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Without sufficient data to work with, FDA advisors were strongly inclined against recommending full approval to obeticholic acid (Ocaliva or OCA) in primary biliary cholangitis (PBC).

On Friday, the agency's Gastrointestinal Drugs Advisory Committee members voted 10-1 (with three abstentions) that the farnesoid X receptor agonist did not have a favorable benefit-risk profile when used as a second-line treatment for eligible adults with PBC and no contraindications.

As for the question of whether there is clinical benefit of obeticholic acid in the first place, the vote was 13-1 no.

One of those voting no to both questions was Daniel Gillen, PhD, a statistician from the University of California Irvine, who said it came down to not seeing a verifiable benefit and a reasonable question of harm.

Safety was an issue for obeticholic acid because the main trial supporting its application (747-302, or ) showed trends of excess liver transplants and death in people taking the drug without contraindications.

Friday's panel spent the day grappling with rocky evidence to support Intercept Pharmaceuticals' supplemental new drug application to get full traditional FDA approval for obeticholic acid as a treatment reducing hepatic decompensation, liver transplant, and death in adults with PBC without cirrhosis or with compensated cirrhosis.

Theo Heller, MD, hepatology chief of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, voted no to both benefit-risk and benefit questions. He described what he saw was a "complete lack of rigor" in the evidence presented by the drug sponsor.

Advisory committee members were told that COBALT failed to show a significant benefit on the expanded primary composite endpoint of liver transplantation, death, and liver-related outcomes in PBC patients with chronic disease. Notably, study investigators had struggled with challenges with functional unblinding and treatment crossover.

Additionally, during the study, the FDA started imposing safety restrictions contraindicating the use of obeticholic acid in patients with advanced cirrhosis due to reported cases of liver damage. This left remaining eligible patients in insufficient numbers to power an efficacy analysis.

"I don't know if OCA is good or not, don't know if it's safe or not ... Design a real study, do a real study, then we can talk about the data," Heller said. Until that happens, "it's not enough to feel comfortable to say it should be available for all patients."

During the advisory committee meeting, the sponsor tried to steer reviewers to more positive real-world evidence in 747-405. However, the FDA deemed this retrospective cohort study not fit for interpretation as it relied on diagnosis codes and did not confirm that patients actually had PBC.

The panel's consumer representative Joy McVey, of Emory Healthcare in Atlanta, echoed Heller's frustration with the data: "My heart hurts so heavy right now and it's because of exactly what you just said, that what we have to work with is just not there. The evidence is not there."

Obeticholic acid had been awarded accelerated approval as a second-line treatment for PBC patients not benefiting from ursodeoxycholic acid (UDCA). That decision had been based on observed improvements in the surrogate endpoints of alkaline phosphatase and total bilirubin.

The drug now risks getting pulled from the market, as the FDA has done recently with multiple cancer drugs that failed their confirmatory trials. The European Commission has already reportedly of obeticholic acid for PBC.

The yes votes for obeticholic acid on Friday came from patient representative and PBC patient Danielle Alstat. "I do think the real-world evidence from [747-405] does show if given in the right dose in the right patient, there is a benefit there that shouldn't be ignored," she said.

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.

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