Oxbryta: which tox species, and why?

“Major findings associated with repeat-dose administration of voxelotor in mice, rats and Cynomolgus monkeys were changes in hematopoietic parameters and gastrointestinal (GI) intolerance that was attributed to local irritation.”

“The exposure in dogs in the 4-week study at the highest tolerated dose was not sufficiently high to cause decreased tissue O2 extraction and dogs did not have erythroid or bone marrow changes, therefore dogs were not further considered as test species.”

“In a fertility and early embryonic development study, voxelotor was administered orally to rats at 15, 50, and 250 mg/kg/day.”

“Major findings associated with repeat-dose administration of voxelotor in mice, rats and Cynomolgus monkeys were changes in hematopoietic parameters and gastrointestinal (GI) intolerance that was attributed to local irritation.”

“Reproductive and developmental toxicity of voxelotor was studied in the fertility and early embryonic development (FEED) study in rats, embryo-foetal developmental (EFD) toxicity studies in rats and rabbits, pre-and postnatal developmental toxicity study in rats and a dose-range finding study in juvenile rats.”

“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”

“Affinity and dissociation constants for voxelotor to Hb for human HbS, HbA and HbF and for the animal equivalents and it is not expected that the voxelotor-Hb binding is different or not-reversible in animals.”