2020年3月18日出版的《新英格兰医学杂志》发表了一项最新研究成果。英国伦敦帝国理工学院Kausik K. Ray研究组探索了Inclisiran治疗低密度脂蛋白胆固醇升高的疗效。

Inclisiran可抑制前蛋白转化酶枯草杆菌蛋白酶kexin-9型的肝合成。此前研究表明，间歇使用Inclisiran可能会持续降低低密度脂蛋白（LDL）胆固醇的水平。

研究组进行了两项试验，其中ORION-10招募了1561名动脉粥样硬化性心血管疾病的患者，ORION-11招募了1617名动脉粥样硬化性心血管疾病或高风险的患者，所有患者虽然接受最大耐受剂量的他汀类药物治疗，但LDL胆固醇水平仍然很高。将这些患者按1：1随机分组，分别接受Inclisiran或安慰剂进行治疗，第1天和第90天注射给药，之后每半年注射一次。

两个试验基线时的平均LDL胆固醇水平分别为104.7±38.3mg/dL和105.5±39.1mg/dL。在第510天，ORION-10试验中，Inclisiran将LDL胆固醇水平降低了52.3%，ORION-11试验中则降低了49.9%，经相应时间校正后，降低率分别为53.8%和49.2%。 每项试验中Inclisiran组和安慰剂组的不良事件相差不大，虽然Inclisiran组的注射部位不良事件更常见，但反应均轻微且短暂。

总之，每6个月皮下注射Inclisiran可使LDL胆固醇水平降低约50%。与安慰剂相比，Inclisiran发生注射部位不良事件更多。

附：英文原文

Title: Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Author: Kausik K. Ray, M.D., M.Phil.,, R. Scott Wright, M.D.,, David Kallend, M.D.,, Wolfgang Koenig, M.D.,, Lawrence A. Leiter, M.D.,, Frederick J. Raal, Ph.D.,, Jenna A. Bisch, B.A.,, Tara Richardson, B.A.,, Mark Jaros, Ph.D.,, Peter L.J. Wijngaard, Ph.D.,, and John J.P. Kastelein, M.D., Ph.D.

Issue&Volume: 2020-03-18

Abstract: AbstractBackgroundInclisiran inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing.MethodsWe enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.ResultsA total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.ConclusionsReductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo.

DOI: 10.1056/NEJMoa1912387

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1912387