Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION THERAPY WITH AN IRON COMPOUND AND A CITRATE
COMPOUND
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent
Application No.
62/275,487 filed January 6, 2017, and U.S. Provisional Patent Application No.
62/432,564,
filed December 9, 2016, is hereby claimed, and the disclosures thereof are
incorporated
herein by reference.
FIELD OF INVENTION
[0002] The present disclosure relates to combination therapy comprising an
iron compound
and a citrate compound for use in treating iron deficiency.
BACKGROUND
[0003] Iron deficiency is the most common micronutrient deficiency in the
world. In
absolute iron deficiency, iron stores are absent, and total body iron is
decreased. In
functional iron deficiency, iron stores are present, but the supply of iron to
plasma transferrin
is inadequate, e.g., due to administration of erythropoiesis-stimulating
agents that increase the
iron requirements above the amounts that can be mobilized from these stores.
Iron is
required for several vital physiological functions, including: (1) oxygen
transport and
utilization, e.g., as a carrier of oxygen from lung to tissues; (2) energy
production; (3) cellular
proliferation; (4) transport of electrons within cells; (5) as a co-factor of
essential heme and
non-heme enzymatic reactions in neurotransmission, synthesis of steroid
hormones, synthesis
of bile salts, and detoxification processes in the liver; and (6) destruction
of pathogens.
Severe iron deficiency, i.e., iron deficiency anemia, is therefore
particularly debilitating.
Among the consequences of iron deficiency anemia are increased maternal and
fetal
mortality, an increased risk of premature delivery and low birth weight,
learning disabilities
and delayed psychomotor development, impaired neurocognitive development in
infancy and
childhood that may be irreversible, reduced work capacity, impaired immunity
(increased risk
of infection), an inability to maintain body temperature, and an
associated/increased risk of
lead poisoning. It is well-known that it is very difficult to treat an iron
deficiency with orally
administered iron supplements. In general, relatively large doses are needed
to achieve a
desired therapeutic effect, and oral administration of iron supplements is
known to be
commonly accompanied by undesirable side effects including nausea, epigastric
pain,
vomiting, constipation and gastric irritation.
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[0004] One type of iron-deficiency anemia known as iron-refractory iron
deficiency
anemia (IRIDA) is a rare autosomal-recessive disorder. IRIDA is characterized
by iron
deficiency anemia unresponsive to oral iron therapy and a delayed, incomplete
response to
parenteral iron treatment (De Falco et al. Haematologica 2013; 98: 845-853;
Finberg et al.
Nat Genet 2008; 40: 569-571; Heeney MM and Finberg KE. Hematol Oncol Clin
North Am
2014; 28: 637-52). IRIDA patients have a congenital microcytic, hypochromic
anemia, low
plasma iron and transferrin saturation, and a normal or decreased serum
ferritin
concentration. The mutations responsible are in the gene TMPRSS6, which
encodes
matriptase-2 (MT-2), a type II plasma membrane serine protease that cleaves
hemojuvelin to
negatively regulate hepcidin, the systemic iron-regulatory protein (Finberg et
al., supra; Du et
al. Science 2008; 320: 1088-1092; Wang et al. Front Pharmacol 2014; 5: 114).
Hepcidin acts
by binding to and inactivating the iron-export protein, ferroportin,
preventing the efflux of
iron from enterocytes, macrophages, and hepatocytes into plasma for transport
by transferrin
to the erythroid marrow and other tissues (Ganz T. Physiol Rev 2013; 93: 1721-
1741). The
TMPRSS6 gene mutations result in inappropriately high plasma hepcidin
concentrations,
leading to iron sequestration resulting from obstruction of both iron
absorption by enterocytes
and iron release from macrophages and hepatocytes. Much more common are other
disorders
that result in elevated concentrations of plasma hepcidin that restrict the
supply of iron to the
erythroid marrow and other iron-requiring tissues (Goodnough et al. Blood
2013; 116: 4754-
4761). In iron-sequestration syndromes, body iron stores are adequate or even
increased, but
cannot be utilized to meet physiological iron requirements because increases
in plasma
hepcidin prevent enterocytes, macrophages, and hepatocytes from supplying
sufficient iron to
transferrin. With both iron sequestration and functional iron deficiency, the
supply of iron to
plasma transferrin is inadequate to meet the needs of the erythroid marrow and
other iron-
requiring tissues. Other diseases associated with sustained abnormally high
hepcidin levels
and iron sequestration include chronic inflammatory conditions, chronic kidney
disease,
autoimmune diseases, chronic infections, bacterial, viral and fungal
infections, rheumatologic
diseases, inflammatory bowel disease, critical illness, a variety of other
chronic diseases, and
cancer (e.g., malignancies).
[0005] Currently available parenteral iron preparations are iron-carbohydrate
complexes
that must first be taken up and processed by reticuloendothelial macrophages
to free the iron
from the carbohydrate for subsequent export via ferroportin. Consequently,
parenteral iron
treatment is unable to circumvent a hepcidin-induced block in iron export and
produces only
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a sluggish, partial correction of microcytic anemia. Patients having iron
deficiency (absolute
and functional), iron sequestration syndrome, anemia and/or elevated hepcidin
levels,
including IRIDA and chronic inflammatory conditions, are in need of improved
iron therapy
options.
[0006] A variety of iron salts and other therapeutic iron compounds have been
used for the
treatment of iron deficiency, including ferrous sulfate, ferrous fumarate,
ferrous gluconate,
ferrous succinate, ferric hydroxide, ferric citrate, ferric maltol, and iron
polysaccharide
complex. Soluble ferric pyrophosphate (SFP) is a class of iron salts which
comprise a
mixture of iron chelated or coordinated to citrate and pyrophosphate and
includes ferric
pyrophosphate citrate (FPC, TRIFERIC, Rockwell Medical, Inc., Wixom, Michigan)
that has
a molecular mass of about 1000 Da and is highly soluble in aqueous solutions.
The
administration of SFP overcomes both absolute and functional iron deficiencies
and iron-
sequestration syndromes in many patients. Upon parenteral administration, SFP-
iron directly
binds to apo-transferrin, thereby delivering SFP-iron to bone marrow directly,
bypassing the
reticuloendothelial system (Gupta et al. J Am Soc Nephrol 2010; 21: 429A;
Pratt et al., J Clin
Pharmacol 2016; DOT: 10.1002/jcph.819). U.S. Patent Nos. 6,689,275; 6,779,468;
and
7,857,977; incorporated herein by reference, disclose the addition of SFP to
liquid
bicarbonate solutions for hemodialysis. U.S. Provisional Patent No.
62/214,908, incorporated
herein by reference, discloses a solid particulate formulation of SFP.
SUMMARY OF INVENTION
[0007] The present disclosure is directed to combination therapy comprising an
iron
compound and a citrate compound. In one aspect, the disclosure provides
pharmaceutical
compositions comprising an iron compound and a citrate compound, optionally
compositions
for oral administration. In one aspect, the pharmaceutical composition
comprises an iron
compound in an amount of about 0.2 mg iron to about 5 mg iron per kg
bodyweight of a
subject, for example, about 5 mg iron to about 500 mg iron. In another aspect,
the
pharmaceutical formulation comprises a citrate compound in an amount of about
0.5 mmol to
about 2 mmol per kg bodyweight of a subject, for example, about 0.5 mmol to
about 100
mmol.
[0008] The disclosure also provides kits comprising an iron compound and a
citrate
compound and instructions for co-administering a therapeutically effective
amount of the iron
compound and the citrate compound to a subject having iron deficiency, with or
without
anemia. In one aspect, the kit comprises an iron compound in an ampule
containing about
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5.44 mg/mL Fe in water. In another aspect, the kit comprises a citrate
compound comprising
citric acid and sodium citrate, for example, about 128 mg/mL citric acid and
about 98 mg/mL
sodium citrate. Optionally, the kit comprises a citrate compound that is a
solution comprising
about 640 mg/5 mL citric acid and about 490 mg/5 mL hydrous sodium citrate in
water, e.g.,
Shohl's solution. In one aspect, the iron compound and/or citrate compound is
in a
pharmaceutical composition for oral administration.
[0009] The present disclosure provides methods and medical uses for treating
iron
deficiency, with or without anemia, in a subject in need thereof. In one
aspect, a method of
treating iron deficiency comprises co-administering a therapeutically
effective amount of an
iron compound and a citrate compound to a subject in need thereof. In another
aspect, the
present disclosure provides an iron compound and a citrate compound for use in
treating iron
deficiency. In still another aspect, the present disclosure provides use of an
iron compound
and a citrate compound in the manufacture of a medicament for treating iron
deficiency. In
another aspect, a method of increasing serum iron comprises co-administering a
therapeutically effective amount of an iron compound and a citrate compound to
a subject in
need thereof, optionally in an amount effective to increase serum iron by at
least 100 i.t.g/dL
compared to baseline. In still another aspect, a method of increasing
hemoglobin levels
comprising co-administering a therapeutically effective amount of an iron
compound and a
citrate compound to a subject in need thereof, optionally in an amount
effective to increase
hemoglobin concentration by at least 1 g/dL compared to baseline. In any of
the foregoing
methods, the iron compound and citrate compound may be administered
concurrently, e.g., in
an admixture, or one component (for example, the citrate compound) may be
administered
first, followed by administration of the second component, optionally within a
period of 15
minutes or less. In one aspect, the iron compound is administered first. In
another aspect, the
citrate compound is administered first. Optionally, the iron compound and/or
citrate
compound is administered orally, for example, both the iron compound and
citrate compound
are administered orally. In various aspects, the iron compound and/or citrate
compound is
administered one, two, or three times per day. Optionally, the iron compound
and/or citrate
compound is administered at least one hour before or two hours after a meal.
