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

“In genetic toxicology studies, siponimod was negative in the in vitro reverse mutation assay in bacterial cell (Ames) and mammalian cell assays and in in vivo clastogenicity assays (micronucleus) in mouse and rat.”

“The carcinogenicity study in mouse was adequate and positive for malignant lymphoma in F at all doses and for hemangiosarcoma and combined hemangioma and hemangiosarcoma in M and F at all doses. The carcinogenicity study in rat was adequate and positive for thyroid follicular cell adenoma and combined follicular cell adenoma and carcinoma in HDM.”

“In the reproductive and development studies, oral siponimod was teratogenic in rats and lethal to fetuses in both rats and rabbits, without a clear NOAEL for fetal toxicity in rats (<1 mg/kg/day) and a NOAEL of 0.1 mg/kg/day in rabbit.”

“In cardiovascular safety pharmacology studies, oral siponimod acutely decreased heart rate and caused second-degree AV block in guinea pigs and monkeys, and decreased blood pressure in guinea pigs, with NOAELs of <0.03 mg/kg in guinea pigs and 60 mg/kg in monkeys.”