Ocaliva recently failed to secure the FDA’s traditional approval for primary biliary cholangitis due to safety concerns.
The FDA on Thursday announced that it has detected cases of serious liver injury in patients with primary biliary cholangitis treated with Intercept’s Ocaliva (obeticholic acid).
This safety signal adds to the growing list of problems for the oral farsenoid X receptor. Since its 2016 approval for primary biliary cholangitis (PBC), Intercept has twice tried and failed to expand Ocaliva into metabolic dysfunction-associated steatohepatitis—once in June 2020 and another in June 2023, the latter of which forced the biotech to scrap its MASH program altogether and let go of a third of its employees.
Intercept was bought by Italian pharma Alfasigma shortly after.
Last month—after a regulatory delay and an overwhelming downvote by the FDA’s Gastrointestinal Drugs Advisory Committee—Ocaliva failed to secure full approval. In its Complete Response Letter, the regulator flagged safety concerns in Intercept’s confirmatory data package.
Now, in its bulletin on Thursday, the agency said that a postmarket clinical trial has found incidents of serious liver injury in Ocaliva-treated PBC patients without liver cirrhosis.
Additionally, in patients for whom Ocaliva is indicated—that is, those who are at a lower risk of disease progression—the drug appears to worsen the likelihood of death or of needing liver transplantation. For instance, of 81 treated patients, seven had to receive a transplant, versus one in 68 placebo comparators. Four patients on Ocaliva died, as compared with only one on placebo.
According to the regulator, liver transplant and death had a hazard ratio of 4.77 in patients without advanced cirrhosis and who are not contraindicated from Ocaliva.
In line with these new signals, the FDA recommends that healthcare professionals monitor patients’ liver tests “frequently” in order to watch for early signs of worsening liver function. Still, the regulator concedes that “based on current data, it is not clear if this monitoring will be sufficient to address the risk of serious liver injury.”
Ocaliva should be discontinued as soon if providers detect evidence of liver disease progression, or if they cannot establish the efficacy of the drug for the patient, the agency added.
Designed to be orally available, Ocaliva is an antagonist of the farsenoid X receptor, a nuclear receptor that is highly expressed in the liver and in the intestine, and which plays a crucial regulatory role in inflammatory, fibrotic and metabolic pathways. Through its mechanism of action, Ocaliva suppresses bile acid synthesis.
