The U.S. Food and Drug Administration (FDA) has delayed its decision regarding the full approval of Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC). Intercept Pharmaceuticals, now a subsidiary of Alfasigma, awaits further notice from the FDA after the original Prescription Drug User Fee Act (PDUFA) date of October 15, 2024, passed without a decision. Ocaliva, an FXR agonist, remains available in the U.S. for PBC patients under its existing accelerated approval status.
The FDA's delay follows a September advisory committee meeting where a majority voted against the available data verifying the clinical benefit and favorable benefit-risk profile of obeticholic acid for PBC. Specifically, the committee voted 13-1 against the verification of clinical benefit and 10-1 (with 3 abstentions) against a favorable benefit-risk assessment.
Ocaliva's Role in PBC Treatment
Ocaliva was granted accelerated approval in 2016 for use in combination with ursodeoxycholic acid (UDCA) for adults with an inadequate response to UDCA, or as a single therapy for adults unable to tolerate UDCA. This approval was based on the reduction of alkaline phosphatase (ALP), a biomarker, in clinical trials. Ocaliva functions as a farnesoid X receptor (FXR) agonist, increasing bile flow from the liver and suppressing bile acid production, thereby reducing hepatic exposure to toxic levels of bile acids.
Context of PBC Treatment Landscape
PBC is a chronic autoimmune disease characterized by the destruction of small bile ducts in the liver, leading to bile buildup, inflammation, and potential cirrhosis. For several years, obeticholic acid was the only second-line therapy available for PBC patients who did not respond to or could not tolerate UDCA. However, in 2024, the FDA granted accelerated approvals to elafibranor (Iqirvo) and seladelpar (Livdelzi), expanding the treatment options for PBC.
Clinical Data and Regulatory History
The initial accelerated approval of Ocaliva was based on data from the Phase 3 POISE trial, where Ocaliva demonstrated superiority to placebo in helping PBC patients achieve normal blood levels of liver damage markers after one year. Intercept's applications for full approval included data from the confirmatory Phase 4 COBALT and Study 401 trials, both of which were terminated early. The COBALT study did not meet its primary endpoint of demonstrating a statistically significant difference between Ocaliva and placebo in the number of patients who died or experienced worsening liver disease. However, a comparison with real-world data suggested a 61% reduction in the risk of negative clinical outcomes with Ocaliva.
Ocaliva's conditional marketing authorization in the European Union was withdrawn in September 2024 following a reassessment of its benefit-risk profile. However, a subsequent appeal suspended the decision, allowing the drug to remain available in Europe for the time being.
