PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1
Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by oxalate overproduction in the liver, leading to hyperoxaluria, calcium oxalate stones, nephrocalcinosis, progressive chronic kidney damage, kidney failure, and systemic oxalate deposition. Nedosiran, an RNA i...
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Elsevier
2025-06-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024925001743 |
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| author | John C. Lieske Gema Ariceta Jaap W. Groothoff Graham Lipkin Shabbir H. Moochhala Gesa Schalk Anne-Laure Sellier-Leclerc Sara Estupiñan Torres Verity Rawson Jing Zhou Bernd Hoppe |
| author_facet | John C. Lieske Gema Ariceta Jaap W. Groothoff Graham Lipkin Shabbir H. Moochhala Gesa Schalk Anne-Laure Sellier-Leclerc Sara Estupiñan Torres Verity Rawson Jing Zhou Bernd Hoppe |
| author_sort | John C. Lieske |
| collection | DOAJ |
| description | Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by oxalate overproduction in the liver, leading to hyperoxaluria, calcium oxalate stones, nephrocalcinosis, progressive chronic kidney damage, kidney failure, and systemic oxalate deposition. Nedosiran, an RNA interference therapy against lactate dehydrogenase subunit A mRNA, has been approved in the USA for treating patients with PH1 who are aged ≥ 9 years and have an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2. PHYOX3 (NCT04042402) is an open-label extension trial evaluating the long-term safety and efficacy of once-monthly nedosiran in patients with primary hyperoxaluria (PH). Methods: This PHYOX3 interim analysis includes 40 participants with PH1 from PHYOX1 (NCT03392896; n = 13) and PHYOX2 (NCT03847909; n = 27) trials. Efficacy was assessed using eGFR, urinary oxalate (Uox) excretion, and clinical outcomes. Safety and efficacy of nedosiran were assessed up to 42 months. Results: At baseline, mean (SD) age was 24.9 (9.7) years (55% females; 42.5% White), mean (SD) eGFR was 80.0 (28.6) ml/min per 1.73 m2, and median number of kidney stone events (KSEs) was 3.0. The mean eGFR range throughout the study was 71.1 to 81.5 ml/min per 1.73 m2, and mean 24-hour Uox excretion declined by ˃ 60%, maintained from month 4 to month 42. Annualized stone event rate decreased from 0.40 at baseline to 0.20 (22 events/108.8 person-years). Eight participants experienced ≥ 1 serious adverse events (AEs), none associated with nedosiran. The most common nonserious treatment-related AEs were injection site reactions (6 participants; 15%). Four participants discontinued treatments (1 pregnancy and 3 withdrawals), and no deaths were reported. Conclusion: Nedosiran was well-tolerated, reduced average Uox levels, reduced kidney stone occurrence, and maintained stable renal function for over 3 years. |
| format | Article |
| id | doaj-art-659aa6c19c224f809eb4c4950472c2f2 |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| spelling | doaj-art-659aa6c19c224f809eb4c4950472c2f22025-08-20T03:46:58ZengElsevierKidney International Reports2468-02492025-06-011061993200210.1016/j.ekir.2025.03.031PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1John C. Lieske0Gema Ariceta1Jaap W. Groothoff2Graham Lipkin3Shabbir H. Moochhala4Gesa Schalk5Anne-Laure Sellier-Leclerc6Sara Estupiñan Torres7Verity Rawson8Jing Zhou9Bernd Hoppe10Mayo Clinic, Rochester, Minnesota, USA; Correspondence: John C. Lieske, Mayo Clinic-Rochester, 200 1st St Sw, Rochester, Minnesota 55905-0002, USA.Pediatric Nephrology. Hospital Vall d’Hebron. University Autonomous Barcelona, Barcelona, SpainDepartment of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The NetherlandsUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UKUCL Department of Renal Medicine, Royal Free Hospital, London, UKKindernierenzentrum Bonn, GermanyService de Néphrologie Rhumatologie et Dermatologie Pédiatriques, Centre de Référence Des Maladies Rénales Rares Néphrogones Filières Maladies Rares ORKID et ERK-Net, Hospices Civils de Lyon, Lyon, Bron, FranceNephrology Department, Complejo Hospitalario Universitario de Canarias, La Laguna, Tenerife, SpainNovo Nordisk A/S, Lexington, Massachusetts, USANovo Nordisk A/S, Lexington, Massachusetts, USAGerman Hyperoxaluria Center, Bonn, GermanyIntroduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by oxalate overproduction in the liver, leading to hyperoxaluria, calcium oxalate stones, nephrocalcinosis, progressive chronic kidney damage, kidney failure, and systemic oxalate deposition. Nedosiran, an RNA interference therapy against lactate dehydrogenase subunit A mRNA, has been approved in the USA for treating patients with PH1 who are aged ≥ 9 years and have an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2. PHYOX3 (NCT04042402) is an open-label extension trial evaluating the long-term safety and efficacy of once-monthly nedosiran in patients with primary hyperoxaluria (PH). Methods: This PHYOX3 interim analysis includes 40 participants with PH1 from PHYOX1 (NCT03392896; n = 13) and PHYOX2 (NCT03847909; n = 27) trials. Efficacy was assessed using eGFR, urinary oxalate (Uox) excretion, and clinical outcomes. Safety and efficacy of nedosiran were assessed up to 42 months. Results: At baseline, mean (SD) age was 24.9 (9.7) years (55% females; 42.5% White), mean (SD) eGFR was 80.0 (28.6) ml/min per 1.73 m2, and median number of kidney stone events (KSEs) was 3.0. The mean eGFR range throughout the study was 71.1 to 81.5 ml/min per 1.73 m2, and mean 24-hour Uox excretion declined by ˃ 60%, maintained from month 4 to month 42. Annualized stone event rate decreased from 0.40 at baseline to 0.20 (22 events/108.8 person-years). Eight participants experienced ≥ 1 serious adverse events (AEs), none associated with nedosiran. The most common nonserious treatment-related AEs were injection site reactions (6 participants; 15%). Four participants discontinued treatments (1 pregnancy and 3 withdrawals), and no deaths were reported. Conclusion: Nedosiran was well-tolerated, reduced average Uox levels, reduced kidney stone occurrence, and maintained stable renal function for over 3 years.http://www.sciencedirect.com/science/article/pii/S2468024925001743eGFRkidney stoneslong-term treatmentprimary hyperoxaluriaurinary oxalate |
| spellingShingle | John C. Lieske Gema Ariceta Jaap W. Groothoff Graham Lipkin Shabbir H. Moochhala Gesa Schalk Anne-Laure Sellier-Leclerc Sara Estupiñan Torres Verity Rawson Jing Zhou Bernd Hoppe PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 Kidney International Reports eGFR kidney stones long-term treatment primary hyperoxaluria urinary oxalate |
| title | PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 |
| title_full | PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 |
| title_fullStr | PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 |
| title_full_unstemmed | PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 |
| title_short | PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1 |
| title_sort | phyox3 nedosiran long term safety and efficacy in patients with primary hyperoxaluria type 1 |
| topic | eGFR kidney stones long-term treatment primary hyperoxaluria urinary oxalate |
| url | http://www.sciencedirect.com/science/article/pii/S2468024925001743 |
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