美国西奈山伊坎医学院Robert S. Rosenson团队研究了Evinacumab治疗难治性高胆固醇血症的效果。2020年11月15日，《新英格兰医学杂志》发表了该成果。

尽管采用最大耐受剂量的降脂疗法进行治疗，但高密度脂蛋白（LDL）胆固醇水平高的难治性高胆固醇血症患者的动脉粥样硬化风险仍会增加。对于这类患者，皮下注射和静脉注射Evinacumab（抗血管生成素样3的全人源单克隆抗体）的功效和安全性尚不明确。

在这项双盲、安慰剂对照的2期临床试验中，研究组招募了272例患或不患杂合型家族性高胆固醇血症的难治性高胆固醇血症的患者，这些患者伴有动脉粥样硬化，LDL胆固醇水平为70 mg/dL或更高，或没有动脉粥样硬化，但LDL胆固醇水平为100 mg/dL或更高。将患者随机分组，分别接受皮下或静脉注射Evinacumab或安慰剂。主要终点是第16周时LDL胆固醇水平相对于基线的变化百分比。

272例患者被随机分为以下几组：其中40例接受每周皮下注射Evinacumab 450 mg，43例接受每周皮注300 mg，39例接受每2周皮注300 mg，41例患者接受皮注安慰剂治疗，39例患者每4周接受一次Evinacumab静脉注射，剂量为15 mg/kg（体重），36例患者每4周接受一次剂量为5 mg/kg（体重）静注，34例患者接受静注安慰剂治疗。

第16周，接受每周450 mg、每周300 mg和每2周300 mg皮下注射Evinacumab的组与安慰剂组相比，LDL胆固醇水平与基线之间的最小二乘均值差异分别为-56.0、-52.9和-38.5个百分点，差异均显著。接受每4周15 mg/kg和5 mg/kg静脉注射Evinacumab的组与安慰剂组之间的差异分别为-50.5个百分点（差异显著）和-24.2个百分点。整个试验中，治疗期间严重不良事件的发生率在3％至16％之间。

研究结果表明，对于难治性高胆固醇血症的患者，使用Evinacumab治疗可显著降低LDL胆固醇水平，最大剂量下可降低50％以上。

附：英文原文

Title: Evinacumab in Patients with Refractory Hypercholesterolemia | NEJM

Author: Robert S. Rosenson, M.D.,, Lesley J. Burgess, M.D., Ph.D.,, Christoph F. Ebenbichler, M.D.,, Seth J. Baum, M.D.,, Erik S.G. Stroes, M.D., Ph.D.,, Shazia Ali, Pharm.D.,, Nagwa Khilla, M.S.,, Robert Hamlin, B.S.,, Robert Pordy, M.D.,, Yuping Dong, Ph.D.,, Vladimir Son, Ph.D.,, and Daniel Gaudet, M.D., Ph.D.

Issue&Volume: 2020-11-15

Abstract:

Background

Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.

Methods

In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo.

Results

In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were 56.0, 52.9, and 38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were 50.5 percentage points (P<0.001) and 24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups.

Conclusions

In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose.

DOI: 10.1056/NEJMoa2031049

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2031049