NZ742524B2 - Use of ferric citrate in the treatment of chronic kidney disease patients - Google Patents
Use of ferric citrate in the treatment of chronic kidney disease patients Download PDFInfo
- Publication number
- NZ742524B2 NZ742524B2 NZ742524A NZ74252413A NZ742524B2 NZ 742524 B2 NZ742524 B2 NZ 742524B2 NZ 742524 A NZ742524 A NZ 742524A NZ 74252413 A NZ74252413 A NZ 74252413A NZ 742524 B2 NZ742524 B2 NZ 742524B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- ferric citrate
- iron
- ferric
- mean
- serum
- Prior art date
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Abstract
Disclosed is the use of ferric citrate for improving iron storage (transferrin saturation (TSAT)) in a non-dialysis chronic kidney disease (ND-CKD) human patient in need thereof by oral administration of a daily dose of one or more tablets comprising about 1 gram of ferric citrate. Preferably the tablets are intended to be administered within one hour of ingestion of a meal or snack. Each tablet preferably comprises approximately 65% to approximately 92% by weight of ferric citrate and preferably also includes between 4.5% to approximately 30% by weight of a binder (e.g. partially or fully pregelatinized starch), and approximately 0.5% to approximately 3% by weight of a lubricant (e.g. calcium stearate) (e.g. KRX-0502). ablets are intended to be administered within one hour of ingestion of a meal or snack. Each tablet preferably comprises approximately 65% to approximately 92% by weight of ferric citrate and preferably also includes between 4.5% to approximately 30% by weight of a binder (e.g. partially or fully pregelatinized starch), and approximately 0.5% to approximately 3% by weight of a lubricant (e.g. calcium stearate) (e.g. KRX-0502).
Description
Patents Form No. 5
New d Patent Application No. 742524
Divided out of Application No. 725920, which
itself is divided out of NZ 630995
NEW ZEALAND
Patents Act 1953
COMPLETE SPECIFICATION
USE OF FERRIC E IN THE TREATMENT OF CHRONIC KIDNEY DISEASE PATIENTS
We, Keryx Biopharmaceuticals Inc., a company of the United States of America of One Marina Park Drive,
Twelfth Floor, Boston, husetts 02210, United States of America,
do hereby declare the invention, for which we pray that a patent may be granted to us, and the method
by which it is to be performed, to be particularly described in and by the following statement:-
(followed by page 1A)
This ation is a divisional application divided out of New Zealand Patent Application
No. 725920, which itself is divided out of NZ 630995 (national phase of
) dated 21 June 2013.
-1A-
Stage Description nine Metabolic consequences
Clearance
(~GFR: ml/min/1.73
Metabolic acidosis
Tendency to hyperkalemia
End stage renal <15 Azotaemia develops
e a)
As indicated in the table above, stage 1 is the least severe and stage 5, or ESRD, the
most severe. In the early stages of CKD, 6.3. stages 1-4, dialysis is typically not required.
Therefore, patients experiencing the earlier stages of CKD are described as having non—
L11 dialysis dependent chronic kidney disease. Such patients are also commonly referred to as
non-dialysis chronic kidney disease D) patients. Anemia typically first appears in
CKD Stage 3 when the GFR is less than 60 cc/min, long before dialysis is necessary,
although anemia may appear at any stage of (7K1). At stage 5, a patient may require dialysis
treatment several times per week. Once the degeneration s of the kidney begins, the
kidney ons in CKD deteriorate irreversibly toward end stage renal disease (ESRD, stage
). Patients suffering from ESRD cannot survive t dialysis or kidney lantation.
According to the US. National Kidney l’oundation, approximately 26 million
American adults have CKD and millions of others are at increased risk. Patients
experiencing the earlier stages of CKD typically incur sed medical costs of US.
$14,000 to US. $22,000 per patient per year, compared to the tched, non—(TKI)
general population. However, there is growing evidence that some of the sed costs and
adverse outcomes associated with CKD can be ted or delayed by preventive measures,
early detection, and early treatment.
h‘on deficiency and anemia are common complications of CKD, including ESRD.
Anemia is the clinical manifestation of a decrease in circulating red blood cell mass and
usually is detected by low blood hemoglobin concentration. The properly functioning kidney
produces erythropoietin, a hormone that stimulates proliferation and differentiation of red
blood cell precursors, which ultimately leads to erythropoiesis (red blood cell production). In
the CKD kidney, erythropoietin production is often impaired, leading to erythropoietin
[Q L11 deficiency and the concomitant deficiency in erythropoiesis. Anemia is associated with
adverse cardiovascular outcomes, ESRD, mortality and diminished quality of life
(Macdougall, Curr Med Res 0pm (2010) 26:473-482). The prevalence of anemia in CKD
increases as kidney function decreases. imately 50% of alysis chronic kidney
disease patients are anemic, and by the time CKD patients start dialysis, up to "10% are
anemic (Macdougall, supra, and McClellan er (1]., Curr Med Res Opin (2004) 20:1501-1510).
Iron deficiency is a significant contributor to anemia in CKD patients. The estimated
prevalence ranges from 25 to 70% (llsu, et (11., J Am Soc Nephrol (2002) 13: 786;
Gotloib et (11., JNephr01(2006) 19: 161—167; Mafra, et 61]., JRen Nutr (2002) 12: 38—41;
Kalantar—Zadeh, er (1]., Am JKidney Dis (1995) 26: 292—299; and Post, er (1]., Int Urol
Nephm/ (2006) 38: 3). The causes include decreased intake or absorption of iron,
iron sequestration as a result of inflammation, blood loss, and increased iron use for red blood
cell production in response to erythropoiesis stimulating agents (ESAs) (Fishbane, et (11., Am
J Kidney Dis (1997) 29: 3197333; Kooistra, et a/., Nephml Dial Transplant (1998) 13: 82*
88; and Akmal, er (1]., C1111 ! (1994) 42: 1987202). Depending on CKD stage, 20—70%
of CKD patients t low iron indices (Quinbi et (11., Nephrol Dial Transplant (2011)
26:1599—1607). More than 1 million CKD stage 3 or 4 patients in the US. are estimated to
suffer from iron deficiency. The presence of either low iron stores (“absolute” iron
deficiency) or inadequate iron available to meet the demand for erythropoiesis tional“
iron deficiency) correlates significantly with reduced hemoglobin levels in CKD patients.
Iron deficiency can arise from any one or more factors including, for example, insufficient
iron from food intake, sed iron utilization, poor gastrointestinal iron absorption, and
generalized malabsorption due to renal failure and bacterial overgrowth, and gastrointestinal
bleeding (Macdougall, supra).
The current standard of care for anemia and/or iron deficiency in CKD patients is
administration of erythropoiesis-stimulating agents (ESAs) and/or iron supplementation. The
National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines
recommend either oral or intravenous iron for patients who have (7K1) stages 1 to 5 and are
not on is (see “Using iron agents: KDOQI clinical practice guidelines and clinical
practice endations for anemia in chronic kidney e,” Am J Kidney Dis (2006) 47:
0). The ferric form of iron (also known as iron(111) or 1e”) has long been known to
have poor bioavailability when administered orally. 'lherefore, oral formulations for iron
supplementation in CKD patients lly contain the s form of iron (also known as
iron(11) or Fe”). Several ferrous oral iron preparations are available for treatment including
ferrous ate, ferrous fumarate, and ferrous sulfate. The most common oral iron
supplement is ferrous sulfate, which can be given up to three times daily in order to provide
an adequate dose for treating iron-deficient CKD patients. However, in some CKD patients,
oral iron is poorly ted because of adverse side effects, or is ctive in maintaining
SUMMARY
The present invention provides for the use of ferric citrate in the manufacture of a
medicament for ing transferrin tion (TSAT) in a non-dialysis chronic kidney
disease D) human t in need thereofby oral administration of one or more tablets
of ferric citrate, wherein the ferric citrate provides for a mean increase in TSAT in said CKD
patient of up to about 20%, and wherein each ferric citrate tablet comprises approximately 1g
of ferric citrate.
The above and other aspects will be described further below. Certain of the
embodiments may form the subject of related applications, NZ 630995, NZ725920 or a
further divisional application. Where a method of medical treatment is described herein it is
also to be taken as describing the use of the active ient, in the preparation of a
medicament, for use in that treatment.
(followed by page 4A)
wed by page 5)
(Mathew, er al., J Am Soc Nephrol (2006) 17: 357A; Voormolen, et al., Nephrol Dial
Transplant (2007) 22: 2909—2916; and Tonelli er al., Circulation (2005) 112: 2627—2633).
Four clinical studies of the ferric citrate disclosed herein (e.g., KRX—0502 (ferric citrate)) in
patients with ESRD have been conducted and reported to the US. lt'ood and Drug
Administration as part of the KRX-0502 (ferric citrate) igational New Drug (IND)
submission. One of those studies, a Phase 3 long term study (described herein), has
confirmed that the ferric citrate disclosed herein (also known as KRX—0502) demonstrates a
highly statistically significant change in seium oms versus placebo over a four—week
cy Assessment Period and can increase in and transferrin saturation (TSAT) and
reduce the use of intravenous iron and erythropoiesis—stimulating agents in liSRl) patients
when ed to active control agents over a 52—week Safety Assessment Period.
In accordance with the present disclosure, it has been ered that the ferric citrate
disclosed herein can be used as a clinically safe and effective phosphate binder to control
and/or reduce serum phosphorus levels, increase serum bicarbonate levels, improve one or
more iron storage parameters (e. g., increase serum ferritin levels, increase transferrin
saturation (TSAT), increase hemoglobin concentration, increase iron absorption), maintain
iron stores, treat iron deficiency, treat anemia, reduce the need for IV iron and/or reduce the
need for erythropoiesis-stimulating agents (ESAs) in CKD patients, including non-dialysis
CKD (ND-CKD) patients and end state renal e (ESRD) patients.
In a one aspect, the present disclosure provides methods of reducing and/or
controlling serum phosphorus in a t in need thereof. In some embodiments, the
methods comprise orally administering ferric citrate to a CKD patient, e.g., an age renal
disease patient, at a dose of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric
citrate provides a mean ion in serum phosphorus of 2.00 2 2.50 mg/dl. In some
embodiments, the ferric citrate is administered in a 1 gram tablet dosage form, each dosage
form comprising 210 mg of ferric iron. In some embodiments, the patient is administered up
to 18 tablet dosage forms per day. In some embodiments, the patient is administered 6 tablet
dosage fonns per day. In some embodiments, the fen‘ic citrate is administered within 1 hour
of the ingestion of a meal or snack by the patient. In some ments, the patient was
treated with thrice—weekly hemodialysis or with peritoneal dialysis for at least 3 months prior
to administration of the ferric citrate. In some embodiments, the ferric e has a BET
active surface area r than about 16 1112/g. In some embodiments, the BET active e
area ranges from about 16 1112/g to about 20 1112/g. In some ments, the BET active
, t 7 7
surl ace area ranges from about 27.9‘) m‘/g to about 32.34 m“/g. In some embodiments, the.
BET active surface area is selected from 27.99 mZ/g, 28.87 nng and 32.34 mz/g. In some
embodiments, the ferric citrate has an intrinsic dissolution rate of 1.88 — 4.0 mg/cmZ/min.
In another aspect, the present disclosure provides methods of reducing serum
phosphorus in a patient in need thereof. In some errrbodiments, the methods comprise orally
administering ferric citrate to a CKD patient, e. g., an end-stage renal disease patient, at a dose
of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric citrate provides: a mean
reduction in serum phosphorus selected from 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97,
1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09 and 2.10 mg/dl when
administered for a period of 12 weeks; a mean reduction in serum orus selected from
2.10, 2.1 1, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24 and 2.25
mg/dl when administered for a period of 24 weeks; a mean reduction in serurrr phosphorus
selected from 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19 and 2.20 mg/dl when
administered for a period of 36 weeks; a mean reduction in serum orus selected from
1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10,
2.11, 2.12, 2.13, 2.14 and 2.15 mg/dl when administered for a period of 48 weeks; and a
mean reduction in serum phosphorus selected from 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01,
2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10, 2.1 1, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17,
2.18, 2.19, 2.20, 2.-1, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29 and 2.30 mg/dl when
administered for a period of 52 weeks. In some embodiments, the ferric citrate provides a
mean reduction in serum phosphorus of 2.00 mg/dl when administered for a period of 12
weeks. In some embodiments, the ferric citrate es a mean reduction in serurrr
phosphorus of 2.20 mg/dl when administered for a period of 24 weeks. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus of 2.20 mg/dl
when stered for a period of 36 weeks. In some embodiments, the ferric citrate
provides a mean reduction in serurrr orus of 2.10 mg/dl when administered for a period
of 48 weeks. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus of 2. 10 mg/dl when administered for a period of 52 weeks.
In yet another aspect, the present sure provides methods of increasing serum
bicarbonate in a patient in need thereof. In some embodiments, the methods comprise orally
administering ferric citrate to a CKD t, e. g., an age renal disease t, at a dose
of ferric iron ranging from 210 mg , 2,520 mg, wherein the ferric citrate provides an increase
in serum bicarbonate selected from 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79
and 0.80 mEq/L when administered for a period of at least 52 weeks. In some embodiments,
the ferric citrate es a mean increase in serum onate concentration of 0.71 mliq/I
In some embodiments, the ferric citrate is stered in a 1 gram tablet dosage form, each
dosage form comprising 210 mg of ferric iron. In some embodiments, the t is
administered up to 18 tablet dosage forms per day. In some embodiments, the patient is
administered 6 tablet dosage forms per day. In some embodiments, the ferric citrate is
administered within 1 hour of the ingestion of a meal or snack by the patient. In some
embodiments, the t was treated with thrice-weekly hemodialysis or with peritoneal
dialysis for at least 3 months prior to administration of the ferric citrate. In some
embodiments, the ferric citrate has a BET active surface area greater than about 16 mz/g. In
some embodiments, the BET active surface area ranges from about 16 nil/g to about 20 mz/g.
l() In some embodiments, the BET active surface area ranges from about 27.99 mZ/g to about
32.34 1112/g. In some embodiments, the BET active surface area is ed from 27.99 1112/g,
28.87 mz/g and 32.34 mZ/g. In some embodiments, the ferric e has an intrinsic
dissolution rate of 1.88 2 4.0 mg/cmz/min.
In yet another , the present disclosure provides methods of maintaining iron
stores in a patient in need thereof. In some embodiments, the methods comprise orally
administering ferric citrate to a CKD t, e. g., a alysis chronic kidney disease
patient or an end stage renal disease patient, in an amount ranging from about I g to about 18
g per day. In some embodiments, the ferric e in administered in a 1 gram tablet dosage
form. In some embodiments, the patient is administered up to 18 tablet dosage forms per
day. In some embodiments, the ferric citrate has a BET active surface area greater than about
16 iiizfg. In some embodiments, the BET active surface area ranges from about 16 mZ/g to
about 20 mZ/g. In some embodiments, the BET active surface area ranges from about 27.99
1112/g to about 32.34 mz/g. In some embodiments, the BET active e area is selected
from 27.99 mZ/g, 28.87 mZ/g and 32.34 mZ/g. In some embodiments, the ferric citrate has an
intrinsic dissolution rate of 1.88 — 4.0 mg/cmZ/min.
In yet another aspect, the present disclosure provides methods of improving one or
more iron storage parameters in a patient, in need thereof. In some embodiments, the methods
comprise orally administering ferric citrate to a CKD patient, e.g., a non—dialysis chronic
kidney disease patient or an end stage renal disease patient, in an amount ranging from about
1 g to about 18 g per day. In some embodiments, the at least one iron storage parameter may
be ed from serum ferritin levels, transferrin saturation ('I‘SA'I‘), hemoglobin
tration, hematocrit, total iron-binding capacity, iron absorption levels, serum iron
levels, liver iron levels, spleen iron levels, and combinations thereof. In some embodiments,
the ferric citrate in administered in a 1 gram tablet, dosage form. In some embodiments, the
patient is administered up to 18 tablet dosage forms per day. In some embodiments, the ferric
e has a BET active surface area greater than about 16 mz/g. In some embodiments, the
BET active e area ranges from about 16 mzlg to about 20 mZ/g. In some embodiments,
the BET active surface area ranges from about 27.99 nil/g to about 32.34 BIZ/g. In some
embodiments, the BET active surface area is selected from 27.99 mZ/g, 28.87 mz/g and 32.34
1112/g. In some embodiments, the ferric e has an intrinsic dissolution rate of 1.88 — 4.0
mg/cmZ/min.
In another embodiment, the at least one iron e parameter is hematocrit, and
improving ses increasing the hematocrit of the patient. In other embodiments, the at
least one iron storage ter is hemoglobin concentration, and improving comprises
increasing the hemoglobin concentration of the patient. In yet other ments, the at least
one iron storage parameter is total iron-binding capacity, and improving ses
decreasing the total iron—binding capacity of the patient. In yet other embodiments, the at
least one iron storage ter is transferrin saturation, and improving comprises increasing
the transferrin saturation of the patient. In yet other embodiments, the at least one iron
storage parameter is serum iron levels, and improving comprises sing the serum iron
levels of the patient. ln yet other embodiments, the at least one iron storage parameter is liver
iron levels, and improving comprises sing the liver iron levels of the patient. In yet
other embodiments, the at least one iron storage parameter is spleen iron levels, and
improving comprises increasing the spleen iron levels of the patient. In yet other
embodiments, the at least one iron storage parameter is serum ferritin levels, and improving
comprises increasing the serum ferritin levels of the patient.
In yet another embodiment, the at least one iron storage parameter is serum ferritin
levels, and the present disclosure provides methods of increasing serum ferritin in a t in
need thereof. In some embodiments, the methods se orally administering ferric citrate
to a CKD patient, e. g., an end-stage renal disease patient at a dose of ferric iron ranging from
210 mg 4 2,520 mg, wherein the ferric citrate provides a mean increase in serum ferritin in the
patient selected from 150 — 310, 151 — 309, 152 — 308, 153 — 307, 154 — 306, 155 — 306, 155
— 305, 155 — 304, 155 — 303 and 155 — 302 ng/ml when administered for a period of at least
52 weeks. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
of 150 4 305 ng/ml. ln some embodiments, the ferric citrate is administered in a 1 gram
tablet dosage form, each dosage form comprising 210 mg of ferric iron. In some
embodiments, the patient is administered up to 18 tablet dosage forms per day. In some
embodiments, the t is administered 6 tablet dosage forms per day. In some
embodiments, the ferric citrate is administered within 1 hour of the ingestion of a meal or
snack by the t. In some embodiments, the patient was treated with thrice-weekly
hemodialysis or with peritoneal dialysis for at least 3 months prior to administration of the
ferric citrate. In some embodiments, the ferric citrate has a BET active surface area greater
than about 16 1112/g. In some embodiments, the BET active surface area ranges from about I6
1112/g to about 20 mZ/g. In sorrre embodiments, the BET active surface area ranges from about
27.99 mZ/g to about 32.34 [HZ/g. In some embodiments, the BET active surface area is
selected from 27.99 mz/g, 28.87 mZ/g and 32.34 mz/g. In some embodiments, the ferric
citrate has an intrinsic dissolution rate of 1.88 — 4.0 mg/cmZ/min.
In yet another embodiment, the at least one iron storage parameter is tr'anslei‘i‘in
tion (TSAT), and the present disclosure provides methods of increasing transferrin
saturation (TSAT) in a patient in need f. In some embodiments, the methods se
orally stering ferric citrate to an a CKD patient, e. g., an end stage renal disease patient,
at a dose of ferric iron ranging from 210 mg 4 2,520 mg, wherein the ferric citrate provides a
mean increase in TSAT of 5 — 10 % when administered for a period of at least 52 weeks. In
sorrre embodiments, the ferric citrate provides a mean increase in transferrin saturation
(TS/\T) in the patient of 6 2 9 “/13 In some embodiments, the ferric citrate provides a mean
se in transferrin saturation (TSAT) in the patient of 8%. In sonre embodiments, the
ferric citrate is administered in a 1 gram tablet dosage form, each dosage form comprising
210 mg of ferric iron. In some embodiments, the patient is administered up to 18 tablet
dosage forms per day. In some embodiments, the patient is administered 6 tablet dosage
forms per day. In some embodiments, the ferric e is stered within 1 hour of the
ingestion of a meal or snack by the patient. In some embodiments, the ferric citrate has a
BET active surface area greater than about 16 BIZ/g. In some embodiments, the BET active
surface area ranges from about 16 mZ/g to about 20 mZ/g. In sorrre embodiments, the BET
active surface area ranges from about 27.99 1112/g to about 32.34 mZ/g. In some embodiments,
the BET active surface area is selected from 27.99 mZ/g, 28.87 IIIZ/g and 32.34 mZ/g. In some
embodiments, the ferric citrate has an intrinsic dissolution rate of 1.88 — 4.0 mg/cmZ/min.
In yet another embodiment, the at least one iron storage ter is hemoglobin
concentration, and the present disclosure provides methods of increasing obin
concentration in a patient in need thereof. In some embodiments, the methods se
orally administering ferric citrate to a CKD patient, e. g., an end-stage renal disease patient, at a
dose of ferric iron ranging from 210 mg — 2,520 mg, n the ferric e provides a mean
se in hemoglobin concentration in the patient of0.3 4 0.6 g/dl when administered for a
period of at least 52 weeks. In some embodiments, the ferric citrate provides a mean increase
in hemoglobin concentration in the patient of 0.3 — 0.5 g/dl. In some embodiments, the ferric
citrate es a mean increase in hemoglobin concentration of 0.4 g/(II. In some
embodiments, the ferric citrate is administered in a 1 gram tablet dosage form, each dosage
form sing 210 mg of ferric iron. In some ments, the patient is administered up
to 18 tablet dosage forms per day. In sorrre embodiments, the patient is administered 6 tablet
dosage forms per day. In some embodiments, the ferric citrate is administered within I hour
of the ingestion of a meal or snack by the patient. In some embodiments, the ferric citrate has
a BET active surface area greater than about 16 mZ/g. In some embodiments, the BET active
I0 surface area ranges from about 16 mZ/g to about 20 mZ/g. In some embodiments, the BET
active surface area ranges from about 27.99 1112/g to about 32.34 1112/g. In some embodiments,
the BET active surface area is selected from 27.99 mZ/g, 28.87 mZ/g and 32.34 mZ/g. In some
embodiments, the ferric citrate has an intrinsic dissolution rate of 1.88 , 4.0 mg/cmZ/min.
In yet another aspect, the present disclosure provides methods of increasing iron
absorption in a patient in need thereof. In some embodiments, the methods comprise orally
administering ferric citrate to a CKD t, e. g., a non-dialysis chronic kidney disease
patient or an end stage renal disease patient, in an amount ranging from about I g to about 18
g per day. In sorrre embodiments, the ferric citrate in administered in a 1 gram tablet dosage
form. In some embodiments, the patient is stered up to 18 tablet dosage forms per
day. In some embodiments, the ferric citrate has a BET active surface area r than about
16 mZI’g. In sonre embodiments, the BET active surface area ranges from about 16 mZ/g to
about 20 mZ/g. In some embodiments, the BET active surface area ranges from about 27.99
1112/g to about 32.34 mz/g. In some embodiments, the BET active surface area is selected
from 27.99 mZ/g, 28.87 mZ/g and 32.34 mZ/g. In some ments, the ferric citrate has an
intrinsic dissolution rate of 1.88 — 4.0 mg/cmZ/min.
In yet another aspect, the present disclosure provides methods of treating iron
deficiency in a patient in need f. In some embodiments, the methods comprise orally
administering ferric citrate to a CKD patient, e. g., a alysis chronic kidney disease
patient or an end stage renal disease patient, in an amount ranging from about 1 g to about 18
g per day. In some ments, the iron deficiency is anemia. In some embodiments, the
treatment provides a hemoglobin level in the patient that is at or above a level selected from
12.0 g/dl and 7.4 mmol/L. In other embodiments, the ent es a hemoglobin level
in the patient that is at or above a level selected from 13.0 g/dl and 8.1 . In yet other
embodiments, the treatment provides a hemoglobin level in the patient that is at or above a
—10-
level selected from 6.8 , 7.1 mmol/L, 7.4 , and 8.1 mmoliL. In yet other
embodiments, the treatment provides a hemoglobin level in the patient that is at or above a
Iev‘l selected from I 1.0 g/(II, 1 1.5 g/dl, 12.0 g/dl, and 13.0 g/dl. In some embodiments, the
treatment reduces at least one symptom of iron deficiency selected from fatigue, dizziness,
pallor, hair loss, bility, weakness, pica, brittle or grooved nails, Plummer-Vinson
syndrome, impaired immune function, pagophagia, restless legs syndrome and combinations
thereof. In some embodiments, the ferric citrate in administered in a 1 gram tablet dosage
form. In some embodiments, the patient is administered up to 18 tablet dosage forms per
day. In some embodiments, the ferric citrate has a BET active surface area greater than about
16 mzfg. In some embodiments, the BET active surface area ranges from about 16 nil/g to
about 20 1112/g. 1n sonre embodiments, the BET active surface area ranges from about 27.99
1112/g to about 32.34 mZ/g. In some embodiments, the BET active surface area is ed
from 27.99 mZ/g, 28.87 nil/g and 32.34 mZ/g. In some ments, the ferric citrate has an
sic dissolution rate of 1.88 4 4.0 mg/cmZ/min.
In yet another , the present disclosure provides methods of reducing intravenous
(IV) iron use in a CKD patient, e. g., an end-stage renal disease patient. In sorrre
embodiments, the methods comprise orally administering ferric citrate to the patient at a dose
of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric citrate reduces the need for
the end—stage renal disease patient to be administered IV iron by an amount selected from 50,
51, 52, 53, 54, 55, 56, 57, 58, 59 and 60 ”/17 when administered for a period of at least 52
weeks. In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake selected from 51.0, 51.1, 51.2, 51.3, 51.4, 51.5, 51.6, 51.7, 51.9
and 52.0 %. In sorrre embodiments, the fen‘ic citrate provides a mean reduction in average
cumulative IV iron intake of 5 1 .6 ‘70. In some embodiments, the ferric citrate is administered
in a 1 gram tablet dosage form, each dosage form comprising 210 mg of ferric iron. In sorrre
embodiments, the t is administered up to 18 tablet dosage forms per day. In some
embodiments, the patient is administered 6 tablet dosage forms per day. In some
embodiments, the ferric e is administered within 1 hour of the ion of a meal or
snack by the patient. In some embodiments, the t was treated with thrice-weekly
hemodialysis or with neal dialysis for at least 3 months prior to administration of the
ferric citrate. In some embodiments, the ferric citrate has a BIi'I‘ active surface area greater
than about 16 1112/g. In some ments, the BET active surface area ranges from about 16
1112/g to about 20 mZ/g. In sorrre embodiments, the BET active surface area ranges from about
7 7
27.99 irr/g to about 32.34 m‘/g. In some embodiments, the Blrl. ,,, . . .
active surIace area is
selected from 27.99 mZ/g, 28.87 mZ/g and 32.34 mZ/g. In some embodiments, the ferric
citrate has an intrinsic dissolution rate of 1.88 — 4.0 /min.
In yet another aspect, the present disclosure provides methods of ng use of
erythropoiesis—stimulating agents (ES/\s) in a CKD patient, e. g., an end—stage renal e
patient. In some embodiments, the methods comprise orally administering ferric citrate to the
patient at a dose of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric citrate
reduces the need for the patient to be administered one or more IESAs by an amount selected
from 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30 % when administered for a period of at least
52 weeks. In sorrre embodiments, the ferric citrate provides a decrease in median ESA intake
selected from 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.9 and 28.0 ‘71; In some
embodiments, the ferric citrate provides a mean reduction in average cumulative 1V iron
intake of 27.1 %. In some embodiments, the ferric citrate is administered in a 1 gram tablet
dosage form, each dosage form comprising 210 mg of ferric iron. In some embodiments, the
patient is administered up to 18 tablet dosage forms per day. In some embodiments, the
patient is administered 6 tablet dosage forms per day. In sorrre embodiments, the ferric citrate
is administered within 1 hour of the ingestion of a meal or snack by the patient. In sorrre
embodiments, the patient was d with thrice—weekly hemodialysis or with peritoneal
dialysis for at least 3 months prior to administration of the ferric citrate. In sorrre
embodiments, the ferric citrate has a BET active surface area greater than about 16 mz/g. In
some embodiments, the BET active e area ranges from about 16 [HZ/g to about 20 mZ/g.
