Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1
Publication Details
Kidney International Reports
December 2021
Author(s)
Sally A Hulton1, Jaap W Groothoff2, Yaacov Frishberg3, Michael J Koren4, J Scott Overcash5, Anne-Laure Sellier-Leclerc6, Hadas Shasha-Lavsky7, Jeffrey M Saland8, Wesley Hayes9, Daniella Magen10, Shabbir H Moochhala11, Martin Coenen12, Eva Simkova13, Sander F Garrelfs2, David J Sas14, Kristin A Meliambro8, Taylor Ngo15, Marianne T Sweetser15, Bahru A Habtemariam15, John M Gansner15, Tracy L McGregor15, John C Lieske16
Affiliations
1Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham, UK; 2Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; 3Division of Pediatric Nephrology, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; 4Jacksonville Center for Clinical Research, Jacksonville, Florida, USA; 5Velocity Clinical Research, San Diego, California, USA; 6Hôpital Femme Mère Enfant and Centre d'Investigation Clinique Institut National de la Santé et de la Recherche Médicale, Hospices Civils de Lyon, ERKnet, Bron, France; 7Pediatric Nephrology Unit, Galilee Medical Center and Azrieli Faculty of Medicine, Bar-Ilan University, Nahariya, Israel; 8Icahn School of Medicine at Mount Sinai, New York, New York, USA; 9Department of Pediatric Nephrology, Great Ormond Street Hospital, London, UK; 10Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel; 11UCL Department of Renal Medicine, Royal Free Hospital, London, UK; 12Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; 13Al Jalila Children's Hospital, Dubai, United Arabs Emirates; 14Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; 15Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 16Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
Abstract
Introduction:
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels.
Methods:
We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran).
Results:
In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs).
Conclusions:
Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.
PMID
35257062
DOI
10.1016/j.ekir.2021.12.001
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