Setanaxib, a first‐in‐class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo‐controlled, phase 2 trial
Open accessAbstract
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.
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In a phase 2 study of setanaxib, after 24 weeks, changes in the PBC-40 fatigue domain score were +2.4 for placebo, +0.3 for setanaxib 400 mg daily, and -9.9 for 400 mg twice daily (p=0.027).
“After 24 weeks of treatment, the changes in the primary biliary cholangitis with a -40 fatigue domain score were encouraging: +2•4 for placebo, +0•3 for setanaxib 400 mg daily, and -9•9 for 400 mg twice daily groups (p=0•027).116,117”
From Primary biliary cholangitis. (2024) · cites this paper as [116]
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- Authors
- Invernizzi, P., Carbone, M., Jones, D., Levy, C., Little, N., Wiesel, P., Nevens, F., & the study investigators
- Affiliations
- University of Milano-Bicocca (IT)
- Newcastle University (GB)
- University of Miami (US)
- Calliditas Therapeutics AB (Sweden) (SE)
- Genkyotex (Switzerland) (CH)
- KU Leuven (BE)
- Corresponding author
- Invernizzi, Pietro
- ORCID
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2023-05-15
- Volume
- 43
- Issue
- 7
- Pages
- 1507-1522
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- OpenAlex
- W4376629896
- Cited by
- 79
- References
- 12
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 17 · 2023: 5
- FWCI
- 13.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Liver International (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Institute for Health and Care Research (NIHR200243, NF-SI-0513-10091)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- primary biliary cirrhosis, ursodeoxycholic acid, liver fibrosis, liver stiffness, gamma-glutamyl transferase, alkaline phosphatase, fatigue, antifibrotic therapy, second-line therapy, drug safety, dose comparison
- MeSH terms
- NADPH Oxidase 1, Alkaline Phosphatase, Animals, gamma-Glutamyltransferase, Humans, Liver Cirrhosis, Biliary, Pyridones, Ursodeoxycholic Acid, Treatment Outcome, Pyrazolones
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