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

“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”

“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”

“In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans”

“Cardiovascular endpoints were assessed in cynomolgus monkeys administered single oral doses of RTA 408 up to 100 mg/kg. There were no drug effects on body temperature, blood pressure, heart rate, or ECG (PR, RR, QRS, and corrected QT intervals).”

“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”

“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”

“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”

“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”

“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”

“Omaveloxolone had no meaningful effect in the in vitro hERG assay and ECG parameters collected after single- and repeat-dose in monkeys identified no safety concern with regard to risk for QT prolongation at the doses tested.”