Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Digestive Disease Week (DDW) 2008

San Diego, California / May 17-21, 2008

A variety of salicylates or agents that contain 5-aminosalicyclate (5-ASA) have been associated with symptom improvement in ulcerative colitis (UC). Differences in efficacy between 5-ASA formulations may be due to specific chemical structures or to the efficacy of strategies developed to deliver active therapy to the colon. Among competing forms of mesalamine, one of the most widely used types of 5-ASA, the technology to maximize exposure to the inflamed tissue has implications not only for efficacy but also for frequency of dosing. In trials testing a technology called the Multi Matrix System (MMX), two goals were tested and confirmed in the landmark studies. The first was to show that the MMX strategy to increase drug delivery to the colon permitted once-daily dosing. The second and more important was to demonstrate reliable and sustained healing. As a result of these studies, “MMX mesalamine is the only mesalamine product with an approved indication for mucosal healing in Canada,” according to Dr. Remo Panaccione, Director, Inflammatory Bowel Disease Clinic and Associate Professor of Medicine, University of Calgary, Alberta.

Corroborative Findings on Sustained Remission

As one of the investigators involved in the MMX mesalamine acute treatment and sustained remission studies, Dr. Panaccione has presented data at previous meetings, including the Canadian Digestive Disease Week (CDDW), demonstrating that this q.d. formulation yields remission rates comparable to b.i.d. dosing, a major potential advantage for long-term compliance.

In the published trial that generated new data for the DDW analysis on time to response, 343 patients with active, mild-to-moderate UC were randomized to 2.4 g/day MMX mesalamine q.d., 4.8 g/day MMX mesalamine q.d., placebo, or a reference delayed-release mesalamine in a t.i.d. dose of 2.4 g/day (Kamm et al. Gastroenterology 2007;132:66-75). The primary end point was the proportion of patients in clinical and endoscopic remission at eight weeks using a very strict definition which included a UC Disease Activity Index (UC-DAI) of <u><</u>1.

In the published results, rates of clinical and endoscopic remission at eight weeks were almost twice as high on either q.d. dose of MMX mesalamine (40.5% for the 2.4 g/day, 41.2% for 4.8 g/day, and 22.1% for placebo: P=0.007 for 4.8 g/day vs. placebo). The remission rates were also higher than the reference delayed-release mesalamine given three times daily (32.6%), which was not statistically superior to placebo (P=0.124).

The same relationship of q.d. MMX mesalamine to placebo for clinical and endoscopic remission at eight weeks was observed in the second published trial, which randomized 280 patients to 1.2 g b.i.d. (2.4 g/day) MMX mesalamine, 4.8 g/day q.d. MMX mesalamine, or placebo (Lichtenstein et al. Clin Gastroenterol Hepatol 2007;5:95-102). While the MMX mesalamine doses were similarly effective for achieving clinical and endoscopic remission at eight weeks, both produced rates that were twice as great as placebo (29.2% for the q.d. regimen vs. 12.9% for placebo; P<0.01).

Maintenance Analysis Results

In a subsequent maintenance analysis that included 459 patients who participated in either of the acute mucosal healing studies, a q.d. strategy with MMX mesalamine yielded very substantial sustained remission rates at 12 months. The maintenance study included those patients who achieved a remission on the initial eight weeks of therapy and those patients who had not healed but accepted a second eight-week course of MMX mesalamine at a dose of 4.8 g/day. The second course of MMX mesalamine was even more effective than the first when evaluated as a per cent response. Of those who received a second course, 61% achieved both a clinical and endoscopic remission and were then eligible for long-term maintenance.

In this maintenance study, patients received either 2.4 g q.d. MMX mesalamine or 1.2 g b.i.d. MMX mesalamine. In the efficacy population (of 377 patients who completed the study), the sustained remission rates were 70.5% for those who had mild disease at entry and 64.2% in those with moderate disease. When the q.d. and b.i.d. formulations were compared, there was no significant efficacy difference for maintaining remission in those who entered with mild (P=0.653) or moderate disease (P=0.352).

Again, remission rates were based on rigorous predefined criteria for clinical and endoscopic remission. While the UC-DAI total score could not exceed 1.0, this score was tightly defined as a score of 0 for rectal bleeding and for stool frequency; a combined Physician’s Global Assessment (PGA) and sigmoidoscopy score of <u><</u>1; a reduction in sigmoidoscopy score of <u>></u>1 point from baseline; and no mucosal friability. Past scoring for remission has permitted mild mucosal friability. Relapse was defined as any medication other than MMX mesalamine or surgery or the need for a dose increase of MMX mesalamine.

The high rates of acute mucosal healing and sustained protection against relapse on q.d. dosing are credited largely to the MMX system, which employs two strategies to increase drug delivery at the site of disease activity. These are a pH-dependent film that coats the pill to protect the active drug from release as it passes through the upper gastrointestinal system, and a matrix that interacts with intestinal fluids through lipophilic and hydrophilic excipients to slowly release active drug as the pill passes through the lumen of the colon. By reducing the rate of dissolution, the therapeutic activity is prolonged, a critical feature for once-daily dosing.

Decreased Time to Resolution

The two large controlled trials indicated that the proportion of acute UC patients who achieve mucosal healing can be doubled by offering a second eight-week course of therapy to those who did not heal in the first eight weeks. This is an important finding in the effort to avoid less well tolerated treatments, such as steroids. However, new data from the study by Kamm et al. has documented a relatively rapid time to resolution of symptoms over the first eight weeks independent of mucosal healing.

In this post-hoc analysis, time to symptom resolution was measured in two ways. The first was the time between first dose and the first day with normalization of stool frequency, absence of rectal bleeding, or both. The second was the time between the first dose and the first three consecutive days of normalization of stool frequency, absence of rectal bleeding, or both. Again, the 2.4 g q.d. and the 4.8 g q.d. doses were compared with the three-times-daily alternative delayed-release mesalamine serving as a reference.

In this intention-to-treat analysis of 341 patients, the average time to the first day free of rectal bleeding was nine days with either the 2.4-g or the 4.8-g dose, which was significantly less than the 14 days required for placebo (P=0.0327) and about the same as the eight days associated with the three-times-daily mesalamine. For normalization of stool frequency, the average time was 20 days for the 2.4-g dose, 23 days for the 4.8-g dose, and 38 days for the placebo (P=0.021 vs. either dose of MMX mesalamine). The average time for the reference mesalamine group was 20 days. For the first day of resolution of both symptoms, the average times were 27 and 29 days, respectively, compared to 44 days (P=0.0282) for placebo. Again, the reference t.i.d. mesalamine was similarly effective with an average time of 30 days. Very similar differences were observed for the time to the first three consecutive days without symptoms. For both symptoms, the average number of days was 37 and 45, respectively, compared to 56 days (P=0.0189) for placebo. The reference medication achieved this end point in an average of 42 days.

“By demonstrating that MMX mesalamine significantly reduces the time it takes patients to achieve relief from symptoms relative to placebo, this analysis is important to patients and to physicians counselling patients about what to expect from therapy,” stated Dr. Gary Lichtenstein, Director, Inflammatory Bowel Disease Program, University of Pennsylvania, Philadelphia.

Summary

Two large studies have demonstrated that MMX mesalamine is effective in a q.d. dose for mucosal healing in patients with UC, a stringent end point that has been associated with greater likelihood of sustained remission. This efficacy is likely to be an important explanation for on-treatment remission rates that exceed 60% at 12 months. The ability to achieve this degree of control with a q.d. formulation has important relevance to the challenges of keeping UC patients compliant to maintenance therapies once their symptoms resolve.