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).

非酒精性脂肪性肝炎 (NASH) 是一种进行性炎症性肝病，尚无批准的药物治疗方法。这项 IIa 期、双盲、安慰剂对照、多中心试验 (ClinicalTrials.gov: NCT03166735) 研究了 BI 1467335（一种胺氧化酶含铜 3 (AOC3) 抑制剂）在欧洲和北美成人 NASH 中的药效学和安全性。来自美国、德国、西班牙、比利时、英国、荷兰、加拿大、法国和爱尔兰 44 个中心的参与者被随机分配（2:1:1:1:2；2017 年 7 月 27 日至 2019 年 6 月 14 日）每日口服 BI 1467335 1 mg ( n  = 16)、3 mg ( n  = 16)、6 mg ( n  = 17)、10 mg ( n  = 32) 或安慰剂 ( n  = 32)，持续 12 周，随访至第 16 周。主要终点是治疗 12 周后给药后 24 小时相对于基线的 AOC3 活性 (%)。次要生物标志物终点包括第 12 周时丙氨酸转氨酶 (ALT) 和 caspase 裂解的细胞角蛋白 18 (CK-18 caspase) 相对于基线的变化。第 12 周相对于基线的平均 AOC3 活性：90.4%（安慰剂；n  = 32）、26.5%（1 mg；n  = 16）、10.4%（3 mg；n  = 16）、5.0%（6 mg；n  = 16） 16), 3.3% (10 毫克; n  = 32)。这些变化表明 BI 1467335 剂量依赖性地抑制 AOC3 活性；≥3 mg 剂量在第 4 周达到 >80% 抑制（< 20% 活性）。在第 12 周，服用 BI 1467335 ≥ 3 mg 剂量后，ALT 和 CK-18 caspase 呈剂量依赖性下降。所有测试的 BI 1467335 剂量均具有良好的耐受性，没有临床相关的治疗紧急安全信号。BI 1467335 强烈抑制 NASH 参与者的 AOC3，剂量≥3 mg 剂量依赖性地降低肝损伤生物标志物 ALT 和 CK-18 的水平。该试验已在 ClinicalTrials.gov (NCT03166735) 和欧盟药物监管机构临床试验数据库 (EudraCT 2016-000499-83) 注册。