Lafayette Richard, Barbour Sean, Israni Rubeen, Wei Xuelian, Eren Necmi, Floege Jürgen, Jha Vivekanand, Kim Sung Gyun, Maes Bart, Phoon Richard K S, Singh Harmeet, Tesař Vladimír, Lin Celia J F, Barratt Jonathan
Division of Nephrology, Department of Medicine, Stanford University, Stanford, California, USA.
Division of Nephrology, Department of Medicine, The University of British Columbia, Vancouver, Canada.
Kidney Int. 2024 Jun;105(6):1306-1315. doi: 10.1016/j.kint.2024.03.012. Epub 2024 Mar 27.
Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.
阿他西普是一种一流的双抗B细胞活化因子-A增殖诱导配体融合蛋白，正处于治疗IgA肾病的临床评估阶段。为比较阿他西普与安慰剂对IgA肾病患者的疗效和安全性，这项随机、双盲、安慰剂对照的2b期临床试验ORIGIN招募了116名经活检证实为IgA肾病的患者。参与者被随机分为阿他西普150毫克、75毫克或25毫克组与安慰剂组，每周一次，持续长达36周。主要和关键次要终点分别是在第24周和第36周时，联合使用阿他西普150毫克和75毫克组与安慰剂组基于24小时尿液收集的尿蛋白肌酐比值变化。在第24周达到了主要终点，联合阿他西普组的平均尿蛋白肌酐比值较基线降低了31%，而安慰剂组为8%，阿他西普组与安慰剂组相比显著降低了25%。在第36周，达到了关键次要终点，联合阿他西普组的平均尿蛋白肌酐比值较基线降低了34%，而安慰剂组增加了2%，阿他西普组与安慰剂组相比显著降低了35%。与安慰剂组在第36周时下降相比，阿他西普组蛋白尿减少的同时终点估算肾小球滤过率（eGFR）保持稳定，导致组间几何平均差异显著为11%，近似于绝对差异5.7毫升/分钟/1.73平方米。与安慰剂相比，终点半乳糖缺陷型IgA1水平较基线显著降低了60%。阿他西普的安全性与安慰剂相似。因此，我们的结果为支持阿他西普在IgA肾病中的关键3期研究提供了证据。
