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

“Weight of evidence indicates that E4 is not considered genotoxic in a full battery of in vitro and in vivo assays (Ames assay, in vitro mouse lymphoma assay, an in vivo rat micronucleus assay, and in vivo rat Comet assay).”

“E4 doses of up to 0.8 mg/kg/day were administered orally to female rats for 104 weeks. At the high-dose of 0.8 mg/kg/day E4 (0.7x the MRHD on an AUC basis), there was an increased incidence of mammary neoplasms”

“The observed fetal growth retardation and developmental effects were likely consequences of maternal toxicity in the pregnant female rat and rabbit. There are no indications for intrinsic teratogenic properties of E4 or DRSP in either rat or rabbit.”

“E4 did not alter the cardiovascular function of telemetered monkeys and did not affect the respiratory functions of rats up to the highest dose tested (100 mg/kg in monkeys and 150 mg/kg in rats), with safety margins of approximately 115 times and 830 times the MRHD on an AUC basis, respectively.”

“Therefore, and overall, the Ames test studies suggest a not fully reproducible mutagenic activity in the strain TA102 perhaps via a cross-linking mode of action.”

“E4 did not display mutagenic activity in the mouse lymphoma assay, either in the presence or in the absence of a rat metabolizing system.”

“E4 did not induce damage to the chromosomes or the mitotic apparatus of rat bone marrow cells after a single oral administration up to 2000 mg/kg.”

“Two-year carcinogenicity studies in rats and mice showed that estetrol is carcinogenic.”

“The tumor findings from the rat and mouse final carcinogenicity studies were reviewed and agreed upon by the Division and ECAC on November 24, 2020.”

“E4 did not interfere with the hERG channel conduction in in vitro patch-clamp experiments using concentrations of E4 that were 480 times the Cmax of E4 at the MRHD.”