Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942
Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942
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DOI：
10.1016/j.ebiom.2018.07.035
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发表时间：
2018-09-01
期刊：
影响因子：
11.1
通讯作者：
Palframan, Roger
中科院分区：
文献类型：
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作者：
Burgess, Gary;Boyce, Malcolm;Palframan, Roger
背景：白介素13(IL-13)是辅助性T细胞2型(Th-2)驱动的哮喘的关键介质，抑制其表达可改善治疗效果。我们测试了VR942的安全性、药代动力学、药效学和免疫原性。VR942是一种含有CDP7766的干粉制剂，CDP7766是一种正在开发的用于治疗哮喘的高亲和力抗人IL13抗原结合抗体片段。方法：我们在英国伦敦的Hammersmith Medicines Research进行了一项随机、双盲、安慰剂对照、剂量递增的阶段研究，该研究现已完成。年龄在18-50岁的健康成年人(n=40)被随机分为3：1的单次吸入剂量VR942 0.5、1.0、5.0、10或20 mg或安慰剂。年龄18~50岁，筛查前6个月诊断为哮喘，且第一秒用力呼气量(FEV1)和用力肺活量(FVC)为筛查时预测值70%的成年人(n=45)，随机分为吸入VR9420.5或10 mg、安慰剂(2：2：1)、VR94220 mg或安慰剂(3：2)，共10天。所有参与者都被随机接受VR942或安慰剂治疗，这是根据一家独立的HMR统计师使用SAS(R)软件(北卡罗来纳州卡里的SAS研究所)准备的随机化列表。主要结果是VR942的安全性和耐受性(安全人群，定义为所有接受至少一剂VR942或安慰剂的人)。这项研究在ClinicalTrials.gov(NCT02473939)上列出。结果：在VR942组和安慰剂组中，报告了10/30(33%)和0/10(0%)的健康参与者以及16/29(55%)和9/16(56%)哮喘参与者的紧急治疗不良事件(TEAE)。7名受试者出现轻度间歇性喘息(VR942 20 mg，n=4；相应的安慰剂，n=3)，在1h内自行消失。所有患者的TEAE均为轻度或中度；无死亡、严重不良事件或生命体征、心电图或实验室参数的临床显著变化。临床上没有显著的免疫原性，只有一名哮喘患者被认为CDP7766治疗相关免疫原性阳性。解释：这项研究被认为是唯一一例通过吸入给予干粉抗IL-13片段抗体的例子，证明单次和重复剂量在长达10天的时间内耐受性良好。快速和持久地抑制部分呼出的一氧化氮(FeNO)(次要结果)提供了在被诊断为轻度哮喘的参与者的呼吸道中与IL-13靶标进行药理作用的证据。这些数据，再加上观察到的剂量前FEV1的数字改善，证明了在更广泛的哮喘患者中对VR942进行进一步的临床评估是合理的，并继续支持开发一种吸入型抗IL-13抗体片段，作为未来替代通过非肠道途径输送的单抗的潜在治疗方法。(C)2018年作者。爱思唯尔出版公司(Elsevier B.V.)
Background: Interleuldn-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-human-IL13 antigen-binding antibody fragment being developed for the treatment of asthma.Methods: We conducted a phase 1, randomized, double-blind, placebo-controlled, ascending-dose study at Hammersmith Medicines Research, London, UK, which is now complete. Healthy adults aged 18-50 years ( n = 40) were randomized 3:1 to a single inhaled dose of VR942 0.5, 1.0, 5.0, 10, or 20 mg, or placebo. Adults aged 18-50 years who were diagnosed with asthma for >= 6 months before screening, and had forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values >= 70% of the predicted values at screening (n = 45), were randomized to once-daily inhaled VR942 0.5 or10 mg, or placebo (2:2:1), or VR942 20 mg or placebo (3:2), for 10 days. All participants were randomized to receive VR942 or placebo based on a randomization list prepared by an independent HMR statistician using SAS (R) software (SAS Institute, Cary, NC). The primary outcome was safety and tolerability of VR942 (safety population, defined as all who received at least one dose of VR942 or placebo). This study is listed on ClinicalTrials.gov (NCT02473939).Findings: In the VR942 and placebo groups, treatment-emergent adverse events (TEAEs) were reported in 10/30 (33%) and 0/10 (0%) healthy participants, and in 16/29 (55%) and 9/16 (56%) participants with asthma, respectively. Mild intermittent wheezing occurred in 7 participants (VR942 20 mg, n = 4; corresponding placebo, n = 3), resolving spontaneously within 1 h. All TEAEs were mild or moderate; there were no deaths, serious adverse events, or clinically significant changes in vital signs, electrocardiograms, or laboratory parameters. There was no clinically significant immunogenicity, with only one participant with asthma considered positive for treatment-related immunogenicity for CDP7766.Interpretation: This study, considered to be the only example of a dry powder anti-IL-13 fragment antibody being administered via inhalation, demonstrated that single and repeat doses were well tolerated over a period of up to 10 days in duration. Rapid and durable inhibition of fractional exhaled nitric oxide (FeNO) (secondary outcome) provided evidence of pharmacological engagement with the IL-13 target in the airways of participants diagnosed with mild asthma. These data, together with the numerical improvements observed for predose FEV1, justify further clinical evaluation of VR942 in a broader population of patients with asthma, and continue to support the development of an inhaled anti-IL-13 antibody fragment as a potential future treatment that is alternative to monoclonal antibodies delivered via the parenteral route. (C) 2018 The Authors. Published by Elsevier B.V.