• Mean area under concentration-time curve from time 0 to the last quantifiable concentration (AUClast) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Area under concentration-time curve from time 0 to infinity (AUCinf) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Maximum observed concentration (Cmax) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Time to maximum observed concentration (Tmax) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Terminal half-life (t½) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Apparent clearance (CL/F) or clearance (CL) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Apparent volume of distribution (Vd/F) or volume of distribution (Vd) [ Time Frame: Vadadustat: Days 1, 2, 8, and 10 (or End of Treatment). Erythropoiesis-stimulating agent: Days 1 and 2 ]
  Vadadustat: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose. Erythropoiesis-stimulating agent: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose
• Tmax for vadadustat metabolite(s) [ Time Frame: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose ]
• AUClast for vadadustat metabolite(s) [ Time Frame: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose ]
• AUCinf for vadadustat metabolite(s) [ Time Frame: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose ]
• Cmax for vadadustat metabolite(s) [ Time Frame: Day 1: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose and prior to dosing. Day 8: predose; 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 10 or End of Treatment: predose ]
• Serum erythropoietin concentration for the erythropoiesis-stimulating agent treatment group [ Time Frame: Day 1: predose; 0.25, 1, 2, 3, 4, 5, 8, and 11 hours post dose. Day 2: 24 hours (-2 hours) post Day 1 dose ]

• Hepcidin concentration [ Time Frame: predose on Days 1, 6, and 10 ]
• Serum erythropoietin concentration [ Time Frame: predose on Days 1, 6, and 10; post dose on Days 1 and 8 ]
• Iron concentration [ Time Frame: predose on Days 1, 6, and 10 ]
• Ferritin concentration [ Time Frame: predose on Days 1, 6, and 10 ]
• Total iron-binding capcity [ Time Frame: predose on Days 1, 6, and 10 ]
• Transferrin saturation [ Time Frame: predose on Days 1, 6, and 10 ]
• Hemoglobin concentration [ Time Frame: post dose on Days 1, 6, and 10 ]
• Reticulocyte concentration [ Time Frame: predose on Days 1, 6, and 10 ]
• Number of participants with any treatment-emergent adverse event [ Time Frame: up to Day 40, plus or minus 3 days ]
• Number of participants with clinically significant electrocardiogram findings [ Time Frame: up to Day 40, plus or minus 3 days ]
• Number of participants with clinically significant vital sign values [ Time Frame: up to Day 40, plus or minus 3 days ]
• Number of participants with clinically significant clinical laboratory values [ Time Frame: up to Day 40, plus or minus 3 days ]

• Drug: Vadadustat
  oral 150 mg tablet
  Other Name: AKB-6548
• Drug: Darbepoetin alfa
  solution intravenous injection
• Drug: Epoetin alfa
  solution for intravenous injection

• Experimental: Vadadustat 600 mg
  Dialysis-dependent chronic kidney disease (DD-CKD) participants converting from erythropoiesis-stimulating agent (ESA) treatment will be administered fixed-dose treatment for 10 days with vadadustat 600 milligrams (mg) daily.
  Intervention: Drug: Vadadustat
• Experimental: Vadadustat 750 mg
  DD-CKD participants converting from ESA treatment will be administered fixed-dose treatment for 10 days with vadadustat 750 mg daily.
  Intervention: Drug: Vadadustat
• Experimental: Vadadustat 900 mg
  DD-CKD participants converting from ESA treatment will be administered fixed-dose treatment for 10 days with vadadustat 900 mg daily.
  Intervention: Drug: Vadadustat
• Erythropoiesis-stimulating agent
  Participants will continue to receive their existing treatment with intravenous erythropoiesis-stimulating agent (ESA; darbepoetin alfa or epoetin alfa) for 10 days.
  Interventions:

  • Drug: Darbepoetin alfa
  • Drug: Epoetin alfa

Inclusion Criteria:

