Note: Descriptions are shown in the official language in which they were submitted.
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METHODS FOR TREATING HYPERURICEMIA IN PATIENTS WITH GOUT
USING HALOFENATE OR HALOFENIC ACID AND A SECOND URATE-
LOWERING AGENT
BACKGROUND
[0001] Conditions associated with elevated serum uric acid levels
(hyperuricemia) include
disorders of urate crystal deposition such as gout arthropathy and tophi,
urolithiasis (urinary tract
stones), urate nephropathy, as well as the sequelae of these disorders.
Hyperuricemia is
associated with an increased risk of developing gout arthropathy, and the risk
of gout increases
with the degree and duration of the hyperuricemia. In addition to gout
arthropathy, chronic
hyperuricemia may lead to the deposition of uric acid crystals in the urinary
tract, renal
parenchyma, and soft tissues, resulting in urolithiasis, urate nephropathy
with chronic kidney
disease, and soft tissue tophi, respectively. Because of limitations and
disadvantages of current
uric acid lowering agents, more effective methods, compositions and therapies
to lower uric acid
are needed.
SUMMARY
[0002] The present application describes methods of lowering the serum uric
acid level of a
subject with hyperuricemia, the method comprising administering to the subject
a first urate-
lowering agent and a second urate-lowering agent, wherein the first urate-
lowering agent is a
compound of Formula (I)
X,0
R
0 0 CX3
(I)
wherein R is selected from the group consisting of hydroxy, lower aralkoxy, di-
lower
alkylamino-lower alkoxy, lower alkanamido-lower alkoxy, benzamido-lower
alkoxy, ureido-
lower alkoxy, N'-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy,
halophenoxy-
substituted lower alkoxy, carbamoyl-substituted phenoxy, carbonyl-lower
alkylamino, N,N-di-
lower alkylamino-lower alkylamino, halo-substituted lower alkylamino, hydroxyl-
substituted
lower alkylamino, lower alkanolyloxy-substituted lower alkylamino, ureido, and
lower alkoxy
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carbonylamino; and each X is independently a halogen; or a pharmaceutically
acceptable salt
thereof.
[0003] Also disclosed are methods of treating a subject having a condition
associated with
hyperuricemia, the method comprising administering to the subject a first
urate-lowering agent
and a second urate-lowering agent, wherein the first urate-lowering agent is a
compound of
Formula (I). Also disclosed are methods of treating hyperuricemia in a subject
with gout
comprising administering to the subject a composition comprising a first urate-
lowering agent
and a second urate-lowering agent, wherein the first urate-lowering agent is a
compound of
Formula (I).
[0004] Also disclosed are compositions and kits comprising a first urate-
lowering agent and a
second urate-lowering agent, wherein the first urate-lowering agent is a
compound of Formula
(I).
[0005] In some aspects, the compound of Formula (I) is (-)-halofenate, (-)-
halofenic acid, or a
pharmaceutically acceptable salt thereof. In some aspects, the second urate-
lowering agent is a
xanthine oxidase inhibitor, an inhibitor of uric acid production, a uricosuric
agent or a uricase.
In some aspects, the second urate-lowering agent is allopurinol or febuxostat.
Other aspects are
provided below.
[0006] Currently available uric acid lowering agents and other therapeutic
agents in
development have limitations in their ability to lower serum uric acid to a
desirable level, and
their use may be limited by various adverse side effects or toxicities. For
example, certain agents
including allopurinol and febuxostat, when used to treat hyperurecimia at
commonly prescribed
doses, often fail to reach the common therapeutic target of serum uric acid
levels of 6 mg/dL or
less. Advantages of the compositions, methods, and kits disclosed herein over
currently
available uric acid lowering agents at commonly prescribed doses and treatment
methods using
such agents may include improved therapeutic benefits; a synergistic effect on
lowering uric acid
(i.e., an additive or over-additive effect as compared to the effects of
single-agent therapies);
beneficial effects on other conditions associated with hyperuricemia and urate
crystal deposition;
and provoking fewer or less intense side effects. In some aspects, the
synergistic effect allows
dose reduction or dosing interval extension relative to a currently available
uric acid lowering
agent taken individually at prescribed doses.
