMX mesalamine,” Dr. Panaccione told delegates. He indicated that many well-informed patients might be likely to seek an opportunity to avoid step-up treatment. Once healed, the likelihood of a sustained response on a maintenance regimen is strong.

Study Findings

Of the two initial phase III studies, one randomized mild-to-moderate UC patients to 2.4 g MMX mesalamine b.i.d., 4.8 g MMX mesalamine q.d., or placebo (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102). The other had a similar design but included an active control arm of a second delayed-release mesalamine preparation in a daily dose of 2.4 g/day administered in three divided doses (Kamm et al. Gastroenterology 2007;132:66-75). In the first study, mucosal healing rates were more than double on MMX mesalamine vs. placebo, reaching nearly 40% overall (the two doses had similar efficacy). In the second study, the rate of healing was about 50% greater relative to the alternative delayed-release mesalamine, which was not statistically superior to placebo.

While those who healed went on to a maintenance trial that evaluated disease control over the subsequent six months, 304 patients who had not achieved clinical and endoscopic remission by the end of the initial eight weeks were entered into an open-label study in which a second course of mesalamine in a dose of 2.4 g b.i.d. (4.8 g/daily) was administered for eight weeks. In all these studies, including the maintenance studies, the primary end point was a strict definition of clinical and endoscopic remission (Figure 1). The criteria included no rectal bleeding, a stool frequency score of zero, UC disease activity index of <u><</u>1, and <u>></u>1 point reduction in sigmoidoscopy score.

Figure 1.

At the end of eight weeks, 181 (59.5%) of the patients had achieved mucosal healing. The rates of healing were substantial whether patients had been previously randomized to placebo, MMX mesalamine, or the alternative mesalamine. Again, the median time to symptom resolution among those who achieved mucosal healing was 15 days.

Mucosal Healing Vital

Once healing is achieved, it is durable. When the 346 patients who went on to MMX mesalamine maintenance after healing on one or two eight-week courses of acute treatment were evaluated, 196 (56.6%) remained relapse-free even when counting the 107 patients who withdrew or were excluded over the course of the 12-month follow-up. Of these early withdrawals, only 69 failed to complete the maintenance course for lack of efficacy. Other reasons for withdrawal included non-compliance, subject request, and loss to follow-up. Only nine patients (<3% of the total mesalamine-treated patients) dropped out due to a potentially treatment-related adverse event. There were no serious adverse events considered to be treatment-related.

As strictly defined in this study, mucosal healing, which disallowed any degree of mucosal friability, may explain the results. In several studies, including those conducted with monoclonal antibodies in more advanced disease, complete mucosal healing has been an important predictor of sustained mucosal healing. While symptom control is the immediate priority for patients, there is a growing body of evidence that the risk of relapse is strongly correlated with the absence of disease activity on endoscopic examination. Based on these data, mucosal healing is now increasingly considered to be the standard for demonstrating treatment efficacy. As UC is a potentially progressive disease, sustained disease protection from flares may have important implications for long-term outcome, including a reduced risk of surgical resection.

Although eight weeks has been previously considered to be an adequate trial of mesalamine before moving to alternative therapies, the more recent data encourage an extended trial and supply specific numbers with which to inform patients about likelihood of response. Many patients may be unwilling to endure further uncontrolled symptoms after an eight-week course of therapy, but steroids are much less well tolerated than 5-ASA medications and pose a significant risk for a number of complications, including steroid dependence. Although a substantial proportion of patients with mild-to-moderate UC will achieve healing on an initial eight-week course of MMX mesalamine, those who do not can be reassured that there is a good chance of both symptom relief and mucosal healing with an extension of therapy, providing an opportunity to avoid steroids.

Summary

New data from the phase III studies with MMX mesalamine have provided objective numbers with which to counsel UC patients about the likelihood of healing on a second eight-week course of therapy when healing has not been achieved on an initial course. Of particular importance to patients with persistent symptoms, the study findings yield an median time to symptom resolution of 15 days, an important variable for individuals attempting to weigh the desire for symptom relief against the relative safety advantages of achieving control on the first-line agent. Once healed, whether on an initial or a second course of MMX mesalamine, disease control over the following year can be anticipated in the majority of patients, underscoring the importance of a healing end point with first-line therapy.