背景:增殖诱导配体(APRIL)与IgA肾病的发病机理有关。Sibeprenlimab是一种人源化IgG2单克隆抗体,可结合并中和APRIL。
方法:在此阶段2,多中心,双盲,随机化,安慰剂对照,平行组试验,我们将活检确诊的IgA肾病患者随机分组,这些患者具有疾病进展的高风险,尽管接受了标准护理治疗,以1:1:1:1的比例接受静脉注射sibeprenlimab,剂量为2、4或8mg/kg体重或安慰剂,每月一次,持续12个月。主要终点是在第12个月时对数转换的24小时尿蛋白与肌酐比率相对于基线的变化。次要终点包括第12个月时估计的肾小球滤过率(eGFR)相对于基线的变化。还评估了安全性。
结果:在155例随机分组的患者中,38以每公斤2毫克的剂量接受sibeprenlimab,41人接受了每公斤4毫克的sibeprenlimab,38以每公斤8毫克的剂量接受sibeprenlimab,38人接受了安慰剂。12个月时,24小时尿蛋白与肌酐比值从基线的几何平均比值降低(±SE)为47.2±8.2%,58.8±6.1%,62.0±5.7%,和20.0±12.6%的sibeprenlimab2-mg,4-mg,8毫克组和安慰剂组,分别。12个月时,eGFR相对于基线的最小二乘平均值(±SE)变化为-2.7±1.8、0.2±1.7、-1.5±1.8和-7.4±1.8ml/分钟每1.73m2,4-mg,8毫克组和安慰剂组,分别。在合并的sibeprenlimab组和安慰剂组开始给药后发生的不良事件发生率为78.6%,在安慰剂组为71.1%。
结论:在IgA肾病患者中,与安慰剂相比,使用sibeprenlimab治疗12个月的蛋白尿明显减少。(由Visterra资助;ENVISIONClinicalTrials.gov编号,NCT04287985;EudraCT编号,2019-002531-29。).
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.
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.
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 m2 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.
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.).