Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

  • Volker H. Haase
    Correspondence
    Correspondence: Volker H. Haase, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, C-3119A MCN, 1161 21st Ave S, Nashville, Tennessee 37232-2372, USA.
    Affiliations
    Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

    Department of Molecular Physiology and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Search for articles by this author
      Hypoxia-inducible factor–prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non–dialysis- and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD.

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      References

        • Kidney Disease: Improving Global Outcomes
        Notice.
        Kidney Int Suppl. 2013; 3: 1-150
        • Besarab A.
        • Coyne D.W.
        Iron supplementation to treat anemia in patients with chronic kidney disease.
        Nat Rev Nephrol. 2010; 6: 699-710
        • Besarab A.
        • Bolton W.K.
        • Browne J.K.
        • et al.
        The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.
        N Engl J Med. 1998; 339: 584-590
        • Finkelstein F.O.
        • Story K.
        • Firanek C.
        • et al.
        Health-related quality of life and hemoglobin levels in chronic kidney disease patients.
        Clin J Am Soc Nephrol. 2009; 4: 33-38
        • Parfrey P.S.
        • Lauve M.
        • Latremouille-Viau D.
        • et al.
        Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: a meta-analysis.
        Clin J Am Soc Nephrol. 2009; 4: 755-762
        • Finkelstein F.O.
        • Finkelstein S.H.
        The impact of anemia treatment on health-related quality of life in patients with chronic kidney disease in the contemporary era.
        Adv Chronic Kidney Dis. 2019; 26: 250-252
        • Singh A.K.
        • Szczech L.
        • Tang K.L.
        • et al.
        Correction of anemia with epoetin alfa in chronic kidney disease.
        N Engl J Med. 2006; 355: 2085-2098
        • Drueke T.B.
        • Locatelli F.
        • Clyne N.
        • et al.
        Normalization of hemoglobin level in patients with chronic kidney disease and anemia.
        N Engl J Med. 2006; 355: 2071-2084
        • Pfeffer M.A.
        • Burdmann E.A.
        • Chen C.Y.
        • et al.
        A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
        N Engl J Med. 2009; 361: 2019-2032
        • Semenza G.L.
        Oxygen sensing, homeostasis, and disease.
        N Engl J Med. 2011; 365: 537-547
        • Schodel J.
        • Ratcliffe P.J.
        Mechanisms of hypoxia signalling: new implications for nephrology.
        Nat Rev Nephrol. 2019; 15: 641-659
        • Loenarz C.
        • Schofield C.J.
        Expanding chemical biology of 2-oxoglutarate oxygenases.
        Nat Chem Biol. 2008; 4: 152-156
        • Tsubakihara Y.
        • Akizawa T.
        • Nangaku M.
        • et al.
        A 24-week anemia correction study of daprodustat in Japanese dialysis patients.
        Ther Apher Dial. 2020; 24: 108-114
        • Akizawa T.
        • Nangaku M.
        • Yonekawa T.
        • et al.
        Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial.
        Clin J Am Soc Nephrol. 2020; 15: 1155-1165
        • Kimura T.
        • Nangaku M.
        • Hamano T.
        • et al.
        Efficacy and safety of daprodustat compared with epoetin beta pegol in Japanese non-dialysis patients with anemia of chronic kidney disease: a 52-week, open-label, randomized controlled phase 3 trial [late-breaking clinical trial].
        ERA-EDTA 2019 Congress. 2019 (Budapest, Hungary)
        • Akizawa T.
        • Ueno M.
        • Shiga T.
        • et al.
        Oral roxadustat three times weekly in ESA-naive and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies.
        Ther Apher Dial. 2020; 24: 628-641
        • Akizawa T.
        • Otsuka T.
        • Reusch M.
        • et al.
        Intermittent oral dosing of roxadustat in peritoneal dialysis chronic kidney disease patients with anemia: a randomized, phase 3, multicenter, open-label study.
        Ther Apher Dial. 2020; 24: 115-125
        • Akizawa T.
        • Iwasaki M.
        • Yamaguchi Y.
        • et al.
        Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan.
        J Am Soc Nephrol. 2020; 31: 1628-1639
        • Nangaku M.
        • Kondo K.
        • Kokado Y.
        • et al.
        Randomized, open-label, active-controlled (darbepoetin alfa), phase 3 study of vadadustat for treating anemia in non-dialysis-dependent CKD patients in Japan [abstract SA-PO229].
