The U.S. Food and Drug Administration (FDA) has rejected Intercept Pharmaceuticals' request for full approval of Ocaliva (obeticholic acid) as a second-line treatment for adults with primary biliary cholangitis (PBC). The agency cited ongoing safety concerns from the Phase 4 COBALT clinical trial and other safety data as the reason for the denial.
The FDA's decision follows a 10-1 vote against full approval by an FDA advisory committee in September, which raised concerns about the evidence supporting Ocaliva's clinical benefits and overall risk-benefit profile. Ocaliva is currently available in the U.S. under conditional approval for PBC patients who have had an inadequate response to, or cannot tolerate, ursodeoxycholic acid, the first-line therapy.
Ocaliva's Current Status and Regulatory History
Ocaliva received conditional approval in both the U.S. and the European Union (EU) in 2016 as a second-line treatment for PBC. This approval was based on early data suggesting the drug's potential efficacy. However, full approval requires additional data confirming its safety and efficacy. The conditional approval in the EU was recently revoked following an advisory committee recommendation that its clinical benefits no longer outweighed the risks, but is temporarily suspended. Advanz Pharma, which markets Ocaliva in Europe, has secured a temporary suspension of the revocation.
In the U.S., Ocaliva's conditional approval stipulates that eligible PBC patients must not have cirrhosis or evidence of portal hypertension if they have compensated cirrhosis. PBC is characterized by inflammation of the bile ducts, leading to bile accumulation in the liver, potentially causing cirrhosis, liver failure, or liver cancer.
Mechanism of Action and Clinical Trial Data
Ocaliva is designed to activate the farnesoid X receptor (FXR), which regulates bile acid production, thereby reducing bile acid levels in the liver. The initial conditional approvals were primarily based on the Phase 3 POISE trial, which demonstrated that Ocaliva outperformed placebo in normalizing blood biomarkers of liver damage after one year of treatment.
The application for full approval included data from the Phase 4 COBALT trial and Study 401, both of which were terminated early. The COBALT trial failed to meet its primary endpoint, showing similar rates of death, liver transplant, and other serious liver-related events between the Ocaliva and placebo groups. However, a pre-specified analysis suggested a 61% reduction in these events compared to real-world data from an external group of untreated patients.
"We remain committed to patients living with PBC who have limited treatment options," said Vivek Devaraj, Intercept’s U.S. president and chairman, in a company press release. "We believe in the totality of evidence supporting Ocaliva and intend to work closely with the FDA on next steps."
