Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4)

David S. Goldfarb, John C. Lieske, Jaap Groothoff, Gesa Schalk, Kerry Russell, Shuli Yu, Blaz Vrhnjak

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)–conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near‐normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.

Original languageEnglish
Article number80
JournalUrolithiasis
Volume51
Issue number1
DOIs
Publication statusPublished - 1 Dec 2023

Keywords

  • Chronic kidney impairment
  • Gene expression
  • Hyperoxaluria
  • Kidney calculi
  • Nephrolithiasis
  • Nephrology
  • RNAi
  • Urology

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