TY - JOUR T1 - Nonclinical Characterization of the HIF-Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment for Anemia of Chronic Kidney Disease JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.265181 SP - jpet.120.265181 AU - Ughetta del Balzo AU - Pierre E Signore AU - Gail Walkinshaw AU - Todd W Seeley AU - Mitchell C Brenner AU - Qingjian Wang AU - Guangjie Guo AU - Michael P Arend AU - Lee A Flippin AU - F. Aisha Chow AU - David C Gervasi AU - Christian H Kjaergaard AU - Ingrid Langsetmo AU - Volkmar Guenzler AU - David Y Liu AU - Steve J Klaus AU - Al Lin AU - Thomas B Neff Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/06/02/jpet.120.265181.abstract N2 - Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for hemoglobin synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1α and HIF-2α proteins, leading to an increase in EPO production, even in the presence of EPO-suppressing inflammatory cytokines. Roxadustat administered intermittently to healthy rats and cynomolgus monkeys increased circulating EPO levels, reticulocytes, blood hemoglobin, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after 5/6th nephrectomy and in a rat model of anemia of inflammation with impaired iron metabolism induced by peptidoglycan polysaccharide (PG-PS). In the PG-PS model, roxadustat significantly decreased hepatic expression of hepcidin, a hormone responsible for iron sequestration and functional iron deficiency, and increased expression of two genes involved in duodenal iron absorption: divalent metal transporter 1 and duodenal cytochrome b. In conclusion, by activating the HIF pathway roxadustat increased EPO production, elevated hemoglobin, corrected anemia, and improved iron homeostasis. The coordinated erythropoietic response stimulated by roxadustat, involving both EPO production and mobilization of iron stores, makes this compound a promising treatment for anemia of CKD and anemia associated with functional iron deficiency.SIGNIFICANCE STATEMENT Roxadustat is a novel orally available small-molecule inhibitor of HIF prolyl hydroxylase enzymes that reversibly stabilizes HIF-α, thus activating transcription of HIF-dependent genes, including EPO and regulators of iron homeostasis. Activation of the HIF pathway by roxadustat induces erythropoiesis in healthy rats and monkeys, and corrects experimentally-induced anemia in rats. The coordinated erythropoietic response that increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of CKD and anemia associated with functional iron deficiency. ER -