From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.).
N Engl J Med. 2021 Apr 1;384(13):1216-1226. doi: 10.1056/NEJMoa2021712.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.
A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.
Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
原发性高草酸尿症 1 型（PH1）是一种罕见的遗传性疾病，由肝脏草酸过度产生引起，导致肾结石、肾钙质沉着症、肾衰竭和全身性草酸过多症。Lumasiran 是一种研究性的 RNA 干扰（RNAi）治疗药物，通过靶向乙醛酸氧化酶来减少肝脏草酸的产生。
在这项双盲、3 期试验中，我们将 6 岁及以上的 PH1 患者随机分配（2:1 比例）接受皮下注射 Lumasiran 或安慰剂治疗 6 个月（在基线和第 1、2、3 和 6 个月时给药）。主要终点是 24 小时尿草酸盐排泄量从基线到第 6 个月的变化百分比（第 3 至 6 个月的平均变化百分比）。次要终点包括血浆草酸盐水平从基线到第 6 个月的变化百分比（第 3 至 6 个月的平均变化百分比）和第 6 个月时 24 小时尿草酸盐排泄量不高于正常范围上限 1.5 倍的患者比例。
共有 39 名患者接受了随机分组；26 名被分配到 Lumasiran 组，13 名被分配到安慰剂组。24 小时尿草酸盐排泄量变化的最小二乘均数差异（Lumasiran 减去安慰剂）为-53.5 个百分点（P<0.001），Lumasiran 组降低了 65.4%，在第 1 个月就出现了效果。所有分层测试的次要终点的组间差异均有统计学意义。血浆草酸盐水平变化的差异（Lumasiran 减去安慰剂）为-39.5 个百分点（P<0.001）。在 Lumasiran 组，84%的患者在第 6 个月时 24 小时尿草酸盐排泄量不高于正常范围上限的 1.5 倍，而安慰剂组为 0%（P<0.001）。在接受 Lumasiran 治疗的患者中，38%报告有轻微、短暂的注射部位反应。
Lumasiran 降低了尿草酸盐排泄量，这是 PH1 进行性肾衰竭的原因。接受 Lumasiran 治疗的大多数患者在 6 个月治疗后，其水平恢复正常或接近正常。（由 Alnylam Pharmaceuticals 资助；ILLUMINATE-A ClinicalTrials.gov 编号，NCT03681184。）
