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Postmarketing data on obeticholic acid (Ocaliva) identified a risk for serious liver injury in primary biliary cholangitis (PBC) patients without cirrhosis, the FDA said in a on Thursday.

The agency's review of a mandated clinical trial "found that some cases of liver injury in patients without cirrhosis resulted in liver transplant. This risk was notably higher for patients taking Ocaliva compared with a placebo," the FDA said.

The FDA in 2016 to the farnesoid X receptor (FXR) agonist as a second-line treatment for adults with PBC, either in combination with ursodeoxycholic acid (UDCA) for those with an inadequate response to the standard therapy or as a single agent in patients unable to tolerate UDCA.

But previous safety concerns in PBC patients with advanced cirrhosis led to a in May 2021 and a contraindication for that group with advanced cirrhosis. The drug is currently limited to PBC patients without cirrhosis or with compensated cirrhosis but no evidence of portal hypertension.

Yet postmarketing trial data of patients appropriately indicated for obeticholic acid showed a higher risk of liver transplant or death compared with patients receiving placebo (HR 4.77, 95% CI 1.03-22.09), with seven of 81 patients on obeticholic acid needing a liver transplant versus one of 68 placebo recipients. Furthermore, there were four deaths in the obeticholic acid group versus one in the placebo group.

And FDA's review found that some PBC patients with advanced cirrhosis still received the drug after the change to the prescribing information. In data from after the contraindication was added, 20 cases of serious liver injury in patients prescribed obeticholic acid were reported to the FDA Adverse Event Reporting System database, including 13 in the U.S. These included seven liver transplants, eight evaluations or listings for liver transplant, and six cases of liver-related death.

"Although we were not able to assess the appropriateness of Ocaliva use for most of these cases because of limited information, we identified three U.S. cases of liver-related events that occurred in patients for whom Ocaliva should have been discontinued based on progression of their liver disease as indicated in the 2021 safety labeling changes," said FDA. "This shows the importance of ongoing monitoring of liver tests and prompt action to withdraw Ocaliva if there is evidence of progression towards cirrhosis."

FDA urged clinicians to conduct frequent liver tests to check for signs of early liver damage in patients on obeticholic acid and said to discontinue treatment if there is any sign of liver disease progression or lack of efficacy.

Physicians should also alert their patients about specific or general symptoms of liver damage that may indicate need for medical attention, the agency said.

Specific symptoms: swollen belly, jaundice, bloody/black stools, coughing/vomiting blood, and changes in mental status (e.g., confusion, slurred speech, personality changes, increased sleepiness).

General symptoms if severe or that do not resolve in a few days: belly pain, nausea/vomiting, diarrhea, loss of appetite, weight loss, new or worsening tiredness, weakness, fever/chills, lightheadedness, and less frequent urination.

PBC is a rare and chronic liver disease that disproportionately affects women. The condition causes the small bile ducts in the liver to become inflamed and destroyed, resulting in damage to liver cells as bile remains trapped. Untreated, PBC can lead to cirrhosis, liver failure, and death.

The agency last month declined to grant full approval to obeticholic acid for PBC, a decision that followed a meeting of the agency's Gastrointestinal Drugs Advisory Committee, which agreed that the FXR agonist did not have a favorable benefit-risk profile as a second-line agent in PBC patients without contraindications. On whether the available data supported a clinical benefit, 13 of the 14 panelists said no.

It is unclear if the agency will seek to withdraw the drug in the future, as it has done with multiple cancer drugs that failed confirmatory trials. In September, the European Commission for PBC.

, the main trial supporting a potential full approval, was hampered by unblinding and treatment crossover but nonetheless failed to demonstrate a significant benefit in the full study population and showed trends of excess liver transplants and death in patients assigned to obeticholic acid without contraindications.

Notably, the FDA this year granted accelerated approval to two other drugs -- seladelpar (Livdelzi) and elafibranor (Iqirvo) -- for PBC.

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