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

“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.”

“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”

“In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg”

“Repotrectinib had no toxicologically significant effects on cardiovascular function in vivo in monkeys or in vitro on hERG, hNaV1.5, or hCaV1.2 channels. Repotrectinib had no effect on respiratory function rats and monkeys.”

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

“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action.”

“In vivo, repotrectinib was positive for genotoxicity in male rats for micronucleated polychromatic erythrocytes (PCEs) in bone marrow at doses ≥500 mg/kg.”

“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”

“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”

“Cmax of unbound repotrectinib was calculated by the FDA clinical and nonclinical team to be 0.092 µM, thus the 18 µM IC50 for hERG channel inhibition corresponds to a 196-fold multiple.”