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DETAILED DESCRIPTION
[0007] As utilized in accordance with the present disclosure, the following
terms, unless
otherwise indicated, shall be understood to have the following meanings:
[0008] "About" when qualifying a number, refers to a range of plus or minus
ten percent of
that value or number, unless indicated otherwise. Without limiting the
application of the
doctrine of equivalents as to the scope of the claims, each number should be
construed in light of
such factors as the number of reported significant digits and the manner or
method (e.g.
instrumentation, sample preparation, etc.) used to obtain that number.
[0009] "Administering" or "administration" refers to the act of giving a drug,
prodrug, or
therapeutic agent to a subject. Exemplary routes of administration are
discussed below.
[0010] "Acute gout" refers to gout present in a subject with at least one
gouty symptom (e.g.,
podagra or other gouty arthritis, gout flare, gouty attack).
[0011] "Arhalofenate" refers to (-)-halofenate, i.e. (-)-(R)-(4-chloro-pheny1)-
(3-
trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl ester.
[0012] "Chronic gout" refers to gout present in a subject having recurrent or
prolonged gout
flares, tophus formation, chronic inflammatory arthritis, or joint
deterioration associated with
gout, and includes the periods following recovery from acute gout and between
acute gout
attacks (i.e. intercritical gout).
[0013] "Composition" or, interchangeably, "formulation" refers to a
preparation that contains a
mixture of various excipients and key ingredients that provide a relatively
stable, desirable, and
useful form of a compound or drug.
[0014] The prefixes "d" and "1" or (+) and (-) are employed to designate the
sign of rotation of
plane-polarized light by the compound, with (+) or d- meaning that the
compound is
"dextrorotatory" and with (-) or 1- meaning that the compound is
"levorotatory". For a given
chemical structure, these isomers or "optical isomers" are identical except
that they are mirror
images of one another. In describing an optically active compound, the
prefixes R and S are
used to denote the absolute configuration of the molecule about its chiral
center(s). There is no
correlation between the nomenclature for the absolute stereochemistry and for
the rotation of an
enantiomer (i.e., the R- isomer can also be the 1- isomer). A specific optical
isomer can also be
referred to as an "enantiomer," and a mixture of such isomers is often called
an "enantiomeric"
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or "racemic" mixture. See, e.g., A. Streitwiesser, & C.H. Heathcock,
INTRODUCTION TO
ORGANIC CHEMISTRY, 2nd Edition, Chapter 7 (MacMillan Publishing Co., U.S.A.
1981).
The optical rotation lab of (-)-halofenate was measured in methyl alcohol.
[0015] "Elevated serum uric acid level" refers to a serum uric acid level
greater than normal
and, in patients with gout, generally refers to a serum uric acid level
greater than or equal to
about 6 mg/dL. In some instances, elevated serum uric acid levels are above
the mean level in a
given population, such as those of a particular gender or age.
[0016] "Effective amount" refers to an amount required (i) at least partly to
attain the desired
response in a subject; (ii) to delay or to prevent the onset of a particular
condition being treated
in a subject; or (iii) or to inhibit or to prevent the progression of a
particular condition being
treated in a subject. The effective amount for a particular subject varies
depending upon the
health and physical condition of the subject to be treated, the taxonomic
group of individual to be
treated, the degree of protection desired, the formulation of the composition,
the assessment of
the medical situation, and other relevant factors. It is expected that the
amount will fall in a
relatively broad range that can be determined through routine trials.
[0017] "First urate-lowering agent" refers to a compound of any of Formulae
(I), (II), (III), or
(IV) or a therapeutically acceptable salt or prodrug thereof.
