The FDA has issued a safety alert regarding obeticholic acid (Ocaliva), a drug used to treat primary biliary cholangitis (PBC), due to the identification of serious liver injury in patients without cirrhosis. This announcement follows a review of postmarketing clinical trial data, which revealed an increased risk of liver transplant or death in PBC patients without advanced cirrhosis who were treated with obeticholic acid.
Increased Risk of Liver Injury
The FDA's review of a mandated clinical trial showed that some cases of liver injury in patients without cirrhosis resulted in liver transplant. The agency noted that this risk was significantly higher for patients taking obeticholic acid compared to those receiving a placebo. Specifically, the 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.
Continued Use in Contraindicated Patients
Despite previous safety concerns that led to a narrower indication in May 2021 and a contraindication for PBC patients with advanced cirrhosis, the FDA's review found that some 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.
Recommendations for Clinicians and Patients
The FDA urges clinicians to conduct frequent liver tests to check for signs of early liver damage in patients on obeticholic acid and 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 the need for medical attention.
Specific symptoms include 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 not resolving in a few days, include belly pain, nausea/vomiting, diarrhea, loss of appetite, weight loss, new or worsening tiredness, weakness, fever/chills, lightheadedness, and less frequent urination.
Background on Obeticholic Acid and PBC
Obeticholic acid, a farnesoid X receptor (FXR) agonist, received accelerated approval in 2016 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. PBC is a rare and chronic liver disease that disproportionately affects women, causing inflammation and destruction of the small bile ducts in the liver, leading to liver cell damage. Untreated, PBC can result in cirrhosis, liver failure, and death.
Regulatory Context and Alternative Treatments
The FDA previously declined to grant full approval to obeticholic acid for PBC. The European Commission has also revoked obeticholic acid's marketing authorization for PBC. The COBALT trial, intended to support full approval, failed to demonstrate a significant benefit and showed trends of excess liver transplants and death in patients assigned to obeticholic acid without contraindications.
In recent times, the FDA has granted accelerated approval to two other drugs for PBC: seladelpar (Livdelzi) and elafibranor (Iqirvo).
