FDA Panel Rejects Ocaliva's Full Approval for Primary Biliary Cholangitis
Key Insights
An FDA advisory committee voted against full approval of obeticholic acid (Ocaliva) for primary biliary cholangitis (search) (PBC (search)) due to insufficient evidence of clinical benefit.
The COBALT trial, intended to confirm Ocaliva's efficacy, failed to demonstrate a significant reduction in liver transplantation, death, or liver-related outcomes.
Safety concerns, including trends of excess liver transplants and death in patients taking Ocaliva, further contributed to the panel's negative recommendation.
An FDA advisory committee has voted against granting full approval to obeticholic acid (Ocaliva) for the treatment of primary biliary cholangitis (search) (PBC (search)), citing a lack of verifiable clinical benefit and raising concerns about potential harm. The Gastrointestinal Drugs Advisory Committee voted 10-1, with three abstentions, that the farnesoid X receptor (search) agonist does not have a favorable benefit-risk profile as a second-line treatment for eligible adults with PBC who have no contraindications. Furthermore, a 13-1 vote indicated the panel's lack of confidence in the drug's clinical benefit.
The decision casts doubt on the future of obeticholic acid as a treatment for PBC (search), a rare autoimmune disease affecting the bile ducts. The FDA granted accelerated approval to obeticholic acid in May 2016 as a second-line treatment for PBC patients not benefiting from ursodeoxycholic acid (UDCA), based on improvements in surrogate endpoints like alkaline phosphatase and total bilirubin. However, full approval hinged on confirmatory trials demonstrating clinical benefit.
Concerns Over Efficacy and Safety
The pivotal COBALT trial, designed to confirm obeticholic acid's efficacy, failed to show a significant benefit on the expanded primary composite endpoint of liver transplantation, death, and liver-related outcomes in PBC (search) patients with chronic disease. According to Daniel Gillen, PhD, a statistician from the University of California Irvine and a panel member, the decision came down to the absence of verifiable benefit and reasonable questions of harm. The trial also faced challenges with functional unblinding and treatment crossover, further complicating the interpretation of results.
Safety concerns also weighed heavily on the committee's decision. The COBALT trial showed trends of excess liver transplants and death in people taking the drug without contraindications. These findings align with existing safety concerns that led to labeling changes for obeticholic acid, including contraindications for patients with advanced cirrhosis due to the risk of serious liver injury.
Real-World Evidence Deemed Insufficient
Intercept Pharmaceuticals (search), the drug's sponsor, attempted to present real-world evidence from study 747-405 to support obeticholic acid's benefit. However, the FDA deemed this retrospective cohort study unfit for interpretation because it relied on diagnosis codes and did not confirm that patients actually had PBC (search). Theo Heller, MD, hepatology chief of the National Institute of Diabetes and Digestive Kidney Diseases, criticized the "complete lack of rigor" in the evidence presented by the sponsor.
Impact on PBC Treatment Landscape
The potential removal of obeticholic acid from the market would leave a gap in the treatment landscape for PBC (search), particularly for patients who do not respond to or cannot tolerate UDCA. While the FDA has recently approved elafibranor (Iqirvo) and seladelpar (Livdelzi) for adults with PBC, the loss of obeticholic acid would reduce available options. The FDA is not required to follow the advice of its advisory committees, but it often does. The agency has assigned a PDUFA target action date of October 15 for obeticholic acid. The European Commission has already revoked marketing authorization of obeticholic acid for PBC.