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

This is a Phase 2, randomized, open-label study to evaluate efficacy and safety of oral
vadadustat for the treatment of anemia in hemodialysis subjects 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 and Part 2 is in a
hemodialysis population that are erythropoiesis stimulating agent (ESA) hyporesponder on
maintenance treatment with epoetin alfa. For all subjects (Main and ESA hyporesponders
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 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 IV epoetin alfa therapy for 8 weeks prior to and including Screening
through SV2

- Eligibility in the Main study and ESA hyporesponder parallel study is based on the
following mean weekly epoetin alfa doses: 1. Main study: Mean weekly epoetin alfa dose
<300 U/kg/week for 8 weeks prior to SV2 and 2. ESA hyporesponder parallel study: Mean
weekly epoetin alfa dose ≥300 U/kg/week for 8 weeks prior to SV2

- Two Hb values measured at least 4 days apart by the central laboratory during
Screening. 1. Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive and 2. -
ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive

- Serum ferritin ≥100 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

Exclusion Criteria:

- Anemia due to a cause other than CKD (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 subject 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. Subjects 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. Subjects with treated
basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or
cervical carcinoma in situ

- 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 (subjects with a history of failed kidney
transplant or corneal transplants are not excluded)

- Scheduled organ transplant from a living donor and subjects 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

- Use of an investigational medication or participation in an investigational study
within 30 days or 5 half-lives of the investigational medication (whichever is
longer), prior to Screening (subjects may participate in another concurrent study only
if that study is a non-interventional, observational investigation)

- Previous participation in this study, or previous participation in a study with
another hypoxia-inducible factor prolyl-hydroxylase inhibitor other than vadadustat

- For female subjects 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, or Not considered post-menopausal (no menses for >1
year with follicle stimulating hormone >40 U/L at Screening)

- Female subjects of childbearing potential: Lack of confirmation of the use of
acceptable forms of contraception* for a minimum of one complete menstrual cycle prior
to Screening or Positive serum pregnancy test at SV2 or 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 subjects 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

- Subjects with bilateral native nephrectomy

- Any other reason, which in the opinion of the Investigator, would make the subject 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.