Objectives Anti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes. Methods Placebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported. Results 90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101. Conclusions We demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.

中文翻译：

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NI-0101（一种抗 Toll 样受体 4 单克隆抗体）对甲氨蝶呤反应不足的类风湿性关节炎患者的疗效和安全性：一项 II 期研究

目的 抗瓜氨酸蛋白抗体 (ACPA) 与瓜氨酸蛋白结合 toll 样受体 (TLR) 4 形成免疫复合物，后者已被提议作为类风湿性关节炎 (RA) 的介质。NI-0101 是一种一流的人源化单克隆抗体，可阻断 TLR4，这已通过在健康志愿者体内抑制脂多糖诱导的细胞因子释放得到证实。本研究旨在确认支持生物标志物驱动方法治疗这些免疫复合物呈阳性的 RA 患者的临床前研究。方法 NI-0101（5 mg/kg，每 2 周一次，持续 12 周）与安慰剂在 ACPA 阳性 RA 患者中对 NI-0101（5 mg/kg，每 2 周一次，持续 12 周）的耐受性和疗效的安慰剂对照、双盲、随机 (2:1) 试验甲氨蝶呤。疗效指标包括疾病活动评分（28 关节计数）与 C 反应蛋白 (DAS28-CRP)、欧洲抗风湿病联盟 (EULAR) 良好和中等反应，以及美国风湿病学会 (ACR) 20、ACR50 和 ACR70 反应。进行了根据生物标志物定义的亚组分析。报告了药代动力学、药效学和安全性。结果 90 名患者被随机分配（NI-0101 (61) 和安慰剂 (29)）；86人完成了研究。没有观察到任何疗效终点的显着组间差异。使用基线参数作为协变量的亚组分析未显示任何人群对 NI-0101 有反应。接受安慰剂的患者中有 51.7% 发生了治疗中出现的不良事件，而接受 NI-0101 的患者则为 52.5%。结论 我们首次证明在 RA 中，作为一种人类免疫介导的炎症性疾病，仅阻断 TLR4 通路并不能改善疾病参数。RA 中先天免疫通路的成功靶向可能需要更广泛和/或更早的抑制方法。