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American Journal of Kidney Diseases

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD

Open AccessPublished:February 24, 2017DOI:https://doi.org/10.1053/j.ajkd.2016.12.011
      Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

      Index Words

      Recombinant human erythropoietin (rHuEPO) was approved for the treatment of anemia in 1989 by the US Food and Drug Administration (FDA).
      • 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.
      • Takeuchi M.
      • Kobata A.
      Structures and functional roles of the sugar chains of human erythropoietins.
      Studies demonstrated that treatment of anemia related to chronic kidney disease (CKD) with rHuEPO and related products (erythropoiesis-stimulating agents [ESAs]) increases hemoglobin (Hb) levels, lessens the need for transfusion, and improves patient quality of life.
      • Stone W.J.
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      • Krantz S.B.
      • et al.
      Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebo-controlled trial.
      However, treatment to higher Hb targets in clinical trials has resulted in higher rates of access thrombosis, cerebrovascular events, and cardiovascular events; earlier requirement for kidney replacement therapy; and higher mortality.
      • Singh A.K.
      • Szczech L.
      • Tang K.L.
      • et al.
      Correction of anemia with epoetin alfa in chronic kidney disease.
      • Drueke T.B.
      • Locatelli F.
      • Clyne N.
      • et al.
      Normalization of hemoglobin level in patients with chronic kidney disease and anemia.
      It is still not known whether the ESA dose or the higher target Hb level was the cause of these adverse events (AEs). Nonetheless, investigators have pursued the “holy grail” of an anemia therapy agent that would increase Hb levels, improve quality of life, reduce transfusion requirements, and avoid AEs.
      There are 2 key causes underlying the development of anemia in CKD: erythropoietin (EPO) deficiency and functional iron deficiency (FID). EPO deficiency represents a blunted, though not absent, response in EPO production to the degree of anemia. FID is a combination of impaired iron mobilization from stores and inadequate delivery of iron to the erythroid marrow in the setting of increased red blood cell (RBC) production induced by pharmacologic treatment with ESAs. Absolute iron deficiency may also occur in patients with CKD due to inadequate provision or absorption of dietary iron and/or blood losses.
      An emerging approach to the treatment of EPO deficiency in anemic patients with CKD is the use of agents that stimulate endogenous EPO production in renal and nonrenal tissues. Such a strategy might decrease adverse outcomes by allowing for a more consistent, although not necessarily continuous, physiologic level of EPO to stimulate RBC production rather than the high intermittent blood levels that result from pharmacologic administration of an exogenous ESA. One class of agents under development works to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. In normoxia, HIF-PH activity leads to rapid degradation of HIF. During hypoxia, HIF-PH activity is suppressed, allowing HIF to accumulate and directly stimulate endogenous EPO production, upregulate transferrin receptor expression, increase iron uptake by proerythrocytes, and promote maturation of erythrocytes replete with Hb. It is hypothesized that the consistent but noncontinuous low-level stimulation of HIF by these agents improves erythropoiesis while minimizing some of the undesirable downstream effects of continuous HIF stimulation. In contrast to a recent overview of all new approaches to the treatment of anemia in patients with CKD,
      • Bonomini M.
      • Del Vecchio L.
      • Sirolli V.
      • Locatelli F.
      New treatment approaches for the anemia of CKD.
      this review focuses on the mechanism of action and results of phase 1 and 2 studies of 4 HIF-PH inhibitors currently under investigation in the United States.

