Vadadustat

Vadadustat (AKB-6548; marketed as Vafseo) is an orally bioavailable small molecule inhibitor of the three human prolyl-4-hydroxylase domain (PHD) isoforms (PHD1, PHD2, PHD3) that regulate the oxygen-sensing hypoxia-inducible factor (HIF) pathway. By competitively displacing the endogenous cofactor 2-oxoglutarate from the PHD active site, vadadustat prevents the hydroxylation and subsequent proteasomal degradation of HIF-alpha subunits, thereby stabilizing HIF-1alpha and HIF-2alpha and activating transcription of erythropoietin, transferrin, transferrin receptor, ferroportin, and other genes that coordinate erythropoiesis and iron homeostasis. The compound was developed by Akebia Therapeutics (Cambridge, Massachusetts) as an alternative to injectable erythropoiesis-stimulating agents (ESAs) for the management of anemia associated with chronic kidney disease (CKD). Vadadustat inhibits all three PHD isoforms with similar low-nanomolar inhibitory constants, and PHD inhibition is competitive with 2-oxoglutarate and insensitive to ambient iron concentration. In preclinical models, a single oral dose in rats potently increased circulating erythropoietin, and daily dosing for 14 days increased red blood cell indices in both healthy rats and the 5/6 nephrectomy model of CKD. In mice and dogs, once-daily repeat oral dosing increased hemoglobin and hematocrit without detectable stimulation of vascular endothelial growth factor.

The clinical development program comprised the global Phase 3 INNO2VATE trials in dialysis-dependent CKD and the PRO2TECT trials in non-dialysis-dependent CKD, both comparing vadadustat to darbepoetin alfa. In the INNO2VATE program, vadadustat met the prespecified noninferiority criteria for both hematologic efficacy and cardiovascular safety. In the PRO2TECT program, vadadustat met the noninferiority criterion for hematologic efficacy but did not meet the noninferiority criterion for cardiovascular safety, with signals of increased major adverse cardiovascular events (MACE), stroke, and hepatic injury relative to darbepoetin alfa. The United States Food and Drug Administration issued a complete response letter in March 2022 citing cardiovascular and hepatotoxicity concerns. Following review of additional post-marketing safety data from Japan (where Vafseo was approved in 2020) and the clinical trial database, the FDA approved vadadustat in March 2024 for the treatment of anemia due to CKD in adults who have been receiving dialysis for at least three months. The approved labeling carries a boxed warning for increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access, and the compound is explicitly not indicated for non-dialysis CKD patients.

Pharmacokinetics are characterized by rapid oral absorption (time to peak concentration approximately 3 to 4 hours in healthy volunteers, 5 to 6 hours in CKD patients), high plasma protein binding (greater than 99 percent), dose-proportional exposure over a wide dose range, and hepatic glucuronidation as the principal metabolic pathway. The elimination half-life is approximately 4.5 hours in healthy volunteers and extends to 7 to 9 hours in patients with advanced CKD. The compound is a potent inhibitor of the breast cancer resistance protein (BCRP) transporter and a moderate inhibitor of organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3), with clinically relevant drug-drug interaction potential for substrates of these transporters. This monograph reviews the chemistry, synthesis, and structural class of vadadustat; the molecular pharmacology of PHD inhibition and HIF stabilization; the comprehensive pharmacokinetic profile; preclinical pharmacology in rodent and canine models; the clinical evidence base from Phase 2 and Phase 3 programs; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signals; and a comparative assessment of five alternative HIF-PHI compounds (roxadustat, daprodustat, molidustat, desidustat, enarodustat) against vadadustat on five standards.