Camzyos: genotox, carcinogenicity and repro: done or skipped?

“Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay.”

“There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, or in a 2-year rat study at mavacamten doses up to 0.6 mg/kg/day.”

“Mavacamten was shown to be teratogenic in both rats and rabbits in embryo-fetal developmental studies. In rats, mavacamten increased post-implantation loss, lowered mean fetal body weight, slightly reduced fetal skeletal ossification, induced heart malformations (total situs inversus), and increased the incidence of skeletal malformations relative to control.”

“In vitro and in silico electrophysiological data indicate low torsadogenic/proarrhythmogenic risk with mavacamten, as shown by the lack of an effect on hERG channel or any action potential parameters.”

“Mavacamten gave negative results in the Ames test up to the limit concentration of 5000 µg/plate and in the in vitro micronucleus assay in human lymphocytes, tested up to cytotoxic concentrations, both with and without metabolic activation.”

“Mavacamten gave negative results in the Ames test up to the limit concentration of 5000 µg/plate and in the in vitro micronucleus assay in human lymphocytes, tested up to cytotoxic concentrations, both with and without metabolic activation.”

“An in vivo bone marrow micronucleus test in rats dosed up to 8 mg/kg (MTD) for 2 consecutive days was negative.”

“There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, or in a 2-year rat study at mavacamten doses up to 0.6 mg/kg/day.”

“The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and the study is currently ongoing.”

“Minimal but statistically significant increased hERG inhibition of 5% and 9.6% in HEK293 cells was noted at 10µM and 60µM, respectively, compared to controls (1%).”