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

“RIS was negative for mutagenicity in an in vitro Ames test but positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells and in vivo in a combined bone marrow micronucleus and comet assay in rat.”

“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day”

“Embryofetal mortality (increased number of late resorptions) and increased incidences of fetal malformations (hydrocephaly) and variations were seen in the rabbit embryofetal development study at the HD (12 mg/kg), which was also maternally toxic.”

“In safety pharmacology studies, RIS concentrations up to 5 mM (said to correspond to ~18000 ng/mL total plasma concentration in human) produced no significant reduction in the outward K+ current in CHO cells expressing recombinant hERG K+ channels. In cynomolgus monkeys, administration of single oral doses up to 7.5 mg/kg had no effects on hemodynamic or ECG parameters at up to 24 hours postdose.”