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

“Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.”

“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”

“External malformations were elevated in the high-dose group fetuses and composed of cleft palates. Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra.”

“The IC50 values for hERG and hCavl.2 inhibition were 1.61 and 2.8 μM, respectively. Dose-dependent lower blood pressure and longer PR intervals were seen after single doses of 40, 120, and 200 mg/kg/day in dogs”

“Under the conditions of this study, ziftomenib was determined to be negative (nonmutagenic) in the bacterial reverse mutation assay.”

“Under the conditions of this study, ziftomenib was considered negative (nonclastogenic/aneugenic) when evaluated in the in vitro micronucleus assay conducted in HPBLs.”

“Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.”

“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”

“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”

“Given that ziftomenib has >99% protein binding, the free drug Cmax-ss will be approximately 0.049 µM, which is 1.3-fold lower than the IC50.”