FDA rejects full approval of Ocaliva as second-line PBC treatment
Agency is still considering safety results from Phase 4 COBALT study
The U.S. Food and Drug Administration (FDA) has turned down a request by Intercept Pharmaceuticals for the full approval of Ocaliva (obeticholic acid) as a second-line treatment for certain adults with primary biliary cholangitis (PBC).
In its response, issued nearly a month after the date a decision was expected on Oct. 15, the agency said it was unable to grant full approval to Ocaliva based on available data. The FDA stated it was still considering safety results from the placebo-controlled Phase 4 COBALT clinical trial (NCT02308111) and other safety information.
“We remain committed to patients living with PBC who have limited treatment options,” Vivek Devaraj, Intercept’s U.S. president and chairman, said 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.”
The decision aligns with a 10-1 vote against full approval by an FDA advisory committee in September. The committee cited insufficient evidence to support Ocaliva’s clinical benefits and favorable benefit-risk profile.
Conditional approvals of Ocaliva
Ocaliva remains available for eligible PBC patients in the U.S. under its conditional approval status, which was supported by early data from clinical trials that suggested the medication’s potential. Conversion to full approval requires additional trial data to confirm its safety and efficacy.
The therapy’s conditional approval in the European Union (EU) was recently revoked following a recommendation by an advisory committee, which said its clinical benefits no longer outweighed its risks. Ocaliva is still available in the EU after Advanz Pharma, which markets it there, won a temporary suspension of that decision, however.
Ocaliva was conditionally approved in the U.S. and EU in 2016 as a second-line PBC treatment for adults who’ve responded inadequately to or cannot tolerate ursodeoxycholic acid, the first-line therapy.
In the U.S., eligible PBC patients must not have cirrhosis, which is permanent liver scarring, or evidence of portal hypertension, that is, high blood pressure in the vein that transports blood from the digestive organs to the liver, if they have compensated cirrhosis.
PBC is a form of cholangitis, or inflammation of the tubes that carry the digestive fluid bile from the liver to the intestines to aid digestion. Inflammatory damage to the bile ducts can cause bile to accumulate in the liver, which leads to cirrhosis, liver failure, or potentially liver cancer.
Ocaliva is designed to activate the farnesoid X receptor, which controls bile acid production, thereby limiting it in the liver. The therapy’s conditional approvals were supported mainly by results from the placebo-controlled Phase 3 POISE trial (NCT01473524), which indicated Ocaliva outperformed a placebo at normalizing blood biomarkers of liver damage after a year of treatment.
Regulatory applications for full approval included data from two confirmatory placebo-controlled Phase 4 studies, COBALT and Study 401 (NCT03633227), which were both terminated early.
Failing to meet its goal, COBALT showed similar rates of death, liver transplant, and/or other serious liver-related events between Ocaliva and placebo groups. A prespecified analysis showed the therapy reduced those events by 61% compared with real-world data from an external group of untreated patients, however.
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