Hulton Sally A, Groothoff Jaap W, Frishberg Yaacov, Koren Michael J, Overcash J Scott, Sellier-Leclerc Anne-Laure, Shasha-Lavsky Hadas, Saland Jeffrey M, Hayes Wesley, Magen Daniella, Moochhala Shabbir H, Coenen Martin, Simkova Eva, Garrelfs Sander F, Sas David J, Meliambro Kristin A, Ngo Taylor, Sweetser Marianne T, Habtemariam Bahru A, Gansner John M, McGregor Tracy L, Lieske John C
Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham, UK.
Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Kidney Int Rep. 2021 Dec 11;7(3):494-506. doi: 10.1016/j.ekir.2021.12.001. eCollection 2022 Mar.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels.
We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran).
In the lumasiran/lumasiran group ( = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group ( = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs).
Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.
1型原发性高草酸尿症（PH1）是一种罕见的遗传性疾病，由肝脏草酸过度生成引起，可导致肾结石、肾钙质沉着症、肾衰竭和全身性草酸中毒。在ILLUMINATE-A研究的6个月双盲期（DBP）中，这是一项针对≥6岁PH1患者的3期随机、安慰剂对照试验，使用RNA干扰疗法鲁马西奈进行治疗，使尿草酸（UOx）水平大幅降低。
我们报告ILLUMINATE-A延长期（EP）至第12个月的数据，包括继续使用鲁马西奈的患者（鲁马西奈/鲁马西奈）或从安慰剂交叉至鲁马西奈的患者（安慰剂/鲁马西奈）。
在鲁马西奈/鲁马西奈组（n = 24）中，24小时UOx水平的降低持续至第12个月（从基线的平均降低幅度，第6个月时为66.9%；第12个月时为64.1%）。安慰剂/鲁马西奈组（n = 13）在接受鲁马西奈治疗6个月后，24小时UOx降低的时间进程和幅度相似（平均降低57.3%）。与同意前12个月相比，两组在接受鲁马西奈治疗6个月后肾结石事件发生率似乎较低，且在鲁马西奈/鲁马西奈组中，这种降低在第12个月时得以维持。在研究开始时，鲁马西奈/鲁马西奈组71%的患者和安慰剂/鲁马西奈组92%的患者患有肾钙质沉着症。在鲁马西奈/鲁马西奈组和安慰剂/鲁马西奈组中，接受鲁马西奈治疗6个月后肾钙质沉着症分级有所改善（分别为13%和8%的患者）。在接受额外6个月的鲁马西奈治疗后，鲁马西奈/鲁马西奈组中有46%的患者肾钙质沉着症分级得到改善。在鲁马西奈治疗过程中，估计肾小球滤过率（eGFR）保持稳定。与鲁马西奈相关的最常见不良事件（AE）为轻度、短暂的注射部位反应（ISR）。
长期使用鲁马西奈治疗能够持续降低UOx水平，安全性可接受，且在临床结局方面取得了令人鼓舞的结果。
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