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

“In the standard genotoxicity battery, selpercatinib was negative in both the Ames and the in vitro micronucleus assay regardless of metabolic activation. In the in vivo micronucleus assay in rats, selpercatinib did cause increases in micronuclei at high dose levels”

“not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”

“Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.”

“LOXO-292 inhibited the hERG potassium current with IC50 of 1.1 μM in the GLP in vitro hERG assay studies, respectively, suggesting low potential for QTc prolongation. In the 28-day minipig study, statistically significant QT prolongation was observed in females administered 5 and 12 mg/kg LOXO-292 when compared to controls”

“Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation.”

“Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation.”

“Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the C max at the human dose of 160 mg twice daily.”

“Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”

“however, as the MTC indication includes patients who can have a prolonged life expectancy, FDA has requested carcinogenicity studies for selpercatinib as postmarketing requirements (PMRs).”

“Though hERG potassium current assays demonstrated low potential for LOXO-292 to cause QTc prolongation, with IC50s of 1.1 or 2.79 μM, respectively, female mini pigs in the 4-week study that received 5 or 12 mg/kg selpercatinib for 28 days had statistically significant QT prolongation compared to controls.”