Vadadustat in HD HAASE Et Al

Nephrol Dial Transplant (2018) 1–10 doi: 10.1093/ndt/gfy055 Effects of vadadustat on hemoglobin concentrations ORIGINAL ARTICLE in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents Volker H. Haase1, Glenn M. Chertow2, Geoffrey A. Block3, Pablo E. Pergola4, Emil M. deGoma5, Zeeshan Khawaja5, Amit Sharma5, Bradley J. Maroni5 and Peter A. McCullough6 1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, 2Stanford University School of Medicine, Palo Alto, CA, USA, 3Denver Nephrology, Denver, CO, USA, 4Renal Associates PA, San Antonio, TX, USA, 5Akebia Therapeutics Inc., Cambridge, MA, USA and 6Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX, USA Correspondence and offprint requests to: Peter A. McCullough; E-mail: [email protected] ABSTRACT Keywords: anemia, erythropoiesis, hemodialysis, hypoxia- Background. Vadadustat, an inhibitor of hypoxia-inducible inducible factor prolyl-4-hydroxylase inhibitor, vadadustat factor prolyl-4-hydroxylase domain dioxygenases, is an oral in- vestigational agent in development for the treatment of anemia secondary to chronic kidney disease. INTRODUCTION Methods. In this open-label Phase 2 trial, vadadustat was eval- Anemia is a common complication of chronic kidney disease uated in 94 subjects receiving hemodialysis, previously main- (CKD), the latter of which represents a major worldwide bur- tained on epoetin alfa. Subjects were sequentially assigned to den on public health, particularly in aging populations [1]. one of three vadadustat dose cohorts by starting dose: 300 mg Anemia affects the majority of patients with advanced CKD [2] once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). and is associated with increased cardiovascular risk, hospitaliza- The primary endpoint was mean hemoglobin (Hb) change tion and mortality [3]. from pre-baseline average to midtrial (Weeks 7–8) and end-of- Anemia in CKD is predominantly due to a relative defi- trial (Weeks 15–16) and was analyzed using available data (no ciency in erythropoietin (EPO) production by the kidney, al- imputation). though concomitant functional and/or absolute iron deficiency Results. Overall, 80, 73 and 68% of subjects in the 300 mg QD, [4] and systemic and local inflammation [5, 6]alsofrequently 450 mg QD, and 450 mg TIW dose cohorts respectively, com- contribute to its induction and maintenance. Correction of an- pleted the study. For all dose cohorts no statistically signiﬁcant emia in patients with CKD has been investigated in many stud- mean change in Hb from pre-baseline average was observed, ies, with variable impact on prespecified outcomes [7, 8]; in and mean Hb concentrations—analyzed using available data— most studies, higher hemoglobin (Hb) concentrations were remained stable at mid- and end-of-trial. There was one subject shown to be associated with improved symptoms, as well as a with an Hb excursion >13 g/dL. Overall, 83% of subjects experi- reduced need for transfusion and/or hospitalization [3, 7–9]. enced an adverse event (AE); the proportion of subjects who The current standard of care for anemia secondary to CKD experienced at least one AE was similar among the three dose is the use of injectable erythropoiesis-stimulating agents cohorts. The most frequently reported AEs were nausea (ESAs), alone, or in combination with intravenous (IV) or oral (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths iron supplementation [10, 11]. While ESAs have been shown to occurred during the study. No serious AEs were attributed to be effective in treating anemia for many patients with CKD, vadadustat. they have some well-recognized limitations. Trials of ESAs in Conclusions. Vadadustat maintained mean Hb concentrations patients with anemia secondary to non-dialysis-dependent in subjects on hemodialysis previously receiving epoetin. These CKD (NDD-CKD) or dialysis-dependent CKD (DD-CKD) data support further investigation of vadadustat to assess its long- have demonstrated an increased risk of cardiovascular events term safety and efﬁcacy in subjects on hemodialysis. associated with higher Hb targets [10–12]. Post hoc analyses VC The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and repro- duction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 1 performed by the federal Food and Drug Administration and Study population others have shown an association between these adverse out- The trial enrolled subjects 18–79 years of age receiving main- comes and ESA dose [13, 14]. Alternative treatments that limit tenance hemodialysis thrice weekly (TIW) for at least 3 