PMID- 32487538 OWN - NLM STAT- MEDLINE DCOM- 20201112 LR - 20220111 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 374 IP - 2 DP - 2020 Aug TI - Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease. PG - 342-353 LID - 10.1124/jpet.120.265181 [doi] AB - 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 Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-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-1alpha and HIF-2alpha 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 Hb, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after five-sixth 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 Hb, 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 of 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-alpha, 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 chronic kidney disease and anemia associated with functional iron deficiency. CI - Copyright (c) 2020 The Author(s). FAU - Del Balzo, Ughetta AU - Del Balzo U AUID- ORCID: 0000-0003-4102-6023 AD - FibroGen, Inc., San Francisco, California udelbalzo@fibrogen.com. FAU - Signore, Pierre E AU - Signore PE AD - FibroGen, Inc., San Francisco, California. FAU - Walkinshaw, Gail AU - Walkinshaw G AD - FibroGen, Inc., San Francisco, California. FAU - Seeley, Todd W AU - Seeley TW AD - FibroGen, Inc., San Francisco, California. FAU - Brenner, Mitchell C AU - Brenner MC AD - FibroGen, Inc., San Francisco, California. FAU - Wang, Qingjian AU - Wang Q AD - FibroGen, Inc., San Francisco, California. FAU - Guo, Guangjie AU - Guo G AD - FibroGen, Inc., San Francisco, California. FAU - Arend, Michael P AU - Arend MP AD - FibroGen, Inc., San Francisco, California. FAU - Flippin, Lee A AU - Flippin LA AD - FibroGen, Inc., San Francisco, California. FAU - Chow, F Aisha AU - Chow FA AD - FibroGen, Inc., San Francisco, California. FAU - Gervasi, David C AU - Gervasi DC AD - FibroGen, Inc., San Francisco, California. FAU - Kjaergaard, Christian H AU - Kjaergaard CH AD - FibroGen, Inc., San Francisco, California. FAU - Langsetmo, Ingrid AU - Langsetmo I AD - FibroGen, Inc., San Francisco, California. FAU - Guenzler, Volkmar AU - Guenzler V AD - FibroGen, Inc., San Francisco, California. FAU - Liu, David Y AU - Liu DY AD - FibroGen, Inc., San Francisco, California. FAU - Klaus, Steve J AU - Klaus SJ AD - FibroGen, Inc., San Francisco, California. FAU - Lin, Al AU - Lin A AD - FibroGen, Inc., San Francisco, California udelbalzo@fibrogen.com. FAU - Neff, Thomas B AU - Neff TB AD - FibroGen, Inc., San Francisco, California. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200602 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Basic Helix-Loop-Helix Transcription Factors) RN - 0 (EPO protein, human) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Isoquinolines) RN - 11096-26-7 (Erythropoietin) RN - 1B37H0967P (endothelial PAS domain-containing protein 1) RN - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases) RN - TE7660XO1C (Glycine) RN - X3O30D9YMX (roxadustat) SB - IM MH - Anemia/*complications/*drug therapy MH - Animals MH - Basic Helix-Loop-Helix Transcription Factors/metabolism MH - Cell Line MH - Erythropoiesis/drug effects MH - Erythropoietin/metabolism MH - Glycine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use MH - Haplorhini MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Hypoxia-Inducible Factor-Proline Dioxygenases/*antagonists & inhibitors MH - Isoquinolines/pharmacokinetics/*pharmacology/therapeutic use MH - Male MH - Rats MH - Renal Insufficiency, Chronic/*complications EDAT- 2020/06/04 06:00 MHDA- 2020/11/13 06:00 CRDT- 2020/06/04 06:00 PHST- 2020/01/16 00:00 [received] PHST- 2020/05/13 00:00 [accepted] PHST- 2020/06/04 06:00 [pubmed] PHST- 2020/11/13 06:00 [medline] PHST- 2020/06/04 06:00 [entrez] AID - jpet.120.265181 [pii] AID - 10.1124/jpet.120.265181 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2020 Aug;374(2):342-353. doi: 10.1124/jpet.120.265181. Epub 2020 Jun 2.