Chronic constipation is a functional gastrointestinal disorder affecting between 2% and 27% of the American population, and responsible for 2.5 million physician visits annually. Although it is a frequent complaint, existing treatment options --primarily fiber-, polyethylene glycol- and lactulose-based laxatives-- are considered unsatisfactory by both patients and physicians. Thus there is a clear need for new and improved bowel function-improving agents for the treatment of chronic constipation.

One such compound is linaclotide acetate, a 14-amino-acid peptide that acts as an agonist of human guanylate cyclase C (GC-C), a transmembrane protein located in intestinal epithelial cells. Activation of intestinal GC-C induces secretion of fluid, sodium and bicarbonate in the intestinal lumen. Linaclotide is being studied in phase III trials for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome (C-IBS). The compound was discovered by Microbia (since renamed Ironwood Pharmaceuticals) and has been licensed to Forest, Almirall and Astellas for various global markets.

Late last year, Ironwood and Forest reported positive topline results from two phase III clinical trials assessing the safety and efficacy of once-daily dosing of linaclotide acetate (133 or 266 mcg) in patients with chronic constipation. In both multicenter, randomized, double-blind, placebo-controlled trials, statistical significance was achieved at the primary endpoint: 12-week complete spontaneous bowel movement (CSBM) overall response at the two doses studied. In both trials, statistical significance was achieved at all prespecified secondary endpoints, which included measures of bloating, abdominal discomfort and average weekly CSBMs. Across both trials, the most common adverse events in linaclotide-treated patients were diarrhea, flatulence and abdominal pain. The companies are currently conducting two additional pivotal phase III trials in North America to assess the agent's safety and efficacy in irritable bowel syndrome with constipation. Results of these additional trials are expected in the second half of 2010.

Results of a phase IIb trial were also published recently (Lembo, A.J. et al., Gastroenterology 2010, 138(3): 886), supporting the efficacy and safety of linaclotide in patients with chronic constipation. Treatment of 310 patients with linaclotide acetate (administered at doses of 75, 150, 300 or 600 mcg p.o.) for 4 weeks led to rapid and sustained improvements in bowel habits, as seen by significant increases in the total weekly number of CSBM at all doses studied as compared to placebo. Improvements were also reported in abdominal symptoms, global relief and quality of life, and the drug was well tolerated, with diarrhea as the most common side effect.