FDA Rejects Full Approval of Obeticholic Acid for Primary Biliary Cholangitis

• The FDA declined to grant full approval to obeticholic acid (Ocaliva) for treating primary biliary cholangitis (PBC), citing concerns over its benefit-risk profile.
• The decision follows a negative recommendation from the agency's advisory committee, which questioned the drug's clinical benefit as a second-line agent.
• Intercept Pharmaceuticals plans to collaborate with the FDA on next steps, while the drug remains available on the market despite safety concerns.
• The FDA has granted accelerated approval to two other drugs, seladelpar (Livdelzi) and elafibranor (Iqirvo), for PBC treatment this year.

The FDA has rejected Intercept Pharmaceuticals' application for full approval of obeticholic acid (Ocaliva) in treating primary biliary cholangitis (PBC). This decision comes after the Gastrointestinal Drugs Advisory Committee questioned the drug's benefit-risk profile in September, particularly for PBC patients without contraindications. The committee voted 13 to 1 against the available data supporting a clinical benefit.

Safety Concerns and Trial Data

The primary trial supporting the full approval, COBALT (Study 747-302), faced challenges due to unblinding and treatment crossover. The trial failed to demonstrate a significant benefit in the overall study population and indicated trends of excess liver transplants and death in patients treated with obeticholic acid without contraindications. These safety concerns, including risks of liver failure and the need for liver transplants, previously led to a narrowed indication for the drug in 2021. Obeticholic acid is now restricted to PBC patients without cirrhosis or with compensated cirrhosis but without evidence of portal hypertension.

Expert Opinions and Future Steps

Hepatology chief Dr. Theo Heller from the National Institute of Diabetes and Digestive and Kidney Diseases expressed uncertainty about obeticholic acid's efficacy and safety during the advisory committee meeting. He emphasized the need for a well-designed study to properly assess the drug's effects. Intercept Pharmaceuticals stated that it would work with the FDA to determine the next steps, while the drug remains available on the market. The FDA's complete response letter indicated ongoing consideration of safety data from Study 747-302, along with other safety information.

PBC Treatment Landscape

Primary biliary cholangitis is a rare, chronic liver disease predominantly affecting women. It leads to inflammation and destruction of small bile ducts in the liver, causing liver cell damage due to trapped bile. Untreated PBC can progress to cirrhosis, liver failure, and death. While obeticholic acid received accelerated approval in 2016 as a second-line treatment for adults with PBC, either in combination with ursodeoxycholic acid (UDCA) or as a single agent for those unable to tolerate UDCA, the FDA has recently granted accelerated approval to two other drugs for PBC: seladelpar (Livdelzi) and elafibranor (Iqirvo).