Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

Autor:	Michael M; Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas. Electronic address: mmichael@bcm.edu., Groothoff JW; Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Shasha-Lavsky H; Pediatric Nephrology Unit, Galilee Medical Center, Azrieli Faculty of Medicine, Bar Ilan University, Nahariya, Israel., Lieske JC; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota., Frishberg Y; Division of Pediatric Nephrology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Simkova E; Nephrology - Medical Affairs, Al Jalila Children's Hospital, Dubai, United Arab Emirates., Sellier-Leclerc AL; Hôpital 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., Devresse A; Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Guebre-Egziabher F; Nephrology and Renal Function Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, INSERM 1060, Lyon, France., Bakkaloglu SA; Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey., Mourani C; Department of Pediatrics, Hôtel-Dieu de France Hospital, Beirut, Lebanon., Saqan R; Pharmaceutical Research Center, Jordan University of Science and Technology, Irbid, Jordan., Singer R; Renal Service, Canberra Health Services, Garran, ACT, Australia., Willey R; Alnylam Pharmaceuticals, Cambridge, Massachusetts., Habtemariam B; Alnylam Pharmaceuticals, Cambridge, Massachusetts., Gansner JM; Alnylam Pharmaceuticals, Cambridge, Massachusetts., Bhan I; Alnylam Pharmaceuticals, Cambridge, Massachusetts., McGregor T; Alnylam Pharmaceuticals, Cambridge, Massachusetts., Magen D; Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
Jazyk:	angličtina
Zdroj:	American journal of kidney diseases : the official journal of the National Kidney Foundation [Am J Kidney Dis] 2023 Feb; Vol. 81 (2), pp. 145-155.e1. Date of Electronic Publication: 2022 Jul 14.
DOI:	10.1053/j.ajkd.2022.05.012
Abstrakt:	Rationale & Objective: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. Study Design: Phase 3, open-label, single-arm trial. Setting & Participants: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m 2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 μmol/L at screening, including patients with or without systemic oxalosis. Intervention: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. Outcome: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. Results: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. Limitations: Single-arm study without placebo control. Conclusions: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. Funding: Alnylam Pharmaceuticals. Trial Registration: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. Plain-Language Summary: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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