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

“Vorasidenib and its major circulating metabolite, AGI-69460, were negative for genotoxicity in a full battery of tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay in human lymphocytes, a chromosomal aberration assay, and an in vivo bone marrow micronucleus assay in rats.”

“Two post-marketing requirements (PMRs) to conduct carcinogenicity studies in mice and rats were communicated to the Applicant.”

“Embryo-fetal toxicity (higher incidence of early resorptions, and visceral malformations of kidney and testes) occurred in rats at the maternally toxic dose of 75 mg/kg/day (approximately 170 times the human exposure based on the AUC at the highest recommended dose).”

“Safety pharmacology assessments conducted in the repeat-dose general toxicity studies resulted in marginal prolongation of the corrected QT interval (QTc) of 32 msec in a single male monkey administered the non-tolerable dose of 40 mg/kg/day.”