In some embodiments, the BET active surface area ranges from about 27.99 mZ/g to about
32.34 mZ/g. In some embodiments, the BET active surface area is selected from 27.99 1112/g,
28.87 mZ/g and 32.34 mz/g. In sorrre embodiments, the ferric e has an intrinsic
ution rate of 1.88 , 4.0 mg/cmZ/min.
DETAILED PTION
In some s, the present disclosure provides methods of using a ferric citrate to
reduce and/or control serum phosphorus levels, increase serum onate levels, improve
one or more iron storage parameters (e. g., increase serum ferritin levels, increase transferrin
saturation (TSAT), increase hemoglobin tration), increase iron absorption, maintain
iron stores, treat iron deficiency, treat anemia, reduce the need for IV iron and/or reduce the
need for erythropoiesis-stimulating agents (ESAs) in c kidney e (CKD) patients.
In each instance, the methods comprise administering ferric citrate to a CKD patient,
including a non—dialysis (7K!) (ND—CK!» patient as well as an end stage renal disease
(ESRD) patient. In some aspects, the administration of ferric citrate occurs over a long
period of time ing, for example, up to and including 52 weeks. In sorrre embodiments,
the administration of ferric citrate occurs over a period up to and including 56 weeks.
In each of these disclosed methods, ferric citrate may be administered to the CKD
patient over a period of time that is at least 52 weeks and, in sorrre ments, up to and
including 56 weeks or longer. Additionally, in each of these s the ferric citrate may
be administered to the (7K!) patient, orally, in a 1 g , or caplet, dosage form that, contains
210 mg of ferric iron. Up to 18 tablets, or caplets, may be administered over the course of a
day.
The present disclosure also provides pharmaceutical compositions, which may also be
an iron ment, which may be administered to CKD patients. The compositions/iron
supplements comprise ferric citrate as well as other pharmaceutically acceptable ients,
as described below. The compositions/iron supplements are formulated to provide iron to
(7K1) ts, and the amount of iron provided by the compositrons/iron supplements is
sufficient to increase iron absorption, improve one or more iron storage parameters, treat iron
deficiency and/or treat anemia in CKD patients. The itions/iron supplements may be
provided in any number of forms, as described below. In particular, the composilions/iron
supplements may be ed as oral tablet dosage forms.
Reference is now made in detail to certain embodiments of ferric citrate, dosage
forms, compositions, methods of synthesis and methods of use. The disclosed embodiments
are not intended to be limiting of the claims. To the contrary, the claims are intended to
cover all alternatives, modifications, and lents.
Therapeutic Uses of Ferric Citrate
As set forth in greater detail below, disclosed herein are methods and dosage forms
that can be used to reduce and/or control serum phosphorus levels, increase serum
bicarbonate levels, improve one or more iron storage ters (e.g., increase serum ['erritin
levels, increase transferrin saturation (TSAT), increase hemoglobin concentration) increase
iron absorption, in iron stores, treat iron deficiency, treat anemia, reduce the need for
IV iron and/or reduce the need for opoiesis—stimulating agents (ESAs) in CKI) patients,
including non—dialysis CK!) (ND—CKD) patients and end state renal disease (I‘ISRID patients.
Therefore, in various aspects, the ferric citrate disclosed herein may be administered
to CKD patients to reduce and/or control serum phosphorus. In various aspects, the ferric
citrate disclosed herein may be administered to (7K!) patients to increase serum bicarbonate.
In various aspects, the ferric citrate disclosed herein may be administered to CKD patients to
e one or more iron storage parameters, including to increase serum ferritin, to increase
transferrin saturation (TS/\T), and to increase hemoglobin concentration. In various aspects,
the ferric citrate disclosed herein may be stered to CKD patients to increase iron
absorption. In various aspects, the ferric citrate sed herein may be administered to
CKD patients to maintain iron stores. In various aspects, the ferric citrate disclosed herein
may be administered to (7K!) patients to treat iron deficiency. In various aspects, the ferric
citrate disclosed herein may be administered to CKD patients to treat . In various
aspects, the ferric e disclosed herein may be administered to CKD ts to reduce the
need for IV iron andx’or erythropoiesis—stimulating agents (liSAs).
Methods of treating CKD patients are also disclosed. In various aspects, the present
disclosure provides methods of reducing and/or controlling serum phosphorus, the methods
comprising orally administering ferric citrate to a CKD patient, wherein the ferric citrate
provides a reduction in serum phosphorus. In s aspects, the present disclosure provides
methods of increasing serum bicarbonate, the methods comprising orally administering ferric
citrate to a CKD patient, wherein the ferric citrate provides an increase in serum bicarbonate.
In various aspects, the present disclosure provides methods of ing one or more iron
storage parameters, the methods comprising orally stering ferric citrate to a CKD
patient, wherein the ferric citrate provides improvement in one or more iron e
parameters. In various aspects, the present disclosure provides methods of increasing serum
ferritin, the methods sing orally administering ferric citrate to a CKD patient, wherein
the ferric citrate provides an increase in serum ferritin. In various s, the t
disclosure es methods of increasing transferrin saturation (TSAT), the methods
comprising orally administering ferric citrate to a (7K!) patient, wherein the ferric citrate
provides an increase in TSAT. In various aspects, the present disclosure provides methods of
increasing hemoglobin concentration, the methods comprising orally administering ferric
e to a (7K1) patient, wherein the ferric citrate es an increase in hemoglobin
concentration. In various aspects, the t disclosure provides methods of increasing iron
absorption, the methods comprising orally administering ferric citrate to a CKD patient,
wherein the ferric citrate provides an increase in iron absorption. In various aspects, the
present disclosure provides methods of maintaining iron stores, the methods comprising
orally administering ferric citrate to a CKD patient, n the ferric citrate provides for
maintenance of iron stores. In various aspects, the present disclosure provides methods of
treating iron deficiency, the methods comprising orally administering ferric citrate to a CKD
patient, wherein the ferric citrate provides treatment of iron deficiency. In various aspects,
the present disclosure provides methods of treating anemia, the s comprising orally
administering ferric citrate to a CKD patient, wherein the ferric citrate es for treatment
of anemia. In various aspects, the present disclosure provides methods of reducing
intravenous (IV) iron use in a CKD patient, the methods sing orally administering
ferric citrate to CKD patient, wherein the ferric citrate reduces the need for the CKD to be
administered IV iron. In various aspects, the present disclosure provides methods of reducing
use of erythropoiesis-stimulating agents (ESAs) in CKD t, the methods comprising
orally administering ferric citrate to the CKD patient, wherein the ferric citrate reduces the
need for the (7K1) patient to be administered one or more liSAs when administered. In each
of the s, the ferric citrate may be administered for a period of time up to and including
52 weeks, including up to and including 56 weeks.
Chronic Kidney e Patients
In various aspects, the ferric citrate disclosed herein is administered to any chronic
kidney disease (CKD) patients to treat any of the conditions and disorders associated with
(7K1), such as bed herein. All individuals with a glomerular tion rate (( ilr‘R) <60
/ 1.73 in2 for 3 months are classified as having CKD, irrespective of the presence or
absence of kidney damage. Those individuals with CKD who require either dialysis or
kidney transplantation are typically re ‘erred to as end—stage renal disease (ESRD) patients.
'l’herefore, a patient is traditionally classified as an ESRD patient when he or she reaches the
conclusion of the non-dialysis dependent, earlier stages, of CKD. Prior to then, those patients
are referred to as non—dialysis dependent CKD patients. However, patients with an advanced
stage of (TKI), such as stage 5, who have not yet started dialysis or who have not been
recommended for transplantation are also typically referred to as non-dialysis dependent
CKD patients.
Non—dialysis (7K!) D) ts are those who have been diagnosed with an
early stage of chronic kidney disease and who have not yet been lly directed to
undergo dialysis. As noted above, the U.S. National Kidney Foundation has defined 5 stages
of chronic kidney disease. Typically, patients progress through stages 1 through 4 before
dialysis is medically necessary.
As used herein, ND—CKD is intended to cover all patients who have been diagnosed
with chronic kidney e but who are not undergoing is during the administration of
ferric citrate. Such patients can include, for example, patients who have never been subjected
to is and, in some embodiments, ts who have been subjected to dialysis but who
are not undergoing dialysis during the administration of ferric citrate.
In various aspects, ESRD patients are typically those who have been diagnosed with a
late stage of chronic kidney disease. In some instances the phrase “end—stage renal disease"
is used to indicate the fifth stage of CKD. Therefore, as used herein, an ESRD patient is a
patient who has an advanced stage of CKD, such as stage 5, and who has begun either
hemodialysis or peritoneal is and/or who has been recommended for kidney
transplantation by a health care provider.
In some embodiments, CKD patients display one or more of the following
characteristics: a serum phosphorus level between 2.5 mgidl. and 8.0 mg/dl.; a serum
phosphoms level r than or equal to 6.0 mg/dL when removed from a phosphate ;
are taking 3 to 18 pills/day of m acetate, calcium carbonate, lanthanum carbonate,
sevelamer (carbonate or hydrochloride or equivalent sevelamer powder), any other agent
serving as a phosphate binder, or a combination of any of the foregoing; have a serum ferritin
level that is less than 1000 mg/L; have a transferrin saturation level (TSAT) that is less than
50% at screening; have a life expectancy of more than 1 year; or a combination of any of the
foregoing.
In addition, CKD patients may be taking phosphorus binding agents other than ferric
citrate, though this is not required. The CKD patients can be mammals and, in some
embodiments, are humans. In some ments, CKD patients are female or male of any
age and/or weight. In some embodiments, CKD patients are males or non—pregnant, non—
breastfeeding females who are at least 18 years of age and have been on thrice-weekly
hemodialysis and/or peritoneal dialysis for at least 3 months.
Serum Phosphorus
Phosphate is critical for a vast array of cellular processes. It is one of the major
ents of the skeleton and an integral component of the nucleic acids that make up
DNA and RNA. In addition, the phosphate bonds of adenosine triphosphate (ATP) can‘y the
energy ed for all cellular functions. ate functions as a buffer in bone, serum, and
urine and the addition and/or on of phosphate groups to/from enzymes and proteins are
common mechanisms for the regulation of their activity. (liven the h of nce
phosphate has, its homeostasis is understandably a highly regulated process.
Patients with CKD typically demonstrate elevated levels of serum phosphate. In non-
(TKI) patients, normal serum phosphate levels should be between 0.81 mmol/I, and 1.45
mmolfL. In a CKD t, however, serum phosphate levels are typically markedly
increased as kidney function is lost and the body loses its y to excrete phosphate through
the urine. This means that CKD patients typically experience hyperphosphatemia, which is
an electrolyte disturbance in which there is an abnormally elevated level of phosphate in the
blood. Hyperphosphatemia develops in the majority of CKD patients and is typically
associated with progression of secondary hyperparathyroidism and renal osteodystrophy. In
addition, hyperphosphatemia has recently been associated with increased cardiovascular
mortality among dialysis patients. Adequate control of serum phosphorus is crucial in the
clinical ment of CKD patients to attenuate the progression of secondary
hyperparathyroidism and to reduce the risk of vascular calcification and cardiovascular
mortality. 'l‘ypical measures taken to control r phosphate levels in CKD patients include
dietary phosphorus restriction, is, and oral phosphate s. Unfortunately, dietary
restriction has limited effect in advanced stages of CKD, such as ESRI). Therefore, oral
phosphate binders are necessary to limit dietary absorption of phosphorus in (7K!) patients.
CKD patients treated ing to the methods disclosed herein may experience an
ement in serum phosphate . In some embodiments, CKD patients treated
according to the methods disclosed herein experience a decrease in serum phosphate levels.
In sorrre embodiments, the present disclosure provides s of reducing serum
phosphorus in a CKD patient, the methods comprising orally administering ferric citrate to
CKD patient, e.g., an end—stage renal disease patient or non—dialysis chronic kidney disease
patient, wherein the ferric citrate provides a reduction in serum phosphorus in the t. In
some embodiments, the present disclosure provides methods for treatment of
hyperphosphatemia in a CKD patient, the methods comprising orally stering ferric
citrate to (7K!) patient, e.g., an end—stage renal disease patient or non—dialysis chronic kidney
disease patient, n the ferric citrate provides a reduction in serum phosphorus in the
patient. In some embodiments, the present disclosure provides methods of reducing serum
phosphorus, the methods comprising orally administering ferric citrate to an end—stage renal
disease patient at a dose of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric
e es a ion in serum phosphorus in the t. In some embodiments, the
ferric e is administered for a period of 12 weeks. In some embodiments for a period of
24 weeks, in some embodiments for a period of 36 weeks, in some embodiments for a period
of 48 weeks, in some embodiments for a period of 52 weeks, and in some embodiments for a
period of up to and including 56 weeks, In some embodiments for a period of 53 weeks. In
some embodiments for a period of 54 weeks, in some embodiments for a period of 55 weeks.
In some embodiments for a period of 56 weeks.
In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus from 1.00 2 3.00 mg/dl. In some embodiments, the ferric citrate provides a mean
reduction in serum phosphorus from 1.10 — 2.90 mg/dl. In some embodiments, the ferric
citrate provides a mean reduction in serum phosphorus from 1.20 — 2.80 mg/dl. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus from 1.30 2
2.70 mg/dl. In some ments, the ferric citrate provides a mean reduction in serum
phosphorus from 1.40 — 2.60 mg/dl. In some embodiments, the ferric e provides a mean
reduction in serum phosphorus from 1.50 2 2.50 mg/dl. In some embodiments, the ferric
citrate provides a mean reduction in serum phosphorus from 1.60 2 2.40 mg/dl. In some
embodiments, the ferric citrate es a mean reduction in serum phosphorus from 1.70 —
2.30 mg/dl. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus from 1.80 2 2.20 mg/dl. In some embodiments, the ferric citrate provides a mean
ion in serum phosphorus from 1.90 — 2.10 mg/dl. The above ranges are disclosed in
this format for purposes of efficiency, and any of the above ranges can be combined with any
method, formulation, or combination thereof.
In some embodiments, the ferric e provides a mean ion in serum
phosphorus of from 1.00 — 1.25 mg/dl, 1.00 — 1.50 mg/dl. In some embodiments, the ferric
citrate provides a mean reduction in serum phosphorus of from 1.00 2 1.75 mg/dl . In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus of from 1.00
— 2.00 mg/dl. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus ed from 2.00 — 2.25 mg/dl. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus selected from 2.00 2 2.50 mg/dl. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus selected from
2.00 — 2.75 mg/dl. In some embodiments, the ferric citrate es a mean reduction in
serum phosphorus selected from 2.00 2 3.00 mg/dl. In some embodiments, the ferric e
provides a mean reduction in serum phosphorus selected from 1.00 — 2.25 mg/dl. In some
embodiments, the ferric citrate provides a mean ion in serum phosphorus selected from
1.00 2 2.50 rug/d1. In some ments, the ferric citrate provides a mean reduction in
serum phosphorus selected from 1.00 2 2.75 mg/dl. In some embodiments, the ferric citrate
es a mean reduction in serum phosphorus selected from 1.00 — 3.00 mg/dl. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus of 2.00 — 2.50
mg/dl. The above ranges are disclosed in this format for purposes of efficiency, and any of
the above ranges can be combined with any method, ation, or combination thereof.
In some embodiments, the ferric e provides a mean reduction in serum
orus that is greater than 1.00. In some embodiments, the ferric citrate provides a nrean
reduction in r phosphorus that is greater than 1.10. In sorrre embodiments, the ferric
citrate provides a mean reduction in serum phosphorus that is selected from r than
greater than 1.20 . In some ments, the ferric cit ‘ate provides a mean reduction in
serurrr phosphorus that is greater than 1.30. In sorrre embodiments, the ferric citrate es
a mean ion in serum phosphorus that is greater than 1.40. In some embodiments, the
ferric cit ‘ate provides a mean ion in serum phosphorus that is greater than 1.50. In
some embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
r than 1.60. In some embodiments, the ferric citrate provides a mean reduction in
serum phosphorus that is greater than 1.70. In some embodiments, the ferric citrate provides
a mean reduction in serum phosphorus that is greater than 1.80. In some embodiments, the
ferric citrate provides a mean reduction in serurrr phosphorus that is greater than 1.90. In
sorrre embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
greater than 2.00. In some embodiments, the ferric cit ‘ate provides a mean reduction in
serurrr phosphorus that is greater than 2.10. In sorrre embodiments, the ferric citrate provides
a mean reduction in serum phosphorus that is greater than 2.20. In some embodiments, the
ferric citrate provides a mean reduction in serum phosphorus that is greater than 2.30. In
sorrre embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
greater than 2.40. In some ments, the ferric citrate provides a mean reduction in
serurrr phosphorus that is r than 2.50. In some embodiments, the ferric citrate provides
a mean reduction in serum phosphorus that is greater than 2.60. In some embodiments, the
ferric citrate provides a mean reduction in serurrr phosphorus that is greater than 2.70. In
sorrre embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
greater than 2.80. In some embodiments, the ferric citrate provides a mean reduction in
serunr phosphorus that is greater than 2.90 mg/dl. The above boundaries are disclosed in this
format for es of ency, and any of the above boundaries can be combined with any
method, formulation, lower boundary as disclosed below, or combination thereof.
In some embodiments, the ferric citrate provides a mean reduction in serum
orus that is less than 3.00 mg/dl. In sorrre embodiments, the ferric citrate provides a
mean reduction in serum phosphorus that is less than 2.90 mg/dl. In some embodiments, the
ferric citrate provides a mean reduction in serum phosphorus that is less than 2.80 mg/dl. In
some embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
less than 2.70 mg/dl. In some embodiments, the ferric citrate provides a mean reduction in
serum phosphorus that is less than 2.60 rrrgidl. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus that is less than 2.50 mgidl. In sorrre
ments, the ferric citrate provides a mean reduction in serum phosphorus that is less
than 2.40 mg/dl. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus that is less than 2.30 rug/d]. In some embodiments, the ferric e provides a
mean reduction in serum orus that is less than 2.20 mg/dl. In some embodiments, the
ferric citrate es a mean reduction in serum phosphorus that is less than 2.10 mg/dl. In
some embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is
less than 2.00 mg/dl. In some embodiments, the ferric citrate provides a mean ion in
serum phosphorus that is less than 1.90 mg/dl. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus that is less than 1.80 rug/(11. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus that is less
than 1.70 mg/dl. In some embodiments, the ferric citrate es a mean reduction in serum
phosphorus that is less than 1.60 mg/dl. In some embodiments, the ferric citrate provides a
mean reduction in serum phosphorus that is less than 1.50 rug/d1. In some embodiments, the
ferric citrate provides a mean ion in serum phosphorus that is less than 140 mg/dl. In
some embodiments, the ferric citrate es a mean reduction in serum phosphorus that is
less than 1.30 rug/d1. In some embodiments, the ferric citrate provides a mean reduction in
serum phosphorus that is less than 1.20 mgidl. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus that is less than 1.10 mg/dl. The above
boundaries are disclosed in this format for purposes of efficiency, and any of the above
ries can be combined with any , formulation, upper boundary disclosed above,
or combination thereof.
In some embodiments, the ferric citrate provides a mean ion in serum
phosphorus ofone of about1.9(), 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 199,200,
2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09 and 2.10 mg/dl when administered for a
period of 12 weeks. In some embodiments, the ferric citrate provides a mean reduction in
serum phosphorus of about 2.00 mg/dl when administered for a period of 12 weeks. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus of one of
about 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24 and
2.25 mg/dl when administered for a period of 24 weeks. In some embodiments, the ferric
e provides a mean reduction in serum phosphorus of about 2.20 mgi’dl when
stered for a period of 24 weeks. In some embodiments, the ferric citrate provides a
mean reduction in serum phosphorus of one of about 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16,
2.17, 2.18, 2.19 and 2.20 mgidl when administered for a period of 36 weeks. In some
embodiments, the ferric citrate provides a mean reduction in serurrr phosphorus of about 2.20
mg/d1 when administered for a period of 36 weeks. In sorrre embodiments, the ferric citrate
provides a mean reduction in serurrr phosphorus of one 1.95 mg/dl, 1.96, 1.97, 1.98, 1.99,
2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10, 2.1 l, 2.12, 2.13, 2.14 and 2.15
mg/d1 when administered for a period of 48 weeks. In sorrre embodiments, the ferric citrate
provides a mean reduction in serurrr phosphorus of about 2.10 mg/dl when administered for a
I0 period of 48 weeks. In some embodiments, the ferric citrate es a mean reduction in
serurrr phosphorus of one of about 1.95 mg/dl.
, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03,
2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19,
2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29 and 2.30 mg/dl when administered for
a period of 52 weeks. In some embodiments, the ferric citrate provides a mean reduction in
serurrr phosphorus of about 2.10 mg/dl when administered for a period of 52 weeks. In sorrre
embodiments, the ferric citrate provides a mean reduction in serum phosphorus of one of
about .20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34 and
0.35 mg/dl when administered for a period of 56 weeks, as measured from a baseline of 52
weeks. In sorrre embodiments, the ferric citrate provides a mean ion in serum
phosphorus of 0.30 mg/dl when administered for a period of 56 weeks, as measured from a
baseline of 52 weeks.
In sorrre embodiments, the ferric citrate provides a mean reduction in serum
orus selected from 20 — 35 %. In sorrre embodiments, the ferric e provides a
mean reduction in serum phosphorus selected from 20 2 35 ‘/r, 22 2 33 % and 25 2 30 ‘Yn. In
sorrre embodiments, the ferric citrate provides a mean reduction in serurrr phosphorus of 27 —
28.5 %. In sorrre ments, the ferric citrate provides a mean reduction in serunr
phosphorus of 27 2 28.4 %. In some embodiments, the ferric citrate provides a mean
reduction in serum orus that is selected from greater than 20, greater than 21, greater
than 22, greater than 23, greater than 24, greater than 25, greater than 26, greater than 27,
greater than 28, greater than 29, greater than 30, greater than 31, r than 32, r than
33 and r than 34 %. In some embodiments, the ferric citrate provides a mean reduction
in serurrr phosphorus that is selected from less than 35, less than 34, less than 33, less than 32,
less than 33, less than 32, less than 31, less than 30, less than 29, less than 28, less than 27,
less than 26, less than 25, less than 24, less than 23, less than 22 and less than 21 %.
In some ments, the ferric citrate provides a mean reduction in serum
phosphorus selected from 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01,
2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09 and 2.10 mg/dl when administered for a period of
12 weeks. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus of 2.00 mg/dl when administered for a period of 12 weeks. In some
ments, the ferric e provides a mean reduction in serum phosphorus selected from
2.10, 2.1 I, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24 and 2.25
mg/dl when administered for a period of 24 weeks. In some embodiments, the ferric citrate
es a mean reduction in serum phosphorus of 2.20 mg/dl when administered for a period
I0 of 24 weeks. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus selected from 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19 and 2.20
mg/d1 when administered for a period of 36 weeks. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus of 2.20 mg/dl when administered for a period
of 36 weeks. In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus selected from 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06,
2.07, 2.08, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14 and 2.15 mg/dl when administered for a period of
48 weeks. In some ments, the ferric citrate provides a mean reduction in serum
phosphorus of 2.10 mg/dl when administered for a period of 48 weeks. In some
embodiments, the ferric citrate provides a mean reduction in serum phosphorus ed from
1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10,
2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26,
2.27, 2.28, 2.29 and 2.30 mg/dl when administered for a period of 52 weeks. In some
embodiments, the ferric citrate provides a mean ion in serum phosphorus of 2.10 mg/dl
when administered for a period of 52 weeks. In some embodiments, the ferric citrate
provides a mean reduction in serum phosphorus selected from 0.20, 0.21, 0.22, 0.23, 0.24,
0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34 and 0.35 mg/dl when administered for
a period of 56 weeks, as measured from a baseline of 52 weeks. In some embodiments, the
ferric citrate provides a mean reduction in serum phosphorus of 0.30 mgfdl when
administered for a period of 56 weeks, as ed from a baseline of 52 weeks.
In some embodiments, the ferric citrate provides a mean reduction in serum
phosphorus as set forth in Table A:
Table A:
Mean Serum Phosphorus (mg/dL) Placebo Ferric
(n=91) Citrate
([1:92)
Baseline (Week 52) 5.3 5.2
End of Treatment1 (Week 56) 7.2 4.9
Change from Baseline at Week 56 1.9 -O.3
Least Squares (LS) Mean Difference from Placebo2 —2.3
p—value2 p<0.0001
Last observation carried forward was used for missing data.
The L8 Mean treatment difference and p-value is created via an ANCOVA model with treatment as the fixed
effect and baseline as the covariate.
LA in some embodiments, the ferric citrate es a mean reduction in serum
phosphorus as set forth in Table B:
Table B:
Week
N=277 ne 12 | 24 36 48 52
Ferric Citrate Mean Serum
7'4 5.4 5.2 5'2 5.3 5.3
Phos horus (m /d L)1
Change from Baseline -2.0 -2.2 -2.2 -2.1 -2.1
% Change from Baseline —27% ‘ —30% —30% —28% —28%
p-value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
1 Last observation carried forward was used for missing data.
In some embodiments, CKD patients, such as ESRD patients, d according to the
s sed herein experience maintenance of their serum phosphorus levels such that
their serum phosphorus levels remain substantially unchanged during administration of the
ferric citrate.
Serum Bicarbonate
Metabolic acidosis is a ion that occurs in CKD patients when the body produces
too much acid and/or when the kidneys are not removing enough acid from the body. [1'
unchecked, lic acidosis leads to acidemia, where the blood pH drops to less than 7.35,
due to increased production of hydrogen by the body and/or the inability of the body to form
bicarbonate (HCOr) in the . The uences of metabolic acidosis in CKD patients
can be serious, including coma and death. It is therefore important that (7K1) patients
maintain a normal level of bicarbonate in their bloodstream. For non-CKD patients, a typical
measure of seium bicarbonate ranges from 22 mEq/L — 28 mEq/L, or from 22 mmol/L to 28
mmolfL, respectively. In a CKD patient, however, the serum bicarbonate concentration can
be greatly reduced as the s lose their ability to produce bicarbonate.
CKD patients treated according to the methods disclosed herein may experience an
increase in serum bicarbonate concentration. In sorrre embodiments, CKD patients treated
ing to the methods disclosed herein experience an increase in serum bicarbonate
concentration. In some embodiments, the present disclosure provides methods of increasing
serum bicarbonate concentration in a (TKI) patient, such as an IiSRI) patient or NI)—(TKI)
t, the methods sing orally administering ferric citrate to a CKD patient, wherein
the ferric citrate provides an increase in serum bicarbonate concentration in the patient. In
I0 some ments, the present disclosure provides methods of increasing serum bicarbonate
concentration, the methods comprising orally administering ferric citrate to a CKD patient at a
dose of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric citrate provides an
increase in serum bicarbonate concentration in the patient. In some embodiments, the t
is administered up to 18 tablet dosage forms per day. In some embodiments, the ferric citrate
is administered for a period of 12 weeks, in some embodiments for a period of 36 weeks, in
some embodiments for a period of 52 weeks, and in some embodiments for a period of up to
and including 56 weeks.
