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

“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”

“The results showed an increased incidence of whole body hemangiosarcomas in 100 mg/kg/day males that was above the historical control value for the test facility but did not reach statistical significance for trend and pairwise comparisons. The study was negative for drug‐related neoplasms in female mice.”

“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”

“There were no nirogacestat‐related adverse effects on the central nervous system, pulmonary function, or the cardiovascular system at single doses up to 500 mg/kg. Nirogacestat blocked the hERG channel with an IC50 of 1 μM; however, this IC50 is greater than 100 times the free Cmax in humans at the 150 mg BID dose.”