Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3
Groothoff, Jaap Sellier-Leclerc, Anne-Laure Deesker, Lisa Bacchetta, Justine Schalk, Gesa Tönshoff, Burkhard Lipkin, Graham Lemoine, Sandrine Bowman, Thomas Zhou, Jing
Groothoff, Jaap
Sellier-Leclerc, Anne-Laure
Deesker, Lisa
Bacchetta, Justine
Schalk, Gesa
Tönshoff, Burkhard
Lipkin, Graham
Lemoine, Sandrine
Bowman, Thomas
Zhou, Jing
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2024-03-04
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Abstract
Introduction: Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH.
Methods: In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months.
Results: Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m2) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of ≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to <0.60 mmol/24h; ≥ULN to <1.3 × ULN) 24-hour Uox excretion. All participants experienced ≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs.
Conclusion: Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing.
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Groothoff J, Sellier-Leclerc AL, Deesker L, Bacchetta J, Schalk G, Tönshoff B, Lipkin G, Lemoine S, Bowman T, Zhou J, Hoppe B. Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3. Kidney Int Rep. 2024 Mar 4;9(5):1387-1396. doi: 10.1016/j.ekir.2024.02.1439.
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