Week 1 Changes in Bowel and Abdominal Symptoms Following Linaclotide Treatment: Results from Two Phase 3 Trials in Chronic Constipation Patients

Abstract

Purpose: Linaclotide, a first-in-class, minimally-absorbed, guanylate cyclase type-C receptor agonist, statistically significantly improved bowel and abdominal symptoms, and patient global assessments in chronic constipation (CC) and irritable bowel syndrome with constipation patients in Phase 2b trials. Two recent, randomized, double-blind, Phase 3 trials (MD-01 and 103-303) in patients with CC demonstrated statistically significant improvements in bowel and abdominal symptoms. The aim of this analysis is to determine the time to onset of symptom changes following treatment initiation in both Phase 3 trials. Methods: 1272 patients who met modified Rome II criteria for CC, and had <3 complete spontaneous bowel movements (CSBM) per week and ≤6 SBMs per week during a 2-week baseline period were randomized to oral once-daily 133 or 266μg linaclotide or placebo for 12 weeks. Results: In pooled analyses, 67% and 57% of linaclotide 133 and 266 μg patients had an SBM within 24 hours following initial study drug dosing, vs. 39% for placebo (both P<0.0001); for CSBM results, 31% and 28% of Linaclotide 133 and 266μg patients had a CSBM vs. 12% for placebo (both p<0.0001). Results by study for bowel symptoms and weekly constipation severity were also statistically significantly improved for linaclotide vs. placebo (p<0.0001) after 1 week of treatment (Table). Statistically significant improvements in bloating and abdominal discomfort were obtained at Week 1 and Week 2 of treatment, respectively. Bowel and abdominal symptom improvements were seen throughout the 12-week treatment period. The week 1 incidence of diarrhea across both studies was 8%, 8%, and 1% for the 133μg, 266μg, and placebo groups, respectively. Conclusion: Once daily doses of linaclotide resulted in early and sustained statistically significant improvements in bowel and abdominal symptoms during treatment of patients with CC. Diarrhea was the most common adverse event.Table: [1303] Week 1 change from baseline in CC symptoms, by doseDisclosure: A. Lembo - Paid Consultant: Ironwood Pharmaceuticals. H. Schneier and S. Shiff - Employees: Forest Research Institute and owner of stock/stock options in Forest Labs. B. Lavins, J. MacDougall, C. Kurtz, O'Dea, M. Currie, and J. Johnston - Employees of and owners of stock/stock options in Ironwood Pharmaceuticals. Disclosure: Funded by Ironwood Pharmaceuticals and Forest Laboratories.