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

“In vivo, vimseltinib administered to rats at doses up to 200 mg/kg/day did not increase bone marrow micronucleated polychromatic erythrocytes, nor did vimseltinib increase liver DNA strand breaks. The overall assessment was that vimseltinib was negative for genotoxicity.”

“In a 6-month transgenic mouse carcinogenicity study at doses up to 12.5 mg/kg/day, vimseltinib was negative for carcinogenic findings. The Applicant is currently conducting a 104-week carcinogenicity study in Sprague Dawley rats to be submitted as a PMR.”

“Structural abnormalities (skeletal variations) occurred at ≥2.5 mg/kg/day (approximately 3 times the exposure at the recommended dose based on AUC). Additional structural abnormalities (cardiac malformations) were observed at the highest dose of 15 mg/kg/day”

“In the dog cardiovascular (CV) safety pharmacology study, no vimseltinib-related qualitative electrocardiogram (ECG) effects or quantitative changes in PR interval, QRS duration, QT interval, QT interval corrected by Fridericia’s formula (QTcF) interval, heart rate (HR), arterial pressure, or body temperature were seen at doses up to 15 mg/kg.”

“Vimseltinib was not mutagenic in the bacterial reverse mutation assay (Ames).”

“In an in vitro micronucleus assay, vimseltinib increased micronuclei after a 24-hour incubation in the absence of metabolic activation.”

“In vivo, vimseltinib administered to rats at doses up to 200 mg/kg/day did not increase bone marrow micronucleated polychromatic erythrocytes, nor did vimseltinib increase liver DNA strand breaks.”

“In a 6-month transgenic mouse carcinogenicity study at doses up to 12.5 mg/kg/day, vimseltinib was negative for carcinogenic findings. The Applicant is currently conducting a 104-week carcinogenicity study in Sprague Dawley rats to be submitted as a PMR.”

“The Applicant is conducting a 104-Week rat carcinogenicity study of vimseltinib in Sprague Dawley rats (DCC-3014-04-0025, eCTD 2.6.7 Table 21).”

“In the in vitro human ether-à-go-go-related gene (hERG) study, the half maximal inhibitory concentration (IC50) values for inhibition of the hERG potassium current by vimseltinib and DP-7005 could not be calculated due to 17% or less inhibition at the maximum concentrations that could be tested at the solubility limits of the two compounds”