Sibeprenlimab 治疗 IgA 肾病患者的 II 期临床试验。
A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.
机构信息
From Visterra, Waltham, MA (M.M., J.Y., B.J.G.P.); John Walls Renal Unit, Leicester General Hospital, Leicester, United Kingdom (J.B.); Nephrology and Transplantation, John Hunter Hospital and University of Newcastle, Newcastle, NSW (B.C.), and the University of Sydney, Sydney (M.G.W.) - both in Australia; the University of Hong Kong, Queen Mary Hospital, Hong Kong (T.M.C.); Colorado Kidney Care, Denver (L.K.); Seoul National University College of Medicine, Seoul, South Korea (K.-H.O.); Osmania General Hospital, Hyderabad, India (M.S.); the Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo (Y.S.); and Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ (J.X.).
出版信息
N Engl J Med. 2024 Jan 4;390(1):20-31. doi: 10.1056/NEJMoa2305635. Epub 2023 Nov 2.
BACKGROUND
A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL.
METHODS
In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed.
RESULTS
Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group.
CONCLUSIONS
In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).
背景
增殖诱导配体（APRIL）与 IgA 肾病的发病机制有关。Sibeprenlimab 是一种人源化 IgG2 单克隆抗体，可与 APRIL 结合并中和其活性。
方法
在这项 2 期、多中心、双盲、随机、安慰剂对照、平行组试验中，我们以 1:1:1:1 的比例随机分配了 155 名经活检证实患有 IgA 肾病且尽管接受了标准治疗仍有疾病进展高风险的成年人，他们每月接受一次静脉注射 sibeprenlimab，剂量分别为 2、4 或 8mg/kg 体重或安慰剂，持续 12 个月。主要终点是第 12 个月时基线 24 小时尿蛋白与肌酐比值的对数变换值的变化。次要终点包括第 12 个月时估计肾小球滤过率（eGFR）的变化。同时还评估了安全性。
结果
在接受随机分组的 155 名患者中，38 名接受 sibeprenlimab 2mg/kg 剂量，41 名接受 sibeprenlimab 4mg/kg 剂量，38 名接受 sibeprenlimab 8mg/kg 剂量，38 名接受安慰剂。第 12 个月时，sibeprenlimab 2mg、4mg 和 8mg 组与安慰剂组的 24 小时尿蛋白与肌酐比值的基线比值降低分别为 47.2±8.2%、58.8±6.1%、62.0±5.7%和 20.0±12.6%。第 12 个月时，sibeprenlimab 2mg、4mg 和 8mg 组与安慰剂组的 eGFR 自基线的最小二乘均值（±SE）变化分别为-2.7±1.8、0.2±1.7、-1.5±1.8 和-7.4±1.8ml/min/1.73m。接受 sibeprenlimab 或安慰剂治疗后开始出现的不良事件发生率在 sibeprenlimab 合并组中为 78.6%，安慰剂组中为 71.1%。
结论
在 IgA 肾病患者中，sibeprenlimab 治疗 12 个月可显著降低蛋白尿，优于安慰剂。（由 Visterra 资助；ENVISION 临床试验.gov 编号，NCT04287985；EudraCT 编号，2019-002531-29。）
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