[0018] "Gout" refers to a group of disorders or symptoms most often associated
with the build
up of uric acid due to an overproduction of uric acid or a reduced ability of
the kidney to excrete
uric acid. Gout is often characterized by the deposition of urate crystals
(uric acid or salts
thereof, e.g. monosodium urate) in the joints (gouty arthropathy) or soft
tissue (tophi). "Gout" as
used herein includes acute gout, chronic gout, moderate gout, refractory gout
and severe gout.
[0019] "Gout-associated inflammation" refers to local or systemic inflammation
due to
immune responses to the deposition of urate crystals.
[0020] "Halofenate" refers to the compound of Formula (III), i.e. (4-
chloropheny1)-(3-
trifluoromethylphenoxy)-acetic acid 2-acetylaminoethyl ester (also referred to
as the 2-
acetamidoethyl ester of 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid.
The term
halofenate and the corresponding chemical names include both the (+) and (-)
enantiomer of
compounds of Formula (III) as well as mixtures thereof, unless otherwise
specified.
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[0021] "Halofenic acid" and "CPTA" refer to the compound of Formula (IV), i.e.
4-
chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid [also referred to as 2-(4-
chloropheny1)-2-
(3-(trifluoromethyl)phenoxy)acetic acid] as well as its pharmaceutically
acceptable salts. The
term halofenic acid and the corresponding chemical names include both the (+)
and (-)
enantiomer of compounds of Formula (II) as well as mixtures thereof, unless
otherwise specified.
[0022] "Hyperuricemia" refers to an elevated serum uric acid level (see
above).
[0023] "Lower," when used to describe chemical substituents of compounds of
Formulae (I)
and (II) such as lower aralkoxy, di-lower alkylamino-lower alkoxy, lower
alkanamido, lower
alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N'-lower alkyl-ureido-
lower alkoxy,
carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbonyl-lower
alkylamino,
N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino,
hydroxy
substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino,
lower
alkoxycarbonylamino, phenyl-lower alkyl, lower alkanamido-lower alkyl, and
benzamido-lower
alkyl refers to groups having from one to six carbon atoms. For example,
"lower alkoxy" means
C1_6alkoxy.
[0024] "Moderate gout" refers to gout present in a subject having at least two
gout flares in the
past 12 months.
[0025] "Pharmaceutically acceptable" refers to that which is useful in
preparing a
pharmaceutical composition that is generally safe, non-toxic, and neither
biologically nor
otherwise undesirable, and includes that which is acceptable for veterinary or
human
pharmaceutical use.
[0026] "Pharmaceutically acceptable salt" includes pharmaceutically acceptable
acid addition
salts and pharmaceutically acceptable base addition salts and includes both
solvated and
unsolvated forms. Representative non-limiting lists of pharmaceutically
acceptable salts can be
found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington:
The Science and
Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams
& Wilkins,
Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby
incorporated by
reference herein.
[0027] "Pharmaceutically acceptable acid addition salt" refers to salts formed
with inorganic
acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid and
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the like, and organic acids such as acetic acid, trifluoroacetic acid,
propionic acid, glycolic acid,
pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
acid, tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic
acid, p-toluenesulfonic acid, salicylic acid, and the like.
[0028] "Pharmaceutically acceptable base addition salt" refers to salts
prepared from the
addition of an inorganic base or an organic base to the free acid. Salts
derived from inorganic
bases include, but are not limited to, the sodium, potassium, lithium,
ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts
derived from
organic bases include, but are not limited to, salts of primary, secondary,
and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines and basic ion
exchange resins, such as isopropylamine, trimethylamine, diethylamine,
triethylamine,
tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine,
ethylenediamine, glucosamine, methylglucamine, theobromine, purines,
piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like.
