• Sander F Garrelfs, Yaacov Frishberg, Sally A Hulton, Michael J Koren, William D O'Riordan, Pierre Cochat, Georges Deschênes, Hadas Shasha-Lavsky, Jeffrey M Saland, William G Van't Hoff, Daniel G Fuster, Daniella Magen, Shabbir H Moochhala, Gesa Schalk, Eva Simkova, Jaap W Groothoff, David J Sas, Kristin A Meliambro, Jiandong Lu, Marianne T Sweetser, Pushkal P Garg, Akshay K Vaishnaw, John M Gansner, Tracy L McGregor, John C Lieske, and ILLUMINATE-A Collaborators.
• 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.

BackgroundPrimary 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.MethodsIn 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.ResultsA 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.ConclusionsLumasiran 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.).Copyright © 2021 Massachusetts Medical Society.

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