FDA Rejects Full Approval of Liver Disease Drug

The FDA declined to grant full approval to obeticholic acid (Ocaliva) for treating primary biliary cholangitis (PBC), Intercept Pharmaceuticals announced on Tuesday.

The decision follows a September meeting of the agency’s Gastrointestinal Drugs Advisory Committee, which agreed that the farnesoid X receptor (FXR) agonist did not have a favorable benefit-risk profile as a second-line agent in PBC patients without contraindications. On whether the available data supported a clinical benefit, 13 of the 14 panelists said no.

Intercept said it will work with the FDA on next steps, and the drug remains on the market.

It is unclear if the agency will seek to withdraw the drug in the future, as it has done with multiple cancer drugs that failed confirmatory trials. In September, the European Commission revoked obeticholic acid’s marketing authorization for PBC.

The FDA in 2016 granted accelerated approval to the FXR agonist as a second-line treatment for adults with PBC, either in combination with ursodeoxycholic acid (UDCA) for those with an inadequate response to the standard therapy or as a single agent in patients unable to tolerate UDCA. Safety concerns in patients taking obeticholic acid — including a risk for liver failure and need for liver transplant — narrowed the indication in 2021. The drug is now limited to PBC patients without cirrhosis or with compensated cirrhosis but no evidence of portal hypertension.

PBC is a rare and chronic liver disease that disproportionately affects women. The condition causes the small bile ducts in the liver to become inflamed and destroyed, resulting in damage to liver cells as bile remains trapped. Untreated, PBC can lead to cirrhosis, liver failure, and death.

COBALT (Study 747-302), the main trial supporting Intercept’s bid for full approval, was hampered by unblinding and treatment crossover but nonetheless failed to demonstrate a significant benefit in the full study population and showed trends of excess liver transplants and death in patients assigned to obeticholic acid without contraindications.

“I don’t know if OCA [obeticholic acid] is good or not, don’t know if it’s safe or not,” Theo Heller, MD, hepatology chief of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, said during the advisory committee meeting in September. “Design a real study, do a real study, then we can talk about the data.”

In its complete response letter, FDA “said it was continuing to consider safety data from Study 747-302, along with other safety information,” according to Intercept.

Notably, the FDA this year granted accelerated approval to two other drugs — seladelpar (Livdelzi) and elafibranor (Iqirvo) — for PBC.

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