Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Bernd Hoppe, Annelize Koch, Pierre Cochat, Sander F. Garrelfs, Michelle A. Baum, Jaap W. Groothoff, Graham Lipkin, Martin Coenen, Gesa Schalk, Aniruddha Amrite, David McDougall, Kelly Barrios, Craig B. Langman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%–100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.

Original languageEnglish (US)
Pages (from-to)626-634
Number of pages9
JournalKidney international
Issue number3
StatePublished - Mar 2022


  • chronic kidney disease
  • gene expression
  • hyperoxaluria
  • pediatric nephrology
  • pharmacokinetics
  • urology

ASJC Scopus subject areas

  • Nephrology


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