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

“Doxecitine and doxribtimine were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vivo rat micronucleus assay. However, doxecitine and doxribtimine induced a statistically significant, dose-dependent increase in chromosomal aberrations in human peripheral blood lymphocytes in the absence of metabolic activation.”

“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”

“In embryofetal development studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal toxicity (decreased body weight gain and food consumption) and fetal malformations (dilated aorta with narrow pulmonary trunk) in the rabbit at 2000 mg/kg/day.”

“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine. In the 13-week toxicity study in dogs, cardiovascular endpoints were evaluated.”