In some embodiments, the ferric citrate provides a mean increase in serum bicarbonate
concentration in the patient of 0.1 — 1.0 anq/L. In some embodiments, the ferric citrate
provides a mean increase in serum bicarbonate concentation in the patient selected from
0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.7‘) and 0.80 rrrEq/L. In sorrre
embodiments, the ferric citrate es a mean increase in serum bicarbonate concentration
in the patient of 0.71 mEq/L.
In some embodiments, the ferric citrate provides a mean increase in serum bicarbonate
concentration r than 0.70 mEq/L. In some embodiments, the ferric citrate provides a
mean increase in serum bicarbonate concentration greater than 0.71 anq/L. In some
embodiments, the ferric citrate es a mean increase in serum bicarbonate concentration
greater than 0.72 mEq/L. In some embodiments, the ferric e provides a mean se in
serum onate concentration greater than 0.73 rnEq/L. In some embodiments, the ferric
e provides a mean increase in serum bicarbonate concentration greater than 0.74 mEq/L.
In some embodiments, the ferric citrate provides a mean increase in serum bicarbonate
concentration greater than 0.75 mEq/L. In some embodiments, the ferric citrate es a
mean increase in serum bicarbonate concentration greater than 0.76 anq/L. In some
ments, the ferric citrate es a mean increase in serum bicarbonate concentration
greater than 0.77 mEq/L. In sonre ments, the ferric citrate provides a mean increase in
serum onate concentration greater than 0.78 mEq/L. In some embodiments, the ferric
citrate provides a mean increase in serum bicarbonate concentration greater than 0.79 mEq/L.
The above ries are sed in this format for purposes of efficiency, and any of the
above boundaries can be combined with any method, formulation, lower ry as
disclosed below, or combination thereof.
In some ments, the ferric citrate provides a mean increase in serum onate
concentration less than 0.80 mEq/L. In some embodiments, the ferric citrate provides a mean
increase in serum bicarbonate concentration less than 0.79 mEq/L. In sorrre ments, the
ferric cit ‘ate provides a mean increase in serum bicarbonate concent‘ation less than 0.78
mlz'q/L. In some embodiments, the ferric citrate provides a mean increase in serum
bicarbonate concentration less than 0.77 mEq/L. In some embodiments, the ferric citrate
provides a mean increase in serum bicarbonate concentration less than 0.76 mEq/Il. In some
embodiments, the ferric citrate provides a mean increase in serum bicarbonate concentration
less than 0.75 mEq/L. In some embodiments, the ferric citrate provides a mean increase in
serum bicarbonate concentration less than 0.74 mEq/L. In some embodiments, the ferric
citrate provides a mean se in serum bicarbonate concentration less than 0.73 mliq/l.. In
sorrre embodiments, the ferric citrate provides a mean increase in serum bicarbonate
concentration less than 0.72 mEq/L. The above boundaries are disclosed in this format for
purposes of efficiency, and any of the above boundaries can be combined with any method,
formulation, upper boundary disclosed above, or combination thereof.
In some embodiments, the ferric citrate provides a mean increase in serum
bicarbonate concentration of 0.71 mEq/L when administered for a period of 52 weeks.
In some embodiments, (7K1) ts, such as liSRl) patients, treated according to the
methods sed herein experience maintenance of their serum bicarbonate concentration
such that their serum bicarbonate level s substantially unchanged during
stration of the ferric citrate.
Iron Storage Parameters
Patients with CKI) may demonstrate low or inadequate markers of systemic iron
status. This means that CK!) patients may not have sufficient iron stored within their bodies
to maintain proper iron levels. Most well—nourished, non—CKD people living in industrialized
countries have approximately 4 to 5 grams of iron stored within their bodies. About 2.5 g of
this iron is contained in hemoglobin, which carries oxygen through the blood. Most of the
remaining approximately 1.5 to 2.5 grams of iron is contained in iron binding complexes that
are present in all cells, but that are more highly concentrated in bone marrow and organs such
as the liver and spleen. The liver’s stores of iron are the y logic reserve of iron
in the non—CKD body. ()f the body’s total iron content, about 400 mg is utilized in proteins
that use iron for cellular ses such as oxygen storage (myoglobin) or ming energy-
producing redox reactions (cytochrome proteins). In addition to stored iron, a small amount
of iron, typically about 3 to 4 mg, circulates through the blood plasma bound to a protein
called transferrin. Because of its toxicity, free soluble ferrous iron (iron(II) or Fe“) is
typically kept at a low concentration in the body.
l() Iron deficiency first depletes the stored iron in the body. Because most of the iron
ed by the body is required for hemoglobin, iron—deficiency anemia is the primary
clinical station of iron deficiency. Oxygen transport to the tissues is so ant to
human life that severe anemia harms or kills people with CKD, ive of ND—CKD
patients and liSRl) patients, by depriving their organs of oxygen. Iron—deficient (7K!)
patients will suffer, and in some instances may die, from organ damage caused by oxygen
depletion well before cells run out of the iron needed for intracellular processes.
There are several markers of systemic iron status that may be measured to determine
whether a CKD patient has sufficient iron stores to maintain adequate health. These markers
may be of circulating iron stores, iron stored in iron-binding complexes, or both, and are also
typically referred to as iron e parameters. Iron storage parameters can include, for
example, hematocrit, hemoglobin concentration (1 lb), total iron—binding capacity ('l‘lBC),
transferrin saturation (TSAT), serum iron levels, liver iron levels, spleen iron , and
serum ferritin levels. Of these, the hematocrit, hemoglobin tration (Hb), total iron-
binding capacity ('l‘lBC), transferrin saturation ('I‘SA'I‘) and serum iron levels are commonly
known as circulating iron stores. The liver iron levels, spleen iron , and serum ferritin
levels are commonly ed to as stored iron or iron stored in iron-binding complexes.
In some embodiments, the present disclosure provides methods of improving one or
more iron storage parameters in a patient in need thereof. In some embodiments, the methods
comprise orally administering ferric citrate to a CKD patient, e.g., a non-dialysis Chronic
kidney disease t or an end stage renal disease patient, in an amount ranging from about
1 g to about 18 g per day. In some embodiments, the at least one iron storage parameter may
be selected from serum ferritin levels, transferrin saturation (TSAT), hemoglobin
concentration, crit, total iron—binding capacity, iron absorption levels, serum iron
levels, liver iron levels, spleen iron levels, and combinations f. In some embodiments,
the ferric citrate in administered in a 1 gram tablet dosage form. In some embodiments, the
patient is administered up to 18 tablet dosage forms per day. In some embodiments, the ferric
citrate is administered for a period of 12 weeks, in some embodiments for a period of 36
weeks, in some embodiments for a period of 52 weeks, and in some embodiments for a
period of up to and including 56 weeks.
In r ment, the at least one iron storage parameter is hematocrit, and
improving comprises sing the hematocrit of the patient. In other embodiments, the at
least one iron storage parameter is obin concentration, and improving comprises
increasing the hemoglobin concentration of the patient. In yet other ments, the at least
one iron sto‘age parameter is total iron—binding capacity, and ing comprises
decreasing the total iron—binding capacity of the patient. In yet other embodiments, the at
least one iron storage parameter is transferrin saturation, and improving comprises increasing
the transferrin saturation of the patient. In yet other embodiments, the at least one iron
storage parameter is serum iron levels, and improving comprises increasing the serum iron
levels of the patient. In yet other embodiments, the at least one iron e parameter is liver
iron levels, and improving comprises increasing the liver iron levels of the patient. In yet
other embodiments, the at least one iron storage pa ‘ameter is spleen iron levels, and
improving comprises increasing the spleen iron levels of the patient. In yet other
embodiments, the at least one iron storage parameter is serum ferritin levels, and improving
ses increasing the serum in levels of the patient.
Scrum [Ferritin
The liver’s stores of in are the primary source of stored iron in the body. Ferritin
is an intracellular protein that stores iron and releases it in a controlled n. Medically,
the amount of ferritin present in a blood sample and/or in a sample of liver tissue reflects the
amount of iron that is stored in the liver (although in is ubiquitous and can be found in
many other tissues within the body in addition to the liver). Ferritin serves to store iron in the
liver in a non—toxic form and to transport it to areas where it is required. In non—(7K!)
ts, a normal ferritin blood serum level, sometimes referred to as the reference interval,
is usually between 30—300 ng/ml for males, and 15—200 ng/ml for females. In a CKD
patient, however, serum ferritin levels are typically markedly reduced as the amount of iron
available to be bound by ferritin and stored in the liver is decreased, which occurs as the body
loses its ability to absorb and store iron.
In some embodiments, CKD patients treated according to the methods disclosed
herein experience an increase in serum ferritin levels. In some embodiments, the present
disclosure provides methods of increasing serum ferritin in a patient in need thereof, the
methods comprising orally administering ferric citrate to an CKD patient, e.g., an ESRD
patient or ND—CKD patient, wherein the ferric e provides an increase in serum ferritin.
In some embodiments, the present disclosure provides methods of sing serurrr ferritin,
the methods sing orally administering ferric citrate to a CKD patient at a dose of ferric
iron ranging from 210 mg — 2,520 mg, wherein the ferric citrate provides an se in serum
in in the patient. In some embodiments, the ferric citrate is administered for a period of
12 weeks, in some embodiments for a period of 24 weeks, in some embodiments for a period
of 36 weeks, in some embodiments for a period of 48 weeks, and in sorrre embodiments for a
period of 52 weeks.
In some embodiments, the ferric citrate es a mean increase in serum ferritin of
100 — 400 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin of l 10 i 390 ng/ml. In some embodiments, the ferric citrate es a mean increase
in serum ferritin of 120 i 380 ng/ml. In some embodiments, the ferric e provides a mean
increase in serum ferritin of 130 — 370 ng/ml. In some embodiments, the ferric citrate
provides a mean increase in serum ferritin of about 140 — 360 ng/ml. In some ments,
the ferric cit ‘ate provides a mean increase in serum ferritin of 150 i 350 ng/ml. In some
embodiments, the ferric citrate provides a mean se in serum ferritin of I60 — 340 ng/ml.
In some ments, the ferric citrate provides a mean increase in serum ferritin of 170 —
330 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
of 1807 320 ng/ml. In some embodiments, the ferric citrate provides a mean increase in
serum ferritin of I90 — 310 ng/ml. In some embodiments, the ferric citrate provides a mean
increase in serum ferritin of 200 — 300 ng/ml. In some embodiments, the ferric citrate
provides a mean increase in serum ferritin of 210 i 290 ng/ml. In some embodiments, the
ferric e provides a mean se in serum ferritin of 220 — 280 ng/ml. In some
embodiments, the ferric citrate provides a mean increase in serum ferritin of 230 — 270 ng/ml.
In some embodiments, the ferric citrate provides a mean increase in serum ferritin of 240 i
260 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin of from 100 — 400 ng/ml. In some embodiments, the ferric citrate provides a mean
increase in serum ferritin of 100 i 375 ng/ml. In some embodiments, the ferric citrate
provides a mean increase in serum ferritin of from 100 i 350 nglml. In some embodiments,
the ferric citrate provides a mean se in serum ferritin of from 100 — 325 ng/ml. In some
embodiments, the ferric citrate provides a mean increase in serum ferritin of from 100 — 300
ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin of
from 100 — 275 ng/ml. In some embodiments, the ferric citrate provides a mean increase in
serum ferritin of from 150 — 310 ng/ml. In some ments, the ferric citrate provides a
mean increase in serum ferritin of from 151 2 309 ng/mI In some embodiments, the ferric
citrate provides a mean increase in serum ferritin of from 152 2 308 ng/ml In some
embodiments, the ferric citrate provides a mean increase in serum ferritin of from 153 — 307
ng/ml In some embodiments, the ferric citrate provides a mean se in serum ferritin of
from 154 2 306 ng/mI In some embodiments, the ferric citrate provides a mean increase in
serum ferritin of from 155 — 306 ng/ml In some embodiments, the ferric citrate provides a
mean increase in serum ferritin of from 155 — 305 ng/ml In some embodiments, the ferric
I0 citrate provides a mean increase in serum ferritin of from 155 2 304 ng/ml In some
embodiments, the ferric e provides a mean se in serum in of from 155 2 303
ng/ml In some ments, the ferric citrate provides a mean increase in serum ferritin of
from 155 2 302 ng/mI. In some embodiments, the ferric citrate provides a mean increase in
serum ferritin of from 150 2 305 ng/mI. The above ranges are disclosed in this format for
purposes of efficiency, and any of the above ranges can be combined with any ,
formulation, or combination f.
In some embodiments, the ferric citrate es a mean increase in serum ferritin of
302 ng/ml when administered over a period of 52 weeks.
In some embodiments, the ferric citrate provides a mean increase in serum ferritin that
is greater than 100 ng/mI. In some embodiments, the ferric citrate provides a mean increase
in serum ferritin that is greater than 110 ng/ml. In some embodiments, the ferric citrate
provides a mean increase in serum ferritin that is greater than 120 ng/ml. In some
embodiments, the ferric citrate es a mean increase in serum ferritin that is greater than
130 ng/mI. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin that is greater than 140 ng/ml. In some embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 150 ng/ml. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin that is greater than 160 ng/mI. In
some ments, the ferric citrate provides a mean increase in serum ferritin that is greater
than 170 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin that is greater than 180 ng/mI. In some embodiments, the ferric citrate es a
mean increase in serum in that is greater than 190 ngimI. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin that is greater than 200 ng/ml. In
some embodiments, the ferric citrate provides a mean se in serum ferritin that is greater
than 210 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin that is greater than 220 ng/ml. In some embodiments, the ferric e provides a
mean increase in serum ferritin that is greater than 230 ng/ml. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin that is r than 240 ng/ml. In
sorrre embodiments, the ferric e provides a mean increase in serum ferritin that is greater
than 250 ng/ml. In some embodiments, the ferric citrate es a mean increase in serurrr
ferritin that is greater than 260 ng/ml. In sorrre embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 270 ngiml. In some embodiments, the
ferric citrate provides a mean increase in serurrr ferritin that is r than 280 ng/nrl. In
sorrre embodiments, the ferric citrate provides a mean increase in serum ferritin that is greater
ll) than 290 ng/ml. In some embodiments, the ferric cit ‘ate provides a mean increase in serum
ferritin that is greater than 300 ng/ml. In some embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 310 ng/ml. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin that is greater than 320 ng/ml. In
some embodiments, the ferric citrate provides a mean increase in serum ferritin that is greater
than 330 ng/ml. In some embodiments, the ferric citrate provides a mean increase in serurrr
ferritin that is greater than 340 ng/ml. In sorrre embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 350 ngiml. In some embodiments, the
ferric citrate provides a mean increase in serunr ferritin that is greater than 360 ng/ml. In
sorrre ernbodirrrents, the ferric citrate provides a mean increase in serum ferritin that is greater
than 370 ng/ml. In some embodiments, the ferric citrate provides a mean se in serum
ferritin that is greater than 380 ng/ml. In sorrre embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 390 ng/ml. The above boundaries are
disclosed in this format for purposes of efficiency, and any of the above boundaries can be
combined with any method, formulation, lower ry as disclosed below, or combination
In sorrre embodiments, the ferric citrate provides a mean increase in serum ferritin that
is selected from less than 400 ng/ml. In some embodiments, the ferric citrate provides a
mean increase in serum in that is less than 390 ng/ml. In some ments, the ferric
citrate provides a mean se in serum ferritin that is less than 380 ng/ml. In some
embodiments, the ferric e provides a mean increase in serum in that is less than 370
ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
that is less than 360 ng/ml. In sorrre embodiments, the ferric citrate provides a mean increase
in serum ferritin that is less than 350 ng/ml. In some embodiments, the ferric citrate es
a mean increase in serum in that is less than 340 ng/ml. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is less than 330 ngfml. In some
embodiments, the ferric citrate provides a mean se in serum ferritin that is less than 320
ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
that is less than 310 ng/ml. In some embodiments, the ferric citrate provides a mean increase
in serum in that is less than 300 ng/ml. In some embodiments, the ferric citrate provides
a mean increase in serum fen‘itin that is less than 290 ng/ml. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is less than 280 ngiml. In some
embodiments, the ferric e provides a mean increase in serum ferritin that is less than 270
ng/ml. In sorrre embodiments, the ferric citrate es a mean increase in serum ferritin
I0 that is less than 260 ng/ml. In some embodiments, the ferric e provides a mean increase
in serum ferritin that is less than 250 ng/ml. In sorrre ments, the ferric citrate provides
a mean se in serum ferritin that is less than 240 ng/ml. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is less than 230 ng/ml. In some
embodiments, the ferric citrate es a mean increase in serum ferritin that is less than 220
ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
that is less than 210 ng/ml. In sorrre embodiments, the fen‘ic citrate provides a mean se
in serum ferritin that is less than 200 ng/ml. In some embodiments, the ferric cit ‘ate provides
a mean increase in serum ferritin that is less than 190 ng/ml. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is less than 180 ng/ml. In some
embodiments, the ferric cit”ate provides a mean increase in serum ferritin that is less than 170
ng/ml. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
that is less than 160 ng/ml. In sorrre embodiments, the ferric citrate provides a mean increase
in serum ferritin that is less than 150 ng/ml. In some embodiments, the ferric citrate provides
a mean increase in serum ferritin that is less than 140 ng/ml. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is less than 130 ng/ml. In some
embodiments, the ferric citrate provides a mean increase in serum ferritin that is less than 120
ng/ml. In some embodiments, the ferric e provides a mean increase in serum ferritin
that is less than 110 ng/ml. 'Ihe above boundaries are disclosed in this format for purposes of
efficiency, and any of the above boundaries can be combined with any method, formulation,
upper boundary as sed above, or ation thereof.
In some embodiments, the ferric citrate provides a mean se in serum ferritin
selected from about 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,
294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309 and 310 mg/dl
when administered for a period of 52 weeks. In some embodiments, the ferric citrate
provides a mean increase in serum ferritin of 302 mg/dl when stered for a period of 52
weeks.
In some embodiments, the ferric citrate provides a mean increase in serum ferritin
from about 1 2 100 %. In some embodiments, the ferric citrate provides a mean increase in
serum ferritin from about10 — 90 %. In some embodiments, the ferric citrate provides a mean
increase in serum ferritin from about 20 — 80 %. In some embodiments, the ferric Citrate
provides a mean increase in serum in from about 30 2 70 %. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin from about 40 — 60 %.
In sonre embodiments, the ferric citrate provides a mean increase in serum ferritin
selected from 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and
60 %. In some embodiments, the ferric citrate provides a mean increase in serum ferritin
selected from 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4,
49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9 and 50.8
%. In some embodiments, the ferric citrate provides a mean increase in serum ferritin of 50.8
%. In some embodiments, the ferric citrate provides a mean increase in serum ferritin of 50.8
% when stered over a period of 52 weeks.
In some embodiments, the ferric citrate provides a mean se in serum ferritin that
is greater than 1%. In some embodiments, the ferric citrate provides a mean increase in
serum ferritin that is greater than 10%. In some embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 20%. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is greater than 30%. In some
embodiments, the ferric e provides a mean increase in serum ferritin that is greater than
40%. In sorrre embodiments, the ferric citrate es a mean increase in serum ferritin that
is greater than 50%. In some embodiments, the ferric citrate es a mean increase in
serum ferritin that is r than 60%. In some embodiments, the ferric citrate provides a
mean increase in serum ferritin that is greater than 70%. In some embodiments, the ferric
citrate provides a mean increase in serum ferritin that is greater than 80%. In some
embodiments, the ferric citrate provides a mean increase in serum in that is r than
90%. The above boundaries are sed in this format for purposes of efficiency, and any
of the above boundaries can be combined with any method, formulation, lower boundary as
sed below, or ation thereof.
In some embodiments, the ferric citrate provides a mean increase in serum ferritin that
is less than 100%. In some embodiments, the ferric citrate provides a mean increase in serum
ferritin that is less than 90%. In some embodiments, the ferric citrate provides a mean
se in serum ferritin that is less than 80%. In some embodiments, the ferric citrate
provides a mean increase in serum in that is less than 70%. In some embodiments, the
ferric citrate provides a mean increase in serum ferritin that is less than 60%. In some
embodiments, the ferric citrate provides a mean increase in serum ferritin that is less than
50%. In some errrbodiments, the ferric citrate provides a mean increase in serum ferritin that
is less than 40%. In some errrbodirrrents, the ferric e provides a mean increase in serum
ferritin that is less than 30%. In some embodiments, the ferric citrate provides a mean
se in serum ferritin that is less than 20%. In sonre embodiments, the ferric citrate
provides a mean increase in serum ferritin that is less than 10 %. The above boundaries are
disclosed in this format for purposes of efficiency, and any of the above ries can be
combined with any method, formulation, upper boundary disclosed above, or combination
thereof.
In sonre embodiments, the ferric citrate provides a mean increase in serum ferritin
selected from 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 39.7, 49.8, 49.9 and 50.0 % when
administered for a period of 52 weeks. In sorrre embodiments, the ferric citrate provides a
mean increase in serum ferritin of 49.2 % when stered for a period of 52 weeks.
ln some embodiments, the ferric citrate provides a mean se in serum ferritin
shown in Table C:
Table C:
Mean Ferritin (ng/m L)1 Active ls Ferric Citrate
(n=134) (n=249)
Baseline (Day 0) 616 595
Week 12 657 751
Week 24 658 847
Week 36 636 863
Week 48 882
Week 52 897
Change from ne at Week 52 302
% Change from Baseline 50.8%
LS Mean Difference from Active Control Group
at Week 522 286
p—value2 p<0.0001
1
Last observation carried forward was used for missing data.
The L8 Mean treatment difference and p-value is created via an ANCOVA model with treatment as the fixed
effect and baseline as the covariate.
In some embodiments, CKD patients, such as ESRD patients, treated according to the
s disclosed herein experience maintenance of their serum ferritin levels such that their
serum ferritin levels remain substantially unchanged during administration of the ferric
citrate.
Transferrin Saturation (TSAT)
ln addition to stored iron, a small amount of iron, typically about 3 to 4 mg, circulates
through the blood plasma bound to a protein called transferrin. Therefore, serum iron levels
can be represented by the amount of iron circulating in the blood that is bound to the protein
transferrin. 'l‘ransl'errin is a glycoprotein produced by the liver that can bind one or two ferric
iron (irontlll) or Fe”) ions. It is the most prevalent and dynamic carrier of iron in the blood,
and therefore is an essential component of the body’s ability to transport stored iron for use
throughout the body. Transferrin tion (or TSAT) is measured as a percentage and is
calculated as the ratio of serum iron and total iron—binding capacity, multiplied by 100. This
value tells a ian how much serum iron is actually bound to the total amount of
transferrin that is ble to bind iron. For instance, a TSAT value of 35% means that 35%
of the available iron—binding sites of transferrin in a blood sample is occupied by iron. In a
non-CKD patient, typical TSAT values are approximately 15—50% for males and 12—45% for
females. In a CKD patient, however, TSAT values are lly markedly reduced as the
amount of iron available to be bound by transferrin is decreased, which occurs as the body
loses its ability to absorb and store iron.
In some embodiments, CKD patients treated according to the methods disclosed
herein experience an increase in TSAT values. In some embodiments, the present disclosure
provides s of increasing transferrin saturation ('l‘SA'l‘) in a patient in need thereof, the
methods sing orally administering ferric citrate to CKD patient, e.g., an ESRD patient
or a ND—CKD t, wherein the ferric e provides an increase in TSAT in the patient.
In some embodiments, the present disclosure provides methods of increasing transferrin
saturation (TSAT), the methods comprising orally administering feiric citrate to an end—stage
renal disease t at a dose of ferric iron ranging from 210 mg — 2,520 mg, wherein the ferric
citrate provides an increase in TSAT in the t. In some embodiments, the ferric citrate is
administered for a period of 12 weeks, in some embodiments for a period of 24 weeks, in
some ments for a period of 36 weeks, in some embodiments for a period of 48 weeks,
and in some embodiments for a period of 52 weeks.
In some embodiments, the ferric citrate provides a mean se in transferrin
tion (TSAT) of 1 — 20 %. In some ments, the ferric citrate provides a mean
increase in transferrin saturation (TS/\T) of l , 15 %. In some embodiments, the ferric citrate
provides a mean increase in transferrin saturation ('I‘SA'I‘) of 1 , 12 %. In some
embodiments, the ferric citrate provides a mean increase in transferrin saturation (TSAT) of 5
— 12 %. In some embodiments, the ferric citrate es a mean se in transferrin
saturation ('I‘SA'I‘) of 5 , l() %. In some embodiments, the ferric cit ‘ate provides a mean
increase in transferrin saturation (TSAT) of 6 — 9 %. In some embodiments, the ferric citrate
provides a mean increase in transferrin saturation (TSAT) of 8%.
In some embodiments, the ferric cit ~ate provides a mean se in transferrin
saturation ('I‘SA'I‘) greater than 1%. In some embodiments, the ferric citrate provides a mean
increase in transferrin tion (TSAT) greater than 2%. In some embodiments, the ferric
citrate provides a mean increase in transferrin tion (TSAT) greater than 3%. In some
embodiments, the ferric citrate provides a mean increase in errin saturation ('I‘SA'I‘)
greater than 4%. In some embodiments, the ferric citrate provides a mean increase in
errin tion (TSAT) greater than 5%. In some embodiments, the ferric citrate
provides a mean increase in transferrin saturation ('I‘SA'I‘) greater than 6%. In some
embodiments, the ferric citrate provides a mean increase in transferrin saturation (TSAT)
greater than 7%. In some embodiments, the ferric citrate provides a mean increase in
errin saturation (TS/\T) greater than 8% In some embodiments, the ferric cit “ate
provides a mean increase in 'I‘SA'I‘ r than 9%. In some embodiments, the ferric citrate
provides a mean increase in TSAT greater than 10%. In some embodiments, the ferric citrate
provides a mean increase in TSAT greater than 11%. In some embodiments, the ferric citrate
provides a mean increase in 'I‘SA'I‘ greater than 12%. In some embodiments, the ferric citrate
es a mean increase in TSAT greater than 13%. In some embodiments, the ferric citrate
provides a mean increase in TSAT greater than 14%. In some embodiments, the ferric citrate
provides a mean increase in 'I‘SA'I‘ greater than 15%. In some embodiments, the ferric e
provides a mean increase in 'I‘SA'I‘ greater than 16%. In some embodiments, the ferric e
provides a mean increase in TSAT greater than 17%. In some embodiments, the ferric citrate
provides a mean increase in TSAT greater than 18%. In some embodiments, the ferric citrate
provides a mean increase in 'I‘SA'I‘ greater than 19%. The above boundaries are disclosed in
this format for purposes of ency, and any of the above ranges can be combined with any
method, formulation, lower boundary as disclosed below, or combination thereof.
In some embodiments, the ferric citrate provides a mean increase in transferrin
saturation (TSAT) less than 20%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 19%. In some embodiments, the ferric citrate provides a mean
increase in 'I‘SA'I‘ less than 18%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 17%. In some ments, the ferric citrate provides a mean
increase in TSAT less than 16%. In sonre embodiments, the ferric citrate provides a mean
increase in 'I‘SA'I‘ less than 15%. In some embodiments, the ferric citrate es a mean
increase in TSAT less than 14%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 13%. In some embodiments, the ferric citrate provides a mean
II) increase in 'I‘SA'I‘ less than 12%. In some embodiments, the ferric cit ‘ate provides a mean
increase in 'I‘SA'I‘ less than 11%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 10%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 9%. In some embodiments, the ferric citrate provides a mean
increase in 'I‘SA'I‘ less than 8%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 7%. In some embodiments, the ferric citrate provides a mean
increase in TSAT less than 6%. In some embodiments, the ferric citrate es a mean
increase in 'I‘SA'I‘ less than 5%. In some ments, the ferric cit ‘ate provides a mean
increase in TSAT less than 4%. In some ments, the ferric citrate provides a mean
increase in TSAT less than 3 %. In some ments, the ferric citrate provides a mean
increase in TSAT less than 2 %. The above ries are disclosed in this format for
purposes of ency, and any of the above ranges can be combined with any method,
formulation, upper ry disclosed above, or combination thereof.
