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

“Baxdrostat was not genotoxic when tested in a battery of in vitro and in vivo assays.”

“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”

“In embryofetal development studies, reduced maternal body weight gain and fetal toxicities were observed in rats (adverse skeletal malformations of skull: mandible/zygomatic arch fusion) and rabbits (decrease in fetal body weight) at exposures >54-fold and >29-fold relative to the clinical exposures at the MRHD.”

“Baxdrostat inhibited the hERG tail current with an IC50 of 360 μM, approximately 15,000-fold above the free Cmax at the clinical dose of 2 mg. A trend toward persistent QTc prolongation (+7%) was observed at 6 hours post-dose in single-dose telemetry study in monkeys at 50 mg/kg.”

“Conclusion: Baxdrostat demonstrated no mutagenic activity in bacterial test systems up to the maximum recommended concentration of 5000 μg/plate, in the absence and presence of a rat liver metabolic activation system (S9).”

“Conclusion: The 24-hour continuous exposure protocol yielded statistically positive results, which were slightly outside the historical control range with statistical significance partly due to an unusually low concurrent vehicle control. No increase in micronuclei formation was observed with the 3-hour exposure protocol.”

“Conclusion: Baxdrostat demonstrated no genotoxic potential in vivo, showing no clastogenic activity in bone marrow or DNA strand breaks in liver.”

“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”

“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”

“Baxdrostat inhibited the hERG tail current with an IC50 of 360 μM, approximately 15,000-fold above the free Cmax at the clinical dose of 2 mg.”