[0010] In any of the foregoing methods, the iron compound and citrate compound
may be
co-administered to a subject in need thereof in an amount effective to improve
at least one
serum iron pharmacokinetic parameter compared to an equivalent dosage of the
iron
compound administered without the citrate compound. In various aspects, co-
administering
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an iron compound and a citrate compound to a subject increases the maximum
serum iron
concentration in a dose interval (Cmax), increases the bioavailability of the
iron compound,
and/or increases the amount of iron absorbed from the iron compound, compared
to an
equivalent dosage of the iron compound administered without the citrate
compound.
[0011] In any of the pharmaceutical compositions, kits, methods, and medical
uses of the
present disclosure, the iron compound is optionally selected from ferrous
sulfate, ferrous
fumarate, ferrous gluconate, ferrous succinate, ferric citrate, ferric
pyrophosphate, SFP, ferric
hydroxide, ferric pyrophosphate citrate, iron polymaltose, iron ascorbate,
ferric (tri)maltol,
heme iron polypeptide, iron EDTA, iron polysaccharide complex, and
combinations thereof.
The iron compound optionally comprises iron in an amount from 7% to 11% by
weight,
citrate in an amount from 14% to 30% by weight, pyrophosphate in an amount
from 10% to
20% by weight, and phosphate in an amount of 2% or less by weight. The iron
compound
may be administered at a dosage of about 0.2 mg iron to about 5 mg iron per kg
bodyweight,
for example, about 3 mg Fe per kg bodyweight. The citrate compound is
optionally selected
from the group consisting of citric acid, sodium citrate, potassium citrate,
calcium citrate,
magnesium citrate, ammonium citrate, combinations of any of the foregoing, and
solutions
thereof. In one aspect, the citrate compound comprises citric acid and sodium
citrate, e.g., in
an aqueous solution such as Shohl's solution. The citrate compound may be
administered at
a dosage of about 0.5 mmol to about 2 mmol per kg bodyweight, for example,
about 0.67
mmol per kg.
[0012] The pharmaceutical formulations, kits, and methods described herein are
used to
treat subjects in need. Suitable subjects include patients having iron
deficiency (absolute and
functional) or iron-sequestration syndrome(s), with or without anemia,
including IRIDA,
renal anemia, anemia of chronic disease, anemia of chronic inflammation,
anemia with
autoimmune and rheumatologic diseases, anemia with inflammatory bowel disease,
anemia
with bacterial, viral and fungal infections, cancer-related anemia,
chemotherapy-related
anemia, anemia caused by impaired production of ESA with ESA treatment,
hypochromic
anemia, anemia of inflammation, and microcytic anemia. Suitable subjects also
include those
exhibiting elevated serum and/or urinary hepcidin levels caused by conditions
such as
IRIDA, inflammatory conditions, chronic kidney disease, autoimmune diseases,
chronic
infections, bacterial, viral and fungal infections, critical illness,
rheumatologic diseases,
inflammatory bowel disease, a variety of other chronic diseases or other
conditions with
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hypoferremia (decreased serum iron and transferrin saturation), and cancer
(e.g.,
malignancies).
[0013] The foregoing summary is not intended to define every aspect of the
invention, and
other features and advantages of the present disclosure will become apparent
from the
following detailed description, including the drawings. The present disclosure
is intended to
be related as a unified document, and it should be understood that all
combinations of
features described herein are contemplated, even if the combination of
features are not found
together in the same sentence, paragraph, or section of this disclosure. In
addition, the
disclosure includes, as an additional aspect, all embodiments of the invention
narrower in
scope in any way than the variations specifically mentioned above. With
respect to aspects of
the disclosure described or claimed with "a" or "an," it should be understood
that these terms
mean "one or more" unless context unambiguously requires a more restricted
meaning. With
respect to elements described as one or more within a set, it should be
understood that all
combinations within the set are contemplated. If aspects of the disclosure are
described as
"comprising" a feature, embodiments also are contemplated "consisting of' or
"consisting
essentially of' the feature. Additional features and variations of the
disclosure will be
apparent to those skilled in the art from the entirety of this application,
and all such features
are intended as aspects of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 depicts the mean absolute total serum iron concentration-time
profile for
subjects at Baseline (no exogenous iron) and treated with Treatment A (ferrous
sulfate
orally), Treatment B (Shohl's solution orally, followed after 10 minutes by
ferrous sulfate),
Treatment C (SFP orally), Treatment D (Shohl's solution orally, followed after
10 minutes by
SFP orally), Treatment E (Shohl's solution orally, followed immediately by SFP
iron orally),
and Treatment F (SFP intravenously (IV) over 4 hours).
[0015] Figure 2 depicts the mean baseline-corrected total serum iron
concentration-time
profile for subjects at Baseline and treated with Treatment A through F.
[0016] Figure 3A depicts a box plot of baseline-corrected total iron Cmax, and
Figure 3B
depicts a box plot of baseline-corrected AUCIast in subjects treated with
Treatment A through
F. Solid line = median; box = 25% and 75% quartiles (interquartile range
[IQR]); whiskers =
lowest/highest values within 1.5*IQR of the lower/upper quartiles; dot symbols
=
observations beyond whiskers; * = mean.
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[0017] Figure 4 depicts a box plot with 5 and 95 percentiles of
bioavailability of iron in
subjects treated with Treatment A through F. Solid line= median, dotted line =
mean.
[0018] Figure 5 depicts mean values for serum hepcidin for subjects at
baseline and
treated with Treatment A through F.
DETAILED DESCRIPTION
[0019] The present disclosure relates to combination therapy comprising an
iron compound
such as SFP and a citrate compound. The combination therapy effectively treats
iron
deficiency (absolute and functional) and iron-sequestration syndromes, with
and without
anemia, including in subjects having iron deficiency with anemia and/or
elevated hepcidin
levels, such as those with IRIDA and/or chronic inflammatory disorders. Upon
entry into the
circulation, SFP can donate iron directly to transferrin without first
requiring macrophage
processing (Gupta et al. J Am Soc Nephrol 2010; 21: 429A; Pratt et al. J Clin
Pharmacol
2016; DOT: 10.1002/jcph.819). Consequently, upon entry into the blood stream,
SFP
provides a means to bypass the hepcidin-induced obstruction of ferroportin
iron export
underlying IRIDA and other conditions having high hepcidin states (e.g., high
plasma
hepcidin concentrations). Citrate, a tricarboxylic anion, can complex with
calcium in the
gastrointestinal tract, opening intracellular tight junctions and permitting
paracellular uptake
of soluble complexes (Lemmer et al. Expert Opin Drug Deliv 2013; 10: 103-114;
Nolan et al.
Kidney Int 1990; 38: 937-941; Froment et al. Kidney Int 1989; 36: 978-984;
Martinez-Palomo
et al. J Cell Biol 1980; 87: 736-745; Coburn et al. Am J Kidney Dis 1991; 17:
708-711;
Drueke TB. Nephrol Dial Transplant 2002; 17 Suppl 2: 13-16). Ferric citrate,
recently
approved in Japan for control of hyperphosphatemia in patients with chronic
kidney disease,
increases transferrin saturation and serum ferritin over 12 weeks of
administration (Gupta A.
Pharmaceuticals 2014; 7: 990-998; Yokoyama et al. Clin J Am Soc Nephrol 2014;
9: 543-
552). Co-administering a citrate compound with an iron compound such as SFP
provides in a
synergistic increase in serum iron levels and whole blood (circulating)
hemoglobin (Hgb)
concentration that is greater than that with the iron compound administered
alone. For
example, one or more iron salts belonging to the SFP class co-administered
with a citrate
compound provides a synergistic increase in serum iron levels and whole blood
Hgb that is
greater than iron salts including SFP administered alone or iron compounds
other than SFP
co-administered with the citrate compound.
[0020] As used herein, the following definitions may be useful in aiding the
skilled
practitioner in understanding the disclosure. Unless otherwise defined herein,
scientific and
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technical terms used in the present disclosure shall have the meanings that
are commonly
understood by those of ordinary skill in the art.
[0021] The term "iron deficiency" refers to both absolute iron deficiency,
wherein iron
stores are absent, and total body iron is decreased, and functional iron
deficiency, wherein
iron stores are present, but the supply of iron from the stores is inadequate.
[0022] The term "soluble ferric pyrophosphate" or "SFP" refers to a soluble
composition
comprising a mixture of iron complexed to pyrophosphate and citrate with other
excipients.
For example, SFP can be a mixture of iron pyrophosphate citrate and sodium
sulfate. In one
aspect, SFP refers to FPC and comprises a mixed-ligand iron compound
comprising iron
chelated with citrate and pyrophosphate, optionally having the following
formula:
Fe4(C6H407)3(H2P207)2(P207) (relative MW 1313 daltons) and/or structure (I):
s'A ft
rs----ss
=
tik\
/ µS;A"/ 1;;NiVe-t1-4,;4 `=,õ
01, 0 WRinot
e
=.= ,õõ ,,, \;"
-0'\
4'
õPL
H H ¨111
Examples of SFP according to the present disclosure are described in U.S.
Patent Nos.
7,816,404 and 8,178,709 and U.S. Provisional Patent No. 62/214,908,
incorporated herein by
reference in their entirety.
[0023] The term "chelate" refers to a metal cation and anions that surround
the metal
cation and are joined to it by electrostatic bonds, for example, a ferric iron
cation surrounded
by and joined by electrostatic bonds to both citrate and pyrophosphate anions.
[0024] The term "citrate compound" refers to a compound suitable for
administering to a
subject, e.g., a mammal such as a human, that yields a citrate anion (C6H5073-
) at
physiological pH. Examples of citrate compounds according to the disclosure
include, but
are not limited to, citric acid and salts of citrate such as sodium citrate,
potassium citrate,
calcium citrate, magnesium citrate, ammonium citrate, ferric citrate, and
combinations of any
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of the foregoing. A citrate compound may solid, semi-solid, or a liquid (e.g.,
an aqueous
solution such as Shohl's solution).
