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.”

“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.”

“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).”

“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.”

“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.”

“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.”

“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.”

“Conclusion was mipomersen was negative in hERG assay.”

“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.”

“In the mouse, there was no evidence of antigenicity. In the 54 tested monkeys, the majority of samples tested were negative for anti-mipomersen Ab. Potentially positive responses were observed in 5 monkeys, but these occurred randomly across dose groups, at scattered time-points, and were not dose-dependent.”

“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.”

“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 (clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).”

“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”

“Nonclinical pharmacology studies with these apoB antisense inhibitors have shown rapid reduction of hepatic apoB mRNA and protein, and reductions in serum apoB, LDL-C and total-C in mouse, hamster, rabbit and monkey models.”

“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.”

“These studies provide proof-of-concept support for the utility of targeting apoB100 using antisense molecules.”