        J Am Soc Nephrol. 2019; 30: 823
        • Nangaku M.
        • Kondo K.
        • Ueta K.
        • et al.
        Randomized, double-blinded, active-controlled (darbepoetin alfa), phase 3 study of vadadustat in CKD patients with anemia on hemodialysis in Japan [abstract TH-OR024].
        J Am Soc Nephrol. 2019; 30: 6
        • Japan Tobacco Inc.
        JT receives manufacturing and marketing approval of Enaroy®tablets 2 mg・4 mg for the treatment of anemia associated with chronic kidney disease in Japan.
        (Available at:)
        • Chen N.
        • Hao C.
        • Liu B.C.
        • et al.
        Roxadustat treatment for anemia in patients undergoing long-term dialysis.
        N Engl J Med. 2019; 381: 1011-1022
        • Chen N.
        • Hao C.
        • Peng X.
        • et al.
        Roxadustat for anemia in patients with kidney disease not receiving dialysis.
        N Engl J Med. 2019; 381: 1001-1010
        • Miyake T.
        • Kung C.K.
        • Goldwasser E.
        Purification of human erythropoietin.
        J Biol Chem. 1977; 252: 5558-5564
        • Jacobs K.
        • Shoemaker C.
        • Rudersdorf R.
        • et al.
        Isolation and characterization of genomic and cDNA clones of human erythropoietin.
        Nature. 1985; 313: 806-810
        • Lin F.K.
        • Suggs S.
        • Lin C.H.
        • et al.
        Cloning and expression of the human erythropoietin gene.
        Proc Natl Acad Sci U S A. 1985; 82: 7580-7584
        • Goldberg M.A.
        • Glass G.A.
        • Cunningham J.M.
        • et al.
        The regulated expression of erythropoietin by two human hepatoma cell lines.
        Proc Natl Acad Sci U S A. 1987; 84: 7972-7976
        • Semenza G.L.
        • Nejfelt M.K.
        • Chi S.M.
        • et al.
        Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene.
        Proc Natl Acad Sci U S A. 1991; 88: 5680-5684
        • Semenza G.L.
        • Wang G.L.
        A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.
        Mol Cell Biol. 1992; 12: 5447-5454
        • Wang G.L.
        • Semenza G.L.
        Purification and characterization of hypoxia-inducible factor 1.
        J Biol Chem. 1995; 270: 1230-1237
        • Wang G.L.
        • Jiang B.H.
        • Rue E.A.
        • et al.
        Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
        Proc Natl Acad Sci U S A. 1995; 92: 5510-5514
        • Wang G.L.
        • Semenza G.L.
        General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.
        Proc Natl Acad Sci U S A. 1993; 90: 4304-4308
        • Maxwell P.H.
        • Pugh C.W.
        • Ratcliffe P.J.
        Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism.
        Proc Natl Acad Sci U S A. 1993; 90: 2423-2427
        • Firth J.D.
        • Ebert B.L.
        • Pugh C.W.
        • et al.
        Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer.
        Proc Natl Acad Sci U S A. 1994; 91: 6496-6500
        • Levy A.P.
        • Levy N.S.
        • Wegner S.
        • et al.
        Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia.
        J Biol Chem. 1995; 270: 13333-13340
        • Jaakkola P.
        • Mole D.R.
        • Tian Y.M.
        • et al.
        Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
        Science. 2001; 292: 468-472
        • Ivan M.
        • Kondo K.
        • Yang H.
        • et al.
        HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
        Science. 2001; 292: 464-468
        • Yu F.
        • White S.B.
        • Zhao Q.
        • et al.
        HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation.
        Proc Natl Acad Sci U S A. 2001; 98: 9630-9635
        • Ivan M.
        • Haberberger T.
        • Gervasi D.C.
        • et al.
        Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor.
        Proc Natl Acad Sci U S A. 2002; 99: 13459-13464
        • Huang J.
        • Zhao Q.
        • Mooney S.M.
        • et al.
        Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3.
        J Biol Chem. 2002; 277: 39792-39800
        • Epstein A.C.
        • Gleadle J.M.
        • McNeill L.A.
        • et al.
        C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
        Cell. 2001; 107: 43-54
        • Bruick R.K.
        • McKnight S.L.
        A conserved family of prolyl-4-hydroxylases that modify HIF.
        Science. 2001; 294: 1337-1340
        • Fandrey J.
        • Schodel J.
        • Eckardt K.U.
        • et al.
        Now a nobel gas: oxygen.
