Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3

Introduction Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is a ribonucleic acid interference therapeutic FDA-approved for treatment of PH1. PHYOX3 is 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 prior kidney/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), respectively, 53.8% were female, and 61.5% were White. Mean estimated glomerular filtration rate remained stable (62–84.2mL/min/1.73m2) 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/24 hours; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to <0.60 mmol/24 hours; ≥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. Conclusions 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 were identified to date. The PHYOX3 study is ongoing.