FDA Reviewers Skeptical of Ocaliva for Rare Bile Duct Disease

FDA advisors on Friday will be asked to find any clinical benefit in the rocky, mostly-null evidence for obeticholic acid (Ocaliva) in primary biliary cholangitis (PBC).

In its present supplemental new drug application, sponsor Intercept Pharmaceuticals seeking full approval for proposing an indication for obeticholic acid to reduce hepatic decompensation, liver transplant, and death in adults with PBC (without cirrhosis or with compensated cirrhosis), who would use these oral tablets in combination with ursodeoxycholic acid (UDCA) or as monotherapy.

However, in background materials released ahead of this week’s meeting of the Gastrointestinal Drugs Advisory Committee, agency reviewers already expressed concerns that the evidence generated post-approval does not support the farnesoid X receptor agonist for adults with PBC either intolerant to or unresponsive to UDCA.

Obeticholic acid was given accelerated approval by the FDA in May 2016 as a second-line treatment for PBC patients not benefiting from UDCA, based not on clinical data back then, but on the surrogate endpoint of alkaline phosphatase (ALP) and total bilirubin.

Given that obeticholic acid decreases bile acid synthesis, the expectation was that it should therefore slow PBC progression when eventually put to clinical study.

However, FDA staff noted, the confirmatory postmarketing randomized COBALT trial 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. Another supporting study, the retrospective cohort study 747-405, also did not demonstrate clinical benefit for obeticholic acid in PBC.

The FDA has recently pulled multiple cancer drugs from the market that failed their confirmatory trials. Last week, it was reported that the European Commission revoked marketing authorization of obeticholic acid for PBC.

On top of that, the COBALT study indicated unfavorable trends with the drug on liver transplantation and mortality — which is in line with existing safety concerns that led to labeling changes for obeticholic acid.

The drug had been contraindicated for some patients with advanced cirrhosis due to the risk of serious liver injury, beginning in May 2021. This followed a 2018 boxed warning about the correct dosing with obeticholic acid, as severe adverse events had been reported in certain patients taking the drug more frequently than recommended.

For Friday’s meeting, the advisory committee will be tasked with interpreting data from the COBALT trial, knowing that 55% of study participants were no longer technically eligible for obeticholic acid due to the 2021 revised contraindications, and that the remaining eligible patients were not enough to power the efficacy analysis.

Ultimately, they will vote on whether a clinical benefit exists and whether the drug’s benefits outweigh the risks in the non-contraindicated population.

PBC is a rare autoimmune disease of the bile ducts, mostly affecting women. Common symptoms include intense itching, skin-crawling sensations, and fatigue.

Friday’s panelists may take into account the unmet need of PBC patients, who have no FDA-approved treatment for their symptoms. Additionally, an estimated 40% have either an incomplete response or are unresponsive to UDCA, while 5% are intolerant to it, according to the FDA briefing documents.

Notably, the agency recently gave accelerated approval to elafibranor (Iqirvo) and seladelpar (Livdelzi) for adults with PBC, both for use in combination with UDCA or as monotherapy if UDCA is not tolerated.

Outside PBC, obeticholic acid got the thumbs down from FDA advisors last year as a treatment for nonalcoholic steatohepatitis with pre-cirrhotic liver fibrosis.

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