PMID- 35257062 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220309 IS - 2468-0249 (Electronic) IS - 2468-0249 (Linking) VI - 7 IP - 3 DP - 2022 Mar TI - Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1. PG - 494-506 LID - 10.1016/j.ekir.2021.12.001 [doi] AB - 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). CONCLUSION: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes. CI - (c) 2022 International Society of Nephrology. Published by Elsevier Inc. FAU - Hulton, Sally A AU - Hulton SA AD - Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham, UK. FAU - Groothoff, Jaap W AU - Groothoff JW AD - Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Frishberg, Yaacov AU - Frishberg Y AD - Division of Pediatric Nephrology, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Koren, Michael J AU - Koren MJ AD - Jacksonville Center for Clinical Research, Jacksonville, Florida, USA. FAU - Overcash, J Scott AU - Overcash JS AD - Velocity Clinical Research, San Diego, California, USA. FAU - Sellier-Leclerc, Anne-Laure AU - Sellier-Leclerc AL AD - Hopital Femme Mere Enfant and Centre d'Investigation Clinique Institut National de la Sante et de la Recherche Medicale, Hospices Civils de Lyon, ERKnet, Bron, France. FAU - Shasha-Lavsky, Hadas AU - Shasha-Lavsky H AD - Pediatric Nephrology Unit, Galilee Medical Center and Azrieli Faculty of Medicine, Bar-Ilan University, Nahariya, Israel. FAU - Saland, Jeffrey M AU - Saland JM AD - Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Hayes, Wesley AU - Hayes W AD - Department of Pediatric Nephrology, Great Ormond Street Hospital, London, UK. FAU - Magen, Daniella AU - Magen D AD - Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel. FAU - Moochhala, Shabbir H AU - Moochhala SH AD - UCL Department of Renal Medicine, Royal Free Hospital, London, UK. FAU - Coenen, Martin AU - Coenen M AD - Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany. FAU - Simkova, Eva AU - Simkova E AD - Al Jalila Children's Hospital, Dubai, United Arabs Emirates. FAU - Garrelfs, Sander F AU - Garrelfs SF AD - Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. FAU - Sas, David J AU - Sas DJ AD - Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA. FAU - Meliambro, Kristin A AU - Meliambro KA AD - Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Ngo, Taylor AU - Ngo T AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. FAU - Sweetser, Marianne T AU - Sweetser MT AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. FAU - Habtemariam, Bahru A AU - Habtemariam BA AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. FAU - Gansner, John M AU - Gansner JM AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. FAU - McGregor, Tracy L AU - McGregor TL AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. FAU - Lieske, John C AU - Lieske JC AD - Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA. LA - eng PT - Journal Article DEP - 20211211 PL - United States TA - Kidney Int Rep JT - Kidney international reports JID - 101684752 PMC - PMC8897294 OTO - NOTNLM OT - RNA interference OT - lumasiran OT - nephrocalcinosis OT - phase 3 clinical trial OT - primary hyperoxaluria type 1 OT - urinary oxalate EDAT- 2022/03/09 06:00 MHDA- 2022/03/09 06:01 PMCR- 2021/12/11 CRDT- 2022/03/08 05:39 PHST- 2021/11/12 00:00 [received] PHST- 2021/12/03 00:00 [accepted] PHST- 2022/03/08 05:39 [entrez] PHST- 2022/03/09 06:00 [pubmed] PHST- 2022/03/09 06:01 [medline] PHST- 2021/12/11 00:00 [pmc-release] AID - S2468-0249(21)01591-6 [pii] AID - 10.1016/j.ekir.2021.12.001 [doi] PST - epublish SO - Kidney Int Rep. 2021 Dec 11;7(3):494-506. doi: 10.1016/j.ekir.2021.12.001. eCollection 2022 Mar.