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  The International Liver Congress™
EASL 2017 - European Association for the
Study of the Liver
Amsterdam, The Netherlands. 2017
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INT 747 (obeticholic acid) fails to achieve goals in Japanese study for non-alcoholic steatohepatitis (NASH)- Intercept Pharma + Sumitomo
Data from Pharmawand - Curated by Toby Galbraith - Date added 30 October 2015
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.
OCA fails to meet primary endpoint in Japanese patients with NASH
October 29, 2015
Results of a phase 2 clinical trial investigating obeticholic acid for the treatment of nonalcoholic steatohepatitis indicated the drug failed to meet its primary endpoint of improving NAFLD Activity Score, according to a business update webinar presented by Intercept Pharmaceuticals.
For the trial, 200 Japanese adult patients were randomly assigned to placebo or one of three doses of obeticholic acid (OCA; 10 mg, 20 mg or 40 mg) once daily. The primary endpoint was an improvement in the NAFLD Activity Score.
"This is a dose ranging trial in 200 Japanese patients with biopsy-proven NASH and an NAFLD Activity Score of a minimum 5 points out of a possible 8 total," Mark Pruzanski, MD, CEO and president of Intercept, said during the webinar. "The primary efficacy analysis was conducted on an intention-to-treat basis, testing the dose-dependent effects of OCA vs. placebo on the primary endpoint of at least 2 point improvement in NAFLD Activity Score with no worsening of fibrosis," Pruzanski said.
According to Pruzanski, the intention-to-treat (ITT) analysis included all patients who received treatment, 50 per group, and patients who discontinued or did not have a repeat biopsy or treated as nonresponders. The results from the primary efficacy on the ITT population showed a dose-dependent increase in the percentage of OCA-treated patients. The increase ranged from 22% to 38%, compared to 20% of placebo patients who achieved the primary endpoint (P = .053), Pruzanski said.
According to a press release on the data, 10 patients in the placebo group (20%), 11 patients who received 10 mg of OCA (22%; P = .807), 14 who received 20 mg of OCA (28%; P = .3378) and 19 who received 40 mg of OCA (38%; P = .0496) showed at least 2-point improvement in NAS and no worsening of fibrosis.
No differences were seen in the OCA groups compared with placebo, Pruzanski said. In a completer analysis, the dose-dependent effects were similar to the ITT analysis, with 51% of patients who received 40 mg of OCA meeting the primary endpoint compared with 22% of patients in the placebo group (P = .0061).
"With the exception of dose-dependent pruritus, OCA appeared to be generally safe and well-tolerated," Pruzanski said. "The number of patients' discontinued due to pruritus were zero in the placebo group, zero in the 10-mg group, two in the 20-mg group and five in the 40-mg OCA groups, respectively."
Pruzanski stated that this trial was different from the FLINT trial.
"When compared to the FLINT trial, there were several noticeable differences in a number of baseline characteristics between the two studies, such as gender mix and metabolic factors like weight, diabetes status and hypertension," he said.
Pruzanski added that this was a small dose-ranging study with only 50 patients per arm and was not powered to detect OCA effect on any other histological endpoint that would require large patient numbers.
"Nonetheless, ... it is an important contribution to the growing global body of research in NASH," Pruzanski said.
"Given [that] this trial has been conducted by our collaborator Sumitomo Dainippon Pharma and we only recently received this data, we will not be providing additional results beyond what has been outlined in the press release," Pruzanski said. "Some patients still have not completed the 24-week off treatment days. The study is still ongoing and expected to end in a few weeks."
Pruzanski noted that these results do not impact the REGENERATE trial.
"We are currently actively enrolling our phase 3 REGENERATE trial, which was designed based on the robust FLINT results to evaluate OCA's safety and efficacy in a similar Western patient population," Pruzanski said.
The FDA granted priority review for OCA for the treatment of primary biliary cirrhosis in September.
Disclosures: Pruzanski is employed by Intercept.