Adcomm: Intercept's liver disease drug not ready for full approval

An FDA advisory committee has overwhelmingly voted against granting full approval for Ocaliva, a rare liver disease drug developed by Alfasigma and Intercept Pharmaceuticals. The committee's 13-1 vote concluded that the confirmatory evidence did not substantiate the drug’s clinical benefits. Although the FDA is not obligated to follow the advisory committee's recommendations, it frequently does, casting doubt on Ocaliva’s future availability in the US market.

In briefing documents released earlier this week, FDA regulators had already indicated their inclination to withdraw Ocaliva’s accelerated approval. The confirmatory study under scrutiny failed to achieve statistical significance and showed that patients on Ocaliva did not fare better than those on placebo, reinforcing the committee's decision.

Christopher Coffey, a biostatistics professor at the University of Iowa, explained that his negative vote was partly due to the significant discrepancies between the FDA’s and Intercept’s interpretations of the data. Coffey remarked, “It’s an unfortunate case where multiple studies have been conducted, yet the initial question remains as unclear, if not more so, than before.”

The panel held a separate vote on the drug’s risk-benefit profile, deciding 10-1 that Ocaliva's benefits did not outweigh its risks, with three members abstaining. The debate centered on two studies conducted by Intercept: Study 302, a traditional randomized and placebo-controlled confirmatory trial, and Study 405, a real-world evidence trial. Intercept argued that the first study was not interpretable due to challenges in running placebo-controlled trials for rare diseases, such as difficulties in patient recruitment and retention. They also noted that the landscape of primary biliary cholangitis, the disease Ocaliva is designed to treat, had evolved since the drug’s accelerated approval in 2016.

Intercept presented Study 405 as an alternative measure of clinical benefit, aiming to mitigate concerns over liver-related side effects that have been under FDA review since at least 2020. However, the FDA held a contrary view, asserting that Study 302 provided sufficient evidence to conclude that Ocaliva’s therapeutic benefit was unconfirmed and that Study 405 could not be the basis for full approval.

Most panel members sided with the FDA, voicing explicit doubts about the drug’s efficacy. One panelist stated the drug did not meet the necessary standards, while another called the data poor, making it impossible to determine the drug’s safety and effectiveness. Concerns about liver toxicity at higher doses of Ocaliva were also raised. Some panelists mentioned that well-designed studies could be conducted even in rare disease settings, but criticized the flaws in Intercept’s studies for leaving too many questions unanswered. They expressed hope for a future well-designed study that addresses these concerns.

The FDA is anticipated to make a final decision on Ocaliva’s status by October 15. Meanwhile, Ocaliva faces challenges in the European Union as well. The European Commission recently revoked its conditional approval of the drug, following a June recommendation by the Committee for Medicinal Products for Human Use (CHMP) that stated the drug's benefits did not outweigh its risks. Advanz Pharma, which markets Ocaliva in the EU, has filed a lawsuit against the Commission to keep the drug on the market for the time being. Consequently, Ocaliva will remain available in the EU "until further notice."