Jörn M Schattenberg1, Albert Pares2, Kris V Kowdley3, Michael A Heneghan4, Stephen Caldwell5, Daniel Pratt6, Alan Bonder7, Gideon M Hirschfield8, Cynthia Levy9, John Vierling10, David Jones11, Anne Tailleux12, Bart Staels12, Sophie Megnien13, Remy Hanf13, David Magrez13, Pascal Birman13, Velimir Luketic14. 1. Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre Mainz, Germany. Electronic address: joern.schattenberg@unimedizin-mainz.de. 2. Hospital Clinic, University of Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain. 3. Liver Institute Northwest, Seattle, USA. 4. Institute of Liver Studies, Kings College Hospital, London, United Kingdom. 5. University of Virginia, Charlottesville, Virginia, USA. 6. Massachusetts General Hospital, Boston, Massachusetts, USA. 7. Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 8. Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada. 9. Division of Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA. 10. Baylor College of Medicine, Houston, Texas, USA. 11. Newcastle University Medical School, Newcastle upon Tyne, United Kingdom. 12. Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. 13. GENFIT, 885 Avenue Eugene Avinee, 59120, Loos, France. 14. Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, Richmond, Virginia, USA.
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.
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.
Authors: Eric M Yoshida; Mark Gordon Swain; Cynthia Tsien; Edward Tam; Robert James Bailey; Dusanka Grbic; Hin Hin Ko; Alnoor Ramji; Nir Hilzenrat; Magdy Elkhashab; Euiseok Kim; Meaghan O'Brien; Marco Amedeo Puglia; Kevork M Peltekian Journal: Can Liver J Date: 2022-08-16
Authors: Vinicius M Alves; Daniel Korn; Vera Pervitsky; Andrew Thieme; Stephen J Capuzzi; Nancy Baker; Rada Chirkova; Sean Ekins; Eugene N Muratov; Anthony Hickey; Alexander Tropsha Journal: Drug Discov Today Date: 2021-10-27 Impact factor: 8.369