Abstract
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.
Highlights
In patients with PH1 or PH2, PD consistent with the nedosiran mechanism of action was observed as a trend in dose-related reductions of 24-hour urinary oxalate (Uox) excretion coincident with dose-related increases in nedosiran systemic exposure
Because oxalate is primarily produced by hepatic lactate dehydrogenase (LDH) activity,[20,21,22,23,24,25] these findings are consistent with nonclinical data showing that nedosiran reaches hepatocytes, where it inhibits LDHA mRNA and LDH enzymatic activity.[13]
The marked reduction in 24-hour Uox excretion following nedosiran administration in patients with PH1 or PH2 was observed throughout the study duration
Summary
Primary hyperoxaluria (PH) represents a family of ultrarare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by overproduction of oxalate, a metabolic end product eliminated almost exclusively by the kidneys.[1,2] In PH, excessive urinary oxalate (Uox) excretion engenders calcium oxalate precipitation, leading to nephrocalcinosis, recurrent urolithiasis, and kidney damage.[1,2,3] Progression to kidney failure occurs over months to years and may be associated with systemic oxalosis and multiple organ failure.[1,2,4,5,6,7,8,9]. Novel therapeutic strategies focus on RNA interference (RNAi) to decrease the levels of enzymes involved in the glyoxylate metabolic pathway and so reduce oxalate production. One such RNAi therapeutic, lumasiran (Alnylam Pharmaceuticals, Inc.), depletes an enzyme (hydroxyacid oxidase 1) responsible for glyoxylate synthesis.[19] Because of its mechanism of action, lumasiran is only approved for use in patients with PH1. The PK and PD data obtained from this study were used in modeling and simulations to select a dose and dosing regimen for future clinical studies
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