From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Department of Cardiology, Mayo Clinic, Rochester, MN (R.S.W.); the Medicines Company, Zurich, Switzerland (D.K.); Deutsches Herzzentrum München, Technische Universität München, and Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, and the Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm - all in Germany (W.K.); Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (F.J.R.); the Medicines Company, Parsippany, NJ (J.A.B., T.R., P.L.J.W.); Summit Analytical, Denver (M.J.), and the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.).
N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18.
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.
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.
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.
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.).
依洛尤单抗可抑制前蛋白转化酶枯草溶菌素 9 的肝合成。先前的研究表明，依洛尤单抗可能通过较少的给药次数提供持续降低 LDL 胆固醇水平的效果。
我们招募了患有动脉粥样硬化性心血管疾病（ORION-10 试验）和患有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等同疾病（ORION-11 试验）的患者，这些患者在接受最大耐受剂量的他汀类药物治疗后，LDL 胆固醇水平仍升高。患者以 1:1 的比例随机分配，接受依洛尤单抗（284mg）或安慰剂治疗，分别在第 1 天、第 90 天和此后每 6 个月皮下注射一次，共 540 天。每个试验的主要复合终点是从基线到第 510 天安慰剂校正的 LDL 胆固醇水平变化百分比和从第 90 天和之后的基线开始至第 540 天的时间调整的 LDL 胆固醇水平变化百分比。
ORION-10 试验和 ORION-11 试验分别有 1561 例和 1617 例患者接受了随机分组。基线时的平均（±SD）LDL 胆固醇水平分别为 104.7±38.3mg/分升（2.71±0.99mmol/L）和 105.5±39.1mg/分升（2.73±1.01mmol/L）。在第 510 天，依洛尤单抗在 ORION-10 试验中降低 LDL 胆固醇水平 52.3%（95%置信区间[CI]，48.8 至 55.7），在 ORION-11 试验中降低 49.9%（95%CI，46.6 至 53.1），相应的时间调整降幅分别为 53.8%（95%CI，51.3 至 56.2）和 49.2%（95%CI，46.8 至 51.6）（与安慰剂相比，所有比较均<0.001）。在每个试验中，依洛尤单抗组和安慰剂组的不良事件通常相似，但依洛尤单抗组的注射部位不良事件发生率高于安慰剂组（ORION-10 试验中分别为 2.6%和 0.9%，ORION-11 试验中分别为 4.7%和 0.5%）；这些反应通常是轻微的，没有严重或持续的反应。
每 6 个月皮下注射依洛尤单抗可使 LDL 胆固醇水平降低约 50%。与安慰剂相比，依洛尤单抗组发生更多的注射部位不良事件。（由 Medicines Company 资助；ORION-10 和 ORION-11 的临床试验.gov 编号为 NCT03399370 和 NCT03400800。）
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