For Intercept Pharmaceuticals’ beleaguered liver disease drug Ocaliva, the hits just keep coming.

Ahead of an advisory committee meeting slated for Friday, the FDA on Wednesday unleashed damning briefing documents calling into question the effectiveness and safety of Intercept’s drug. The U.S. regulator specifically raised an eyebrow at the post-marketing trials Intercept has used in a bid to keep hold of the accelerated approval it won back in 2016.

Ocaliva was initially approved in the U.S. in 2016 in primary biliary cholangitis (PBC), an autoimmune disease in which the liver’s bile ducts become inflamed and are slowly destroyed.

The advisory committee meeting will specifically consider whether Intercept has fulfilled its post-marketing requirements under Ocaliva's accelerated FDA nod. Companies that win accelerated approval from the FDA must run additional studies to prove their drugs’ merits.

Intercept is looking forward to Friday’s expert meeting in the hopes that it can ultimately secure a full approval for Ocaliva in second-line PBC treatment, a company spokesperson said over email. He added that the FDA has set an action date of Oct. 15 for its final approval decision on Intercept’s drug.

“This Advisory Committee meeting is an important step in the regulatory process that will give us the opportunity to address the benefit-risk profile of Ocaliva for the expert panel the FDA has assembled,” Paul Nitschmann, M.D., senior vice president of regulatory affairs at Intercept, said in an attached statement. “We have compiled a comprehensive data package that includes data from randomized placebo-controlled trials, as well as multiple real-world evidence studies and eight years of post-marketing patient experience, that speaks to the treatment impact Ocaliva is making for patients with PBC.”

The FDA’s briefing documents largely focus on two Intercept studies: the placebo-controlled 747-302 study and the observational cohort trial 747-405.

The 747-302 trial failed to demonstrate a statistically significant benefit for Ocaliva in PCB and put patients at a higher risk of requiring a liver transplant or death, the FDA said.

Meanwhile, the 747-405 study “[did] not meet regulatory standards for an adequate and well-controlled clinical investigation,” the FDA continued.

Ocaliva has encountered numerous hurdles since its introduction in 2016. After Intercept attempted to shift the drug into nonalcoholic steatohepatitis (NASH) following its PBC approval, Ocaliva suffered several delays before receiving an outright rejection from the FDA in the summer of 2020. 

At the time, the regulator said the predicted benefit of Ocaliva in NASH remained uncertain and didn’t warrant safety risks. NASH is now known as metabolic dysfunction-associated steatohepatitis (MASH).

By September of that same year, Intercept revealed plans to lay off roughly 25% of its workforce, or about 170 jobs, in connection with the FDA snub.

Even a second application attempt didn’t convince the FDA of Ocaliva’s merit in MASH. Last June, the agency again rebuffed Intercept’s drug, prompting the company to discontinue all MASH-related investments and restructure its operations. Once again, layoffs were put on the table, this time affecting about one-third of Intercept’s staff. 

Last September, the setbacks prompted Intercept to sell itself to Italy’s Alfasigma in a deal worth roughly $800 million.

Elsewhere, U.K.-based Advanz Pharma picked up the rights to Ocaliva outside the U.S. for $405 million in 2022. The liver disease drug has faced regulatory scrutiny over efficacy and safety in the EU as well.

Last week, the European Commission (EC) moved to revoke the drug’s conditional marketing nod in PBC.

Still, Intercept and Advanz have won a reprieve, at least for now. The General Court of the European Union temporarily suspended the EC’s decision, meaning Ocaliva will continue to be available for new and existing PBC patients across EU member states as well as Iceland, Liechtenstein and Norway.

Editor's note: This story was updated with comments from Intercept Pharmaceuticals.