Revusiran sodium

Cynomolgus monkeys (2-3 years old; sexually mature 5-6 years old for 39-week study; male for safety pharmacology and acute toxicity)^[1]

10 mg/kg, 30 mg/kg, 100 mg/kg (Safety pharmacology); 300 mg/kg (Acute toxicity); 30 mg/kg, 100 mg/kg, 300 mg/kg (6-week repeat-dose); 15 mg/kg, 75 mg/kg, 200 mg/kg (39-week repeat-dose)

s.c. (single doses on separate days, Safety pharmacology); s.c. (single dose, Acute toxicity); s.c. (5 consecutive daily doses then 5 weekly doses, 6-week repeat-dose); s.c. (5 consecutive daily doses then 39 weekly doses, 39-week repeat-dose)

Showed no effects on cardiovascular or respiratory function at doses up to 100 mg/kg; no neurological abnormalities in repeat-dose studies at doses up to 300 mg/kg.
Reduced serum TTR by 80% relative to baseline on day 8 and 90% on day 15 at 300 mg/kg acute dose; no changes in complement split products or plasma cytokines.
Reduced serum TTR by ≥95% from baseline by day 15, maintained throughout dosing, with partial recovery at 30 and 100 mg/kg, or sustained reduction at 300 mg/kg post-recovery in 6-week repeat-dose studies; reduced vitamin A by 88%-93% from baseline, and thyroxine by 26%-50% from baseline at end of dosing, with partial/full recovery post-recovery; caused reversible elevations in ALP and minimal, partially recoverable microscopic findings at ≥100 mg/kg.
Reduced serum TTR by ≤98% from baseline, vitamin A by ≤95% from baseline, and thyroxine by ≤36% from baseline, with full recovery post-recovery in 39-week repeat-dose studies; caused reversible elevations in ALP, 27% reduction in mean body weight in high-dose males, and full/partially recoverable microscopic/ultrastructural findings at ≥15 mg/kg; no mitochondrial changes observed.