In sorrre embodiments, the ferric citrate provides a mean increase in transferrin
saturation ('I‘SA'I‘) selected from 5 %, 6 %, 7 %, 8 %, 9 %, 10 ‘70, l l %, I2 %, I3 %, l4 %, 15
%, l6 %, l7 % and 18 % when stered for a period of 52 weeks. In sorrre
embodiments, the ferric citrate provides a mean increase in transferrin saturation (TSAT) of 8
% when administered fora period of 52 weeks.
In some embodiments, the ferric citrate provides a mean increase in transferrin
saturation (TSAT) shown in Table D:
Table D:
Mean TSAT (°/o)l Active Controls Ferric Citrate
(n=131) (n=244)
ne (Day 0) 31 31
Change from Baseline at Week 52 8
% Change from Baseline 25.8%
LS Mean Difference from Active l Group
ammwsfi 10
o-value2 «0.0001
Last observation carried forward was used for missing data.
2 The L8 Mean treatment difference and p-value is created via an ANCOVA model with treatment as the fixed
effect and baseline as the covariate.
In some embodiments, (7K1) patients, such as liSRl) patients, treated according to the
methods disclosed herein experience maintenance of their TSAT values such that their
transferrin saturation (TSAT) value remains substantially unchanged during administration of
the ferric citrate.
Hematocrir
The hematocrit, also ed to as packed cell volume or erythrocyte volume fraction,
is the volume percentage of red blood cells in the blood. lior non—(7K!) ts, the
hematocrit is typically about 45% of blood volume for men and about 40% of blood volume
for women. In CKD ts, r, the crit is often icantly depleted due to
poor iron absorption and/or poor iron storage capacity.
The ferric citrate disclosed herein may be administered to CKD patients to increase
hematocrit. The exact timing of administration will necessarily vary from patient to patient,
depending upon, for example, the severity of CKD experienced by the CKD patient, the level
of iron absorption the t is or is not experiencing, and the judgment of the treating health
care professional. In some embodiments, the present disclosure provides methods of
increasing hematocrit in a patient in need thereof, the methods comprising orally
administering ferric citrate to a CKD patient, e.g., an ESRD patient or ND—CKD patient,
wherein the ferric citrate provides for an increase in the hematocrit of the patient. In sorrre
embodiments, the present disclosure es methods of sing hematocrit in a CKI)
patient, the methods comprising orally administering ferric citrate to the patient at, a dose of
ferric iron ranging from 210 mg — 2,520 nrg, wherein the ferric e provides for an se
in the ocrit of the patient. In some embodiments, the ferric e is administered for a
period of 52 weeks. In some embodiments, the increase is from 1% to 30%. In some
embodiments, the increase is from 1% to 20%. In sonre embodiments, the increase is from
1% to 15%, in sorrre embodiments the increase is from 1% to 12%, in sorrre embodiments the
increase is from 1% to 10%, in some embodiments the increase is from 1% to 9%, in some
embodiments the increase is from 1% to 8%, in sorrre embodiments the increase is from 1%
to 7%, in sonre embodiments the increase is from 1% to 6%, in some embodiments the
increase is from 1% to 5%, in some embodiments the increase is from 1% to 4%, in some
ments the increase is from 1% to 3%, and in some embodiments the increase is from
1% to 2%.
In sorrre embodiments, CKD patients, such as ESRD patients, treated according to the
s disclosed herein experience maintenance of their hematocrit level such that their
l volume of red blood cells in the blood remains substantially unchanged during
administration of the ferric citrate.
Hemoglobin Concentration
Hemoglobin tration, also referred to as the mean corpuscular hemoglobin
concentration or MCHC, is a measure of the concentration of hemoglobin protein in a given
volume of packed red blood cells. It, is typically calculated by dividing the total amount of
hemoglobin protein by the hematocrit. Hemoglobin concentration may also be measured as a
rrrass or weight fraction and presented as a percentage (%). Numerically, r, the rrrass
or molar measure of hemoglobin concentration and the mass or weight fraction (%) are
identical, assuming a red blood cell density of 1g/ml and negligible hemoglobin loss in the
blood plasma. For non-CKD patients, a typical rrrass or molar measure of hemoglobin
concentration ranges from 32 g/dl , 36 g/dl, or from 4.9 mmol/L to 5.5 , respectively.
In a CKI) patient, however, the hemoglobin concentration can be greatly reduced as the body
loses its ability to absorb and store iron.
In sorrre embodiments, CKD patients treated according to the methods sed
herein experience an increase in hemoglobin concentration. In some embodiments, the
present disclosure provides methods of increasing hemoglobin concentration in a patient in
need thereof, the methods comprising orally administering ferric citrate to a CKD patient, e.g.,
an ESRI) patient or ND—CKD t, n the ferric citrate es an increase in
hemoglobin concentration in the patient. In some embodiments, the present disclosure
provides methods of increasing obin tration, the methods comprising orally
stering ferric citrate to a CKD patient at a dose of ferric iron ranging from 210 mg —
2,520 mg, wherein the ferric citrate provides an increase in hemoglobin concent‘ation in the
patient. In some embodiments, the ferric citrate is stered for a period of 12 weeks, in
some embodiments for a period of 24 weeks, in some embodiments for a period of 36 weeks,
I0 in some embodiments for a period of 48 weeks, and in some embodiments for a period of 52
weeks.
In some embodiments, the ferric citrate provides a mean increase in hemoglobin
concentration of 0.1 2 5.0 g/dI. In some embodiments, the ferric citrate provides a mean
se in hemoglobin concentration of 0.1 2 4.0 g/dI. In sonic embodiments, the ferric
citrate provides a mean se in hemoglobin concentration of 0.1 — 3.0 g/d1. In some
embodiments, the ferric citrate provides a mean increase in hemoglobin concentration of 0.1 —
2.0 g/dI. In sonre embodiments, the ferric e provides a mean increase in hemoglobin
concentration of 0.1 — 1.0 g/dl. In some embodiments, the ferric citrate provides a mean
se in hemoglobin concentration of 0.2 — 0.9 g/dl. In some embodiments, the ferric
citrate provides a mean increase in hemoglobin concentation of 0.3 2 0.8 g/dl. In some
embodiments, the ferric citrate provides a mean increase in hemoglobin concentration of 0.3 2
0.7 g/dl. In sonre embodiments, the ferric citrate provides a mean increase in hemoglobin
concentration of 0.3 — 0.6 g/d1. In some embodiments, the ferric citrate provides a mean
increase in hemoglobin tration of 0.3 2 0.5 g/dI. In sonre embodiments, the ferric
citrate provides a mean increase in hemoglobin concentration of 0.4 g/dl.
In sonre embodiments, the ferric citrate provides a mean increase in hemoglobin
concentration greater than 0.1 g/dI, In some embodiments, the ferric citrate provides a mean
increase in hemoglobin concentration r than 0.2 g/dl. In some embodiments, the ferric
citrate provides a mean increase in hemoglobin concentration r than 0.3 g/dl. In some
embodiments, the ferric citrate provides a mean increase in hemoglobin tration greater
than 0.4 g/dI. In some embodiments, the ferric e provides a mean increase in
hemoglobin concentration greater than 0.5 g/dl. In some embodiments, the ferric citrate
provides a mean increase in hemoglobin concentration greater than 0.6 g/dl. In sonre
embodiments, the ferric citrate provides a mean increase in hemoglobin concentration greater
than 0.7 g/dl. In sorrre ments, the ferric citrate provides a mean increase in
hemoglobin concentration greater than 0.8 g/dl. In some embodiments, the ferric citrate
provides a mean increase in hemoglobin concentration greater than 0.9 g/dl. The above
boundaries are disclosed in this format for purposes of efficiency, and any of the above
boundaries can be combined with any method, formulation, lower boundary as disclosed
below, or combination thereof.
In some ments, the ferric citrate es a mean increase in obin
concentration of less than 1.0 g/dl. In some embodiments, the ferric citrate provides a mean
increase in hemoglobin concentration less than 0.9 g/dl. In sorrre embodiments, the ferric
I0 citrate provides a mean increase in hemoglobin concentration less than 0.8 g/dI. In some
embodiments, the ferric citrate provides a mean increase in hemoglobin concentration less
than 0.7 g/dl. In some embodiments, the ferric citrate provides a mean increase in
hemoglobin concentration less than 0.6 g/dl. In some embodiments, the ferric citrate provides
a mean increase in hemoglobin concentration less than 0.5 g/dl. In some ments, the
1 5 ferric e provides a mean se in hemoglobin concentration less than 0.4 g/dl. In
sorrre embodiments, the ferric citrate provides a mean increase in hemoglobin concentration
less than 0.3 gidl. In some embodiments, the ferric citrate es a mean increase in
hemoglobin concentration less than 0.2 g/dl. The above ries are disclosed in this
format for purposes of efficiency, and any of the above boundaries can be combined with any
method, ation, upper boundary disclosed above, or ation f.
In some embodiments, the ferric citrate provides a mean increase in hemoglobin
concentration shown in Table E:
Table E:
Mean Hemoglobin (gi’dL)1 Active Controls Ferric Citrate
(n=130) (n=244)
Baseline (Day 0) 11.7 11.6
Week52 11.1 11.4
Change from Baseline at Week 52 —O.6 —0.2
L8 Mean Difference from Active Control Group
at Week 522 0.4
p-value2 p=0.0105
Last observation carried forward was used for missing data.
[0 L11 2 The L8 Mean treatment difference and p—value is created via an ANCOVA model with treatment as the fixed
effect and baseline as the covariate.
In some embodiments, CKD patients, such as ESRD patients, treated according to the
methods disclosed herein experience nance of their hemoglobin concentration such
that their hemoglobin level remains ntially unchanged during administration of the
ferric citrate.
Total Iron Binding Capacity (TIBC)
Total iron-binding capacity (TIBC) is a measure of the blood’s capacity to bind iron
with the n errin. TIBC is typically measured by drawing a blood sample and
measuring the maximum amount of iron that the sample can carry. 'I‘hus, 'I‘IBC indirectly
measures transferrin, which is a protein that transports iron in the blood. For non-CKD
patients, a typical mass or molar measure of TIBC is in the range of 250—370 ug/dL or 45-66
I0 umoI/Ii, respectively. In (7K1) ts, however, the 'I‘IBC is typically increased above these
, as the body rrrust produce more transferrin in an attempt to deliver iron to erythrocyte
precursor cells to produce hemoglobin.
In sonre embodiments, CKD patients treated according to the methods disclosed
herein experience a reduction in 'I‘IBC. In some embodiments, the present disclosure
provides methods of reducing TIBC in patient in need thereof, the methods comprising orally
administering ferric citrate to a CKD t, e. g., an ESRD t or ND-CKD patient,
wherein the ferric citrate provides for a reduction in the 'I‘IBC of the patient. In some
embodiments, the t disclosure provides s of reducing TIBC in a CKD patient,
the methods comprising orally administering ferric citrate to the t at a dose of fen‘ic iron
ranging from 210 mg 2 2,520 mg, wherein the ferric citrate provides for a reduction in the
TIBC of the t. In sorrre embodiments, the ferric citrate is administered for a period of 52
weeks. In some embodiments, the reduction is from 0.1% to 30%, in some embodiments the
reduction is from 0.1% to 28%, in some embodiments the reduction is from 0.1% to 26%, in
sonre embodiments the reduction is from 0. 1% to 25%, in sonre ments the reduction is
from 0.1% to 24%, in some embodiments the reduction is from 0.1% to 23%, in some
embodiments the reduction is from 0.1% to 22%, in some embodiments the reduction is from
0.1% to 21%, in sorrre embodiments the reduction is from 0.1% to 20%, in sorrre
embodiments the reduction is from 0.1% to 15%, in some embodiments the reduction is from
0.1% to 10%, and in some embodiments the reduction is from 0.1% to 5%.
In some embodiments, CKD patients, such as ESRD patients, treated according to the
methods disclosed herein experience maintenance of their 'I‘IBC such that their 'I‘IBC IeveI
remains substantially unchanged during administration of the ferric citrate.
Iron Absorption
CKD patients may suffer from low or inadequate iron absorption that can lead to other
health concerns such as iron depletion and anemia. For humans, the majority of iron
absorbed from food or supplements is absorbed in the small intestine, particularly in the
duodenum, by specialized cyte cells present in the duodenal lining. These cells have
specialized transporter molecules that allow them to move iron from the intestinal lumen into
the body. To be absorbed, dietary iron must be present as part of a protein, such as heme, or
it must be in ferrous (iron(II) or Fe“) form. Enterocytes express a ferric reductase enzyme,
Dcytb, which reduces ferric iron (iron(III) or Fe“) to ferrous iron. A divalent metal
l() transporter protein then transports the iron across the enterocyte's cell membrane and into the
cell.
In a non-CKD person, the body tes iron levels by changing the expression level
of the proteins relating to one or more of these steps. For example, in response to iron—
deficiency anemia, cells may produce more of the l)cytb enzyme and more of the metal
orter protein in order to se the amount of iron absorbed from the intestinal lumen.
In CKD patients, the body’s ability to regulate one or nrore of these steps is impaired, which
in turn leads to reduced or inadequate iron absorption.
CKD patients treated according to the s sed herein may experience
increased iron absorption. In some embodiments, the iron that is absorbed is provided by the
ferric citrate that is administered to the CKD patients; it is the ferric iron ion that is absorbed
into the body from the intestinal lumen. Because the ferric citrate is administered orally, the
sed iron absorption occurs through the intestine. While not wishing to be bound by any
theory, it is ed that the increased iron absorption may be attributable to the presence of
citrate in the ferric citrate administered to the CKD patient. Some studies have shown that
administration of iron in combination with citrate (the conjugate base of citric acid) serves to
significantly increase (e.g., by several fold) the amount of iron absorbed from dietary sources
(see, (Ag, Ballot, cl ((1., Br. J. Null: (1987) 57, 3317343; (lillooly, ('l (1]., Br. J. Nutr. (1983)
49, 331—342; Zhang, et (11., Eur. J. Nutr. (2007) 46, 95—102; and Salovaara, er 0]., J. Agric.
Food Chem. (2002) 50, 6233—6338).
The ferric citrate disclosed herein may be stered to CKD patients to increase
iron absorption. The exact timing of administration will necessarily vary from patient to
t, ing upon, for example, the stage of CKD experienced by the CKD patient, the
level of iron absorption the patient is or is not experiencing, and the judgment of the treating
health care professional. ln sonre embodiments, the present disclosure es methods of
increasing iron absorption in an end-stage renal disease patient, the methods comprising orally
administering ferric citrate to the patient, wherein the ferric citrate provides for an increase in
the amount of iron ed by the patient. In some embodiments, the present disclosure
provides methods of increasing iron absorption in an end—stage renal disease patient, the
methods comprising orally administering ferric citrate to the patient at a dose of ferric iron
ranging from 210 mg — 2,520 mg, wherein the ferric citrate es for an increase in the
amount of iron absorbed by the patient. In some embodiments, the ferric citrate is
administered for a period of 52 weeks.
II) Iron Deficiency and Anemia
As stated above, most well—nourished, D people living in rialized
countries have approximately 4 to 5 grams of iron stored within their bodies in some manner
(9. g., as ating iron or stored iron or both). A decrease in this amount represents an iron
deficiency, which is commonly seen in (TKI) patients. Symptoms of iron deficiency can
occur in CKD patients before the condition has progressed to iron-deficiency anemia.
ms of iron deficiency can include, for e, fatigue, ess, pallor, hair loss,
irritability, weakness, pica, brittle or grooved nails, I’Iummer—Vinson syndrome (painful
atrophy of the mucous membrane covering the tongue, pharynx and esophagus), impaired
immune function, pagophagia, and restless legs syndrome, among others.
CKD patients treated according to the methods disclosed herein may ence an
improvement in iron deficiency. In some embodiments, CKD patients treated according to
the methods disclosed herein experience a decrease in iron deficiency. This se may
occur as the total amount of iron in the body of the CKD patient is increased through the
administration of the ferric citrate disclosed . In some embodiments, (TKI) patients
treated according to the methods disclosed herein ence a decrease in one or more
symptoms of iron deficiency, n the symptoms are selected from fatigue, dizziness,
pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, I’Iummer—Vinson
syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and
esophagus), impaired immune on, pagophagia, restless legs syndrome and combinations
of the foregoing. In some ments, CKD patients d according to the methods
disclosed herein experience the elimination of one or more symptoms of iron deficiency,
wherein the symptoms are selected from fatigue, dizziness, pallor, hair loss, irritability,
weakness, pica, brittle or grooved nails, Plummer—Vinson syndrome (painful atrophy of the
mucous membrane covering the tongue, pharynx and esophagus), impaired immune on,
pagophagia, restless legs syndrome and ations of the foregoing.
In some embodiments, the iron ency is anemia. In some embodiments, the iron
ency is iron—deficiency anemia. Iron—deficiency anemia is characterized by low levels
of circulating red blood cells and, in CKD patients, can be caused by insufficient dietary
intake, tion and/or storage of iron. Red blood cells, which contain iron bound in
hemoglobin proteins, and are typically not formed when the amount of iron in the body is
deficient.
Iron-deficiency anemia is typically characterized by pallor (pale color resulting from
reduced oglobin in the skin and mucous membranes), fatigue, lightheadedness, and
weakness. However, signs of iron—deficiency anemia can vary between CKD patients.
Because iron deficiency in CKD patients tends to develop slowly, adaptation to the disease
can occur and it can go unrecognized for some time. In some instances, patients with CKD
can p dyspnea (trouble breathing), pica (unusual obsessive food cravings), anxiety
often resulting in OCD-type corrrpulsions and obsessions, irritability or“ sadness, angina,
constipation, sleepiness, tinnitus, mouth ulcers, palpitations, hair loss, ng or feeling
faint, depression, breathlessness on exertion, twitching muscles, pale yellow skin, tingling
(numbness) or“ g sensations, missed menstrual cycle(s), heavy menstrual period(s),
slow social development, glossitis (inflammation or infection of the tongue), angular cheilitis
(inflammatory lesions at the mouths comers), koilonychia (spoon—shaped nails) or nails that
are weak or brittle, poor appetite, pruritus (generalized itchiness), Plummer—Vinson syndrome
(painful atrophy of the mucous membrane covering the , pharynx and esophagus), and
restless legs syndrome, among others.
Anemia is typically diagnosed based on a complete blood count measured from a
blood sample from a patient. lly, automatic rs are utilized that report the total
number of red blood cells in a sample, the hemoglobin level, and the size of the red blood
cells by [low cytometry. However, a d blood smear on a irricroscope slide can be
examined using a microscope in order to count the total number of red blood cells in a sample
and diagnose anemia. In many countries, four parameters (red blood cell count, hemoglobin
concentration, mean corpuscular volume and red blood cell distribution width) are measured
to determine the presence of anemia. The World Health Organization has set certain
threshold values for hemoglobin levels (Hb), such that when an CKD patient’s hemoglobin
levels fall below those values, a sis of anemia may be made. Those values are: for
en (1575.0 yrs of age, [1b = l 1.0 g/dI. or 6.8 mmol/I.; for children 5712 yrs years of
age, Hb = 11.5 g/ dL or 7.1 mmol/L; for teens 12—15 yrs of age, Hb = 12.0 g/ dL or 7.4
mmol/L; for non-pregnant women 15 years of age and older, Hb = 12.0 g/ dL or 7.4 mmol/L;
for pregnant women, Hb = 1 1.0 g/ d]. or 6.8 mmol/I.; and for men greater than 15 yrs of age,
Mb 2 13.0 g/ dL or 8.1 mmolfL.
CKD patients treated according to the methods disclosed herein may experience an
improvement in anemia. CKD patients treated according to the methods disclosed herein
may experience an improvement in iron—deficiency . In some embodiments, (7K1)
patients treated according to the s disclosed herein experience a se in one or
more symptoms of anemia or iron-deficiency anemia. In some embodiments, CKD patients
I0 treated according to the methods disclosed herein experience the elimination of one or more
ms of anemia or eficiency anemia. In some embodiments, the one or more
symptoms of anemia or iron-deficiency anemia are selected from pallor, fatigue,
lightheadedness, weakness, dyspnea, pica, anxiety, bility or sadness, angina,
constipation, ness, tinnitus, mouth ulcers, palpitations, hair loss, ng or feeling
faint, depression, breathlessness on exertion, twitching muscles, pale yellow skin, tingling
(numbness) or burning sensations, missed ual s), heavy menstrual period(s),
slow social development, glossitis, angular cheilitis, koilonychia, poor appetite, pruritus,
Plummer-Vinson syndrome, restless legs syndrome and ations of the foregoing.
In sorrre ments, CKD patients treated according to the methods disclosed
herein may experience an improvement in anemia and/or iron—deficiency anemia because
hemoglobin levels are raised and/or maintained above a threshold level. In sonre
embodiments, a method of treating anemia in a CKD patient is disclosed, the method
comprising orally administering ferric citrate to the CKD patient, wherein the ferric citrate
provides a hemoglobin level in the (7K!) patient that is at or above a level g from 1 1.0
g/dL - 13.0 g/dL, including a level selected from 11.0 g/dL, 11.5 g/dL, 12.0 g/dL, and 13.0
g/dL. In sorrre embodiments, a method of treating anemia in a CKD patient is disclosed, the
method comprising orally administering ferric e to the (7K1) patient, wherein the ferric
citrate provides a hemoglobin level in the CKD patient that is at or above a level selected
from 6.8 , 7.1 mmol/L, 7.4 mmol/L, and 8.1 mmol/L. In some embodiments, a
method of treating anemia in a male CKD patient is disclosed, the method comprising orally
administering ferric citrate to the male CKI) patient, wherein the ferric citrate provides a
hemoglobin level in the male CKD patient that is at or above a level selected from 13.0 g/dL
and 8.1 mmol/L. In some embodiments, a method of treating anemia in a female CKD
patient is disclosed, the method comprising orally stering ferric citrate to the female
CKD patient, n the ferric citrate provides a hemoglobin level in the female CKD
patient that is at or above a level selected from 12.0 g/dL and 7.4 mmol/L.
In some embodiments, ferric e for use in a method of treating anemia in a CKD
patient is disclosed, wherein the ferric citrate provides a obin level in the CKD patient
that is at or above a level g from 11.0 g/dL - 13.0 g/dL, including a level selected from
11.0 g/dL, 11.5 g/dL, 12.0 g/dL, and 13.0 g/dL. In some embodiments, ferric citrate for use
in a method of treating anemia in a (7K!) patient is disclosed, wherein the ferric citrate
provides a obin level in the CKD patient that is at or above a level selected from 6.8
mmol/L, 7.1 mmol/L, 7.4 , and 8.1 mmol/L. In some embodiments, ferric citrate for
use in a method of treating anemia in a male (7K1) patient is disclosed, wherein the ferric
citrate provides a hemoglobin level in the male CKD patient that is at or above a level
selected from 13.0 g/dL and 8.1 mmol/L. In some embodiments, ferric citrate for use in a
method of treating anemia in a female CKD patient is disclosed, wherein the ferric citrate
provides a hemoglobin level in the female (7K1) patient that is at or above a level selected
from 12.0 g/dL and 7.4 mmol/L.
enous Iron
Patients with CKD may be at risk for, or may suffer from, iron deficiency. Iron
deficiency, also referred to as sideropenia or rremia, is a common type of ional
deficiency, and can occur in a CKD patient as the body loses its ability to absorb iron from
the intestinal lumen and/or to store iron for long—term use. When a loss of or decrease in iron
in the body is not compensated for by, for example, a ient intake of iron from the diet,
iron deficiency can develop over time. When a state of iron deficiency is left uncorrected, it
can lead to iron—deficiency . 'l‘herefore, a direct consequence of untreated, long—term
iron deficiency can be iron—deficiency anemia and, in some instances, anemia.
In CKD patients, there are typically three means by which iron-deficiency anemia can
be treated. The first approach is by eating foods that are high in iron. If that is insufficient,
then a clinician may prescribe oral iron supplements. However, many oral iron supplements
cause numerous adverse side effects in CKD patients, which leads to patient non-compliance.
In those instances where a CKD patient cannot take oral iron supplements, he or she may
have to have intravenous iron supplementation.
Intravenous (IV) iron supplementation is a method of delivering iron by ion with
a needle, either through a muscle or into a vein. CKD patients who are receiving IV iron
usually do so because they cannot take oral iron. In particular, ICSRI) patients are on dialysis
and often lose blood during dialysis. These patients are y also taking an erythr‘opoiesis-
ating agent (ESA — see below) and may need extra iron because of that as well.
enous iron is delivered into the CKD patient’s vein h a needle that is attached to
an IV bag that contains an iron solution. The procedure takes place in a doctor’s office or a
clinic and may take up to several hours, depending on which treatment the physician has
prescribed. The CKD patient usually receives iron ions over the course of several visits
until his or her iron levels are correct. In some instances, an (7K1) patient may require
permanent IV iron supplementation.
The side effects of IV iron supplementation include: gastrointestinal pains, including
nausea and c “amps; problems breathing; skin problems, including ‘ash; chest pain; low blood
pressure; and anaphylaxis, among others.
CKD patients treated according to the methods disclosed herein may experience a
decrease in the need for IV iron supplementation. In some embodiments, CKD patients
treated according to the s disclosed herein experience a decrease in cumulative IV
iron supplementation. In some embodiments, the present disclosure provides methods of
reducing intravenous (IV) iron use in a patient in need thereof, the methods comprising orally
administering ferric cit‘ate to a (7K1) patient, particularly an ISSRI) patient, wherein the ferric
citrate provides for a reduction in IV iron use in the patient. In some embodiments, the
present disclosure es methods of reducing intravenous (IV) iron use in an end-stage
renal disease patient, the methods sing orally administering ferric e to the patient
at a dose of ferric iron ranging from 210 mg , 2,520 mg, wherein the ferric citrate provides for
a reduction in IV iron use in the patient. In some embodiments, the ferric citrate is
administered for a period of 52 weeks.
In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake from I — 100%. In sorrre embodiments, the ferric citrate provides a
mean reduction in average cumulative IV iron intake from 10 — 90 %. In some embodiments,
the ferric citrate es a mean reduction in average cumulative IV iron intake from 20 , 80
%. In some embodiments, the ferric citrate provides a mean ion in average cumulative
IV iron intake from 30 — 70 ‘70 . The above ranges are disclosed in this format for purposes of
ency, and any of the above ranges can be combined with any method, formulation, or
combination thereof.
In some embodiments, the ferric citrate provides a mean reduction in e
cumulative IV iron intake from 40 — 60 ‘70. In some embodiments, the ferric citrate provides
a mean reduction in e cumulative IV iron intake selected from 50, 51, 52, 53, 54, 55,
56, 57, 58, 59 and 60 %. In some embodiments, the ferric citrate provides a mean reduction
in average cumulative IV iron intake selected from 51.0, 51.1, 51.2, 51.3, 51.4, 51.5, 51.6,
51.7, 51.9 and 52.0 %. In some embodiments, the ferric citrate provides a mean reduction in
average cumulative IV iron intake of 5 1.6 %. In some ments, the ferric e
provides a mean reduction in e cumulative IV iron intake of 51.6 % when stered
over a period of 52 weeks.
In some embodiments, the ferric citrate provides a mean reduction in ave ‘age
cumulative IV iron intake that is greater than 10%. In some embodiments, the ferric citrate
provides a mean reduction in average cumulative IV iron intake that is greater than 20%. In
some embodiments, the ferric citrate es a mean reduction in ave ‘age cumulative IV
iron intake that is greater than 30%. In some embodiments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that is greater than 40%. In some
embodiments, the ferric citrate provides a mean reduction in average cumulative IV iron
intake that is greater than 50%.