        Pflugers Arch. 2019; 471: 1343-1358
        • McIntosh B.E.
        • Hogenesch J.B.
        • Bradfield C.A.
        Mammalian Per-Arnt-Sim proteins in environmental adaptation.
        Annu Rev Physiol. 2010; 72: 625-645
        • Kaelin Jr., W.G.
        • Ratcliffe P.J.
        Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
        Mol Cell. 2008; 30: 393-402
        • Mahon P.C.
        • Hirota K.
        • Semenza G.L.
        FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.
        Genes Dev. 2001; 15: 2675-2686
        • Lando D.
        • Peet D.J.
        • Gorman J.J.
        • et al.
        FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.
        Genes Dev. 2002; 16: 1466-1471
        • Rankin E.B.
        • Biju M.P.
        • Liu Q.
        • et al.
        Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.
        J Clin Invest. 2007; 117: 1068-1077
        • Kapitsinou P.P.
        • Liu Q.
        • Unger T.L.
        • et al.
        Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
        Blood. 2010; 116: 3039-3048
        • Koury M.J.
        • Haase V.H.
        Anaemia in kidney disease: harnessing hypoxia responses for therapy.
        Nat Rev Nephrol. 2015; 11: 394-410
        • Sanghani N.S.
        • Haase V.H.
        Hypoxia-inducible factor activators in renal anemia: current clinical experience.
        Adv Chronic Kidney Dis. 2019; 26: 253-266
        • Semenza G.L.
        Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology.
        Trends Mol Med. 2001; 7: 345-350
        • Barrett T.D.
        • Palomino H.L.
        • Brondstetter T.I.
        • et al.
        Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats.
        Br J Pharmacol. 2015; 172: 4078-4088
        • Nemeth E.
        • Tuttle M.S.
        • Powelson J.
        • et al.
        Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.
        Science. 2004; 306: 2090-2093
        • Weiss G.
        • Ganz T.
        • Goodnough L.T.
        Anemia of inflammation.
        Blood. 2019; 133: 40-50
        • Ganz T.
        • Olbina G.
        • Girelli D.
        • et al.
        Immunoassay for human serum hepcidin.
        Blood. 2008; 112: 4292-4297
        • van Swelm R.P.L.
        • Wetzels J.F.M.
        • Swinkels D.W.
        The multifaceted role of iron in renal health and disease.
        Nat Rev Nephrol. 2020; 16: 77-98
        • Ganz T.
        • Nemeth E.
        Hepcidin and iron homeostasis.
        Biochim Biophys Acta. 2012; 1823: 1434-1443
        • Nicolas G.
        • Chauvet C.
        • Viatte L.
        • et al.
        The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation.
        J Clin Invest. 2002; 110: 1037-1044
        • Pak M.
        • Lopez M.A.
        • Gabayan V.
        • et al.
        Suppression of hepcidin during anemia requires erythropoietic activity.
        Blood. 2006; 108: 3730-3735
        • Ashby D.R.
        • Gale D.P.
        • Busbridge M.
        • et al.
        Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin.
        Haematologica. 2010; 95: 505-508
        • Talbot N.P.
        • Lakhal S.
        • Smith T.G.
        • et al.
        Regulation of hepcidin expression at high altitude.
        Blood. 2012; 119: 857-860
        • Ganz T.
        Erythropoietic regulators of iron metabolism.
        Free Radic Biol Med. 2019; 133: 69-74
        • Arezes J.
        • Foy N.
        • McHugh K.
        • et al.
        Erythroferrone inhibits the induction of hepcidin by BMP6.
        Blood. 2018; 132: 1473-1477
        • Volke M.
        • Gale D.P.
        • Maegdefrau U.
        • et al.
        Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors.
        PLoS One. 2009; 4e7875
        • Liu Q.
        • Davidoff O.
        • Niss K.
        • et al.
        Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
        J Clin Invest. 2012; 122: 4635-4644
        • Mastrogiannaki M.
        • Matak P.
        • Mathieu J.R.
        • et al.
        Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis.
        Haematologica. 2012; 97: 827-834
        • Yeh T.L.
        • Leissing T.M.
        • Abboud M.I.
        • et al.
        Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
        Chem Sci. 2017; 8: 7651-7668
        • Hara K.
        • Takahashi N.
        • Wakamatsu A.
        • et al.
        Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.
        Drug Metab Pharmacokinet. 2015; 30: 410-418
        • Kansagra K.A.
        • Parmar D.
        • Jani R.H.
        • et al.
