Obeticholic acid

The U.S. Food and Drug Administration (FDA) made an important decision on Tuesday, denying full approval of Intercept Pharmaceuticals' liver disease drug. The decision raises questions about the drug's future market prospects. Still, Intercept Pharmaceuticals said that despite the FDA's denial of full approval, their drug Ocaliva will continue to receive accelerated approval in the United States. Under the accelerated approval pathway, the FDA requires additional trials to verify a drug's benefits. If data from these trials do not prove a drug's effectiveness, regulators can require companies to withdraw the drug from the market. Ocaliva received accelerated FDA approval in 2016 to treat patients with primary cholangitis. Primary cholangitis is a rare disease that causes inflammation of the small bile ducts in the liver and eventually destroys them. Because of the rarity of the disease, recruiting patients for confirmatory trials has become very difficult. According to the American Liver Foundation, fewer than 200,000 cases of primary cholangitis are recorded in the United States each year. Intercept Pharmaceuticals said it will continue to submit safety data on the drug to health regulators. The FDA's decision is in line with recommendations made by an independent panel of experts in September. The panel said the available data did not definitively prove the drug's effectiveness or dispel doubts about its safety. "I think the future of this drug is now very much up to the applicants and potential patients who will participate in the new trial," Julia Wattacheril, an assistant professor at Columbia University's Wagelow Snake School of Surgery, said before the FDA decision. She also added that it is unclear whether there is the will to devote more resources to gathering further data on the drug. Ocaliva and ursodecylcholic acid were among the first treatments. Since then, several other drugs, including Gileads Livdeizi, have been made available to patients. In June, the European drug regulator revoked Ocaliva's conditional authorization, saying its efficacy had not been proven.

The FDA rejected the full approval submission for Intercept Pharmaceuticals and Alfasigma’s primary biliary cholangitis treatment Ocaliva after safety concerns dogged the product, casting its future into doubt. While Intercept said it plans to keep selling Ocaliva and is talking with the FDA about next steps, most drugs that fail confirmatory trials and are rejected for full approval face a request by regulators to pull themselves off the market. The FDA did not immediately respond when asked whether that request has been made. Some companies fight those asks, which can lead to protracted legal battles. But the FDA almost always wins, eventually. Ocaliva won accelerated approval in 2016 as a second-line treatment for PBC, an autoimmune condition that impacts the bile ducts and disproportionately affects women. A black box warning was added two years later after it was being incorrectly dosed, and the FDA said in 2020 that it was investigating the risk of liver disorder. Italian pharma Alfasigma acquired Intercept for $800 million in September 2023. Debate over full approval of Ocaliva came to a head in September, when FDA advisory committee members voted resoundingly against granting full approval and said that the benefits of the drug didn’t outweigh its risks. At the center of the full approval debate was a confirmatory trial that failed and showed an increased risk of disease progression or death in patients getting the drug, according to the FDA. Intercept tried to offset safety concerns by referring to real-world observational data, but regulators and advisors were unswayed, and said the data weren’t enough to validate full approval. Intercept said Ocaliva will remain on the US market under accelerated approval. Regulators are continuing to review safety data from the confirmatory trial, the company said. Intercept US president and chairman Vivek Devaraj expressed commitment to the asset, saying in a statement that the company believes in the “totality of evidence supporting Ocaliva and intend[s] to work closely with the FDA on next steps.” “This isn’t a question of a failed trial, but a failed drug,” Yale assistant professor and health services researcher Reshma Ramachandran said. “So it’s imperative the FDA uses its authority to act and protect patients.” The commercial prospects for the drug are bleaker in Europe, after regulators pulled conditional marketing authorization ahead of the FDA advisory meeting. The rejection is a boost to Gilead and Ipsen , both of which snagged accelerated approval for their PBC candidates earlier this year. Gilead acquired the rights to its drug through its $4.3 billion acquisition of CymaBay Therapeutics earlier this year, while Ipsen licensed elafibranor (marketed as Iqirvo) from Genfit for $136 million upfront in 2021. That deal gave Ipsen access to most markets except select countries in East Asia. Zachary Brennan contributed reporting.