A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA

Abstract

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.

Keywords: PBC; alkaline phosphatase; cholestatic liver disease; second-line therapy.

Conflict of interest statement

Conflict of interest JMS reports consultancy: BMS, Boehringer Ingelheim, Echosens, Galmed, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Nordic Bioscience, Novartis, Pfizer, Roche, Sanofi, Zydus. Research Funding: Gilead Sciences. AP has received grant funding, personal fees, and advisory board fees from Intercept Pharmaceuticals; advisory board fees and fees for teaching from Novartis; and personal fees from CymaBay Therapeutics and Inova Diagnostics. KVK: serves as consultant to or an advisory boards for Conatus, CymaBay, Gilead, Intercept, La Jolla, Merck and Novartis. He receives research support from Genfit, Gilead, High Tide, Intercept, NGM Biopharma and Novartis and serves as a speaker for Abbvie, Gilead Sciences and Intercept. MAH: Consultancy for Roche, Novartis, Falk and Intercept. SC received research support from Genfit, Gilead and Zydus. DP: nothing to disclose. AB: nothing to disclose. GMH has consulted for Intercept, Genfit, Novartis, GSK, Cymabay and Gilead. CL reports research grants: Gilead, Intercept, CymaBay, Genfit, Genkyotex, Enanta, GSK, Novartis, NGM, High Tide, Durect, Alnylam, Zydus, Cara Therapeutics, Target PharmaSolutions; Consulting fees/Advisory boards: CymaBay, GSK, Shire, Pliant, Target PharmaSolutions, Flashlight Therapeutics, Cara Therapeutics; Royalties: Up-to-date; other: Editorial board Liver Transplantation. JV Research Grants: Allergan, Arena, CymaBay, Enanta, Genkyotex, Intercept, Lilly, NGM Pharmaceuticals, Novartis, TaiwanJ, Scientific Advisor: Arena, BioIncept, Blade, CymaBay, Enanta, Genkyotex, Glaxo-Smith-Kline, Intercept, Lilly, Novartis, TaiwanJ, Authorship: Up-to-Date Immunosuppression in Liver Transplantation; AASLD Writing Committee AIH Guidance In Press, 2019. DJ reports consultancy and grant funding from Intercept and Consultancy from Novartis. AT has nothing to disclose. BS is consultant and president of the SAB of Genfit SA. SM was a former Genfit employee and has currently no COI. RH, DM and PB are Genfit employees. VL reports consultancy for Genfit.

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