Nancy Reau, MD: Obeticholic Acid’s Future in PBC After FDA Advisory Committee Meeting

The primary biliary cholangitis (PBC) treatment landscape recently expanded with the addition of 2 new second-line treatment options, elafibranor (Iqirvo) and seladelpar (Livdelzi). However, obeticholic acid (Ocaliva), previously the sole second-line treatment for PBC after earning accelerated approval in 2016, is at risk of no longer being an option for patients.^1,2,3

On September 13, 2024, a US Food and Drug Administration Gastrointestinal Drug Advisory Committee meeting yielded a negative opinion on the verification of obeticholic acid’s benefit on clinical outcomes in PBC as well as its benefit versus risk profile.⁴

Specifically, the advisory committee voted 13 to 1 with no abstentions that the benefits of obeticholic acid on clinical outcomes in patients with PBC could not be verified with available data from the postmarketing requirement confirmatory trial 747-302 and the observational study 747-405. The committee also voted 10 to 1, with 3 abstentions, that obeticholic acid did not have a favorable benefit-risk assessment for use as a second-line treatment in the United Stated Prescribing Information population.

With the October 15, 2024, Prescription Drug User Fee Act (PDUFA) target action date looming around the corner, the advisory committee vote against obeticholic acid’s approval is not binding upon the FDA but will be taken into account during review of Intercept Pharmaceuticals’ supplemental New Drug Application.⁵ Of note, the European Commission recently revoked the conditional marketing authorization of obeticholic acid in Europe for the second-line treatment of patients with PBC based on a June 2024 recommendation from the Committee for Medicinal Products for Human Use of the European Medicines Agency.⁶

“Obeticholic acid has been around for a while, but it's kind of been on a preliminary trajectory with the FDA,” Nancy Reau, MD, associate director of solid organ transplantation and section chief of hepatology at Rush University Medical Center, told HCPLive, explaining how the understanding of biochemical remission in PBC has changed over time and, as a result, many patients have required treatment with obeticholic acid in addition to first-line ursodeoxycholic acid (UDCA) to achieve it. She also highlighted a subset of patients who cannot tolerate UDCA and who instead rely on obeticholic acid alone as their sole treatment option.

“I worry that maybe this is a little short-sighted, because they're grading the outcome on a long-term surrogate. Most of our patients with PBC don't get outcomes in 5 to 7 years, they get outcomes in 10 to 30 years,” Reau said about the FDA advisory committee meeting. “When you're looking for benefit in a semi-short period of time and in a group of individuals that might have been a little bit healthier because that's how we use the drug, maybe it's too soon to see that signal. And ultimately, it might not be the only signal that we care about.”

She described patients who are doing well on obeticholic acid as being “a bit of a clinical conundrum” because if it is no longer available, clinicians do not know if stopping obeticholic acid and starting a different second-line agent will achieve the biochemical remission patients may already have on obeticholic acid. In patients who are newly diagnosed with PBC and have not yet started second-line therapy, Reau noted they will likely be started on a newly approved PPAR to see if it helps them achieve biochemical remission, but if it does not, “we’re going to be a little bit stuck.”

“I do understand the EU and the FDA reasoning, I just think that it's going to leave a portion of our patients in a bit of a lurch,” Reau said.

References

1. ^{Brooks, A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed September 20, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}
2. ^{Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed September 20, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc}
3. ^{US Food and Drug Administration. FDA approves Ocaliva for rare, chronic liver disease. May 31, 2016. Accessed September 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-ocaliva-rare-chronic-liver-disease}
4. ^{US Food and Drug Administration. Gastrointestinal Drug Advisory Committee meeting – Sept. 13, 2024. FDA Briefing Document. https://www.fda.gov/media/181747/download}
5. ^{Intercept Pharmaceuticals. Company Statement on FDA Advisory Committee Meeting. September 13, 2024. Accessed September 20, 2024. https://www.interceptpharma.com/about-us/news/?id=2946202}
6. ^{Brooks, A. European Commission Revokes Obeticholic Acid (Ocaliva) CMA for Primary Biliary Cholangitis. HCPLive. September 3, 2024. Accessed September 20, 2024. https://www.hcplive.com/view/european-commission-revokes-obeticholic-acid-ocaliva-cma-primary-biliary-cholangitis}