European Commission Revokes Obeticholic Acid (Ocaliva) CMA for Primary Biliary Cholangitis

Steffen Wagner

Credit: Advanz Pharma

The European Commission has revoked the conditional marketing authorization (CMA) of obeticholic acid (Ocaliva) in Europe for the second-line treatment of patients with primary biliary cholangitis (PBC).¹

The decision is based on a June 2024 recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) to revoke the CMA of obeticholic acid across Europe following a non-pharmacovigilance Article 20 procedure to reassess the benefit-risk profile of the medicine in PBC. According to a press release from Advanz Pharma, this was not based on any safety concerns.^1,2

“We strongly disagree with the European Commission’s decision to withdraw the conditional marketing authorisation for OCALIVA®, the only FXR agonist for patients with PBC, and until now the only approved and available second-line treatment option in Europe,” Steffen Wagner, CEO at Advanz Pharma, said in a press release.¹ “The removal of OCALIVA® could have a profoundly negative impact on the lives of the thousands of patients with PBC across Europe who have benefitted from this important treatment over many years. The decision puts them at increased risk of disease progression, including serious liver harm, liver transplantation or death.”

The revocation comes weeks ahead of the October 15, 2024, PDUFA date for obeticholic acid in the US. With this decision right around the corner, the US Food and Drug Administration plans to hold an advisory committee meeting on September 13, 2024, to discuss Intercept Pharmaceuticals’ supplemental New Drug Application for obeticholic acid 5 mg titrated to 10 mg oral tablets to fulfill accelerated approval postmarketing requirements in the US.³

Although seladelpar (Livdelzi) and elafibranor (Iqirvo), both peroxisome proliferator-activated receptor agonists, recently received accelerated approval from the US Food and Drug Administration as second-line therapies for PBC in the United States, neither drug is currently approved in Europe, where obeticholic acid was the sole approved and available second-line option for patients. Although ursodeoxycholic acid (UDCA) has long been the mainstay of treatment for PBC and continues to be the only first-line therapy, many patients do not respond to or are unable to tolerate UDCA and thus require a second-line therapy to prevent progression to cirrhosis and eventual liver failure as well as to improve symptom burden.^4,5

At the time of its CMA in 2016, obeticholic acid was shown to reduce the blood levels of alkaline phosphatase (ALP) and bilirubin in patients with PBC. However, its clinical benefits needed to be demonstrated in further studies, which were requested by EMA as part of the conditions of the CMA.²

Upon review of findings from the phase 4 Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) study, real-world data, data from supportive studies, and other available evidence, the committee determined the clinical benefits of obeticholic acid had not been confirmed and thus recommended its marketing authorization be revoked in the European Union.²

In a press release, Advanz Pharma asserted the CHMP recommendation did not adequately consider the totality of available data supporting the efficacy and safety of obeticholic acid in PBC, especially the positive real-world evidence gathered from more than 7 years of clinical use representing more than 47,000 patient-years of treatment experience. Rather, it largely relied on findings from COBALT.¹

In COBALT, patients randomized to obeticholic acid 5–10 mg were compared with placebo in a randomized controlled trial or external control. The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation.⁶

Findings were published in the American Journal of Gastroenterology and showed the primary endpoint occurred in 28.6% (n = 168) of obeticholic acid and 28.9% (n = 166) of placebo patients (intent-to-treat analysis hazard ratio [HR], 1.01; 95% CI, 0.68–1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Of note, correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor obeticholic acid. In the external control (n = 1051), the weighted primary endpoint occurred in 10.1% of obeticholic acid and 21.5% of non-obeticholic acid patients (HR, 0.39; 95% CI, 0.22–0.69; P = .001).⁶

According to the press release, subject to local laws and regulations, the EMA has referenced the ability of Advanz Pharma to continue to supply obeticholic acid in the EU on a compassionate access or named patient program basis for existing patients.¹

“We are committed to supporting patients with PBC and will consider all available potential routes to maintain availability of this important treatment option. We will continue to work with the relevant authorities across the EU to help ensure OCALIVA® remains available for patients who require it,” Wagner concluded.¹

References

1. ^{Advanz Pharma. ADVANZ PHARMA’s response to European Commission revocation of conditional marketing authorisation for OCALIVA® in rare disease Primary Biliary Cholangitis (PBC). September 3, 2024. Accessed September 3, 2024. https://www.advanzpharma.com/news/2024/advanz-pharmas-response-to-european-commission-revocation-of-conditional-marketing-authorisation-for-ocaliva-in-rare-disease-primary-biliary-cholangitis-pbc}
2. ^{European Medicines Agency. EMA recommends revoking conditional marketing authorisation for Ocaliva. June 28, 2024. Accessed September 3, 2024. https://www.ema.europa.eu/en/news/ema-recommends-revoking-conditional-marketing-authorisation-ocaliva}
3. ^{US Food and Drug Administration. September 13, 2024: Meeting of the Gastrointestinal Drugs Advisory Committee Meeting Announcement. Advisory Committee Calendar. August 29, 2024. Accessed September 3, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-13-2024-meeting-gastrointestinal-drugs-advisory-committee-meeting-announcement-09132024}
4. ^{Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed September 3, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}
5. ^{Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed September 3, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc}
6. ^{Kowdley KV, Hirschfield GM, Coombs, CME, et al. COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls. The American Journal of Gastroenterology. doi:10.14309/ajg.0000000000003029}