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

“Daraxonrasib was not mutagenic in the GLP in vitro Ames assay, not clastogenic in the GLP in vitro micronucleus assay with human peripheral blood lymphocytes, and not genotoxic in the GLP in vivo micronucleus study in mice.”

“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”

“In an embryo-fetal development study in mice (25, 50, and 75 mg/kg/day), daraxonrasib caused embryo-fetal toxicity at ≥50 mg/kg/day (2.5x exposure at the recommended dose based on AUC).”

“In a standalone good laboratory practice (GLP) cardiovascular study in monkey, daraxonrasib demonstrated decreased heart rate, prolonged QT, shortened QTc (secondary to heart rate decrease), and increased blood pressure at all dose levels tested (3, 10, and 30 mg/kg).”

“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”

“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”

“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”

“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”

“FDA concurs. Carcinogenicity studies were not required for this Application per ICH S9.”

“daraxonrasib inhibited hERG current by 13.3% at 0.8 µM and 36.0% at 2.7 µM versus 0.4% in vehicle control. The IC50 for the inhibitory effect of daraxonrasib on hERG potassium current was not calculated but was estimated to be greater than 2.7 µM.”