A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis

• Published in: Nature communications Vol. 14; no. 1; p. 7151
• Main Authors: Newsome, Philip N., Sanyal, Arun J., Neff, Guy, Schattenberg, Jörn M., Ratziu, Vlad, Ertle, Judith, Link, Jasmin, Mackie, Alison, Schoelch, Corinna, Lawitz, Eric
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-11-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 631/154/436/108; 692/4020/4021/1607/2751; 82/1; Adults; Alanine; Alanine transaminase; Biomarkers; Caspase; Clinical trials; Copper; Cytokeratin; Drug therapy; Health services; Humanities and Social Sciences; Inhibitors; Injury prevention; Liver; Liver diseases; multidisciplinary; Oxidase; Pharmacodynamics; Placebos; Safety; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42398-w

Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg (
n
 = 16), 3 mg (
n
 = 16), 6 mg (
n
 = 17), 10 mg (
n
 = 32) or placebo (
n
 = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks’ treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo;
n
 = 32), 26.5% (1 mg;
n
 = 16), 10.4% (3 mg;
n
 = 16), 5.0% (6 mg;
n
 = 16), 3.3% (10 mg;
n
 = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition ( < 20% activity) at Week 4. At Week 12 following doses of BI 1467335 ≥ 3 mg, ALT and CK-18 caspase decreased dose-dependently. All tested BI 1467335 doses were well tolerated, with no clinically relevant treatment-emergent safety signals. BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83).
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.