Ferric Citrate in ESRD Pilot Project

Iron deficiency anemia is very prevalent in end stage renal disease (ESRD) patients. Patients
with ESRD require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating
agents (ESAs) and intravenous (IV) iron for anemia. In patients with ESRD, iron deficiency
occurs more frequently, because of increased external losses of iron, decreased availability
of the body's storage of iron, and perhaps a deficit in intestinal iron absorption.

ESRD patients tend to lose about 3 grams of iron every year from chronic bleeding, frequent
phlebotomy and blood trapping in the dialysis apparatus. Total body iron stores of about
20-25 mg are mostly maintained by recycling from senescent red blood cell (RBC) count by
macrophages of the reticulo-endothelial system. In addition, to true iron deficiency, many
ESRD patients have functional iron deficiency, characterized by impaired iron release from
body stores that is unable to meet the demand for erythropoiesis (also called
reticuloendothelial cell iron blockade). These patients have low serum transferrin saturation
(TSAT, a measure of circulating iron) and normal or high serum ferritin (a marker of body
iron stores). Dietary iron absorption under usual circumstances accounts for only 1-2 mg/day
and is almost equal to daily iron losses from intestinal and skin cell shedding.

For treatment of anemia caused by chronic renal disease, the United States Food and Drug
Administration (FDA) has approved the use of ESA therapy. There are two ESAs licensed for the
treatment of anemia of CKD in the Unites States: epoetin alfa and darbopoetin alfa. Both are
glycoproteins that are manufactured using recombinant DNA technology. They stimulate
erythropoiesis through the same mechanism of action as endogenous erythropoietin. The
starting dose of epoetin is 50 units/kg (3000-4000 units/dose) once or twice a week, and
darbepoetin is started at 0.45 mcg/kg and can be administered every 2-4 weeks. To avoid
impaired erythropoiesis caused by true iron deficiency or functional iron deficiency, iron
stores should be fully replenished before and during ESA therapy. ESA therapy is considered
safe. However, major adverse effects should be acknowledged, including an increased risk of
death, thromboembolic complications, stroke, heart attack, aplastic anemia, tumor
progression, and others. To minimize risks of these adverse events, careful monitoring of
hemoglobin levels, along with adjustment of ESA dosing, to maintain the lowest hemoglobin
level clinically needed is recommended.

Given that ESRD is a pro-inflammatory condition, substantial elevation in serum ferritin is
very common in ESRD patients. The role of iron replacement therapy in ESRD patients with high
serum ferritin but low transferrin saturation is not clear at all. In fact, most anemia
management protocols recommend stopping iron replacement when ferritin levels are greater
than 1,200 ng/ml, even if the TSAT is below 20%. The United States Renal Data System (USRDS)
reports for that 55% of prevalent ESRD patients (2012-2014) have a ferritin >800 ng/ml and
22% had ferritin>1200 ng/ml. In one of our local dialysis centers, close to 45% of patients
seem to have a ferritin greater than 1,200 ng/ml and about 20% have a combination of low TSAT
and high ferritin.

Ferric citrate (Auryxia) is a novel, iron-based phosphate binder that increases iron stores
and decreases IV iron and ESA usage while maintaining hemoglobin levels, and may decrease the
cost of ESRD care. By binding phosphate in the GI tract and decreasing absorption, ferric
citrate lowers the phosphate concentration in the serum. In addition to effects on serum
phosphorus levels, Auryxia has been shown to increase serum iron parameters, including
ferritin, iron and TSAT. In dialysis patients treated with Auryxia in a 52-week study in
which IV iron could also be administered, mean (SD) ferritin levels rose from 593 (293) ng/mL
to 895 (482) ng/mL, mean (SD) TSAT levels rose from 31% (11) to 39% (17) and mean (SD) iron
levels rose from 73 (29) mcg/dL to 88 (42) mcg/dL. In contrast, in patients treated with
active control, these parameters remained relatively constant.

Inclusion Criteria:

1. Signed informed consent prior to any study specific procedures

2. Male and females aged 18 years and older

3. In the Investigator's opinion, expected to survive at least 3 months

4. Able to tolerate phosphate binders

5. ESRD and on dialysis for over 90 days

6. Deemed stable by Investigator

7. Serum Ferritin >1000 ng/ml (measured as average of at least 2 values in the last 3
months +/- 10 days)

8. TSAT < 30% ( measured as average of at least 2 values in the last 30 days, +/- 10
days)

9. Hemoglobin < 12g/dl (measured as average of at least 2 values in the last 30 days, +/-
10 days)

10. Currently on ESA for at least 1 month, as per dialysis unit protocol

Exclusion Criteria:

1. Inability or refusal to give informed consent

2. Subject unwilling to take study medication for 3 months

3. Currently on IV Iron

4. Currently on Auryxia as phosphate binder (or received in prior 3 months)

5. Deemed non-compliant by care team for dialysis or medication

6. Active gastrointestinal bleed

7. Inflammatory bowel disease

8. History of malignancy within 5 years before screening (exceptions: squamous and basal
cell carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy that
in the opinion of the investigator, with concurrence with the sponsor's medical
monitor, is considered cured with minimal risk of recurrence).

9. Known allergy to oral iron products

10. Pregnant

11. Breastfeeding