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

“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).”

“A single oral administration of alpelisib induced a dose-independent increase in systolic and diastolic blood pressure in dogs at all doses tested (5, 15, 30 mg/kg) in the conducted safety pharmacology study. Alpelisib had no adverse effects on ECG, respiration, or neurological behavior in animals.”

“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”

“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”

“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”

“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”

“The FDA agrees that no carcinogenicity studies are required for the proposed indication.”

“In vitro inhibition of hERG channels (IC50 of 9.4 µM) was shown at concentrations ~13-fold higher than the exposure in humans, at the recommended dose of 300 mg/day.”