        Phase I clinical study of ZYAN1, a novel prolyl-hydroxylase (PHD) inhibitor to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers.
        Clin Pharmacokinet. 2018; 57: 87-102
        • Fukui K.
        • Shinozaki Y.
        • Kobayashi H.
        • et al.
        JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-alpha protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor.
        Eur J Pharmacol. 2019; 859: 172532
        • Pai S.M.
        • Connaire J.
        • Yamada H.
        • et al.
        A mass balance study of (14) C-labeled JTZ-951 (enarodustat), a novel orally available erythropoiesis-stimulating agent, in patients with end-stage renal disease on hemodialysis.
        Clin Pharmacol Drug Dev. 2020; 9: 728-741
        • Bottcher M.
        • Lentini S.
        • Arens E.R.
        • et al.
        First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.
        Br J Clin Pharmacol. 2018; 84: 1557-1565
        • Beck H.
        • Jeske M.
        • Thede K.
        • et al.
        Discovery of molidustat (BAY 85-3934): a small-molecule oral HIF-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of renal anemia.
        ChemMedChem. 2018; 13: 988-1003
        • Shibata T.
        • Nomura Y.
        • Takada A.
        • et al.
        Evaluation of food and spherical carbon adsorbent effects on the pharmacokinetics of roxadustat in healthy nonelderly adult male Japanese subjects.
        Clin Pharmacol Drug Dev. 2019; 8: 304-313
        • Chavan A.B.
        • Paulson S.K.
        • Burke L.
        • et al.
        Effect of moderate hepatic impairment on pharmacokinetics of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) [abstract TH-PO369].
        J Am Soc Nephrol. 2019; 30: 210
        • Akizawa T.
        • Maeda K.
        • Miyazawa Y.
        • et al.
        Phase 3 study to compare the efficacy and safety of enarodustat (JTZ-951), an oral HIF-PH inhibitor, with darbepoetin alfa in anemic patients with CKD receiving maintenance hemodialysis [abstract TH-PO1186].
        J Am Soc Nephrol. 2019; 30: B4
        • Akizawa T.
        • Matsui A.
        • Miyazawa Y.
        • et al.
        Phase 3 study to compare the efficacy and safety of enarodustat (JTZ-951), an oral HIF-PH inhibitor, with darbepoetin alfa in anemic patients with CKD not requiring dialysis [abstract TH-PO1185].
        J Am Soc Nephrol. 2019; 30: B4
        • Caltabiano S.
        • Cizman B.
        • Burns O.
        • et al.
        Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure.
        Clin Kidney J. 2019; 12: 693-701
        • Macdougall I.C.
        • Akizawa T.
        • Berns J.S.
        • et al.
        Effects of molidustat in the treatment of anemia in CKD.
        Clin J Am Soc Nephrol. 2019; 14: 28-39
        • Johnson B.M.
        • Stier B.A.
        • Caltabiano S.
        Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863.
        Clin Pharmacol Drug Dev. 2014; 3: 109-117
        • Shibata T.
        • Nomura Y.
        • Takada A.
        • et al.
        Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects.
        J Clin Pharm Ther. 2018; 43: 633-639
        • Eichner D.
        • Van Wagoner R.M.
        • Brenner M.
        • et al.
        lmplementation of the prolyl hydroxylase inhibitor roxadustat (FG-4592) and its main metabolites into routine doping controls.
        Drug Test Anal. 2017; 9: 1768-1778
        • Groenendaal-van de Meent D.
        • den Adel M.
        • van Dijk J.
        • et al.
        Effect of multiple doses of omeprazole on the pharmacokinetics, safety, and tolerability of roxadustat in healthy subjects.
        Eur J Drug Metab Pharmacokinet. 2018; 43: 685-692
        • Caltabiano S.
        • Mahar K.M.
        • Lister K.
        • et al.
        The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects.
        Pharmacol Res Perspect. 2018; 6e00327
        • Akizawa T.
        • Iekushi K.
        • Matsuda Y.
        • et al.
        P1866 to investigate the efficacy and safety of molidustat in non-dialysis patients with renal anemia who are not treated with erythropoiesis-stimulating agents: Miyabi Nd-C.
        Nephrol Dial Transplant. 2020; 35: iii2177
        • Akizawa T.
        • Iekushi K.
        • Matsuda Y.
        • et al.
        P1868 to investigate the efficacy and safety of molidustat in non-dialysis patients with renal anemia who are treated with erythropoiesis-stimulating agents: Miyabi Nd-M.
