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Efficacy and Safety of Lumasiran for Advanced Primary Hyperoxaluria Type 1: 24-Month Follow-Up of the Phase 3 Illuminate-C Trial

Publication Details

American Journal of Kidney Diseases

March 2025

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Author(s)

Anne-Laure Sellier-Leclerc¹, Daniella Magen², Hadas Shasha-Lavsky³, Eva Simkova⁴, Arnaud Devresse⁵, Fitsum Guebre-Egziabher⁶, Mini Michael⁷, John C Lieske⁸, Yaacov Frishberg⁹, Sevcan A Bakkaloglu¹⁰, Chebl Mourani¹¹, Rola Saqan¹², Richard Singer¹³, Isabella Guzzo¹⁴, Nune Makarova¹⁵, Richard Willey¹⁵, Cristin Kaspar¹⁵, John M Gansner¹⁵, Jaap W Groothoff¹⁶

Affiliations

¹Hôpital Femme Mère Enfant en Centre d'Investigation Clinique INSERM, Hospices Civils de Lyon, ERKnet, Bron, France; ²Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel; ³Pediatric Nephrology Unit, Galilee Medical Center, Nahariya, Israel; ⁴Nephrology - Medical Affairs, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates; ⁵Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; ⁶Nephrology and Renal Function Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, INSERM 1060, Lyon, France; ⁷Division of Pediatric Nephrology, Department of Pedatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas; ⁸Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; ⁹Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University, Jerusalem, Israel; ¹⁰Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey; ¹¹Pediatrics, Hôtel Dieu de France Hospital (HDF), Beirut, Lebanon; ¹²Pharmaceutical Research Center - Jordan University of Science and Technology, Irbid, Jordan; ¹³Renal Service, Canberra Health Services, Garran, Australia; ¹⁴Nephrology, Dialysis, and Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; ¹⁵Alnylam Pharmaceuticals, Cambridge, Massachusetts; ¹⁶Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Abstract

Background:

Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx).

Methods:

ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged ≥6 years with PH1 and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month 36.

Results:

Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion ≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88–2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46–0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions.

Conclusions:

In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.