Positive topline results from pivotal phase III REGENERATE study of obeticholic acid in patients with liver fibrosis due to NASH.- Intercept Pharma

Intercept Pharmaceuticals, Inc. announced positive results from its pivotal Phase III REGENERATE study of obeticholic acid (OCA) in patients with liver fibrosis due to nonalcoholic steatohepatitis (NASH). In the primary efficacy analysis, once-daily OCA 25 mg met the primary endpoint of fibrosis improvement (greater than 1 stage) with no worsening of NASH at the planned 18-month interim analysis (p=0.0002 vs. placebo). In the primary efficacy analysis, a numerically greater proportion of patients in both OCA treatment arms compared to placebo achieved the primary endpoint of NASH resolution with no worsening of liver fibrosis, but this did not reach statistical significance. As agreed with the FDA, in order for the primary objective to be met, the study was required to achieve one of the two primary endpoints.

Based on these results, Intercept intends to file for approval in the U.S. and Europe in the second half of 2019. OCA remains the only investigational drug to have received Breakthrough Therapy designation from the FDA for NASH with fibrosis. REGENERATE results will be presented at the European Association for the Study of the Liver (EASL): The International Liver CongressTM 2019..

The primary efficacy analysis (Intent-to-Treat (ITT) assessed efficacy at 18 months in 931 patients with stage 2 or 3 liver fibrosis due to NASH. Overall study discontinuations in the primary efficacy analysis population were balanced across treatment arms: 16% in placebo, 17% in OCA 10 mg and 15% in OCA 25 mg. An additional pre-specified full efficacy analysis at 18 months added an exploratory cohort of 287 NASH patients with stage 1 liver fibrosis and additional risk factors who were at increased risk of progression to cirrhosis (N=1,218). Patients with biopsy proven NASH with fibrosis were randomized 1:1:1 to receive placebo, OCA 10 mg or OCA 25 mg once daily. A repeat biopsy was conducted after 18 months for histologic endpoint assessment. Patients without a repeat biopsy due to study discontinuation or other reason were treated as non-responders in the primary and full efficacy analyses.

The safety population in this planned 18-month analysis of REGENERATE included 1,968 randomized patients who received at least one dose of investigational product (OCA or placebo). Adverse events were generally mild to moderate in severity and the most common were consistent with the known profile of OCA. The frequency of serious adverse events was similar across treatment arms (11% in placebo, 11% in OCA 10 mg and 14% in OCA 25 mg) and no serious adverse event occurred in >1% of patients in any treatment arm. There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg: glioblastoma) and none were considered related to treatment.

The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to moderate, with severe pruritus occurring in a small number of patients (<1% in placebo><1% in oca 10 mg and 5 in oca 25 mg. a higher incidence of pruritus associated treatment discontinuation was observed for oca 25 mg><1% in placebo><1% in oca 10 mg and 9 in oca 25 mg. according to the clinical study protocol investigator assessed severe pruritus mandated treatment discontinuation. consistent with observations from previous nash studies oca treatment was associated with an increase in ldl cholesterol with a peak increase of 22.6 mg dl at 4 weeks and subsequently reversing and approaching baseline at month 18 4.0 mg dl increase from baseline. triglycerides rapidly and continually decreased in the oca treatment arms through month 18. there were few and varied serious cardiovascular events and incidence was balanced across the three treatment arms 2 in placebo 1 in oca 10 mg and 2 in oca 25 mg.>

Comment: The data marks a major milestone for the NASH field, the result comes with several qualifications to this success. Treatment with obeticholic acid did not resolve NASH in significantly more patients than did placebo, and the drug's safety profile could raise challenges if approved. .