Tenapanor: A Comprehensive Monograph on a First-in-Class NHE3 Inhibitor for Gastroenterological and Nephrological Disorders

Executive Summary

Tenapanor is a first-in-class, orally administered, small-molecule inhibitor of the intestinal sodium/hydrogen exchanger isoform 3 (NHE3).[1] Characterized by its minimal systemic absorption, Tenapanor exerts its pharmacological effects locally within the gastrointestinal tract, a property that underpins both its therapeutic efficacy and its distinct safety profile.[4] This targeted action has led to its approval for two separate and mechanistically distinct indications.

For gastroenterological applications, Tenapanor is marketed as Ibsrela® for the treatment of adults with Irritable Bowel Syndrome with Constipation (IBS-C).[1] By inhibiting NHE3, it reduces sodium absorption from the gut, leading to an osmotic influx of water into the lumen. This "retainagogue" effect softens stool, increases bowel movement frequency, and alleviates constipation. Concurrently, preclinical and clinical evidence suggests Tenapanor reduces visceral hypersensitivity, thereby addressing the abdominal pain and bloating characteristic of IBS-C.[4] Its efficacy was established in the comprehensive T3MPO Phase 3 clinical trial program, which demonstrated statistically significant and sustained improvements in the composite endpoint of abdominal pain and bowel movement frequency compared to placebo.[8]