Study of FG-4592 in Subjects With End-Stage Renal Disease Receiving Maintenance Hemodialysis

Key Inclusion Criteria:

1. Age 18 to 75 years
2. End-stage renal disease (ESRD) and receiving maintenance hemodialysis

3. Two most recent hemoglobin values obtained during screening period must be within the ranges set below:

   • Croup A. Normoresponder Criteria: Hb range in the 8 weeks prior to randomization within 9.0 to 13.5 g/dL
   • Group B. Hyporesponder Criteria: Hb range in the 8 weeks prior to randomization within 8.5 to 13.5 g/dL

4. Epoetin alfa, dose requirements:

   • Group A. Normoresponder Criteria - Cohorts A-1 to A-12: Stable IV epoetin alfa dose at baseline (i.e., no more than a 30% fluctuation in the weekly dose) during the 4 weeks prior to study Day -3

     • Cohorts A-1 to A-4: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 85 IU/kg/dose, three times a week (TIW); weekly dose between 75 and 255 IU/kg/week
     • Cohort A-5: Current and previous (past 4 weeks) epoetin alfa dose range =/>85 to 115 IU/kg/dose, TIW; total weekly dose between 255 and 335 IU/kg/week
     • Cohort A-9: Current and previous (past 4 weeks) epoetin alfa dose range =/>85 to 150 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week
     • Cohorts A-6 to A-8: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 115 IU/kg/dose, TIW, and two times a week (BIW); total weekly dose between 75 and 345 IU/kg/week
     • Cohorts A-10 to A-12: Optional cohorts TBD, dosing frequency and dose range to be determined by sponsor

   • Group B. Hyporesponder Criteria:

     • Cohort B-1 (completed): Current and previous (past 4 weeks) epoetin alfa dose range 125 to 400 IU/kg/dose, TIW; weekly dose between 375 and 1200 IU/kg/week
     • Cohort B-2 to B-4: Current and previous (past 4 weeks) epoetin alfa dose range >115 IU/kg/dose, TIW; total weekly dose >345 IU/kg/week no requirement for stability of epoetin alfa doses
5. Complete Blood Count (CBC), Hematology, liver function blood tests, serum folate and vitamin B12 within acceptable limits
6. Absence of active or chronic gastrointestinal bleeding
7. hsCRP <60 mg/L for normoresponders Cohorts A-8 through A-12 enrolled under Amendment 3; no hsCRP criteria for hyporesponders
8. Body weight: 40 to 140 kg (dry weight)
9. Body mass index (BMI): 18 to 45 kg/m2
10. Dialysis vascular access via native arteriovenous fistula or synthetic graft, or permanent (tunneled) catheter (not via temporary catheter); permanent and temporary catheters, however, are still prohibited in Cohort A-5

Key Exclusion Criteria:

1. Anticipated change in hemodialysis prescription
2. Any clinically significant infection or evidence of an underlying infection
3. Positive for any of the following: Human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab)
4. History of chronic liver disease
5. New York Heart Association Class III or IV congestive heart failure
6. Chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
7. History of myelodysplastic syndrome
8. History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
9. Active hemolysis or diagnosis of hemolytic syndrome
10. Known bone marrow fibrosis
11. Uncontrolled or symptomatic secondary hyperparathyroidism
12. Any prior organ transplantation
13. Drug-treated gastroparesis or short-bowel syndrome
14. History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the subject
15. Prior treatment with FG-4592
16. Diagnosis or suspicion of renal cell carcinoma
17. RBC transfusion within 12 weeks prior to Day 1, or anticipated need for RBC transfusion during the dosing period
18. IV iron supplement within 2 weeks prior to Day 1 and/or unwilling to withhold IV iron during the dosing/Treatment period