[0025] The terms "co-administering" and "combination therapy" mean that an
iron
compound and a citrate compound are administered in a manner that permits both
to exert
physiological effects during an overlapping period of time. In combination
therapy
comprising an iron compound and a citrate compound, the compounds may be
administered
in the same pharmaceutical composition (e.g., an admixture) or in separate
compositions, via
the same or different routes of administration. An iron compound and a citrate
compound
may be co-administered concurrently, i.e., simultaneously, or at different
times, as long as
both exert physiological effects during an overlapping period of time. For
example, an iron
compound and a citrate compound may both be administered to a subject within a
time period
of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5
minutes, about
minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30
minutes, about 1
hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 4
hours, about 5
hours, or longer. If the iron compound and citrate compound are not co-
administered
concurrently, either the iron compound or citrate compound may be administered
first. As
long as the subsequent compound is administered while a physiological effect
of the first
administered compound is present, the iron compound and citrate compound are
considered
to be co-administered and used in combination therapy in accordance with the
teachings of
the disclosure.
[0026] The term "iron compound" refers to a compound containing iron (e.g.,
ferric or
ferrous) that is suitable for administration to a subject, e.g., an orally
active therapeutic
compound. Examples of iron compounds include, but are not limited to, ferrous
sulfate,
ferrous fumarate, ferrous gluconate, ferrous succinate, ferric citrate, ferric
pyrophosphate,
soluble ferric pyrophosphate, ferric hydroxide, ferric pyrophosphate citrate,
iron polymaltose,
iron ascorbate, ferric (tri)maltol, heme iron polypeptide, iron EDTA, iron
polysaccharide
complex, and combinations thereof.
[0027] The terms "therapeutically effective amount" and "effective amount"
refer to an
amount of a single agent or combination therapy effective to achieve a desired
biological,
e.g., clinical, effect. A therapeutically effective amount varies with the
nature of the disease
being treated, the length of time that activity is desired, and the age and
the condition of the
subject. In one aspect, a therapeutically effective amount is an amount
effective to increase
serum iron levels and/or Hgb concentration compared to baseline.
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[0028] The term "synergistic increase" refers to an improvement in a
therapeutic effect
from administration of combination therapy comprising an iron compound and a
citrate
compound compared to the sum of the therapeutic effects of the iron compound
and citrate
compound alone or compared to the therapeutic effects of combination therapy
comprising a
non-SFP iron compound and the citrate compound.
[0029] The present disclosure provides pharmaceutical compositions, kits,
methods of
treatment, and medical uses comprising an iron compound and a citrate
compound. In one
aspect, the iron compound comprises a mixture of ferric pyrophosphate and
sodium citrate.
In another aspect, the iron compound comprises a mixture of ferric
pyrophosphate, sodium
pyrophosphate, ferric citrate, and sodium citrate. In various aspects, the
iron compound
comprises iron in an amount from 7% to 11% by weight, citrate in an amount of
at least 14%
by weight (e.g., 14% to 30% by weight), and pyrophosphate in an amount of at
least 10% by
weight (e.g., 10% to 20% by weight). Optionally, the iron compound comprises
an iron
composition described in any of U.S. Patent Nos. 7,816,404 and 8,178,709 or
U.S.
Provisional Patent Application No. 62/214,908. For example, in one aspect, the
iron
compound is SFP that is a FPC composition comprising a mixed-ligand iron
compound
comprising iron chelated with citrate and pyrophosphate, optionally having the
formula
Fe4(C6H407)3(H2P207)2(P207) and/or structure (I) described herein.
[0030] In one aspect, the citrate compound is selected from the group
consisting of citric
acid, sodium citrate, potassium citrate, calcium citrate, magnesium citrate,
ammonium citrate,
ferric citrate, combinations of any of the foregoing, and solutions thereof.
In one aspect, the
citrate compound is an aqueous solution comprising citric acid and sodium
citrate.
Optionally, the citrate compound comprises citric acid or sodium citrate or
both citric acid
and sodium citrate, in a concentration of about 50 g/L to about 200 g/L, for
example, about
50 g/L, about 60 g/L, about 70 g/L, about 80 g/L, about 90 g/L, about 100 g/L,
about 110 g/L,
about 120 g/L, about 130 g/L, about 140 g/L, about 150 g/L, about 160 g/L,
about 170 g/L,
about 180 g/L, about 190 g/L, or about 200 g/L. For example, in one aspect,
the citrate
compound comprises about 130 g/L to about 140 g/L citric acid and about 100
g/L hydrous
sodium citrate. In one aspect, the citrate compound is Shohl's solution, a
buffer of sodium
citrate and citric acid commonly used for prolonged treatment of children with
cystinuria and
some forms of renal tubular acidosis.
[0031] The present disclosure provides a pharmaceutical composition comprising
an iron
compound and a citrate compound. In one aspect, the pharmaceutical composition
comprises
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a dosage of an iron compound of about 0.2 mg iron to about 5 mg iron per
kilogram body
weight of the subject, for example, about 1 mg, about 2 mg, about 3 mg, about
4 mg, or about
mg, per kilogram body weight of the subject. Optionally, the pharmaceutical
composition
comprises an iron compound in an amount from about 5 mg iron to about 500 mg
iron, for
example, about 5 mg iron, about 10 mg iron, about 20 mg iron, about 30 mg
iron, about 40
mg iron, about 50 mg iron, about 60 mg iron, about 70 mg iron, about 80 mg
iron, about 90
mg iron, about 100 mg iron, about 150 mg iron, about 200 mg iron, about 250 mg
iron, about
300 mg iron, about 350 mg iron, about 400 mg iron, about 450 mg iron, or about
500 mg
iron. Optionally, the pharmaceutical composition comprises an iron
concentration of about
110 i.t.g/L or about 2 t.M. In another aspect, the pharmaceutical composition
comprises a
dosage of a citrate compound of about 0.5 mmol to about 5 mmol per kilogram
body weight
of the subject, for example, about 0.5 mmol, about 0.6 mmol, about 0.7 mmol,
about 0.8
mmol, about 0.9 mmol, about 1 mmol, about 1.5 mmol, about 2 mmol, about 2.5
mmol, about
3 mmol, about 3.5 mmol, about 4 mmol, about 4.5 mmol, or about 5 mmol, per
kilogram
body weight of the subject. Optionally, the pharmaceutical composition
comprises a citrate
compound in an amount from about 0.5 mmol to about 100 mmol, for example,
about 0.5
mmol, about 1 mmol, about 2 mmol, about 3 mmol, about 4 mmol, 5 mmol, about 10
mmol,
about 15 mmol, about 20 mmol, about 25 mmol, about 30 mmol, about 35 mmol,
about 40
mmol, about 45 mmol, about 50 mmol, about 55 mmol, about 60 mmol, about 65
mmol,
about 70 mmol, about 75 mmol, about 80 mmol, about 85 mmol, about 90 mmol,
about 95
mmol, or about 100 mmol.
[0032] In one aspect, the pharmaceutical composition comprises an iron
compound, a
citrate compound, and a pharmaceutically acceptable carrier including, but not
limited to,
water, saline, phosphate buffered saline, dialysate, and combinations thereof.
Other
excipients, including buffering agents, dispersing agents, and preservatives,
are known in the
art and may be included in the pharmaceutical composition. Further examples of
components that may be employed in pharmaceutical compositions of the
disclosure are
presented in Remington's Pharmaceutical Sciences, 16th Ed. (1980) and 20th Ed.
(2000), Mack
Publishing Company, Easton, Pa. A pharmaceutical composition may be in any
suitable
dosage form including, but not limited to, tablets, capsules, liquids,
lozenges, and gels. In
one aspect, the pharmaceutical composition is for oral administration and is
in the form of a
tablet, capsule, gel, lozenge, or liquid.
11
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[0033] The present disclosure also provides a kit comprising an iron compound
and a
citrate compound in separate pharmaceutical compositions and instructions for
co-
administration of a therapeutically effective amount of the iron compound and
citrate
compound to a subject having iron deficiency, with or without anemia, e.g.,
IRIDA, using the
methods described herein. In one aspect, a kit of the present disclosure
comprises an iron
compound and/or a citrate compound in a formulation to be administered orally.
In one
aspect, the kit comprises an iron compound in a solid form, for example, in a
capsule or
ampule that is broken, a blister pack that is pierced or peeled, or a sachet
that is opened, to
allow for the iron compound contained therein to be added to an aqueous
solution for oral or
parenteral administration. Optionally, an iron compound is formed into a mass,
e.g., a tablet
or wafer, that can be added directly to an aqueous solution, or stored within
a dissolvable
package that is soluble in an aqueous solution. In another aspect, the kit
comprises an iron
compound in a liquid form, for example, in an ampule, optionally an iron
compound at a
concentration of about 5 mg/mL iron to about 6 mg/mL iron (e.g., 5.44 mg/mL
iron), in
water, for example. In another aspect, a kit comprises a citrate compound
which is an
aqueous solution, e.g., Shohl's solution, optionally comprising about 640
mg/5mL citric acid
and/or about 490 mg/5mL hydrous sodium citrate.
[0034] The present disclosure provides methods of treatment and medical uses
to treat a
subject in need thereof comprising co-administering a therapeutically
effective amount of an
iron compound and a citrate compound to the subject. In one aspect, a method
of treating
iron deficiency (e.g., anemia) comprises co-administering a therapeutically
effective amount
of an iron compound and a citrate compound to a subject in need thereof. In
another aspect,
the present disclosure provides an iron compound and a citrate compound for
use in treating
iron deficiency (e.g., anemia). In still another aspect, the present
disclosure provides use of
an iron compound and a citrate compound in the manufacture of a medicament for
treating
iron deficiency (e.g., anemia). In one aspect, the iron compound and citrate
compound are
administered concurrently, for example, admixed into a single composition
prior to
administration. In another aspect, the citrate compound is administered before
the iron
compound. In still another aspect, the iron compound is administered before
the citrate
compound. In combination therapy, the iron compound and citrate compound are
administered in a manner that permits both to exert physiological effects
during an
overlapping period of time. In one aspect, the compounds are administered
within 30
minutes of each other, for example, in a window of about 5 minutes to 15
minutes, e.g., 5
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minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes,
12 minutes, 13
minutes, 14 minutes, or 15 minutes, with either the iron compound or a citrate
compound
administered first. In various aspects, the iron compound and/or citrate
compound is
administered one, two, or three times per day. Optionally, the iron compound
and/or citrate
compound is administered at least one hour before or two hours after a meal.
