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

“Vamorolone was negative in an adequately conducted battery of genotoxicity studies that consisted of an in vitro bacterial reverse mutation assay, an in vitro mammalian gene mutation assay in mouse lymphoma cells, and an in vivo micronucleus assay in mouse.”

“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”

“Because the intended patient population is almost exclusively male, a standard battery of reproductive and developmental toxicology studies was not needed to support a marketing application”

“Vamorolone did not inhibit human ether-a-go-go-related gene (hERG) potassium currents up to the highest concentration of 20 µM in vitro. Accordingly, oral vamorolone doses up to 50 mg/kg did not impair cardiovascular and respiratory function in telemetered dogs.”

“In vitro, vamorolone was negative for increased reverse mutations in Ames tests in bacteria and for chromosomal aberrations, polyploidy and endoreduplication in mouse lymphoma cells and a micronucleus assay in CHO-K1 cells, respectively.”

“In vitro, vamorolone was negative for increased reverse mutations in Ames tests in bacteria and for chromosomal aberrations, polyploidy and endoreduplication in mouse lymphoma cells and a micronucleus assay in CHO-K1 cells, respectively.”

“Vamorolone did also not increase the formation of micronuclei in polychromatic erythrocytes of mouse bone marrow in vivo.”

“Because the intended patient population is almost exclusively male, a standard battery of reproductive and developmental toxicology studies was not needed to support a marketing application; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”

“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”

“The core battery of safety pharmacology studies of vamorolone revealed no inhibition of hERG currents up to 20 µM vamorolone in vitro. The applicant claims that this 20 µM concentration translates into a 45-fold safety margin compared to the free vamorolone plasma level of 0.44 µg/ml at the MRHD.”