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Abstract: SA-OR037

Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Zuk, Anna, Akebia Therapeutics, Inc., Natick, Massachusetts, United States
  • Si, Zhihai, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States
  • Loi, Sally, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States
  • Bommegowda, Santhosh K., Akebia Therapeutics Inc., Cambridge, Massachusetts, United States
  • Danthi, Sanjay, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States
  • Molnar, Gyongyi, Akebia Therapeutics Inc., Cambridge, Massachusetts, United States
  • Rabinowitz, Michael, Akebia Therapeutics, Inc., Natick, Massachusetts, United States
Background

We summarize preclinical pharmacological characterization of the small molecule hypoxia inducible factor-prolyl-4-hydroxylase (HIF-PHD) inhibitor, vadadustat (AKB-6548), an investigational drug in phase 3 development for the treatment of anemia in patients with chronic kidney disease (CKD). Pharmacological inhibition of PHD enzymes lead to the stabilization of hypoxia-inducible factor (HIF), a transcription factor which activates target genes that increase erythropoietin (EPO) synthesis, resulting in the production of new red blood cells.

Methods

Enzymatic IC50 values of vadadustat against the full-length human PHD isoenzymes, PHD1, PHD2, and PHD3, were measured by time-resolved fluorescence resonance energy transfer assay. Stabilization of HIF-1α and HIF-2α in the human hepatocarcinoma cell line Hep3B was measured by meso scale discovery technology. EPO and vascular endothelial growth factor (VEGF) were quantitated by ELISA. In vivo studies measured the pharmacokinetics and pharmacodynamics of vadadustat.

Results

Vadadustat inhibits PHD1, PHD2 and PHD3 at approximately equivalent nanomolar concentrations. Vadadustat metabolites are approximately 100-200 fold less potent for PHD2 compared to the parent compound. Moreover, vadadustat shows 2-oxoglutarate competitive inhibition against the human HIF-PHDs and vadadustat activity is insensitive to the presence of added iron. In Hep3B cells, PHD inhibition by vadadustat leads to the time-dependent stabilization of both HIF-1α and HIF-2α, which in turn results in the synthesis and secretion of EPO; stimulation of VEGF was not detectable. In vivo, single dose administration of vadadustat potently increases circulating levels of EPO, but not VEGF. Moreover, once daily oral dosing in mice and rats significantly increases hemoglobin, hematocrit and reticulocytes. Vadadustat exhibits a relatively short half-life in all non-clinical species evaluated and does not accumulate upon repeat dosing.

Conclusion

The pharmacology and safety of vadadustat support development for renal anemia. Vadadustat is an equipotent pan-PHD inhibitor which activates erythropoiesis through stabilization of both HIF-1α and HIF-2α without stimulation of VEGF in the preclinical setting.

Funding

  • Commercial Support