Tenapanor is a small-molecule inhibitor of the intestinal sodium/hydrogen exchanger 3 (NHE3) that is little absorbed and authorized for the treatment of irritable bowel syndrome with constipation (IBS-C). Tenapanor reduced intestinal permeability, suppressed TRPV1 signaling, and was related to decreased visceral hypersensitivity and abdominal discomfort in preclinical trials. Using data from T3MPO-2, a long-term phase 3 research of tenapanor, researchers sought to assess the effects of tenapanor on the multi-item abdominal score.
During a 2-week screening period, patients with IBS-C who had <3 weekly full spontaneous bowel movements and a weekly abdominal pain score of ≥3 (0-10 scale) were assigned to tenapanor 50 mg or placebo twice a day in a 26-week randomized treatment period (RTP). Using an eDiary, patients assessed 5 abdominal symptoms on an 11-point scale (0=no symptom to 10=worst possible discomfort). The average of the weekly scores for stomach pain, discomfort, and bloating is known as the abdominal score 3 (AS3). The average weekly score for cramping, bloating, fullness, and abdominal pain is known as the abdominal score 5 (AS5). Using mixed-effects models with repeated measurements, the overall change from baseline (CFB) in the 26-week RTP and the week 26 CFB in AS3 and AS5 were compared across arms. Along with the Wilcoxon rank sum test, the cumulative distribution of CFB in AS3 or AS5 at week 26 was compared. Pearson’s chi-square test was used to compare the 13/26-week AS3 or AS5 response, which was defined as attaining a decrease of ≥2 points in AS3 or AS5 for ≥13 weeks of the 26-week RTP.
A total of 620 participants were randomized in T3MPO-2. Tenapanor had a larger mean decrease in AS3 than placebo over the 26-week RTP (-2.74 vs -2.15, P=0.0001) and at week 26 (-3.27 vs -2.60, P=0.0007) in the intent-to-treat analysis set (tenapanor, n=293; placebo, n=300). Cumulative distribution of CFB at week 26 was substantially more favorable to tenapanor than to placebo (P=0.0094). Additionally, the 13/26-week AS3 response rate was greater in the tenapanor arm than the placebo (46.4% vs. 35.7%, P=0.0078). Tenapanor similarly enhanced the mean CFB (P=0.0001), distribution of CFB at week 26 (P=0.0121), and 13/26-week response rate (P=0.0015) for AS5.
Few IBS-C therapies reduce or eliminate bloating, pain, or discomfort in the abdomen. The post hoc study showed that tenapanor considerably reduced abdominal symptoms linked to IBS-C with an early beginning of activity that was maintained over the course of treatment.