In some embodiments, the ferric citrate provides a mean reduction in e
tive IV iron intake that is selected from less than 100%. In some embodiments, the
ferric cit ‘ate provides a mean reduction in average cumulative IV iron intake that is less than
90%. In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake that is less than 80%. In some embodiments, the ferric citrate
es a mean reduction in average cumulative IV iron intake that is less than 70%. In
some embodiments, the ferric citrate provides a mean reduction in average cumulative IV
iron intake that is less than 60%. In some ments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that is less than 50%. In some embodiments,
the ferric citrate provides a mean reduction in average cumulative IV iron intake that is less
than 40%. In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake that is less than 30%. In some embodiments, the ferric citrate
provides a mean ion in average cumulative IV iron intake that is less than 20%. In
some embodiments, the ferric e provides a mean reduction in average cumulative 1V
iron intake that is less than 10 %. The above boundaries are disclosed in this format for
purposes of efficiency, and any of the above boundaries can be combined with any method,
formulation, upper boundaiy as disclosed above, or combination thereof.
In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake that is r than 60%. In some embodiments, the ferric e
provides a mean reduction in average cumulative IV iron intake that is greater than 70%. In
some embodiments, the ferric citrate provides a mean reduction in average cumulative IV
iron intake that is greater than %. In some embodiments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that is greater than 90 “/0. The above
ries are disclosed in this format for es of efficiency, and any of the above
boundaries can be combined with any method, formulation, lower boundary as sed
below, or ation thereof.
In some embodiments, (7K1) patients, such as IISRI) patients, treated according to the
s disclosed herein experience maintenance of the amount of IV iron supplementation
needed such that the total amount of IV iron supplementation ed by the CKD patient
It) remains substantially unchanged during stration of the ferric citrate.
opoiesis-Stimulating Agents
In addition to the means of controlling iron—deficiency anemia in CKD patients set
forth above, (TKI) patient, particularly an IISRI) patient, may also take one or more
erythropoiesis-stimulating agents (ESAs) in an effort to control anemia. ESAs work by
helping the body to produce red blood cells. These red blood cells are then released from the
bone marrow into the bloodstream where they help maintain blood iron levels.
Erythropoiesis-stimulating agents, commonly abbreviated as ESAs, are agents that are similar
in structure and/or function to the cytokine erythropoietin, which stimulates red blood cell
production n‘opoeisis) in the body. Typical ESAs, structurally and biologically, are
similar to naturally occurring protein erythropoietin. Examples of commercially available
ESAs include Erythropoietin (Epo), Epoetin alfa (Procrit/Epogen), Epoetin beta
(NeoRecormon), Darbepoetin alfa sp), and Methoxy polyethylene glycol—epoetin beta
(Mircera). The two IISAs presently ed for marketing in the IIS. are Iipoetin aIfa
(Procrit, Epogen), and Darbepoietin alfa (Aranesp).
ESAs are commonly given to ESRD patients. These patients usually have lower
hemoglobin levels because they can’t produce enough erythropoietin. The side effects that
occur most often with BSA use include: high blood pressure; swelling; fever; dizziness;
nausea; and pain at the site of the injection, among . In addition to these side effects,
there are several safety issues that result, from ESA use. ESAs increase the risk of venous
thromboembolism (blood clots in the veins). IiSAs can also cause hemoglobin to rise too
high, which puts the patient at higher risk for heart attack, stroke, heart failure, and death.
CKD ts treated according to the methods disclosed herein may experience a
decrease in the amount, of IISAs needed to maintain hemoglobin levels. In some
embodiments, CKD patients treated according to the methods disclosed herein experience a
se in ESA use. In sonre embodiments, the present disclosure provides methods of
reducing ESA use in a CKI) patient, particularly an ESRD patient, the methods comprising
orally stering ferric citrate to the patient, wherein the ferric citrate provides for a
ion in ESA use in the patient. In some embodiments, the present sure provides
methods of reducing ESA use in an end-stage renal disease patient, the methods comprising
orally administering ferric citrate to the patient at a dose of ferric iron ‘anging from 210 mg 2
2,520 mg, wherein the ferric citrate provides for a reduction in ESA use in the patient. In
some embodiments, the ferric citrate is administered for a period of 52 weeks.
I0 In some embodiments, the ferric cit‘ate provides a decrease in median IiSA intake is
from I 2 50 %. In some embodiments, the ferric citrate provides a decrease in median BSA
intake is from 10 — 40 %. In some embodiments, the ferric citrate provides a se in
median ESA intake is from 20 2 30 %. In some embodiments, the ferric citrate provides a
decrease in median ICSA intake selected from 20, 21, 22, 23, 24, 25, 26, 27, 28, 2‘) and 30 %.
In some ments, the ferric citrate provides a decrease in median ESA intake selected
from 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.9 and 28.0 %. In some embodiments,
the ferric cit‘ate provides a decrease in median IiSA intake of 27.1 %. In some embodiments,
the ferric citrate es a decrease in median ESA intake of 27.1 % when administered over
a period of 52 weeks.
In some embodiments, the ferric e es a mean reduction in average
cumulative IV iron intake that is greater than 20%. In some embodiments, the ferric e
provides a mean reduction in average cumulative IV iron intake that is greater than 21%. In
some embodiments, the ferric citrate es a mean reduction in average cumulative IV
iron intake that is greater than 22%. In some embodiments, the ferric citrate provides a mean
ion in average cumulative IV iron intake that is greater than 23%. In some
embodiments, the ferric Citrate provides a mean reduction in average cumulative IV iron
intake that, is greater than 24%. In some embodiments, the ferric e provides a mean
reduction in average tive IV iron intake that is greater than 25%. In some
embodiments, the ferric Citrate provides a mean reduction in average cumulative IV iron
intake that is greater than 26%. In some embodiments, the ferric e provides a mean
reduction in average cumulative IV iron intake that, is greater than 27%. In some
embodiments, the ferric Citrate provides a mean reduction in average cumulative IV iron
intake that is greater than 28 %. In some embodiments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that, is greater than 2‘) %. The above
ries are sed in this format for es of efficiency, and any of the above
boundaries can be combined with any method, formulation, lower ry as disclosed
below, or ation thereof.
In some embodiments, the ferric e provides a mean reduction in average
cumulative IV iron intake that is less than 30%. In some embodiments, the ferric e
es a mean reduction in average cumulative IV iron intake that is less than 29%. In
some embodiments, the ferric citrate provides a mean reduction in e cumulative IV
iron intake that is less than 28%. In some embodiments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that is less than 27%. In some embodiments,
the ferric cit ‘ate provides a mean reduction in average cumulative IV iron intake that is less
than 26%. In some embodiments, the ferric citrate provides a mean reduction in average
cumulative IV iron intake that is less than 25%. In some embodiments, the ferric citrate
provides a mean reduction in average cumulative IV iron intake that is less than 24%. In
some embodiments, the ferric citrate provides a mean reduction in average cumulative IV
iron intake that is less than 23%. In some embodiments, the ferric citrate provides a mean
reduction in average cumulative IV iron intake that is less than 22%. In some embodiments,
the ferric cit ‘ate provides a mean reduction in ave ‘age cumulative IV iron intake that is less
than 21 %. The above boundaries are disclosed in this format for purposes of efficiency, and
any of the above boundaries can be combined with any method, formulation, upper boundary
as disclosed above, or combination thereof.
In some embodiments, CKD patients, ularly ESRD patients, treated according to
the methods disclosed herein experience maintenance of the amount of ESAs needed to
maintain hemoglobin levels such that the total amount of BSA use by the patient s
substantially unchanged during administration of the ferric citrate.
Oral Iron Supplement
In some embodiments, the present disclosure provides an oral iron supplement
comprising ferric citrate in an amount effective to increase iron tion in CKD patients.
In some embodiments, the present disclosure provides an oral iron supplement comprising
ferric citrate in an amount effective to maintain iron stores in CKD ts. In some
ments, the present disclosure provides an oral iron supplement comprising ferric
citrate in an amount effective to improve one or more iron storage parameters in CKD
patients. In some embodiments, the one or more iron storage parameters are selected from
hematocrit, hemoglobin concentration (1 lb), total iron—binding capacity ('l‘IBC), transferrin
saturation (TSAT), serum iron levels, liver iron levels, spleen iron levels, and serum ferritin
levels. In sonre embodiments, the present disclosure provides an oral iron supplement
sing ferric citrate in an amount effective to treat iron deficiency in CKD patients. In
sorrre embodiments, the present disclosure provides an oral iron supplement comprising ferric
citrate in an amount effective to treat anemia in CKD patients.
In sorrre embodiments, the present disclosure es an oral iron supplement
sing ferric cit ‘ate having a dose of ferric iron ofllf) mg. In some embodiments, the oral
iron supplements comprising ferric citrate can be administered so that the dose of ferric iron
ranges from 210 mg — 2,520 mg.
If) In some ments, the t disclosure provides ferric cit ‘ate for use in the
manufacture of an oral iron supplement to se iron absorption in CKD patients. In sonre
embodiments, the present disclosure provides ferric citrate for use in the manufacture of an
oral iron supplement to maintain iron stores in CKD patients. In some embodiments, the
present disclosure provides ferric citrate for use in the manufacture of an oral iron supplement
to improve one or more iron storage parameters in CKD patients. In some ments, the
one or more iron storage ters are selected from hematocrit, hemoglobin concentration
(11b), total iron—binding ty ('I‘IBC), transferrin saturation ('I‘SA'I‘), serum iron levels,
liver iron levels, spleen iron , and serum ferritin levels. In some embodiments, the
present disclosure provides ferric citrate for use in the manufacture of an oral iron supplement
to treat iron deficiency in CKD patients. In some embodiments, the present disclosure
provides ferric citrate for use in the manufacture of an oral iron supplement to treat anemia in
CKD patients.
In sorrre ments, the present disclosure provides ferric citrate for use in the
manufacture of an oral iron supplement comprising a dose of ferric iron onlO mg.
Ferric e
In various aspects, the present disclosure relates to the use of ferric citrate to reduce
and/or control serum phosphorus levels, increase serum bicarbonate levels, improve one or
more iron storage parameters (e.g., increase serum ferritin , increase transferrin
saturation (TSAT), increase hemoglobin concentration) increase iron absorption, maintain
iron stores, treat iron deficiency, treat anemia, reduce the need for IV iron and/or reduce the
need for erythropoiesis-stimulating agents (ESAs) in CKD patients. In various aspects, the
t disclosure relates to the use of pharmaceutical compositions comprising ferric citrate
and a pharmaceutically acceptable binder to reduce and/or control serum orus levels,
increase serum bicarbonate levels, improve one or more iron storage parameters (e.g.,
increase serum ferritin levels, increase transferrin saturation (TSAT), increase hemoglobin
concentration) increase iron absorption, maintain iron stores, treat iron deficiency, treat
anemia, reduce the need for IV iron and/or reduce the need for erythropoiesis—stimulating
agents (ESAs) in CKD ts.
Therefore, disclosed herein are preparations of ferric citrate and pharmaceutical
itions comprising the ferric eit‘ate. In various embodiments, the ferric cit ‘ate
preparations, and the pharmaceutical compositions comprising the ferric e preparations,
meet certain dissolution, tableting and disintegration standards. In various aspects, the
I0 pharmaceutical compositions can include ferric citrate as the active ingredient and a binder.
The pharmaceutical compositions also can include a lubricant and/or a disintegrant (which, in
some embodiments, can be the same as the binder).
Certain embodiments of the ferric citrate preparations disclosed for use herein are also
disclosed in 11.8. Patent Nos. 7,767,851, 423, 8,299,298 and 8,338,642, and PCT
Publication Nos. , , ,
and . Certain embodiments of the ferric citrate preparations, however, are
unique to this sure. The ferric eit‘ate preparations disclosed herein display an ed
BET active surface area compared to commercially available or chemical grade forms of
ferric citrate. BET theory explains the physical adsorption of gas les onto a solid
surface. The theory serves as the basis for the measurement of the specific surface area of a
material. This theory allows the calculation of surface areas of materials in a very accurate
manner and is thus e of distinguishing ences between separate preparations of
what would otherwise appear to be the same material. For example, activated carbon is a
form of carbon that has been processed to make it extremely porous and thus to have a very
large e area. Activated carbon has been experimentally determined, using calculations
derived from BET theory, to have a surface area of around 3000 m2 g'l. This surface area is
icantly higher than the active surface areas of other preparations of carbon even though
they are made of the same material.
In some embodiments, the ferric citrate ations disclosed herein have a BET
active surface area exceeding 16 mZ/g. In some embodiments, the high purity ferric e
preparations disclosed herein have a BET active surface area exceeding 20 nil/g. In some
embodiments, the high purity ferric citrate preparations disclosed herein have a BET active
surface area exceeding 25 mZ/g. In some embodiments, the high purity ferric citrate
preparations disclosed herein have a Bltl active e area exceeding 30 m /g. In some
embodiments, the high purity ferric citrate preparations disclosed herein have a BET active
surface area exceeding 35 rrrz/g. In some embodiments, the high purity ferric citrate
preparations sed herein have a BET active surface area exceeding 40 1112/g. In some
embodiments, the high purity ferric citrate preparations disclosed herein have a BET active
surface area ing 45 mZ/g. In sonre embodiments, the high purity ferric citrate
preparations disclosed herein have a BET active surface area exceeding 50 1112/g. In sorrre
embodiments, the ferric citrate preparations disclosed herein have a BET active surface area
ranging from 16.17 mZ/g to 19.85 mz/g. In some embodiments, the ferric e preparations
disclosed herein have a BET active surface area selected from 16.17 nrz/g and 19.85 1112/g. In
some ments, the ferric citrate preparations disclosed herein have a BET active surface
area exceeding 27 mZ/g. In some ments, the ferric citrate ations sed herein
have a BET active surface area ranging from 27.99 mz/g to 32.34 rnZ/g. In sorrre embodiments,
the ferric citrate preparations disclosed herein have a BET active surface area ranging from
28.5 mZ/g to 31.5 nil/g. In some embodiments, the ferric citrate preparations disclosed herein
have a BET active e area selected from 27.99 mZ/g, 28.87 mz/g and 32.34 mz/g. In sorrre
embodiments, the ferric citrate preparations disclosed herein have a BET active surface area
selected from 28.5 mZ/g, 29.1 nil/g, 30.6 irrzlg and 31.5 nil/g. This is in sharp contrast to other
preparations of ferric citrate such as chemical-grade preparations that are known and
commercially available as of the filing date of this disclosure. Commercial grade preparations
of ferric citrate have BET active surface areas that are substantially lower than the ferric citrate
preparation of the present disclosure. Therefore, the ferric citrate preparations disclosed herein
have a significantly larger surface area available for adsorption or al reactions, making
the ations of ferric citrate disclosed herein substantially rrrore reactive than commercial
preparations.
The BET active surface areas determined for five ferric citrate preparations produced
by the methods disclosed in PCT Publication No. /O74444 have been determined.
Those B] {T active surface areas are yed in Table 1, below, compared to the B] {T active
surface area of comrrrercial—grade preparations of ferric citrate:
Table 1. BET active surface areas of various forms of ferric citrate
Sample Mean Dissolution BET Active
Rates Surface Area
(mg/cm2/min)
Rl’S—12—1 (sigrrra / ercially available)
0.76 0.61
RFS-l2-2 (sigma / cially available)
STM—134-1 (reference material 1)
2.47 16.17
STM— 134—2 ence material 2)
STM1 (lab-scale 500 g batch 1)
2.61 19.85
STM—182-2 cale 500 g batch 2)
The BET active surface areas determined for five ferric citrate preparations produced
by the methods disclosed in PCT Publication No. WO2011/011541 have been determined.
Those BET active surface areas are displayed in Table 2, below, compared to the BET active
surface area of corrmrercial—grade preparations of ferric citrate:
Table 2. BET active surface areas
Sample BET Active Surface Area (mZ/g)
Rl’S—l2—l (sigma / commercially available)
0.61
2—2 (sigma / commercially available)
Sample #10—1 ranulation(API+ProSolv)) 27.99
Sample #10-2 (Pre-granulation(API+ProSolv))'
Sample #1 1—1 anulation(API+ProSolv))‘
Sample #l [—2 (Pre—granulation(/\Pl+ProSolv))4 28.87
Sample #1 1—3 (Pre—granulation(APl+ProSolv))5
The BET active surface areas for four additional ferric citrate preparations produced by
methods disclosed herein have also been determined. Those Bli'l‘ active surface areas are
displayed in Table 3, below, compared to the BET active surface area of cormrrercial-grade
preparations of ferric citrate:
:rom Example 10 of PCT Publication No. W0 201 1/01 1541.
Irom lixample 10 of PCT Publication No. W() 201 1/01 1541.
Erom Example 11 of PCT Publication No. .
Erom Example 11 of PCT Publication No r
Irom le l l of l)("l‘ Publication No. W()2011/01 1541.
Table 3. BET active surface areas
Sample BET Active Surface Area (ml/g)
RFS—l2—1 (sigma / commercially available)
0 61
Rl’S— 12—2 (sigma / commercially available) ‘
Batch No. 35102 30.6
Batch No. 35103 29.1
Batch No. 35105 31.5
Batch No. 35106 28.5
The BET active surface areas of the embodiments of ferric citrate preparations
disclosed in Tables 1, 2 and 3 are thus significantly higher than those of commercial grade
ferric citrate.
Table 4 illustrates the assay content of ferric iron of the ferric citrate disclosed herein.
The assay content of ferric iron represents the amount of ferric iron in each of the
preparations of ferric e shown in Table 4. In some embodiments, the assay t of
ferric iron is greater than or exceeds about 20% wfw. In some ments, the assay
content of ferric iron is 21.2% w/w. In sorrre embodiments, the assay content of ferric iron is
22.1% w/w. In sorrre ments, the assay content of ferric iron is 22.4% w/w. In sorrre
embodiments, the assay content of ferric iron is between 21% w/w and 23% Wlw.
Table 4: Ferric Iron Content
d Mat
lmpurity
Batch Material Bal. (mat % Fe(|||)
Content
balance + Water bal+water)
A 94.60 1.9 96.50 3.5 21.2
B 94.40 2.1 96.50 3.5 21.2
C 93.40 2.0 95.40 4.6 22.4
D 92.90 2.2 95.10 4.9 22.1
The ferric citrate disclosed herein is a complex of iron(III) and citric acid. In some
aspects, the molar ratio of iron (III) to citric acid is from 1: 0.70 to 1: 0.78. In some aspects,
the molar ratio of iron (Ill) to citric acid is from 1: 0.69 to l: 0.87. In some aspects, the molar
ratio of iron ([11) to citric acid is from 1: 0.75 to 1: 1.10. In some aspects, the molar ratio of
iron (III) to citric acid is from 1: 0.78 to 1: 0.95. In sonre aspects, the molar ratio of iron (III)
to citric acid is from 1: 0.80 to 1: 0.92. In sorrre aspects, the molar ratio of iron (III) to citric
acid is from I: 0.81 to l: 0.91. In some aspects, the molar ratio of iron (III) to citric acid is
from 1: 0.75 to 1: 1.15. In some aspects, the molar ratio of iron (III) to citric acid is from 1:
0.80 to 1: 1.10.
In some aspects, the molar ratio of iron (III) to water is from 1: 0.32 to 1: 0.42. In
sorrre aspects, the molar ratio of iron (III) to water is from 1: 0.32 to l: 0.46. In some s,
the molar ratio of iron (III) to water is from 1: 1.8 to l: 3.2. In some aspects, the molar ratio
of iron (111) to water is from 1 : 1.8 to 1: 3.2. In some aspects, the molar ratio of iron (111) to
water is from 1: 2.4 to l: 3.1. In some aspects, the molar ratio of iron (III) to water is from 1:
2.7 to 1: 3.1.
The ferric citrate preparations disclosed herein are more e compared to
commercially available or chemical grade forms of ferric e. In dissolution testing, the
percentage of ferric citrate of the t disclosure dissolved within 5 tes is 91% or
more, within 15 minutes is 96% or more, within 30 minutes is 96% or more and within 60
minutes is 95% or more in dissolution testing conducted on the ferric citrate preparations in
USP <711> vessels using Apparatus II. Table 5 illustrates dissolution testing data for four
exemplary batches of ferric citrate according to the present disclosure. The particular
standard used for the dissolution testing establishes a ne of 100 so to the extent that a
batch may have a dissolution greater than 100%, it is a dissolution rate relative to that
standard.
Table 5. Dissolution testing data
Batch 5 s 15 minutes 30 minutes 60 minutes
A 101% 102% 101% 101%
B 1 01% 1 02% 102% 1 02%
C 97% 97% 97% 97%
D 91 % 96% 96% 95%
Thus, in sorrre embodiments, the percentage of ferric citrate dissolved within 15
minutes is 80% or more in dissolution testing conducted in USP <71 1> vessels using
Apparatus 11. In some embodiments, the percentage of ferric citrate dissolved within 15
minutes is 85% or rrrore in dissolution testing conducted in USP <711> vessels using
Apparatus II. In sorrre embodiments, the percentage of ferric citrate dissolved within 15
minutes is 90% or more in dissolution g conducted in USP <71 l> vessels using
Apparatus II. In sorrre embodiments, the tage of ferric e dissolved within 15
rrrinutes is 91% or rrrore in dissolution testing conducted in USP <711> vessels using
Apparatus I]. In some embodiments, the percentage of ferric citrate dissolved within 15
minutes is 95% or more in dissolution testing conducted in USP <711> vessels using
Apparatus II. In sorrre embodiments, the tage of ferric citrate dissolved within 15
minutes is 96% or more in dissolution testing conducted in USP <71 l> vessels using
Apparatus II. In sorrre embodiments, the percentage of ferric citrate dissolved within 15
rrrinutes is 97% or rrrore in ution testing ted in USP <711> vessels using
Apparatus II. In some embodiments, the percentage of ferric citrate ved within 15
minutes is 100% or more in dissolution testing conducted in USP <711> vessels using
tus II.
The ferric. citrate preparations disclosed herein are more soluble compared to
commercially available or chemical g ‘ade forms of ferric citrate. This increase in solubility of
the ferric citrate pr ions disclosed herein is believed to be, a result. of tit-re unique,
significantly large aetive sur‘fae 2 area of the ferric citrate preparations disc’ >--osed herein. The
intrinsic dissolution rate is defined as the dissolution rate of pure substances under the
condition of eenstant surface area ll‘i‘ie intrinsic dissi’aiutii’in rate and bioavailabiliiy of a time
substance is inlruenced by its solid state properties including: erystallinity, at ioiphisni,
nolymorphisrn, hydration, soiyation, particle size and particle surface area 'l‘lre rneasureii14.x
intrinsic dissolution rate is dependent on these solidrtate properties and is iypieally
deteniiined by exposing a nt surface area of a material to an appropriate t’iissolutii‘in
medium while maintaining nt temperature, stirring rate, and pH.
In some embodiments, the ferric citrate preparations disclosed herein have an intrinsic
dissolution rate of r than 2.28 mg/cmZ/min. In some embodiments, the ferric citrate
preparations disclosed herein have an intrinsic dissolution rate ing 2.28 mg/cmz/min.
In some ments, the ferric e preparations disclosed herein have an intrinsic
dissolution rate of 2.99 mg/cmZ/min. In some ments, the ferric citrate preparations
disclosed herein have an intrinsic dissolution rate ranging from 2.28 mg/cmZ/min to 2.99
mg/cmz/min. In sorrre embodiments, the ferric citrate preparations disclosed herein have an
intrinsic dissolution rate selected from 2.28 mg/cmZ/min and 2.99 mg/cmZ/min. This is in
sharp contrast to other preparations of ferric citrate such as chemical-grade preparations that are
known and commercially available. Commercial grade preparations of ferric citrate have an
intrinsic dissolution rate that is ntially lower than the ferric citrate preparation of the
present disclosure. Therefore, the ferric citrate preparations disclosed herein have a significantly
higher intrinsic dissolution rate, making the preparations of ferric citrate disclosed herein
substantially more soluble than commercial preparations.
The intrinsic dissolution rate was determined for a preparation of ferric citrate produced
according to the present disclosure. The mean intrinsic dissolution rate is displayed in Table 6,
below, compared to the ution rate of a cial-grade preparation of ferric citrate:
Table 6. sic ution Rates
Sample Mean sic Dissolution Rates
(mg/cmzlmin)
R1 “S — l 2 (sigma/corrrnrercially available) 0.83
High Purity Ferric Citrate 2.64
The intrinsic dissolution rate of the ferric citrate preparation disclosed in Table 6 is
thus significantly higher than that of commercial grade ferric citrate.
Methods ofMamifacture
Exemplary methods of manufacture of preparations of ferric citrate provided by this
disclosure are disclosed in US. Patent Nos. 7,767,851, 8,093,423, 298 and 8,338,642,
and PCT Publication Nos. W0 2004/074444, W0 22435, W0 2007/089571, W0
l 0 2007/089577 and W0 20] 1/01 1541.
Modes ofAdministration
The ferric citrate disclosed herein may be advantageously used in human ne.
As disclosed herein, the ferric citrate disclosed herein is useful to reduce and/or control serum
phosphorus levels, increase serum bicarbonate levels, improve one or rrrore iron storage
parameters (e.g., increase serum ferritin levels, increase transferrin saturation (TS/\T),
increase hemoglobin tration) increase iron absorption, maintain iron stores, treat iron
ency, treat anemia, reduce the need for IV iron and/or reduce the need for
erythropoiesis—stimulating agents (ESAs) in CKD patients. The ferric citrate disclosed herein
may also be advantageously used as an iron supplement. In various aspects, the ferric citrate
disclosed herein can be administered orally. In sorrre embodiments, the ferric citrate is
administered in an oral dosage form. In some embodinrents, the ferric citrate is administered
in an oral tablet dosage form. In some embodiments, the tablet is in the form of a caplet.
When used to treat the above diseases andfor conditions, or when used as an iron
supplement, the ferric citrate disclosed herein may be administered or d singly, or in
combination with other agents. The ferric citrate disclosed herein may also be stered
or applied singly or in combination with other pharnraceutically active agents, including other
agents known to reduce and/or control serum phosphorus levels, increase serum bicarbonate
levels, e one or more iron storage parameters (e. g., increase serum ferritin levels,
increase transferrin saturation (TSAT), increase hemoglobin concentration) increase iron
absorption, maintain iron stores, treat iron deficiency, treat anemia, reduce the need for IV
iron and/or reduce the need for erythropoiesis—stimulating agents (ES/\s) in CKI) patients.
Methods of treatment are disclosed above and include orally administering ferric
citrate to the patient at a dose of ferric iron ranging from 210 mg — 2,520 mg. The ferric citrate
sed herein can ore be administered orally. In various aspects, the ferric citrate
disclosed herein may be stered in an oral tablet dosage form that comprises 1 gram of
ferric citrate and a dose of ferric iron of about 210 mg.
The ferric citrate disclosed herein serves to e the absorption of iron from the
intestinal lumen and to e/maintain the storage of iron after absorption. It is believed
that the enhanced absorption and storage of iron may be due to the presence of citrate in the
ferric citrate administered to the CKD patient. While not wishing to be bound by any theory,
some studies have shown that administration of iron in combination with citrate (the
conjugate base of citric acid) serves to significantly increase (e.g., by several fold) the
amount of iron absorbed from dietary sources (see, e.g., Ballot, et ((1., Br. J. Nutr. (1987) 57,
331—343; Gillooly, et (1]., Br. J. Nun: (1983) 49, 331—342; Zhang, et (1]., Eur. J. Nutr. (2007)
46, 957102; and Salovaara, cl ((1., J. Agric. Food Chem. (2002) 50, 623376238).
The ferric citrate disclosed herein can be stered in some embodiments once per
day, in some embodiments twice per day, in some embodiments three times per day, and in
some ments more than twice per day. In various aspects, the ferric citrate may be
administered in the forrrr of a daily dose that is split up during the course of a single day. By
way of e, a single daily dose of ferric citrate may be 6 grams and that 6 grams may be
spread out over the course of the day such that 2 grams is taken in the morning, 2 grams in
the afternoon, and the final 2 grams in the evening, for a total of 6 grams over the course of a
day.
