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

“Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.”

“Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors.”

“There were no effects on fertility in male or female animals dosed with ozanimod. Embryolethality and developmental effects (e.g., incomplete skeletal ossification, malpositioned vertebrae, malformed or absent arteries, anasarca, malpositioned testes, and cleft palate) occurred in pregnant rats and/or rabbits exposed to ozanimod and its metabolites during gestation.”

“Cardiovascular: In a GLP in vitro hERG assay, ozanimod and the major human metabolite, CC112273, were determined to be potent hERG inhibitors (IC50 of 0.2 and 0.6 µM, respectively; 100503.SJD, 170531.SFD).”

“Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC112273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays.”

“Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay.”

“Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays.”

“Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors.”

“Adequate coverage for ozanimod and the three major metabolites was achieved in the 6-month carcinogenicity study conducted in mouse. In the 2-year carcinogenicity study conducted in rat, adequate exposure (> 50% exposure at the MRHD) to the parent, RP101124, and CC112273 was achieved”

“potent hERG inhibitors in vitro (ICso of 0.2 and 0.6 µM, respectively), but QTc prolongation was not observed in monkeys dosed with ozanimod.”