PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1

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).

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.

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.

Nedosiran was well-tolerated, reduced average Uox levels, reduced kidney stone occurrence, and maintained stable renal function for over 3 years.