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

“Zongertinib was negative for genotoxicity in the following studies: an in vitro bacterial reverse mutation (Ames) assay in the presence or absence of microsomal (S9) mix, and an in vivo peripheral blood micronucleus test coupled with comet assays conducted in hepatic and duodenal tissue isolated from male rats”

“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”

“Zongertinib caused delayed development of the urinary system and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose).”

“Zongertinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 11.41 µM in a safety pharmacology assessment, which is approximately 380-fold higher than the human free steady-state Cmax of 30 nM. Additional cardiovascular safety pharmacology assessments did not reveal cardiovascular toxicity in telemetered conscious dogs”

“To clarify, under the conditions of the Ames assay (Study # n00282239), zongertinib did not induce concentration-dependent increases in revertants in vitro.”

“Zongertinib did not induce dose-dependent increases in micronuclei or increases in the Comet tail intensity (a measure of DNA damage) in liver or duodenum tissue in male rats under the condition of the assay.”

“Consistent with the principles discussed in the ICH S9 guidance, carcinogenicity studies are not expected for development of a drug intended for the treatment of patients with advanced cancer.”

“FDA agrees that carcinogenicity studies are not warranted to support the use of zongertinib in the currently proposed indication per ICH S9.”

“Zongertinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 11.41 µM in a safety pharmacology assessment, which is approximately 380-fold higher than the human free steady-state Cmax of 30 nM.”