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.”

“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”

“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”

“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”

“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”

“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”

“Xanomeline did not cause QTc prolongation. 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.”