Background/Aims Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with autoantibodies. Despite the use of targeted therapies, up to half of patients fail to achieve remission or low disease activity (LDA). Anti-citrullinated protein antibodies (ACPAs), key autoantibodies that predict progression of joint destruction in RA, are largely an immunoglobulin G (IgG) isotype. Nipocalimab is a high affinity, fully human, IgG1 monoclonal antibody that is designed to selectively block the neonatal Fc receptor (FcRn), preventing recirculation and thereby lowering IgG levels, potentially including ACPAs and other pathogenic antibodies. In this phase 2a proof-of-concept study (IRIS-RA; NCT04991753), we report the efficacy and safety of nipocalimab in patients with moderate to severe, active RA. Methods Eligible adult patients with moderate to severe RA (≥6 swollen/tender joints), positive for ACPA or rheumatoid factor, and ≥1 advanced therapies, were randomized 3:2 to receive intravenous 15 mg/kg nipocalimab or placebo every 2 weeks for 10 weeks. The primary endpoint was the change from baseline in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints included the proportion of patients who achieved ACR20, ACR50, ACR70, and ACR90 responses, DAS28-CRP remission, and change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 12. Results In total, 53 patients were enrolled (nipocalimab, n = 33; placebo, n = 20). Most patients were female (67.9%) and white (90.6%) with a median age of 59 (range, 26-74) years. Demographic and baseline disease characteristics were comparable between groups except higher CRP in placebo. At Week 12, patients treated with nipocalimab showed a numerically greater mean (standard deviation [SD]) change in DAS28-CRP score compared to the placebo group (-1.17 [1.34] vs -0.62 [0.96]; mean difference [95% confidence interval], -0.45 [-1.17-0.28]; p=0.224). A numerically higher proportion of patients achieved ACR20, ACR50, ACR70, and ACR90 responses compared to placebo. In the nipocalimab group, 7 (21.2%) patients achieved DAS28-CRP remission compared to 2 (10.0%) patients in the placebo group (treatment difference, 9.9% [-9.5-29.3%]; p=0.456). Similarly, patients in the nipocalimab group had a numerically greater mean (SD) improvement in HAQ-DI score (-0.27 [0.55] vs -0.11 [0.36], respectively). The proportion of patients with treatment-emergent adverse events (TEAEs) were 81.8% vs 60.0% in the nipocalimab vs placebo groups. In the nipocalimab group, 3 serious TEAEs were reported, including burn infection, infusion-related reaction, and deep-vein thrombosis. There were no TEAEs that led to death. Conclusion Treatment with nipocalimab resulted in consistent and numerically higher improvements across ACR20, ACR50, ACR70, and ACR90 responses, as well as DAS28-CRP, DAS28-CRP remission, and HAQ-DI, with acceptable safety profile. Nipocalimab showed activity in patients with moderate to severe RA and warrants further investigation to understand the predictors of nipocalimab response. Disclosure P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Sanofi, Aqtual, and UCB. Grants/research support; Galapagos. G. Schett: None. F. Ibrahim: Corporate appointments; Employee of Janssen Research & Development. B. Zhou: Corporate appointments; Employee of Janssen Research & Development. J. Leu: Corporate appointments; Employee of Janssen Research & Development. S. Liva: Corporate appointments; Employee of Janssen Research & Development. Q. Wang: Corporate appointments; Employee of Janssen Research & Development. R. Rojo Cella: Corporate appointments; Employee of Janssen Research & Development. C.S. Karyekar: Corporate appointments; Employee of Janssen Research & Development. K. Fei: Corporate appointments; Employee of Janssen Research & Development.