      Hypoxia-Inducible Factor

      Mechanism of Action

      HIF is a key transcription factor that produces a physiologic response to reduced tissue oxygen levels by activating the expression of certain genes. The purpose of this adaptive homeostatic response is to restore oxygen balance and protect against cellular damage while oxygen levels are being restored.
      • 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.
      • Wang G.L.
      • Jiang B.H.
      • Rue E.A.
      • Semenza G.L.
      Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
      HIF is a heterodimer with an α and β subunit. The β subunit is present consistently and is also known as the aryl hydrocarbon receptor nuclear translocator (ARNT) protein. The α subunit is the limiting factor in the creation of the functional dimer. The HIF-α subunit joins with the β subunit in the nucleus and binds to DNA sequences called hypoxia response elements (HREs) and thus induces the expression of target genes. There are 3 isoforms of the α subunit: HIF-1α, HIF-2α, and HIF-3α, any of which can combine with the β subunit to induce the expression of different combinations of target genes. The primary means of HIF activity regulation is hydroxylation at 2 proline residues by a family of HIF-PH enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, of which there are 3 members: PHD1, PHD2, and PHD3
      • 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.
      • Ivan M.
      • Kondo K.
      • Yang H.
      • et al.
      HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
      (Fig 1). PHD2 is the main regulator of HIF activity in normoxia.
      • Vogel S.
      • Wottawa M.
      • Farhat K.
      • et al.
      Prolyl hydroxylase domain (PHD) 2 affects cell migration and F-actin formation via RhoA/rho-associated kinase-dependent cofilin phosphorylation.
      • Lee D.C.
      • Sohn H.A.
      • Park Z.Y.
      • et al.
      A lactate-induced response to hypoxia.
      HIF-α subunits are also regulated by hydroxylation at a carboxy-terminal asparagine residue by factor-inhibiting HIF (FIH).
      • Lando D.
      • Peet D.J.
      • Whelan D.A.
      • Gorman J.J.
      • Whitelaw M.L.
      Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.
      Factor-inhibiting HIF prevents the recruitment of transcriptional coactivators, thereby limiting HIF activity.
      • Lando D.
      • Peet D.J.
      • Gorman J.J.
      • Whelan D.A.
      • Whitelaw M.L.
      • Bruick R.K.
      FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.
      Several experiments have demonstrated that HIF-2α is the main subunit involved in upregulating EPO gene expression and iron transport in hypoxia.
      • Tanaka T.
      • Nangaku M.
      Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents.
      HIF-2α is expressed in peritubular fibroblasts, which are thought to be the primary site of renal EPO production.
      • Rosenberger C.
      • Mandriota S.
      • Jurgensen J.S.
      • et al.
      Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys.
      HIF-1α is expressed in nearly all cell types, whereas HIF-2α has a more limited distribution. HIF-1α is expressed under normoxic baseline conditions, in contrast to HIF-2α. From this, HIF-2α appears to be a key element in the hypoxic response; however, in certain situations, HIF-1α controls the early response to hypoxia.
      Figure thumbnail gr1
      Figure 1Hypoxia-inducible factor (HIF) pathway. Abbreviations: DcytB, duodenal cytochrome B; DMT1, divalent metal transporter 1; EPO, erythropoietin; PH, prolyl hydroxylase.
      PHD1, PHD2, and PHD3 are nonheme iron-containing dioxygenases that require oxygen and 2-oxoglutarate as cosubstrates and iron and ascorbate as cofactors for their enzymatic activity. Oxygen-dependent regulation of HIF mainly involves the degradation of HIF-α subunits, which starts with hydroxylation of HIF-α by HIF-PH enzymes.
      • 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.
      HIF-PH enzymes require oxygen for their catalytic activity to regulate HIF. Thus, when oxygen levels decrease, prolyl hydroxylation does not occur, which allows HIF-α to dimerize with its partner HIF-β and accumulate in the nucleus to regulate HIF target genes.
      • 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.
      • Ivan M.
      • Kondo K.
      • Yang H.
      • et al.
      HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
      HIF stabilization increases gene transcription by binding to HREs, thus upregulating EPO and other genes.
      • Masson N.
      • Willam C.
      • Maxwell P.H.
      • Pugh C.W.
      • Ratcliffe P.J.
      Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.
      In a mouse model in which tamoxifen is used to conditionally knock out exon 2 of the PHD2 gene, enhanced angiogenesis and increased vascular endothelial growth factor (VEGF)-A and EPO levels are observed.
      • Takeda K.
      • Ho V.C.
      • Takeda H.
      • Duan L.J.
      • Nagy A.
      • Fong G.H.
      Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2.
      • Takeda K.
      • Cowan A.
      • Fong G.H.
      Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system.
      The other important mechanism contributing to anemia in CKD is FID, typically associated with pharmacologic ESA use. In FID, the serum ferritin level is typically normal or high and transferrin saturation (TSAT) is low.
      • Lankhorst C.E.
      • Wish J.B.
      Anemia in renal disease: diagnosis and management.
      FID is mediated by hepcidin, an acute-phase reactant protein produced in the liver that prevents the release of iron from macrophages to circulating transferrin and inhibits intestinal iron absorption. HIF also regulates iron metabolism and handling. HIF-2α appears to be the isoform primarily responsible for regulating iron metabolism genes in liver, with HIF-1α playing a smaller role.
      • Kapitsinou P.P.
      • Liu Q.
      • Unger T.L.
      • et al.
      Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
      HIF upregulates transferrin, ceruloplasmin, and transferrin receptor 1, the latter facilitating increased plasma transport of iron to tissues.
      • Rolfs A.
      • Kvietikova I.
      • Gassmann M.
      • Wenger R.H.
      Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1.
      • Bianchi L.
      • Tacchini L.
      • Cairo G.
      HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation.
      • Tacchini L.
      • Bianchi L.
      • Bernelli-Zazzera A.
      • Cairo G.
      Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation.
      HIF-2α boosts intestinal absorption of iron by upregulating duodenal cytochrome b and divalent metal transporter 1, 2 important genes in iron uptake and export.
      • Kapitsinou P.P.
      • Liu Q.
      • Unger T.L.
      • et al.
      Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia.
      • Mastrogiannaki M.
      • Matak P.
      • Keith B.
      • Simon M.C.
      • Vaulont S.
      • Peyssonnaux C.
      HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice.
      EPO production induced by HIF leads to the production by erythroblasts of erythroferrone, which limits the gene expression of liver hepcidin.
      • Peyssonnaux C.
      • Zinkernagel A.S.
      • Schuepbach R.A.
      • et al.
      Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).
      • Liu Q.
      • Davidoff O.
      • Niss K.
      • Haase V.H.
      Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
      These functions of HIF complement its effect on erythropoiesis by coordinating EPO-stimulated RBC production with increased available iron.
      HIF-1α plays a critical role in the cell-cycle regulation of hematopoietic stem cells.
      • Takubo K.
      • Goda N.
      • Yamada W.
      • et al.
      Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.
      Hematopoietic stem cells are considered to be localized in the hypoxic niches of bone marrow; they usually stay quiescent, but have the potential to divide into multiple blood progenitor cells. In response to stresses such as blood loss, hematopoietic stem cells rapidly expand and differentiate to regenerate RBCs.
      • Forristal C.E.
      • Winkler I.G.
      • Nowlan B.
      • Barbier V.
      • Walkinshaw G.
      • Levesque J.P.
      Pharmacologic stabilization of HIF-1alpha increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation.
      Stabilization of HIF-1α using HIF-PH inhibitors has been reported to stimulate hematopoiesis through manipulating the niches of bone marrow stem cells in vivo.
      • Forristal C.E.
      • Winkler I.G.
      • Nowlan B.
      • Barbier V.
      • Walkinshaw G.
      • Levesque J.P.
      Pharmacologic stabilization of HIF-1alpha increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation.
      The effect on bone-marrow stem cells seems independent of EPO, which indicates that HIF-PH inhibitors may increase Hb levels through an additional pathway as compared with conventional ESAs. The hematopoietic effects of HIF are illustrated in Fig 2.
      Figure thumbnail gr2
      Figure 2Erythropoietic effects of hypoxia-inducible factor (HIF). (1) HIF upregulates divalent metal transporter 1 (DMT1) and duodenal cytochrome B (DcytB) to increase intestinal iron (Fe) absorption; (2) transferrin transports Fe to transferrin receptors in the bone marrow; (3) Fe is released from transferrin into the developing erythrocyte; (4) HIF upregulates the erythropoietin (EPO) receptor (EPO-R) and endogenous EPO production; (5) HIF upregulates transferrin receptor, increasing iron uptake by proerythrocytes; (6) HIF promotes the formation of fully functional mature erythrocytes replete with hemoglobin (Hb); (7) after a lifespan averaging approximately 120 days, exhausted erythrocytes are scavenged in the liver and the Fe is returned for reuse. Abbreviation: GI, gastrointestinal.

