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

“Revumenib was tested in GLP in vitro bacterial reverse mutation and mammalian cell micronucleus assays and an in vivo micronucleus assay in Sprague Dawley rats. There were no revumenib-related genotoxic effects in vitro or in vivo.”

“Carcinogenicity studies were not warranted for the proposed indication.”

“There was a dose-dependent increase in the number of resorptions (including total litter resorption at 300 mg/kg/day), post-implantation loss, and malformations at all revumenib doses, suggesting potential fetal toxicity at exposures 0.6 times the human exposure (AUC) at the recommended dose of 270 mg twice daily.”

“The IC50 values for hERG inhibition were 4.75 and 3.46 µM for revumenib and M1, respectively, and suggest that M1 contributes to the effects of hERG inhibition. Increased QTc interval duration and premature atrial contractions were seen after repeated dosing with 225 mg/kg/day in dogs.”

“Key findings: No toxicity or precipitate was observed, and no positive mutagenic responses were observed in any tester strains with or without S9 mix.”

“Revumenib was tested in GLP in vitro bacterial reverse mutation and mammalian cell micronucleus assays and an in vivo micronucleus assay in Sprague Dawley rats. There were no revumenib-related genotoxic effects in vitro or in vivo.”

“Administration of revumenib by once daily oral gavage to Sprague Dawley rats at dose levels of 100, 200, and 400 mg/kg/day for 2 consecutive days resulted in a negative response for induction of micronuclei in young erythrocytes (ie, reticulocytes) in peripheral blood in males and females at all dose levels.”

“Carcinogenicity studies have not been conducted with revumenib. In a repeat dose toxicity study in rats treated with revumenib for 13 weeks, lymphoma was observed in multiple organs”

“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”

“The IC50 values for hERG inhibition were 4.75 and 3.46 µM for revumenib and M1, respectively, and suggest that M1 contributes to the effects of hERG inhibition. Increased QTc interval duration and premature atrial contractions were seen after repeated dosing with 225 mg/kg/day in dogs.”