提示: 手机请竖屏浏览!

inclisiran治疗LDL胆固醇升高的心血管高危患者
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol


Kausik K. Ray ... 心脑血管疾病 • 2017.04.13
相关阅读
• 一种新型PCSK9抑制剂inclisiran通过了2期试验 • 长效PCSK9靶向RNAi治疗性抑制剂 • 靶向PCSK9的另外一种方式

摘要


背景

在之前的一项研究中,研究者发现单次注射inclisiran——一种化学合成的针对PCSK9信使RNA的小干扰RNA可以使健康志愿者的低密度脂蛋白(LDL)胆固醇水平降低,且这一效果在84日期间可持续。

 

方法

我们进行了一项2期、多中心、双盲、安慰剂对照、多次给药剂量递增的临床试验,试验中将inclisiran皮下注射用于LDL胆固醇水平升高的心血管疾病高危患者。患者被随机分组,接受单次给药的安慰剂或者200 mg、300 mg或500 mg的inclisiran,或者两次给药(第1日和第90日)的安慰剂或100 mg、200 mg或300 mg的inclisiran。主要临床终点是LDL胆固醇水平在第180日与基线水平相比的变化。安全性数据至第210日均可得到;而LDL胆固醇及前蛋白转化酶枯草溶菌素9(PCSK9)水平至第240日均可得到。

 

结果

共有501例患者被随机分组。接受了inclisiran注射的患者有剂量依赖性的PCSK9和LDL胆固醇水平降低。在第180日,LDL胆固醇水平的最小二乘均值(least-squares mean)降幅在单次给药组中是27.9%~41.9%,而在两次给药组中是35.5%~52.6%(与安慰剂之间的所有比较P值均<0.001)。300 mg inclisiran两次给药方案对LDL胆固醇水平的降幅最大:在第180日,48%接受这一方案的患者LDL胆固醇水平低于50 mg/dL(1.3mmol/L)。在第240日,PCSK9和LDL胆固醇水平在所有方案的inclisiran治疗组中均维持在显著低于基线值的水平。严重不良事件发生于11%接受inclisiran的患者及8%接受安慰剂的患者。接受inclisiran注射的患者有5%发生了注射部位反应。

 

结论

在本试验中,我们发现inclisiran可以降低LDL胆固醇水平升高的心血管高危患者的PCSK9和LDL胆固醇水平(由Medicines Company资助;ORION-1在ClinicalTrial.gov编号为NCT02597127)。





作者信息

Kausik K. Ray, M.D., Ulf Landmesser, M.D., Lawrence A. Leiter, M.D., David Kallend, M.D., Robert Dufour, M.D., Mahir Karakas, M.D., Tim Hall, M.D., Roland P.T. Troquay, M.D., Traci Turner, M.D., Frank L.J. Visseren, M.D., Peter Wijngaard, Ph.D., R. Scott Wright, M.D., and John J.P. Kastelein, M.D., Ph.D.
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.). 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. Dunstan’s Rd., London W6 8RP, United Kingdom, or at k.ray@imperial.ac.uk.

 

参考文献

1. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161:161-172

2. Ridker PM, Mora S, Rose L. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J 2016;37:1373-1379

3. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526-534

4. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-1272

5. Watts GF, Chan DC, Dent R, et al. Factorial effects of evolocumab and atorvastatin on lipoprotein metabolism. Circulation 2017;135:338-351

6. Reyes-Soffer G, Pavlyha M, Ngai C, et al. Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation 2017;135:352-362

7. Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet 2015;16:543-552

8. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature 2004;431:338-342

9. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell 2009;136:642-655

10. Bernards R. Exploring the uses of RNAi — gene knockdown and the Nobel Prize. N Engl J Med 2006;355:2391-2393

11. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51

12. Nakamura M, Kayamori Y, Iso H, et al. LDL cholesterol performance of beta quantification reference measurement procedure. Clin Chim Acta 2014;431:288-293

13. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010;375:895-905

14. Bangalore S, Breazna A, DeMicco DA, Wun CC, Messerli FH. Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial. J Am Coll Cardiol 2015;65:1539-1548

15. Bangalore S, Fayyad R, Messerli FH, et al. Relation of variability of low-density lipoprotein cholesterol and blood pressure to events in patients with previous myocardial infarction from the IDEAL Trial. Am J Cardiol 2017;119:379-387

16. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. DOI: 10.1056/NEJMoa1615664

17. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-1509

18. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-1499

19. KYNAMRO (mipomersen sodium) prescribing information. Cambridge, MA: Genzyme (http://medlibrary.org/lib/rx/meds/kynamro-1/).

20. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:998-1006

21. Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today 2017 January 31 (Epub ahead of print)

服务条款 | 隐私政策 | 联系我们