      HIF Stabilizers Currently Under Development

      Overview

      Several molecules that inhibit HIF-PH enzymes are under development for treating anemia in patients with CKD. This section reviews the available evidence from abstracts and peer-reviewed publications. Characteristics of the 4 HIF-PH inhibitors most advanced in the development pipeline are summarized in Table 1. Use of these agents consistently results in dose-related increases in Hb levels, while decreasing hepcidin and ferritin levels and decreasing TSAT by increasing total iron-binding capacity.
      • 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.
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
      • 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.
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      Table 1Characteristics of HIF-PH Inhibitors Under Development
      Generic NameInvestigational NameSponsorHalf-Life, hDosing FrequencyInvestigational Status
      RoxadustatFG-4592FibroGen, Astellas, & AstraZeneca12-133×/wkPhase 3
      VadadustatAKB-6548Akebia4.5DailyPhase 3
      DaprodustatGSK-1278863GlaxoSmithKline4DailyPhase 2 (US)

      Phase 3 (Japan)
      MolidustatBAY 85-3934BayerNADailyPhase 2
      Abbreviations: HIF-PH, hypoxia-inducible factor prolyl hydroxylase; NA, not available (data not published).
      The first promising molecule in the HIF-PH inhibitor class was FibroGen’s FG-2216. In phase 2a studies performed in 2005, FG-2216 was observed to increase Hb levels in healthy volunteers and hemodialysis patients.
      • Seeley T.W.
      Novel and beneficial pharmacodynamic properties of endogenous EPO and ‘complete erythropoiesis’ induced by selective HIF prolyl hydroxylase inhibitors.
      In patients treated by hemodialysis who had kidneys, the increase varied but tended to be much greater than the response in anephric patients, implying that FG-2216 induced EPO production in nonfunctioning kidneys. Data from phase 2 studies showed that modest increases in endogenous EPO induced by FG-2216 (1/10 to 1/40 of blood EPO levels observed with rHuEPO therapy) are sufficient to mediate erythropoiesis in patients with non–dialysis-dependent (NDD) CKD without increasing the incidence of hypertension or thrombosis.
      • Klaus S.
      • Langsetmo T.
      • Neff A.
      • Liu D.
      Beneficial pharmacodynamic effects resulting from ‘complete erythropoiesis’ induced by novel HIF prolyl hydroxylase inhibitors FG-2216 and FG-4592.
      The studies to test FG-2216 were suspended because 1 participant of a later trial died of fulminant hepatitis, although the death was subsequently determined not to be caused by the drug.
      • Eltzschig H.K.
      • Bratton D.L.
      • Colgan S.P.
      Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases.

      Roxadustat (FG-4592)

