Date: 2015-10-28
Type of
information: Results
phase: 2
Announcement: results
Company: Intercept Pharmaceuticals (USA - NY) Sumitomo Dainippon Pharma (Japan)
Product: obeticholic acid (OCA)
Action
mechanism:
- farnesoid X receptor agonist. Obeticholic acid (OCA) is a bile acid analog and a first-in-class farnesoid X receptor (FXR) agonist being developed for primary biliary cirrhosis (PBC), NASH and other chronic liver indications. Intercept has initiated a rolling New Drug Application with the FDA for PBC, and expects to complete the NDA and MAA submission in 2Q 2015. The commercial launch of OCA in the U.S. and Europe is planned in 2016. OCA was also recently granted breakthrough therapy designation by FDA for the treatment of NASH with liver fibrosis.
Disease: NASH (non-alcoholic steatohepatitis)
Therapeutic
area: Liver diseases - Hepatic diseases
Country: Japan
Trial
details:
- In this dose-ranging study, 202 Japanese biopsy-proven NASH patients (NAS 5-8) were randomized into one of four arms to receive either a 10mg, 20mg or 40mg dose of OCA, or placebo, and 200 of these patients - 50 per group - initiated treatment for a 72-week double-blind treatment phase, followed by a 24-week off treatment phase which is still ongoing. The primary endpoint was histologic improvement defined as at least a two point improvement in NAFLD activity score (NAS) with no worsening of fibrosis. The primary efficacy analysis tested the dose dependent effects of OCA versus placebo on the primary endpoint.
Latest
news:
- • On October 28, 2015, Intercept Pharmaceuticals announced the results of a 72-week Phase 2 dose ranging trial of obeticholic acid (OCA), Intercept\'s lead FXR agonist, in adult patients with nonalcoholic 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 (10mg, 20mg and 40mg) 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 randomized 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, 10mg, 20mg and 40mg OCA groups, respectively).
- The ITT results in the table below show a dose dependent increase in the percentage of OCA treated patients compared to placebo who achieved the primary endpoint (p=0.053, not significant). The 40mg 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.
| |
placebo |
10mg |
20mg |
40mg |
|
| ITT results |
N=50 |
N=50 |
N=50 |
N=50 |
|
| NAS improvement ?2 points
with no worsening of fibrosis |
10 (20%) |
11 (22%)
p=0.8070** |
14 (28%)
p=0.3378** |
19 (38%)
p=0.0496** |
p=0.053* |
- * Primary efficacy analysis is a stratified Cochran-Armitage test with multiple contrast coefficients. Statistical significance is based on a p-value < 0.05.
- ** The secondary efficacy analysis is a CMH (Cochran-Mantel-Haenszel) test stratified by baseline fibrosis stage for pairwise comparison of each OCA group vs. placebo group. The multiplicity was not adjusted.
- In the completer analysis, similar dose dependent effects were observed, with 51% of patients in the 40mg dose group compared to 22% in the placebo group meeting the primary endpoint (p=0.0061). With the exception of dose dependent pruritus, OCA appeared to be generally safe and well tolerated. The number of pruritus associated discontinuations were 0, 0, 2 and 5 patients in the placebo, 10mg, 20mg and 40mg OCA groups, respectively. Changes in lipid parameters, including LDL-C, HDL-C and triglycerides, appeared to be consistent with previously reported lipid changes in Western NASH patients. No other meaningful differences in the rate of adverse events between the OCA and placebo groups were noted.
- Intercept Pharmaceuticals is currently the Phase 3 REGENERATE trial, which was designed based on the FLINT results to evaluate OCA's safety and efficacy in a similar Western patient population.
Is
general: Yes
