Ekterly: what flexibility did regulators accept, and why?

“According to ICHS1, selection of high dose for carcinogenicity study should be based on a 50-fold exposure ratio (AUC) in TgrasH2 mice and 25-fold for the 2-year rat study. While the dose range chosen in the carcinogenicity studies performed can be acceptable, it cannot be excluded with absolute certainty a lack of carcinogenic potential, as the 50-fold and 25-fold exposure ratio are not met.”

“In the absence of significant increase in the incidence of any malignant tumours, the high dose can be used to calculate safety margins for malignant tumours formation. Safety margins of 5.7 would be obtained based on unbound AUC.”

“Per ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010), toxicology studies of 6 months’ duration in nonrodents are considered acceptable for products developed as chronic intermittent treatments for indications such as hereditary angioedema.”

“Regarding species selection, rabbits cannot be considered as pharmacologically active species since PD data showed IC50 values higher than 40,000 nM regarding inhibition of rabbit plasma kallikrein enzyme (in other words, fold to human Ki was 12.3 and >6623 for rat and rabbit, respectively). However, according to ICH S5, this can still be accepted since PD effect was clearly confirmed in rats.”