[0029] "Refractory gout" refers to gout in patients who are unresponsive or
poorly responsive,
or have experienced or are at an increased risk of experiencing an adverse
event, after being
administered either (1) one or more second urate-lowering agents but not a
first urate-lowering
agent or (2) a first-urate lowering agent but not a second urate-lowering
agent. The terms
"unresponsive" and "poorly responsive" in this context include (1) no or
insignificant lowering
of serum uric acid, (2) failure to reach a target serum uric acid level (e.g.
as determined by a
physician or other medical practitioner), and (3) the persistence of one or
more gouty conditions
or symptoms such as gout flares, gouty tophus, gouty arthritis, or other
associated conditions
regardless of any lowering of serum uric acid levels.
[0030] "Second urate-lowering agent" refers to a therapeutic agent that lowers
serum uric acid
levels that is not a first urate-lowering agent. Second urate-lowering agents
include currently
available agents (i.e. an agent approved by the FDA or other appropriate
regulatory authority as
of the filing date of this application) that lower serum uric acid, as well as
compounds currently
in development or under regulatory review. Examples of second urate-lowering
agents are
provided below.
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[0031] "Subject" and "patient" refer to animals such as mammals, including
humans, other
primates, domesticated animals (e.g. dogs, cats), farm animals (e.g. horses,
cattle, goats, sheep,
pigs), rats and mice.
[0032] "Severe gout" refers to gout present in a subject having tophaceous
deposits in the
joints, skin, or kidneys resulting in chronic arthritis, joint destruction,
subcutaneous tophi, or
kidney dysfunction, and, in some cases, with subsequent deformity and/or
disability.
[0033] "Substantially free from" when used in reference to (-)-halofenate or (-
)-halofenic acid
(or a salt thereof) being substantially free from the corresponding (+)
enantiomer (i.e. (+)-
halofenate, (+)-halofenic acid, or a salt thereof) refers to a composition
containing a high
proportion of a compound's (-) enantiomer in relation to the (+) enantiomer.
In one
embodiment, the term means that by weight, the compound included in the
composition is at
least 85% (-) enantiomer and at most 15% (+) enantiomer. In one embodiment,
the term means
that by weight, the compound included in the composition is at least 90% (-)
enantiomer and at
most 10% (+) enantiomer. In other embodiments, the term means that by weight,
the compound
included in the composition is at least 91% (-) enantiomer and at most 9% (+)
enantiomer, at
least 92% (-) enantiomer and at most 8% (+) enantiomer, at least 93% (-)
enantiomer and at most
7% (+) enantiomer, at least 94% (-) enantiomer and at most 6% (+) enantiomer,
at least 95% (-)
enantiomer and at most 5% (+) enantiomer, at least 96% (-) enantiomer and at
most 4% (+)
enantiomer, at least 97% (-) enantiomer and at most 3% (+) enantiomer, at
least 98% (-)
enantiomer and at most 2% (+) enantiomer, or at least 99% (-) enantiomer or
greater than 99%
(-) enantiomer. Other percentages of the (-) and (+) enantiomers may also be
provided. These
percentages are based upon the amount of the enantiomer relative to the total
amount of both
enantiomers of the compound in the composition.
[0034] "Therapeutically effective dose," "therapeutically effective amount,"
or,
interchangeably, "pharmacologically acceptable dose" and "pharmacologically
acceptable
amount" mean that a sufficient amount of a therapeutic agent, therapeutic
agents, or metabolites
thereof will be present in order to achieve a desired result, e.g., lowering
uric acid levels to a
target goal or treating gout in its various forms or treating conditions
associated with
hyperuricemia.
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[0035] "Treatment" and "treating" of a disease, disorder, condition or symptom
refer to (1)
preventing or reducing the risk of developing the disease, disorder or
condition, i.e., causing the
clinical symptoms of the disease, disorder or condition not to develop in a
subject who may be
exposed to or predisposed to the disease, disorder or condition but who does
not yet experience
or display symptoms of the disease, disorder or condition (i.e. prophylaxis);
(2) inhibiting the
disease, disorder or condition, i.e., arresting or reducing the development of
the disease, disorder
or condition or its clinical symptoms; and (3) relieving the disease, disorder
or condition, i.e.,
causing regression, reversal, or amelioration of the disease, disorder or
condition or reducing the
number, frequency, duration or severity of its clinical symptoms. The term
"management" may
be used synonymously.
