Safety, Pharmacokinetics, and Exposure–Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease

Abstract

AbstractNedosiran is an investigational RNA‐interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non‐PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure–response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open‐label, single‐dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30 mL/min/1.73 m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10 participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2; Group 3) received a single dose of subcutaneous nedosiran sodium 170 mg. Group 1a received nedosiran 8 hours before beginning hemodialysis, Group 1b received nedosiran 2 hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic–pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non‐PH participants with CKD Stages 4/5 was approximately 2‐fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24‐hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.