Department of Renal Medicine, University College London, London, United Kingdom.
Royal Free Hospital London, London, United Kingdom.
Clin J Am Soc Nephrol. 2024 Aug 1;19(8):995-1004. doi: 10.2215/CJN.0000000000000458. Epub 2024 Jun 3.
Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression. There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint. The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo.
Preclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression.
This study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility.
Forty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: =19; placebo: =9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1) and −5 (−10.2 to 0.8) ml/min per 1.73 m per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48.
While anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed.
: NCT02855268.
在有发生快速疾病进展风险的 Alport 综合征成人患者中，反义 miR-21 疗法 lademirsen 的耐受性通常良好。 lademirsen 治疗组和安慰剂治疗组在任何时间点的 eGFR 均无显著差异。 lademirsen 组和安慰剂组在第 24 周和第 48 周时 eGFR 按预定标准降低的参与者比例无显著差异。
疾病的临床前模型表明，针对 microRNA-21（miRNA-21）可能会减缓 Alport 综合征（AS）患者肾功能下降的速度。本研究旨在探讨抗 miRNA-21 寡核苷酸 lademirsen 对有快速疾病进展风险的 AS 成人患者 eGFR 下降速度的影响。
这是 lademirsen 的一项 2 期临床试验，包括随机、双盲、安慰剂对照期和开放标签期。具有 AS、eGFR＞35 至＜90ml/min/1.73m²和快速进行性肾功能障碍证据的成人患者按 2：1 比例随机分配至 lademirsen 110mg 皮下注射，每周一次或安慰剂治疗 48 周。在计划的中期分析（24 名随机参与者完成第 48 周研究访视或在第 48 周前停药后）后，由于无效，试验提前终止。
43 名 AS 成人患者（26 名男性，17 名女性）参与了研究（平均年龄 34 岁），其中 28 名（lademirsen：19 名；安慰剂：9 名）完成了 48 周的双盲治疗。两组所有患者均发生治疗出现的不良事件，主要为呼吸道感染、头痛、头晕、代谢/电解质紊乱和贫血。在双盲期，有 3 名 lademirsen 治疗者和 1 名开放标签期的参与者因治疗出现的不良事件而停止治疗。 lademirsen 组和安慰剂组在 48 周时 eGFR 斜率（95%置信区间）的最小二乘均值分别为-5（-8.7 至-1.1）和-5（-10.2 至 0.8）ml/min/1.73m²/年。两组在任何时间点的 eGFR 或在第 24 周或第 48 周时 eGFR 按预定标准降低的参与者比例均无显著差异。
虽然 lademirsen 的反义 miR-21 治疗耐受性良好，安全性可接受，但在有发生快速疾病进展风险的 AS 成人患者中，并未观察到肾功能下降速度的有意义改善。
NCT02855268。
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