Department of Cardiology, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University Third Hospital, 49 North Garden Road, Haidian Distrct, Beijing, 100191, China.
Drug Clinical Trial Center, Peking University Third Hospital, 49 North Garden Road, Haidian Distrct, Beijing, 100191, China.
Am J Cardiovasc Drugs. 2020 Oct;20(5):489-503. doi: 10.1007/s40256-020-00394-1.
The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction.
Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects.
In this double-blind, placebo-controlled, phase I study, 35 Chinese subjects (aged 21-45 years) with baseline LDL-C > 100 mg/dL (2.59 mmol/L) were randomized to receive a single 1 mL subcutaneous injection of alirocumab 75, 150, or 300 mg, or placebo, and followed up for ~ 12 weeks.
Treatment-emergent adverse events, most frequently nasal congestion and dry throat, were reported in three of seven or eight subjects in each alirocumab dose group (two of seven in the placebo group). One patient receiving alirocumab 300 mg had a mild local injection-site reaction. No alirocumab recipients demonstrated antidrug antibodies. Maximum alirocumab serum concentrations (6-34 mg/dL) occurred at a median of 3-7 days across the dose groups. Maximum mean LDL-C reductions from baseline were observed on days 8, 15, and 22 with alirocumab 75 (55.3%), 150 (63.7%), and 300 mg (73.7%), respectively. Mean free PCSK9 levels were reduced to below the lower limit of quantification within 4 h of dosing. Total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were reduced with alirocumab.
In Chinese subjects, alirocumab 75, 150, and 300 mg was safe and well-tolerated. Pharmacokinetic/pharmacodynamic parameters, including clinically meaningful reductions in LDL-C and other lipids/lipoproteins, were consistent with data from Japanese and Western populations. Clinicaltrials.gov identifier: NCT02979015.
在背景他汀类药物治疗的基础上添加阿利西尤单抗（一种针对前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9 [PCSK9] 的全人源单克隆抗体）可显著降低低密度脂蛋白胆固醇（LDL-C）并降低心血管事件风险。
我们的目的是评估健康中国受试者单次递增剂量阿利西尤单抗的安全性、耐受性、药代动力学和药效学。
在这项双盲、安慰剂对照、I 期研究中，35 名基线 LDL-C＞100mg/dL（2.59mmol/L）的中国受试者（年龄 21-45 岁）按 1:1:1:1 随机分配至接受 1 次皮下注射 75、150 或 300mg 阿利西尤单抗或安慰剂治疗，并随访约 12 周。
治疗后出现的不良事件（最常见的是鼻塞和咽干）在每个阿利西尤单抗剂量组的 7 或 8 名受试者中有 3 至 8 人报告，安慰剂组有 2 人报告。1 名接受阿利西尤单抗 300mg 治疗的患者出现轻度局部注射部位反应。无阿利西尤单抗使用者出现抗药物抗体。在各剂量组中，阿利西尤单抗血清浓度（6-34mg/dL）的最大浓度在中位 3-7 天达到。阿利西尤单抗 75mg（55.3%）、150mg（63.7%）和 300mg（73.7%）组分别在第 8、15 和 22 天观察到 LDL-C 从基线的最大平均降低。阿利西尤单抗治疗后 4 小时内，游离 PCSK9 水平降低至定量下限以下。总胆固醇、非高密度脂蛋白胆固醇和载脂蛋白 B 随阿利西尤单抗降低。
在中国受试者中，阿利西尤单抗 75、150 和 300mg 安全且耐受良好。药代动力学/药效学参数包括 LDL-C 和其他脂质/脂蛋白的临床显著降低，与日本和西方人群的数据一致。临床试验.gov 标识符：NCT02979015。
