Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study
Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study
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DOI：
10.1016/s1473-3099(18)30397-9
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发表时间：
2018-08-01
影响因子：
56.3
通讯作者：
Lipsich, Leah
中科院分区：
文献类型：
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作者：
Sivapalasingam, Sumathi;Kamal, Mohamed;Lipsich, Leah
背景REGN 3470 -3471-3479是靶向埃博拉病毒上三个非重叠表位的三种人单克隆抗体的共配制混合物。我们调查了安全性，耐受性，药代动力学，和抗药物抗体在健康adults.Methods这个随机，双盲，安慰剂对照，剂量递增的研究是在1期单位在美国。将体重指数为18.0-30.0 kg/m2的18-60岁健康成人随机分配（3：1）至4个连续静脉给药剂量递增队列（3 mg/kg、15 mg/kg、60 mg/kg和150 mg/kg）之一，在第1天（基线）接受REGN 3470 -3471-3479或安慰剂单次静脉给药。研究中心研究者和受试者对治疗分配设盲，而研究中心准备和生成研究药物的指定人员了解随机化治疗分配。主要结局是安全性，次要结局是药代动力学特征和免疫原性。在研究药物给药前一天、给药当天、第2天（出院前）、第3、4、8、15、29、57、85、113和141天以及第169天研究结束时进行研究评估。安全性分析包括所有接受研究药物的随机化受试者。该试验注册于ClinicalTrials.gov，编号NCT 0 02777151。结果在2016年5月18日至2016年10月27日期间，对70名成年人进行了筛选，24名参与者参加了研究。18例受试者被分配并接受REGN 3470 -3471-3479，6例受试者被分配并接受安慰剂单次静脉输注。REGN 3470 -3471-3479联合治疗组发生19起治疗后出现的不良事件，安慰剂联合治疗组发生4起治疗后出现的不良事件。不良事件为一过性，严重程度为轻度至中度。最常见的治疗后出现的不良事件是头痛（REGN 3470 -3471-3479联合组18例受试者中有6例[33%] vs安慰剂组6例受试者中无一例）。头痛的严重程度为轻度至中度，发作时间为研究药物输注开始后2小时至27天。未发生死亡、严重不良事件或导致研究中止的不良事件。每种抗体的药代动力学呈线性，REGN 3471、REGN 3470和REGN 3479的平均半衰期分别为27.3天、21.7天和23.3天。无受试者的抗REGN 3470、抗REGN 3471或抗REGN 3479抗体检测呈阳性。解读REGN 3470 -3471-3479耐受性良好，显示线性药代动力学，未导致可检测的免疫原性。这些数据支持REGN 3470 -3471-3479作为急性埃博拉病毒感染单次给药治疗药物的进一步临床开发。版权所有（c）2018 Elsevier Ltd.保留所有权利。
Background REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults.Methods This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18-60 years, with a body-mass index of 18.0-30.0 kg/m(2) were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg). Site investigators and participants were masked to the treatment assignment, whereas designated personnel at the site who prepared and generated the study medication were aware of the randomisation treatment assignments. The primary outcome was safety and the secondary outcomes were the pharmacokinetic profiles and immunogenicity. Study assessments were done the day before study drug administration, on the day of drug administration, on day 2 (before discharge), on days 3, 4, 8, 15, 29, 57, 85, 113, and 141, and at the end of study on day 169. The safety analysis included all randomised participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT0 02777151.Findings Between May 18, 2016, and October 27, 2016, 70 adults were screened and 24 participants were enrolled in the study. 18 participants were assigned to and received REGN3470-3471-3479, and six participants were assigned to and received placebo as a single intravenous infusion. 19 treatment-emergent adverse events occurred in the combined REGN3470-3471-3479 treatment groups, and four treatment-emergent adverse events occurred in combined placebo groups. Adverse events were transient and mild-to-moderate in severity. The most common treatment-emergent adverse event was headache (six [33%] of 18 participants in the combined REGN3470-3471-3479 group vs none of six participants in the placebo group. Headaches were mild-to-moderate in severity, with onset between 2 h and 27 days after start of study drug infusion. There were no deaths, serious adverse events, or adverse events that led to study discontinuation. The pharmacokinetics of each antibody was linear, with mean half-lives of 27.3 days for REGN3471, 21.7 days for REGN3470, and 23.3 days for REGN3479. No participants tested positive for anti-REGN3470, anti-REGN3471, or anti-REGN3479 antibodies.Interpretation REGN3470-3471-3479 was well tolerated, displayed linear pharmacokinetics, and did not lead to detectable immunogenicity. These data support further clinical development of REGN3470-3471-3479 as a single-dose therapeutic drug for acute Ebola virus infection. Copyright (c) 2018 Elsevier Ltd. All rights reserved.