Onpattro: which tox species, and why?

“As a consequence, general toxicology studies have been performed in cynomolgus monkeys (pharmacologically active) and rats (off-target).”

“Patisiran is a siRNA directed against human TTR mRNA and has cross-reactivity in the cynomolgus monkeys, but not in rat mouse or rabbit.”

“To evaluate on-target reproductive and developmental toxicities related to siRNA- mediated reduction in serum TTR concentrations (TTR reduction and associated reductions in vitamin A and thyroxine) the rodent reproductive and developmental toxicity studies included a rodent surrogate siRNA (AD-18534).”

“As a consequence, general toxicology studies have been performed in cynomolgus monkeys (pharmacologically active) and rats (off-target).”

“In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”

“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”

“To evaluate on-target reproductive and developmental toxicities related to siRNA- mediated reduction in serum TTR concentrations (TTR reduction and associated reductions in vitamin A and thyroxine) the rodent reproductive and developmental toxicity studies included a rodent surrogate siRNA (AD-18534).”