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

“DM4 and S-methyl-DM4 were negative in the vitro bacterial reverse mutation assay but positive in the in vivo rat bone marrow micronucleus assay.”

“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”

“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.”

“Additionally, mirvetuximab soravtansine did not have effects on the nervous, cardiovascular, or respiratory systems in monkeys after repeated IV dosing up to 8 mg/kg (4-fold the exposures at the recommended dose based on AUC) based on ECG analysis and clinical observation.”

“DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.”

“DM4 and the active metabolite S-methyl DM4 were assessed in vitro for the genotoxic potential in a bacterial reverse mutation assay and in vivo in Sprague Dawley rats for the clastogenicity.”

“DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study.”

“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”

“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”

“In safety pharmacology studies, inhibition of hERG channels was not evaluated with mirvetuximab soravtansine; however, up to 60 µM DM4 and metabolite S-methyl-DM4 had < 50% inhibition on hERG potassium channels.”