Details

Autor(en) / Beteiligte

• Newsome, Philip N
• Sanyal, Arun J
• Neff, Guy
• Schattenberg, Jörn M
• Ratziu, Vlad
• Ertle, Judith
• Link, Jasmin
• Mackie, Alison
• Schoelch, Corinna
• Lawitz, Eric

Titel

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

Ist Teil von

• Nature communications, 2023-11, Vol.14 (1), p.7151-7151, Article 7151

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract 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).