HONOLULU — A novel, once-daily high-strength formulation of 5-aminosalicylic acid proved effective for the induction of remission and other end points in patients with active, mild to moderate ulcerative colitis in two large, multicenter, phase III clinical trials presented at the annual meeting of the American College of Gastroenterology.
Mesavance, an investigational agent, has two key advantages over standard mesalamine, noted Gary R. Lichtenstein, M.D. It is released throughout the colon, creating the potential for enhanced efficacy, and can be given once daily, rather three or four times per day as with current oral formulations of mesalamine.
“Once-daily administration is likely to increase patient convenience and compliance, and hence is likely to improve outcomes,” observed Dr. Lichtenstein, professor of medicine at the University of Pennsylvania, Philadelphia.
The compliance issue has recently taken on increased visibility as a result of a study by Sunanda Kane, M.D., of the University of Chicago, who found up to 68% of ulcerative colitis patients don't take their prescribed mesalamine regularly (Practical Gastroenterology 2004;28:16–22).
Mesavance consists of 5-aminosalicylic acid incorporated into a proprietary drug delivery system. Each tablet contains 1.2 g of 5-aminosalicylic acid in a lipophilic matrix dispersed within a hydrophilic matrix. The tablet is coated with a polymer film that breaks down at pH 7 in the terminal ileum, where the hydrophilic matrix begins to erode, and the 5-aminosalicylic acid starts diffusing out of the lipophilic matrix.
William J. Sandborn, M.D., reported on 343 patients who were randomized to 8 weeks of Mesavance at 2.4 g or 4.8 g once daily, Asacol at 0.8 g t.i.d., or placebo.
The primary end point in the double-blind study was induction of remission, rigorously defined by an Ulcerative Colitis Disease Activity Index score of 1 or less, together with a rectal bleeding and stool frequency score of zero and at least a 1-point reduction in sigmoidoscopy score from baseline. Both doses of Mesavance proved to be more effective than placebo at achieving remission. In contrast, Asacol showed only a nonsignificant trend to be better than placebo. (See box.)
Patients in both Mesavance arms also showed significantly greater clinical improvement, clinical remission, and sigmoidoscopic improvement than did those in the placebo group. The clinical remission rate, as defined by complete resolution of symptoms, wasn't significantly greater with Asacol than with placebo.
The study was not large enough to allow statistically meaningful direct comparisons of efficacy between Mesavance and Asacol, said Dr. Sandborn, professor of medicine at the Mayo Medical School, Rochester, Minn.
Dr. Lichtenstein presented a separate, double-blind study involving 280 ulcerative colitis patients randomized to 8 weeks of Mesavance at 1.2 g b.i.d. or 4.8 g once daily, or placebo. The primary end point—induction of remission—was achieved in 34% of patients on twice-daily Mesavance, in 29% with once-daily Mesavance, and in 13% with placebo. The remission rate in the Mesavance groups diverged from placebo as early as week 2.
Physician global assessment ratings ranked 64% of patients as significantly improved on twice-daily Mesavance, as were 66% on once-daily Mesavance and 39% on placebo, the gastroenterologist said. Mesavance was well tolerated in both studies, exhibiting a minimal side effect profile similar to that of available oral mesalamine products.
Dr. Lichtenstein and Dr. Sandborn are consultants to Shire Pharmaceuticals Group. It plans to file for marketing approval for Mesavance with the Food and Drug Administration by year's end.