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

“Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats.”

“Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC).”

“There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC).”

“A cardiovascular safety assessment of danicopan was conducted in conscious telemetry-instrumented male beagle dogs after single oral (gavage) doses up to 500 mg/kg and no effects on hemodynamic or electrocardiogram endpoints were observed for up to 24 hrs postdosing (ACH-15-072, GLP-compliant).”

“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”

“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”

“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”

“Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC).”

“Danicopan was not carcinogenic at any dose assessed in WH rats and hemizygous TgRasH2 mice.”

“An IC50 for the inhibitory effect of danicopan on hERG potassium channel current could not be calculated but was estimated to be greater than 10µM. Based on the in vitro protein binding data, the highest danicopan concentration assessed in this assay (10µM) is 106-fold higher than the estimated free-fraction concentration of danicopan (0.094µM) at the MRHD (200 mg, TID).”