Kynamro: which tox species, and why?

“Mipomersen toxicity has been assessed primarily in the mouse, rat and monkey, with studies of up to 2-years duration (carcinogenicity studies) available for evaluation in the rodents and up to 1-year for the monkey.”

“Species-specific differences in the nucleotide sequence of apoB mRNA caused a reduction (monkey) or complete loss (mouse, rat, dog and rabbit) of the intended pharmacological activity of mipomersen in these species.”

“For this reason, most pharmacology studies have been conducted with surrogate molecules that optimize base pairing between the ASO and the species-specific apoB target mRNA. Pivotal toxicology studies in rodents have also included an arm with the species-specific surrogate.”

“Repeat-dose toxicity studies with mipomersen were performed using a subcutaneous injection for time intervals of 3 and 6 months in mice, 13 weeks and 5 months in rats, and 5 weeks, 13 weeks, and 12 months in cynomolgus monkeys.”

“The toxicology programme of mipomersen includes repeat dose studies in mouse, rat and monkey, in vitro and in vivo genotoxicity studies, reproductive and developmental studies in mouse, rat and rabbit, carcinogenicity studies in mouse and rat, and special toxicity studies such as immunotoxicity in mouse and juvenile toxicology in rat.”

“2-year carcinogenicity studies were conducted in both the mouse and the rat with mipomersen and the relevant species-specific surrogate.”

“For this reason, most pharmacology studies have been conducted with surrogate molecules that optimize base pairing between the ASO and the species-specific apoB target mRNA. Pivotal toxicology studies in rodents have also included an arm with the species-specific surrogate.”