Plecanatide, a Guanylate Cyclase C Agonist, Improves Bowel Habits and Symptoms Associated with Chronic Constipation in a Phase IIa Clinical Study

Abstract

Purpose: Plecanatide is a superior analog of uroguanylin, which is a physiological ligand of GC-C receptors that are expressed on the luminal surface of epithelial cells lining the GI mucosa. Activation of GC-C receptors stimulates production of cyclic guanosine monophosphate (cGMP), resulting in activation of cystic fibrosis transmembrane conductance regulator (CFTR) and in secretion of ions and fluid in the GI lumen. Sufficient fluid secretion is critical for normal bowel movement. This study evaluated the safety and effectiveness of once daily plecanatide in patients with chronic constipation (CC). Methods: Patients who met modified Rome III criteria for CC and had < 6 SBMs and < 3 CSBMs in each of two pre-treatment weeks were randomized into one of four plecanatide dose groups (0.3, 1.0, 3.0, and 9.0 mg) utilizing a double blind placebo controlled, dose-escalation and repeated dose trial design for 14 days. A total of 84 patients were enrolled (22 placebo; 62 plecanatide) and 74 completed the study per protocol (17 placebo; 57 plecanatide). Patients recorded constipation symptoms and number of bowel movements in a diary. Results: Daily treatment with plecanatide resulted in rapid improvements in bowel habits including complete spontaneous bowel movements (CSBMs), spontaneous bowel movements (SBMs), stool consistency, and straining. Abdominal discomfort, constipation severity and overall relief were also improved. The median change from baseline in CSBMs was 3.0 for patients receiving 1.0 mg plecanatide vs. 0.5 for placebo patients. The median time to first bowel movement in plecanatide-treated patients was considerably shorter than that in placebo patients. At Day 14, a greater proportion of patients treated with plecanatide compared to placebo-treated patients had either complete or considerable relief of constipation (42 vs 24%), and none or very mild abdominal discomfort (56 vs 29%). Plecanatide was well tolerated and there was no detectable systemic absorption, and none of the patients treated with plecanatide experienced diarrhea. Conclusion: Plecanatide was safe, well tolerated, and it improved bowel habits when compared with placebo across all doses. Moreover, the effects tended to be rapid and sustained. A large multicenter trial is planned to study plecanatide in CC patients to further evaluate efficacy and safety. Disclosure: Kunwar Shailubhai, Employee of Synergy Pharma Laura Barrow, Employee of Synergy Pharma Stephen J. Comiskey, Employee of Synergy Pharma John Foss, Employee of Synergy Pharma Rong Feng, Employee of Synergy Pharma Alan Joslyn, Director, Synergy Pharma Gary Jacob, Employee of Synergy Pharma.Figure: No Caption available.