Abstract：
Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial \"alarmin\" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.
摘要：
Tozorakimab是一种中和白介素（IL）-33的人单克隆抗体。IL-33是一种在慢性阻塞性肺疾病（COPD）患者肺组织中上调的广泛作用的上皮alarmin细胞因子。这个第一个人类，第一阶段，随机，双盲,安慰剂对照研究（NCT03096795）评估了安全性，耐受性,药代动力学，免疫原性,目标交战,和tozorakimab的药效学。这是一个三部分的研究。在第1部分中，56名有特应性病史的健康参与者接受了单次递增剂量的静脉内或皮下tozorakimab或安慰剂。在第2部分中，24名COPD患者接受了多次递增剂量的皮下tozorakimab或安慰剂。在第3部分中，8名健康的日本参与者接受了单次静脉内剂量的tozorakimab或安慰剂。收集的安全性数据包括治疗引起的不良事件（TEAE），生命体征,和临床实验室参数。药代动力学的生物样品，免疫原性,目标交战,收集药效学生物标志物分析。在活性组和安慰剂组之间没有观察到TEAE频率的有意义的差异。3名接受tozorakimab治疗的COPD患者经历了因治疗引起的严重不良事件。皮下或静脉注射tozorakimab表现为线性，时间独立的药代动力学，平均半衰期为11.7-17.3天。治疗时出现的抗药物抗体频率低。证明了tozorakimab与血清和鼻气道中内源性IL-33的相互作用。与安慰剂相比，Tozorakimab显着降低COPD患者的血清IL-5和IL-13水平。总的来说,tozorakimab耐受性良好，用一个线性的，与时间无关的血清药代动力学特征。此外,生物标志物研究证明了机制。总的来说,这些数据支持了tozorakimab在COPD和其他炎症性疾病中的进一步临床开发.
