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

“Selumetinib was not mutagenic or clastogenic in vitro . Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ).”

“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”

“In embryo-fetal development studies in mice at doses > 2.5 mg/kg twice daily (~5-times the human exposure based on area under the curve [AUC] at the clinical dose of 25 mg/m 2 twice daily), selumetinib caused increases in post-implantation loss, a reduction in mean fetal and litter weights, and an increased occurrence of open eye and cleft palate”

“At doses of up to 100 mg/kg selumetinib had no remarkable effects on open field behavior or respiratory parameters in Sprague-Dawley rats. In a cardiovascular safety study in Gottingen minipigs, oral administration of selumetinib twice daily had no remarkable effects on electrocardiograms or circulatory function”

“but negative in both the presence and absence of metabolic activation for mutagenicity in the in vitro Ames Assay and for chromosomal aberrations in the in vitro mammalian cell gene mutation assay using the L5178Y/TK+/- mouse lymphoma cells.”

“but negative in both the presence and absence of metabolic activation for mutagenicity in the in vitro Ames Assay and for chromosomal aberrations in the in vitro mammalian cell gene mutation assay using the L5178Y/TK+/- mouse lymphoma cells.”

“Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human C max at the clinical dose of 25 mg/m 2 ).”

“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”

“The Applicant’s Position: Selumetinib showed no evidence of carcinogenicity in 6-month CByB6F1/Tg rasH2 transgenic mouse and 2-year Han Wistar rat studies.”

“In the hERG assay, selumetinib was evaluated in stably transfected HEK293 cells at concentrations of 0.1, 0.3, 1 and 3 and 10 µM, which produced no concentration-dependent inhibition of hERG tail current. This maximum test concentration was 390-fold greater than the unbound plasma Cmax of selumetinib”