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Background: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects., Aims: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC., Methods: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years., Results: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2., Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year., Clinicaltrials: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16., (© 2023 CymaBay Therapeutics, Inc and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid., Methods: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8., Results: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events., Conclusions: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus., Gov Number: NCT02955602 CLINICALTRIALSREGISTER., Eu Number: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores., Competing Interests: Conflict of interest Christopher Bowlus has received grants from Arena Pharmaceuticals, Cara Therapeutics, Genfit, Genkyotex, and Novartis and grants and personal fees from CymaBay Therapeutics, Eli Lilly, Gilead, GlaxoSmithKline, and Intercept. Michael Galambos has received consulting and investigator fees from CymaBay Therapeutics. Richard Aspinall owns stock in CymaBay Therapeutics. Gideon M. Hirschfield has received personal fees from CymaBay Therapeutics, Genfit, GlaxoSmithKline, HighTide, Intercept Pharma, Mirum, and Pliant. David E. Jones has received personal fees from Abbott and Falk and personal fees and a grant from Intercept. Stuart C. Gordon has received personal fees and advisory board compensation from CymaBay Therapeutics and research support was paid to his institution by AbbVie, Brigham and Women’s Hospital, CymaBay Therapeutics, DURECT, Eiger, Genfit, Gilead, GlaxoSmithKline, Intercept, Merck, Pliant, Shire, and Viking. Stephen A. Harrison has received personal fees from AgonAB, Altimmune, Boston Pharmaceuticals, B Riley FBR, Canfite Biopharma, Echosens North America, Fibronostics, Foresite Labs, Fortress Biotech, GNS Healthcare, Histoindex Pte, Inipharm, Ionis, Kowa Research Institute, Medpace, Microba Pty, Nutrasource, Piper Sandler & Co, Prometic Pharma Smt, Ridgeline Therapeutics, Sonic Incytes Medical Corporation, and Terns; grants from Cirius Therapeutics, Galmed Research & Development, Hepion Pharmaceuticals, and Pathai; personal fees and grants from Akero Therapeutics, Axcella Health, Civi Biopharma, CymaBay Therapeutics, Enyo Pharma S.A., Galectin Therapeutics, Genfit, Gilead Sciences, High Tide, Intercept, Madrigal Pharmaceuticals, Metracrine, NGM Biopharmaceuticals, Northsea Therapeutics B.V., Novartis, Novo Nordisk, Poxel, Sagimet Biosciences, and Viking Therapeutics; advisory board compensation from 89Bio, Akero Therapeutics, Altimmune, Arrowhead Pharmaceuticals, Axcella Health, Civi Biopharma, CymaBay Therapeutics, Echosens North America, Foresite Labs, Galectin Therapeutics, Galmed Research & Development, Genfit, Gilead, Hepion Pharmaceuticals, High Tide, Histoindex Pte, Indalo Therapeutics, Intercept, Madrigal Pharmaceuticals, Medpace, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Prometic Pharma Smt, Ridgeline Therapeutics, Sagimet Biosciences, Terns, and Theratechnologies; and owns stock in Akero Therapeutics, Cirius Therapeutics, Galectin Therapeutics, Genfit, Hepion Pharmaceuticals, Histoindex Pte, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics B.V., and Pathai. Andreas E. Kremer has received personal fees from AbbVie, Bayer, CymaBay Therapeutics, Eisai, Eli Lilly, Escient, Falk, FMC, Gilead, GlaxoSmithKline, Mirum, MSD, Myr, Newbridge, Novartis, and Zambon and personal fees and a grant from Intercept. Marlyn J. Mayo has received consulting and investigator fees from CymaBay Therapeutics. Paul J. Thuluvath has received a grant from CymaBay Therapeutics. Cynthia Levy has received grants from Genkyotex, Gilead, High Tide, Intercept, Novartis, and Zydus and grants and personal fees from Cara Therapeutics, CymaBay Therapeutics, Genfit, and GlaxoSmithKline. Mark Swain has received grants from CymaBay Therapeutics and Genfit and a grant and personal fees from Intercept. Yvonne Dörffel, Guy Neff, David Sheridan, Carmen Stanca, Christoph Berg, and Aparna Goel have nothing to disclose. Mitchell L. Shiffman has received grants from CymaBay Therapeutics, High Tide, and Genfit and grants and personal fees from Intercept. John M. Vierling has received grants from Gilead, GlaxoSmithKline, and Intercept; personal fees from Intercept and Novartis; and personal fees and grants from CymaBay Therapeutics. Pol Boudes is a former employee of CymaBay Therapeutics who owns stock in CymaBay Therapeutics and holds a patent broadly relevant to this work. Alexandra Steinberg is a former employee of CymaBay Therapeutics who owns stock in CymaBay Therapeutics. Yun-Jung Choi is an employee of and owns stock in CymaBay Therapeutics. Charles McWherter is an employee of and owns stock in CymaBay Therapeutics and holds patents broadly relevant to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)