ORP-101 in Irritable Bowel Syndrome With Diarrhea: A Phase II Randomized, Controlled Trial

Safe and effective treatment for irritable bowel syndrome with diarrhea (IBS-D) is needed. ORP-101 is a novel partial μ receptor agonist and full κ receptor antagonist designed to act peripherally without central nervous system exposure. This study evaluated the efficacy and safety of ORP-101 in IBS-D.

In this randomized, double-blind, adaptive design placebo-controlled trial, eligible participants were randomized to receive ORP-101 50 mg, 100 mg, or placebo once daily for 12 weeks. As part of the adaptive design, the 50 mg ORP-101 dose was discontinued after interim analysis. The primary endpoint was composite response status of improvement in abdominal pain (improvement of 30% from baseline) and stool consistency (average daily stool consistency <5 on the Bristol Stool Form Scale, or 30% improvement in abdominal pain if no bowel movement) for 50% of days over 12-week treatment period.

A total of 320 participants with IBS-D were randomized to ORP-101 50 mg (n = 65), 100 mg (n = 127), or placebo (n = 128). The proportion of primary endpoint responders for ORP-101 50 mg, 100 mg, and placebo participants was 16.9%, 28.3%, and 21.9%, respectively (P = .79 for the 3 groups and P = .12 for ORP-101 100 mg vs placebo). Secondary and exploratory endpoints favored ORP-101 100 mg vs placebo across multiple endpoints. ORP-101 was well-tolerated, including in those without gallbladders.

In this phase II trial, ORP-101 100 mg did not achieve a statistically significant difference vs placebo for the primary endpoint; however, it showed higher response across multiple key endpoints. Future studies will study ORP-101 in other chronic pain conditions.

gov, Number: NCT04129619.