Plecanatide, a Novel Uroguanylin Analog: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate Efficacy and Safety in Patients With Irritable Bowel Syndrome With Constipation (IBS-C)

Introduction: Plecanatide is a minimally absorbed peptide analog of uroguanylin, the naturally occurring ligand for the human intestinal guanylate cyclase-C receptor. The objective of this trial was to assess the safety and efficacy of a range of plecanatide doses in patients with IBS-C. Methods: We performed a multicenter, double-blind, placebo-controlled, parallel-group study of 424 patients with IBS-C. Patients were randomly assigned to groups given 0.3, 1.0, 3.0, or 9.0 mg oral tablet plecanatide or placebo once daily for 12 weeks. The primary and secondary efficacy assessments were evaluated over 12 weeks of treatment. Primary efficacy endpoint was change from baseline in complete spontaneous bowel movements (CSBMs). Key secondary efficacy endpoints included change from baseline in worst abdominal pain intensity (0-10 point severity scale), the Food and Drug Administration’s (FDA’s) overall responder endpoint for IBS-C (responder: a patient who reported (i) improvement of ≥ 30% from baseline in average daily worst abdominal pain score and (ii) increase of ≥ 1 CSBM from baseline, both in the same week for ≥ 6/12 weeks), change in stool consistency using the Bristol Stool Form Scale (BSFS), and other secondary endpoints based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. Results: Plecanatide 1.0, 3.0, and 9.0 mg dose groups had significantly improved weekly rates of CSBM frequency (primary endpoint) compared with placebo; the increases were 2.12, 2.74, and 2.44 for plecanatide doses 1.0, 3.0, and 9.0 mg, respectively (p ≤. 05 for each pair-wise comparison). Notably, plecanatide 3.0 mg dose significantly improved all important secondary endpoints: change from baseline in worst abdominal pain intensity, FDA overall responder endpoint, stool consistency and straining. The 9.0 mg dose demonstrated statistical improvement on the FDA overall responder endpoint, stool consistency and straining and numerical improvement on worst abdominal pain intensity. The most common adverse event was diarrhea (9.4% at 1.0 mg, 9.3% at 3.0 mg, and 11.8% at the highest 9.0 mg dose). Conclusion: Plecanatide therapy was safe and well-tolerated and produced rapid and clinically relevant improvement of bowel habits and abdominal pain in patients with IBS-C. Disclosure - Kunwar Shailubhai, Laura Barrow, Patrick Griffin, Gary Jacob are employees of Synergy Pharmaceuticals, Inc. Phil Miner is a consultant to Synergy Pharmaceuticals, Inc.