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inclisiran治疗LDL胆固醇升高患者的两项3期试验
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol


Kausik K. Ray ... 心脑血管疾病 • 2020.04.16
相关阅读
• evinacumab治疗纯合子家族性高胆固醇血症 • inclisiran治疗LDL胆固醇升高的心血管高危患者 • 长效PCSK9靶向RNAi治疗性抑制剂 • 一种新型PCSK9抑制剂inclisiran通过了2期试验

异军突起的RNA药物:半年注射一次的动脉粥样硬化降脂治疗新选择

 

郑博,霍勇*

北京大学第一医院心内科

*通讯作者

 

引文

20世纪初,人们发现了胆固醇与动脉粥样硬化密切相关,自此拉开了与高胆固醇血症百年战争的序幕。随后,包括Framingham研究在内的大型队列研究进一步证实了胆固醇升高是动脉粥样硬化性心血管疾病(ASCVD)重要的危险因素,然而直到20世纪60年代他汀类药物的出现,我们才真正拥有了制衡胆固醇的武器。

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摘要


背景

inclisiran可抑制肝脏内前蛋白转化酶枯草溶菌素9的合成。既往研究提示,inclisiran有可能以很低的给药频率持久降低低密度脂蛋白(LDL)胆固醇水平。

 

方法

我们纳入了在接受最大耐受剂量他汀类药物治疗的情况下LDL胆固醇水平仍升高的动脉粥样硬化性心血管疾病患者(ORION-10试验)以及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等危症(risk equivalent)患者(ORION-11试验)。我们以1∶1的比例将患者随机分组,分别接受inclisiran(284 mg)或安慰剂治疗,给药时间和给药方式是第1日、第90日及之后540日期间每6个月1次皮下注射。各试验的联合主要终点均为LDL胆固醇水平从基线至第510日的安慰剂校正的变化百分比,以及LDL胆固醇水平从基线至第90~540日期间(不包含第90日)的时间校正的变化百分比。

 

结果

在ORION-10和ORION-11试验中,分别共有1,561例和1,617例患者被随机分组。基线时的平均(±SD)LDL胆固醇水平分别为104.7±38.3 mg/dL(2.71±0.99 mmol/L)和105.5±39.1 mg/dL(2.73±1.01 mmol/L)。第510日时,在ORION-10试验和ORION-11试验中,inclisiran分别使LDL胆固醇水平降低了52.3%(95%置信区间[CI],48.8~55.7)和49.9%(95% CI,46.6~53.1),相应的时间校正的降幅分别为53.8%(95% CI,51.3~56.2)和49.2%(95% CI,46.8~51.6)(与安慰剂之间的所有比较,P<0.001)。在各试验中,inclisiran组和安慰剂组的不良事件一般相似,但inclisiran组的注射部位不良事件发生率高于安慰剂组(ORION-10试验中为2.6% vs. 0.9%;ORION-11试验中为4.7% vs. 0.5%);这些反应通常为轻度,无重度或持续不良事件。

 

结论

每6个月1次皮下给药的inclisiran使LDL胆固醇水平降低了约50%。inclisiran组的注射部位不良事件发生率高于安慰剂组(由麦迪逊医药公司[Medicines Company]资助,ORION-10和ORION-11在ClinicalTrials.gov注册号分别为NCT03399370和NCT03400800)。





作者信息

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. for the ORION-10 and ORION-11 Investigators*
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.). Address reprint requests to Dr. Ray at the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, Reynolds Bldg., St. Dunstans Rd., London W6 8RP, United Kingdom, or at k.ray@imperial.ac.uk. *A list of the ORION-10 and ORION-11 investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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