Tegsedi: which tox species, and why?

“Inotersen is pharmacologically active in cynomolgus monkey but not rodent or rabbit.”

“The target sequence of inotersen is conserved between monkeys and humans, but contains 8 mismatches in rodents and 4 mismatches in rabbits.”

“For this reason, mouse- and rat-specific analogues of inotersen were included in the toxicology evaluations in order to distinguish toxicity associated with reduction of the target (TTR) from toxicities related to the chemistry of the oligonucleotide”

“The toxicity of repeated s.c. injections of inotersen was investigated for up to 26 weeks in mice and rats and for up to 39 weeks in monkeys using comparable drug substance as tested in the clinical program.”

“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”

“No carcinogenic potential was identified in a short-term carcinogenicity study in transgenic rasH2 mice. A 2 year carcinogenicity study in rats is currently ongoing and results will be submitted post approval.”

“For this reason, mouse- and rat-specific analogues of inotersen were included in the toxicology evaluations in order to distinguish toxicity associated with reduction of the target (TTR) from toxicities related to the chemistry of the oligonucleotide”