Optionally, the
iron compound and/or citrate compound is administered orally, for example,
both the iron
compound and citrate compound are administered orally, or the citrate compound
is
administered orally and the iron compound is administered parenterally, e.g.,
by injection or
infusion.
[0035] Purely by way of illustration, the methods of the present disclosure
comprise
administering (1) an iron compound in an amount from about 0.2 mg/kg/day iron
to about 20
mg/kg/day iron or more, e.g., about 0.5 mg/kg/day, about 1 mg/kg/day, about 2
mg/kg/day,
about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 6 mg/kg/day,
about 7
mg/kg/day, about 8 mg/kg/day, about 9 mg/kg/day, about 10 mg/kg/day, about 11
mg/kg/day,
about 12 mg/kg/day, about 13 mg/kg/day, about 14 mg/kg/day, about 15
mg/kg/day, about 16
mg/kg/day, about 17 mg/kg/day, about 18 mg/kg/day, about 19 mg/kg/day, or
about 20
mg/kg/day, of iron based on the body weight of the subject; and (2) a citrate
compound in
amount from about 0.5 mmol/kg/day to about 15 mmol/kg/day or more, based on
the body
weight of the subject. In some aspects, the daily dosage of an iron compound
ranges from
about 0.3 mg/kg to about 3 mg/kg iron, about 1 mg/kg to about 5 mg/kg iron,
about 3 mg/kg
to about 5 mg/kg iron, or about 5 mg/kg to about 10 mg/kg iron. In related
aspects, the daily
dosage of a citrate compound ranges from about 1 mmol/kg to about 5 mmol/kg,
about 2
mmol/kg to about 10 mmol/kg, about 0.5 mmol/kg to about 3 mmol/kg, or about 1
mmol/kg
to about 10 mmol/kg. The foregoing dosages for use in the methods,
compositions, and kits
of the present disclosure are exemplary of the average case, but there can be
individual
instances in which higher or lower dosages are merited, and such are within
the scope of this
disclosure.
[0036] In one aspect, the methods and medical uses of the disclosure comprise
co-
administering an iron compound and a citrate compound to a subject in need
thereof in an
amount effective to achieve and/or maintain a serum iron concentration of
about 50 i.t.g/dL to
about 250 i.t.g/dL, for example, about 50 i.t.g/dL to about 150 i.t.g/dL,
about 50 i.t.g/dL to about
120 i.t.g/dL, about 60 i.t.g/dL to about 175 i.t.g/dL, about 100 i.t.g/dL to
about 250 i.t.g/dL, or
about 100 i.t.g/dL to about 200 i.t.g/dL. In some aspects, an iron compound
and a citrate
13
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compound are co-administered in an amount effective to achieve or maintain a
serum iron
concentration at least above about 50 i.t.g/dL, for example, above about 60
i.t.g/dL, above about
70 i.t.g/dL, above about 80 i.t.g/dL, above about 90 i.t.g/dL, above about 100
i.t.g/dL, above about
110 i.t.g/dL, or above about 120 i.t.g/dL. In another aspect, the methods
comprise co-
administering an iron compound and a citrate compound in an amount effective
to increase
serum iron by at least about 25 i.t.g/dL, for example, at least about 50
i.t.g/dL at least about 75
i.t.g/dL, or at least about100 i.t.g/dL, compared to before treatment with the
combination
therapy or to administering the iron compound without the citrate compound.
[0037] The present disclosure also provides methods of co-administering an
iron
compound and a citrate compound to a subject in need thereof in an amount
effective to
maintain or increase Hgb levels. For example, an iron compound and a citrate
compound are
co-administered in amount effective to increase Hgb levels high enough to
adequately
oxygenate the subject's tissues or provide improved oxygenation of the
subject's tissues.
Preferably, the dose of an iron compound and a citrate compound co-
administered increases
or maintains the Hgb level of the subject at a level of about 9 g/dL to 10
g/dL or greater,
thereby reducing the need for blood transfusions, reducing fatigue, improving
physical and
cognitive functioning, improving cardiovascular function, improving exercise
tolerance and
enhancing quality of life. In various aspects, an iron compound and a citrate
compound are
co-administered in an amount effective to increase Hgb levels to or maintain
Hgb levels at a
target level ranging from 9 g/dL to 10 g/dL, at a target level ranging from 9
g/dL to 12 g/dL,
at a target level ranging from 10 g/dL to 12 g/dL, at a target level ranging
from 9 g/dL to 14
g/dL, at a target level ranging from 10 g/dL to 14 g/dL, or at a target level
ranging from 12
g/dL to 14 g/dL. In addition, the disclosure provides for methods of co-
administering a dose
of an iron compound and a citrate compound effective to increase Hgb to or
maintain Hgb at
a target level of at least about 9 g/dL, of at least about 10 g/dL, of at
least about 11 g/dL, of at
least about 12 g/dL, of at least about 13 g/dL, or of at least about 14 g/dL.
The disclosure
also provides for methods of increasing Hgb concentration by at least about
0.1 g/dL, for
example, at least about 0.1 g/dL, at least about 0.2 g/dL, at least about 0.3
g/dL, at least about
0.4 g/dL, at least about 0.5 g/dL, at least about 0.6 g/dL, at least about 0.7
g/dL, at least about
0.8 g/dL, at least about 0.9 g/dL, at least about 1.0, at least about 1.1
g/dL, at least about 1.2
g/dL, at least about 1.3 g/dL, at least about 1.4 g/dL, or at least about 1.5
g/dL, compared to
before treatment.
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[0038] The disclosure also provides for any of the preceding methods or uses
wherein an
iron compound and a citrate compound are co-administered at a therapeutically
effective dose
that (i) increases at least one marker of iron status selected from the group
consisting of
serum iron, transferrin saturation, reticulocyte Hgb, serum ferritin,
reticulocyte count, and
whole blood Hgb; and (ii) decreases or eliminates the need for erythropoiesis
stimulating
agents (ESA) administration to achieve or maintain target hemoglobin levels,
or the need for
transfusion of whole blood, packed red blood cell or blood substitutes. In
addition, any of the
preceding methods or uses carried out in a subject can reduce fatigue,
increase physical and
cognitive ability, or improve exercise tolerance in the subject. The methods
and uses of the
disclosure can be used to increase serum iron, Hgb concentration, and/or
another marker of
iron status and maintain the increased level for a prolonged period of time,
e.g., at least one
month, at least two months, at least three months, at least four months, at
least five months, at
least six months, or more.
[0039] In one aspect, the methods and medical uses of the disclosure comprise
co-
administering an iron compound and a citrate compound to a subject in need
thereof in an
amount effective to improve at least one serum iron pharmacokinetic parameter
compared to
an equivalent dosage of the iron compound administered without the citrate
compound. In
one aspect, co-administering an iron compound and a citrate compound to a
subject increases
the maximum serum iron concentration in a dose interval (Cmax) compared to the
Cmax of
an equivalent dosage of the iron compound administered without the citrate
compound. In
various aspects, an iron compound and a citrate compound are co-administered
in an amount
effective to increase the Cmax by at least 10 i.t.g/dL, at least 20 i.t.g/dL,
at least 30 i.t.g/dL, at
least 40 i.t.g/dL, at least 50 i.t.g/dL, at least 60 i.t.g/dL, at least 70
i.t.g/dL, at least 80 i.t.g/dL, at
least 90 i.t.g/dL, or at least 100 i.t.g/dL, and/or by at least 10%, at least
20%, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least
90%, at least 100%,
at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at
least 160%, at
least 170%, at least 180%, at least 190%, or at least 200%, compared to the
Cmax of an
equivalent dosage of the iron compound administered without the citrate
compound. In
another aspect, co-administering an iron compound and a citrate compound to a
subject
increases the bioavailability of the iron compound compared to the
bioavailability of an
equivalent dosage of the iron compound administered without the citrate
compound. In
various aspects, an iron compound and a citrate compound are co-administered
in an amount
effective to increase the bioavailability by at least 10%, at least 20%, at
least 30%, at least
CA 03010771 2018-07-05
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40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at
least 100%, at
least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at
least 160%, at least
170%, at least 180%, at least 190%, or at least 200%, compared to the
bioavailability of an
equivalent dosage of the iron compound administered without the citrate
compound. In still
another aspect, co-administering an iron compound and a citrate compound to a
subject
increases the amount of iron absorbed from the iron compound compared to the
amount of
iron absorbed from an equivalent dosage of the iron compound administered
without the
citrate compound. In various aspects, an iron compound and a citrate compound
are co-
administered in an amount effective to increase the amount of iron absorbed by
at least 0.5
mg, at least 1 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3
mg, at least 3.5 mg,
at least 4 mg, at least 4.5 mg, or at least 5 mg, and/or by at least 10%, at
least 20%, at least
30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at
least 90%, at least
100%, at least 110%, at least 120%, at least 130%, at least 140%, at least
150%, at least
160%, at least 170%, at least 180%, at least 190%, or at least 200%, compared
to the amount
of iron absorbed from an equivalent dosage of the iron compound administered
without the
citrate compound.
