FDA Finds Obeticholic Acid (Ocaliva) Linked to Serious Liver Injury in Noncirrhotic PBC

Credit: US Food and Drug Administration

The US Food and Drug Administration has announced the identification of cases of serious liver injury among patients being treated for primary biliary cholangitis (PBC) with obeticholic acid (Ocaliva) who did not have cirrhosis.¹

The new safety information was announced in an update to a previous FDA Drug Safety Communication in 2021 restricting the use of obeticholic acid in patients with PBC and advanced cirrhosis. Now, findings from an FDA review of postmarket clinical trial data for obeticholic acid show an increased risk of liver injury in patients without cirrhosis.

Obeticholic acid, which was previously granted accelerated approval for PBC in 2016, received a Complete Response Letter (CRL) from the FDA on November 12, 2024. In the CRL, the agency stated that it was unable to approve Intercept Pharmaceuticals' supplemental New Drug Application for obeticholic acid in its current form, consistent with the outcome of a Gastrointestinal Drugs Advisory Committee meeting held in September 2024 that yielded a negative opinion on the verification of obeticholic acid’s benefit on clinical outcomes in PBC as well as its benefit versus risk profile. At the time of the CRL, Intercept stated obeticholic acid would continue to be available for the treatment of appropriate patients living with PBC in the US under accelerated approval status.²

The FDA previously restricted the use of obeticholic acid in patients with PBC and advanced cirrhosis in 2021 based on an observed increased risk of serious liver injury requiring liver transplant in these patients, adding a new contraindication to the prescribing information and patient Medication Guide. However, the most recent review of submitted case reports suggests some patients with PBC and advanced cirrhosis were still taking the medicine despite these restrictions.

According to a press release from the FDA, frequent liver test monitoring is now necessary to identify worsening liver function and ensure appropriate discontinuation of obeticholic acid, even in patients without cirrhosis.

Obeticholic was initially granted accelerated approval for the treatment of PBC in 2016 based on a reduction in alkaline phosphatase (ALP) observed in clinical trials, although the FDA indicated an additional postmarket clinical trial would be necessary to verify obeticholic acid’s clinical benefit and support its continued approval.

The FDA evaluated liver safety in the postmarket clinical trial in patients who were eligible for treatment with obeticholic acid based on the approved indication in the prescribing information. Of note, the risk of liver transplant and death was found to be higher in patients receiving obeticholic acid than in those receiving placebo. Specifically, 7/81 patients who received obeticholic acid needed a liver transplant compared to 1/68 patients who received placebo. An additional 4 patients receiving obeticholic acid died compared with 1 receiving placebo.

Analyses assessing the risk of liver transplant and death resulted in a hazard ratio of 4.77 (95% confidence interval, 1.03-22.09) for patients without advanced cirrhosis and not contraindicated from receiving the drug.

Following the addition of the contraindication for patients with PBC and advanced cirrhosis in May of 2021, the FDA identified 20 cases reporting ≥ 1 of the following events in patients treated with obeticholic acid: liver transplant (n = 7), evaluation or listing for liver transplant (n = 8), or liver-related death (n = 6) between May 26, 2021, and September 18, 2024.

According to the release from the FDA, the agency is notifying health care professionals and patients of this new safety information and that frequent liver test monitoring is necessary to identify worsening liver function and ensure appropriate discontinuation of obeticholic acid, additionally detailing plans to continue to monitor the medicine’s safety and provide follow-up if additional information becomes available.

References

1. ^{FDA. Serious liver injury being observed in patients without cirrhosis taking Ocaliva (obeticholic acid) to treat primary biliary cholangitis. December 12, 2024. Accessed December 12, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/serious-liver-injury-being-observed-patients-without-cirrhosis-taking-ocaliva-obeticholic-acid-treat?utm_medium=email&utm_source=govdelivery}
2. ^{Brooks, A. FDA Issues CRL to Obeticholic Acid (Ocaliva), Denies Full Approval for PBC. HCPLive. November 12, 2024. Accessed December 12, 2024. https://www.hcplive.com/view/fda-issues-crl-obeticholic-acid-ocaliva-denies-full-approval-pbc}