title: Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
abstract: Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.
authors.affiliation: Renal Associates, San Antonio, Texas, USA.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Pergola
authors.affiliation: Division of Nephrology, New York-Presbyterian/Queens, Flushing, New York, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Spinowitz
authors.affiliation: Akebia Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Hartman
authors.affiliation: Akebia Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Maroni
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Electronic address: volker.haase@vanderbilt.edu.
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
mesh_terms: D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010848:Picolinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000150:complications*
chemical_list: D010848:Picolinic Acids; C000624313:vadadustat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine
keywords: anemia; chronic kidney disease; erythropoietin; hypoxia-inducible factor; prolyl-4-hydroxylase