From the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital and Hospital Israelita Albert Einstein, São Paulo (R.D.S.); Amgen, Thousand Oaks, CA (A.R., C.E.K, A.H.); the Departments of Vascular Medicine (G.K.H., J.J.P.K.) and Pediatrics (A.W., I.L.), Amsterdam UMC, Amsterdam; the Cardiology Department, Geneva University Hospital, Geneva (F.M.); the Biostatistics Department, Amgen, Cambridge (I.B.), and the Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham (S.S.) - both in the United Kingdom; the Rare Diseases and Clinical Genetics Unit, Academic Pediatric Department, Bambino Gesù Children's Hospital (A.B.), and the Department of Molecular Medicine, Umberto I Hospital, Sapienza University of Rome (C.S.), Rome; the Lipid Clinic, Department of Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec (J.B.), and the Clinical Lipidology and Rare Lipid Disorders Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Chicoutimi, QC (D.G.) - both in Canada; the 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary (T.S.); the Department of Internal Medicine, Centres Hospitaliers Jolimont, La Louvière, Belgium (O.S.D.); and the Division of Pediatric Pulmonology, Allergology, and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna (S.G.-P.).
N Engl J Med. 2020 Oct 1;383(14):1317-1327. doi: 10.1056/NEJMoa2019910. Epub 2020 Aug 29.
BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).
背景：依洛尤单抗是一种针对前蛋白转化酶枯草溶菌素 9 的全人单克隆抗体，广泛用于降低成年患者的低密度脂蛋白（LDL）胆固醇水平。但其在杂合子家族性高胆固醇血症儿科患者中的作用尚不清楚。
方法：我们进行了一项 24 周、随机、双盲、安慰剂对照试验，以评估依洛尤单抗在杂合子家族性高胆固醇血症儿科患者中的疗效和安全性。在筛选前接受了至少 4 周稳定降脂治疗且 LDL 胆固醇水平≥130mg/分升（3.4mmol/L）且三酰甘油水平≤400mg/分升（4.5mmol/L）的 10 至 17 岁患者，按 2:1 的比例随机分配，每月接受皮下注射依洛尤单抗（420mg）或安慰剂。主要终点为从基线到第 24 周时 LDL 胆固醇水平的变化百分比；关键次要终点为从基线到第 22 周和第 24 周时 LDL 胆固醇水平的平均变化百分比以及从基线到第 24 周时 LDL 胆固醇水平的绝对变化。
结果：共有 157 名患者接受了随机分组，接受了依洛尤单抗（104 名）或安慰剂（53 名）治疗。在第 24 周时，依洛尤单抗组 LDL 胆固醇水平从基线的平均变化百分比为-44.5%，安慰剂组为-6.2%，差异为-38.3 个百分点（P<0.001）。依洛尤单抗组 LDL 胆固醇水平的绝对变化为-77.5mg/分升（-2.0mmol/L），安慰剂组为-9.0mg/分升（-0.2mmol/L），差异为-68.6mg/分升（-1.8mmol/L）（P<0.001）。所有次要脂质变量的结果均显示依洛尤单抗优于安慰剂。依洛尤单抗组和安慰剂组治疗期间不良反应的发生率相似。
结论：在这项涉及家族性高胆固醇血症儿科患者的试验中，依洛尤单抗降低了 LDL 胆固醇水平和其他脂质参数。（由安进公司资助；HAUSER-RCT ClinicalTrials.gov 编号，NCT02392559。）
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