      The second-generation HIF-PH inhibitor from FibroGen, Astellas, and AstraZeneca is roxadustat (FG-4592). In a single-blinded placebo-controlled study, 117 participants with NDD CKD stages 3 to 4 randomly assigned to roxadustat (4 doses escalating from 0.7, 1.0, 1.5, and 2.0 mg/kg daily) were found to have a higher mean Hb level increase compared to placebo.
      • Besarab A.
      • Hulter H.N.
      • Klaus S.
      • et al.
      FG-4592, a novel oral HIF prolyl hydroxylase inhibitor, elevates hemoglobin in anemic stage 3/4 CKD patients.
      In a phase 1 open-label study in healthy participants, roxadustat was observed to have a half-life of approximately 12 to 13 hours.
      • Groenendaal-van de Meent D.
      • Adel M.
      • Noukens J.
      • et al.
      Effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor.
      In phase 2 studies of incident dialysis patients, roxadustat at titrated doses was reported to increase mean Hb levels by ≥2.0 g/dL within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality.
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
      Such results are promising in patients with side effects from intravenous or oral iron.
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      FG-4592, an oral hypoxia-inducible factor prolyl hydroxylase-inhibitor, corrects anemia without iron supplementation in incident dialysis patients.
      In another phase 2 study from Provenzano et al,
      • 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.
      144 patients with end-stage renal disease on maintenance hemodialysis therapy whose Hb levels had been previously maintained (mean Hb ≥ 11 g/dL) by epoetin alfa were randomly assigned to roxadustat or to continue epoetin alfa. This trial was designed to assess the efficacy of roxadustat in maintaining Hb levels when converting from an ESA and to establish the optimal starting dose and dose adjustment regimen to maintain target Hb values. Participants with baseline stable epoetin alfa doses were randomly assigned (3:1) to roxadustat or epoetin alfa. Part 1 comprised 54 participants treated for 6 weeks (41 roxadustat and 13 epoetin alfa); part 2 comprised 90 participants treated for 19 weeks (67 roxadustat and 23 epoetin alfa). Hb level responder rates in part 1 were reported to be 79% in pooled roxadustat 1.5 to 2.0 mg/kg thrice weekly compared to 33% in the epoetin alfa control arm (P = 0.03). The roxadustat dose for Hb level maintenance ranged from 0.5 to 3.4 (mean dose, ∼1.7) mg/kg thrice weekly. The effect lasted for the duration of the study.
      Hepcidin, serum ferritin, and C-reactive protein levels were analyzed in a double-blinded multicenter study of roxadustat versus placebo in 145 participants with NDD CKD.
      • 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.
      During the first 16 weeks of treatment, hepcidin levels decreased by 16.9% (P = 0.004), reticulocyte Hb content was preserved, and Hb levels increased by a mean ± standard deviation of 1.83 ± 0.09 g/dL (P < 0.001). Meanwhile, ferritin levels decreased by 85.9 ± 112.6 ng/mL (30.9%; P < 0.001) and total iron-binding capacity increased by 40.4 ± 41.0 mg/dL (15.3%; P < 0.001). Although TSAT and ferritin levels declined during the first few weeks of the intervention, they subsequently stabilized. Roxadustat significantly decreased total cholesterol levels in these patients with NDD CKD in a dose-dependent manner. Of note, a decrease in total cholesterol level by roxadustat in comparison to epoetin alfa was seen in the Provenzano et al
      • 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.
      study, which was performed in dialysis patients.
      In a phase 2b study in patients with NDD CKD and hemodialysis patients, 36-Item Short Form Health Survey (SF-36) and Functional Assessment of Cancer Therapy-Anemia (FACT-AN) scores were reported to be significantly improved from baseline after treatment with roxadustat, particularly in patients presenting with low baseline scores.
      • Szczech L.H.
      • Besarab A.
      • Saikali K.G.
      • Poole L.
      • Yu K.H.P.
      • Neff T.B.
      TH-OR039 anemia correction with roxadustat improves health related quality of life (HRQOL) in chronic kidney disease (CKD) patients.
      Moreover, a preliminary report of a pooled analysis of 5 completed roxadustat phase 2 studies
      • Szczech L.
      • Besarab A.
      • Saikali K.G.
      • et al.
      TH-PO648 anemia correction with roxadustat lowers cholesterol in chronic kidney disease (CKD) patients.
      demonstrated a consistent reduction from baseline in total cholesterol levels that was greatest in patients with the highest baseline levels. In contrast, patients in comparator groups (placebo or epoetin alfa) showed an increase from baseline. AE rates from roxadustat were consistent with background disease in the end-stage renal disease population,
      • 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.
      and none of the serious AEs observed in the NDD CKD population was attributed to study drug.
      • 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.
      Completed phase 2 studies of roxadustat are summarized in Table 2. A number of phase 3 studies in patients with end-stage renal disease and NDD CKD are currently underway with durations of 24 weeks to 3 years. All roxadustat studies are shown in Table S1 (available as online supplementary material).
      Table 2Completed Phase 2 and 3 Studies of Roxadustat (FG-4592), Vadadustat (AKB-6548), Daprodustat (GSK-1278863), and Molidustat (BAY-85-3934) in Anemia of CKD
      IdentifierStatusParticipantsStudy DesignNEnd PointTreatment DurationCD
      Roxadustat (FG-4592)
      NCT00761657Completed; published
      • 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.
      US; NDD CKD3-4 with Hb ≤ 11 g/dLPhase 2, randomized, P-C, S-B, dose-ranging116Safety/efficacy4 wk (+12-wk F/U)June 2010