[0040] The methods, medical uses, pharmaceutical compositions, and kits of the
present
disclosure are used to treat a subject in need. Suitable subjects are those
that would benefit
from iron supplementation, including subjects suffering from iron deficiency
or iron-
sequestration syndrome(s), with or without anemia. Examples of anemia that may
be treated
using the pharmaceutical formulations, kits, and methods of the present
disclosure include,
but are not limited to, iron-deficiency anemia including IRIDA, anemia of
chronic disease,
anemia of chronic inflammation, renal anemia, cancer-related anemia,
chemotherapy-related
anemia, anemia caused by impaired production of ESA, anemia of inflammation,
anemia in
patients with inflammatory bowel disease, anemia in patients with congestive
heart failure,
anemia in chronic infections such as hepatitis B or hepatitis C, tuberculosis,
HIV, anemia in
patients with rheumatological diseases such as lupus and rheumatoid arthritis,
microcytic
anemia and/or hypochromic anemia. Suitable subjects include those exhibiting
elevated
serum and/or urinary hepcidin levels (e.g., serum/urinary hepcidin greater
than 10 ng/mL or a
hepcidin level that is inappropriately high given the patient's iron status)
caused by
conditions such as IRIDA, inflammatory conditions, chronic kidney disease,
autoimmune
diseases, chronic infections, rheumatologic diseases, inflammatory bowel
disease, chronic
disease, and cancer.
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[0041] The present disclosure will be more readily understood by reference to
the
following Examples, which are provided by way of illustration and are not
intended to be
limiting.
EXAMPLES
[0042] The following Examples describe clinical studies demonstrating that an
iron
compound co-administered with a citrate compound is safe and effective for the
treatment of
IRIDA.
Example 1
[0043] A Phase 1, open-label, randomized sequence, single-dose study was
conducted to
assess the safety, pharmacokinetics, and absolute bioavailability of iron from
ferrous sulfate
(FER-IN-SOL, Mead Johnson, Glenview, IL) or SFP (TRIFERIC, Rockwell Medical,
Inc.)
with and without a citrate compound (ORACIT Shohl's solution, CMC Pharma,
Farmville,
NC) in healthy male and female volunteers. A total of 14 healthy male and
female subjects
between the ages of 18 and 65 years, inclusive, who had a body mass index of
<35 kg/m2 at
screening were enrolled in the study. Subjects were required to have values
within the
reference ranges for each gender for hemoglobin (males, >13 g/dL; females, >12
g/dL), mean
corpuscular volume, reticulocyte count, and serum ferritin (males, 23-336
ng/mL; females,
11-306 ng/mL); a TSAT >20%; and a serum TIBC concentration >250 g/dL at
screening.
Subjects agreed to discontinue use of all iron preparation for 14 days before
baseline.
[0044] The study included a screening period (Days -28 to -1), a baseline
period (Day 1), a
treatment period (Days 2-12), and a follow-up period (Day 13 on), for a total
duration of
participation of up to 6 weeks for each subject. Eligible subjects were
enrolled in the study
on the next morning (Day 1) and underwent serial pharmacokinetic blood
sampling over
24 hours (at 0, 1, 2, 4, 6, 8, 12, 16, and 24 hours) to determine diurnal
variation of iron
(baseline, no exogenous iron). An overview of the study design is provided in
Table 1.
17
CA 03010771 2018-07-05
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TABLE 1
COnfinement in Clinical Reseaich Unit
'rum at 2, 4, S, 12. 16, and 24 anal's,
c).7 inUrkg oral
X .X
Triferie. 3 nag ofal X X: _X
n X
.Botline iron piofile:
2 4, 8,1 13:8
udy II:
¨
Treaunent were ran;1611iii.aqnelD:e ."!--111
e.eictile Er 404.0:0Taerfa:itott.
Da7,, 12.
before Fer-in-Soi Of.Trfi.If 031
feric ironw administ&ed nninelAtely afte:
" froiinthedinicalmseartia thamaraitygoiDay.I3,
[0045] Subjects were confined to the clinical research unit (CRU) from the
time of
admission (Day -1) until the morning after administration of the last study
treatment
(Day 13). Subjects were given a low-iron diet while confined to the CRU.
Subjects were
required to fast overnight (nothing by mouth but water from midnight to 8 Am)
on the
evening before the baseline assessments (Day 1), on the evening before
administration of the
study treatments on Days 2, 4, 6, 8, 10, and 12, and on the evening before
collection of the
final blood samples on the morning of discharge from CRU (Day 13). Subjects
were
discharged from the CRU and from the study after all of the study assessments
on the
morning of Day 13 had been completed. Subjects received 5 oral iron treatments
in
randomized order on Days 2, 4, 6, 8, and 10: Treatment A: FER-IN-SOL, 3 mg
iron/kg
orally; Treatment B: Shohl's solution, 0.7 mL/kg orally, followed after 10
minutes by FER-
IN-SOL, 3 mg iron/kg orally; Treatment C: TRIFERIC, 3 mg iron/kg orally;
Treatment D:
Shohl's solution, 0.7 mL/kg orally, followed after 10 minutes by TRIFERIC, 3
mg iron/kg
orally; Treatment E: Shohl's solution, 0.7 mL/kg orally, followed immediately
by
TRIFERIC, 3 mg iron/kg orally; and Treatment F: TRIFERIC, 6.6 mg iron via
continuous IV
infusion over 4 hours. TRIFERIC was supplied in sterile 5-mL ampules
containing
5.44 mg/mL of iron in water for injection (stock solution). Each ampule
contained
27.2 mg/5 mL of TRIFERIC iron. ORACIT was supplied as 640 mg/5 mL citric acid
and
490 mg/mL sodium citrate. FER-IN-SOL was supplied as a liquid preparation
containing
15 mg iron/5 mL.
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Pharmacokinetic Analysis
[0046] Blood samples for pharmacokinetic determinations of iron parameters
were
obtained immediately before dosing (0 hour) and at 1, 2, 4, 6, 8, 12, 16, and
24 hours after
dosing on each dosing day. Each subject's iron stores were estimated using the
serum soluble
transferrin receptor (sTfR) and ferritin concentrations before administration
(i.e., at 0 hour) of
each of the study treatments. The primary pharmacokinetic endpoints were the
mean
absolute and baseline-corrected values for maximum drug concentration in serum
(Cmax),
time to reach maximum drug concentration (Tmax), time of last quantified
concentration
(Tiast), area under the serum concentration-time curve from time zero to the
time of the last
quantified concentration (AUCIast), area under the serum concentration-time
curve from time
zero to the end of the infusion of study drug (AUC0nd,1' _ area
under the serum concentration-
time curve from time zero extrapolated to infinity (AUCH,f), terminal phase
rate constant (kz),
terminal phase half-life (t1/2), systemic clearance (CL), and oral clearance
(CL/F). The
pharmacokinetic population for analysis included all enrolled subjects who
received at least
one dose of study drug and had sufficient pharmacokinetic samples to include
in the
pharmacokinetic assessments. The secondary pharmacokinetic endpoints were the
absolute
quantity of iron absorbed from each study treatment as assessed by comparison
to the Cma,,
and AUCIast of a single IV dose of TRIFERIC iron, the bioavailability of iron
from each study
treatment as assessed by comparison of the amount of iron administered in each
study
treatment to the amount of TRIFERIC iron administered, the effect of study
treatments on
serum ferritin concentration and TSAT, and the effect of the study treatments
on serum
hepcidin concentration at 8 and 24 hours after dosing.
[0047] Serum concentrations and absolute and baseline-corrected
pharmacokinetic
parameters for sFe were derived for each study treatment from the serum
concentration-time
profiles, using noncompartmental methods in PHOENIX WINNONLIN version 6.3
(Pharsight Corporation, St. Louis, Missouri, USA). Summary statistics
(arithmetic mean,
coefficient of variation expressed as a percentage [CV%], SD of the arithmetic
mean,
minimum median, minimum, maximum, geometric mean, and CV% of the geometric
mean)
were presented for serum concentrations of sFe and for the pharmacokinetic
parameters
(except Tmax and Tiast) of sFe. Median, minimum, and maximum values were
presented for
Tmax and Tiast. An exploratory analysis, using clinical laboratory data, was
also conducted
because of the large number of pharmacokinetic samples that had sFe
concentrations below
the limit of quantitation (BLQ) of the bioanalytical assay.
19
CA 03010771 2018-07-05
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[0048] The baseline sFe profile (Day 1, no exogenous iron) demonstrated a
clear cyclic
pattern of endogenous iron concentration, with peak mean concentration
observed
approximately 1 hour after the start of the study (8 Am), followed by a
decrease to the lowest
mean concentration at 12 hours (77.7 p.g/dL), and then an increase in mean
concentration at
24 hours (146 p.g/dL) (Figure 1). Mean absolute sFe concentrations following a
4-hour
infusion of 6.6 mg of TRIFERIC iron (Treatment F) peaked at the end of the
infusion and
remained higher than the baseline (Day 1) profile until the 16-hour sample.
Mean absolute
sFe concentrations peaked between 1 and 2 hours after administration of Fer-In-
Sol iron oral
solution alone (Treatment A) and FER-IN-SOL iron oral solution with Shohl's
solution
(Treatment B). Oral TRIFERIC iron alone (Treatment C), showed serum iron
concentrations
similar to baseline. Oral TRIFERIC iron with Shohl's solution (Treatments D
and E) showed
increases in serum iron greater than TRIFERIC alone (Treatment C).
[0049] Mean baseline-corrected sFe concentrations increased relative to the
time-matched
baseline (Day 1) values for all 6 of the study treatments (Figure 2). The
predose and 24 hour
samples from the baseline iron profile were generally higher than the predose
and 24 hour
values after exogenous administration of iron. This made it difficult to
produce fully
corrected time-matched serum iron values for all treatments. Thus, calculation
of clearance
parameters Xz and Xz-dependent parameters was possible for only a minority of
subject iron
profiles. Mean baseline-corrected sFe concentration peaked at the end of the 4-
hour IV
infusion of TRIFERIC iron (Treatment F) and remained higher than the baseline
profile until
the 16-hour sample. Mean baseline-corrected sFe concentrations peaked at 4
hours after
administration of the oral FER-IN-SOL iron treatments (Treatments A and B) and
between 6
and 8 hours after administration of the oral TRIFERIC iron treatments
(Treatments C-E).
Concentrations returned to baseline at around 16 hours for each of the oral
iron treatments.