The ferric citrate disclosed herein can be used to reduce and/or control serum
phosphorus levels, se serum bicarbonate levels, improve one or more iron storage
parameters (e. g., increase serum ferritin levels, increase transferrin saturation (TSAT),
increase hemoglobin tration) increase iron absorption, maintain iron stores, treat iron
ency, treat anemia, reduce the need for IV iron and/or reduce the need for
opoiesis—stimulating agents (HS/\s) in CKD patients, while also reducing adverse drug
effects associated with known forms of oral iron supplements (such as ferrous iron-containing
supplements) and/or IV iron supplements.
Pharmaceutical Compositions and Iron Supplements
sed herein are ferric citrate-containing pharmaceutical compositions comprising
the ferric citrate preparations sed herein and a . In some embodiments, the
pharmaceutical compositions can be provided to CKD patients as iron supplements. In some
embodiments, the pharmaceutical compositions can be provided to CKD patients as
phosphate binders and/or to reduce and/or control serum phosphorus levels, increase serum
bicarbonate levels, improve one or more iron storage parameters (e.g., increase serum ferritin
, increase transferrin saturation (TSAT), increase hemoglobin concentration) increase
iron absorption, in iron stores, treat iron deficiency, treat anemia, reduce the need for
IV iron and/or reduce the need for erythropoiesis—stimulating agents (liSAs) in (K!) patients.
In various embodiments, the ceutical compositions meet certain dissolution, tableting
and/or disintegration standards. In various aspects, the pharmaceutical compositions can
include ferric citrate as the active ingredient and a . The pharmaceutical itions
also can include a lubricant and/or a disintegrant (which, in some embodiments, can be the
same as the ). In some embodiments, the pharmaceutical compositions are oral tablet
dosage forms.
(Tertain embodiments of the pharmaceutical compositions and oral tablet dosage
forms provided by this sure are disclosed in PCT Publication No. .
Other embodiments, however, are unique to this disclosure.
Oral Tablet Dosage Forms and Oral Iron Supplements
In one aspect, the pharmaceutical compositions are tablets that include ferric citrate
and a binder. As is used herein, a “tablet” is a material produced by compression force, such
as with a tableting machine. In other embodiments the tablets can include ferric citrate, a
, a lubricant and a egrant. In some embodiments, a single tablet comprises 1
gram of ferric citrate having a 210 mg dose of ferric iron. In some embodiments, the tablets
can be used to reduce and/or control serum phosphorus , increase serum bicarbonate
levels, improve one or more iron storage parameters (e.g., increase serum fen‘itin ,
se transferrin saturation (TSAT), increase hemoglobin concentration) increase iron
absorption, maintain iron stores, treat iron deficiency, treat anemia, reduce the need for IV
iron and/or reduce the need for erythropoiesis—stimulating agents (HS/\s) in CKD patients. In
some embodiments, the tablets can be stered to CKD patients as oral iron supplements.
In some embodiments, the tablets and/or oral iron supplements can be characterized
as highly drug loaded with the ferric citrate present in the tablets and/or oral iron supplements
at values of greater than imately 65% by weight of the formulation, greater than
approximately 70% by weight of the formulation, greater than approximately 75% by weight
of the formulation, r than imately 80% by weight of the formulation, greater
than approximately 85% by weight of the formulation, greater than approximately 90% by
weight of the formulation and as high as approximately 92% of the formulation. Intermediate
values such as approximately 80% by weight ferric e, approximately 85% by weight
ferric citrate and approximately 90% by weight ferric citrate also can be used in the ferric
citrate tablets and/or oral iron supplements. The characteristics of the tablets and/or oral iron
supplements produced at these highly loaded weight percentages are controlled by variables
such as binder, binder amount, disintegrant, egrant amount, formulation method used
(6. g, granulation, direct compression), tableting parameters, etc. Thus if a tablet and/or oral
iron supplement is made and it has a slight amount of lamination or capping, by varying one
or more of the above les, the tion or capping can be corrected.
In various embodiments, the tablets and/or oral iron supplements contains one or
more components selected from among one or more binders, one or more lubricants, and one
or more disintegrants.
The binder can be any binder known in the art. Without limitation, es of the
binder can include one or more of ypropyl cellulose (HPC), hydroxypropylmethyl
cellulose (HPMC), sodium te, alginic acid, guar gum, acacia gum, xanthan gum,
carbolpol, cellulose gum (carboxy methyl cellulose), ethyl cellulose, maltodextrin, PVP/VA,
povidone, oc1ystalline cellulose, starch, partially or fully prcgelatinized starch, and
methyl cellulose. The maltodextrin, PVP/VA, and methyl cellulose function as immediate
release binders when used in the ferric citrate tablets and/or oral iron supplements.
It also should be understood that combinations of binders can be used to control and
vary the effect of the binder. For example, a binder system can be made up of hydroxypropyl
cellulose and polyvinyl pyrrolidone (povidone) with or without microcrystalline cellulose.
()ne or both of the hydroxypropyl cellulose and nc can be replaced with atinixed
starch.
In various aspects, the tablets and/or oral iron supplements can include a lubricant. As
an example of a lubricant for the ferric citrate tablets and/or oral iron supplements,
magnesium stearatc, calcium stearatc, sodium stcaiyl fumarate and combinations can be used.
Other suitable lubricants include one or more of polyethylene glycol (molecular weight above
3350), sodium lauryl e, talc, mineral oil, leucine, and poloxamer.
In various aspects, the tablets and/or oral iron supplements can include a disintegrant.
The disintegrant can be included in the tablets and/or oral iron supplements. The disintegrant
can be the same as or different from the binder. By way of example and not limitation,
rystalline cellulose has both binder and disintegrant properties and rystalline
cellulose can be used as the sole /disintegrant in the tablets and/or oral iron
supplements. Examples of other suitable disintegrants include croseannellose sodium,
crospovidone, sodium starch ate, and starch.
The binder can be present in the tablets and/or oral iron supplements in an amount
ranging from imately 4.5% by weight to approximately 30% by weight. The
disintegrant, can be present in the s and/or oral iron supplements in an amount, ranging
from approximately 1.5% by weight to approximately 15% by weight. In various
embodiments, some non-starch disintegrants are often used at lower weight percents, e. g., as
low as 0.25% and thus the disintegrant present in the tablets andfor oral iron ments can
be as low as 0.25% in some conditions.
The lubricant can be present in the tablets and/or oral iron supplements in an amount
g from imately 0.5% by weight to approximately 3% by weight. It should be
understood that some components, such as microcrystalline cellulose, can function with both
disintegrant and binder properties.
The weight of individual tablets and/or oral iron ments can depend upon the
final dosage to be produced; e.g. 125mg, 250mg, 500mg, 667mg, 750mg and 1,000mg of
ferric citrate. In some embodiments, the tablets comprise 1 gram of ferric e and
therefore a dose of 210 mg of ferric iron.
In various embodiments, tablets and/or oral iron supplements are coated to a weight
gain of approximately 2% to 5% using an ()padry suspension or equivalent in a perforated
pan coater. Calcium stearate and Opadry purple can be replaced with or used with a different
lubricant or coating system, respectively.
In other variations, the tablets and/or oral iron supplements have reduced water
content. In one embodiment, the water t of the , as measured by LOD %, is less
than 20%. In another embodiment, the water content of the tablet, as ed by LOD %, is
less than 19%. In another embodiment, the water content of the tablet, as measured by LOD
%, is less than 18%. In another embodiment, the water content, of the tablet, as measured by
LOD %, is less than 17%. In another embodiment, the water content of the tablet, as
measured by LOD %, is less than 16%. In another embodiment, the water content of the
tablet, as measured by 1.0!) %, is less than 15%. In another embodiment, the water content
of the tablet, as measured by LOD %, is less than 14%. In another embodiment, the water
content of the tablet, as measured by LOD %, is less than 13%. In another embodiment, the
water t of the tablet, as measured by 1.01) % is less than 12%. In another embodiment,
the water content as measured by 1.01) % is less than 11%. In another embodiment, the
water content as ed by LOD % is less than 10%. In another embodiment, the water
content of the tablet, as measured by LOD %, is less than 9%. In another embodiment, the
water content of the tablet, as measured by 1.01) %, is less than 8%. In another embodiment,
the water content of the tablet, as measured by LOD %, is less than 7%. In another
embodiment, the water content of the tablet, as measured by LOD %, is less than 6%. In
r embodiment, the water content, of the tablet, as measured by 1.01) %, is less than 5%.
LOD (loss on drying) is a method of thermogravimetric moisture determination. In
theimogravimetric processes, the moisture of a al includes substances that volatilize
during warming, and therefore contribute to the material's loss of mass. Alongside water this
may also include l or decomposition products. When using thermogravimetric
measurement methods (drying using infrared, halogen, microwaves or ovens) no ction
is made between water and other volatile components.
In some embodiments, the tablets and/or oral iron supplements comprise an amount of
ferric citrate selected from approximately 1000 mg, approximately 667 mg, imately
500 mg, approximately 250 mg and approximately 125 mg. In some embodiments, the
tablets and/or oral iron supplements comprise 1 gram (1000mg) of ferric citrate. In some
embodiments, the tablets andfor oral iron supplements comprise 1 gram of ferric citrate
containing approximately 210 mg of ferric iron.
In some embodiments, the tablets and/or oral iron supplements comprise 1.3 grams of
ferric citrate. In some embodiments, the tablets and/or oral iron supplements comprise 1.5
grams of ferric citrate. In some embodiments, the tablets and/or oral iron supplements
comprise 1.6 grams of ferric citrate. In some embodiments, the s and/or oral iron
supplements se an amount of ferric citrate selected from 100mg, 125mg, 150mg,
175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg,
450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg,
725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg,
1000111g, , , 1075mg, 1 100mg, 1 125mg, 1 150mg, 1 175mg, 1200mg, 1225mg,
1250mg, 1275mg, 1300mg, , 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg,
1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg,
l750mg, l775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, l925mg, l950mg, l975mg
and 2000mg.
In some embodiments, the tablets and/or oral iron supplements comprise between
approximately 65 wt% and 92 wt% ferric citrate; n approximately 4.5 wt% and 30
wt% binder; and between 0.5 wt% and 3 wt% lubricant. In some embodiments, the lubricant
is selected from one or more of magnesium stearate, m stearate, and sodium stearyl
fumarate.
In some embodiments, the tablets and/or oral iron supplements comprise 65 % by
weight to 92 % by weight of ferric citrate and 4.5 % by weight to 30 % by weight of a binder,
I0 wherein the mean surface area to mass ratio of said tablet is equal to or greater than I in2 per
gram, and wherein the LOD % water of the tablet is less than 20% water w/w. In some
embodiments, the mean surface area to mass ratio of the tablets and/or oral iron supplements
can be equal to or greater than 5 in2 per gram. In some embodiments, the mean surface area
to mass ratio of the tablets and/or oral iron supplements is equal to or greater than 10 in2 per
gram. In some ments, the tablets and/or oral iron supplements comprise at least 70
weight percent ferric citrate. In some embodiments, the tablets and/or oral iron supplements
comprise at least 80 weight percent ferric citrate. In some ments, the tablets and/or
oral iron supplements comprise at least 90 weight percent ferric citrate. In some
embodiments, the binder comprises one or more of hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (IIPIVIC), sodium alginate, alginic acid, guar gum, acacia
gum, xanthan gum, carbolpol, cellulose gum (carboxymethyl cellulose), ethyl cellulose,
maltodextrin, PVP/VA, povidone, rystalline cellulose, starch (partially or fully
pregelatinized starch) and methyl cellulose. In some embodiments, the LOD % water of the
tablets and/or oral iron supplements is less than 15% water w/w. In some embodiments, the
LOD % water of the tablets and/or oral iron supplements is less than 10% water w/w. In
some embodiments, the tablets and/or oral iron supplements further comprise a disintegrant
selected from one or more of microcrystalline cellulose, rmellose sodium,
crospovidone, sodium starch glycolate, and starch. In some embodiments, the tablets and/or
oral iron supplements r comprise a lubricant selected from one or more of ium
stearate, calcium stearate, and sodium stearyl fumarate. In some ments, the s
and/or oral iron supplements comprise between 0.5% and 3% lubricant. In some
embodiments, the binder comprises pregelatinized starch. In some embodiments, the
lubricant comprises calcium te and sodium stearyl fumarate. In some ments, at
least 80% of the ferric citrate in the tablets and/or oral iron ments is dissolved in a time
less than or equal to 60 minutes as measured by test method USP <711>. In some
embodiments, the tablets and/or oral iron ments comprise approximately 1000 111g of
ferric e. In some elllbodiments, the tablets and/or oral iron supplements comprise
approximately 667 mg of ferric citrate. In some embodiments, the tablets and/or oral iron
supplements comprise approximately 500 mg of ferric citrate.
Table 7 provides a formulation for a ferric citrate tablet and/or oral iron supplement
according to one embodiment of the present disclosure:
Table 7. Formulation for a Ferric Citrate Tablet and/or Oral Iron Supplement
Theoretical
Materlal Descrlptlon. . . % w/w,
Ferric Citrate 14.89 87.6
Purified Water 1530* N/A‘
Core Tablet Total 17.00 100.0
Opadry Purple 03K100000 0.51 15.0
Purified Water 850*
Coated Tablet Total 100.0
55‘
, Purified water is removed during a drying phase in the lllanufacturing process
Table 8 provides a formulation for a ferric citrate tablet and/or oral iron supplement
according to one embodiment of the present disclosure:
Table 8:
Target Theoretical % w/w % w/w Coated
Material DescriPtion
kg/Batch 100 kg/Lot dual Tablet
Ferric e 14. 9 80.0 — 90.0 80.0 — 90.0 76.2 — 88.2
Plegelalini/ed Slalch — 8.0 , 15.0 8.0 , 15.0 7o , 14.7
calciulll Stealate (1) 1.0 , 3.0 1.0 , 3.0 0.9 , 2.9
OR— Sodium Stearyl 2.0 — 3.0 2.0 — 3.0 1.9 — 2.9
Fumalate (1)
ed Water 153* | 35.0=1= *
Core Tablet Total 17.90 | 100.0 100.0
Opadly Pulple 5.3 15.0
Purified Water - 8510* —
Coated Tablet Total 17.5 to 17.9 -. 100.0 100. 0
(1) 2 use either calcium stearate or sodium stearyl fumarate as lubricant
, Purified water is removed
Table 9 provides a formulation for a ferric citrate tablet and/or oral iron supplement
ing to one embodiment of the present disclosure:
Table 9:
Material Description I Target kg/Batch I % w/w Individual
Ferric Citrate 14.89 87.6
-0
Purified Water 15.30 N/A
Core Tablet Total 17. 00 100.0
.0
85-0
1000
Table 10 provides a formulation for a ferric citrate tablet and/or oral iron ment
according to one embodiment of the present disclosure:
Table 10:
al / ent Formula Composition % w/w
Ferric Citrate 70.0 to 99.0
Starch 0.0 to 30.0
Microcryslalline Cellulose 0.0 to 30.0
Polyvinylpyrrolidone 0.0 to 30.0
Calcium Stearate 0.0 to 3.0
Sodium Stearyl Furrrarate 0.0 to 3.0
Purified Water N/Ail‘
Core Caplet Total 1000
Film coating 0.0 to 5.0
Purified Water N/A’i
Coated Caplet Total 100.0
’i‘ The purified water is removed.
Table 11 provides a formulation for a ferric citrate tablet and/or oral iron supplement
according to one embodiment of the present disclosure:
Table 11:
Material Weight mg i 10%
1’erric (Titrate 1,500
Starch 1 50
Microcrystalline Celluose O
Polyvinylpyn‘olidone 0
Calcium Stearate 16
Sodium Stearyl l’umarate 0
Purified Water N/At“
Core Caplet Total - mg 1,666
Film coating 50
Purified Water N/A*
Coated Caplet Total - mg 1,766
* The purified water is removed.
Dosing
LA 'l‘he tablets and/or oral iron supplements disclosed herein can be made to
odate a number of doses of ferric citrate. The weight of individual s and/or oral
iron supplements can depend upon the final dosage to be produced; e. g., 125mg, 250mg,
500mg, 667mg, 750mg and 1,()()()mg of ferric e per tablet. In various aspects, the ferric
citrate is provided in a tablet dosage form comprising 1 gram of fen‘ic citrate containing
imately 210 mg of ferric iron. The number of tablets and/or oral iron supplements
administered can be adjusted to conform to the d amount of ferric citrate to be
stered. l’or example, if a (7K1) patient is directed to take 4 grams of ferric citrate daily
in a single dose, the CKD t may take 4 tablets and/or oral iron supplements, each
comprising 1 gram of ferric citrate, or may take 8 tablets and/or oral iron supplements, each
comprising 500mg of ferric citrate.
In some embodiments, a daily dose of ferric citrate administered to CKD patients can
be from 1 gram — 18 grams, at a dose of fen‘ic iron ranging from 210 mg — 3,780 mg. In some
embodiments, one or more tablets comprising 1 gram of ferric citrate, each tablet having a
dose of ferric iron of 210 mg, is/are administered to reduce and/or control serum phosphorus
levels, increase serum onate levels, improve one or more iron storage parameters (e.g.,
increase serum in levels, increase transferrin saturation (TSAT), increase hemoglobin
concentration) increase iron absorption, maintain iron stores, treat iron deficiency, treat
anemia, reduce the need for IV iron and/or reduce the need for erythropoiesis-stimulating
agents (ESAs) in CKD patients.
In some embodiments, the ferric citrate is administered at a daily dose of 1 tablet per
day, the tablet comprising 1 gram of ferric citrate containing 210 mg of ferric iron, for a total
daily dose of 1 gram of ferric citrate and 210 mg ferric iron. In some embodinrents, the ferric
citrate is administered at a daily dose of 2 tablets per day, each tablet comprising 1 gram of
ferric citrate containing 210 mg of ferric iron, for a total daily dose of 2 grams of ferric citrate
and 420 mg ferric iron. In sorrre embodiments, the ferric citrate is administered at a daily
dose of 3 tablets per day, each tablet sing I gram of ferric e containing 2 I0 mg of
ferric iron, for a total daily dose of 3 grams of ferric citrate and 630 mg ferric iron. In sonre
embodiments, the ferric citrate is administered at a daily dose of 4 tablets per day, each tablet
I0 comprising I gram of ferric citrate containing 210 mg of ferric iron, for a total daily dose of 4
grams of ferric e and 840 mg ferric iron. In some embodiments, the ferric citrate is
administered at a daily dose of 5 tablets per day, each tablet comprising 1 gram of ferric
citrate containing 210 mg of ferric iron, for a total daily dose of 5 grams of ferric citrate and
1,050 mg ferric iron. In some embodiments, the ferric citrate is administered at a daily dose
of 6 tablets per day, each tablet comprising 1 gram of ferric citrate containing 210 mg of
ferric iron, for a total daily dose of 6 grams of ferric citrate and 1,260 mg ferric iron. In sorrre
ments, the ferric citrate is stered at a daily dose of7 tablets per day, each tablet
comprising 1 gram of ferric citrate containing 210 mg of ferric iron, for a total daily dose of 7
grams of ferric e and 1,470 mg ferric iron. In some errrbodirnents, the ferric citrate is
administered at a daily dose of 8 tablets per day, each tablet comprising 1 gram of ferric
citrate containing 210 mg of ferric iron, for a total daily dose of 8 grams of ferric citrate and
1,680 mg ferric iron. In some ments, the ferric citrate is administered at a daily dose
of 9 tablets per day, each tablet comprising 1 gram of ferric citrate containing 210 mg of
ferric iron, for a total daily dose of 9 grams of ferric citrate and 1,890 mg ferric iron. In some
embodiments, the ferric citrate is administered at a daily dose of 10 tablets per day, each
tablet comprising I gram of ferric citrate containing 210 mg of ferric iron, for a total daily
dose of 10 grams of ferric citrate and 2, I00 mg ferric iron. In some embodiments, the ferric
citrate is administered at a daily dose of 11 tablets per day, each tablet sing 1 gram of
ferric citrate containing 210 mg of ferric iron, for a total daily dose of 11 grams of ferric
citrate and 2,310 mg ferric iron. In some embodiments, the ferric citrate is stered at a
daily dose of I2 s per day, each tablet comprising I gram of ferric citrate containing 210
mg of ferric iron, for a total daily dose of 12 grams of ferric citrate and 2,520 mg ferric iron.
In some embodiments, the ferric citrate is administered at a daily dose of 13 tablets per day,
each tablet, comprising I gram of ferric citrate containing 210 mg of ferric iron, fora total
daily dose of 13 grams of ferric citrate and 2,730 mg ferric iron. In some embodiments, the
ferric citrate is administered at a daily dose of 14 tablets per day, each tablet comprising 1
gram of ferric citrate ning 210 mg of ferric iron, for a total daily dose of 14 grams of
ferric citrate and 2,940 mg ferric iron. In some embodiments, the ferric citrate is
administered at a daily dose of 15 tablets per day, each tablet comprising 1 gram of ferric
citrate containing 210 mg of ferric iron, for a total daily dose of 15 grams of ferric e and
3,150 mg ferric iron. ln some embodiments, the ferric citrate is administered at, a daily dose
of 16 tablets per day, each tablet comprising 1 gram of ferric citrate containing 210 mg of
ferric iron, for a total daily dose of 16 grams of ferric citrate and 3,360 mg ferric iron. In
some embodiments, the ferric citrate is administered at, a daily dose of 17 s per day,
each tablet comprising 1 gram of ferric e containing 210 mg of ferric iron, for a total
daily dose of 17 grams of ferric citrate and 3,570 mg ferric iron. In some embodiments, the
ferric citrate is administered at a daily dose of 18 tablets per day, each tablet comprising 1
gram of ferric citrate containing 210 mg of ferric iron, for a total daily dose of 18 grams of
ferric citrate and 3,780 mg ferric iron.
EXAMPLES
The following example describes in detail the use of the ferric citrate disclosed herein.
It will be apparent to those skilled in the art that many modifications, both to materials and
methods, may be practiced without departing from the scope of the disclosure.
Example 1
A Three-Period, 58-Week Trial Of Ferric Citrate As A Phosphate Binder In Patients
With End-Stage Renal Disease (ESRD) On Dialysis
The primary objectives of this trial were as follows:
1. To determine the long-term safety over 52 weeks of up to twelve (12) caplets/day of
KRX—0502 (ferric citrate) in patients with end—stage renal e undergoing either
hemodialysis or peritoneal dialysis.
!9 To determine the efficacy of KRX-0502 (ferric citrate) in a four-week, randomized,
open—label, placebo—controlled Efficacy Assessment Period.
Study Rationale
Previous clinical trials have demonstrated the ability of ferric e to lower serum
orus levels in ts with ESRD who are on thrice-weekly alysis. These
trials used a maximum of approximately 12 g/day of ferric citrate for four weeks.
—70-
This clinical trial determined the long-term safety of ferric citrate in controlling and
managing serum phosphorus levels over a 56-week treatment period when compared to an
active control for 52 weeks in the Safety ment Period and to placebo in a randomized,
open—label, placebo—controlled four—week Efficacy Assessment Period.
Study Design
This trial was a three-period, multicenter, safety and efficacy clinical trial. The first
period was a two—week washout (the Washout Period), the second period was a 52—week
randomized, open-label, active control safety assessment (the Safety Assessment Period), and
the third period was a four-week, ized, open—label, placebo-controlled, efficacy
assessment (the lifficacy Assessment Period) in only patients randomized to treatment with
ferric citrate during the Safety Assessment Period.
Period 1 (Washout Period). Patients were washed out from their current phosphate
binder for up to approximately two weeks. Only patients who achieve a serum phosphorus
26.0 mg/dl. during the Washout Period were moved into the Safety Assessment Period.
Patients who did not achieve a serum phosphorus 26.0 mg/dL during washout were screen
failures.
Period 2 (Safety Assessment Period). l’ollowing washout, patients were randomized
2:1 to either the ferric citrate group or an active-control group of either calcium acetate,
sevelamer carbonate, or any combination of calcium e and sevelamer carbonate at the
discretion of the Pl and/or t. Both ferric citrate and the active—control medications were
provided by the sponsor. Patients were followed on their randomized assignment for safety
assessments over 52 weeks. If a patient was 2 80% ant with 12 caplets/day of ferric
citrate or 12 pills/day of m e and/or sevelanrer carbonate at least 2 visits in a row,
and had a serum phosphorus > 8.0 mg/dl., the patient was considered a treatment e and
stopped study drug but continued to complete all trial visits. The ferric citrate or activecontrol
drug was stopped and the patient returned to the care of their primary nephrologist,
but continued to be followed for all trial visits and outcomes.
Period 3 Efficac Assessment Period . ing the Safety Assessment Period,
those patients ized to ent with ferric citrate entered a eek, randomized,
open—label, placebo—controlled Efficacy Assessment Period. Patients entering the Efficacy
Assessment Period were re—randomized 1:1 to treatment with ferric citrate or o.
A Dietician provided a study-supplied list of Vitamin D-rich foods to the t
either during the Washout Period or at the Randomization Visit and instructed the patient to
keep their diet tent in Vitamin l)—rich food throughout the trial as much as possible.
Within 30 days before the start of the Efficacy Assessment Period, the Dietician again
reviewed the list of Vitamin D-rich foods with the t and reminded the patient to try to
keep their diet consistent in terms of Vitamin D-rich foods until the end of the trial, if
possible. The Dietician was blinded as to assignment to ferric e or placebo during the
Efficacy Assessment Period.
Laboratory measurements were ted throughout the study to assess safety and
efficacy. The dose and specific IV iron preparation administered (if necessary) were at the
discretion of the PI. Oral iron therapy was not permitted. m-containing drugs were not
permitted if given within two hours of food ingestion (calcium-containing drugs were
permitted two hours or more prior to or following food ingestion or at bedtime for the
purpose of raising the serum calcium). No Vitamin C supplements were permitted. Patients
were allowed to take daily water soluble vitamins that include a small amount of Vitamin C
(e.g., Centrum, Nephrocaps, Renaphro), but those patients were instructed to take them two
hours or more prior to or following food ion or at bedtime. IV iron therapy was not
permitted if the ferritin level is > 1000 micrograms/L or the TSAT is > 30%. If it was
deemed in the patient’s best interest to receive IV iron outside these parameters, the Clinical
Coordinating Center ((TCC) was consulted, and when ed and nted, was not
considered a protocol exception.
Study Duration
The duration of the trial was approximately 18 to 24 months, with approximately six
to eight months allocated for t Screening, Washout Period, and Randomization, 12
months for the Safety Assessment Period, and one (1) month for the Efficacy Assessment
Period.
Study Population
ESRD patients on -weekly hernodialysis or on peritoneal dialysis for at least
three months prior to the ing Visit (Visit 0) who were currently taking 23 and £18
pills/day ofcalcium acetate, calcium ate, lanthanum carbonate, and/or mer
(carbonate or hydrochloride or mer powder equivalent to sevelamer tablets), or any
other agent serving as a phosphate binder, or any combination of these agents were eligible
for enrollment. It was anticipated that there would be approximately 20 to 40 centers in the
United States and approximately 5 to 10 centers in Israel. Up to approximately 775 ts
were screened to randomize approximately 350 patients to the ferric Citrate group or active-
control group. Each of approximately 25 to 50 sites were asked to randomize no more than
approximately 35 patients.