[0036] "Urate" refers to uric acid (7,9-dihydro-1H-purine-2,6,8(3H)-trione)
and ions and salts
thereof.
[0037] This application describes compositions, kits and methods for the
treatment of
hyperuricemia, that is, for lowering serum uric acid levels. One aspect of the
current disclosure
relates to a composition comprising a first urate-lowering agent and a second
urate-lowering
agent, wherein said first urate-lowering agent is a compound of Formula (I)
X,0
R
0 0 CX3
(I)
wherein R is selected from the group consisting of a hydroxy, lower aralkoxy,
di-lower
alkylamino-lower alkoxy, lower alkanamido-lower alkoxy, benzamido-lower
alkoxy, ureido-
lower alkoxy, N'-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy,
halophenoxy
substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower
alkylamino, N,N-di-
lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy
substituted
lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, and
lower
alkoxycarbonylamino; and each X is independently a halogen; or a
pharmaceutically acceptable
salt thereof.
[0038] In certain aspects, the first urate-lowering agent is a compound of
Formula (II)
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X 0
0
0R2
0 is cx3
(II)
wherein R2 is selected from the group consisting of phenyl-lower alkyl, lower
alkanamido-lower
alkyl, and benzamido-lower alkyl; and each X is independently a halogen, or a
pharmaceutically
acceptable salt thereof.
[0039] In other aspects, the first urate-lowering agent is a compound of
Formula (III), also
referred to as halofenate
CI 00
H
ONyCH3
0 0 CF3 0
(III)
or a pharmaceutically acceptable salt thereof.
[0040] In other aspects, the first urate-lowering agent is a compound of
Formula (IV), also
referred to as halofenic acid
CI ei0
OH
0 0 CF3
(IV)
or a pharmaceutically acceptable salt thereof.
[0041] It should also be noted that any carbon atom with unsatisfied valences
in the formulae
and examples herein is assumed to have the hydrogen atom to satisfy the
valences.
[0042] In certain embodiments the compound is a compound that generates the
compound of
Formula (IV) or a pharmaceutically acceptable salt thereof via a chemical
reaction after being
administered, as discussed in more detail below.
[0043] Another aspect provides for methods of treating a condition associated
with an elevated
serum uric acid level comprising administering to a subject in need thereof a
pharmaceutical
composition comprising a first urate-lowering agent, wherein said first urate-
lowering agent is a
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compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable
salt thereof; and a
second urate-lowering agent. Another aspect provides a method of lowering the
serum uric acid
level in a subject comprising administering to a subject in need thereof a
pharmaceutical
composition comprising a first urate-lowering agent, wherein said first urate-
lowering agent is a
compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable
salt thereof; and a
second urate-lowering agent.
[0044] In certain embodiments, the first urate-lowering agent is (-)-
halofenate (i.e. (-)-(R)-(4-
chloro-pheny1)-(3-trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl
ester, also referred
to as arhalofenate). In other embodiments, the first urate-lowering agent is (-
)-halofenic acid (i.e.
(-)-4-chlorophenyl-(3-trifluoromethylphenoxy) acetic acid) or a
pharmaceutically acceptable salt
thereof. In certain embodiments, the (-)-halofenate, (-)-halofenic acid, or
pharmaceutically
acceptable salt thereof is substantially free from the corresponding (+)
enantiomer.
[0045] The enantiomers (stereoisomers) of compounds of Formulae (I), (II),
(III) or (IV) and
pharmaceutically acceptable salt thereof can be prepared by using reactants or
reagents or
catalysts in their single enantiomeric form in the process wherever possible
or by resolving the
mixture of stereoisomers by conventional methods including use of microbial
resolution,
resolving the diastereomeric salts formed with chiral acids or chiral bases
and chromatography
using chiral supports. See, also U.S. Patent No. 7,199,259 (Daugs), U.S.
