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

“Although the Ames and micronucleus assays were negative for the induction of genetic toxicity, there was an increase in structural abnormalities in the chromosome aberration assay.”

“Although the Sponsor did not definitively identify the MOA for tumor development in rodents, the overall weight of evidence indicates that the rodent liver neoplasms were most likely mediated by rodent-specific CAR activation which is not relevant in humans.”

“Embryofetal development studies revealed increased fetal resorptions and altered morphological development in rats and rabbits at exposures greater than 100-fold and 7-fold, respectively, the exposure at the MRHD.”

“Observations included inhibition of the hERG current at > 50-fold the MRHD, prolongation of the QRS, QT, and QTc levels in dogs at 11-fold following intravenous though not oral dosing, and in NHPs at >15-fold the MRHD.”

“Osilodrostat did not induce mutations when adequately tested in five histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA102) at concentrations up to 5000 μg/plate in the absence and in the presence of a rat liver metabolic activation system (S9).”

“Osilodrostat induced structural chromosome aberrations when adequately tested in cultured human peripheral blood lymphocytes in both the absence and presence of a rat liver metabolic activation system (S9).”

“Osilodrostat did not show any evidence of chromosomal aberrations in vivo in the rat bone marrow micronucleus test when adequately tested up to a single oral dose of 300 mg/kg. Osilodrostat did not induce any DNA damage when adequately tested in the Comet assay in hepatocytes or leukocytes of rats dosed twice orally up to 150 mg/kg.”

“Long-term carcinogenicity studies have been performed in mice and rats with dosing at 1, 3 and 30 mg/kg/day for up to 103/104 weeks and 104 weeks, respectively.”

“Sponsor submitted safety report regarding observations from rat and mouse carcinogenicity studies”

“LCI699 concentration-dependently inhibited hERG channels at >10 µM and the IC50 was calculated to be 54 µM (12.3 µg/mL) which is 42-fold higher than the steady state Cmax for total drug (1.3 µM) predicted for 30 mg doses in humans.”