一项评估布罗达卢单抗（一种人抗 IL-17R 抗体）在甲氨蝶呤耐药性类风湿关节炎中的安全性、药代动力学和早期临床反应的 Ib 期多递增剂量研究。
A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis.
出版信息
Arthritis Res Ther. 2013 Oct 25;15(5):R164. doi: 10.1186/ar4347.
INTRODUCTION
The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA).
METHODS
This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥ 6/66 swollen and ≥ 8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics.
RESULTS
Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70.
CONCLUSIONS
Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT00771030.
介绍
本研究旨在评估 Brodalumab（AMG 827）在中度至重度类风湿关节炎（RA）患者中的安全性、药代动力学和临床反应。方法：这是一项 Ib 期、随机、安慰剂对照、双盲、递增剂量研究，纳入了中度至重度 RA（≥ 6/66 个肿胀关节和≥ 8/68 个触痛关节）患者。受试者按 3：1 随机分配接受 Brodalumab（皮下注射 50mg、140mg 或 210mg，每两周一次，每组 6 个剂量；或静脉注射 420mg 或 700mg，每四周一次，每组 2 个剂量）或安慰剂。主要终点包括不良事件（AE）发生率和药代动力学。探索性终点包括药效学和 RA 临床指标的改善。结果：40 名受试者被随机分配至研究药物组；1 名受试者因 RA 恶化（安慰剂组）而退出。该研究未设计用于评估疗效。安慰剂组 70%（7/10）和 Brodalumab 组 77%（22/30）的受试者报告了 AE。两名受试者报告了 3 例严重 AE；无机会性感染。Brodalumab 治疗导致白细胞循环中 IL-17 受体信号和受体占有率的抑制。RA 疾病活动的个别指标未观察到治疗效果。在第 85 天（第 13 周），Brodalumab 组 37%（11/30）和安慰剂组 22%（2/9）的受试者达到 ACR20；Brodalumab 组 7%（2/30）和安慰剂组 11%（1/9）的受试者达到 ACR50；Brodalumab 组 0%（0/30）和安慰剂组 0%（0/9）的受试者达到 ACR70。结论：在活动性 RA 患者中，多次给予 Brodalumab 是可以耐受的。RA 患者中未观察到 Brodalumab 的临床反应。试验注册：ClinicalTrials.gov，NCT00771030。
Zotero 插件