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

“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”

“Per the review by Dr. Feleke Eshete in DPT-CHEN and discussion by the Executive Carcinogenicity Assessment Committee, there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”

“In animal embryo-fetal development studies, oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥ 10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose).”

“Relacorilant showed no remarkable adverse central nervous system or respiratory effects in rats, or cardiovascular system effects in monkeys, following single oral doses of up to 200 mg/kg (highest dose tested). No clinically meaningful human Ether-à-go-go-Related Gene (hERG) inhibition was seen in vitro.”

“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”

“Relacorilant was not genotoxic in the bacterial reverse mutation (Ames) assay, an in vitro human lymphocyte micronucleus assay, or an in vivo micronucleus assay in rats.”

“Relacorilant at doses up to and including 250 mg/kg was concluded to be negative in the in vivo micronucleus assay in rats.”

“Carcinogenicity studies were conducted in rats over 104 weeks (≤ 10 mg/kg for males and ≤ 3 mg/kg for females; up to 1.3 and 0.7 times the human exposure at the recommended dose for males and females, respectively, based on AUC) and in RasH2 mice over 26 weeks (≤100 mg/kg).”

“there was no evidence of drug-related neoplasms in rats in the 2-year study or in mice in the 26-week study.”

“At the highest nominal concentration of relacorilant that was soluble (2.5 µM [1466 ng/mL]) the hERG current was inhibited by a mean of 26.5%. Plasma levels of free relacorilant in human at the maximum dose (150 mg) are expected to be < 10 ng/mL (after adjusting for > 99% protein binding), > 10-fold lower than the concentrations that impacted ERG currents.”