WELCOME TO THE BRITISH ASSOCIATION FOR THE STUDY OF THE LIVER

A statement from Dr Palak Trivedi in his role as BASL/BSG Immune Liver Disease SIG Chair

I write with reference to a statement released by the United States Food and Drug Administration (FDA) at the beginning of September 2025, as relates to Obeticholic acid (OCA, Ocaliva) for the treatment of primary biliary cholangitis (PBC).

In their statement, the FDA issued notice that Intercept Pharma (who do not operate in the United Kingdom) have withdrawn the license for OCA to treat individuals with PBC in the United States. This recommendation was made following that of the European Medicines Association (EMA) in 2024, which itself came after results of a post-market approval, phase IV randomised controlled clinical trial (COBALT trial, 747-302). To recap, COBALT was specifically designed to treat patients with advanced liver disease / high-risk PBC, with the primary efficacy outcome being a reduction in liver event free survival (hepatic decompensation, hepatocellular carcinoma, need for transplantation and/or death). As per previous statements from BASL, the patient population in COBALT (a) represented a minority (<20%) of the overall PBC group eligible to receive second-line therapy, and (b) this trial took place at a time period when OCA was available for commercial use as part of routine clinical care. This meant that recruitment to the COBALT programme was challenging, as the vast majority of patients with high-risk liver disease opted for commercially available drug rather than take a chance at being on placebo for up to 7 years. Consequently, the COBALT trial was not able to recruit the required number of patients according to pre-specified power calculations and sample size, and was terminated early.

Following review of clinical trial data, and the inability to recruit to COBALT, the FDA claimed that the clinical benefits of OCA did not impart benefit to patients beyond certain on-treatment biochemical changes, and that:

• Use of OCA outside its clinical label (cirrhosis with clinically significant portal hypertension) may be associated with harm, with an increased risk of clinical events
• Certain individuals without cirrhosis also developed clinical events in the COBALT study (i.e. high risk individuals with very high levels of bilirubin in the absence of cirrhosis, in keeping with the premature ductopenic PBC variant.
Notably, these claims were made despite no new safety concerns / adverse safety data being provided to the FDA since their last review of OCA''s place as a PBC treatment. It is also important to highlight that the FDA did not take into account any of the published real-world evidence evaluating OCA over several years (at a population level), nor the wealth of clinical evidence and patient testimonials from countries where OCA is actually available and used (such as the UK). Indeed, data from multiple sources show a significant improvement in liver biochemical markers and a reduction in clinical event rate in patients with earlier stage PBC - .Abbas et al. APT 2025 (in press); Ampuero et al. Hepatology 2023

As it stands OCA is still licensed in several western markets, including the UK, Australia and Canada, with off-label access in many European countries (e.g. Spain). With regards the UK specifically, there are as yet no changes to recommendations on the use of OCA in PBC from the MHRA or NICE. As such, the FDA recommendation has NO direct impact on the use of OCA in routine clinical practice, or in clinical trials (e.g. the OPERA study or the OACS programme).

Thus, we, categorically, DO NOT recommend that any patient empirically stop Obeticholic acid therapy at present, nor do we suggest that any patient eligible to receive OCA de novo be stopped from doing so following the EMA recommendation.

End

Read the BASL special issue of Frontline Gastroenterology online.
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A collection of papers discussing all current and relevant topics in hepatology.

This special edition has been made to celebrate BASL's affiliation with Frontline Gastroenterology.

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Participants:

Dr Oliver Tavabie - Deputy Editor at Frontline Gastroenterology and Consultant Hepatologist at the Leeds Liver Unit
Dr Louise China - Lead Associate Editor at Frontline Gastroenterology and Consultant Hepatologist at the Royal Free
Dr Tim Cross - BASL President, Associate Editor at Frontline Gastroenterology and Consultant Hepatologist at the Royal Liverpool Hospital

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