依洛尤单抗治疗难治性高胆固醇血症患者的疗效。

Evinacumab in Patients with Refractory Hypercholesterolemia.

机构信息

From the Icahn School of Medicine at Mount Sinai, New York (R.S.R.), and Regeneron Pharmaceuticals, Tarrytown (S.A., N.K., R.H., R.P., Y.D., V.S.) - both in New York; TREAD Research, Cardiology Unit, Department of Internal Medicine and Tygerberg Hospital, Parow, South Africa (L.J.B.); the Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria (C.F.E.); Excel Medical Clinical Trials, Department of Integrated Medical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton (S.J.B.); the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.G.S.); and the Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Montreal, and ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, QC - both in Canada (D.G.).

出版信息

N Engl J Med. 2020 Dec 10;383(24):2307-2319. doi: 10.1056/NEJMoa2031049. Epub 2020 Nov 15.

DOI:10.1056/NEJMoa2031049

PMID:33196153

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. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

摘要

背景

尽管接受了最大耐受剂量的降脂治疗，但低密度脂蛋白（LDL）胆固醇水平仍较高的难治性高胆固醇血症患者，其动脉粥样硬化风险增加。在这些患者中，皮下和静脉注射依那西普（一种针对血管生成素样 3 的全人源单克隆抗体）的疗效和安全性尚不清楚。

方法

在这项双盲、安慰剂对照的 2 期试验中，我们招募了患有或不患有杂合子家族性高胆固醇血症的难治性高胆固醇血症患者，这些患者的筛选 LDL 胆固醇水平在有动脉粥样硬化的情况下为每分升 70 毫克或更高，或在没有动脉粥样硬化的情况下为每分升 100 毫克或更高。患者被随机分配接受皮下或静脉注射依那西普或安慰剂。主要终点是与安慰剂相比，第 16 周时依那西普治疗后 LDL 胆固醇水平的基线百分比变化。

结果

共有 272 名患者被随机分配到以下组：每周皮下注射依那西普 450mg（40 名患者）、每周 300mg（43 名患者）或每 2 周 300mg（39 名患者）或安慰剂（41 名患者）；或每周静脉注射依那西普 15mg/kg（39 名患者）或每 4 周 5mg/kg（36 名患者）或安慰剂（34 名患者）。第 16 周时，每周皮下注射依那西普 450mg、每周 300mg 和每 2 周 300mg 组与安慰剂组 LDL 胆固醇水平的最小二乘均值变化分别为-56.0%、-52.9%和-38.5%（所有比较均 P<0.001）。每周静脉注射依那西普 15mg/kg 和 5mg/kg 组与安慰剂组的差异分别为-50.5%（P<0.001）和-24.2%。治疗期间严重不良事件的发生率在各试验组之间为 3%至 16%。