Cemdisiran 治疗成人 IgA 肾病的 2 期临床试验：一项随机对照试验。
Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial.
机构信息
Department of Cardiovascular Medicine, University of Leicester, Leicester, United Kingdom.
Mount Elizabeth Novena Hospital, Singapore, Singapore.
出版信息
Clin J Am Soc Nephrol. 2024 Apr 1;19(4):452-462. doi: 10.2215/CJN.0000000000000384. Epub 2024 Jan 15.
BACKGROUND
IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression.
METHODS
In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments.
RESULTS
Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%).
CONCLUSIONS
These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.
背景
IgA 肾病是最常见的原发性肾小球肾炎。IgA 肾病的临床特征包括蛋白尿，这是导致肾功能衰竭进展的最强已知替代指标。补体途径的激活是 IgA 肾病中炎症和组织损伤的关键驱动因素。Cemdisiran 是一种研究性的 RNA 干扰治疗药物，可抑制肝脏产生补体成分 5（C5），从而可能减少 IgA 肾病中的蛋白尿。我们评估了 cemdisiran 在有进展为肾病高风险的 IgA 肾病成年患者中的疗效和安全性。
方法
在这项为期 36 周的 2 期、双盲研究中，将蛋白尿≥1 g/24 小时的 IgA 肾病成年患者随机（2:1）分组，接受皮下注射 cemdisiran 600 mg 或安慰剂，每 4 周一次，同时接受标准治疗。主要终点是通过 24 小时尿液收集测量的基线时尿液蛋白与肌酐比值（UPCR）的第 32 周的百分比变化。其他终点包括通过随机尿液测量的 UPCR 基线变化、血清 C5 水平以及安全性评估。
结果
31 名患者被随机分组（cemdisiran，N=22；安慰剂，N=9）。cemdisiran 治疗患者的 24 小时 UPCR 经安慰剂校正的几何均数变化为-37.4%（cemdisiran 校正的几何均数比值与基线相比 [SEM]，0.69 [0.10]），第 32 周时。随机尿液 UPCR 的变化与 24 小时 UPCR 的安慰剂校正变化一致，为-45.8%（cemdisiran 校正的几何均数比值与基线相比 [SEM]，0.73 [0.11]）。第 32 周时，血清 C5 水平与基线相比的平均（SD）变化分别为-98.7%（1.2）和 25.2%（57.7）。在 36 周期间，大多数不良事件为轻度或中度且短暂；cemdisiran 治疗后最常见的不良事件是注射部位反应（41%）。
结论
这些发现表明，cemdisiran 治疗可降低第 32 周时的蛋白尿，且耐受性良好。
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