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

“Xanomeline was not mutagenic or clastogenic in a battery of genetic toxicity tests. These tests included in vitro bacterial reverse mutation (Ames), mouse lymphoma TK, unscheduled DNA synthesis in rat hepatocytes, in vitro chromosome aberration in mammalian (CHO) cells and in vivo bone marrow micronucleus assay in mice.”

“Xanomeline did not increase the incidence of tumors in rats treated for 2 years via the diet at doses up to 37 mg/kg/day in males and 46/mg/kg/day in females, respectively, which is slightly higher than the xanomeline dose at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on body surface area (BSA).”

“At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.”

“Although xanomeline dose dependently inhibited the hERG channel (IC50=70nM), no abnormal cardiac rhythm or QTc prolongation was observed in qualitative ECG evaluation or post hoc analysis of the ECG tracing data in monkey studies at xanomeline concentrations up to 12 times the clinical Cmax.”