Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial.
NADPH oxidase 1/4 inhibitor
cholestasis
fibrosis
primary biliary cholangitis
setanaxib
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
revised:
14
04
2023
received:
13
12
2022
accepted:
15
04
2023
medline:
15
6
2023
pubmed:
15
5
2023
entrez:
15
5
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
setanaxib
45II35329V
NADPH Oxidase 1
EC 1.6.3.-
Ursodeoxycholic Acid
724L30Y2QR
Alkaline Phosphatase
EC 3.1.3.1
gamma-Glutamyltransferase
EC 2.3.2.2
Banques de données
ClinicalTrials.gov
['NCT03226067']
Types de publication
Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1507-1522Informations de copyright
© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.
Références
Younossi ZM, Bernstein D, Shiffman ML, et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48-63.
Hasegawa S, Yoneda M, Kurita Y, et al. Cholestatic liver disease: current treatment strategies and new therapeutic agents. Drugs. 2021;81(10):1181-1192.
Reshetnyak VI. Primary biliary cirrhosis: clinical and laboratory criteria for its diagnosis. World J Gastroenterol. 2015;21(25):7683-7708.
European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172.
Hirschfield GM, Dyson JK, Alexander GJM, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67(9):1568-1594.
Shah RA, Kowdley KV. Current and potential treatments for primary biliary cholangitis. Lancet Gastroenterol Hepatol. 2020;5(3):306-315.
Montano-Loza AJ, Corpechot C. Definition and management of patients with primary biliary cholangitis and an incomplete response to therapy. Clin Gastroenterol Hepatol. 2020;19(11):2241-2251.
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147(6):1338-49.e5; quiz e15.
Gerussi A, Bernasconi DP, O'Donnell SE, et al. Measurement of gamma glutamyl transferase to determine risk of liver transplantation or death in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2020;19(8):1688-1697.
Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751-761.e8.
Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of Obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643.
Bowlus CL, Pockros PJ, Kremer AE, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2020;18(5):1170-1178.e6.
Zhou J, Huang N, Guo Y, et al. Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis. Acta Pharm Sin B. 2019;9(3):526-536.
Corpechot C, Poupon R, Chazouillères O. New treatments/targets for primary biliary cholangitis. JHEP Rep. 2019;1(3):203-213.
Electronic Medicines Compendium. Fibrazate XL 400 mg Modified Release Tablets. 2021 [November 2022]. Available from: https://www.medicines.org.uk/emc/product/6547
Corpechot C, Gaouar F, El Naggar A, et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology. 2014;146(4):970-979; quiz e15-6.
Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology (Baltimore, Md). 2012;56(1):198-208.
Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology (Baltimore, Md). 2000;32:1196-1199.
Kremer AE, Mayo MJ, Hirschfield G, et al. Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis. Liver Int. 2021;00:1-12.
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md). 2019;69(1):394-419.
de Vries E, Bolier R, Goet J, et al. Fibrates for itch (FITCH) in fibrosing cholangiopathies: a double-blind, randomized, placebo-controlled trial. Gastroenterology. 2021;160(3):734-743.e6.
Aoyama T, Paik YH, Watanabe S, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology (Baltimore, Md). 2012;56(6):2316-2327.
Jiang JX, Chen X, Serizawa N, et al. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med. 2012;53(2):289-296.
Bettaieb A, Jiang J, Sasaki Y, et al. Hepatocyte nicotinamide adenine dinucleotide phosphate reduced oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of Steatohepatitis in mice. Gastroenterology. 2015;149(2):468-480.
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005;54(11):1622-1629.
Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. NEJM. 2016;375(7):631-643.
Onofrio FQ, Hirschfield GM, Gulamhusein AF. A practical review of primary biliary cholangitis for the gastroenterologist. Gastroenterol Hepatol (N Y). 2019;15(3):145-154.
Rodrigues PM, Banales JM. Editorial: bezafibrate in the treatment of patients with primary biliary cholangitis-are we there yet? Aliment Pharmacol Ther. 2022;55(2):247-248.
Sorda J, Ballerga E, Barreyro F, et al. Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5 years of follow up. Aliment Pharmacol Ther. 2021;54:1202-1212.
Schattenberg JM, Pares A, Kowdley KV, et al. A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA. J Hepatol. 2021;74(6):1344-1354.
Yoo JJ, Seo YS, Kim YS, et al. The influence of histologic inflammation on the improvement of liver stiffness values over 1 and 3 years. J Clin Med. 2019;8(12):2065.
Karsdal MA, Daniels SJ, Holm Nielsen S, et al. Collagen biology and non-invasive biomarkers of liver fibrosis. Liver Int. 2020;40(4):736-750.
Hirschfield GM, Chazouillères O, Drenth JP, et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol. 2019;70(3):483-493.
Jopson L, Newton JL, Palmer J, et al. RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMJ Open. 2015;5(8):e007985.
Corpechot C, Chazouillères O, Rousseau A, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378(23):2171-2181.
Electronic Medicines Compendium. Ursodeoxycholic acid 250 mg capsules. 2016 Available from: https://www.medicines.org.uk/emc/product/7253/smpc#gref
Afdhal NH, Bacon BR, Patel K, et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clin Gastroenterol Hepatol. 2015;13(4):772-779.
Oeda S, Tanaka K, Oshima A, et al. Diagnostic accuracy of FibroScan and factors affecting measurements. Diagnostics (Basel). 2020;10(11):940.