Advanz Pharma’s response to European Commission revocation of conditional marketing authorisation for Ocaliva (obeticholic acid) in rare disease primary biliary cholangitis

The EC decision is based on a recommendation in June 2024, from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), to revoke the CMA of Ocaliva across Europe, following a non-pharmacovigilance Article 20 procedure to reassess the benefit-risk profile of the medicine in PBC. This was not based on any safety concerns.

Advanz Pharma disagrees with the EC’s decision, which leaves thousands of patients with PBC who are responding well to Ocaliva at increased risk of disease progression with limited treatment options. The Company is currently considering all options to help ensure continued access to Ocaliva.

Steffen Wagner, CEO at Advanz Pharma, commented: “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. 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 Company maintains that the CHMP recommendation did not adequately consider the totality of available data supporting the efficacy and safety of Ocaliva in PBC, in particular the wealth of positive real-world evidence (RWE) gathered from more than seven years of clinical use representing over 47,000 patient-years of treatment experience. Instead, it largely relied on one analysis based on a single, randomised placebo-controlled trial, Study 747-302 (COBALT), which had multiple limitations, including the fact that patients in the placebo arm unsurprisingly chose to switch to commercially available therapy, but were required to be analysed as placebo treated patients under the Intention to Treat (ITT) methodology.

The findings from the COBALT study, recently published in the American Journal of Gastroenterology, highlight the challenges of conducting long term outcomes studies in rare diseases when therapies are commercially available.

The patient community, leading experts, physicians, and hepatology and gastroenterology scientific societies, have all raised concerns to the EC that the removal of Ocaliva will leave patients without an important treatment option for this life-threatening rare liver disease. All major scientific societies recommend Ocaliva as a second-line treatment option in their clinical guidelines.

The EMA has referenced the ability for Advanz Pharma to continue – subject to local laws and regulations – to supply Ocaliva in the EU on a compassionate access or named patient programme basis for existing patients. Advanz Pharma is committed to supporting patients and will ensure supplies are available depending on national competent authority approved provisions. After reviewing the available evidence, the committee concluded that the clinical benefits of Ocaliva have not been confirmed. In particular, study 747-302 failed to show that Ocaliva was more effective than placebo (a dummy treatment) in terms of the number of patients whose disease worsened or who died, both in the overall population and in a group of patients with early stage PBC. The committee also considered that the data from supportive studies and real-world data were not sufficient to confirm the benefits of Ocaliva and could not counterbalance the negative results of study 747-302. The CHMP therefore concluded that the benefits of Ocaliva do not outweigh its risks and recommended that its marketing authorisation be revoked in the European Union (EU).

See-COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls Kowdley, Kris V. MD1; Hirschfield, Gideon M. PhD; Coombs, Charles ME; Malecha, Elizabeth S. PhD; Bessonova, Leona PhD, MBA; Li, Jing PhD; Rathnayaka, Nuvan PhD; Mells, George PhD; Jones, David E. PhD; Trivedi, Palak J. MD, PhD; et al., The American Journal of Gastroenterology ():10.14309/ajg.0000000000003029, August 14, 2024. | DOI: 10.14309/ajg.0000000000003029.