Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase 
(PHD) inhibitor in development for treatment of anemia of chronic kidney 
disease. Daprodustat's biological activity simulates components of the natural 
response to hypoxia; inhibition of PHDs results in HIF stabilization and 
modulation of HIF-controlled gene products, including erythropoietin. The 
carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity 
studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were 
administered. The mouse study also included evaluation of daprodustat's 3 major 
circulating human metabolites. There were no neoplastic findings that were 
considered treatment related in either study. Exaggerated pharmacology resulted 
in significantly increased red cell mass and subsequent multiorgan congestion 
and secondary non-neoplastic effects in both species, similar to those observed 
in chronic toxicity studies. In rats, these included aortic thrombosis and an 
exacerbation of spontaneous rodent cardiomyopathy, which contributed to a 
statistically significant decrease in survival in high-dose males (group 
terminated in week 94). Survival was not impacted in mice at any dose. Systemic 
exposures (area under the plasma concentration-time curve) to daprodustat at the 
high doses in rats and mice exceed predicted maximal human clinical exposure by 
≥143-fold. These results suggest that daprodustat and metabolites do not pose a 
carcinogenic risk at clinical doses.