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

“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”

“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”

“At the dose of 20 mg/kg daily (approximately 0.4 times the estimated clinical exposure at 150 mg), fetal malformations associated with the cardiovascular and skeletal systems were observed.”

“A single dose of ripretinib in beagle dogs resulted in increases in heart rate of up to 129% with secondary decreases in QT and PR intervals, as well as increases in diastolic and mean arterial pressure starting at 7 mg/kg; however, ripretinib did not appear to influence QTc intervals.”

“Both ripretinib and DP-5439 were found negative in the bacterial mutation assay.”

“Ripretinib, but not DP-5439, was found positive in the in vitro micronucleus assay using human peripheral blood lymphocytes.”

“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”

“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”

“The Regulatory Authorities agree that carcinogenicity was not warranted for the proposed indication.”

“The average hERG IC50 value = 7.9 μM for ripretinib. Given the single‐ and double‐digit nanomolar inhibition of KIT and PDGFRα mutants in vitro, the high concentrations required for inhibition of the hERG channel in this assay would likely result in negligible inhibition in vivo.”