From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.), and Knowle House Surgery, Plymouth (T.H.) - both in the United Kingdom; the Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin Institute of Health and German Center for Cardiovascular Research, Berlin (U.L.), and University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg (M.K.) - all in Germany; the Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Medicines Company, Parsippany, NJ (D.K., P.W.); Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal (R.D.); the Department of Cardiology and Interventional Cardiology, VieCuri Medical Center for Northern Limburg, Venlo (R.P.T.T.), University Medical Center, Utrecht (F.L.J.V.), and the Department of Vascular Medicine, Academic Medical Center-University of Amsterdam, Amsterdam (J.J.P.K.) - all in the Netherlands; the Metabolic and Atherosclerosis Research Center, Medpace, Cincinnati (T.T.); and the Department of Cardiology, Mayo Clinic, Rochester, MN (R.S.W.).
N Engl J Med. 2017 Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Epub 2017 Mar 17.
BACKGROUND: In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS: We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS: A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS: In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).
背景：在之前的一项研究中，一种名为 inclisiran 的化学合成小干扰 RNA 单次注射，旨在针对 PCSK9 信使 RNA，被发现可在健康志愿者中持续降低 LDL 胆固醇水平，持续 84 天。
方法：我们进行了一项 2 期、多中心、双盲、安慰剂对照、多剂量递增试验，将 inclisiran 作为皮下注射给药，用于心血管疾病高危且 LDL 胆固醇水平升高的患者。患者被随机分配接受单次安慰剂或 200、300 或 500 mg inclisiran 或两次安慰剂（第 1 天和第 90 天）或 100、200 或 300 mg inclisiran。主要终点是 180 天时 LDL 胆固醇水平与基线相比的变化。安全性数据可获得至第 210 天，LDL 胆固醇和前蛋白转化酶枯草溶菌素 9（PCSK9）水平的数据可获得至第 240 天。
结果：共有 501 名患者接受了随机分组。接受 inclisiran 的患者 PCSK9 和 LDL 胆固醇水平呈剂量依赖性降低。在第 180 天，单次剂量的 inclisiran 可使 LDL 胆固醇水平降低 27.9%至 41.9%，两次剂量可降低 35.5%至 52.6%（与安慰剂相比，所有比较均<0.001）。两剂量 300mg inclisiran 方案使 LDL 胆固醇水平降低最大：48%接受该方案的患者在第 180 天 LDL 胆固醇水平低于 50mg/分升（1.3mmol/L）。在第 240 天，所有 inclisiran 方案与基线相比，PCSK9 和 LDL 胆固醇水平仍显著降低。接受 inclisiran 的患者中有 11%发生严重不良事件，接受安慰剂的患者中有 8%发生严重不良事件。接受 inclisiran 注射的患者中有 5%发生注射部位反应。
结论：在我们的试验中，发现 inclisiran 可降低心血管疾病高危且 LDL 胆固醇水平升高的患者的 PCSK9 和 LDL 胆固醇水平。（由 Medicines Company 资助；ORION-1 ClinicalTrials.gov 编号，NCT02597127）。
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