FDA rejects approval of Intercept's obeticholic acid in NASH

Intercept Pharmaceuticals said Monday that the FDA issued a complete response letter regarding a filing seeking approval of obeticholic acid for the treatment of fibrosis due to non-alcoholic steatohepatitis (NASH), sending shares in the company down as much as 38%. CEO Mark Pruzanski commented "we are disappointed to see the determination the agency has reached based on an apparently incomplete review, and without having provided medical experts and patients the opportunity to be heard at the anticipated Adcom."

Last month, the FDA postponed an advisory committee meeting tentatively scheduled for June 9 to discuss the marketing application for obeticholic acid to give the agency time to review additional data that it requested. The meeting had already been pushed back from its original date in April due to the COVID-19 pandemic. At the time, Intercept indicated that it expected the previous, already-extended June 26 target action date for the filing to also be deferred.

Benefit "uncertain"

According to Intercept, in its complete response letter, the FDA determined that the predicted benefit of obeticholic acid based on a surrogate histopathologic endpoint "remains uncertain and does not sufficiently outweigh the potential risks to support accelerated approval." The regulator recommended the submission of additional post-interim analysis efficacy and safety data from the ongoing pivotal Phase III REGENERATE study in support of potential accelerated approval."

The application is based on data from the REGENERATE trial, with results showing that once-daily obeticholic acid met the primary endpoint of fibrosis improvement of at least one stage or more, with no worsening of NASH, in 23.1% of patients compared to 11.7% for placebo at the planned 18-month interim analysis.

Very high bar

"At no point during the review did the FDA communicate that [obeticholic acid] was not approvable on an accelerated basis, and we strongly believe that the totality of data submitted to date both meet the requirements of the agency's own guidance and clearly support the positive benefit-risk profile," remarked Pruzanski. The executive added "the FDA has progressively increased the complexity of the histologic endpoints, creating a very high bar that only [obeticholic acid] has so far met in a pivotal Phase III study."

The drug, a farnesoid X receptor agonist, is already approved in the US under the name Ocaliva to treat certain patients with primary biliary cholangitis.

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