Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor

Abstract

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.

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

“…153 To date, animal studies have shown no evidence that prolonged exposure to HIF-PHIs is prooncogenic. 140,154,155 Although preliminary data from phase 3 roxadustat studies indicated that the rates of neoplasm-related AEs were not increased compared with placebo or epoetin alfa in patients with NDD CKD or DD CKD, 156 long-term observations in humans are needed to rule out any possible prooncogenic properties of HIF-PHIs. Given the multiple theoretical safety concerns and the exclusion of patients with a history of cancer (<2-5 years) from clinical trials, the use of HIF-PHIs in patients with cancer should not be recommended, as safety data are not available.…”

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF‐PH inhibitors

“…At least two agents have been assessed regarding their potential for cancer development in longer‐term murine studies: roxadustat and daprodustat 34,35 . Roxadustat is usually administered to humans at doses up to 1.5 mg/kg daily or thrice‐weekly (TIW).…”

“…At least two agents have been assessed regarding their potential for cancer development in longer-term murine studies: roxadustat and daprodustat. 34,35 Roxadustat is usually administered to humans at doses up to 1.5 mg/kg daily or thrice-weekly (TIW). At doses of up to 10 (rats) and 60 (mice) mg/kg administered TIW and followed for up to 104 weeks, there was no effect in either animal on survival or on the development of neoplastic lesions.…”

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

“…and Mol [148]. Daprodustat PHD1>PHD3>PHD2 -High doses of drugs did not show carcinogenic potential in vivo [150].…”

“…Daprodustat [156], developed by GlaxoSmithKline, preferentially inhibits PHD1 and PHD3 [145] and both HIF1α and HIF2α isoforms stabilize upon treatment, attesting to its efficacy in activating the hypoxia pathway. Importantly, no carcinogenicity potential was detected for this compound even at high pharmacological doses [150]. Daprodustat was also effective in a mouse LLC model as it resulted in better normalization of the tumor vessels with enhanced pericyte coverage that was linked to diminished presence of angiogenic factors.…”