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

“Aficamten was not mutagenic or clastogenic in a standard battery of genotoxicity studies including the Ames assay and a combined in vivo micronucleus assay and comet assay.”

“There were no aficamten-related tumor findings in a 26-week carcinogenicity study in transgenic rasH2 mice at doses up to 2.0 mg/kg/day or in a 2-year carcinogenicity study in Sprague Dawley rats at doses up to 3 mg/kg/day (corresponding to 4-times the exposure at the MRHD based on AUCunbound).”

“A rat embryofetal development (EFD) study demonstrated an increase in external malformations (kinked tail) at aficamten exposures higher than clinical exposures at the MRHD.”

“Effects observed on electrocardiogram readings after repeated aficamten dosing are typical of cardiac compensation due to the intended pharmacologic action of aficamten. Aficamten and its metabolites did not have inhibitory effects on the hERG channel at clinically relevant concentrations.”

“Aficamten was not genotoxic in the in vitro bacterial (Ames) mutagenicity assay or the combined in vivo micronucleus assay and comet assay in rat.”

“GLP-compliant Ames assays and in vitro micronucleus assays were conducted for the two major metabolites of aficamten, with a follow-up combined in vivo micronucleus assay and comet assay conducted for metabolite M1a. Collectively, the metabolites were also negative for genotoxicity and clastogenicity.”

“Aficamten was not genotoxic in the in vitro bacterial (Ames) mutagenicity assay or the combined in vivo micronucleus assay and comet assay in rat.”

“There was no evidence of carcinogenicity with oral administration of aficamten at dose levels up to 2.0 mg/kg/day in the mouse or 3 mg/kg/day in the rat (corresponding to 4-fold the MRHD based on free AUC).”

“There were no aficamten-related tumor findings in a 26-week carcinogenicity study in transgenic rasH2 mice at doses up to 2.0 mg/kg/day or in a 2-year carcinogenicity study in Sprague Dawley rats”

“The in vitro IC50 for aficamten against hERG was not determined due to insolubility of the drug above 10µM (3,400 ng/mL). At 3μM and 10μM aficamten, hERG was inhibited by 3% and 3.7% respectively (Nonclin-0003).”