Setanaxib, a first‐in‐class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo‐controlled, phase 2 trial

Abstract 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.