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Lookup NU author(s): Professor David Jones
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© 2023 CymaBay Therapeutics, Inc and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. 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.
Author(s): Mayo MJ, Vierling JM, Bowlus CL, Levy C, Hirschfield GM, Neff GW, Galambos MR, Gordon SC, Borg BB, Harrison SA, Thuluvath PJ, Goel A, Shiffman ML, Swain MG, Jones DEJ, Trivedi P, Kremer AE, Aspinall RJ, Sheridan DA, Dorffel Y, Yang K, Choi Y-J, McWherter CA
Publication type: Article
Publication status: Published
Journal: Alimentary Pharmacology and Therapeutics
Year: 2024
Volume: 59
Issue: 2
Pages: 186-200
Print publication date: 01/01/2024
Online publication date: 30/10/2023
Acceptance date: 26/09/2023
ISSN (print): 0269-2813
ISSN (electronic): 1365-2036
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1111/apt.17755
DOI: 10.1111/apt.17755
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