Inclusion criteria:
Males or non-pregnant, non-breast-feeding females
Age 2 18 years
On thrice—weekly alysis or on peritoneal dialysis for at least the previous three
months prior to ing Visit (Visit 0)
Serum phosphorus levels 325 mg/dL and :80 mg/dL at Screening Visit (Visit 0)
Serum phosphorus 36.0 mgde during the Washout Period (Visits 2 or 3)
Taking 3 to 18 pills/day of calcium acetate, calcium carbonate, lanthanum ate,
and/or sevelamer (carbonate or hydrochloride or equivalent sevelamer powder) or any
I0 other agent serving as a phosphate binder, or any combination ol‘ these agents as
reported by the patient at Screening Visit (Visit 0)
Serum ferritin <1000 micrograms/L and TSAT < 50% at the Screening Visit (Visit 0)
Willing to be discontinued l‘rom current phosphate binder and randomized to l‘erric
citrate or active—control group
Willing and able to give informed consent
Life expectancy >1 year
Exclusion Criteria:
Parathyroidectomy within six months prior to ing Visit (Visit 0)
Actively symptomatic gastrointestinal bleeding or inflammatory bowel e
Serum phosphorus levels 310.0 mg/dL documented in all ol‘ the three monthly
laboratories (done routinely in the dialysis unit) in the 3 months prior to the Screening
Visit (Visit 0)
History ol‘ 111alignancy in the last live years (treated cervical or non—melanomatous
skin cancer may be permitted if approved by the CCC)
Absolute requirement for oral iron therapy
Absolute requirement for Vitamin C vitamins ocaps, Renaphro, etc]
allowed)
Absolute requirement for calcium-, magnesium-, or um-containing drugs with
meals
Intolerance to oral iron—containing products
Intolerance to orally administered m acetate and sevelamer carbonate
Study Drug
KRX-0502 (ferric citrate) was the drug under igation in this study. The drug
was administered as caplets, each caplet, comprising 1 gram (1,000 mg) of ferric citrate
containing approximately 210 mg of ferric iron.
Study Drug Administration
The target goal for serum phosphorus was 3.5 to 5.5 mg/dL.
lt‘erric citrate, active control, and placebo were considered study drugs. liligible
patients with a serurrr phosphorus level /dL after the Washout Period were
randomized in a 2:1 ratio to the ferric citrate group or the active-control group. For patients
ized to ferric citrate, the starting dose was 6 caplets/day. For patients randomized to
the active—control group, the starting dose of phosphate binder was the last dose that was
administered immediately prior to the start of the Washout Period (if the t remained on
the same phosphate binder) or at the discretion of the PI, guided by the package insert, if the
patient, changed binders. However, for patients whose previous dose of phosphate binder
exceeded 12 day, if ized to the active-control group, their starting dose of active-
control drug was at the discretion of the PI, but will not exceed 12 pills/day. Calcium e
667 mg capsules and sevelamer carbonate 800 mg tablets were used and were supplied by
Keryx Biopharmaceuticals, Inc. (Keryx) for the duration of the trial.
Serum phosphorus and calcium were checked at Visit 5 (Week 1), and every two
weeks during the first 12 weeks after Visit 4 mization Visit), and monthly for the rest
of the Safety Assessment Period. During the Efficacy Assessment Period, serum phosphorus
and calcium were drawn weekly. These values guided study drug administration. While on
study drug, the use of other ate binders was not ted. Dose adjustments in ferric
citrate were guided by a titration schedule. The titration of calcium e and sevelamer
carbonate throughout the 52—week Safety Assessment Period were according to the current
package inserts for these agents and/or at the discretion of the site PI.
Patients took study drug orally with or within one hour of meals or snacks. Patients
were instructed not to take the study drug if greater than one hour has passed since the
ingestion of their meals or snacks. The P1 or ee at each site dispensed the study drug to
the patient and instructed the patient on how to administer it. It was recognized that some
patients required a different distribution in pills in a given day due to snacks or missed meals.
If the t was receiving the total number of pills per day required by protocol in any
distribution with meals, there was no need for approval by the CCC (for example, a patient on
asMfihg<kmeofRnnnnUMe6gkhynwytdwlampktwnhbmahha,lwfihasnmk,2
with lunch, and 2 with dinner).
laboratory Assessments
l“or patients on hemodialysis, blood samples were ed pre—dialysis on the second
or third dialysis session of the week, if possible. For patients who are on hemodialysis who
dialyze on , Wednesday or Friday, all blood samples were drawn pre-dialysis on
Wednesday or l’riday, if possible. For patients who dialyze on Tuesday, Thursday or
Saturday, all blood samples were drawn pre-dialysis on Thursday or Saturday, if le.
UmwcdkamnmdmflswaembwaHOMKMEmmflnmwsmlflwlThumdammmmfi
blood collected from each patient for trial—related analyses was approximately 15 ml per visit.
For patients who were on peritoneal dialysis, blood s were collected either at
the dialysis unit or the clinic as per the study protocols.
SmumrMoqmonmandcmcmniwemrmflbnnahnScmemng(VEHOP\mmkW(mnng
the Washout Period after Visit 1 (Week —2); at Visit, 4 (Randomization ; at Visits 5
(Week 1), 6 (Week 2), 7 (Week 4), 8 (Week 6), 9 (Week 8), 10 (Week 10), 11 (Week 12), 12
(Week 16), 13 (Week 20), 14 (Week 24), 15 (Week 28), 16 (Week 32), 17 (Week 36), 18
(Week 40), 19 (Week 44), 20 (Week 48), and 21 (Week 52) of the k Safety
Assessment Period; and at Visits 22 (Week 53), 23 (Week 54), 24 (Week 55) and 25 (Week
56) of the Efficacy Assessment Period.
Complete Blood Count (CBC) (white blood cell [WBC] count, white blood cell types
[WBC ential], red blood cell [RBC] count, crit [llC'l‘], hemoglobin [11gb], red
blood cell indices, platelet [thrombocyte] count) was done at the Randomization Visit (Visit
4); at Visits 11 (Week 12), 14 (Week 24), 17 (Week 36), 20 (Week 48), and 21 (Week 52) of
the 52—week Safety Assessment Period; and at Visit, 25 (Week 56) of the lifficacy Assessment,
Pernad.
Complete Chemistry Profile (sodium, potassium, chloride, blood urea nitrogen
(BUN), creatinine, e [random], aspartate aminotransferase ], alanine
aminotransferase [ALT], alkaline phosphate [ALP], total bilirubin, total protein, albumin, and
albumin-adjusted calcium) was done at the Randomization Visit (Visit 4); at Visits 11 (Week
12), 14 (Week 24), 17 (Week 36), 20 (Week 48), and 21 (Week 52) of the 52—week Safety
Assessment Period; and at Visit 25 (Week 56) of the lil‘l‘icacy Assessment Period.
Iron studies including serum iron, ferritin, TSAT, and total iron—binding capacity were
done at Screening (Visit 0); at the Randomization Visit (Visit 4); at Visits 7 (Week 4), 9
(VVeek.8) ll(\Veek.l2),12(\Neek.16),13(XNeek.20),14(XNeek.24),15(XVeek.28),l6
(Week 32), 17 (Week 36), 18 (Week 40), 19 (Week 44), 20 (Week 48), and 21 (Week 52) of
the 52-week Safety Assessment Period; and at Visit 25 (Week 56) of the Efficacy Assessment
Period.
lntact parathyroid hormone (iP'l‘ll) levels were done at the Randomization Visit (Visit,
4); at Visits 11 (Week 12), 17 (Week 36), and 21 (Week 52) during the Safety Assessment
Period; and at Visit 25 (Week 56) of the Efficacy Assessment Period.
Serum vitamins (25—dihydroxy—vitamin D3, vitamin A, vitamin B— 12, vitamin If,
vitamin K, and folic acid) were done at the Randomization Visit (Visit 4,); and at Visits 11
(Week 12), 17 (Week 36), and 21 (Week 52) during the Safety Assessment Period.
A lipid profile (total cholesterol, nsity lipoprotein IliDlil, high—density
lipoprotein [HULL and triglycerides) was done at the Randomization Visit (Visit 4); at Visits
11 (Week 12), 17 (Week 36), and 21 (Week 52) during the Safety Assessment Period.
Serum aluminum was done at the Randomization Visit (Visit 4) and at Visit 21 (Week
52).
Serum bicarbonate was performed at a local laboratory and was done at the
Randomization Visit (Visit 4); at Visits 11 (Week 12), 14 (Week 24), 17 (Week 36), 20
(Week 48) and 21 (Week 52) during the Safety Assessment Period; and at Visit, 25 (Week 56)
of the Efficacy Assessment Period.
Except for serum bicarbonate, which was collected and measured locally, all labs
were med by Spectra Clinical Research, igh, NJ, USA.
Statistical Considerations: Efficacy
Unless otherwise stated, all hypotheses were tested at a d significance level of
0.05 and the 95% confidence interval was two-sided. All analyses were performed using
SAS Version 9.
Prior to the se lock, a detailed Statistical is Plan (SAP) was completed
and placed on file. The Data Analysis Plan contained a more hensive explanation
than described below of the ology used in the tical analyses. The Data Analysis
Plan also contained the rules and data handling conventions used to perform the analyses, and
the procedure used for accounting for missing data.
Summary tabulations yed the number of observations, mean, standard deviation,
median, minimum, maximum, and appropriate percentiles for continuous variables, and the
number and percentage by category for categorical data. Summaries present data by
treatment arm and overall, if appropriate. The data listings include all available efficacy and
safety data.
The efficacy analyses were based on Full is (FA) population that consisted of
all patients who took at least one dose of study medication and provided baseline and at least
one post—baseline efficacy assessment. The safety analyses were based on safety population
that was tent of all patients who took at least, one dose of study medication.
There were two unique and distinct baseline assessments. The baseline for the Safety
Assessment Period was the Randomization Visit (Visit 4) and was defined as “Week
baseline.” The baseline for the Efficacy Assessment, Period was the last visit of the Safety
Assessment Period (Visit 21, Week 52) and was defined as “study-baseline.”
The primary efficacy outcome of this trial was the effect of ferric citrate vs. placebo
on the change in serum phosphorus from study—baseline (Visit 21, Week 52) to end of the
Efficacy Assessment Period (Visit 25, Week 56). The primary efficacy variable was
ed via an ANCOVA model with treatment as the fixed effect and baseline as the
covariate. Between—treatment differences were estimated and two—sided 95% confidence
intervals for the differences were presented.
The secondary endpoints for this trial include the following:
1. CHANGE FROM BASELINE IN FERRITIN AT WEEK 52
Change from baseline in ferritin at Week 52 as compared to baseline (Visit, 4). This
variable will be analyzed using LOCF methodology. ANCOVA will be ed. The
model will include treatment (fixed effect), and baseline (covariate). A sensitivity analysis
will be performed using MMRM method.
2. CIIANGE PROM BASELINE lN TSAT AT WEEK 52
Change from baseline in TSAT at Week 52 as compared to baseline (Visit 4). This
variable will be ed using LOCF methodology. ANCOVA will be employed. The
model will include ent (fixed effect), and baseline (covariate). A sensitivity is
will be performed using MMRM .
3. CUMULATIVE USE OF IV IRON OVER 52 WEEKS
The cumulative IV iron intake from randomization to Week 52 will be compared
between ent groups. This variable will be similarly analyzed as the y efficacy
variable using ANCOVA method. The two-sided 95% confidence intervals of treatment
differences for all above comparisons will be presented.
4. CUMULA'I‘IVE USE ()l“ EPO (ESA) OVER 52 WEEKS
The cumulative EPO (ESA) administrated from ization to Week 52 will be
compared between treatment groups. This variable will be similarly analyzed as the primary
efficacy variable using ANCOVA method. The two—sided 95% confidence intervals of
treatment differences for all above isons will be presented.
Treatment differences between ferric citrate and all active control binders as well as
the differences between ferric citrate and sevelamer carbonate as a single agent, at Week 12
(Visit 11) in terms of change from Visit-4 baseline in serum phosphorus, phosphorus times
calcium product, and in serum m will be analyzed. These variables will be analyzed
using LOCI“ methodology. ANCOVA will be employed. The model will include treatment,
(fixed effect), and Visit-4 baseline (covariate). An analysis using MMRM method will be
ted as a sensitivity analysis. The least square mean estimates of the treatment s
as well as the 2—sided 95% confidence intervals (CI) of the treatment effects will be derived.
Non—inferiority will be claimed if the lower—bound of the two—sided 95% confidence interval
of the treatment difference is within 20% of least square mean of the control.
. PERCENTAGE OF PATIENTS ACHIEVING ORUS GOAI.
tage of patients achieving phosphorus goal (35.5mg/dl.) at Weeks 12, 24, 36, 48,
52 and 56 — These variables will be analyzed via chi-square tests. Between-treatment
differences in the percentages will be estimated and two-sided 95% confidence intervals
for the differences will be calculated using normal approxirrration without, continuity
correction.
!Q Percentage of patients achieving the phosphorus goal (35.5mg/dL) at Week 56 for
patients remaining on study medication during the four—week Efficacy Assessment Period
2 These variables will be analyzed via chi—square tests. Between—treatment differences in
the percentages will be estimated and two-sided 95% confidence als for the
differences will be calculated using normal approximation without continuity correction.
L») Percentage of patients obtaining a serum phosphorus 2 9.0mg/dl. at any time during the
four-week Efficacy Assessment Period — These variables will be ed via chi—square
tests. Between-treatment differences in the percentages will be estimated and two-sided
95% confidence als for the differences will be calculated using normal
approximation without uity tion.
6. CHANGE IN SERUM PHOSPHORUS CONCENTRATION
Change in serum phosphorus concentration at Weeks 12, 24, 36, 48, and 52 as ed
to baseline (Visit, 4). This variable will be analyzed using LOCI“ odology.
ANCOVA will be employed. The model will include ent (fixed effect), and
ne (covariate).
7. CHANGE IN OTHER LABORATORY MEASURES
Change in serum calcium concentration at Weeks 12, 24, 36, 48, and 52 as compared to
baseline (Visit 4). This variable will be analyzed using LOCF methodology. ANCOVA
will be employed. The model will include treatment (fixed effect), and baseline
iate).
!\.) Change in ferritin, and TSAT at Weeks 12, 24, 36 and 48 as compared to ne (Visit
4). This variable will be analyzed using LOCI“ methodology. ANCOVA will be
employed. The model will include treatment (fixed effect), and baseline (covariate).
Change in serum iron and TIBC at Weeks 12, 24, 36, 48, and 52 as compared to baseline
ll) (Visit 4). This variable will be analyzed using LOCI" methodology. ANCOVA will be
employed. The model will include treatment (fixed effect), and baseline (covariate).
Change in Ca x P product at Weeks 12, 24, 36, 48, and 52 as compared to baseline (Visit
4). This variable will be analyzed using LOCF methodology. ANCOVA will be
employed. The model will include ent (fixed effect), and baseline iate).
U] Change in iPTH at Weeks 12, 36, 52, and 56 as compared to ne (Visit 4). This
le will be analyzed using LOCF methodology. ANCOVA will be employed. The
model will include treatment (fixed effect), and baseline (covariate).
Change in serum 25-dihydroxy-Vitamin D3, vitamin A, vitamin B—12, vitamin E, Vitamin
K and folic acid at Weeks 12, 36, and 52 as compared to baseline (Visit 4). This variable
will be ed using LOCF methodology. ANCOVA will be employed. The model
will include treatment (fixed effect), and baseline (covariate).
Change in serum bicarbonate concentration at Weeks 12, 36, and 52 as ed to
baseline (Visit 4). This le will be analyzed using LOCF methodology. ANCOVA
will be employed. The model will include treatment (fixed effect), and baseline
(covariate).
Change in IV iron intake at Weeks 12, 24, 36, 48, and 52 as compared to baseline (Visit
4). This variable will be analyzed using LOCI“ methodology. ANCOVA will be
employed. The model will include treatment (fixed effect), and baseline (covariate).
Change in the use of EPO (ESA) administered at Weeks 12, 24, 36, 48, and 52 as
compared to baseline (Visit 4). This variable will be analyzed using LOCF methodology.
ANCOVA will be employed. The model will include treatment (fixed ), and
baseline (covariate).
. Change in the use of Vitamin D mentation (and its analogs) and Sensipar
(cinacalcet) at Weeks 12, 24, 36, 48, and 52 as compared to baseline (Visit 4). This
variable will be analyzed using LOCF methodology. ANCOVA will be employed. The
model will include treatment (fixed effect), and baseline (covariate).
1 1. Change in IDL, HDL, and triglycerides at Weeks 12, 36, and 52 as compared to baseline
(Visit 4). This variable will be analyzed using LOCI" methodology. ANCOVA will be
employed. The model will include treatment (fixed effect), and baseline (covariate).
Statistical Considerations: Safety
Safety was assessed by recording and monitoring adverse events, concomitant
medication use, al examinations, and sequential blood by treatment assignment. Rates
of e events were ized overall and by organ system class, preferred term,
severity, and suspected onship to study drug by treatment assignment. Alis were
summarized for the Washout Period, Safety Assessment Period, and Efficacy Assessment
Period separately by treatment assignment. The changes from baseline in laboratory
parameters over time were summarized by treatment assignment.
Statistical Considerations: Power
imately 434 patients were randomized in a 2:1 ratio to either ferric e
(approximately 288 patients) or active—control (approximately 146 patients), to be treated
during the Safety ment Period. This sample size provided at, least 90% power to detect
a ent difference between ferric citrate and placebo at a 5% significance level, assuming
that the treatment difference is 1.2 and the common rd deviation is 2.
Results
Summary of Treatment Differences in Serum Phosphorus, orus times Calcium
Product and Serum Calcium Change from Study-baseline at Week 12 between Ferric Citrate
and Sevelarner Carbonate as a Single Agent (ANCOVA Method), Full Analysis Population —
shown in Table 12:
Table 12:
KRX—0502 in Safety Sevelamer Carbonate in Safety
Assessment Period Assessment Period Treatment
Statistics (N=288) (N=73) Differences[l]
Phosphorus (MG/DL)
X 277 "2
Mean (SD) “.337 (1.557) 7.3: 2.633)
lel»m /.’/U '.’-U
(Vim, Mix) :2./, Myst (as, 1733}
Wee< :2
X 277 22
learn (SD) 7R (1.374) E 2” r 713)
Xedian 5.10 3.30
”Airs, Max) 71.4, ‘7.‘7) (2.7, ’14.1)
KRX—0502 in Safety Sevelamer Carbonate in Safety
Assessment Period Assessment Period Treatment
Statistics (N=288) (N=73) Differences[1]
Week 12 Change fISY Baseline
(70.21, C E4)
0.16 (0.1?)
0.3906
Product Of Calcium And
Phosphorus
277 72
(SD) 65.e075 (15.47697‘ 68.0872 (16.29263)
edian 62.7000 0
' Max) (23.920, 123.210) (39.9:s, 123.840)
Week 12
N 277 72
Mean (SD) 0 (12.93765‘ : (14.36518)
Median 47.5000 45.2800
(Min, Max) (2;.440, 92.650) (22.50;, 109.980)
Week :2 Change fro? 3ase1ine
M 2//
Mean (SD) 716.9’ q
(16.97535)
Median 716.7400
(Min, Max) 60, 42.700
CI fie7.47, 50.48)
Mean (SE) 42.97 (0.77)
*Veva1ue
Calcium (MG/DL)
278 72
3.843 (0.8048) 9.056 (0.7291)
8.900 ".150
(Min, Mix) (6.30, 11.10) 10.10)
Week 12
N 278 72
Mean (SD) 3.089 (0.7568) 9.251 (0.7210)
Median 9.100 3.400
(Min, Max) {6.30, 12.00) (7.0;, 10.60)
Wr‘r‘k "/1 tilmtutw [rim ~1r‘h1 110‘
N 2/8
Mean (SD) 0.245 (0.7486)
Median 0.200
(Min, Max) 72.80, 3.00)
A * CI ’9.04, 9.19)
Mean (SE) 3.11 (0.04)
J’VilUQ
Note: I l ].'l‘he LS Mean treatment difference and pavalue for the change in Serum Phosphorus, (‘21 x l) and (‘21 is
created Via an ANCOVA model with treatment as the fixed effect and Day—0 baseline as the covariate.
Between—treatment differences are calculated as the LS Mean (KKK—0502) — LS Mean (Control). Only subjects
with both a baseline and post baseline observations for the ter of interest were included.
Summary of Mean Serum Phosphonis Values at Weeks 12, 24, 36, 48, and 52 and
Change from baseline by Treatment A Method), Full Analysis Population —
shown in Table 13:
Table 13:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[1]
Day 0 Baseline
N 277 144
Mean (SD) 7.39 ) 7 55 (1.750)
Median 7.20 7.40
(Min, Max) (2.7, 12.3) (4 3, 12 9)
Week 12
N 277 144
Mean (SD) 5 38 (1.374) E 34 )
Median 5.10 5.05
(Min, Max) (2.4, 9.9) (2 5, 14.1)
Week 12 Change from Baseline
277 144
(SD) 72.01 (1.887) ,2 21 (2 086)
72 00 72.25
Max) (7 6, 4.6) (78 9, 6 7)
(70.23, 0.36)
0.07 (0.15)
0.6594
Mean (SD) 5.24 (1.455)
Median 5.10
(Min, Max) (1.3, 10.7)
Week 24 Change from Baseline
N 277
Mean (SD) 42.14 (1.844)
Median 2.10
(Min, Max) 47.5, 3.9)
95% C1 (5.08, (70.51, 0.08)
LS Mean (SE) ..26 (0.09) 70.21 (0.15)
0.1510
Week 36
277 144
Mean (SD) 5.22 (1.348) 5 32 (1.557)
Median 5.10 5 '0
(Min, Max) (1.1, 9.5)
Week 36 Change from Baseline
N 277 144
Mean (SD) 72.16 ) 72.24 (2.037)
Median 42.10 72.10
(Min, Max) (7.4, 3.2) 0 f
.40) m,\ 35% C1 (5.08, fl (J1 m
LS Mean .0.“:JH
(SE) ..24 (0.08)
Mean (SD)
Median
(Min, Max)
Week 48 Change from Baseline
N 277 144
Mean (SD) 72.07 (1.828) 72.07 (2.036)
Median 72.10 71.90
(Min, Max) (77.8, 6.7)
3.3 Cl (5.22, 5.69) (70.42, 0.17)
LS Mean (SE) 5.40 (0.12) 70.12 (0.15)
Jevalue 0.4086
Week 52
Mean (SD)
Median
-82—
KRX—0502 in Safety Control in Safety
ment Period Assessment Period
Statistics (N=288) (N=l46) Treatment Differences[1]
Max) (1.1, 10.7) (2.6, 14.1)
Week 5? Chanqe fron :aseline
N y// (J
' (SD) 74 0? (1.834) 74.1” :z.zzu)
an 72.20 72 10
, Max) (77.1, 3.7) (79.5, 6.7)
C1 (5.16, 5.51) (5.10, 5 58) (70.30,
ean (SE) 5 33 (0.09) 5 34 o 12) 70.01
alue 0.“
Note: [1']. The LS Mean treatment difference and pivalue for the change in in is created Via an ANCOVA
model with treatment as the fixed effect and Day—O ne as the covariate. Between—treatment differences are
calculated as the LS Mean (KRX—OSOZ) — LS Mean (control).
Only subjects with both a baseline and post baseline ations for the parameter of interest were included.
Summary of Mean Serum Phosphoms Values and Change from Week-SZ-baseline by
Treatment and Visit during the Efficacy Assessment Period (ANCOVA Method), Full
Analysis tion 7 shown in Table 14:
Table 14:
KRX—0502 in
Efficacy Placebo in
Assessment Efficacy
Period Assessment Period
Statistics (N=92) (N=9l) Treatment Differences[l]
(1 efi:
Min, Max‘ 8.
L‘JDDK ‘U‘x
Week
72.13, 71.32)
71 .fiE (0.21)
<;.0001
Teek 54 Change from Baseline
thn (SL‘
(Nil/H1
(Min, Mex‘
95% C1
as Mean 5 E)
pivalue
Teek 55
KRX—0502 in
cy Placebo in
Assessment Efficacy
Period Assessment Period
Statistics (N=92) (N=91) Treatment Differences[l]
pan (st 4.79 (1.93? (3-9“ (1-59”:
Vii‘iil/lll /l.(lU /.UU
(Min, Max‘ (2.8, 9.5} (2.7, 10.5‘
eek 55 Change from Baseline
ean (5P 70.41 (1.44:
edian 70 50
(thn, Mm (“.j, 4.41
““ i‘[ (4.4“, l 0«
4 76 (0 14
85 82
ean (:L\ 4 32 (1.322“ 7 :4 (1,8,2
Vi! llll /( (‘0 /’/‘V
(Mil, Mix) (2 3, l (5 0, 10 r
Tfeek 56 Change from Baseline
85 82
ean (SE9 70.23 , 1.99 (1.923?
edian 70.50 2.20
(Min, Maxf (72.9, 4.4T (72.7, 4’ V
in (mm, myc‘ («mtg '/.~:~ ('2. '«., 1.217}
1:1 Mean (53‘ 4.94 9 /.22 (0.1" 72.26 (0.23}
devalue <L . 0001
Note: [1]. The LS Mean treatment difference and p—Value for the change in Seium Phosphorus is created Via an
ANCOVA model with treatment as the fixed effect and Week—52 baseline as the covariate. Between—treatment
ences are calculated as the LS Mean (KRXrOSOZ) 7 LS Mean (Placebo). Only subjects with both a
baseline and post baseline observations for the parameter of st were included.
Summary of Mean Ferritin at Weeks 12, 24, 36, 48, and 52 and Change from Study-
baselinc by 'l‘reat1nent(/\NC()V/\ Method), l’ull Analysis Population 7 shown in Table 15:
Table 15:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[l]
L ay 0 Lasoiino
l 249 134
lean (SD) 335.00 (293.894? 615.76 (302 9‘42)
ledian 587.00 574.’
(Min, Max,l ’22.0, 1612.0? (11.0, 12,7
Week 24
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[1]
ean (SD) 846.90 (414.672) 658.44 (301.698
edian 830.00 675.0;
(Min, Max) {91.0, 2413.0) (11.0, )
Weex 24 Change frcm Baseline
ean (SD) 232.49 (326.299
edian 220.00
(Min, Max) (7628.0, 1594.0
95% CI {814.24, 890.79
.8 Mean (SF) 352.52 )
a V :1 1 u r),
Weex 56
ean (SD) 863.18 (444.094
edian 818.00
(Min, Max) {51.0, 3181.0)
Weex 36 Change fr:m baseline
247 13
ean (SD) 268.77 92‘ 20 20 (
edian 223.00 11.
(Min, Max) (7754.0, 2193 0) 0,
95% CI .50, 912.72) (566.30, (135 99, 316.49
1S Me:n (SE) 8 11 (22 38‘ 626.87 241 24 (38.27)
leHfl :U.0001
Weex 48
247 134
ean (SD) T?2.10 (461.772‘ 626.63 (3
edian 850.00 597
(Min, Max) {44.0, 3188.0) (84.0,
WWW dfltflwngv H‘"ih«WWlHfl
247 134
ean (SD) 257.69 (395.752‘ 10.87 (352 066)
edian 233.00 13.50
(Min, Max) (7667.0, 2032.0) (71184.0, 1409.0)
95% CI {840.95, 933.86) (553.76, , (132.20, 348.93)
IS Mean (SE) 887.41 (23.53) 616.85 27(.56 (39.85)
Vivaine :0.0001
Weex 52
ean (SD) 837.12 (485.296‘ 625.30 _,.
edian 858.00 576.0V
(Min, Max) {44.0, 3144.0) (33.0, 1783.0)
ka 52¥Mamw~frmifmwflinv
249 1’
ean (SD) 302.11 (435.183‘ 9.54 (360
edian 224.00 21
(Min, Max) (7785.0, 2032.0‘ .0,
95% CI (852.25, 951.66) (548.54, (2;1.58, 369.7D
IS Mean (SE) 301.95 (25.28) 616.31 285.65 (42.76)
:evalue <0.0001
Note: [l]. The [S Mean treatment ence and pivalue for the change in l’erritin is created via an AN(‘()VA
model with treatment as the fixed effect and Day—O baseline as the covariate. Between—treatment differences are
calculated as the LS Mean (KRX—OSOZ) — LS Mean (control).
