FDA Reports Serious Liver Injury in Patients Without Cirrhosis Using Obeticholic Acid to Treat PBC

The FDA has announced cases of serious liver injury among patients with primary biliary cholangitis (PBC) who are receiving treatment with obeticholic acid (Ocaliva; Intercept Pharmaceuticals, Inc.) and did not have cirrhosis of the liver. This follows the FDA’s review of a required clinical trial, which presented some cases of liver injury in which patients without cirrhosis required a liver transplant. For patients taking obeticholilc acid compared with a placebo, the risk was observed to be much higher.¹

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PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most common in women over 40 years of age. The disease causes bile acid to build up in the liver, which results in inflammation and scarring, also called fibrosis, which can lead to cirrhosis, a liver transplant, or death if left untreated.²

Initially approved by the FDA in May 2016, obeticholic acid had demonstrated improvements in alkaline phosphatase (ALP) in patients with PBC who did not respond well enough to ursodeoxycholic acid. The original clinical trial showed decreases in ALP that supported an accelerated approval.^1,3

In May 2021, after the FDA identified that patients with PBC with advanced cirrhosis were at risk of serious liver injury while on obeticholic acid, the prescribing information and medication guide were updated to restrict its use in this patient population. Additionally, in November 2024, the FDA announced that it was unable to approve a supplemental new drug application for full approval of treatment in patients with PBC.^2,3

When evaluating liver safety in the postmarket clinical trial in patients who were eligible for treatment with obeticholic acid, the FDA found that the risk of liver transplant and death were higher among those receiving the study drug (n = 7 of 81) compared with placebo (n = 1 of 68). An additional 4 patients receiving obeticholic acid had died compared to 1 patient receiving placebo. Analyses evaluating the risk of liver transplant and death showed a hazard ratio of 4.77 (95% CI: 1.03, 22.09) for patients without advanced cirrhosis and who were not contraindicated from receiving the drug.¹

Following the addition of the May 2021 contraindication, the FDA noted it had identified a total of 20 cases, of which 13 were domestic, between May 26, 2021, and September 18, 2024. These cases reported 1 or more of the following events in patients treated with obeticholic acid: liver transplant (n = 7), evaluation or listing for liver transplant (n = 8), or death related to the liver (n = 6). Additionally, 3 US cases of liver-related events had occurred in patients who should have discontinued obeticholic acid based on progression of their liver disease as indicated, per the May 2021 guidelines.^1,3 The FDA emphasizes that these updates showcase that ongoing monitoring of liver tests and swift action is crucial in reducing progression towards cirrhosis.¹

With this update in guidelines, the FDA is notifying health care professionals and patients of the new safety information. They urge frequent liver test monitoring to help identify worsening liver function and ensure that obeticholic acid is appropriately discontinued. Health care professionals should also educate patients with PBC on obeticholic acid about the signs and symptoms of worsening liver injury.¹

Further, the FDA urges patients to communicate with their health care professionals about the safety risks and potential benefits of continuing obeticholic acid treatment. The FDA also recommends that patients inform health care professionals of symptoms including swollen belly, yellow eyes or skin, bloody or black stool, coughing up or vomiting blood, and mental status changes (eg, confusion, slurred speech, mood swings, changes in personality, or increased sleepiness or difficulty waking up). Additionally, health care professionals should be informed if patients experience the following severe symptoms or if they do not go away after a few days: belly pain; nausea, vomiting, or diarrhea; loss of appetite or weight loss; new or worsening tiredness; weakness; fever and chills; lightheadedness; and less frequent urination.¹

REFERENCES

1. US Food & Drug Administration. Serious liver injury being observed in patients without cirrhosis taking Ocaliva (obeticholic acid) to treat primary biliary cholangitis. News release. 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

2. Intercept Pharmaceuticals. Intercept Receives Complete Response Letter from FDA Addressing OCALIVA supplemental New Drug Application (sNDA). News release. November 12, 2024. Accessed December 12, 2024. https://www.interceptpharma.com/about-us/news/?id=2979130

3. US Food & Drug Administration. Due to risk of serious liver injury, FDA restricts use of obeticholic acid (Ocaliva) in primary biliary cholangitis (PBC) patients with advanced cirrhosis. Updated January 11, 2022.Accessed December 12, 2024. https://www.fda.gov/drugs/fda-drug-safety-podcasts/due-risk-serious-liver-injury-fda-restricts-use-obeticholic-acid-ocaliva-primary-biliary-cholangitis