Waylivra: which tox species, and why?

“Monkey is considered the most relevant species to humans based on the general pharmacokinetic behavior of 2’-MOE ASOs (plasma AUC, Cmax, and clearance).”

“While monkeys share the same sequence at this site, due to a lack of sequence homology in other species, different 2′-MOE ASOs”

“Because of the divergence between the mouse, hamster and human apoC-III sequences, species-specific ASOs were employed in their respective in vivo evaluations.”

“Formal studies evaluating local tolerance were not conducted however the injection sites were evaluated as part of the repeat-dose studies in mice, rats and monkeys which did not reveal any evidence of substantive irritation.”

“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”

“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”

“An assessment of pre- and postnatal toxicity was performed using subcutaneous administration of volanesorsen or the murine-specific apoC-III inhibitor (ISIS 440670) on alternate days to pregnant female mice at doses up to 87.5 mg/kg/wk from Day 6 of gestation to Day 21 postpartum.”