        Nephrol Dial Transplant. 2020; 35: iii2179
        • Akizawa T.
        • Yamaguchi Y.
        • Otsuka T.
        • et al.
        A phase 3, multicenter, randomized, two-arm, open-label study of intermittent oral dosing of roxadustat for the treatment of anemia in Japanese erythropoiesis-stimulating agent-naive chronic kidney disease patients not on dialysis.
        Nephron. 2020; 144: 372-382
        • Akizawa T.
        • Iwasaki M.
        • Otsuka T.
        • et al.
        A phase 3, multicenter, randomized, open-label, active comparator conversion study of roxadustat in non-dialysis-dependent (NDD) patients with anemia in CKD [abstract PO0269].
        J Am Soc Nephrol. 2020; 31: 134
        • Esposito C.
        • Csiky B.
        • Tataradze A.
        • et al.
        Two phase 3, multicenter, randomized studies of intermittent oral roxadustat in anemic CKD patients on (PYRENEES) and not on (ALPS) dialysis [abstract SA-PO225].
        J Am Soc Nephrol. 2019; 30: 822
        • Coyne D.W.
        • Roger S.D.
        • Shin S.K.
        • et al.
        ANDES: a phase 3, randomized, double-blind, placebo controlled study of the efficacy and safety of roxadustat for the treatment of anemia in CKD patients not on dialysis [abstract SA-PO228].
        J Am Soc Nephrol. 2019; 30: 822
        • Fishbane S.
        • El-Shahawy M.A.
        • Pecoit-Filho R.
        • et al.
        OLYMPUS: a phase 3, randomized, double-blind, placebo-controlled, international study of roxadustat efficacy in patients with non-dialysis-dependent (NDD) CKD and anemia [abstract TH-OR023].
        J Am Soc Nephrol. 2019; 30: 6
        • Barratt J.
        • Andre B.
        • Tataradze A.
        • et al.
        Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomised, open-label, active-controlled study.
        Nephrol Dial Transplant. 2020; 35: iii101-iii102
        • Chertow G.M.
        • PRO2TECT Author Group
        Global phase 3 clinical trials of vadadustat vs. darbepoetin alfa for treatment of anemia in patients with non-dialysis-dependent CKD [abstract FR-OR54].
        J Am Soc Nephrol. 2020; 31: B2
        • Akizawa T.
        • Yamada H.
        • Nobori K.
        • et al.
        Results from a phase 3 study comparing the efficacy and safety of molidustat vs. darbepoetin alfa in patients receiving hemodialysis and treated with erythropoiesis-stimulating agents (ESAs) [abstract PO2623].
        J Am Soc Nephrol. 2020; 31: B4
        • Provenzano R.
        • Evgeny S.
        • Liubov E.
        • et al.
        HIMALAYAS: a phase 3, randomized, open-label, active-controlled study of the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis patients [abstract TH-OR021].
        J Am Soc Nephrol. 2019; 30: 5
        • Fishbane S.
        • Pollock C.A.
        • El-Shahawy M.A.
        • et al.
        ROCKIES: an international, phase 3, randomized, open-label, active-controlled study of roxadustat for anemia in dialysis-dependent CKD patients [abstract TH-OR022].
        J Am Soc Nephrol. 2019; 30: 6
        • Charytan C.
        • Manllo-Karim R.
        • Martin E.R.
        • et al.
        SIERRAS: a phase 3, open-label, randomized, active-controlled study of the efficacy and safety of roxadustat in the maintenance treatment of anemia in subjects with ESRD on stable dialysis [abstract SA-PO227].
        J Am Soc Nephrol. 2019; 30: 822
        • Eckardt K.U.
        • INNO2VATE Author Group
        Global phase 3 clinical trials of vadadustat vs darbepoetin alfa for treatment of anemia in patients with dialysis-dependent CKD [abstract TH-OR01].
        J Am Soc Nephrol. 2020; 31: 1
        • Brigandi R.A.
        • Johnson B.
        • Oei C.
        • et al.
        A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: a 28-day, phase 2A randomized trial.
        Am J Kidney Dis. 2016; 67: 861-871
        • Holdstock L.
        • Cizman B.
        • Meadowcroft A.M.
        • et al.
        Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants with chronic kidney disease.
        Clin Kidney J. 2019; 12: 129-138
        • Holdstock L.
        • Meadowcroft A.M.
        • Maier R.
        • et al.
        Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia.