      NCT01244763Completed; published
      • 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.
      US; NDD CKD3-4 with Hb ≤ 10.5 g/dLPhase 2, randomized, O-L, dose-ranging145Safety/efficacy16 or 24 wkSept 2012
      NCT01599507Completed; abstract
      • Qian J.
      • Chen N.
      • Chen J.
      • et al.
      FR-OR011 A randomized, double-blind, placebo controlled trial of FG-4592 for correction of anemia in subjects with chronic kidney disease in China.
      CN; NDD CKD with Hb < 10 g/dLPhase 2, randomized, P-C, D-B, dose-ranging91Safety/efficacy8 wkJan 2013
      NCT01596855CompletedCN; ESRD on stable HD with Hb 9-12 g/dLPhase 2, randomized, A-C (epoetin alfa), O-L,96Safety/efficacyNAJan 2013
      NCT01414075Completed; published
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
      US, Asia, RU; ESRD on HD or PD with Hb < 10 g/dLPhase 2, randomized O-L, dose ranging60Safety/efficacy12 wkMay 2013
      NCT01147666Completed; published
      • 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.
      US; ESRD on maintenance HDPhase 2, randomized, S-B, P-C, A-C (epoetin)161Safety/efficacy20 wkJuly 2013
      NCT01888445CompletedJP; ESRD on HD (3×/wk for ≥12 wk)Phase 2, randomized, O-L, D-B, A-C (epoetin)130Safety/efficacy6 wk (+28 wk F/U)Sept 2014
      NCT01964196CompletedJP; NDD CKD with eGFR ≤ 89 mL/min/1.73 m2 and Hb < 10.0 g/dLPhase 2, randomized, D-B, P-C107Safety/efficacy6 wk (+28 wk F/U)Dec 2015
      Vadadustat (AKB-6548)
      NCT01235936Completed; abstract
      • Hartman C.
      • Smith M.T.
      • Flinn C.
      • et al.
      AK-6548 a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia.
      US; NDD CKD3-4 with Hb < 10.5 g/dLPhase 2a, O-L, pilot, SGA10Safety/efficacy28 dMay 2011
      NCT01381094Completed; abstract
      • Shalwitz R.
      • Hartman C.
      • Flinn C.
      • et al.
      AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin in chronic kidney disease patients without increasing basal erythropoietin levels.
      • Roger S.
      • Bock A.
      • Carrera F.
      • et al.
      SO048 IV ferric carboxymaltose (FCM) is a convenient and well-tolerated first-line therapy for the treatment of anaemia in patients with iron deficiency and non-dialysis dependent chronic kidney disease (ND-CKD): results of the randomised find-CKD study.
      US; NDD CKD3-5 with Hb ≤10.5 g/dLPhase 2a, randomized, D-B, P-C, dose-ranging91Safety/efficacy42 dMar 2012
      NCT01906489Completed; published
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      US; NDD CKD3a-5 with Hb ≤ 10.5 g/dL; ≥ 9.5-≤ 12.0 g/dL (EPO users)Phase 2b, randomized. D-B, P-C, dose titration210Safety/efficacy20 wkOct 2014
      NCT02260193CompletedUS; ESRD on HD (CKD5 for ≥3 mo)Phase 2, randomized, O-L, dose-ranging94Safety/efficacy16 wkAug 2015
      Daprodustat (GSK-1278863)
      NCT01047397Completed; published
      • 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.
      Asia-Pacific, RU; NDD CKD3-5 with Hb ≤ 11 g/dLPhase 2a, randomized, S-B, P-C, dose-ranging107Safety/efficacy28 dFeb 2011
      NCT01587898Completed; published
      • 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.
      US, CA, DE; NDD CKD with Hb 8.5-11 g/dLPhase 2a, randomized, D-B, P-C, dose-ranging74Safety/efficacy4 wkMay 2013
      NCT01587924Completed; published
      • 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.
      US, CA, EU; HD with Hb 9.5-12 g/dLPhase 2a, randomized, D-B, A-C (epoetin), dose-ranging86Safety/efficacy4 wkMay 2013
      NCT02019719Completed published
      • Endo Y.
      • Kohno T.
      • Imai Y.
      • et al.
      SA-P0819 A 4-week dose response study of the hypoxia inducible factor-prolyl hydroxylase inhibitor GSK1278863 in Japanese anemic hemodialysis subjects.
      JP; HD with Hb 8.5-10.5 g/dLPhase 2a, randomized, D-B, P-C, dose-ranging97Efficacy4 wkAug 2014
      NCT01977573CompletedUS, CA, EU, Asia-Pacific; NDD-CKD Hb 8.0-11.0 g/dL (EPO naive); 9.0-11.5 g/dL (EPO users)Phase 2b, randomized, S-B, A-C (epoetin)252Safety/efficacy24 wkMay 2015
      NCT01977482CompletedUS, CA, EU, Asia-Pacific, RU; HD with Hb 9.0-11.5 g/dLPhase 2b, randomized, D-B, P-C, dose-ranging216Safety/efficacy24 wkFeb 2015
      NCT02075463CompletedUS; HD (EPO hyporesponsive) with Hb 8.0-10.5 g/dLPhase 2a, O-L, SGA15Safety/efficacy16 wkMarch 2016
      Molidustat (BAY 85-3934)
      NCT02021370Completed abstract
      • Macdougall I.C.
      • Akizawa T.
      • Berns J.
      • Lentini S.
      • Bernhardt T.
      Molidustat increases hemoglobin in erythropoiesis stimulating agents (ESA) - naive anaemic patients with chronic kidney diseases not on dialysis (CKD-ND).
      NDD CKD3-5 with Hb < 10.5 g/dLPhase 2b, randomized, D-B, P-C, dose-ranging123Safety/efficacy16 wkSept 2015
      NCT02021409Completed; abstract
      • Macdougall I.C.
      • Akizawa T.
      • Berns J.
      • Lentini S.
      • Bernhardt T.
      • Krüger T.
      SP309 Safety and efficacy of molidustat in erythropoiesis stimulating agents (ESA) pre-treated anaemic patients with chronic kidney disease not on dialysis (CKD-ND) [abstract].
      NDD CKDPhase 2, randomized, O-L, A-C (epoetin), dose-ranging126Safety/efficacy16 wkNov 2015
      NCT01975818CompletedHD, Hb 9.0-11.5 g/dLPhase 2, randomized, O-L, A-C (epoetin), dose-ranging201Safety/efficacy16 wkDec 2015
      Note: Based on information available in ClinicalTrials.gov as of October 2016.
      Abbreviations: A-C, active-controlled; CA, Canada; CD, completion date; CKD, chronic kidney disease; CN, China; D-B, double-blind; DE, Germany; ESRD, end-stage renal disease; EU, European Union; F/U, follow-up; Hb, hemoglobin; HD, hemodialysis; JP, Japan; NA, not available; NDD, non–dialysis dependent; O-L, open-label; P-C, placebo-controlled; PD, peritoneal dialysis; RU, Russia; S-B, single-blind; SGA, single-group-assignment.