[0050] The sFe concentration-time profiles that were obtained from an
exploratory analysis
using the sFe concentrations that were obtained from the clinical laboratory
were similar to
those obtained using the data from the bioanalytical assay. A high correlation
(R2 >0.9) was
observed between the concentrations determined by the clinical laboratory and
the
concentrations determined by the bioanalytical laboratory. No BLQ values were
reported by
the clinical laboratory. In contrast, 52 BLQ values were reported by the
bioanalytical
laboratory because the lower limit of quantitation (LLQ) was 50 p.g/dL for the
bioanalytical
assay. In contrast, the LLQ for the clinical laboratory (autoanalyzer) was 5
p.g/dL.
[0051] Absolute total serum iron pharmacokinetic parameters are summarized in
Table 2.
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
TABLE 2
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1445.43 4.43534
32 344 84314 NC 81.43 * :34,4
32..7 rcitõ.31g 4.
4.3.34.5.54543 374 433: -203821 2432
1-4-1444,4 :34.14
G5333:"V".14 2,211 3432 .48.1 5iC" 22.4:
24,7
/ croz 2:43:8:z
334441454 257 2.55 233543. ,..4.1-. .3.44
a3t-eit- It3 1,3131,23..0
44:154 4434 1440 2540: 4.84 7 143
85144 244 447.4: arXip r....-. N.
2.24, 542
341 I 1 34 fa4 24 14 14.
54.44.3 I R3 =.37.1= ;ZS* :M.- 3481, 7.
..43
lr 5555 4.-4.1 82.3 5.84 -133c. "831)3. :0::, 45:: 2715
1 55
184524.1"4 1. CV% 22..2 143: z.e;:s ::;,..-: :: 1.2
6 ..= 5 c..- i',..e.kg .,i- ..ei=ce. i'.41241,. 15,s. NC .24.00.
,..::: is :,:::
's ri.iirsri, Pq11. 324441410.11 7:747 M-., 41. -3INN
.3 siig =3&.,=2=15z3, 333:3133i.,431:Kstil3:
:33133i_33=;ar:3 1..: *-*P 4.20: 4 $33
4845 3.8.1: 144471 3;32 1.428
8.52
5.1142, 3234 '5...W 441,3 3:. 3' 4::.:
4' 84
3.4 14.
342.544 1.4;7 51:1`. 12234 4.04 5 442
: :i...s..,..3
822. 33473 W.: 447 MT: :, ta
c`eri4s. ,3.143 63/1" 14%8:
P: -7
TO* obi i 0.eie ed: 0 2344 4514344. 244: NC 243,333. 50.1-
1*.il'ili re ?&?.s rii¾V 334447411, 1741 * 4:1
444II
343454355 .424 ,47-31:8 C.542" 33 (4:3
4.5115 3.137 41S: -203.... 442 4:4:"
2.444 343.44
PA 4.4 358 443333 ..430. ::.,,,,,c :,: -
,...;.¶-...
[0052] Median absolute Tmax values for sFe were 2.0 hours (range, 1.0-4.0
hours) after
administration of FER-IN-SOL iron oral solution alone (Treatment A), 1.0 hours
(range, 1.0-
4.0 hours) after administration of FER-IN-SOL iron oral solution with Shohl's
solution
(Treatment B), 2.0 hours (range, 1.0-24.0 hours) after administration of oral
TRIFERIC iron
alone (Treatment C), 1.5 hours (range, 1.0-4.0 hours) after administration of
oral TRIFERIC
iron 10 minutes after Shohl's solution (Treatment D), and 1.0 hour (range, 1.0-
6.0 hours)
after administration of oral TRIFERIC iron immediately after Shohl's solution
(Treatment E).
The median absolute Tmax value for sFe was 4.05 hours (range, 4.05-4.08 hours)
after IV
administration of TRIFERIC iron.
[0053] Baseline-corrected total serum iron pharrnacokinetic parameters are
summarized in
Table 3.
21
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
TABLE 3
it,:52.mtW 1:&t.t2
.::: t thi
NI 12 0 :3
0%.7. 1'3 t=it 52,... 38: 04 IV
.i.,..i.
m ,:klt SE.4 52'3 t...i;- :2eg
V.2 31:22
1%.:,:kcov.2 4 214 Sgi., MC 4.7 8..:, i* I. ..0
=Sot: 2.c.xo 1.3;i: Fc 2* ".1.C2 :* 122
t,3.1
*rm. Fott 5:::-.,:= co, $.=µi. * gio 4.-: Nc-.
4,,$:
12.2 AO 00 -1.4/.. W,
222 tri22 2A:i W: 1 t.. 2.,47
=.242 212) .4.42 :: 12.2 :
/2 :
.2 S2 1.2
2..loxo SZ,S W. CSS.t. .:::7its. i÷
$ i:?=ki 3;:s ;
fe...,zsirstrt#:0
0`?;:tli =Z 'Z.A.. NI: f: w a* 'f's;.. ?ik: Of
5ik ,:t" N. 222 SIS
c.., tetexto 1.,-,NA 3..4.4
1c4;440 t.',N :.S.-S NC :43 INA
:
041,V... =-:% =:- :;,-,, mi:.=,,.
vm .:-.:. -_;..n. 2N.,./ ' - = '
I's 1 ,K22
Si S 0
:,084:1 4 S.,4 Nt.: 0 . ,: .V .,,,,
su. 4õ,3. NC. .,.,1 NC `.1C- 3.43
2:0
Tiwiltiotte op,: 70 * * ,,,.. ,iF:: *:=,,
,:::e.,.:
28.3 W. :20 W SC 2
lit M.P0.4 NU00,s. 05.-: It: *pt 4 2k i4:i.
,;3.3
.21Sx2St 43
WI ,.., 0 t..(1: ,:23 ;.:t: St.
00 073'
w .:.N.: .k-.1 stk:
N 't 3 * z.:
IS 125 S25 it li
3S8 52,3 W. 'i..:..1. 1.11.
0 : W 00 JC.5
iii,? rm.04, 4;
..S1..i.e.s. , ZS ? 4 .1,1.' 112 4: ain
1 :::==
.Z.1 W 0,2 6.i.i2 NC: .ivA
co s- .t* 310: 4.S2 111.
3ftrz ID r:252.2t, Wei 22 : 20 * 122 NC 2.21 4.
t..;,;
2:k11: :22.21 j41:21 W. 14..c k al
N :2 12: :12 . . * .4
.21W 2.52 22ii 0:8 4.0
i rsibtniima n :sap 0: i.:27 1i2 *
.1.,40
tic NC 8.3.:4
D.:.1.2,4;,: t= 2,1.3.tet ,:::.3 * 2.i'S. :f4; 2i2
;144
Tr2.t,k {.1 Stmt= CV's.=:7:7!..i: SC 212 NC
SC 14.. :2,2
3 mg kikg m=mtici6:.Ay m&=::4 fa,: :Iy..,:co *a: k iw :1 ka
1.25
2.(12 :.:C NC :0.8$=:$ 1
NtU M iiSN tF17) r:71.
:W 4.Sf 71.2
S: 51 31 1:
Ou.'t U$.
1C=
0, =:..t.2 w. a K ?=ic". A q
4 * a
174: =psc *. :i...60
T4**1'...' 64 WN 5.,=C't,'N 3 SN Pii: 44:6 * $ter.
4:: *
MSxkiSyl 3:N: z:edx xii: hfc. :Nc.
45,e.t.i 0,0
A:1:s, '...3 :..ks -:,:=, 4 .4 t-kci
3S.0
Mkt is.: S IN: 1:326 NC NC 2 a
2
[0054] Baseline-corrected values for sFe Cmax and AUCIast showed absorption
and
exposure relationships between iron treatments that were consistent with those
based on
absolute values, as did absolute and baseline-corrected values for sFe Cmax
and AUCIas, based
on clinical laboratory data. Variability in serum iron parameters was observed
across all
subjects and within treatments, primarily due to the differences in baseline
iron status. For
the FER-IN-SOL treatments (Treatments A and B), the highest Cmax and AUCIas,
values were
observed in those subjects with the lowest baseline hepcidin and ferritin
concentrations.
[0055] Baseline-corrected sFe using the clinical laboratory assay gave more
reliable
estimates of Cmax and AUCIast because of the fewer BLQ values (Figure 3A and
3B).
Administration of TRIFERIC iron alone (Treatment C) showed minimal iron
absorption. Co-
administration of TRIFERIC iron with Shohl's solution (Treatments D and E)
showed a net
increase in Cmax and AUCIas, values as compared with TRIFERIC iron alone
(Treatment C).
22
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
Intravenous TRIFERIC iron (Treatment F, reference treatment) also showed a
range of Cma,,
and AUCIast values that were similar to those of FER-IN-SOL alone (Treatment
A).
[0056] The baseline-corrected AUCIast value for the IV administration of 6.6
mg of
TRIFERIC iron was used to estimate the absorption of iron from FER-IN-SOL and
TRIFERIC after oral administration with and without Shohl's solution. Because
of the
variability in baseline sFe, full correction of the basal iron led to many
values BLQ. The best
estimate of iron absorption was based on the clinical laboratory measurements
of sFe, which
resulted in the fewest values being BLQ. Iron absorption was variable across
and within
subjects. In general, absorption of ferrous iron (FER-IN-SOL) led to the
highest quantity of
iron absorption both without and with Shohl's solution (Figure 4). TRIFERIC
iron
administered orally demonstrated very little absorption as would be expected
for a ferric iron
product. However, co-administration of TRIFERIC iron with Shohl's solution led
to an
increase in iron absorption relative to oral TRIFERIC iron alone. Without
intending to be
bound by theory, the increase in absorption is likely mediated via
paracellular pathways
opened by the complexation of gastrointestinal (GI) calcium by citrate,
increasing
permeability to molecules like TRIFERIC (SFP). Once in the blood, SFP can
donate iron to
transferrin for delivery to iron-requiring tissues.
