Povetacicept治疗IgA肾病3期试验的中期分析
完整摘要 · 中文译文
背景：B细胞激活因子（BAFF）和增殖诱导配体（APRIL）在产生IgA的B细胞群中具有不同的作用，并且似乎是IgA肾病发病机制的核心。Povetacicept是一种增强型变异跨膜激活剂及钙调亲环素配体相互作用分子（TACI）-Fc片段融合治疗药物，经工程化设计以双重抑制BAFF和APRIL。 方法：在这项正在进行的3期双盲安慰剂对照试验中，经活检证实为IgA肾病且接受稳定背景治疗的参与者按2：1比例随机接受每4周皮下注射80 mg剂量的povetacicept或安慰剂。本预设中期分析的主要终点为第36周时24小时尿蛋白与肌酐比值的变化。次要终点为第36周时半乳糖缺陷型IgA1水平的变化，以及基线有血尿的参与者第36周时血尿的缓解情况。 结果：共有557名参与者接受了povetacicept（372名参与者）或安慰剂（185名参与者）。疗效分析包括首批199名已接受随机分组的参与者（povetacicept组131名，安慰剂组68名）。至第36周时，povetacicept组的24小时尿蛋白与肌酐比值下降52.0%，安慰剂组下降4.3%（校正差异，-49.8个百分点；95%置信区间[CI]，-58.6至-39.2；P<0.001）。povetacicept组的半乳糖缺陷型IgA1水平下降77.4%，安慰剂组升高9.1%（校正差异，-79.3个百分点；95% CI，-82.2至-75.9；P<0.001）。在基线时有血尿的参与者中，povetacicept组85%实现血尿消退，安慰剂组为23%（校正差异，62个百分点；95% CI，45至78；P<0.001）。不良事件发生率（povetacicept组75%，安慰剂组78%）和严重不良事件发生率（分别为3%和4%）在试验各组间相似。 结论：在IgA肾病患者中，至第36周时，povetacicept较安慰剂显著更大程度地降低了24小时尿蛋白与肌酐比值。（由Vertex Pharmaceuticals资助；RAINIER AIS-D08 ClinicalTrials.gov注册号，NCT06564142。）
完整摘要 · 英文原文
BACKGROUND: B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have distinct roles in IgA-producing B-cell populations and appear to be central to the pathogenesis of IgA nephropathy. Povetacicept, an enhanced, variant transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)-Fc fragment fusion therapeutic, is engineered for dual inhibition of BAFF and APRIL. METHODS: In this ongoing, phase 3, double-blind, placebo-controlled trial, participants with biopsy-proven IgA nephropathy receiving stable background therapy were randomly assigned in a 2:1 ratio to receive povetacicept at a dose of 80 mg or placebo subcutaneously every 4 weeks. The primary end point of this prespecified interim analysis was the change in the 24-hour urinary protein-to-creatinine ratio at week 36. Secondary end points were the change at week 36 in galactose-deficient IgA1 levels and hematuria resolution at week 36 among participants with baseline hematuria. RESULTS: A total of 557 participants received povetacicept (372 participants) or placebo (185 participants). Efficacy analyses included the first 199 participants who had undergone randomization (131 in the povetacicept group and 68 in the placebo group). The 24-hour urinary protein-to-creatinine ratio decreased by 52.0% with povetacicept and by 4.3% with placebo by week 36 (adjusted difference, -49.8 percentage points; 95% confidence interval [CI], -58.6 to -39.2; P<0.001). Galactose-deficient IgA1 levels decreased by 77.4% with povetacicept and increased by 9.1% with placebo (adjusted difference, -79.3 percentage points; 95% CI, -82.2 to -75.9; P<0.001). Among the participants with baseline hematuria, resolution occurred in 85% with povetacicept and in 23% with placebo (adjusted difference, 62 percentage points; 95% CI, 45 to 78; P<0.001). The incidence of adverse events (75% with povetacicept and 78% with placebo) and serious adverse events (3% and 4%, respectively) were similar in the trial groups. CONCLUSIONS: Povetacicept led to a significantly greater reduction in the 24-hour urinary protein-to-creatinine ratio than placebo by week 36 in participants with IgA nephropathy. (Funded by Vertex Pharmaceuticals; RAINIER AIS-D08 ClinicalTrials.gov number, NCT06564142.).