      Vadadustat (AKB-6548)

      Vadadustat from Akebia (AKB-6548), an HIF-PH inhibitor, is currently in the phase 3 stage of development for the treatment of anemia secondary to CKD. In a phase 1a single-dose study in 8 healthy men (6 receiving vadadustat and 2 receiving placebo), vadadustat was observed to have a half-life of approximately 4.5 hours.
      • Shalwitz R.
      • Hartman C.
      • Flinn C.
      • Shalwitz I.
      • Logan D.K.
      AKB-6548, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while it increases reticulocyte production and total iron binding capacity in healthy adults.
      In a double-blind placebo-controlled phase 2a trial in 93 patients with NDD CKD, vadadustat increased EPO levels in a manner comparable to the expected physiologic diurnal response.
      • Shalwitz R.
      • Hartman C.
      • Flinn C.
      • et al.
      AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin in chronic kidney disease patients without increasing basal erythropoietin levels.
      In a phase 2a dose-escalation study, 10 patients with CKD received vadadustat once daily for 28 days at a dose adjusted according to stage of CKD, beginning at 400 mg daily in CKD stage 3 and 300 mg in CKD stage 4.
      • Hartman C.
      • Smith M.T.
      • Flinn C.
      • et al.
      AK-6548 a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia.
      Overall, patients demonstrated an increase in Hb levels, from 9.91 g/dL at baseline to 10.54 g/dL by day 29. Ferritin levels decreased from 334.1 ng/mL at baseline to 271.7 ng/mL by day 29.
      A phase 2b, multicenter, double-blind, randomized, parallel-group, placebo-controlled study including 210 participants with NDD CKD has been published by Pergola et al.
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      There were 3 study groups based on ESA status at screening: ESA naive (Hb ≤ 10.5 g/dL), previously treated with ESAs (Hb ≤ 10.5 g/dL), and currently treated with ESAs (Hb ≥ 9.5 to ≤12.0 g/dL). Within each group, patients were randomly assigned 2:1 to receive vadadustat or placebo and stratified by CKD stage and diabetes status. ESA treatment was discontinued in the third group. Compared with those in the placebo group, a successful Hb level response, defined as either mean Hb level ≥ 11.0 g/dL or an increase in Hb level by ≥1.2 g/dL from baseline, was achieved in a greater percentage of vadadustat-treated patients (54.9% vs 10.3%; P < 0.0001).
      Similar results were observed in a trial that enrolled 94 hemodialysis patients (Hb, 9-12 g/dL) maintained on ESAs prior to study entry.
      • Haase V.H.
      • Hartman C.S.
      • Maroni B.J.
      • Farzeneh-Far R.
      • McCullough P.A.
      Vadadustat, a novel, oral treatment for anemia of chronic kidney disease, maintains stable hemoglobin levels in dialysis patients converting from erythropoiesis-stimulating agents [abstract].
      Patients were switched from an ESA to vadadustat and placed in 1 of 3 dose cohorts: 300 mg once daily; 450 mg once daily; or 450 mg thrice weekly. All patients were iron replete from baseline through the end of the study; IV iron use was permitted. Within each dose cohort, mean change in Hb levels stayed stable throughout the study (change from baseline to week 16 ranged from −0.02 to −0.04 g/dL). There were 78 (83.0%) AEs and 13 (13.8%) serious AEs reported; no serious events were considered drug related.
      In the Pergola et al
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      study, the most commonly reported drug-related AEs in the vadadustat group included diarrhea (4.3%) and nausea (4.3%), whereas diarrhea (2.8%) was the most commonly reported drug-related AE in the placebo group. Ten (7.2%) vadadustat-treated patients and 3 (4.2%) placebo-treated patients discontinued the study because of AEs. Hypertension was reported as an AE more frequently in the vadadustat group than the placebo group, although all vadadustat-treated patients for whom hypertension was reported had a history of elevated blood pressure and there was no pattern of blood pressure changes in this group. There was no impact on blood cholesterol levels.
      In healthy volunteers, vadadustat has been reported to decrease hepcidin and ferritin levels, but only at 900 mg/d was this finding statistically significant.
      • Shalwitz R.
      • Hartman C.
      • Flinn C.
      • Shalwitz I.
      • Logan D.K.
      AKB-6548, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while it increases reticulocyte production and total iron binding capacity in healthy adults.
      • Shalwitz R.
      • Hartman C.
      • Flinn C.
      • et al.
      AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin in chronic kidney disease patients without increasing basal erythropoietin levels.
      In the Pergola et al
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      phase 2b study of patients with NDD CKD, there was a significant reduction in serum ferritin and hepcidin levels at 20 weeks. A reduction of ferritin and TSAT levels in dialysis patients has also been reported.
      • Haase V.H.
      • Hartman C.S.
      • Maroni B.J.
      • Farzeneh-Far R.
      • McCullough P.A.
      Vadadustat, a novel, oral treatment for anemia of chronic kidney disease, maintains stable hemoglobin levels in dialysis patients converting from erythropoiesis-stimulating agents [abstract].
      The completed phase 2 studies of vadadustat are summarized in Table 2 and all studies in Table S2.
      In terms of phase 3 studies, Akebia announced the INNO2VATE program, consisting of 2 studies designed to evaluate vadadustat in patients undergoing dialysis who have anemia related to CKD. Akebia's ongoing phase 3 PRO2TECT program in patients with NDD-CKD with anemia related to CKD commenced at the end of 2015.

      Daprodustat (GSK-1278863)

      GlaxoSmithKline is investigating an HIF-PH inhibitor, daprodustat (GSK-1278863). In a phase 1 study, daprodustat was well tolerated and increased EPO levels in apparently healthy individuals proportional to dose.
      • Hara K.
      • Takahashi N.
      • Wakamatsu A.
      • Caltabiano S.
      Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.
      In phase 2a studies in NDD CKD and end-stage renal disease reported by Holdstock et al,
      • 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.
      patients were randomly assigned 1:1:1:1 to a once-daily dose of 0.5, 2, and 5 mg and placebo for 4-week treatment with daprodustat. A mean Hb level increase of 1 g/dL was achieved in the 5-mg treatment arm at 4 weeks in the NDD-CKD ESA-naive population. In the hemodialysis population, Hb levels remained stable after the transition from rHuEPO in the 5-mg treatment arm, but not with lower (0.5 and 2 mg) daprodustat doses. A study examining the rate of Hb level increase, safety, and tolerability demonstrated that 10- and 25-mg daily doses were observed to produce effective erythropoiesis with modest daily endogenous EPO production.
      • 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.
      These doses also resulted in a high Hb level (>13 g/dL) in some individuals, leading to early discontinuation from the study. Similar high Hb level increases also occurred at the 50- and 100-mg daily doses for the CKD stages 3 to 5 group and, along with other non–Hb level tolerability-related AEs, led to early discontinuation and withdrawals. In an open-label, phase 1, single-dose study in healthy individuals, daprodustat demonstrated a half-life up to 4 hours.
      • Johnson B.M.
      • Stier B.A.
      • Caltabiano S.
      Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863.
      Ferritin levels decreased at 4 weeks, whereas transferrin levels and total iron-binding capacity were increased in the 5-mg-daily daprodustat group. Hepcidin levels did not decline in the 5-mg daprodustat group, and an increase was noted in the 0.5- and 2-mg groups. In the studies reported by Holdstock et al,
      • 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.
      a trend of decreasing serum ferritin levels was evident with increasing doses of daprodustat. Markers of iron metabolism such as total iron-binding capacity and unsaturated iron-binding capacity showed an increase through day 29.
      Like other agents in the class, the most common AE observed in the phase 2 studies was nausea.
      • 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.
      • 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.
      Completed phase 2 studies of daprodustat are summarized in Table 2, and all studies, in Table S3.

