INT 747 (obeticholic acid) fails to achieve goals in Japanese study for non-alcoholic steatohepatitis (NASH)- Intercept Pharma + Sumitomo

Intercept Pharmaceuticals announced the results of a 72-week Phase II dose ranging trial of obeticholic acid (OCA), Intercept's lead FXR agonist, in adult patients with non-alcoholic steatohepatitis (NASH) in Japan. The trial was conducted by Intercept's collaborator, Sumitomo Dainippon Pharma. This trial is the first to evaluate the safety and efficacy of OCA in Japanese NASH patients. The primary efficacy analysis was conducted on an intention to treat (ITT) basis, testing the dose dependent effects of once daily OCA (10, 20 and 40 mg) versus placebo on the primary endpoint of a two point improvement in the NAFLD Activity Score (NAS) with no worsening of fibrosis. The ITT analysis included all randomised patients who received treatment (50 per group), and patients who discontinued or did not have a repeat biopsy were treated as non-responders. A pre-specified completer analysis was conducted on the patients who had biopsies at both baseline and 72 weeks (45, 44, 44 and 37 patients in the placebo, 10 mg, 20 mg and 40 mg OCA groups, respectively).

The ITT results showed a numerical dose-dependent increase in the percentage of OCA treated patients compared to placebo who achieved the primary endpoint (p=0.053, not significant). The 40 mg OCA dose group achieved statistical significance on the primary endpoint compared to placebo (p=0.0496). Dose-dependent trends not reaching statistical significance were also observed for several other pre-specified histologic endpoints, including the proportion of patients with steatosis and inflammation improvement, ballooning resolution and NASH resolution. No difference was seen in fibrosis improvement in the OCA groups compared to placebo. In the completer analysis, similar-dose dependent effects were observed, with 51% of patients in the 40 mg dose group compared to 22% in the placebo group meeting the primary endpoint (p=0.0061).

Comment: Sumitomo Dainippon Pharma tested three doses of the drug against placebo in this 200-patient trial, surveying whether the treatment, obeticholic acid, could register a two-point improvement on a common measure of liver disease without worsening scarring. Intercept's drug failed to get a statistically significant number of patients to that goal, with only the highest doses, 20 mg and 40 mg, achieving a p value under 0.05. The drug also failed to reach statistical significance on secondary endpoints including liver fat, inflammation, ballooning and resolution of NASH symptoms.