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.”

“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.”

“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.”

“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.”

“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”

“In the 6‐month carcinogenicity study (Study 20174162), a significant increase in hemangiosarcomas was noted in both male and female transgenic mice with the incidence above historical control values of the test facility. Therefore, SpringWorks requested a waiver for the 2‐year carcinogenicity study in rats”

“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. Consistent with these findings, nirogacestat did not have effects on QT prolongation clinically or in in vivo nonclinical studies.”