Only subjects with both a baseline and post baseline observations for the parameter of interest were included.
Summary of Mean TSAT at Weeks 12, 24, 36, 48, and 52 and Change from Study-
baseline by Treatment (ANCOVA ), Full is Population — shown in Table 16:
Table 16:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[l]
Day 0 ne
244 131
ean (SD) 31.0 ) 31.0 (11.75)
edian 29.5 29.0
(Min, Max) (10, 83) (10, 73)
Week 12
V :38 131
ean (SD) 40.2 (16.00) 31.4 (12.13)
edian 37.0 29.0
(Min, Max) (12, 85) (10, 79)
Week 12 Change from Baseline
238 131
ean (SD) 9 2 (17 95) 0.5 (15.91)
edian 7.0 1.0
(Min, Max) (761, 62) (754, 51)
95% C1 , 42.03} (28.92, 33.94) (5 ’1, 11.87
is Mean (SE) 40.17 (0.95) 31.43 (1.28) 8 74 (1.59)
pevalue 1
Week 24
242 131
ean (SD) 39 9 (15.52) 31.6 (11 96)
edian 38.0 29.0
(Min, Max) (13, 92) (11, 79)
Week 24 Change from Baseline
242 131
ean (SD) 8.9 (17.49) 0 6 (15.40)
edian 7.0 0.0
(Min, Max) (,43, 63) (752, 43)
95% C1 (38.11, 41.70} (29 18, 31 06) (5.25, 11.31
is Mean (SE) 39.90 (0.91) 31 62 (1 24) 8.28 (1.54)
pevalue <0.0001
Week 36
ean (SD) 30.4 (10.88)
edian 28.0
(Min, Max) (13, 67)
Week 36 Change from Baseline
242 131
ean (SD) 8.8 (17.47) 70.6 (14.99
edian 7.0 71.0
(Min, Max) ( 57, 63) ( 45, &0)
95% C1 (38.03, 41.57} (27.95, 32.76) (6.45, 12.43)
is Mean (SE) 39.80 (0.90) 30.36 (1.22) 9.44 (1.52)
pevalue <0.0001
Week 48
242 131
ean (SD) 40 6 (16 94) 29.4 (10.7D
.dian 38.0 28.0
(Min, Max) (13, 86) (10, 74)
Week 48 Change from Baseline
242 131
ean (SD) 9.6 (19.25) 71.5
edian 7.0 7
(Min, Max) (745, 67) (748,
95% CI (38.71, 42.49} (26.85 (7.97, 14.37
Mean (SE) 40.60 (0.96) 29.43 11.17 (1.62)
pevalue <0.0001
Week 52
244 131
ean (SD) 39.4 (16.81) 29.7 (11.49
edian 35.0 28.0
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=l46) Treatment Differences[1]
(Min, Max) (7, 88) (10, 72‘
fieek 52 Chanqe fram Fa9e1ine
N 7’14 13'
Mean (SD) 8.3 (17.97} 71.3 (14.34
Median 6.0 0.;
(Min, Max) (760, 62) (e 3, e2)
95% C1 (37.48, 41.23 (27 14, 22.25) _€.49, 12.83)
LS Mean (5; 39.35 (0.,5) 29.69 (1.30) 3.66 (1.61)
pevalue <0.0001
Note: [1']. The 1.8 Mean treatment difference and pevalue for the change in Ferritin is created Via an ANCOVA
model with treatment as the fixed effect and Day—O baseline as the ate. Between—treatment differences are
calculated as the LS Mean (KRX—OSO2) — LS Mean ol).
Only subjects with both a baseline and post baseline observations for the parameter of interest were ed.
Summary of Mean Hemoglobin at Weeks 12, 24, 36, 48, and 52 and Change from
Study—baseline by Treatment (ANCOVA method), Full Analysis Population — shown in Table
Table 17:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
tics ) (N=146) Treatment Differences[1]
7ay 0 f~w<~1 im‘
/ /1/1 13
ean (SD) 11.61 (1.21: 11.72 (A 26F)
edian 11.45 11.7-
(Min, Max) (8.7, 15 R (8.7, 1: 7)
eek 12
231 122
wan (Sh) 11.”? (1.37" 11.5% ( .kéflfl
,edian 11.70 11.1“
(Min, Max) (7.5, 17.4 (6.7, 14.“
eek 12 Change fzom Baseline
ean (SD)
Qd11n
(Mi 1), Max
)5» Ci
is Mean (tT
Lek 24
241 13s
flan (5‘11) 11.55 (1.40“ 11./17 (7.755)
(”Ii-1411) 11.'§U 11./-.
(Min, Max? (6.6, 17.3? (9.2, if.4)
eek 24 Change fram Baseline
ean (SD) 70.08 (1.40?
edian 70.10
(Min, MAXI ( «.1, 3,Hj
“Ni 1% (11.41, 11.
. “.14, U.1R)
is Mean (57‘ 11.56 (O.U~ ;.12 (0.13)
wivalue 0.3756
Teek 36
241 13;
ean (SD) 11.54 (1.432) 11.31 (1.205)
Wwdiiri 11.7U 11.?“
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=l46) Treatment Differences[1]
(Min, Max? (8.6, 17.4? (8.9, 14.9)
Tfeek 36 t'ihfinqe :‘V'rvm Flaseline
74l 130
ean (SD) 70.08 (l.
edian 70.10 0._,
(Min, Max) (75.1, 3.3” (73.8, e.6)
95% CI (11.39, 11.7: , 3.50) _;.00, 0.54)
is Mean (’5; 11.55 (0.08) 11.28 (0.11) ;.27 (0.14)
e 0.0482
”wk 4;:
241 130
ean (SD) 11.50 (1.502‘ 11.25 (1 2‘3"»)
edian 11.20 11.1;
(Min, Max? (6.7, 18.2? (7.9, i .1)
T'Teek 4‘8 Change from Baseline
will (:JLJ.‘
edian
(Min, Max.“ . .,:
95% CI (11.35, 11.<:? ’;.03, 0.58)
is Mean ('5; 11.52 (0.06) 11.21 (;.11) ;.30 (0.14)
e 0 . 0322
rpk ‘/
244 13:;
ean (SD) 11.42 (1.474‘ 11.11 (1.403)
edian 11.20 11.00
(Min, Max? (8.3, 16.6? (7.1, 13.3)
T'Teek .52 Change from Baseline
2/14 17.“
(‘JH (Hit) 0.70 ( .il'fl‘ 0.61 ('."?9l)
edian 0.20 0.7
(Min, Max? (73.9, 3.7 (74.9,
95% CI (11.27, 11.60‘ (10.85, ’;.09, 0.64)
is Mean ('5: 11.44 (0.08‘ 11.07 (0.11) ;.36 (0.14)
devalue 0.0105
Note: [1]. The LS Mean treatment difference and prvalue for the change in in is created Via an ANCOVA
model with ent as the fixed effect and Day/70 baseline as the covariate. Betweenetreatment differences are
calculated as the LS Mean (KRX—OSOZ) — LS Mean (control).
Only ts with both a baseline and post baseline observations for the parameter of interest were included.
Sunnnaiy of Mean Serum Bicarbonate Concentration at Weeks 1’)A, _"’4, 36, 48 and 52
and Change from Study-baseline by Treatment (ANCOVA Method), Full Analysis
Population — shown in Table 18:
Table 18:
KRX—0502 in
Safety Assessment Control in Safety
Period Assessment Period Treatment
Statistics (N=288) (N=l46) Differences [1]
i‘ty f) i t ll t
N '/‘l/l t
Mean (:t 23 92 (3 4;?
Median 24 00
(Min, Max (13 0, 34 L
Week 12
N 190 1;,
MN til (:711.‘ Watt") (1 /t .2“ ’Z‘JlRl)
KRX—0502 in
Safety Assessment Control in Safety
Period Assessment Period Treatment
Statistics (N=288) (N=146) Differences[1]
Median 25.00 26.00
(Min, Max) (15.0, 36.0) (16.0, 34.0)
Week 12 Change from Baseline
N 101
Mean (SD) 2.41 (3.813)
Median 2.00
(Min, Max) (710.0, 14.0)
95% C1 (25.73, 26.9D
LS Mean (SE) 26.32 (0.30)
Week 24
N 200 113
Mean (SD) 25.39 ) 25.66 (3.953)
Median 25.45 26.00
(Min, Max) (16.0, 36.0) (16.0, 34.0)
Week 24 Change from Baseline
200 113
ean (SD) 1.48 (3.499) 1.99 (3.854)
edian 1.00 2.00
(Min, Max) (713.0, 13.0) (76.0, 14.0)
95% CI (24.90, 25.79) (25.15, 26.33) (71.13, 0.35)
Mean (SE) 25.35 (0 23) 25.74 (0.30) 70.3 k9 ,« 0.38)
e 0 .2 KI) 74
Week 36
212 117
ean (SD) 25.27 (3.152) 25.29 (3.700)
edian 25.00 25.00
(Min, Max) (17.0, 33.0) (17.0, 36.0)
Week 36 Change from Baseline
ean (SD) 1.36 (3.441)
edian 1.00
(Min, Max) (710.0, 16.0)
95% CI (24.82, 25.62) (70.82, 0.53)
is Mean (SE) 25.22 (0.20) 70.15 (0.34)
devalue 0.6706
Week 48
212 117
ean (SD) 24.81 (3.177) 25.24 (3.634)
edian 25.00 25.20
(Min, Max) (15.0, 33.0) (15.0, 34.0)
2 W. (D W 48 Change from Baseline
ean (SD) 0.91 (3.614)
edian 1.00
(Min, Max) (712.0, 14.0)
95% CI (24.36, 25.20) (71.23, 0.18)
is Mean (SE) 24.78 (0.21) 70.52 (0.36)
e 0.1458
Week 52
214 117
ean (SD) 24.63 (4.049) 25.25 (3.871)
edian 25.00 25.00
(Min, Max) (79.0, 33.0) (15.0, 35.0)
Week 52 Change from Baseline
214 117
ean (S‘) 0.71 (4.369) 1.59 ( >I> .668)
edian 1.00 1.00
(Min, Max) (737.0, 15.0) (79.0, 14.0)
95% CI (24.08, 25.11) (24.60, 26.0w (71.57, 0.16)
is Mean (SE) 24.60 (0.26) 25.30 (0.36) 70.70 (0.44)
pevalue 0.1117
Note: [1]. The LS Mean ent ence and p—value for the change in Ferritin is created via an ANCOVA
model with treatment as the fixed effect and Day—O baseline as the covariate. Between—treatment differences are
calculated as the LS Mean (KRX-0502) — LS Mean (control).
Only subjects with both a baseline and post ne observations for the parameter of interest were included.
Summary of Cumulative IV iron intake to Week 52 by Treatment, Full Analysis
Population, Method 1 to Handle Overlapping Doses 7 shown in Table 19:
Table 19:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[l]
Average Daily I
'riill in) tkt‘ Izur‘mi
in NW titlmiil.‘ vr‘
:Y iron int <e to
week 52 (Visit 7
Zl)[2,3l
N 278 138
Mean (SD) 2.35 (4.260) 4.86 (4.3De
Median 1.86 3.84
(Min, Max‘ (“.9, dd.fi) (0.0, 74.}
[1 ‘x/“lillr‘LL‘ <U.000)
Note: [1]. The LS Mean treatment difference and p—value for cumulative lV iron intake is created via an
ANCOVA model with treatment as the fixed . n—treatment differences are ated as the LS
Mean (KRX—0502) — LS Mean (control).
Note: [2]. Average Daily IV iron intake based on the (‘umulative IV iron intake to week 52 is calculated as the
total Cumulative lV iron intake divided be the total number of days on study drug.
Note: [3]. The Method 1 to Handle Overlapping Doses is the following: For the overlapping doses will be pro—
rated based on days to only include a dose for the period of time on study drug during the Safety Assessment
l’eriod.
Note: [4]. In the case where basic assumptions are not met for ANCOVA, the Wilcoxon Rank Sum Test is used
to ate the p—value, and the Cl and LS Mean removed.
Sunnnaiy of Cumulative lil’O (158A) stered to Week 52 by 'l‘reatment, l’ull
is Population, Method 1 to Handle Overlapping Doses — shown in Table 20:
Table 20:
KRX—0502 in Safety Control in Safety
Assessment Period Assessment Period
Statistics (N=288) (N=146) Treatment Differences[l]
Ev 7e Daily EPS
- intake ba
,ae Cumulati
EBA) intake ::
52 (Visit e e
7" >1, :2]
‘v 2590
Mean (SD) 1077.ET (1291.33M
Median T2:.24 :
(Min, Max) (0.0, 11015.0) (0.0, BLDL.9)
pevalue[4] 0.0322
Note: [1]. The LS Mean treatment difference and p—value for cumulative EPO (ESA) intake is created Via an
ANCOVA model with treatment as the fixed effect. Between—treatment d'fferences are calculated as the LS
Mean (KRX-0502) — LS Mean (control).
Note: [2]. Average Daily IV iron intake based on the (‘umulative liPO (liSA) intake to week 52 is calculated as
the total Cumulative EPO (ESA) intake divided be the total number of days on study drug.
Note: [3]. The Method 1 to Handle pping Doses is the following: For the overlapping doses will be pro—
rated based on days to only include a dose for the period of time on study drug during the Safety Assessment
l’eriod.
Note: [4]. 1n the case where basic tions are not met for ANCOVA, the Wilcoxon Rank Sum Test is used
to ate the p—value, and the CI and LS Mean d.
Example 2
A Study of KRX-0502 (Ferric Citrate) in Managing Serum Phosphorus and Iron
Deficiency in Anemic Subjects with Stage III to V Chronic Kidney e Not on
Dialysis
A phase 2, proof of concept, multicenter, randomized, placebo—controlled, open—label
clinical trial is med.
The study lasts approximately five to seven months, with imately eight to 12
weeks being allocated for subject ing, two weeks for washing subjects out, of their
current ate binders (if taking them), and 12 weeks allocated for treatment with study
drug, which is either the ferric citrate disclosed herein, or placebo. For purposes of this
lixample, the ferric citrate disclosed herein is referred to as 02 (ferric citrate).
The objectives of the study are to determine the efficacy and safety of KRX—O502
(ferric citrate) in managing serum phosphorus and iron deficiency in anemic subjects with
[Q LA non—dialysis dependent Stage III to V chronic kidney disease (CKD).
Up to approximately 200 subjects are screened to randomize approximately 140
subjects. Eligible subjects are randomized in a 1:1 ratio to either KRX-0502 (ferric citrate) or
placebo. There are approximately 70 ts randomized per treatment arm. The t
rate during the two—week washout and 12—week treatment s is approximately 20% and
therefore approximately 110 subjects complete 12 weeks of treatment with study drug (KRX-
0502 (ferric citrate) or placebo). There are approximately 55 subjects completing 12 weeks of
treatment, with study drug (KRX—()5()2 (ferric citrate) or placebo).
The trial consists of three periods: screening, two—week washout, and 12—week
treatment periods. It takes approximately eight to 12 weeks to screen approximately 200
subjects at imately 10 to 15 sites. The two-week washout period is only for subjects
currently taking a phosphate binder.
The trial enrolls two different types of anemic Stage III to V CKD subjects. They are
as follows: 1) Subjects with a serum phosphorus 2 4.5 mgidL and < 6.0 mg/dL who have
failed a low phosphate diet and have not been initiated on any phosphate binder (de novo
subjects) and have a documented history of anemia; or 2) Subjects who are currently taking
ate binders to manage their serum phosphorus and have a nted history of
anemia. De novo subjects do not enter a washout period and subjects currently taking
phosphate binders enter a two-week washout period. Following two weeks of washout, these
subjects have a serum phosphorus 3 4.5 mgidl. and < 6.0 mg/dl. in order to enter the 12—week
treatment period.
Enrollment is not stratified for de novo subjects vs. subjects currently taking
phosphate binders.
Study Design/Methodology
This trial is a three-period clinical trial ting of a screening period, a two—week
washout period, and a 12-week treatment period. After a subject is determined to be eligible
for enrollment, the subject is ized to either KRX—0502 (ferric citrate) or placebo.
Subjects are randomized in a 1:1 ratio to either KRX-0502 (ferric citrate) or placebo.
Subjects currently taking a phosphate binder are entered into a two-week washout
period and, following the completion of the two—week washout period, are ized to
either 02 c citrate) or placebo. L’ligible subjects not taking a phosphate binder
immediately start on study drug (KRX-0502 (ferric citrate) or placebo). There is no t
period in this subject population. All subjects have a serum phosphorus 2 4.5 mg/dL in order
to enter the 12—week ent period.
After starting treatment with study drug (KRX-0502 (ferric citrate) or placebo),
ts are titrated to therapeutic goal (serum phosphorus between 3.0 to 4.0 mg/dL). If a
subject has a serum phosphorus 2 6.0 mg/dl. for at least two Visits in a row during the 12—
week treatment period, the subject is considered a treatment failure, stops study drug and
exits the study.
The use of IV iron and erythropoietin stimulating agents (ESAs) is not permitted
during the two—week washout and 12—week treatment periods. If a subject’s hemoglobin level
(Hgb) is < 9.0 g/dL during the two-week washout, the subject is a screen e. If a
subject’s Hgb is < 9.0 g/dL for at least two Visits in a row during the 12-week treatment
period, the subject is considered a treatment failure, stops study drug and exits the study.
Seium phosphorus, serum calcium, serum creatinine (used to estimate glomeiular
filtration rate), intact fibroblast growth factor 23 (FGF23), intact parathyroid e (iPTH)
and several hematological parameters (ferritin, TSAT, unsaturated iron binding capacity
(UIBC), 'l‘lBC, serum iron, hematocrit (MCI) and llgb) are determined at screening, during
the t period, prior to the administration of study diug (KRX-0502 (ferric citrate) or
placebo) at Visit 4 (Week 0), and weekly during the 12-week treatment period.
Urinary phosphorus is determined prior to the administration of study drug (KRX—
0502 (ferric citrate) or placebo) at Visit 4 (Week 0), at Visit 7 (Week 4) and Visit 9 (Week 8)
during the 12-week treatment period and at the end of the 12-week treatment period (Visit ll,
Week 12).
The inclusion criteria for this trial are as s:
1. Males and non-pregnant, non-lactating females;
2. Age > 18 years;
3. Stage III to V (7K!) ts not on dialysis who have failed a low phosphate diet to
control serum phosphorus and: (i) are currently taking a ate binder to manage their
serum phosphorus and have a serum phosphoius at ing > 2.5 mg/dL and < 6.0 mg/dL,
or (ii) are not taking a phosphate binder and have a serum orus level at screening 3 4.5
mg/dL and < 6.0 mgde;
4. Documented history of anemia;
5. Serum ferritin < 200 ng/mL and TSAT 20%;
6. llemoglobin > 9.5 g/dL and < 11.5 g/dL;
7. Glomerular filtration rate (GFR) < 60 mL/min;
8. If currently on a phosphate binder, willing to be discontinued from current
phosphate binder(s), enter a washout period and be randomized to either KRX—0502 (ferric
citrate) or o; and
9. g and able to give ed consent.
The exclusion criteria for this trial are as follows:
1. Parathyroidectomy within six months prior to Screening Visit (Visit 0);
2. Symptomatic gastrointestinal bleeding within three months prior to Screening Visit
(Visit 0) and inflammatory bowel disease;
3. ()n dialysis;
4. IV iron administered within 60 days prior to randomization (Visit 4, Week 0);
. Blood transfusion within 60 days prior to randomization (Visit 4, Week 0);
6. Kidney transplant or start of dialysis expected within three (3) months of
randomization (Visit 4, Week 0);
7. Causes of anemia other than iron deficiency;
8. Serum parathyroid hormone >1000 pg/iul;
9. History of multiple drug ies;
. History of malignancy in the last five years (treated cervical or skin cancer may be
permitted; upon al);
11. Previous intolerance to oral ferric e;
12. Absolute ement for oral iron therapy;
13. Absolute requirement for Vitamin (7; however; multivitamins (i.e., (Tentrum,
Nephrocaps, Renaphro, etc.) are allowed;
14. Absolute requirement for calcium-, magnesium-, or aluminum-containing drugs
with meals;
[5. Psychiatric disorder that interferes with the subject’s ability to comply with the
study protocol;
16. Planned surgery or hospitalization during the study (scheduled outpatient access
surgery allowed);
17. Any other medical condition that renders the t unable to or unlikely to
complete the study or that would interfere with optimal participation in the study or produce
significant risk to the subject;
18. Receipt of any investigational drug within 30 days of randomization (Visit 4,
Week 0); and
19. Inability to ate with study personnel or history of noncompliance.
Study Drug Administration
KRX—OSOZ (ferric citrate) is supplied as l-gram caplets of ferric citrate containing
approximately 210 mg of ferric iron to those subjects randomized to ferric citrate.
Matching o is supplied to those subjects randomized to placebo.
All subjects are initiated on study drug with a fixed dose of KKK—0502 (ferric citrate)
of 3 caplets per day ximately 3 grams of ferric citrate as approximately 630 mg of
ferric iron) or placebo (approximately 3 matching caplets per day). The target level for serum
phosphorus is 3.0 to 4.0 mg/dl.. ts are titrated as follows:
1. If serum phosphorus is at target (3.0 to 4.0 mg/dL), no adjustment in dose is
required.
2. If serum phosphorus is < 3.0 mg/dL, the dose of KRX-0502 (ferric citrate) or
placebo is decreased by 1 caplet per day and the subject’s serum phosphorus is re-checked
within seven days.
3. 1f the serum phosphorus is > 4.0 mg/dL, the dose of KKK—0502 (ferric citrate) or
placebo is increased by 1 caplet per day and the subject’s serum phosphorus is re-checked
within seven days.
The maximum number of KRX—0502 (ferric citrate) or placebo caplets per day is 12,
or 12 g/day of ferric citrate. If a subject has a serum phosphorus 2 6.0 mg/dL for at least two
visits in a row during the l2-week treatment period, the subject is ered a treatment
failure, stops study drug and exits the study.
If a subject’s Hgb is < 9.0 gde during the two—week washout, the subject is a screen
failure. If a subject’s Hgb is < 9.0 g/dL for at least two visits in a row during the 12-week
treatment period, the t is considered a treatment e, stops study drug and exits the
study.
Subjects take KRX-0502 (ferric citrate) or placebo orally with meals or snacks or
within one hour after their meals or snacks. Subjects are instructed not to take KRX-0502
(ferric citrate) or o if greater than one hour has passed since the ingestion of their meals
or snacks.
Statistical Considerations: Efi‘icacy
Change in serum phosphorus, ferritin and TSAT levels from baseline to end of
treatment after 12 weeks are the primary endpoints.
This study trates that KRX—0502 c citrate) is statistically or to
placebo in managing serum phosphorus and iron deficiency in anemic Stage III to V CKD
subjects, not on dialysis, requiring phosphate binders from baseline (Visit 4, Week 0) to
endpoint (Visit 11, Week 12).
Change in calcium x phosphorus product, serum calcium, estimated glomerular
filtration rate (eGl'R), urinary phosphorus, onate levels, serum iron, UIBC, 'I‘IBC,
iP'l‘H, and intact fibroblast growth factor 23 (l-‘GF23) from baseline (Visit 4, Week 0) to the
end of ent (Visit 11, Week 12) are also assessed as secondary endpoints.
Statistical Considerations: Sample Size
Up to approximately 200 subjects are screened to randomize approximately 140
subjects. Eligible subjects are ized in a 1:1 ratio to either KRX-0502 (ferric citrate) or
o. There are approximately 70 subjects randomized per treatment arm. The t
rate during the ek washout and [2—week treatment periods is approximately 20% and
therefore approximately 110 subjects complete 12 weeks of treatment with study drug (KRX-
0502 (ferric citrate) or placebo). There are approximately 55 subjects completing 12 weeks of
treatment with study drug (KRX—0502 (ferric citrate) or placebo).
The ending serum phosphorus at Visit 1 1 (Week 12) is approximately 4.3 mg/dL in
the 02 (ferric citrate) group and 4.6 mg/dL in the placebo-treated group. The
common standard deviation is approximately 0.5 mg/dL. Based on these ters, the trial
has at least 80% power to detect a ence between the two groups (alpha 2 0.05, two
sided).
The ending ferritin level at Visit 11 (Week 12) is approximately 300 ng/mL in the
KRX—0502 (ferric citrate) group and 150 ng/ml. in the placebo—treated group. The common
standard deviation is approximately 75 ng/mL. Based on these parameters, the trial has at
least 80% power to detect a difference n the two groups (alpha = 0.05, two sided).
The ending TSAT level at Visit 1 1 (Week 12) is approximately 25% in the KRX—0502
(ferric citrate) group and 17%: in the placebo—treated group. The common standard deviation
is approximately 5%. Based on these parameters, the trial has at least 80% power to detect a
difference between the two groups (alpha = 0.05, two sided).
Finally, it should be noted that there are alternative ways of implementing the
embodiments disclosed herein. Accordingly, the present embodiments are to be ered
as illustrative and not restrictive. Furthermore, the claims are not to be d to the details
given herein, and are ed their full scope and equivalents thereof.
Claims (15)
1. Use of ferric e, in the manufacture of a medicament, for improving transferrin saturation (TSAT) in a non-dialysis chronic kidney disease (ND-CKD) human patient in need thereof by oral administration of a daily dose of one or more tablets of ferric citrate, wherein the ferric citrate provides for a mean increase in TSAT in said ND-CKD t of up to about 20%, and wherein each ferric citrate tablet comprises approximately 1g of ferric e.
2. The use of claim 1, wherein the administration of ferric citrate s the need for IV iron.
3. The use of claim 1 or 2, wherein the administration of ferric citrate reduces the need for erythropoiesis-stimulating agents (ESAs).
4. The use of any one of claims 1-3, wherein the patient is not receiving intravenous iron and/or erythropoiesis-stimulating .
5. The use of any one of claims 1-4, wherein one or more tablets are administered within one hour of ingestion of a meal or snack.
6. The use of any one of claims 1-5, wherein each tablet comprises approximately 80% to approximately 92% by weight ferric citrate.
7. The use of any one of claims 1-5, wherein each tablet comprises approximately 85% to approximately 92% by weight ferric citrate.
8. The use of any one of claims 1-5, wherein each tablet comprises approximately 90% to approximately 92% by weight ferric citrate.
9. The use of any one of claims 1-5, wherein each tablet comprises approximately 4.5% to approximately 30% by weight of a binder.
10. The use of claim 9, n the binder is a partially or fully pregelantinized starch.
11. The use of any one of claims 1-10, wherein each tablet comprises approximately 0.5% to approximately 3% by weight of a ant.
12. The use of claim 11, wherein the ant is calcium stearate.
13. The use of any one of claims 1-12, wherein the oral administration comprises administration of 3-18 tablets of ferric citrate.
14. The use of any one of claims 1-13, wherein the oral administration comprises administration of an initial dose of 6 tablets of ferric citrate.
15. The use of any one of claims 1-14, wherein the oral administration comprises administration of a daily dose of ferric citrate for at least 12 weeks.
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261662565P | 2012-06-21 | 2012-06-21 | |
US61/662,565 | 2012-06-21 | ||
US201361757229P | 2013-01-28 | 2013-01-28 | |
US61/757,229 | 2013-01-28 | ||
US201361801050P | 2013-03-15 | 2013-03-15 | |
US201361800618P | 2013-03-15 | 2013-03-15 | |
US61/800,618 | 2013-03-15 | ||
US61/801,050 | 2013-03-15 | ||
NZ725920A NZ725920A (en) | 2012-06-21 | 2013-06-21 | Use of ferric citrate in the treatment of chronic kidney disease patients |
NZ63099513 | 2013-06-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ742524A NZ742524A (en) | 2020-10-30 |
NZ742524B2 true NZ742524B2 (en) | 2021-02-02 |
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