BACKGROUND Inclisiran 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. METHODS We 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. RESULTS A 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. CONCLUSIONS Reductions 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. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).

中文翻译：

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LDL胆固醇升高的患者进行的两次Inclisiran 3期试验。

背景技术Inclisiran抑制9型前蛋白转化酶枯草杆菌蛋白酶-kexin的肝合成。先前的研究表明，inclisiran可以通过不频繁给药而持续降低低密度脂蛋白（LDL）胆固醇水平。方法我们招募了尽管接受最大耐受剂量的他汀类药物治疗但LDL胆固醇水平升高的动脉粥样硬化性心血管疾病患者（ORION-10试验）和动脉粥样硬化性心血管疾病或动脉粥样硬化性心血管疾病风险当量患者（ORION-11试验）。将患者按1：1比例随机分配，以接受inclisiran（284 mg）或安慰剂，于第1天，第90天和之后每6个月经540天经皮下注射。每个试验的共同主要终点是从基线到510天，安慰剂校正的LDL胆固醇水平的百分比变化以及从基线90天到540天为止的LDL胆固醇水平的时间校正百分比变化。结果总计1561在ORION-10和ORION-11试验中，分别对1617例患者进行了随机分组。基线时的平均（±SD）LDL胆固醇水平分别为104.7±38.3 mg /分升（2.71±0.99 mmol /升）和105.5±39.1 mg /分升（2.73±1.01 mmol /升）。在第510天，在ORION-10试验中，inclisiran将LDL胆固醇水平降低了52.3％（95％置信区间[CI]，从48.8至55.7），在ORION-11试验中降低了49.9％（95％CI，从46.6至53.1）。 ，相应的时间调整后的减少幅度为53.8％（95％CI，51.3至56.2）和49.2％（95％CI，46.8至51.6）（P <0。所有比较与安慰剂均为001）。在每项试验中，inclisiran和安慰剂组的不良事件通常相似，尽管inclisiran的注射部位不良事件比安慰剂更为频繁（ORION-10试验为2.6％vs. 0.9％，在ORION-10试验中为4.7％vs. 0.5％。 ORION-11试验）；这种反应通常是轻微的，没有一个是严重的或持续的。结论每6个月皮下注射inclisiran可降低LDL胆固醇水平约50％。与安慰剂相比，inclisiran发生的注射部位不良事件更多。（由药品公司提供； ORION-10和ORION-11 ClinicalTrials.gov编号，NCT03399370和NCT03400800。）。尽管inclisiran的注射部位不良反应发生率高于安慰剂（ORION-10试验为2.6％，0.9％，ORION-11试验为4.7％，0.5％）；这种反应通常是轻微的，没有一个是严重的或持续的。结论每6个月皮下注射inclisiran可降低LDL胆固醇水平约50％。与安慰剂相比，inclisiran发生的注射部位不良事件更多。（由药品公司提供； ORION-10和ORION-11 ClinicalTrials.gov编号，NCT03399370和NCT03400800。）。尽管inclisiran的注射部位不良反应发生率高于安慰剂（ORION-10试验为2.6％，0.9％，ORION-11试验为4.7％，0.5％）；这种反应通常是轻微的，没有一个是严重的或持续的。结论每6个月皮下注射inclisiran可降低LDL胆固醇水平约50％。与安慰剂相比，inclisiran发生的注射部位不良事件更多。（由药品公司提供； ORION-10和ORION-11 ClinicalTrials.gov编号，NCT03399370和NCT03400800。）。结论每6个月皮下注射inclisiran可降低LDL胆固醇水平约50％。与安慰剂相比，inclisiran发生的注射部位不良事件更多。（由药品公司提供； ORION-10和ORION-11 ClinicalTrials.gov编号，NCT03399370和NCT03400800。）。结论每6个月皮下注射inclisiran可降低LDL胆固醇水平约50％。与安慰剂相比，inclisiran发生的注射部位不良事件更多。（由药品公司提供； ORION-10和ORION-11 ClinicalTrials.gov编号，NCT03399370和NCT03400800。）。