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

“Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.”

“In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC 24 at the human therapeutic dose of 45 mg, respectively.”

“In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats.”

“This translates into a 350-fold difference between human free Cmax at MRHD and IC50 value in hERG assay, indicating that no effects on the cardiovascular system with regard to ventricular repolarization and proarrhythmic risk are to be expected in humans.”

“The GLP-compliant in vitro Ames test and chromosome aberration test in human peripheral blood lymphocytes, conducted according to OECD guidelines 471 and 473, respectively, were clearly negative.”

“The GLP-compliant in vitro Ames test and chromosome aberration test in human peripheral blood lymphocytes, conducted according to OECD guidelines 471 and 473, respectively, were clearly negative.”

“There were no statistically significant increases in the percentage of micronucleated reticulocytes at any dose level in male or female animals sampled on either Day 4 or Day 30.”

“Carcinogenicity of fezolinetant was investigated in the 104-week carcinogenicity study with Wistar rats administered the test substance at the dose levels of 10, 30 and 100 mg/kg/day by oral gavage, and in the 26-week study with transgenic RasH2 mice.”

“Carcinogenicity studies were done in rats and transgenic mice. The final study reports were presented at the 10/25/22 Executive Carcinogenicity Assessment (ECAC) meeting and both studies were considered negative.”

“This translates into a 350-fold difference between human free Cmax at MRHD and IC50 value in hERG assay, indicating that no effects on the cardiovascular system with regard to ventricular repolarization and proarrhythmic risk are to be expected in humans.”