Probity Medical Research Inc., Waterloo, ON, Canada.
Skin Center for Dermatology, Probity Medical Research Inc., Queen's University, Peterborough, ON, Canada.
J Eur Acad Dermatol Venereol. 2017 Aug;31(8):1324-1332. doi: 10.1111/jdv.14313. Epub 2017 Jun 14.
OX40 (CD134) is expressed in lesional but not healthy skin of patients with psoriasis. KHK4083 is a fully human monoclonal antibody against OX40.
The primary aim of this first-in-human phase 1 study was to determine the safety and tolerability of ascending single doses of KHK4083 in patients with mild to moderate plaque psoriasis. Secondary aims were to determine the pharmacokinetics and immunogenicity of KHK4083, and an exploratory objective was to assess clinical activity.
In phase 1a, single doses of KHK4083 0.003 and 0.001 mg/kg IV were administered open label in two cohorts (each n = 6). Phase 1b had a multicentre, randomized, double-blind, placebo-controlled, ascending single-dose design in seven cohorts. Randomization was performed 3 : 1 to KHK4083 (n = 6) or placebo (n = 2) within each cohort. Ascending doses of KHK4083 were 0.03, 0.1, 0.3, 1.0, 3.0 and 10 mg/kg IV, and 1.0 mg/kg SC.
There were no severe or serious adverse events (AEs), or discontinuations because of AEs. The most frequent treatment-related AEs in the 55 patients who received KHK4083 were mild or moderate chills (9.1%), and infusion/injection site reactions (7.3%). No clinically meaningful or dose-related changes from baseline in laboratory values, vital signs, ECG recordings or physical examinations were observed. Some KHK4083 recipients (10/54) developed anti-KHK4083 antibodies following treatment. Mean elimination half-life (t ) increased with dose, maximum serum concentration increased in a dose-proportional manner, and area under the serum concentration-time curve increased in a more than dose-proportional manner with increasing IV dose. Absolute bioavailability following SC administration was 73%. There was some indication of improvement in Psoriasis Area Severity Index (PASI) and sPGA scores at the highest IV doses (1.0 and 10 mg/kg) and the SC dose (1.0 mg/kg). The largest PASI 50 response and improvement in sPGA score ≥2 occurred with KHK4083 1.0 mg/kg SC.
KHK4083 administration as a single dose up to 10 mg/kg IV or 1.0 mg/kg SC was generally safe and well tolerated in patients with mild to moderate plaque psoriasis with no dose-limiting AEs.
OX40（CD134）在银屑病患者的皮损部位表达，但在健康皮肤中不表达。KHK4083 是一种针对 OX40 的全人源单克隆抗体。
这项首次人体 I 期研究的主要目的是确定单剂量递增的 KHK4083 在轻至中度斑块型银屑病患者中的安全性和耐受性。次要目的是确定 KHK4083 的药代动力学和免疫原性，探索性目的是评估临床疗效。
在 I 期 a 部分，以开放标签方式在两个队列（每组 n=6）中单次静脉注射 KHK4083 0.003 和 0.001 mg/kg。I 期 b 为多中心、随机、双盲、安慰剂对照、递增单剂量设计，共 7 个队列。每个队列按 3:1 随机分为 KHK4083（n=6）或安慰剂（n=2）组。递增剂量的 KHK4083 为 0.03、0.1、0.3、1.0、3.0 和 10 mg/kg，静脉注射和皮下注射剂量均为 1.0 mg/kg。
55 名接受 KHK4083 治疗的患者均未发生严重或严重不良事件（AE），也未因 AE 而停药。55 名接受 KHK4083 治疗的患者中最常见的与治疗相关的 AE 为轻度或中度寒战（9.1%）和输注/注射部位反应（7.3%）。未观察到实验室值、生命体征、心电图记录或体格检查有任何有临床意义或剂量相关的基线变化。一些 KHK4083 接受者（10/54）在治疗后产生了抗-KHK4083 抗体。平均消除半衰期（t ）随剂量增加而延长，最大血清浓度呈剂量比例增加，随着静脉注射剂量的增加，血清浓度-时间曲线下面积呈超剂量比例增加。皮下注射后绝对生物利用度为 73%。在最高 IV 剂量（1.0 和 10 mg/kg）和 SC 剂量（1.0 mg/kg）时，银屑病面积严重程度指数（PASI）和 sPGA 评分有一定的改善迹象。最大的 PASI50 反应和 sPGA 评分≥2 的改善发生在 KHK4083 1.0 mg/kg SC 时。
在轻至中度斑块型银屑病患者中，单次静脉注射或皮下注射高达 10 mg/kg 的 KHK4083 一般安全且耐受良好，无剂量限制的 AE。
