Long Regulatory Saga for Intercept Pharma Liver Drug Ends a Decade After Speedy FDA Approval

While the path for any drug to go from lab research to commercialization takes years, Intercept Pharmaceuticals now stands as another example that a product’s market exit can also be long and winding. Nearly a decade after Intercept’s drug for a rare liver disease received accelerated FDA approval, the company is withdrawing the product.

Intercept said Thursday its withdrawal of the drug, Ocaliva, is voluntary. But the company noted its decision follows an FDA request. Intercept also said the regulator has placed a clinical hold on all clinical trials involving the active pharmaceutical ingredient in the product.

Ocaliva was developed to treat primary biliary cholangitis, or PBC. This rare disease develops when the immune system mistakenly attacks the bile ducts of the liver, leading to inflammation in the organ. For decades, standard treatment has been ursodiol, an old gallstone-dissolving medication that expanded its label to PBC in 1997. Ocaliva’s main pharmaceutical ingredient, obeticholic acid, is an analog of a bile acid found in humans. The oral small molecule binds to and activates FXR, a receptor in the liver and intestines that plays a role in regulating bile acid and inflammation.

Ursodiol does not work for all PBC patients. Ocaliva’s accelerated FDA approval in 2016 made the pill a second-line treatment for those whose disease does not respond to first-line ursodiol therapy. But the Intercept drug has had a rocky regulatory history since. In 2021, the FDA added a black box warning to Ocaliva’s label flagging the risk of severe liver complications in patients who have liver cirrhosis.

Ocaliva’s accelerated approval required the company to conduct a confirmatory clinical trial. Last year, the FDA rejected Intercept’s application seeking to convert the drug’s status to full approval in PBC. Soon after, the agency issued a safety communication for Ocaliva warning of the risk of severe liver injury in patients without cirrhosis. In Europe, where Ocaliva was marketed by partner Advanz Pharma, the European Commission revoked the product’s conditional marketing authorization.

Intercept also stumbled in its efforts to expand Ocaliva to other indications. The FDA twice rejected the Intercept drug as a treatment for the fatty liver disease now known as metabolic dysfunction-associated steatohepatitis (MASH). After the second rejection in 2023, Intercept restructured and then was acquired by Alfasigma, a privately held company based in Italy.

PBC treatment options have expanded since Ocaliva first entered the market. Last year, the FDA awarded accelerated approvals to two new PBC drugs: Ipsen’s Iqirvo and Gilead Sciences’ Livdelzi. These products bring a different mechanism of action to the disease. The regulatory decisions cover use of the medicines as second-line treatments, putting them on par with Ocaliva. But the Ipsen and Gilead drugs do not have black box warnings on their labels. With safer treatment alternatives now available to PBC patients, the FDA apparently no longer sees the need for Ocaliva to remain on the market under accelerated approval status.

Executives for Intercept, which continues to operates as a U.S.-based subsidiary of Alfasigma, said they believe the totality of clinical and real-world evidence supports Ocaliva in PBC. But the company is done clashing with the FDA about the matter.

“While our view of Ocaliva’s benefit-risk profile differs from FDA’s, we respect its request and have made this difficult decision to provide clear guidance for patients and prescribers,” Vivek Devaraj, U.S. president at Intercept, said in a prepared statement.

Image: Sakramir, Getty Images