The FDA appeared ready to pull its accelerated approval of Alfasigma and Intercept Pharmaceuticals’ rare liver disease drug Ocaliva, bluntly laying out its rationale in briefing documents ahead of Friday’s advisory committee meeting.
Assessing post-marketing trials conducted to confirm Ocaliva’s clinical benefit, regulators said the pivotal study both missed on statistical significance and resulted in an increased risk of disease progression or death in the main study population. The FDA had formally told Intercept as early as 2020 that it was investigating liver-related side effects in this study.
An observational study that Intercept used to try to assuage those concerns also didn’t pass the smell test, as it “does not meet regulatory standards for an adequate and well-controlled clinical investigation,” regulators said. FDA not only emphasized that there were significant limitations to the study, but also raised questions about whether the primary endpoint analysis was improper.
“The limitations of Study 747-405 to meet the standards of an adequate and well-controlled investigation, and the limitations of the analyses conducted by both the Applicant and the Agency to estimate a clinically and statistically interpretable endpoint, suggest that Study 747-405 cannot serve as an adequate study to verify the clinical benefit,” the documents said.
Ocaliva won accelerated approval to treat primary biliary cholangitis in 2016. The FDA added a boxed warning in 2018 after the drug was incorrectly dosed on a daily basis, as opposed to a weekly basis, possibly increasing the risk of more severe liver damage.
Intercept attempted to bring Ocaliva into a broader liver disease called metabolic dysfunction-associated steatohepatitis (MASH, previously known as NASH), but the FDA twice rejected its application in 2020 and 2023. The rejections resulted in Intercept pivoting away from MASH entirely and laying off about one-third of its staff.
Alfasigma acquired Intercept in September 2023, about three months after the second MASH rejection.
As the FDA prepares to convene the advisory committee, Ocaliva continues to face scrutiny overseas. Earlier this month, the European Commission revoked its conditional approval of Ocaliva following a CHMP recommendation in June, which said the benefits of the drug did not outweigh the risks.
But the drug will remain available “until further notice” after the EU’s General Court suspended the EC decision. Advanz Pharma, the company that sells Ocaliva in the EU, sued the Commission to keep it on the market.