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Nonclinical Characterization of the HIF-Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment for Anemia of Chronic Kidney

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Nonclinical Characterization of the HIF-Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment for Anemia of Chronic Kidney JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 Nonclinical Characterization of the HIF-Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment for Anemia of Chronic Kidney Disease Ughetta del Balzo*, Pierre E. Signore*, Gail Walkinshaw, Todd W. Seeley, Mitchell C. Brenner, Qingjian Wang, Guangjie Guo, Michael P. Arend, Lee A. Flippin, F. Aisha Chow, David C. Gervasi, Christian H. Kjaergaard, Ingrid Langsetmo, Volkmar Guenzler, David Y. Liu, Steve J. Klaus, Al Lin, and Thomas B. Neff. Downloaded from Primary laboratory of origin: FibroGen, Inc., 409 Illinois Street, San Francisco, CA jpet.aspetjournals.org 94158 USA Affiliations: FibroGen, Inc., 409 Illinois Street, San Francisco, CA 94158 USA (U.d.B, at ASPET Journals on September 26, 2021 P.E.S., G.W., T.W.D., M.C.B., Q.W., G.G., M.P.A., L.A.F., F.A.C., D.C.G., C.H.K, I.L., V.G., D.Y.L., S.J.K., A.L., T.B.N.) *Contributed equally to the study. 1 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 Running title: Nonclinical Profile of Roxadustat for Anemia Corresponding Author: Ughetta del Balzo FibroGen, Inc. 409 Illinois Street San Francisco, CA 94158 USA Downloaded from Telephone: 415 978 1852 Email: udelbalzo@fibrogen.com jpet.aspetjournals.org Number of text pages: 47 Number of tables: 1 Number of figures: 9 at ASPET Journals on September 26, 2021 Number of references: 64 Number of words in abstract: 248 Number of words in introduction: 745 Number of words in discussion: 1557 List of non-standard abbreviations: αKG α-ketoglutarate ACD anemia of chronic disease BPE bovine pituitary extract BUN blood urea nitrogen CKD chronic kidney disease 2 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 DCYTB duodenal cytochrome b Dcytb gene coding for DCYTB protein DMEM Dulbecco’s Modified Eagle’s Medium DMSO dimethyl sulfoxide DMT1 divalent metal transporter 1 Dmt1 gene coding for DMT1 protein EGF epidermal growth factor Downloaded from EPO erythropoietin ESA erythropoiesis-stimulating agents jpet.aspetjournals.org FBS fetal bovine serum FIH factor inhibiting HIF GM-CSF granulocyte-macrophage colony-stimulating factor at ASPET Journals on September 26, 2021 Hamp gene coding for hepcidin HIF hypoxia-inducible factor HIF-PH HIF prolyl hydroxylase IL interleukin LC-MS liquid chromatography-mass spectrometry MCHC mean corpuscular hemoglobin concentration MIP macrophage inflammatory protein MCV mean corpuscular volume PBS phosphate-buffered saline PCR polymerase chain reaction PG-PS peptidoglycan-polysaccharide 3 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 PHD prolyl hydroxylase PK pharmacokinetic qRT-PCR quantitative real-time polymerase chain reaction Slc11a2 gene coding for DMT1 protein TNF tumor necrosis factor WBC white blood cells Downloaded from Section assignment: Drug Discovery and Translational Medicine jpet.aspetjournals.org at ASPET Journals on September 26, 2021 4 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 ABSTRACT 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 Downloaded from 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 jpet.aspetjournals.org 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, at ASPET Journals on September 26, 2021 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 5 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 production and mobilization of iron stores, makes this compound a promising treatment for anemia of CKD and anemia associated with functional iron deficiency. Downloaded from jpet.aspetjournals.org at ASPET Journals on September 26, 2021 6 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 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 Downloaded from increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of CKD and anemia associated with functional iron deficiency. jpet.aspetjournals.org at ASPET Journals on September 26, 2021 7 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 Introduction Anemia is a frequent and serious complication of chronic kidney disease (CKD) that affects millions of patients worldwide (Kassebaum et al, 2014; Stauffer and Fan, 2014; Thomas et al., 2008). Anemia of CKD contributes to decreased quality of life and increased risk of morbidity and mortality (Finkelstein et al., 2009; Thorp et al., 2009). Key factors responsible for anemia of CKD are a relative deficiency in erythropoietin Downloaded from (EPO) production and a decrease in iron availability for hemoglobin (Hb) synthesis (Babitt and Lin, 2012; Locatelli et al., 2017; Yilmaz et al., 2011). Currently, anemia of CKD is managed by iron supplementation and, in more severe cases, by administration jpet.aspetjournals.org of supraphysiologic doses of erythropoiesis-stimulating agents (ESAs), such as human recombinant EPO, in combination with adjuvant iron therapy (Biggar and Kim, 2017). However, some patients are hyporesponsive to ESAs and need even larger doses at ASPET Journals on September 26, 2021 because of functional iron deficiency associated with inflammation (Yilmaz et al., 2011; MacDougall and Cooper, 2005; Adamson, 2009). High doses of ESAs increase the risk of serious adverse events, including death, myocardial infarction, congestive heart failure, and stroke (Szczech et al., 2008; Pfeffer et al., 2009). Thus, to effectively treat anemia of CKD, new therapies need to address both impaired EPO production and functional iron deficiency (Locatelli et al., 2017). The observation that low blood oxygen levels lead to increased EPO production was made decades ago (Prentice and Mirand, 1961; Naets, 1963), but the transcription factors responsible for this hypoxic response were not identified until the 1990s (Semenza and Wang, 1992; Wang and Semenza, 1995; Wang et al., 1995; Tian et al., 1997). Since then, these hypoxia-inducible factors (HIFs) have been found to be part of 8 JPET Fast Forward. Published on June 2, 2020 as DOI: 10.1124/jpet.120.265181 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265181 an oxygen-sensing pathway that is evolutionarily conserved among metazoans (Kaelin, 2005; Kaelin and Ratcliffe, 2008). HIFs function as heterodimers comprising an oxygen- regulated α-subunit and a constitutively expressed β-subunit. There are two major HIF-α isoforms, HIF-1α and HIF-2α, both of which dimerize with the same β-subunit to form functional HIF-1 and HIF-2 transcription factors, respectively. In the presence of oxygen, HIF-α subunits are hydroxylated on specific proline residues by a family of HIF prolyl hydroxylase (HIF-PH) enzymes
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