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Lookup NU author(s): Professor David Jones
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 European Association for the Study of the Liver. Background & Aims: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. Methods: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). Results: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5’-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. Conclusion: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. Lay summary: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. Clinical trial registration number: Clinical Trials.gov NCT03124108
Author(s): Schattenberg JM, Pares A, Kowdley KV, Heneghan MA, Caldwell S, Pratt D, Bonder A, Hirschfield GM, Levy C, Vierling J, Jones D, Tailleux A, Staels B, Megnien S, Hanf R, Magrez D, Birman P, Luketic V
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Year: 2021
Volume: 74
Issue: 6
Pages: 1344-1354
Print publication date: 01/06/2021
Online publication date: 21/01/2021
Acceptance date: 05/01/2021
Date deposited: 18/09/2024
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.jhep.2021.01.013
DOI: 10.1016/j.jhep.2021.01.013
Data Access Statement: Data is available from the Study Sponsor Genfit SA.
PubMed id: 33484775
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