Patent Nos. 6,646,004;
6,624,194; 6,613,802; and 6,262,118 (each to Luskey et al.), U.S. Patent No.
7,714,131 (Zhu et
al.), U.S. Patent No. 7,432,394 (Cheng et al.) and U.S. Publication No.
2010/0093854 (Broggini
et al.) each of which are incorporated herein by reference in their
entireties.
[0046] The chemical synthesis of racemic mixtures of (3-trihalomethylphenoxy)
(4-
halophenyl) acetic acid derivatives can also be performed by the methods
described in U.S.
Patent No. 3,517,050, the teachings of which are incorporated herein by
reference. The
individual enantiomers can be obtained by resolution of the racemic mixture of
enantiomers
using conventional means known to and used by those of skill in the art. See,
e.g., Jaques, J., et
al., in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York
(1981).
Other standard methods of resolution known to those skilled in the art,
including but not limited
to, simple crystallization and chromatographic resolution, can also be used
(see, e.g.,
Stereochemistry of Carbon Compounds (1962) E. L. Eliel, McGraw Hill; J.
Lochmuller,
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Chromatography, 113, 283-302 (1975)). Additionally, halofenate, halofenic
acid, or a
pharmaceutically acceptable salt thereof, i.e., the optically pure isomers,
can be prepared from
the racemic mixture by enzymatic biocatalytic resolution. Enzymatic
biocatalytic resolution has
been generally described previously (see, e.g., U.S. Patent Nos. 5,057,427 and
5,077,217, the
disclosures of which are incorporated herein by reference). Other generic
methods of obtaining
enantiomers include stereospecific synthesis (see, e.g., A.J. Li et al.,
Pharm. Sci. 86, 1073-77
(1997).
[0047] One embodiment provides a composition comprising a pharmaceutically
acceptable salt
of halofenate or halofenic acid. The neutral forms of the therapeutic agents
may be regenerated
by contacting the salt with a base or acid and isolating the parent
therapeutic agent in the
conventional manner. The parent form of the therapeutic agent differs from the
various salt
forms in certain physical properties, such as solubility in polar solvents,
but otherwise the salts
are equivalent to the parent form.
[0048] The second urate-lowering agent may be any other agent (i.e. not a
first urate-lowering
agent, as defined herein) that lowers serum uric acid levels. These second
urate-lowering agents
include inhibitors of uric acid production (e.g. xanthine oxidase inhibitors
and purine nucleoside
phosphorylase inhibitors), uricosuric agents and uricases.
[0049] For example, in some embodiments, the second urate-lowering agent is a
xanthine
oxidase inhibitor. Xanthine oxidase inhibitors lower the amount of urate in
blood by decreasing
the synthesis of uric acid. Xanthine oxidase is involved in purine metabolism
and inhibiting the
enzyme reduces uric acid levels. Xanthine oxidase inhibitors include, but are
not limited to:
allopurinol, febuxostat, oxypurinol, tisopurine, an inositol and propolis. In
some embodiments,
the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol,
tisopurine, inositol, phytic
acid, myo-inositiol, kaempferol, myricetin4 and quercetin. Allopurinol (1,5-
dihydro-4H-
pyrazolo [3,4-dlpyrimidin-4-one), a xanthine oxidase inhibitor, is the current
first line standard
of care for lowering urate levels. Another xanthine oxidase inhibitor,
febuxostat (2-(3-cyano-4-
isobutoxypheny1)-4-methy1-1,3-thiazole-5-carboxylic acid), was approved for
treatment of gout
in February 2009. In one embodiment, halofenate, halofenic acid or a
pharmaceutically
acceptable salt thereof, is administered before, concurrently or subsequent to
administration of
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allopurinol. In one embodiment, halofenate, halofenic acid or a
pharmaceutically acceptable salt
thereof is administered before, concurrently or subsequent to administration
of febuxostat.
