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

“Despite a transient positive chromosomal aberration result at precipitating concentrations in vitro, the overall evidence strongly indicates that tovorafenib lacks clinically relevant genotoxic potential, a conclusion reinforced by negative in vivo micronucleus testing.”

“Tovorafenib was not carcinogenic in the 6-month study in transgenic rasH2 mice that received oral doses up to 100 mg/kg/day.”

“In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses.”

“Both evidenced a dose-dependent increase in HR due to tovorafenib treatment, QT shortening and increase in SAP and MAP.”

“Tovorafenib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay.”

“Tovorafenib induced chromosomal aberrations in cultured human lymphocytes with metabolic activation at a single concentration in vitro.”

“Tovorafenib was not genotoxic in an in vivo rat bone marrow micronucleus assay.”

“In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks. It was concluded that tovorafenib was well tolerated at all doses with no effects on carcinogenicity, survival rate, or adverse findings.”

“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”

“In vitro testing revealed potential for hERG inhibition by tovorafenib with an IC50 of 8.9 µM, resulting in an exposure margin of 32-fold compared to unbound clinical Cmax in adult of 0.280 µM.”