months. EPO exposure may be useful additions to the therapeutic arma- Subjects were expected to remain on hemodialysis for the dur- mentarium for renal anemia. ation of the trial. For the 3 months before screening, all subjects In addition to reduced EPO production, iron absorption and were required to have received epoetin alfa (EpogenVR ) for the mobilization are frequently reduced in patients with CKD [6]. treatment of anemia secondary to ESRD and IV iron to main- Hb production depends on iron availability and is carefully tain adequate iron stores for erythropoiesis. Subjects receiving orchestrated by coordinated signaling from the liver, kidney, epoetin alfa doses >24 000 U/week in the preceding 4 months and bone marrow. Under normal conditions, EPO induces were excluded from the study (further details are provided in erythroblast secretion of erythroferrone [15], a protein that sup- the Supplementary Materials). presses hepcidin production in the liver [16]. Hepcidin acts as the master regulator of iron homeostasis [17]. Lower serum Interventions hepcidin concentrations allow for increased iron absorption Eligible subjects continued their ESA therapy during screen- and mobilization, while higher serum hepcidin concentrations ing, but were required to discontinue ESA therapy prior to their block iron release from internal stores. In a large proportion of baseline visit, at which time they were assigned to one of three patients with CKD, hepcidin concentrations are high despite dose cohorts irrespective of baseline characteristics or prior concurrent anemia; therefore, red blood cell (RBC) production medical history: vadadustat 300 mg once daily (QD), 450 mg remains impaired due to functional iron deficiency [18]. QD, or 450 mg TIW. The first dose of vadadustat was adminis- Several lines of evidence suggest that altitude is associated tered during the baseline visit and subsequently self- with improved outcomes in end-stage renal disease (ESRD) administered on an outpatient basis for 16 consecutive weeks. [19–22]. This process is thought to be mediated by the action of Dose cohorts were dosed sequentially. hypoxia-inducible factors (HIFs) [23]. HIFs are oxygen-sensitive Hb concentrations were measured at each study visit and transcription factors that play a key role in the physiologic adap- used to guide dose adjustment or interruption (Supplementary tation to hypoxia by regulating the expression of multiple genes, data, Table S1). Vadadustat dose increase up to 600 mg per day including EPO and others involved in iron metabolism and was permitted beginning at Week 8 and through Week 12; dose erythropoiesis [4, 24]. HIF activity is controlled by prolyl-4- decrease was allowed at any time for either intolerance or Hb hydroxylase domain (PHD) proteins, which function as oxygen level concerns. ESA administration was not allowed during the sensors [24]. Under normoxia, PHDs target the HIF-a subunit 16-week study period. for degradation. Under hypoxic conditions, PHD activity is sub- In this trial, IV iron supplementation was utilized to main- stantially decreased, which reduces HIF degradation. HIF stabil- tain serum ferritin concentrations between 100 and 1200 ng/ ization results in increased expression of HIF target genes, mL. Oral iron was not permitted. including EPO [4, 24], which then stimulates RBC production and the concomitant release of erythroferrone (which reduces Trial endpoints hepcidin production), resulting in both iron mobilization and The primary endpoint was the mean change in Hb concen- increased Hb production [18]. trations between the pre-baseline average (mean of the three Vadadustat is an oral inhibitor of HIF-PHDs, in development values obtained prior to dosing at screening visit 1, screening for the treatment of anemia in patients with CKD. In clinical tri- visit 2 and the baseline visit), the mid-study average (mean of als to date, vadadustat has been shown to increase and maintain the two values obtained at Weeks 7–8 visits) and the end-of- mean Hb in the target range in patients with NDD-CKD [25, study average (mean of the two values obtained at Weeks 15–16 26]. In this report, we present data from a Phase 2 clinical trial visits). evaluating vadadustat in subjects receiving hemodialysis whose Secondary endpoints included: absolute and percent change anemia was previously controlled with ESA therapy. from baseline in Hb levels; reticulocyte count, reticulocyte Hb content (CHr); iron-related indices [iron, transferrin saturation MATERIALS AND

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