中文翻译：

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OA04 尼泊卡利单抗对中重度活动性类风湿关节炎患者的疗效和安全性：多中心、随机、双盲、安慰剂对照 2a 期 IRIS-RA 研究

背景/目标类风湿性关节炎（RA）是一种与自身抗体相关的慢性炎症性疾病。尽管使用了靶向治疗，仍有多达一半的患者未能达到缓解或低疾病活动度（LDA）。抗瓜氨酸蛋白抗体 (ACPA) 是预测 RA 关节破坏进展的关键自身抗体，主要是免疫球蛋白 G (IgG) 同种型。 Nipocalimab 是一种高亲和力、全人源 IgG1 单克隆抗体，旨在选择性阻断新生儿 Fc 受体 (FcRn)，防止再循环，从而降低 IgG 水平，可能包括 ACPA 和其他致病性抗体。在这项 2a 期概念验证研究（IRIS-RA；NCT04991753）中，我们报告了尼泊卡利单抗对中度至重度活动性 RA 患者的疗效和安全性。方法 符合条件的中重度 RA（≥6 个肿胀/压痛关节）、ACPA 或类风湿因子阳性且≥1 种晚期治疗的成年患者按 3:2 随机分配，接受静脉注射 15 mg/kg 尼泊卡利单抗或安慰剂，每 2 周一次，持续治疗10周。主要终点是第 12 周使用 C 反应蛋白 (DAS28-CRP) 得出的疾病活动评分 28 相对于基线的变化。次要终点包括达到 ACR20、ACR50、ACR70 和 ACR90 反应的患者比例、DAS28-CRP缓解，以及第 12 周健康评估问卷 - 残疾指数 (HAQ-DI) 相对于基线的变化。 结果 总共 53 名患者入组（尼泊卡利单抗，n = 33；安慰剂，n = 20）。大多数患者为女性 (67.9%) 和白人 (90.6%)，中位年龄为 59 岁（范围为 26-74）岁。除了安慰剂组的 CRP 较高外，各组之间的人口统计学和基线疾病特征具有可比性。第 12 周时，与安慰剂组相比，接受尼泊卡利单抗治疗的患者 DAS28-CRP 评分的平均值（标准差 [SD]）变化更大（-1.17 [1.34] vs -0.62 [0.96]；平均差异 [95% 置信度]间隔]，-0.45 [-1.17-0.28]；p=0.224)。与安慰剂相比，达到 ACR20、ACR50、ACR70 和 ACR90 缓解的患者比例更高。在尼泊卡利单抗组中，有 7 名患者 (21.2%) 达到 DAS28-CRP 缓解，而安慰剂组有 2 名患者 (10.0%) 达到缓解（治疗差异，9.9% [-9.5-29.3%]；p=0.456）。同样，尼泊卡利单抗组患者的 HAQ-DI 评分平均数 (SD) 改善更大（分别为 -0.27 [0.55] 和 -0.11 [0.36]）。尼泊卡利单抗组与安慰剂组中出现治疗引起的不良事件 (TEAE) 的患者比例分别为 81.8% 和 60.0%。尼泊卡利单抗组报告了 3 例严重 TEAE，包括烧伤感染、输液相关反应和深静脉血栓形成。没有导致死亡的 TEAE。结论 尼泊卡利单抗治疗在 ACR20、ACR50、ACR70 和 ACR90 反应以及 DAS28-CRP、DAS28-CRP 缓解和 HAQ-DI 方面取得了一致且数值更高的改善，且安全性可接受。尼泊卡利单抗在中度至重度 RA 患者中表现出活性，需要进一步研究以了解尼泊卡利单抗反应的预测因素。披露 PC Taylor：咨询；艾伯维、百健、礼来、费森尤斯、加拉帕戈斯、吉利德科学、葛兰素史克、杨森、Nordic Pharma、辉瑞公司、赛诺菲、Aqtual 和 UCB。赠款/研究支持；加拉帕戈斯群岛。 G.谢特：没有。 F. Ibrahim：公司任命；杨森研发部员工。 B.周：公司任命；杨森研发部员工。 J. Leu：公司任命；杨森研发部员工。 S. Liva：公司任命；杨森研发部员工。 Q. Wang：公司任命；杨森研发部员工。 R. Rojo Cella：公司任命；杨森研发部员工。 CS Karyekar：公司任命；杨森研发部员工。 K. Fei：公司任命；杨森研发部员工。