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evinacumab治疗纯合子家族性高胆固醇血症
Evinacumab for Homozygous Familial Hypercholesterolemia


Frederick J. Raal ... 心脑血管疾病 • 2020.08.20
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• ANGPTL3的遗传学和药理学失活与心血管疾病 • inclisiran治疗LDL胆固醇升高患者的两项3期试验

摘要


背景

纯合子家族性高胆固醇血症的特征是低密度脂蛋白(LDL)胆固醇水平显著升高引起早发心血管疾病。该疾病与导致LDL受体活性几乎缺失(无效-无效)或受损(非无效)的遗传变异相关。血管生成素样蛋白3编码基因(ANGPTL3)的失活变异与低脂血症及针对动脉粥样硬化性心血管疾病的防护作用相关。evinacumab是抗ANGPTL3的单克隆抗体,已对纯合子家族性高胆固醇血症患者显示出潜在益处。

 

方法

在这项双盲、安慰剂对照、3期试验中,我们以2∶1的比例将正在接受稳定降脂治疗的65例纯合子家族性高胆固醇血症患者随机分组,两组分别每4周1次静脉输入evinacumab(剂量为15 mg/kg体重)或安慰剂。主要结局是第24周时LDL胆固醇水平相对于基线的变化百分比。

 

结果

基线时,即使接受最大剂量的背景降脂治疗,两组患者的平均LDL胆固醇水平仍达到255.1 mg/dL。第24周时,evinacumab组患者的LDL胆固醇水平相对于基线降低了47.1%,而安慰剂组却升高了1.9%,组间最小二乘均值差异为-49.0个百分点(95%置信区间[CI],-65.0~-33.1;P<0.001);LDL胆固醇水平的组间最小二乘均值绝对差异为-132.1 mg/dL(95% CI,-175.3~-88.9;P<0.001)。在有无效-无效变异的患者(-43.4% vs. +16.2%)和有非无效变异的患者(-49.1% vs. -3.8%)中,evinacumab组的LDL胆固醇水平均低于安慰剂组。两组的不良事件相似。

 

结论

在接受最大剂量降脂治疗的纯合子家族性高胆固醇血症患者中,24周时evinacumab组的LDL胆固醇水平相对于基线有所降低,而安慰剂组却小幅度升高,因此导致组间差异为49.0个百分点(由再生元制药[Regeneron Pharmaceuticals]资助,ELIPSE HoFH在ClinicalTrials.gov注册号为NCT03399786)。





作者信息

Frederick J. Raal, M.D., Ph.D., Robert S. Rosenson, M.D., Laurens F. Reeskamp, M.D., G. Kees Hovingh, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Paolo Rubba, M.D., Shazia Ali, Pharm.D., Poulabi Banerjee, Ph.D., Kuo-Chen Chan, Ph.D., Daniel A. Gipe, M.D., Nagwa Khilla, M.S., Robert Pordy, M.D., David M. Weinreich, M.D., George D. Yancopoulos, M.D., Ph.D., Yi Zhang, Ph.D., and Daniel Gaudet, M.D., Ph.D. for the ELIPSE HoFH Investigators*
From the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (F.J.R.); the Cardiometabolics Unit, Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York (R.S.R.), and Regeneron Pharmaceuticals, Tarrytown (S.A., P.B, K.-C.C., D.A.G., N.K., R.P., D.M.W. G.D.Y., Y.Z.) — both in New York; the Department of Vascular Medicine, University of Amsterdam, Amsterdam (L.F.R., G.K.H., J.J.P.K.); the Department of Internal Medicine and Surgery, Federico II University, Naples, Italy (P.R.); and the Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Lipid Clinic Chicoutimi Hospital and ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, QC, Canada (D.G.). Address reprint requests to Dr. Raal at the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, or at frederick.raal@wits.ac.za; or to Dr. Gaudet at the Department of Medicine, Université de Montréal Community Gene Medicine Center, Chicoutimi, QC, Canada, or at daniel.gaudet@umontreal.ca. *A list of the ELIPSE HoFH investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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