Frishberg Yaacov, Groothoff Jaap W, Hulton Sally-Anne, Harambat Jerome, Hogan Julien, Sellier-Leclerc Anne-Laure, Hayes Wesley, Coenen Martin J, Willey Richard, Gansner John M, Magen Daniella
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Nephrol Dial Transplant. 2025 Sep 22. doi: 10.1093/ndt/gfaf188.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder of hepatic oxalate overproduction leading to kidney failure and systemic oxalosis. Lumasiran is an RNA interference therapeutic approved for lowering urinary oxalate (UOx) and plasma oxalate (POx) in PH1. This Phase 2 open-label extension (OLE) study evaluated the safety and efficacy of long-term lumasiran treatment (up to 54 months) in patients with PH1 who had completed the Phase 1/2 parent study.
The Phase 2 OLE (NCT03350451) included patients with PH1 6 to 64 years old, 24-hour UOx excretion > 0.7 mmol/1.73m2/day, and estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73m2 who enrolled within 12 months of parent study completion. Patients initiated subcutaneous lumasiran at parent study dosage. Endpoints included adverse event (AE) incidence (primary) and change over time in efficacy measures, including 24-hour UOx and eGFR.
All 20 patients (median age 11.5 years; 65% female) who completed the parent study entered and completed the Phase 2 OLE. Of 21 treatment-related AEs over 427 doses, 13 were transient injection site reactions (ISRs), affecting 8/20 patients (40%); all ISRs were mild in severity. After Month (M) 18 through M51 (last dosing), no ISRs were reported. No treatment-related severe or serious AEs were reported. Lumasiran treatment led to a substantial mean reduction in 24 h UOx from baseline to M54 of - 1.5 mmol/24 h/1.73m2. At visits M42 through M54, 24-hour UOx was ≤ 1.5 × ULN in 89-94% of patients at each visit. The mean annual change in eGFR was - 0.4 mL/min/1.73m2/year overall; eGFR was also stable in those patients with baseline eGFR < 90 mL/min/1.73m2.
These data represent the longest published follow-up of lumasiran-treated patients with PH1 (ages: 6-43 years) to date. Long-term lumasiran treatment for PH1 had acceptable safety and led to sustained and substantial reduction of UOx with preservation of kidney function.
1型原发性高草酸尿症（PH1）是一种罕见的遗传性疾病，肝脏草酸生成过多，可导致肾衰竭和全身草酸沉积症。鲁马西奈是一种经批准用于降低PH1患者尿草酸（UOx）和血浆草酸（POx）的RNA干扰疗法。这项2期开放标签扩展（OLE）研究评估了在完成1/2期母研究的PH1患者中，长期使用鲁马西奈治疗（长达54个月）的安全性和有效性。
2期OLE（NCT03350451）纳入了年龄在6至64岁、24小时UOx排泄量>0.7 mmol/1.73m2/天且估计肾小球滤过率（eGFR）>45 mL/min/1.73m2的PH1患者，这些患者在母研究完成后的12个月内入组。患者以母研究剂量开始皮下注射鲁马西奈。研究终点包括不良事件（AE）发生率（主要终点）以及疗效指标随时间的变化，包括24小时UOx和eGFR。
所有20名完成母研究的患者（中位年龄11.5岁；65%为女性）均进入并完成了2期OLE。在427剂治疗相关AE中，有21例，其中13例为短暂性注射部位反应（ISR），影响了8/20名患者（40%）；所有ISR严重程度均为轻度。在第18个月至第51个月（最后一次给药）之后，未报告ISR。未报告与治疗相关的严重或重大AE。鲁马西奈治疗导致24小时UOx从基线到第54个月平均大幅降低，降幅为-1.5 mmol/24小时/1.73m2。在第42个月至第54个月的访视中，每次访视时89%-94%的患者24小时UOx≤1.5×ULN。eGFR的年平均变化总体为-0.4 mL/min/1.73m2/年；基线eGFR<90 mL/min/1.73m2的患者中，eGFR也保持稳定。
这些数据代表了迄今为止已发表的对接受鲁马西奈治疗的PH1患者（年龄6-43岁）最长的随访结果。PH1患者长期使用鲁马西奈治疗具有可接受的安全性，可使UOx持续大幅降低，并保留肾功能。
