An Open Label Long-Term Safety Trial (T3MPO-3) of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation (IBS-C): Presidential Poster Award

Abstract

Introduction: Tenapanor is a locally acting, minimally absorbed, and selective small molecule inhibitor of the intestinal sodium-hydrogen exchanger-3 (NHE3), which increases intestinal sodium and fluid in a dose-dependent fashion. In preclinical models, tenapanor has also been shown to reduce abdominal pain through inhibition of TRPV-1 signaling and by decreasing intestinal cell permeability. In two previously completed phase 3 trials (T3MPO-1 and T3MPO-2), tenapanor 50 mg twice daily met the primary endpoint and significantly improved the key symptoms of IBS-C compared to placebo (NCT02621892 and NCT02686138). The objective of this trial was to evaluate the long term safety of tenapanor in patients for the treatment of IBS-C in an up to 39 week extension study. Methods: In this open label safety study (NCT02727751), patients who completed either the T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) trial were eligible for enrollment. Visits were scheduled approximately every 13 weeks at which time patients underwent safety assessments at these visits, which including a physical exam, ECG, vital signs, and clinical labs. Adverse events and concomitant medications were recorded. Results: The intention-to-treat population included 240 patients, mean age = 49.6, and 80.8% women. Based on enrollment from each parent study the intended treatment duration ranged from 44 to 56 weeks. 84% of patients completed the study with a mean drug compliance rate of 97.9%. There were no deaths and three SAEs that were not drug related (leukocytosis, cervical fracture, and endometriosis). Overall, no notable changes over time in serum chemistry, hematology, or urinalysis were observed and there was no evidence of differences between cohorts. No notable changes from baseline or evidence of differences between cohorts were observed in physical examination or vital signs. There were no notable changes from baseline in heart rate, QTc interval, QTcB interval, QTcF interval, PR interval, or QRS interval during the study and no evidence of differences between cohorts. No patients experienced abnormal (clinically significant) ECG findings during the study.Diarrhea was the most common adverse event during the treatment period at a rate of 9.2% resulting in a discontinuation rate of 1.6%; there were no cases of severe diarrhea. The overall rate of discontinuations due to AEs was 2.1%. Conclusion: Tenapanor 50 mg BID was generally safe and well-tolerated when administered for up to 52 consecutive weeks.