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Lookup NU author(s): Professor David Jones
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Liver International published by John Wiley & Sons Ltd. Background: Primary biliary cholangitis (PBC) is a rare liver disease with significant unmet need for second-line/add-on treatments. Setanaxib, a NOX1/4 inhibitor, has shown anti-fibrotic effects in in vitro and animal studies. This phase 2, randomized, multicentre study investigated the efficacy and safety of setanaxib in patients with PBC. Methods: Patients with ≥6 months of ursodeoxycholic acid (UDCA) treatment were randomized 1:1:1 to oral setanaxib 400 mg once daily (OD), twice daily (BID), or placebo, in addition to UDCA for 24 weeks. Other inclusion criteria included alkaline phosphatase (ALP) ≥1.5 × ULN and gamma-glutamyl transferase (GGT) ≥1.5 × ULN. The primary endpoint was percentage change from baseline in GGT at Week 24; secondary endpoints included change from baseline in ALP, liver stiffness (LS; via transient elastography), fatigue at Week 24, and safety outcomes. p values compare setanaxib 400 mg BID and placebo groups. Results: Of patients randomized (setanaxib 400 mg OD and BID: 38, and 36; placebo: 37), 104/111 completed Week 24. Mean (standard deviation [SD]) change in GGT to Week 24 was −4.9% (59.6%) for setanaxib 400 mg OD, −19.0% (28.9%) for setanaxib 400 mg BID, and −8.4% (21.5%) for placebo; p =.31. Patients treated with setanaxib 400 mg OD and BID showed decreased serum ALP levels from baseline to Week 24 (p =.002: setanaxib BID versus placebo). Patients treated with setanaxib 400 mg OD and BID showed mean (SD) percentage increases in LS to Week 24 of 3.3% (35.0%) and 7.9% (43.7%), versus 10.1% (33.1%) for placebo (p =.65). Changes in mean (SD) PBC-40 fatigue domain scores to Week 24 were +0.3% (24.9%) for setanaxib 400 mg OD, −9.9% (19.8%) for setanaxib 400 mg BID and +2.4% (23.1%) for placebo, p =.027. Two patients (one placebo, one setanaxib 400 mg BID) experienced serious treatment-emergent adverse events, deemed unrelated to study drug. Conclusions: The primary endpoint was not met. However, the secondary endpoints provide preliminary evidence for potential anti-cholestatic and anti-fibrotic effects in PBC, supporting the further evaluation of setanaxib in a future phase 2b/3 trial.
Author(s): Invernizzi P, Carbone M, Jones D, Levy C, Little N, Wiesel P, Nevens F
Publication type: Article
Publication status: Published
Journal: Liver International
Year: 2023
Volume: 43
Issue: 7
Pages: 1507-1522
Print publication date: 01/07/2023
Online publication date: 15/05/2023
Acceptance date: 15/04/2023
Date deposited: 18/09/2024
ISSN (print): 1478-3223
ISSN (electronic): 1478-3231
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1111/liv.15596
DOI: 10.1111/liv.15596
Data Access Statement: Study data, including individual participant data, will not be made available to others after publication. The study protocol is available at https://clinicaltrials.gov/ct2/show/study/NCT03226067. No additional related documents will be made available.
PubMed id: 37183520
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