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

“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”

“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice at doses up to 1500 mg/kg/day or in rats at exposures approximately 8x and 98x the MRHD in males and female rats, respectively.”

“Remibrutinib did not affect fertility and was nonteratogenic in rats. In rabbits, remibrutinib treatment resulted in maternal toxicity and adverse developmental outcomes at doses ≥300 mg/kg/day. In the rat pre- and postnatal development study, remibrutinib treatment resulted in increased number of stillborn pups, dead pups, and a smaller litter size at 1000 mg/kg/day.”

“The GLP study indicated hERG inhibition at concentration which was over 230-fold higher than the unbound clinical Cmax, providing a wide safety margin. In a GLP single-dose dog study, remibrutinib was well tolerated at high doses with no adverse cardiovascular effects or mortality.”