      Molidustat (BAY 85-3934)

      Bayer Healthcare is currently evaluating an HIF-PH inhibitor, molidustat (BAY 85-3934). In animal models, molidustat was shown to be effective in renal and inflammatory anemia and, unlike ESA therapy, it reduced blood pressure in a CKD model. The endogenous EPO levels induced during treatment were close to the normal physiologic range of EPO.
      • Flamme I.
      • Oehme F.
      • Ellinghaus P.
      • Jeske M.
      • Keldenich J.
      • Thuss U.
      Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects.
      In apparently healthy men, single 37.5- and 50-mg doses of molidustat were found to be absorbed quickly and engender a dose-dependent increase in endogenous EPO levels and an increase in reticulocyte count.
      • Boettcher M.F.
      • Lentini S.
      • Kaiser A.
      • Flamme I.
      • Kubitza D.
      • Wensing G.
      First-in-man study with BAY 85-3934—a new oral selective HIF-PH inhibitor for the treatment of renal anemia.
      A phase 2b, randomized, double-blind, placebo-controlled study of once- and twice-daily administration of different fixed dosages of molidustat in anemic ESA-naive patients with NDD CKD included 101 patients randomly assigned to molidustat and 20 patients randomly assigned to placebo.
      • Macdougall I.C.
      • Akizawa T.
      • Berns J.
      • Lentini S.
      • Bernhardt T.
      Molidustat increases hemoglobin in erythropoiesis stimulating agents (ESA) - naive anaemic patients with chronic kidney diseases not on dialysis (CKD-ND).
      Forty percent of patients receiving molidustat and 90% of those receiving placebo completed the 16-week trial period. Discontinuation of molidustat treatment was mainly due to Hb levels > 13 g/dL or increasing >1 g/dL in 2 weeks (44 of 61; none due to Hb < 8.0 g/dL); higher dosages of molidustat resulted in a higher discontinuation rate due to Hb criteria.
      Molidustat is currently in active phase 2 trials. Its effects on iron metabolism and inflammatory markers have yet to be reported. The completed phase 2 studies of molidustat are summarized in Table 2 and all studies in Table S4.

      Current Therapies Versus HIF-PH Inhibitors

      Clinical Outcomes

      Although parenteral ESA treatment produces high levels of the ESA in blood, treatment with HIF-PH inhibitors results in a relatively small increase in EPO blood levels.
      • Klaus S.
      • Langsetmo T.
      • Neff A.
      • Liu D.
      Beneficial pharmacodynamic effects resulting from ‘complete erythropoiesis’ induced by novel HIF prolyl hydroxylase inhibitors FG-2216 and FG-4592.
      • Hartman C.
      • Smith M.T.
      • Flinn C.
      • et al.
      AK-6548 a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia.
      This may confer a potential advantage to HIF-PH inhibitors because they lead to endogenous EPO levels close to the physiologic range and adequately stimulate the high-affinity receptor responsible for hematopoiesis. However, it should be noted that many genes unrelated to erythropoiesis are regulated by HIF, and their activity could potentially be affected by HIF-PH inhibitors.
      In published clinical trials of HIF-PH inhibitors to date, the studies were designed to target Hb levels to <11 g/dL. When Hb levels were >12 g/dL, either the drug treatment was discontinued or the dose was decreased.
      • Drueke T.B.
      • Locatelli F.
      • Clyne N.
      • et al.
      Normalization of hemoglobin level in patients with chronic kidney disease and anemia.
      • 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.
      • Macdougall I.C.
      • Akizawa T.
      • Berns J.
      • Lentini S.
      • Bernhardt T.
      Molidustat increases hemoglobin in erythropoiesis stimulating agents (ESA) - naive anaemic patients with chronic kidney diseases not on dialysis (CKD-ND).
      The consequences to cardiovascular health of maintaining physiologic levels of endogenous EPO with HIF-PH inhibitors have yet to be determined, as does the impact of normalizing Hb levels with these agents. For patients with CKD, the FDA product information for all currently approved ESAs states that

      Amgen. ARANESP® (darbepoetin alfa) injection, for intravenous or subcutaneous use. http://pi.amgen.com/united_states/aranesp/ckd/aranesp_pi_hcp_english.pdf. Accessed February 14, 2017.

      Amgen. Epogen® (epoetin alfa) injection, for intravenous or subcutaneous use. http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf. Accessed February 14, 2017.

      :In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a Hb level of greater than 11 g/dL. No trial has identified a Hb target level, ESA dose, or dosing strategy that does not increase these risks.
      Long-term trials with hard outcomes will determine whether these statements also apply to HIF-PH inhibitors. Given the experience with ESAs, it is likely that the FDA will proceed with caution and studies with HIF-PH inhibitors targeting Hb levels > 11 g/dL will not be undertaken in the near future.

      Iron Metabolism

      Nearly 10% of the hemodialysis population is ESA resistant, a state frequently caused by FID.
      • Kanbay M.
      • Perazella M.A.
      • Kasapoglu B.
      • Koroglu M.
      • Covic A.
      Erythropoiesis stimulatory agent- resistant anemia in dialysis patients: review of causes and management.
      • Ganz T.
      Hepcidin and the global burden of iron deficiency.
      A direct correlation has been reported between hepcidin level and ESA dose.
      • Ashby D.R.
      • Gale D.P.
      • Busbridge M.
      • et al.
      Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease.
      • Onuma S.
      • Honda H.
      • Kobayashi Y.
      • et al.
      Effects of long-term erythropoiesis-stimulating agents on iron metabolism in patients on hemodialysis.
      It has been proposed that hypoxia per se, possibly via the HIF family of transcription factors, provides a stimulus for transcriptional suppression of hepcidin.
      • Peyssonnaux C.
      • Zinkernagel A.S.
      • Schuepbach R.A.
      • et al.
      Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).
      However, others have argued that hepcidin suppression does not result from hypoxia directly,
      • Liu Q.
      • Davidoff O.
      • Niss K.
      • Haase V.H.
      Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
      • 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.
      but rather from the hypoxia-induced increase in erythropoietic drive. Recently, numerous mediators have been proposed as the link between erythropoiesis and hepcidin suppression (growth-differentiation factor 15, soluble transferrin receptor, EPO, and the novel hormone erythroferrone), with erythroferrone most likely playing the largest role.
      • Kautz L.
      • Jung G.
      • Valore E.V.
      • Rivella S.
      • Nemeth E.
      • Ganz T.
      Identification of erythroferrone as an erythroid regulator of iron metabolism.
      HIF-PH inhibitor therapy increases the availability of iron for effective erythropoiesis. The mechanism of hepcidin suppression appears to be an indirect effect through erythropoiesis regulators with HIF activation. Three agents have demonstrated a decrease in ferritin and TSAT values, and 2 agents have demonstrated a decrease in hepcidin levels. Phase 3 trials will demonstrate the clinical benefit of these observations, if it exists.

