Linaclotide Significantly Improved Abdominal Pain, Constipation and Global Assessments in Adults with Irritable Bowel Syndrome with Constipation

This is the authors' abstract. We don't add key points for this paper.

Purpose: Linaclotide, a first-in-class, minimally absorbed peptide agonist of human intestinal guanylate cyclase type-C receptors, is a novel treatment for irritable bowel syndrome with constipation (IBS-C). Linaclotide significantly relieved visceral hyperalgesia in several animal pain models and, in a large Phase 2 study in patients with chronic constipation, significantly improved bowel function and abdominal symptoms. A Phase 2 study was conducted to evaluate the safety and efficacy of a range of linaclotide doses in adults with IBS-C. Methods: This randomized, multicenter, double-blind, placebo-controlled, dose-range-finding, parallel-group study evaluated the effects of 75, 150, 300 or 600 μg linaclotide or placebo administered orally once daily to adults meeting modified Rome II criteria for IBS-C. Participants underwent 2-week-baseline, 12-week-treatment, and 2-week-post-treatment evaluations with daily assessments of bowel habits and symptom severity, and weekly global assessments using an interactive voice response system. During the baseline period patients had to demonstrate < 3 complete spontaneous bowel movements (CSBM)/week and mean daily abdominal pain of at least mild severity. Treatment effects in the intent-to-treat (ITT) population were estimated using an analysis of covariance and the Cochran-Mantel Haenszel test. Results: Of the 420 patients randomized, 419 were in the ITT population and 337 completed the study. Abdominal pain was clinically and statistically significantly improved in all linaclotide treatment groups compared to placebo and, in the 26% of patients with severe/very severe baseline abdominal pain, improvement was even more pronounced (see Table). The change from baseline vs placebo for CSBM frequency (primary endpoint) was significant at all linaclotide dose levels. Results for other abdominal symptoms and bowel habits, and for 3 global assessments (binary adequate relief, 7-point balanced degree of relief, and 5-point IBS symptom severity) were highly statistically significant for the 300 μg and 600 μg dose groups. Treatment effects of linaclotide were rapid in onset (within the first week of treatment) and were maintained throughout the entire 12-week treatment period; there was no indication of rebound clinical effects following cessation of treatment. The most common adverse event was diarrhea; however, there were no associated dehydration or electrolyte abnormalities and discontinuations for diarrhea were infrequent (see Table).TableConclusion: Once daily oral linaclotide across a wide dose range improved all measured bowel habits, abdominal symptoms and global assessments in patients with IBS-C with a safety and tolerability profile that supports advancing this novel compound into Phase 3 clinical trials.