Genfit released an interim analysis of the Phase III RESOLVE-IT trial Monday showing that its experimental dual PPAR agonist elafibranor did not have a significant effect on the primary endpoint of non-alcoholic steatohepatitis (NASH) resolution without worsening of fibrosis in the intent-to-treat population (ITT). CEO Pascal Prigent called the readout "highly disappointing," saying the company will review the results and conduct additional analyses, which will be shared with regulatory bodies in the coming months to determine next steps regarding the extension phase evaluating elafibranor on clinical outcomes.
RESOLVE-IT tested elafibranor against placebo in an ITT population of 1070 patients with biopsy-proven NASH as defined by a NAS score of at least 4, and fibrosis stage 2 or 3. Participants were randomly assigned either once-daily elafibranor or placebo. A follow-up liver biopsy was performed at 72 weeks to evaluate histologic improvement, including the primary endpoint of NASH resolution without worsening of fibrosis, as well as fibrosis improvement of at least one stage, which is a key secondary endpoint of the trial. Another main goal of the study will look at a composite long-term outcome composed of all-cause mortality, cirrhosis and liver-related clinical outcomes.
In the interim analysis, Genfit said the response rate among the 717 patients in the trial who received elafibranor was 19.2%, compared to 14.7% for placebo. On the key secondary endpoint, 24.5% of patients given elafibranor achieved fibrosis improvement of at least one stage, versus 22.4% in the placebo group. The company noted that other key secondary goals related to changes in metabolic parameters also failed to demonstrate significance.
Meanwhile, Genfit said the safety profile of elafibranor in the study was similar to what has been observed in previous trials. It added that the full dataset will be presented at one of the international hepatology congresses that will take place in the second half of 2020. Earlier this year, the company said unblinding of the RESOLVE-IT data would "be delayed to incorporate the latest FDA insights expected by the end of March."
Prigent noted that Genfit will nevertheless continue as planned with its Phase III primary biliary cholangitis (PBC) programme, where elafibranor is also being investigated. "We will provide updated guidance on our global corporate strategy later in the year, once we have more clarity on the regulatory implications of the RESOLVE-IT interim readout, as well as more visibility on the evolution of the impact of the worldwide pandemic on our ongoing studies," he added.
In 2015, Genfit decided to move ahead with its late-stage NASH programme for elafibranor, formerly known as GFT505, despite the drug having failed to meet the main goal of the Phase IIb GOLDEN-505 trial, at the time citing an "unexpected rate of resolution" of NASH in patients who had been given placebo.
Intercept Pharmaceuticals' obeticholic acid is currently under priority review by the FDA for the treatment of liver fibrosis due to NASH. An advisory committee meeting is tentatively scheduled for June 9, having been delayed from its original April date because of the COVID-19 pandemic, while the agency is expected to render its decision by June 26. Intercept's drug is already approved in the US under the name Ocaliva to treat certain patients with PBC.
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