[0057] The predose and 24-hour samples from the subjects' baseline profiles
were
generally higher than the predose and 24-hour samples from the profiles after
subjects
received exogenous iron administration. Despite attempts to collect fully time-
matched
baseline samples, the calculation of Xz and Xz-dependent parameters were
possible for only a
minority of profiles. Because both bioavailability and estimated amount of
iron absorbed, as
calculated from AUCo_t, depend on Xz, the results are absent or provided as
"NC" (Not
Calculated) in Tables 2 and 3. The bioavailability (F), assuming mean body
weight of 70 kg
to calculate the dose administered, and estimated amount of iron absorbed
(Abs) from the
treatments as calculated from baseline-corrected Cmax are summarized in Table
4.
TABLE 4
Treatment F Abs (mg Fe)
A: FER-IN-SOL only 3.7% 7.8
B: Shohl's and 2.1% 4.3
FER-IN-SOL after 10
minutes
C: TRIFERIC PO only 1.1% 2.4
D: Shohl's and 2.0% 4.2
TRIFERIC PO after 10
23
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
minutes
E: Shohl's and 1.8% 3.7
TRIFERIC PO
immediately
F: TRIFERIC IV 100.0% 6.6
[0058] Mean values for serum hepcidin at 8 hours were highest after
administration of
FER-IN-SOL iron oral solution alone (Treatment A) and lowest after
administration of oral
TRIFERIC iron alone (Treatment C) (Figure 5). Mean values for serum hepcidin
at 8 hours
were lower after administration of each of the oral TRIFERIC iron treatments
(Treatments C,
D, and E), as well as lower after IV administration of TRIFERIC iron
(Treatment F), than at 8
hours in the baseline profile. In contrast, mean values for serum hepcidin at
8 hours were
higher after administration of both FER-IN-SOL iron oral solution treatments
(Treatments A
and B) than at 8 hours in the baseline profile. Mean values for serum hepcidin
had returned
to baseline by 24 hours after administration of each of the 6 iron treatments.
Mean and
median values were within normal limits for serum hepcidin (<0.5-14.7 nm for
males and <5
12.3 nm for premenopausal females) at 8 hours in the baseline profile and
after
administration of each of the iron treatments. Values above the upper limit of
normal for
serum hepcidin were observed at 8 hours after administration of an iron
treatment on 3
occasions in only 1 subject (after administration of FER-IN-SOL iron oral
solution alone,
after administration of Fer-In-Sol iron oral solution with Shohl's solution,
and after
administration of oral TRIFERIC iron 10 minutes after Shohl's solution).
Values were well
within normal limits for males at 24 hours after dosing.
Safety Study
[0059] Safety was evaluated through an assessment of the nature, frequency,
and severity
of adverse events and through assessments of vital signs and clinical
laboratory tests
(hematology, serum chemistry, and urinalysis). The safety population for
analysis included
all subjects who signed the study-specific informed consent document and
received at least
one dose of study drug.
[0060] Blood samples for a safety serum iron profile (serum iron [sFe],
ferritin, transferrin
saturation [TSAT], and total iron-binding capacity [TIBC]) were obtained at 0
hour
(approximately 8 Am) and at 1, 2, 4, 6, 8, 12, 16, and 24 hours later on Day 1
(baseline, no
exogenous iron) and immediately before dosing (0 hour) and at 1, 2, 4, 6, 8,
12, 16, and
24 hours after dosing on Days 2, 4, 6, 8, 10, and 12. Blood samples for
determination of
24
CA 03010771 2018-07-05
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serum hepcidin concentrations were obtained at 0 hour and 8 and 24 hours on
Days 1, 2, 4, 6,
8, 10, and 12.
[0061] Single doses of oral TRIFERIC iron (3 mg iron/kg) and FER-IN-SOL iron
oral
solution (3 mg iron/kg) were well tolerated when administered without and with
Shohl's
solution. Gastrointestinal-related adverse events were the most commonly
reported adverse
events across all 5 of the oral study treatments. The incidence of GI-related
adverse events
was greater after administration of FER-IN-SOL iron oral solution alone
(50.0%, 7 of 14)
than after administration of oral TRIFERIC iron alone (7.1%, 1 of 14). Co-
administration of
oral TRIFERIC iron with Shohl's solution was associated with an increase in
the incidence of
GI-related adverse events as compared with administration of oral TRIFERIC
iron alone. At
least one GI-related adverse event was reported in 42.9% (6 of 14) of the
subjects when oral
TRIFERIC iron was administered 10 minutes after Shohl's solution and in 35.7%
(5 of 14) of
the subjects when oral TRIFERIC iron was administered immediately after
Shohl's solution,
whereas one GI-related adverse event (nausea) was reported in 7.1% (1 of 14)
of the subjects
after administration of oral TRIFERIC iron alone.
[0062] The reported GI-related events after co-administration of oral TRIFERIC
iron with
Shohl's solution were those that are commonly reported after administration of
oral iron
products (e.g., abdominal discomfort, abdominal distension, abdominal pain,
defecation
urgency, diarrhea, flatulence, nausea). No clinically meaningful difference in
the incidence
of any individual GI-related event was observed based on the time of
administration of oral
TRIFERIC iron relative to Shohl's solution (i.e., 10 minutes after Shohl's
solution or
immediately after Shohl's solution). All of the GI-related events were mild or
moderate in
severity. None of the GI-related events were serious, and none led to
premature
discontinuation of any subject from the study. Fewer subjects experienced GI-
related events
when oral TRIFERIC iron was administered 10 minutes after (42.9%, 6 of 14) or
immediately after (35.7%, 5 of 14) Shohl's solution than when FER-IN-SOL iron
oral
solution was administered alone (50.0%, 7 of 14). Most notably, nausea was
reported less
frequently when oral TRIFERIC iron was administered 10 minutes after Shohl's
solution
(21.4%, 3 of 14) or immediately after Shohl's solution (14.3%, 2 of 14) than
when
FER-IN-SOL iron oral solution was administered alone (42.9%, 6 of 14). The
incidence of at
least one GI-related adverse event after co-administration of oral TRIFERIC
iron with
Shohl's solution, either 10 minutes after (42.9%, 6 of 14) or immediately
after (35.7%, 5 of
14) administration of Shohl's solution, was comparable to that after co-
administration of
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
FER-IN-SOL iron oral solution with Shohl's solution (35.7%, 5 of 14).
Individual GI-related
events (e.g., diarrhea, flatulence, nausea) after co-administration of oral
TRIFERIC iron with
Shohl's solution were reported at incidences comparable to those after co-
administration of
FER-IN-SOL iron solution with Shohl's solution. No serious adverse events were
reported,
and there were no discontinuations due to adverse events after administration
of any of the
iron treatments.
[0063] The safety iron profile of oral TRIFERIC iron without and with Shohl's
solution
was consistent with the administration of an iron-replacement product and with
the safety
iron profiles of FER-IN-SOL (with and without Shohl's solution) and IV
TRIFERIC iron.
Increases from baseline in sFe and TSAT were observed after administration of
oral
TRIFERIC iron without Shohl's solution and after administration of oral
TRIFERIC iron
minutes after or immediately after administration of Shohl's solution, with
concentrations
of sFe higher after administration of oral TRIFERIC iron with Shohl's solution
than after
administration of oral TRIFERIC iron without Shohl's solution. Concentrations
of sFe after
administration of oral TRIFERIC iron, with or without Shohl's solution, were
lower than
after administration of FER-IN-SOL iron oral solution without Shohl's
solution. Serum
ferritin and TIBC concentrations remained relatively unchanged from baseline
after
administration of oral TRIFERIC iron without or with Shohl's solution. None of
the TSAT
values exceeded 100% after administration of oral TRIFERIC iron without or
with Shohl's
solution. No adverse effects of any study treatment were observed on systolic
or diastolic
blood pressure, pulse rate, or safety laboratory measurements.
Summary
[0064] The results of this study demonstrated that administration of TRIFERIC
with
Shohl's solution increased iron absorption, potentially by the paracellular
pathway. Shohl's
solution led to significant increases in iron absorption after administration
of TRIFERIC iron
(Treatment D) when administered 10 minutes before TRIFERIC iron or when
administered
sequentially (Treatment E). There was virtually no iron absorption when
TRIFERIC 3 mg
iron/kg was administered orally alone (Treatment C). The estimated quantities
of iron from
Shohl's plus TRIFERIC iron ranged from 0.8 mg iron to 11.1 mg iron, with a
mean of 4.6 mg
iron for Treatment D and 5.5 mg iron for Treatment E. Baseline (Day 1) serum
iron
concentrations were variable across subjects and may have reflected
differences in body iron
status prior to admission to the CRU as evidenced by the range of baseline
hepcidin
concentrations. Total serum iron after IV infusion of TRIFERIC 6.6 mg
(Treatment F)
26
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
showed an increase, with peak concentration at approximately 4 hours and a
return to
baseline concentrations by 16 hours after the start of infusion.
Administration of 3 mg
iron/kg FER-IN-SOL led to higher iron exposure (Treatment A) than 3 mg iron
/kg FER-IN-
SOL with Shohl's solution (Treatment B). Serum iron parameters were similar
between the
bioanalytical laboratory and the clinical laboratory determinations, with
fewer BLQ values
obtained by the clinical laboratory measurement of sFe. TRIFERIC iron without
and with
co-administered Shohl's solution was generally well tolerated. Adverse events
were
generally mild to moderate, occurred primarily in the GI system, abated
rapidly after dosing,
and were similar in frequency to FER-IN-SOL administered with Shohl's
solution.
[0065] The clinical study provided evidence that co-administration of SFP with
a citrate
compound results in paracellular absorption of SFP and subsequent donation of
iron to
transferrin for utilization by the erythroid marrow and other tissues. The
pharmacokinetic
and safety results from this study supported that SFP co-administered with a
citrate
compound can provide sufficient iron to improve the anemia in patients with
constitutive
elevations of hepcidin, such as patients with IRIDA and anemia of chronic
inflammation.
