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Final Results of the ILLUMINATE-A Phase 3 Clinical Trial of Lumasiran for Primary Hyperoxaluria 1

Publication Details

Clinical Journal of the American Society of Nephrology

December 2025

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Author(s)

Frishberg, Yaacov¹; Saland, Jeffrey M.²; Lieske, John C.³; Du, Weiming⁴; Coenen, Martin⁵; Hogan, Julien⁶; Sellier-Leclerc, Anne-Laure⁷; Groothoff, Jaap W.⁸; Kaspar, Cristin⁴; Gansner, John M.⁴; Hulton, Sally-Anne⁹; on behalf of the ILLUMINATE-A study investigators

Affiliations

¹Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel and Faculty of Medicine, Hebrew University, Jerusalem, Israel; ²Icahn School of Medicine at Mount Sinai, New York, New York; ³Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; ⁴Alnylam Pharmaceuticals, Cambridge, Massachusetts; ⁵Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; ⁶Pediatric Nephrology Department, Hôpital Robert-Debré, APHP, Centre Référence Maladie Rares MARHEA, ERKnet, Paris, France; ⁷Hôpital Femme Mère Enfant en Centre d'Investigation Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon, ERKnet, Bron, France; ⁸Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands; ⁹Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom

Abstract

Background:

Primary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1.

Methods:

ILLUMINATE-A (nct03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a 6-month double-blind, placebo-controlled period (6M DB), followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, eGFR ≥30 ml/min per 1.73 m², and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24 h per 1.73 m².

Results:

Of 39 patients enrolled, 24 of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At month 60 relative to study baseline, the mean (SEM) 24-hour UOx percentage reductions were 54 (6) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and the mean (SEM) plasma oxalate concentrations had decreased by 35 (5) and 38% (7%). eGFR remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval, 0.36 to 0.62) and 0.54 (0.37 to 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity.

Conclusions:

Lumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved health-related quality of life. Clinical Trial registry name and registration number: ClinicalTrials.gov NCT03681184.