Abstract：
PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF-06817024 doses in healthy participants (Part 1), a single dose of PF-06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF-06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF-06817024 was generally well tolerated in all participant populations. Most participants experienced a treatment-emergent adverse event (healthy participants, 78.4% and 100%; participants with chronic rhinosinusitis with nasal polyps, 90.9% and 88.9%; and participants with atoptic dermatitis, 60.0% and 62.5% in the PF-06817024 and placebo groups, respectively). No substantial deviations from dose proportionality were observed for single intravenous doses of 10-1000 mg, indicating linear PK in healthy participants. Mean terminal half-life ranged from 83 to 94 days after single intravenous administration in healthy participants and was similar to that observed after administration in the studied patient populations. Incidences of antidrug antibodies in the studied populations were 10.8%, 9.1%, and 5.0% for healthy participants, participants with chronic rhinosinusitis with nasal polyps, and participants with atoptic dermatitis, respectively. In addition, dose-dependent increases were observed in total serum interleukin-33 levels of treated participants, indicating target engagement. Overall, the PK and safety profile of PF-06817024 supports further investigation of the drug as a potential treatment for allergic diseases.
摘要：
PF-06817024是一个高亲和力，人源化抗体结合白细胞介素（IL）-33，促炎2型细胞因子，从而具有抑制下游2型炎症的潜力。第一阶段，随机化，安慰剂对照研究分三个部分进行，以评估安全性，耐受性,药代动力学（PK），免疫原性,以及在健康参与者中逐步增加单次和有限重复PF-06817024剂量的药效学（PD）（第1部分），单剂量的PF-06817024慢性鼻-鼻窦炎伴鼻息肉（CRSwNP;第2部分）的参与者，在中度至重度特应性皮炎（AD;第3部分）的参与者中重复使用PF-06817024。PF-06817024在所有参与者人群中通常具有良好的耐受性。大多数参与者经历了因治疗引起的不良事件(健康参与者，78.4%和100%；CRSwNP参与者，90.9%和88.9%；AD患者，PF-06817024和安慰剂组的60.0%和62.5%，分别)。对于10-1000mg的单次静脉（IV）剂量，未观察到剂量比例的实质性偏差，表明健康参与者的线性PK。在健康参与者中单次IV给药后，平均终末半衰期为83-94天，与在研究的患者人群中给药后观察到的相似。研究人群中抗药物抗体的发生率为10.8%，9.1%，健康参与者为5.0%，CRSwNP的参与者，和AD的参与者，分别。此外,观察到治疗参与者的总血清IL-33水平呈剂量依赖性增加，指示目标交战。总的来说,PF-06817024的PK和安全性支持进一步研究该药物作为过敏性疾病的潜在治疗方法.本文受版权保护。保留所有权利。