[0050] In other embodiments, the second urate-lowering agent is a purine
nucleoside
phosphorylase (PNP) inhibitor. Purine nucleoside phosphorylase inhibitors
represent a relatively
new approach to lowering serum uric acid levels in patient with hyperuricemia,
gout, and related
conditions. In some embodiments, the PNP inhibitor is forodesine (BCX-1777)
(BioCryst
Pharmaceuticals, Inc.). In other embodiments, the PNP inhibitor is BCX-4208 (7-
(((3R,4R)-3-
hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)methyl)-3H-pyrrolo113,2-dlpyrimidin-
4(5H)-one)
(BioCryst Pharmaceuticals, Inc.). BCX4208 monotherapy administered at 40, 80,
120, 160 and
240 mg/day has been shown to rapidly and significantly reduced serum uric acid
in gout patients.
[0051] In some embodiments, the second urate-lowering agent is a uricosuric
agent.
Uricosuric agents enhance renal excretion of uric acid and generally act by
lowering the
absorption of uric acid from the kidney proximal tubule back to the blood,
e.g., by inhibiting
urate transporters, e.g, SLC22Al2. Uricosuric agents include, but are not
limited to, probenecid,
2-((5-bromo-4-(4-cyclopropylnaphthalen-1-y1)-4H-1,2,4-triazol-3-yl)thio)acetic
acid (RDEA594,
lesinurad), potassium 4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-y1)-4H-1,2,4-
triazol-3-
yl)thio)acetamido)-3-chlorobenzoate (RDEA806), RDEA684, benzbromarone,
sulfinpyrazone,
amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan,
adrenocorticotropic hormone, and
cortisone. Probenecid is the most commonly used uricosuric agent in the U.S.
and may be given
in combination with allopurinol to some gout patients. Benzbromarone and
sulfinpyrazone are
also used as first line uricosuric agents. Guaifenesin, losartan,
atorvastatin, amlodipine,
adrenocorticotropic hormone (ACTH or corticotropin), fenofibrate and cortisone
also have
uricosuric effects. In one embodiment, a first urate-lowering agent (e.g. (-)-
halofenate, (-)-
halofenic acid or a pharmaceutically acceptable salt thereof) is administered
before, concurrently
or subsequent to administration of a uricosuric agent. In one embodiment, a
first urate-lowering
agent (e.g. (-)-halofenate, (-)-halofenic acid or a pharmaceutically
acceptable salt thereof) is
administered before, concurrently or subsequent to administration of
probenecid, benzbromarone
or sulfinpyrazone.
[0052] In some embodiments, the second urate-lowering agent is a uricase
enzyme, or a
fragment or pegylated derivative thereof. Uricase or urate oxidase enzymes are
found in many
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mammals but not in humans. They can lower uric acid levels by converting uric
acid into
allantoin, a benign end metabolite which is easily excreted in the urine.
Uricase enzymes
include, but are not limited to, rasburicase or a pegylated uricase enzyme
(PEG-uricase). In
some embodiments, the pegylated uricase enzyme is Krystexxa (PURICASEC);
pegloticase)
(Savient Pharmaceuticals, Inc.) which is approved in the U.S. for the
treatment of chronic gout in
adult patients refractory to conventional therapy.
[0053] The present disclosure also provides for methods of treating one or
more conditions
associated with an elevated serum uric acid level, i.e. hyperuricemia, the
methods comprising
administering to a subject in need thereof a pharmaceutical composition
comprising a first urate-
lowering agent, wherein said first urate-lowering agent is a compound of
Formulae (I), (II), (III)
or (IV) or a pharmaceutically acceptable salt thereof; and a second urate-
lowering agent.
