Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study.

BACKGROUND: Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. METHODS: Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. KEY RESULTS: A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. CONCLUSIONS: Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.

Plecanatide Improves Symptoms of Irritable Bowel Syndrome with Constipation: Results of an Integrated Efficacy and Safety Analysis of Two Phase 3 Trials.

Purpose: Patients with irritable bowel syndrome with constipation (IBS-C) experience abdominal pain with altered bowel movements. Plecanatide is indicated as IBS-C treatment in adults. This integrated analysis further characterizes plecanatide efficacy and safety in IBS-C. Patients and Methods: Data pooled from 2 identically designed phase 3 trials included adults with IBS-C randomized to plecanatide 3 mg or 6 mg, or placebo once daily for 12 weeks. A daily diary recorded stool frequency/symptoms, with abdominal pain, bloating, cramping, discomfort, fullness, and straining intensity individually rated. Overall response (primary endpoint) was defined as ≥30% improvement from baseline in average worst abdominal pain severity and increase of ≥1 complete spontaneous bowel movement, during same week (composite), for ≥6 of 12 weeks. Secondary endpoints included sustained response (overall response, plus meeting weekly composite criteria during ≥2 of last 4 treatment weeks) and changes from baseline in individual symptoms. Safety assessments included adverse event monitoring. Results: Overall, 2176 patients (74.0% female; mean [SD] age, 43.5 [14.1] years) were included in efficacy analyses (plecanatide 3 mg [n = 724], 6 mg [n = 723], placebo [n = 729]). A significantly greater percentage of patients achieved overall response with plecanatide 3 mg (25.6%) and 6 mg (26.7%) versus placebo (16.0%; both P < 0.001 vs placebo). A significantly greater percentage of patients were sustained responders with plecanatide 3 mg (24.3%) and 6 mg (25.6%) versus placebo (15.6%; both P < 0.001 vs placebo). Significant improvements from baseline in abdominal discomfort, abdominal fullness, abdominal pain, bloating, and cramping occurred as early as Week 1 (Week 2 for abdominal pain) with plecanatide and were maintained through Week 12 versus placebo. Diarrhea, the most common adverse event, occurred in 4.3% (3 mg), 4.0% (6 mg) and 1.0% (placebo) of patients, leading to study discontinuation in 1.2%, 1.4%, and 0 patients, respectively. Conclusion: Plecanatide is safe and effective for treating global and individual IBS-C symptoms.

Plecanatide Is Effective and Safe in the Treatment for Chronic Idiopathic Constipation: Results of a Phase II Trial.

BACKGROUND: Many patients with chronic idiopathic constipation (CIC) remain unsatisfied with their treatment options. Plecanatide is a pH-sensitive uroguanylin analog that increases fluid and ion movement into the gastrointestinal lumen, softening stools and encouraging motility, while limiting the risk of diarrhea. AIMS: The objective of this phase 2 study is to evaluate the safety and efficacy of once-daily oral plecanatide in patients with CIC and identify the most effective dose. METHODS: A 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in patients aged 18-75 years and diagnosed with CIC based on modified Rome III criteria (< 3 complete spontaneous bowel movements [CSBMs] per week and infrequent loose stools without the use of laxatives). Participants were randomized to placebo or plecanatide 0.3, 1.0, or 3.0 mg. The primary efficacy endpoint was the proportion of overall CSBM responders. Key secondary endpoints included time to first CSBM, change in CSBM and spontaneous bowel movement (SBM) frequency rates, patient-reported outcomes, safety, and tolerability. RESULTS: Of 951 randomized participants, 946 were included in the modified intent-to-treat population. Plecanatide 0.3 and 3.0 mg significantly increased overall CSBM responder rates compared with placebo (0.3 mg, P = 0.016; 3.0 mg, P = 0.009). Plecanatide was associated with decreased time to first CSBM, significant increases in CSBM and SBM frequency, and decreased patient-reported constipation severity compared with placebo. Diarrhea was the most frequently reported treatment-emergent adverse event. CONCLUSIONS: Plecanatide is a well-tolerated treatment that relieved the symptoms of CIC with a relatively low incidence of diarrhea.