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

“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”

“Given the intermittent clinical dosing, lack of obvious pharmacology-based concerns, and the technical challenges for conducting long-term studies in rodents with the intended intranasal route of administration, rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen.”

“In pregnant rats, intravenous administration of etripamil throughout the period of organogenesis did not result in any adverse effects on embryofetal development at doses up to 0.375 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD.”

“Safety pharmacology studies did not identify any neurologic, respiratory, or cardiovascular liabilities that would impact clinical development. Prolongation of the PR-interval observed in the cardiovascular assessment in monkeys was consistent with the expected pharmacological effect of etripamil.”

“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”

“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”

“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”

“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”

“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”

“The IC50 for the inhibitory effect of etripamil [(-) MSP-2017] on hERG potassium current was 0.12 μM (n=3, 0.8× clinical free Cmax of 145.4nM).”