GlaxoSmithKline, Collegeville, PA, USA.
GlaxoSmithKline, Stockley Park, Uxbridge, UK.
Arthritis Res Ther. 2021 Mar 16;23(1):85. doi: 10.1186/s13075-021-02468-0.
Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA).
Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85.
A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms.
These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA.
ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.
受体相互作用蛋白激酶 1（RIPK1）是通过细胞死亡和产生促炎细胞因子来介导炎症的关键介质。这项多中心、随机、双盲（研究者设盲）、安慰剂对照的实验性医学研究评估了 RIPK1 抑制剂 GSK2982772 在中度至重度类风湿关节炎（RA）患者中的安全性、药代动力学（PK）和初步疗效。
接受过≥12 周稳定剂量传统合成改善病情抗风湿药物（csDMARD）治疗的中度至重度 RA 患者，按 2:1 的比例随机（双盲）分为 GSK2982772 60mg 或安慰剂，每日口服 2 或 3 次，共 84 天。在第 43 天和第 85 天评估安全性、PK、疾病活动度、关节损伤和药效学（PD）生物标志物。
共有 52 名患者被随机分配（安慰剂组 18 名；GSK2982772 组 34 名）。安慰剂组（每日 2 次组 n=3；每日 3 次组 n=10）和 GSK2982772 组（每日 2 次组 n=3；每日 3 次组 n=17）各有 13 名（72%）和 20 名（61%）患者发生不良事件（AE）。所有治疗相关 AE 均为轻/中度，除 1 例患者在第 49 天发生重度斑秃和第 66 天发生视网膜静脉血栓（导致退出研究）外，GSK2982772 每日 3 次组。28 关节 C 反应蛋白（DAS28-CRP）评分、ACR20/50/70 应答、低疾病活动度和缓解率在安慰剂组和 GSK2982772 组之间相似。
这些结果表明，在评估的 GSK2982772 暴露水平下抑制 RIPK1 活性并不能转化为 RA 的有意义的临床改善。
ClinicalTrials.gov 标识符：NCT02858492。2016 年 8 月 8 日注册。
