Kygevvi: what flexibility did regulators accept, and why?

“The Applicant submitted a weight-of-evidence assessment in lieu of a 2-year rat carcinogenicity study. The Agency agreed with the Applicant’s weight-of-evidence assessment that a 2-year rat carcinogenicity study would not add value”

“Provided the endogenous nature of the compounds, up to 10 years clinical experience of the use of the compounds, and that no evidence of tumorigenicity observed in the 26-week toxicity study in juvenile rats and in the 13-week toxicity study in dogs, it is agreed that the potential for doxecitine and doxribtimine to cause carcinogenicity is low and a two-year carcinogenicity study can be waived.”

“The Applicant did not conduct a 9-month dog toxicity study, carcinogenicity studies, and a rat PPND study with doxecitine and doxribtimine.”

“The Agency also confirmed that the 39-week repeat-dose toxicity study in dogs could be conducted as a PMR.”

“Based on the negative findings in the EFD and juvenile toxicity studies in rats at high exposure margins, a rat PPND study is considered unwarranted.”

“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine.”

“The exposure margin of these toxicology studies were at least 25-fold higher than human exposure based on baseline-adjusted AUC0-24. The safety pharmacology is considered sufficiently addressed.”

“This exposure level represents approximately -fold exceedance of the 1.5 μg TTC for genotoxic impurities established in ICH M7(R2) guidance.”

“Postmarket assessments will be required to characterize the mutagenic and clastogenic potential of alpha-hydroxythymidine in the presence of doxecitine and doxribtimine.”