FDA Issues CRL to Obeticholic Acid (Ocaliva), Denies Full Approval for PBC

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Intercept Pharmaceuticals’ obeticholic acid (Ocaliva) for the treatment of primary biliary cholangitis (PBC).¹

According to a press release from Intercept, the FDA informed the company that it is unable to approve the supplemental New Drug Application in its current form, consistent with the outcome of a Gastrointestinal Drugs Advisory Committee meeting held in September 2024 that 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.^1,2

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 States Prescribing Information population.²

The CRL comes nearly a month after the original Prescription Drug User Fee Act (PDUFA) target action date of October 15, 2024, which was extended on October 17, 2024, with no new anticipated date provided by the FDA.^1,3

In the November 12, 2024, CRL, the FDA also said it was continuing to consider safety data from Study 747-302, along with other safety information. As described in the release from Intercept, obeticholic acid’s safety profile is based on extensive data from long-term clinical trials, published real-world evidence and external-control studies, and 8 years of post-marketing patient experience collectively spanning 42,000 patient-years.¹

“We believe in the totality of evidence supporting OCALIVA and intend to work closely with the FDA on next steps,” Vivek Devaraj, US President and Chairman at Intercept, said in a press release.¹ “We remain committed to patients living with PBC who have limited treatment options.”

Of note, according to the press release, obeticholic acid continues to be available for the treatment of appropriate patients living with PBC in the US under accelerated approval status.¹

For years, obeticholic acid was the sole second-line therapy in PBC and was the only option for patients who did not respond to or could not tolerate ursodeoxycholic acid (UDCA). In 2024, over the span of 2 months, the FDA granted accelerated approvals to both elafibranor (Iqirvo) and seladelpar (Livdelzi), making them the second and third approved second-line therapies in PBC, respectively.^4,5

References

1. ^{Intercept Pharmaceuticals. Intercept Receives Complete Response Letter from FDA Addressing OCALIVA supplemental New Drug Application (sNDA). November 12, 2024. Accessed November 12, 2024. https://www.interceptpharma.com/about-us/news/?id=2979130}
2. ^{Brooks, A. Nancy Reau, MD: Obeticholic Acid’s Future in PBC After FDA Advisory Committee Meeting. HCPLive. September 20, 2024. Accessed November 12, 2024. https://www.hcplive.com/view/nancy-reau-md-obeticholic-acid-future-pbc-fda-advisory-committee-meeting}
3. ^{Brooks, A. FDA Extends Review of Obeticholic Acid (Ocaliva) sNDA for Primary Biliary Cholangitis. HCPLive. October 17, 2024. Accessed November 12, 2024. https://www.hcplive.com/view/fda-extends-review-obeticholic-acid-ocaliva-snda-primary-biliary-cholangitis}
4. ^{Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed November 12, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc}
5. ^{Brooks, A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed November 12, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}