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

“Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.”

“Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day”

“In the dose-range finding embryo-foetal development studies, embryofoetal lethality was observed from the non-maternotoxic dose levels of 0.64 and 0.3 mg/kg/day in rats and rabbits, respectively.”

“Mirdametinib at 100 µM reduced significantly the mean hERG current amplitude by 39.5% (IC50 >100 µM).”

“Mirdametinib was negative in an in vitro bacterial reverse mutation test (Ames assay) and an in vitro human lymphocyte chromosomal aberration assay.”

“Mirdametinib was negative in an in vitro bacterial reverse mutation test (Ames assay) and an in vitro human lymphocyte chromosomal aberration assay.”

“Considering the totality of the data from both in vivo genotoxicity studies, the FDA has determined mirdametinib to be positive for aneugenicity.”

“In a 6- month carcinogenicity study in CByB6F1/Tg rasH2 hemizygous mice, the FDA concluded that no carcinogenic effect related to mirdametinib administration was observed at any dose level tested (up to 5 mg/kg/day).”

“The Applicant is currently conducting a 2-year carcinogenicity study in rats and a post-marketing requirement (PMR) will be issued for the submission of the final study report.”

“Mirdametinib at 100 µM reduced significantly the mean hERG current amplitude by 39.5% (IC50 >100 µM). No significant effect was observed at 10 µM (12000-fold greater than the unbound plasma Cmax at the intended dose).”