Kynamro

“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.”

“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.”

“A 13-Week Toxicity Study and Pharmacokinetic Study of ISIS 301012 Administered by Intravenous Infusion or Subcutaneous Injection to Cynomolgus Monkeys, with a 13-Week Recovery Period”

“Mipomersen sodium did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using a mouse lymphoma cell line, and an in vivo micronucleus assay in mice.”

“The Committee concluded that hepatocellular adenomas and combined hepatocellular adenomas or carcinomas were drug-related in female mice administered 60 mg/kg/week mipomersen.”

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

“Heart rate, mean arterial pressure and EKG were evaluated by telemetry in monkeys after single and repeat doses of 3 to 35 mg/kg/wk for 13 weeks (Study AS02).”

“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.”

“In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week”

“Complement activation was apparent in monkeys at SC doses of > 20 mg/kg (~7x clinical exposure) and at intravenous (IV) doses as low as 12 mg/kg, as evidenced by transient rises in the level of the complement factor B split product, Bb, and the depletion of complement factor C3 with repeated dosing.”

“The organs showing the highest tissue levels in all species are kidney, liver, spleen, lymph nodes and bone marrow, with the kidney and liver showing the highest concentrations. Little to no drug distributes to skeletal muscle, eye or the brain.”

“The major findings observed in repeat-dose toxicity studies were similar to the toxicity profile previously observed with other antisense oligodeoxynucleotides: poor local tolerance, increased coagulation time, complement activation, haematotoxicity, stimulation of the immune system, and uptake of the test article in kidney and liver with subsequent lesions.”