Without co-administration of a citrate compound, minimal amounts of SFP were
absorbed,
but with the citrate compound, mean SFP iron absorption was about 4 mg, or
approximately
four times the daily iron requirement of an adult male ( about 1 mg/day). For
patients with
IRIDA or anemia of chronic inflammation, this magnitude of paracellular iron
absorption
should be sufficient to correct the anemia, raising the hemoglobin
concentration to normal or
near-normal levels.
Example 2
[0066] A Phase 2, open-label, 3-period study assessing the safety, efficacy,
and
pharmacokinetics of SFP (TRIFERIC, Rockwell Medical, Inc.) and a citrate
compound
(ORACIT Shohl's solution, CMC Pharma, Farmville, NC) administered orally to
patients
with IRIDA is conducted. A total of 28 patients stratified by 4 age groups
(age 0 to <6 years,
age 6 to <12 years, age 12 to <18 years, and age >18 years) is studied. The
study design
schematic is shown in Table 5.
27
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
TABLE 5
Fe504 Shohl's Triferic
3 mg Fe/kg 3 mg Fe/kg
Shohl's FeSO4
3 mg Fe/kg
Follow-up
D-1 ID PO Shohl s inferc
Week: -4 1 2 3 4 8 12 1Ã 20 28 38 44 45
Visit: 1 2 3 4 5 6 7 8 9 10 11 12 13
ittr iftFehA =;:;
[0067] Patients are enrolled only if a patient has: (1) history of congenital
hypochromic
microcytic anemia; (2) mean corpuscular volume (MCV) <75 fL at screening; (3)
serum
transferrin saturation <15% at screening; (4) history of no or incomplete
response to oral iron
therapy and intravenous iron administration; (5) history of an elevated
hepcidin concentration
with respect to the range found in iron-deficiency anemia; (6) documentation
of homozygous
or compound heterozygous pathogenic mutations in TMPRSS6 from a CLIA-certified
laboratory; (7) appropriate laboratory values for their disease state at
screening (per
investigator judgment); and (8) no significant abnormal findings on physical
examination at
screening that would preclude participation in the study (per investigator
judgment). Oral
and IV iron products, including oral multivitamins containing iron, are
prohibited from 2
weeks prior to Visit 2 until all blood samples have been collected after the
Follow-up/Early
Termination Visit. Blood transfusions are prohibited from 3 months prior to
Visit 2.
Aluminum-containing compounds (e.g., MAALOX, ALTERNAGEL, ALU-CAP,
DIALUME, AMPHOJEL, ALU-TAB, ALOH-GEL, etc.) are prohibited from Day 1 of the
study through the date of the patient's last dose of the citrate compound.
[0068] Ferrous sulfate (FER-IN-SOL, Mead Johnson, Glenview, IL) is supplied as
50-mL
bottles containing 15 mg Fe/mL and administered at a dose of 3 mg Fe/kg at
Visits 2 and 3.
At Visit 3, the dose is given 5 minutes to 15 minutes after the dose of the
citrate compound.
The citrate compound is supplied as 500-mL bottles containing citric acid USP
640 mg/5 mL
and hydrous sodium citrate USP 490 mg/5 mL. Other commercially-available
preparations
of Shohl's solution or other citrate compounds may also be used. The Shohl's
solution is
28
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
administered at 0.67 mmol/kg at Visits 3-4. The SFP is supplied as sterile 5-
mL ampules
containing 5.44 mg/mL of iron in water. Each 5-mL ampule contains 27.2 mg of
SFP iron.
The SFP is administered at a dose of 3 mg Fe/kg at Visit 4, 5 minutes to 15
minutes after the
dose of the citrate compound. At each of Visits 5, 7, 9, 10, and 11,
sufficient amounts of the
SFP and citrate compound to provide at least 60 days of dosing are dispensed
to the patient.
On study visit days, patients do not take their SFP and citrate compound doses
until after the
study visit. Patients stop taking SFP and the citrate compound after Visit 12.
[0069] Blood samples are obtained at various times to analyze for changes in
CBC,
reticulocyte count, the reticulocyte Hgb concentration (CHr), the serum iron
profile (serum
iron, ferritin, transferrin TSAT, TIBC, and UIBC), other serum iron parameters
(TBI, NTBI,
and LPI), and soluble transferrin receptor (sTfR) and hepcidin concentrations.
Patients are
also monitored for safety parameters, including adverse events, clinical
laboratory
parameters, and vital signs, during the study.
[0070] In Period 1 (Visits 2-4, Weeks 1-3), patients undergo oral iron
absorption testing
during 3 visits to confirm that they adequately absorb iron from the SFP when
it is
administered with the citrate compound. Patients are dosed during Period 1 as
follows: oral
FeSO4, 3 mg Fe/kg body weight at Visit 2; oral citrate compound, 0.67 mmol/kg
body
weight, followed after 5 minutes to 15 minutes by oral FeSO4, 3 mg Fe/kg body
weight at
Visit 3; and oral citrate compound, 0.67 mmol/kg body weight, followed after 5
minutes to 15
minutes by oral SFP, 3 mg Fe/kg body weight at Visit 4. At each of Visits 2-4,
blood
samples for serum iron parameters (serum iron, TSAT, TBI, NTBI, and LPI) are
collected
within 30 minutes prior to the oral iron dose and at 1 hr, 2 hr, and 4 hr
following the oral iron
dose. Following Visit 4, the patient's Visit 4, serum iron Cma,, is compared
to the Visit 4, Hr
0 serum iron concentration. If the Visit 4, serum iron Cma,, is >100 g/dL
higher than the Visit
4, Hr 0 serum iron concentration, the patient is designated a "SFP responder"
and proceeds to
Period 2. If not, the patient proceeds to the early termination visit to occur
approximately 1
week after Visit 4.
[0071] In Period 2 (dose titration; Visits 5-9, Weeks 4-20), Period 1 "SFP
responders"
receive SFP and the citrate compound orally up to 3 times per day for 4
months, titrated as
needed based on laboratory results and patient tolerance, to determine whether
their
hemoglobin levels respond to this treatment. Venous blood is collected and
analyzed for
hematology, reticulocyte count, CHr, chemistry, the serum iron profile, and
sTfR and
hepcidin concentrations. Following Visit 9, the patient's Visit 9 hemoglobin
level is
29
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
compared to the Visit 5 hemoglobin level. If the Visit 9 hemoglobin level is
>1 g/dL higher
than the Visit 5 level, the patient is designated a "hemoglobin responder" and
proceeds to
Period 3. If not, the patient proceeds to the early termination visit to occur
within
approximately 1 week after Visit 9.
[0072] In Period 3 (hemoglobin maintenance, Visits 10-12, Weeks 21-44), Period
2
"hemoglobin responders" receive SFP and the citrate compound orally up to 3
times per day
for an additional 6 months to confirm that the hemoglobin response observed in
Period 2 is
sustainable. During Period 3, the dose and frequency of the SFP and the
citrate compound
continue to be titrated as needed based on laboratory results and patient
tolerance. Venous
blood is collected and analyzed for hematology, reticulocyte count, CHr,
chemistry, the
serum iron profile, and sTfR and hepcidin concentrations. During Periods 2 and
3, it is
recommended that the patients take the SFP and citrate compound orally at
least one hour
before or two hours after meals.
[0073] A follow-up visit occurs approximately 1 week after Visit 12. Blood is
collected
and analyzed for hematology, chemistry, and the serum iron profile. The
reticulocyte count,
CHr, and sTfR and hepcidin concentrations are collected if not collected
within the previous
30 days. The duration from screening to the last study visit is approximately
12 months.
[0074] The primary efficacy endpoint is the change from baseline in hemoglobin
concentration, e.g., at 4 months. Key secondary efficacy endpoints include:
(1) change from
baseline in serum iron and TSAT, e.g., at 4 months; (2) change from baseline
in Hgb, RBC,
MCV, reticulocyte count, CHr, serum iron, TIBC, ferritin, UIBC, TSAT, and sTfR
and
hepcidin concentrations, e.g., every 4 weeks and at end-of-treatment (EoT);
(3) incidence of
hemoglobin responders (patients with an increase from baseline in Hgb
concentration >1.0
g/dL), e.g., every 4 weeks and at EoT; (4) serum iron Cn,a,, e.g., at Visit 4;
and (5) incidence
of SFP responders (patients with a maximal increase from baseline in serum
iron
concentration >1001..t.g/dL), e.g., at Visit 4. Safety endpoints include
incidence of treatment-
emergent adverse events and serious adverse events and changes in clinical
laboratory tests,
vital signs, and weight.
[0075] Combination therapy comprising SFP and a citrate compound produces a
sustained
increase in serum iron of >100 i.t.g/dL and in hemoglobin concentration of >1
g/dL in a
majority of the treated patients. Co-administering SFP and a citrate compound
is more
effective at increasing serum iron and hemoglobin concentrations than
combination therapy
comprising conventional ferrous sulfate and the citrate compound. Without
being bound to
CA 03010771 2018-07-05
WO 2017/120311 PCT/US2017/012300
theory, in patients with IRIDA, oral co-administration of SFP with the citrate
compound
bypasses the hepcidin-mediated block of enterocyte iron uptake by permitting
paracellular
absorption (i) of intact SFP that reaches the proximal duodenum and jejunum,
with
subsequent direct donation of iron to transferrin, and (ii) of iron derived
from SFP. The
therapeutic efficacy of combination therapy comprising SFP and a citrate
compound in
IRIDA patients previously unresponsive to iron therapy demonstrates the
ability of such
combination therapy to treat a wide variety of patients suffering from iron
deficiency,
anemia, and/or high hepcidin levels.
[0076] Although the foregoing invention has been described in some detail by
way of
illustration and example for purposes of clarity of understanding, it will be
readily apparent to
those of ordinary skill in the art in light of the teachings of this
disclosure that certain changes
and modifications may be made thereto without departing from the spirit or
scope of the
appended claims.
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