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

“Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Futibatinib was clastogenic in an in vitro chromosomal aberration assay after a 6 hour treatment. Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (comet) assay.”

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

“Fetal survival was unaffected at 0.5 mg/kg per day; however, once daily oral administration of futibatinib at the 0.5 mg/kg dose level (approximately 0.2 times the recommended clinical dose of 20 mg based on BSA) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.”

“Futibatinib had no toxicologically significant effects on cardiovascular function in telemetered dogs or on neurobehavioral and respiratory functions in rats.”

“Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.”

“Futibatinib was clastogenic in an in vitro chromosomal aberration assay.”

“Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (Comet) assay.”

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

“The FDA’s Assessment: Carcinogenicity studies are not recommended for the proposed indication.”

“Futibatinib inhibited hERG current (Study No. 8215) but at concentrations that were much higher (IC50 value: 3105 ng/mL) than the Cmax observed at a severely toxic dose (531 ng/mL) in dogs and the peak exposure in humans at the recommended clinical dose of futibatinib (20 mg QD ).”