• Gideon M Hirschfield, Christopher L Bowlus, Marlyn J Mayo, Andreas E Kremer, John M Vierling, Kris V Kowdley, Cynthia Levy, Alejandra Villamil, Alma L Ladrón de Guevara Cetina, Ewa Janczewska, Ehud Zigmond, Sook-Hyang Jeong, Yusuf Yilmaz, Yiannis Kallis, Christophe Corpechot, Peter Buggisch, Pietro Invernizzi, Maria Carlota Londoño Hurtado, Sandrin Bergheanu, Ke Yang, Yun-Jung Choi, Daria B Crittenden, Charles A McWherter, and RESPONSE Study Group.
• From the Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto General Hospital, Toronto (G.M.H.); the Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento (C.L.B.), and CymaBay Therapeutics, Newark (K.Y., Y.-J.C., D.B.C., C.A.M.) - both in California; the University of Texas Southwestern Medical School, Dallas (M.J.M.), and the Departments of Medicine and Surgery, Baylor College of Medicine, Houston (J.M.V.) - both in Texas; the Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (A.E.K.); Liver Institute Northwest, Seattle (K.V.K.); the Division of Digestive Health and Liver Diseases, University of Miami, Miami (C.L.); the Liver Autoimmunity Unit, Hospital Italiano de Buenos Aires, Buenos Aires (A.V.); Centro de Investigación y Gastroenterología, Mexico City (A.L.L.G.C.); the Department of Basic Medical Sciences, Faculty of Public Health in Bytom, Medical University of Silesia, Bytom, Poland (E.J.); the Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (E.Z.); the Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University, College of Medicine, Seongnam, South Korea (S.-H.J.); the Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey (Y.Y.); Barts Liver Centre, Blizard Institute, Queen Mary University of London, London (Y.K.); the Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, French Network for Rare Liver Disease in Children and Adults FILFOIE, European Reference Network RARE-LIVER, Saint-Antoine Hospital and Research Center, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris (C.C.); Liver Centre Hamburg at Ifi-Institute, Hamburg, Germany (P.B.); the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, and the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori - both in Monza, Italy (P.I.); the Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBEREHD, European Reference Network on Hepatological Diseases (ERN-LIVER), University of Barcelona, Barcelona (M.C.L.H.); and Saberg Clinical Research, the Hague, the Netherlands (S.B.). Dr. Hirschfield is the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at Toronto General Hospital.
• N. Engl. J. Med. 2024 Feb 29; 390 (9): 783794783-794.

BackgroundEffective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.MethodsIn this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).ResultsOf the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.ConclusionsIn this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).Copyright © 2024 Massachusetts Medical Society.

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