GSK, Cambridge, UK.
Centre for Human Drug Research, Leiden, The Netherlands.
Clin Transl Sci. 2024 Sep;17(9):e13873. doi: 10.1111/cts.13873.
C-C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G-protein coupled CC-chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high-affinity, first-in-class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single-center, double-blind, placebo-controlled, three-period, incomplete-block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co-primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty-one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry-over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug-related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.
C-C 基序趋化因子配体 17（CCL17）是一种趋化因子，通过 G 蛋白偶联的 CC-趋化因子受体 4 结合并发出信号，并且与炎症性和关节炎性疼痛的发展有关。GSK3858279 是一种高亲和力的、首创的、单克隆抗体，特异性结合 CCL17 并抑制下游信号。在这项 I 期、随机、单中心、双盲、安慰剂对照、三周期、不完全块交叉研究（NCT04114656）中，评估了静脉内 GSK3858279 在一系列诱发急性疼痛评估中的镇痛效果和安全性，这些评估是在健康的成年（年龄≥18 岁）男性参与者中进行的。参与者按照 1:1 的比例随机分配，接受一种安慰剂（0.9%w/v NaCl）剂量，然后接受两种 GSK3858279 剂量（PAA 治疗顺序），或接受一种 GSK3858279 剂量，然后接受两种安慰剂剂量（APP 治疗顺序）。主要共同终点是紫外线 B 热痛觉检测阈值（°C）、冷压时间至疼痛耐受阈值（PTT，sec）和电 PTT（mA，单次刺激）。共纳入 21 名参与者（PAA=11；APP=10）。PAA 的平均年龄（标准差）为 29.3（7.9）岁，APP 为 31.1（7.7）岁。在任何终点，GSK3858279 与安慰剂相比，镇痛效果均无显著差异。在第 1 期（APP 序列）和第 2 期和第 3 期（PAA 序列）之间，GSK3858279 的暴露情况相似，存在一定的 GSK3858279 残留。血清 CCL17 水平的变化与 GSK3858279 的预期活性一致。所有与药物相关的不良事件均为轻度，且无停药事件。在这种急性疼痛模型中未观察到疗效信号并不排除在慢性疼痛状态下的疗效。
