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Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized,
Pietro Invernizzi1,2, Marco Carbone1,2, David Jones3
1Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
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.
Insights
Setanaxib did not meet its primary endpoint in treating primary biliary cholangitis (PBC). However, secondary outcomes suggest potential anti-cholestatic and anti-fibrotic benefits, warranting further investigation in larger trials.
Area of Science:
- Hepatology
- Pharmacology
- Clinical Trials
Background:
- Primary biliary cholangitis (PBC) is a rare liver disease with limited second-line treatment options.
- Setanaxib, a NOX1/4 inhibitor, demonstrated anti-fibrotic properties in preclinical studies.
- This study evaluated setanaxib as an add-on therapy for PBC patients already on ursodeoxycholic acid (UDCA).
Purpose of the Study:
- To assess the efficacy and safety of setanaxib in patients with primary biliary cholangitis.
- To determine the effect of setanaxib on liver enzymes, liver stiffness, and fatigue.
- To explore setanaxib's potential as a novel treatment for PBC.
Main Methods:
- A phase 2, randomized, multicenter trial involving 111 patients with PBC.
- Patients received oral setanaxib (400 mg once or twice daily) or placebo alongside UDCA for 24 weeks.
- Primary endpoint was the change in gamma-glutamyl transferase (GGT); secondary endpoints included alkaline phosphatase (ALP), liver stiffness, and fatigue.
Main Results:
- The primary endpoint (change in GGT) was not met (p=0.31).
- Setanaxib (twice daily) significantly reduced ALP levels compared to placebo (p=0.002).
- Improvements in fatigue scores were observed with setanaxib twice daily (p=0.027), while liver stiffness showed no significant difference.
Conclusions:
- While the primary endpoint was not met, setanaxib showed potential for anti-cholestatic and anti-fibrotic effects in PBC.
- The observed improvements in ALP and fatigue warrant further investigation.
- Setanaxib's efficacy and safety require evaluation in larger phase 2b/3 trials for PBC.
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