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Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis
Kris V Kowdley1, Christopher L Bowlus1, Cynthia Levy1
1From Liver Institute Northwest, Seattle (K.V.K.); the Division of Gastroenterology and Hepatology, UC Davis School of Medicine, Sacramento (C.L.B.); Schiff Center for Liver Diseases, University of Miami, Miami (C.L.); the Department of Gastroenterology, Ege University Faculty of Medicine, İzmir, Turkey (U.S.A.); Gastroenterology and Hepatology Division, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (M.R.A.-S.); Medicina Interna Metabolica, Baggiovara Hospital, Azienda Ospedaliero-Universitaria di Modena and Università di Modena e Reggio Emilia, Modena (P.A.), and the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, and the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza (P.I.) - all in Italy; Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago (M.A.), and Sección de Gastroenterología, Hospital San Juan de la Serena, Coquimbo (J.M. Valera) - both in Chile; the Reference Center for Inflammatory Biliary Disease and Autoimmune Hepatitis, European Reference Network RARE-LIVER, Saint-Antoine Hospital and Research Center, AP-HP, Sorbonne University, Paris (C.C.), GENFIT, Loos (J.-M.G., D.R., B.T.), and Ipsen, Boulogne-Billancourt (S.M.) - all in France; the Department of Gastroenterology and Hepatology, Antwerp University Hospital, and InflaMed Center of Excellence, Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Antwerp University - both in Antwerp, Belgium (S.M.F.); the Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London (M.A.H.), the Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Center, Newcastle University, Newcastle Upon Tyne (D.J.) - all in the United Kingdom; the Department of Gastroenterology and Hepatology, Mediclinic Durbanville, and Tiervlei Trial Centre - both in Cape Town, South Africa (F.C.K.); the Texas Liver Institute, University of Texas Health, San Antonio (E.L.), the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas (M.J.M.), and the Departments of Medicine and Surgery, Baylor College of Medicine, Houston (J.M. Vierling) - all in Texas; the Liver Institute of Virginia, Bon Secours Mercy Health, Richmond (M.L.S.); the Liver Unit, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (M.G.S.); Liver Unit, European Reference Network RARE-LIVER, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CiberEhd, Barcelona (V.V.); Hepatic Autoimmunity Unit, Hospital Italiano de Buenos Aires, Buenos Aires (A.V.); GENFIT (C.A., J.D.) and Ipsen (B.M., J.S., C.O.Z.) - both in Cambridge, MA; and the Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, and the Department of Medicine II, Saarland University and Saarland University Medical Center, Homburg - both in Germany (J.M.S.).
Background:
Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.
Methods:
In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).
Results:
A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.
Conclusions:
Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).
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