      Angiogenesis

      VEGF promotes angiogenesis and increases vascular permeability, but also affects tumor stem cell function and tumor initiation.
      • Goel H.L.
      • Mercurio A.M.
      VEGF targets the tumour cell.
      Because transcription of the VEGF gene is regulated by HIF-1α and HIF-2α binding to HREs,
      • Krock B.L.
      • Skuli N.
      • Simon M.C.
      Hypoxia-induced angiogenesis: good and evil.
      there is a clear theoretical concern that HIF stabilization will increase the risk for neoplasia and diabetic retinopathy, with resulting poor outcomes. However, in phase 2a studies, vadadustat and daprodustat demonstrated no change in VEGF over the dose range planned for phase 3 clinical trials.
      • Pergola P.E.
      • Spinowitz B.S.
      • Hartman C.S.
      • Maroni B.J.
      • Haase V.H.
      Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
      • 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.
      • 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.

      Systemic Hypertension

      Within the HIF-mediated transcriptional cascade are a number of genes involved in vasomotor control. Emerging evidence supports a small blood pressure–lowering effect of HIF-PH inhibitors. Molidustat has been reported to lower blood pressure in an animal model.
      • Flamme I.
      • Oehme F.
      • Ellinghaus P.
      • Jeske M.
      • Keldenich J.
      • Thuss U.
      Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects.
      In rats, systolic blood pressure was found to be significantly lower in animals receiving 5 mg/kg of molidustat compared with the control and rHuEPO-treated groups.
      • Flamme I.
      • Oehme F.
      • Ellinghaus P.
      • Jeske M.
      • Keldenich J.
      • Thuss U.
      Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (molidustat) stimulates erythropoietin production without hypertensive effects.
      In this study, the effect of molidustat on mean systolic blood pressure was essentially the same as that of enalapril. A mean blood pressure reduction of 2.6 ± 9.6 mm Hg from baseline was observed in the phase 2b trial of 16 and 24 weeks of treatment with roxadustat.
      • Besarab A.
      • Provenzano R.
      • Fishbane S.
      • et al.
      FG-4592 Oralhypoxia-inducible factor prolyl hydroxylase inhibitor corrects anemia in nondialysis CKD patients without IV iron.
      In an open-label phase 2b trial of roxadustat, the most frequent AE (10%) was hypertension requiring a modification to antihypertensive medication.
      • Besarab A.
      • Chernyavskaya E.
      • Motylev I.
      • et al.
      Roxadustat (FG-4592): correction of anemia in incident dialysis patients.
      In a phase 2a dose escalation study, treatment with vadadustat in 10 patients with CKD for 28 days was associated with a small reduction in mean blood pressure.
      • Hartman C.
      • Smith M.T.
      • Flinn C.
      • et al.
      AK-6548 a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia.

      Conclusions

      HIF-PH inhibitors are likely to become an important tool for anemia management in patients with CKD. Given the biology of the HIF pathway, it is likely that targeting PHD enzymes will lead to pleiotropic effects. HIF-PH inhibition leads to endogenous EPO production and enhances the availability of iron to the erythron. Published clinical trials show increased Hb levels with physiologic blood levels of endogenous EPO. The oral route of administration may be of advantage over intravenous/subcutaneous ESAs, especially in patients with NDD CKD and those undergoing peritoneal dialysis. Although manipulating HIF-PH may have several benefits, concerns regarding safety must be dealt with. One significant concern regarding the long-term use of these agents is the possible effect on tumors because HIF activation in hypoxic environments may help already existing tumors survive and grow. The long-term effects on VEGF and angiogenesis have also yet to be determined. Pending results of long-term studies comparing HIF-PH inhibitors and ESA therapy, it is not possible to state whether HIF-PH inhibitors offer an advantage regarding cardiovascular end points at comparable target Hb levels. Results of ongoing trials will elucidate the short- and long-term benefit versus risk profile of these agents to better define their role as an alternative to ESAs and iron supplementation in patients with CKD with anemia.

      Acknowledgements

      Support: Editorial support (literature search, article retrieval, and assistance with tables and figures) was provided by Prime Medica and funded by AstraZeneca. Prime Medica and AstraZeneca were not involved in deciding the main points to be communicated in the manuscript, had no role in the writing of the manuscript, and did not require approval of the manuscript, which is entirely the work of the authors. The authors received no compensation for writing this manuscript, and no grant support from AstraZeneca was received by the authors. AstraZeneca paid the open access fee for this article.
      Financial Disclosure: Dr Wish has served as consultant and/or advisory board member to FibroGen, Hospira/Pfizer, Sandoz, Amgen, Vifor, and DaVita Healthcare Partners and is on the speaker’s bureau for Hospira/Pfizer and Keryx. Dr Gupta declares that she has no other relevant financial relationships.
      Peer Review: Evaluated by 2 external peer reviewers, Deputy Editor Weiner, and Editor-in-Chief Levey.

      Supplementary Material

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      Linked Article

      • Erratum Regarding “Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD” (Am J Kidney Dis. 2017;69[6]:815-826)
        American Journal of Kidney DiseasesVol. 69Issue 6
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          In the Narrative Review entitled “Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD” appearing in this (June 2017) issue of AJKD (Gupta & Wish, volume 69, issue 6, pages 815-826), there was an error in the third sentence of the “Systemic Hypertension” subsection appearing on page 823. The sentence originally made reference to humans, but has been corrected to read “In rats, systolic blood pressure was found to be significantly lower in animals receiving 5 mg/kg of molidustat compared with the control and rHuEPO-treated groups.” This correction was made to the HTML and PDF versions of the article as of April 6, 2017 and the printed article contains the corrected version.
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