Kynamro: what was done before first-in-human, and what came after?

“In addition, on the basis of these non-clinical studies the applicant estimated an acceptable safe starting dose for humans based on the results observed.”

“As it was commented above the primary effects of mipomersen after 12 months of dosing were limited to the 30 mg/kg/week dose group and included decreases in platelet count, a decrease in total complement factor C3, as well as minimal degenerative changes Kynamro Page 26/114 and vacuolation in tubular epithelial cells in the kidney, most of which were recovered to baseline levels during a 6 month recovery period.”

“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.”

“Mipomersen was not teratogenic in mice or rabbits at doses providing modest margins of exposure (2 to 5 times) compared to humans.”

“The NOAEL for pre- and post-natal development in the rat is considered to be 7 mg/kg/week based on reduced bodyweight gain and impaired performance in the visual placing response and grip strength.”

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

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

“Two year carcinogenicity studies of mipomersen were conducted in rats and mice. The Executive Carcinogenicity Assessment Committee found the studies adequate.”