• Male or female ≥18 years of age at the time of informed consent
• Receiving chronic, outpatient in-center hemodialysis three times a week for end-stage renal disease for at least 12 weeks prior to Screening
• Maintained on intravenous erythropoiesis-stimulating agent (ESA) therapy (mean dose of <1.5 micrograms per kilogram per week for darbepoetin alfa, or mean dose of <300 Units per kilogram per week for epoetin alfa) for 8 weeks prior to randomization
• Two hemoglobin values between 8.5 and 10.5 grams per deciliter, inclusive, measured at least 4 days apart within 28 days prior to randomization
• Investigator determines the participant is not likely to need rescue therapy (ESA administration or red blood cell transfusion) or require interruption or discontinuation of study drug within the next 30 days
• Serum ferritin ≥100 nanograms per milliliter and transferrin saturation ≥20% within the 28-day screening period prior to randomization
• Folate and vitamin B12 measurements ≥ lower limit of normal within the 28-day screening period prior to randomization
• Hemodialysis adequacy (Kt/Vurea) as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 12 weeks prior to randomization
• Female participants of childbearing potential who are non-lactating, not pregnant as confirmed by a negative serum pregnancy test at Screening within 9 days prior to dosing on Day 1, and using, and agree to continue using, an acceptable method of contraception for at least 4 weeks prior to first dose of study drug until 30 days after the last dose of study drug. Acceptable contraceptive use is outlined in the protocol.
• Female participants of non-childbearing potential who are either surgically sterile (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) or post-menopausal (>12 months of spontaneous and continuous amenorrhea in a female >55 years old, or >12 months of spontaneous and continuous amenorrhea with a follicle stimulating hormone [FSH] level >40 International Units per Liter in a female <55 years old)
• Female participants of childbearing potential who agree not to donate ova during the study and for at least 30 days after the last dose of study drug
• Male participants who have not had a vasectomy must agree to use an acceptable method of contraception from time of first dose of study drug until 30 days after the last dose of the study drug, and to not donate sperm during the study and for at least 30 days after the last dose of study drug. Acceptable contraceptive use is outlined in the protocol.
• Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure

Exclusion Criteria:

• Treated with any HMG-CoA reductase inhibitor (statin) other than atorvastatin, pravastatin, simvastatin, or rosuvastatin within the 28-day screening period prior to randomization. Within the 28-day screening period prior to randomization, the maximum allowable dose of simvastatin is 20 milligrams (mg) daily, and the maximum allowable dose of rosuvastatin is 10 mg daily. These restrictions also apply to the dosing period.
• Treated with clinically relevant substrates of the breast cancer resistant protein (BCRP) transporter (e.g., sulfasalazine, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, topotecan, tenofovir, glecaprevir, pibrentasir, or sofosbuvir) within 30 days prior to randomization
• Anemia with a cause other than chronic kidney disease (e.g., sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia)
• Active bleeding or blood loss within 8 weeks prior to randomization
• Red blood cell transfusion within 8 weeks prior to randomization
• Anticipated to discontinue hemodialysis or change dialysis modality during the study
• History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver)
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin >1.5× upper limit of normal (ULN) within the 28-day screening period prior to randomization. Participants with a history of Gilbert's syndrome may participate in the study if they are not jaundiced, have a total bilirubin <3 × ULN and AST and ALT are not >1.5× ULN.
• Current uncontrolled hypertension that would contraindicate the use of darbepoetin alfa or epoetin alfa as determined by the investigator
• Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for heart failure (HF) or New York Heart Association Class IV HF, or stroke within 12 weeks prior to randomization
• History of new or recurrent malignancy within 2 years prior to Screening or currently receiving treatment or suppressive therapy for cancer. Participants with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ may participate on the study.
• History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to randomization
• History of hemosiderosis or hemochromatosis
• History of bilateral native nephrectomy
• History of functioning organ transplantation other than corneal transplant
• Scheduled organ transplant from a living donor or on the kidney transplant wait list or expected to receive a transplant during the study
• History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)
• Known hypersensitivity to vadadustat excipients, or to darbepoetin alfa or epoetin alfa
• Use of an investigational drug within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization
• Prior administration of an hypoxia-inducible factor prolyl-hydroxylase, including vadadustat
• Any other reason, which in the opinion of the investigator, would make the participant not suitable for participation in the study
• Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration