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

“Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay.”

“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”

“Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD”

“Mitapivat inhibited hERG potassium channel current at an IC50 of 29.4µM and an IC20 of 8.6µM (Hill coefficient, 1.1), suggesting a low potential for inhibition of the hERG current at the clinical exposure”

“Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay.”

“Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay.”

“Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay.”

“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”

“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”

“Mitapivat inhibited hERG potassium channel current at an IC50 of 29.4µM and an IC20 of 8.6µM (Hill coefficient, 1.1), suggesting a low potential for inhibition of the hERG current at the clinical exposure (clinical Cmax: 935.2 ng/mL).”