REVERSE phase III study of obeticholic acid in compensated cirrhosis due to NASH did not meet its endpoint

No new safety signals for OCA were observed in this population of patients with cirrhosis.

REVERSE is one of Intercept’s two Phase III studies evaluating different populations in NASH. The Company’s planned NDA for its lead indication of liver fibrosis due to NASH will be supported by positive Phase III data from the REGENERATE study and is unaffected by the efficacy results of REVERSE. The Company is on track to resubmit its NDA in liver fibrosis due to NASH by the end of the year.

“Achieving statistical significance on a histology endpoint in compensated cirrhosis due to NASH has proven to be an extremely high bar in clinical trials and underscores the importance of treating liver fibrosis due to NASH before it progresses to cirrhosis,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “We remain confident in the potential role that OCA can play in liver fibrosis due to NASH and the Intercept team is focused on resubmitting our NDA in this indication based on the positive Phase III REGENERATE data.”

In the REVERSE study of 919 randomized subjects with compensated cirrhosis due to NASH, 11.1% (p=NS) of subjects who were randomized to receive once-daily oral OCA 10 mg and 11.9% (p=NS) of subjects who were randomized to receive OCA 10 mg titrated to 25 mg (OCA 10-to-25 mg) after three months achieved a greater than 1-stage improvement in fibrosis with no worsening of NASH after up to 18 months of treatment, compared with 9.9% of subjects who received placebo. Though the REVERSE study did not succeed on the histological evaluation of the primary endpoint, a positive impact on liver stiffness as defined by transient elastography was noted in both OCA 10 mg and OCA 10-to-25 mg arms. Safety was evaluated in 916 subjects who took at least one dose of study drug (placebo, OCA 10 mg or OCA 10-to-25 mg). Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs) and deaths were balanced across all treatment groups in REVERSE.

The most common TEAE was pruritus (31% in placebo, 41% in OCA 10 mg and 57% in OCA 10-to-25 mg) and pruritus was the most common reason for treatment discontinuation. Serious gallbladder-related events were balanced across arms (0.6% in placebo, 1.0% in OCA 10 mg, 1.0% in OCA 10-to-25 mg). Consistent with the known mechanism of action of FXR-agonists, the OCA 10-to-25 mg arm had a higher incidence of gallstones.

Independent experts reviewed certain categories of safety events to provide a blinded adjudication as specifically requested by FDA. These included events pertaining to hepatic safety, cardiovascular safety and renal safety. There was a numerical increase in the number of adjudicated hepatic safety events for the OCA-treated arms; most were mild in severity and related to biochemical changes. There were no severe or fatal adjudicated hepatic safety events in any treatment arm. Frequency of adjudicated kidney events and adjudicated major cardiac adverse events were balanced across treatment groups.