Study of Vadadustat in Hemodialysis Participants With Anemia Switching From Epoetin Alfa

Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment of Anemia in Hemodialysis Subjects Converting From Epoetin Alfa (FO2RWARD-2)

This is a Phase 2 open-label efficacy, safety, and pharmacokinetic/pharmacodynamic (PK/PD) study to evaluate oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy.

This is a Phase 2, randomized, open-label study to evaluate efficacy and safety of oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy. The study will be conducted in two parts running in parallel: Part 1, Main Study in a hemodialysis population on maintenance treatment with Epoetin Alfa; Part 2 is in a hemodialysis population that are erythropoiesis-stimulating agent (ESA) hyporesponders on maintenance treatment with Epoetin Alfa. For all participants (Main and ESA hyporesponder parallel study), the study will include a Screening Period, a Treatment Period, and a Safety Follow-Up Period. PK and PD sampling will be done throughout the study. The aim is to achieve and maintain hemoglobin (Hb) levels within the target range of 10.0 to 11.0 grams per deciliter (g/dL), inclusive, while targeting the middle of the range and minimizing excursions outside the target range.

Inclusion Criteria:

• ≥18 years of age, providing informed consent

• Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal disease for at least 12 weeks prior to Screening

• Maintained on intravenous Epoetin Alfa therapy for 8 weeks prior to and including Screening through Screening Visit 2 (SV2)

• Eligibility in the Main study and erythropoiesis-stimulating agent (ESA) hyporesponder parallel study is based on the following mean weekly Epoetin Alfa doses:

  1. Main study: Mean weekly Epoetin Alfa dose <300 Units per kilogram per week (U/kg/week) for 8 weeks prior to SV2;
  2. ESA hyporesponder parallel study: Mean weekly Epoetin Alfa dose ≥300 U/kg/week for 8 weeks prior to SV2

• Two Hb values measured by the central laboratory at least 4 days apart between Screening Visit 1 (SV1) and SV2 as indicated:.

  1. Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive;
  2. ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 grams per deciliter (g/dL), inclusive

• Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening

• Folate and vitamin B12 measurements ≥ lower limit of normal during Screening

• Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 8 weeks prior to or during Screening

• Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure

Exclusion Criteria:

• Anemia due to 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 recent blood loss within 8 weeks prior to randomization

• Red blood cell (RBC) transfusion within 8 weeks prior to randomization

• Anticipated to discontinue hemodialysis during the study

• Judged by the Investigator that the participant is likely to need rescue therapy (ESA administration or RBC transfusion) immediately after enrollment in 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 x upper limit of normal (ULN) during Screening. Participants with a history of Gilbert's syndrome are not excluded.

• Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of Epoetin Alfa

• 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 or during Screening

• History of new or recurrent malignancy within 2 years prior to and during 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 are not excluded.

• History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening

• History of hemosiderosis or hemochromatosis

• History of prior organ transplantation (participants with a history of failed kidney transplant or corneal transplants are not excluded)

• Scheduled organ transplant from a living donor and participants on the kidney transplant wait-list who are expected to receive a transplant within 6 months

• History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)

• Known hypersensitivity to Vadadustat, Epoetin Alfa, or any of their excipients

• Any prior use of a hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitor or any use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to randomization

• For female participants of non-childbearing potential:

  1. inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) at least 1 month prior to Screening;
  2. not considered post-menopausal (no menses for >1 year with follicle stimulating hormone >40 U/Liter at Screening)

• For female participants of childbearing potential:

  1. lack of confirmation of the use of acceptable forms of contraception* for a minimum of one complete menstrual cycle prior to Screening;
  2. positive serum pregnancy test at SV2;
  3. unwilling to use two acceptable forms of contraception* (at least one of which must be a barrier method) starting Baseline/Day 1, throughout the Treatment Period and for 30 days after the final study drug administration

• Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the final study drug administration

• Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after the final study drug administration

• Male participants who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception* during the study and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of Vadadustat

• Participants with bilateral native nephrectomy

• Any other reason, which in the opinion of the Investigator, would make the participant not suitable for participation in the study

  • Acceptable forms of contraception include:

    • Established use of oral, injected or implanted hormonal methods of contraception;
    • Placement of an intrauterine device or intrauterine system;
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.