        J Am Soc Nephrol. 2016; 27: 1234-1244
        • Parmar D.V.
        • Kansagra K.A.
        • Patel J.C.
        • et al.
        Outcomes of desidustat treatment in people with anemia and chronic kidney disease: a phase 2 study.
        Am J Nephrol. 2019; 49: 470-478
        • Akizawa T.
        • Nangaku M.
        • Yamaguchi T.
        • et al.
        A placebo-controlled, randomized trial of enarodustat in patients with chronic kidney disease followed by long-term trial.
        Am J Nephrol. 2019; 49: 165-174
        • Akizawa T.
        • Macdougall I.C.
        • Berns J.S.
        • et al.
        Iron regulation by molidustat, a daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in patients with chronic kidney disease.
        Nephron. 2019; 143: 243-254
        • Besarab A.
        • Provenzano R.
        • Hertel J.
        • et al.
        Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.
        Nephrol Dial Transplant. 2015; 30: 1665-1673
        • Chen N.
        • Qian J.
        • Chen J.
        • et al.
        Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
        Nephrol Dial Transplant. 2017; 32: 1373-1386
        • Provenzano R.
        • Besarab A.
        • Sun C.H.
        • et al.
        Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD.
        Clin J Am Soc Nephrol. 2016; 11: 982-991
        • Akizawa T.
        • Iwasaki M.
        • Otsuka T.
        • et al.
        Roxadustat treatment of chronic kidney disease-associated anemia in Japanese patients not on dialysis: a phase 2, randomized, double-blind, placebo-controlled trial.
        Adv Ther. 2019; 36: 1438-1454
        • Martin E.R.
        • Smith M.T.
        • Maroni B.J.
        • et al.
        Clinical trial of vadadustat in patients with anemia secondary to stage 3 or 4 chronic kidney disease.
        Am J Nephrol. 2017; 45: 380-388
        • Pergola P.E.
        • Spinowitz B.S.
        • Hartman C.S.
        • et al.
        Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
        Kidney Int. 2016; 90: 1115-1122
      1. Nangaku M, Farag YMK, deGoma E, et al. Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, for treatment of anemia of chronic kidney disease: two randomized phase 2 trials in Japanese patients [epub ahead of print]. Nephrol Dial Transplant. doi.org/10.1093/ndt/gfaa060. Accessed February 9, 2021.

        • Akebia Therapeutics
        Akebia presents results from its PRO2TECT global phase 3 program of vadadustat for the treatment of anemia due to chronic kidney disease in adult patients not on dialysis during late-breaking session at American Society of Nephrology Kidney Week 2020 Reimagined.
        (Available at:)
        • Kautz L.
        • Jung G.
        • Valore E.V.
        • et al.
        Identification of erythroferrone as an erythroid regulator of iron metabolism.
        Nat Genet. 2014; 46: 678-684
        • Meadowcroft A.M.
        • Cizman B.
        • Holdstock L.
        • et al.
        Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis.
        Clin Kidney J. 2019; 12: 139-148
        • Akizawa T.
        • Tsubakihara Y.
        • Nangaku M.
        • et al.
        Effects of daprodustat, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor on anemia management in Japanese hemodialysis subjects.
        Am J Nephrol. 2017; 45: 127-135
        • Bailey C.K.
        • Caltabiano S.
        • Cobitz A.R.
        • et al.
        A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis.
        BMC Nephrol. 2019; 20: 372
        • Akizawa T.
        • Nangaku M.
        • Yamaguchi T.
        • et al.
        Enarodustat, conversion and maintenance therapy for anemia in hemodialysis patients: a randomized, placebo-controlled phase 2b trial followed by long-term trial.
        Nephron. 2019; 143: 77-85
        • Provenzano R.
        • Besarab A.
        • Wright S.
        • et al.
        Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study.
        Am J Kidney Dis. 2016; 67: 912-924
        • Haase V.H.
        • Chertow G.M.
        • Block G.A.
        • et al.
        Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.
        Nephrol Dial Transplant. 2019; 34: 90-99
        • Besarab A.
        • Chernyavskaya E.
        • Motylev I.
        • et al.
        Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
        J Am Soc Nephrol. 2016; 27: 1225-1233
        • Provenzano R.
        • Fishbane S.
        • Wei L.J.
        • et al.
        Pooled efficacy and cardiovascular (CV) analyses of roxadustat in the treatment of anemia in CKD patients on and not on dialysis [abstract FR-OR131].
        J Am Soc Nephrol. 2019; 30: B1
        • Fishbane S.
        • Besarab A.
        Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets.
        Clin J Am Soc Nephrol. 2007; 2: 1274-1282
        • Wagner M.
        • Alam A.
        • Zimmermann J.
        • et al.
        Endogenous erythropoietin and the association with inflammation and mortality in diabetic chronic kidney disease.
        Clin J Am Soc Nephrol. 2011; 6: 1573-1579
        • Lonnberg M.
        • Garle M.
        • Lonnberg L.
        • et al.
        Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis.
        J Pharm Biomed Anal. 2013; 81–82: 187-192
        • de Seigneux S.
        • Lundby A.K.
        • Berchtold L.
        • et al.
        Increased synthesis of liver erythropoietin with CKD.
        J Am Soc Nephrol. 2016; 27: 2265-2269
        • Flamme I.
        • Oehme F.
        • Ellinghaus P.
        • et al.
        Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects.
        PLoS One. 2014; 9e111838
        • Bernhardt W.M.
        • Wiesener M.S.
        • Scigalla P.
        • et al.
        Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.
        J Am Soc Nephrol. 2010; 21: 2151-2156
        • Shinfuku A.
        • Shimazaki T.
        • Fujiwara M.
        • et al.
        Novel compound induces erythropoietin secretion through liver effects in chronic kidney disease patients and healthy volunteers.
        Am J Nephrol. 2018; 48: 157-164
        • Agarwal A.K.
        Iron metabolism and management: focus on chronic kidney disease.
        Kidney Int Suppl. 2021; 11: 46-57
        • Macdougall I.C.
        • Hutton R.D.
        • Cavill I.
        • et al.
        Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously.
        BMJ. 1989; 299: 157-158
        • Rutherford C.J.
        • Schneider T.J.
        • Dempsey H.
        • et al.
        Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response.
        Am J Med. 1994; 96: 139-145
        • Raichoudhury R.
        • Spinowitz B.S.
        Treatment of anemia in difficult-to-manage patients with chronic kidney disease.
        Kidney Int Suppl. 2021; 11: 26-34
        • Del Balzo U.
        • Signore P.E.
        • Walkinshaw G.
        • et al.
        Nonclinical characterization of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat, a novel treatment of anemia of chronic kidney disease.
        J Pharmacol Exp Ther. 2020; 374: 342-353
        • Eltzschig H.K.
        • Bratton D.L.
        • Colgan S.P.
        Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.
        Nat Rev Drug Discov. 2014; 13: 852-869
        • Taylor C.T.
        • Doherty G.
        • Fallon P.G.
        • et al.
        Hypoxia-dependent regulation of inflammatory pathways in immune cells.
        J Clin Invest. 2016; 126: 3716-3724
        • Cizman B.
        • Sykes A.P.
        • Paul G.
        • et al.
        An exploratory study of daprodustat in erythropoietin-hyporesponsive subjects.
        Kidney Int Rep. 2018; 3: 841-850
        • Haase V.H.
        • Khawaja Z.
        • Chan J.
        • et al.
        Vadadustat maintains hemoglobin (Hb) levels in dialysis-dependent chronic kidney disease (DD-CKD) patients independent of systemic inflammation or prior dose of erythropoiesis-stimulating agent (ESA) [abstract TH-PO960].
        J Am Soc Nephrol. 2016; 27: 318A
        • Sandner P.
        • Gess B.
        • Wolf K.
        • et al.
        Divergent regulation of vascular endothelial growth factor and of erythropoietin gene expression in vivo.
        Pflugers Arch. 1996; 431: 905-912
        • Seeley T.W.
        • Sternlicht M.D.
        • Klaus S.J.
        • et al.
        Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer.
        Hypoxia. 2017; 5: 1-9
        • PMDA
        Japanese Pharmaceutical and Medical Devices Agency report on roxadustat.
        (Available at:)
        https://www.pmda.go.jp/files/000234811.pdf
        Date accessed: July 22, 2020
        • Akebia Therapeutics
        Akebia presents results from its INNO2VATE global phase 3 program; demonstrated efficacy and cardiovascular safety of vadadustat for the treatment of anemia due to chronic kidney disease in adult patients on dialysis.
        (Available at:)
        • Cozzolino M.
        • Mangano M.
        • Stucchi A.
        • et al.
        Cardiovascular disease in dialysis patients.
        Nephrol Dial Transplant. 2018; 33: iii28-iii34
        • Gansevoort R.T.
        • Correa-Rotter R.
        • Hemmelgarn B.R.
        • et al.
        Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
        Lancet. 2013; 382: 339-352
        • Kapitsinou P.P.
        • Haase V.H.
        Molecular mechanisms of ischemic preconditioning in the kidney.
        Am J Physiol Renal Physiol. 2015; 309: F821-F834
        • Hwang S.
        • Nguyen A.D.
        • Jo Y.
        • et al.
        Hypoxia-inducible factor 1alpha activates insulin-induced gene 2 (Insig-2) transcription for degradation of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the liver.
        J Biol Chem. 2017; 292: 9382-9393
        • Shen G.M.
        • Zhao Y.Z.
        • Chen M.T.
        • et al.
        Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia.
        Biochem J. 2012; 441: 675-683
        • Caltabiano S.
        • Collins J.
        • Serbest G.
        • et al.
        A randomized, placebo- and positive-controlled, single-dose, crossover thorough QT/QTc study assessing the effect of daprodustat on cardiac repolarization in healthy subjects.
        Clin Pharmacol Drug Dev. 2017; 6: 627-640
        • FibroGen
        FibroGen announces positive phase 3 pooled roxadustat safety and efficacy results for treatment of anemia in chronic kidney disease.
        (Available at:)
        • Lin M.
        • Chen Y.
        • Jin J.
        • et al.
        Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Muller cells.
        Diabetologia. 2011; 54: 1554-1566
        • West J.B.
        • Schoene R.B.
        • Milledge J.S.
        High Altitude Medicine and Physiology.
        4th ed. Hodder Arnold, London, England2007
        • Semenza G.L.
        The genomics and genetics of oxygen homeostasis.
        Annu Rev Genomics Hum Genet. 2020; 21: 183-204
        • Chappell J.C.
        • Payne L.B.
        • Rathmell W.K.
        Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers.
        J Clin Invest. 2019; 129: 442-451
        • Beck J.
        • Henschel C.
        • Chou J.
        • et al.
        Evaluation of the carcinogenic potential of roxadustat (FG-4592), a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase in CD-1 mice and Sprague Dawley rats.
        Int J Toxicol. 2017; 36: 427-439
        • Adams D.F.
        • Watkins M.S.
        • Durette L.
        • et al.
        Carcinogenicity assessment of daprodustat (GSK1278863), a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor.
        Toxicol Pathol. 2020; 48: 362-378
        • Coyne D.W.
        • Fishbane S.
        • Pergola P.E.
        • et al.
        Roxadustat is not associated with an increased risk of neoplasm in patients with CKD and anemia [abstract TH-OR04].
        J Am Soc Nephrol. 2020; 31: 1
        • Cowburn A.S.
        • Crosby A.
        • Macias D.
        • et al.
        HIF2alpha-arginase axis is essential for the development of pulmonary hypertension.
        Proc Natl Acad Sci U S A. 2016; 113: 8801-8806
        • Kapitsinou P.P.
        • Rajendran G.
        • Astleford L.
        • et al.
        The endothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 axis regulates pulmonary artery pressure in mice.
        Mol Cell Biol. 2016; 36: 1584-1594
        • Shimoda L.A.
        • Yun X.
        • Sikka G.
        Revisiting the role of hypoxia-inducible factors in pulmonary hypertension.
        Curr Opin Physiol. 2019; 7: 33-40
        • Kaneko M.
        • Minematsu T.
        • Yoshida M.
        • et al.
        Compression-induced HIF-1 enhances thrombosis and PAI-1 expression in mouse skin.
        Wound Repair Regen. 2015; 23: 657-663
        • Gordeuk V.R.
        • Prchal J.T.
        Vascular complications in Chuvash polycythemia.
        Semin Thromb Hemost. 2006; 32: 289-294
        • Kraus A.
        • Peters D.J.M.
        • Klanke B.
        • et al.
        HIF-1alpha promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease.
        Kidney Int. 2018; 94: 887-899
        • Liu J.
        • Wei Q.
        • Guo C.
        • et al.
        Hypoxia, HIF, and associated signaling networks in chronic kidney disease.
        Int J Mol Sci. 2017; 18: 950
        • Mokas S.
        • Lariviere R.
        • Lamalice L.
        • et al.
        Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification.
        Kidney Int. 2016; 90: 598-609
        • Flamme I.
        • Ellinghaus P.
        • Urrego D.
        • et al.
        FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase.
        PLoS One. 2017; 12e0186979