一项在活动性溃疡性结肠炎患者中进行的 RIPK1 抑制剂 GSK2982772 的随机、安慰剂对照研究。

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis.

机构信息

Immunology and Inflammation, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

Biostatistics, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.

出版信息

BMJ Open Gastroenterol. 2021 Aug;8(1). doi: 10.1136/bmjgast-2021-000680.

DOI:10.1136/bmjgast-2021-000680

PMID:34389633

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8365785/

Abstract

OBJECTIVE

Tumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This phase IIa, randomised, double-blind experimental medicine study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of the RIPK1 inhibitor GSK2982772 in patients with active UC.

DESIGN

In part A, prior to a protocol amendment, one patient was randomised to receive GSK2982772 60 mg twice daily for 42 days. After the amendment, patients were randomised 2:1 to receive GSK2982772 60 mg or placebo three times daily for 42 days. In part B, all patients switched to open-label GSK2982772 60 mg three times daily for 42 days. Safety, PK, PD biomarkers, histological disease activity, clinical efficacy and quality of life were assessed at days 43 and 85.

RESULTS

Thirty-six patients were randomised (n=12, placebo/open-label GSK2982772; n=24, GSK2982772/open-label GSK2982772). Most adverse events were mild, with headache reported the most frequently across groups (placebo/open-label GSK2982772, n=2 (17%); GSK2982772/open-label GSK2982772, n=8 (33%)). GSK2982772 was well distributed into colonic tissue, with generally higher concentrations in colonic biopsy samples versus plasma. No apparent differences between treatment groups were observed for PD, histological disease activity, clinical disease activity or quality-of-life measures. At screening, all patients had Mayo endoscopic scores of 2 or 3. At day 43, no patients in the placebo/open-label GSK2982772 group achieved Mayo endoscopic scores of 0 or 1 vs 3/24 (13%) for GSK2982772/open-label GSK2982772. At day 85, 1/9 (11%) achieved scores of 0 or one for placebo/open-label GSK2982772 vs 3/22 (14%) for GSK2982772/open-label GSK2982772.

CONCLUSION

GSK2982772 was generally well tolerated, with no treatment-related safety concerns identified. However, no significant differences in efficacy were observed between treatment groups, suggesting that GSK2982772 as monotherapy is not a promising treatment for patients with active UC.

TRIAL REGISTRATION NUMBER

NCT02903966.

摘要

目的

肿瘤坏死因子通过受体相互作用蛋白激酶 1（RIPK1）通路的信号传导调节结肠炎症，表明 RIPK1 抑制可能是溃疡性结肠炎（UC）的潜在治疗靶点。这项 2a 期、随机、双盲实验医学研究调查了 RIPK1 抑制剂 GSK2982772 在活动期 UC 患者中的安全性、药代动力学（PK）、药效学（PD）和初步疗效。

设计

在方案修订前，A 部分有 1 名患者被随机分配接受 GSK2982772 60mg 每日两次，共 42 天。修订后，患者被随机分为 2:1 接受 GSK2982772 60mg 或安慰剂每日三次，共 42 天。B 部分所有患者均切换至开放标签 GSK2982772 60mg 每日三次，共 42 天。在第 43 天和第 85 天评估安全性、PK、PD 生物标志物、组织学疾病活动、临床疗效和生活质量。

结果

36 名患者被随机分配（n=12，安慰剂/开放标签 GSK2982772；n=24，GSK2982772/开放标签 GSK2982772）。大多数不良事件为轻度，各治疗组中头痛报告最常见（安慰剂/开放标签 GSK2982772，n=2（17%）；GSK2982772/开放标签 GSK2982772，n=8（33%））。GSK2982772 在结肠组织中分布良好，结肠活检样本中的浓度通常高于血浆。在 PD、组织学疾病活动、临床疾病活动或生活质量测量方面，治疗组之间未观察到明显差异。在筛选时，所有患者的 Mayo 内镜评分均为 2 或 3。在第 43 天，安慰剂/开放标签 GSK2982772 组无患者达到 Mayo 内镜评分 0 或 1，而 GSK2982772/开放标签 GSK2982772 组为 24 例中的 3 例（13%）。在第 85 天，安慰剂/开放标签 GSK2982772 组有 1/9（11%）达到 0 或 1 分，而 GSK2982772/开放标签 GSK2982772 组有 22 例中的 3 例（14%）。