Intercept Pharmaceuticals, a wholly owned biopharmaceutical subsidiary of Alfasigma S.p.A., announced its decision to voluntarily withdraw OCALIVA® (obeticholic acid) from the US market for the treatment of primary biliary cholangitis (PBC) following a request from the US Food and Drug Administration (FDA). The FDA has also placed a clinical hold on all Intercept clinical trials conducted under a US IND involving obeticholic acid.
"We continue to believe the totality of clinical and real-world evidence supports OCALIVA's use for appropriate patients, and we are proud of the contribution OCALIVA has made in advancing care for people living with PBC," said Vivek Devaraj, US President at Intercept. "While our view of OCALIVA's benefit-risk profile differs from FDA's, we respect its request and have made this difficult decision to provide clear guidance for patients and prescribers."
Regulatory History and Safety Concerns
OCALIVA received FDA accelerated approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid (UDCA). The drug, a farnesoid X receptor (FXR) agonist, was approved based on a reduction in alkaline phosphatase (ALP), with the caveat that an improvement in survival or disease-related symptoms had not been established.
In November 2024, OCALIVA was denied full approval in the US market, with the FDA citing concerns that the data did not clearly demonstrate the drug's safety or effectiveness. The agency had identified liver injury in patients administered the drug, raising significant safety concerns about the treatment's benefit-risk profile.
The drug faced similar regulatory challenges internationally. In June 2024, OCALIVA had its conditional authorization revoked by European medicines regulators, who claimed the treatment's benefits had yet to be confirmed.
Clinical Trial Challenges
Recruitment to OCALIVA's confirmatory trial was halted due to difficulties finding participants with PBC and other rare diseases. This challenge is particularly significant given that approximately 200,000 cases of rare diseases are recorded within the US annually, making patient enrollment for confirmatory studies exceptionally difficult.
Julia Wattacheril, associate professor at Columbia University Vagelos College of Physicians and Surgeons, previously commented on OCALIVA's future when it did not receive full FDA approval, stating, "I think the future of the drug is now largely up to the applicant and potential patients who would enroll in new trials."
Safety Profile and Warnings
OCALIVA carries a boxed warning for hepatic decompensation and failure in primary biliary cholangitis patients with cirrhosis. Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with either compensated or decompensated cirrhosis.
The drug is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension. Among post-marketing cases, the median time to hepatic decompensation was 4 months for patients with compensated cirrhosis, while the median time to a new decompensation event was 2.5 months for patients with decompensated cirrhosis.
Impact on Primary Biliary Cholangitis Treatment
Primary biliary cholangitis is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women over the age of 40, with approximately 1 in 10,000 affected. PBC causes bile acid to build up in the liver, resulting in inflammation and scarring (fibrosis), which, if left untreated, can lead to cirrhosis, liver transplant, or death.
Since its approval, OCALIVA has played a meaningful role in the treatment landscape for patients living with this rare disease. Patients currently prescribed OCALIVA for PBC treatment are advised to consult their healthcare professionals before making any changes to their treatment regimen.
Company Response and Future Commitment
Despite the withdrawal, Intercept maintains its commitment to hepatology innovation. The company will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process. Healthcare professionals with questions about OCALIVA can contact Intercept Medical Information, while patients can reach out to the company's Patient Support Services.
