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

“Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.”

“Crinecerfont did not show oncogenic effects in transgenic mice. In the 2-year rat study, crinecerfont increased the incidence of thyroid gland follicular cell adenoma and carcinoma in females at 100 mg/kg crinecerfont (4-fold MRHD exposure).”

“No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD.”

“Crinecerfont showed no potential for clinical arrhythmia risk based on human ether-à-go-go-related gene (hERG) current (<5% inhibition) or isolated rabbit Purkinje fiber action potential assays at up to 10µM crinecerfont concentrations.”

“Negative for mutagenic potential in five Salmonella typhimurium strains (TA98, TA100, TA1535, TA102 and TA1537) at 50-2500 µg/plate concentration (±S9 metabolic activation).”

“In vitro gene mutation assay at the locus TK+/- in mouse lymphoma L5178Y cells/LYM0101 GLP compliance: Yes Valid study: Yes Negative for mutagenic potential at concentration of 12.5- 250 µg/mL (±S9 metabolic activation).”

“No increase in micronucleated polychromatic erythrocytes in bone marrow at oral doses of 500-2000 mg/kg daily for 2 days (at exposure ~3-fold MRHD).”

“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies. Crinecerfont did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 5, 50, 500 or 1500 mg/kg/day.”

“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”

“Crinecerfont showed no potential for clinical arrhythmia risk based on human ether-à-go-go-related gene (hERG) current (<5% inhibition) or isolated rabbit Purkinje fiber action potential assays at up to 10µM crinecerfont concentrations.”