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

“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”

“The Applicant was therefore informed in a Type C meeting (May 11, 2020) that, due to the nature of the proposed indication (i.e., DMD), carcinogenicity studies for givinostat may be deferred until post approval.”

“In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring.”

“Givinostat inhibited hERG currents with an IC50 of 1.4 µM and slightly prolonged action potential duration in rabbit Purkinje fibres at ≥3 µM during simulated bradycardia conditions in vitro, but did not significantly alter heart rate, ECG and respiratory parameters in dogs and monkeys.”