Conditions associated with hyperuricemia include, but are not limited to gout;
acute gout;
chronic gout; moderate gout; refractory gout; severe gout; deposition of uric
acid crystals in the
urinary tract, renal parenchyma, soft tissues, joints, cartilage or bones;
urolithiasis; urate
nephropathy; tophi; podagra; acute inflammatory gouty arthritis; joint
destruction; urinary tract
infections; renal impairment; chronic kidney disease; kidney stones; local
inflammation;
systemic inflammation; immune-related disorders; cardiovascular disease
including peripheral
vascular disease, coronary artery disease and cerebrovascular disease; insulin
resistance;
diabetes; fatty liver disease; dementia including vascular dementia;
dyslipidemia; preeclampsia;
hypertension; obesity; muscle spasm; localized swelling; pain including joint
pain, muscle
fatigue; and stress feelings.
[0054] A variety of factors increase the risk that a patient will have gout or
will experience one
or more of its symptoms. In addition to hyperuricemia, these factors include
obesity, diabetes,
chronic kidney failure, hypertension, use of diuretic drugs and certain other
drugs (e.g.
salicylates, pyrazinamide, ethambutol, nicotinic acid, cyclosporin, 2-
ethylamino-1,3,4-
thiadiazole, fructose and cytotoxic agents), overeating or fasting, a high
purine diet, a high
fructose diet, exposure to lead, consumption of red meat and protein, alcohol
intake, and injury
or recent surgery. Acute gout can be precipitated by perioperative ketosis in
surgical patients,
reduced body temperature, e.g., while sleeping, and by dehydration, e.g., by
use of diuretic
drugs. Genetic risk factors for gout and hyperuricemia have also been
identified.
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[0055] In various embodiments, the methods described herein may be used to
treat any of the
aforementioned conditions or disorders. That is, in one embodiment, the
condition associated
with an elevated serum uric acid level is gout. In some embodiments, the
subject has acute gout.
In some embodiments, the subject has chronic gout. In some embodiments the
subject has
moderate gout. In some embodiments the subject has refractory gout. In some
embodiments the
subject has severe gout. For example, one method provides for the management
of
hyperuricemia in a subject with gout. Certain methods provide for the
treatment or management
of hyperuricemia in a subject with gout comprising administering a
pharmaceutical composition
comprising a first urate-lowering agent and a second urate-lowering agent. In
some
embodiments the first urate-lowering agent is (-)-halofenate, (-)-halofenic
acid or a
pharmaceutically acceptable salt thereof. In certain embodiments, the
treatment can be for about
four weeks or longer, for about one month or longer, for about 12 weeks or
longer, for about
three months or longer, for about six months or longer, for about one year or
longer, for about
two years or longer, for about five years or longer, for about 10 years or
longer. In certain
embodiments the treatment can be indefinite, e.g. for the remainder of the
lifetime of the subject.
In certain embodiments the second urate-lowering agent is selected from the
group consisting of
a uric acid synthesis inhibitor, a uricase, and a uricosuric agent, and
pharmaceutically acceptable
salts thereof. In certain embodiments the second agent may be allopurinol or
febuxostat.
[0056] In various embodiments the methods comprise treating gout. In some
embodiments,
the methods comprise treating gout by preventing gout flares. In another
embodiment the
method comprises reducing the number, frequency, duration or severity of one
of more gout
flares. In another embodiment the method comprises preventing, reducing or
reversing uric acid
crystal formation. In some embodiments of the methods for treating uric acid
crystal formation,
the uric acid crystal formation is in one or more of the joints, under skin,
and kidney. In some
embodiments, the formations include tophaceous deposits. In some embodiments,
the subject
has uric acid crystal formation determined by aspiration of tophi or by
aspiration of synovial
fluid of an inflamed joint. In another embodiment the method comprises
reducing uric acid
burden. In another embodiment the method comprises reducing the size or number
of tophi. The
size or number of tophi may be assessed by known methods, for example, use of
CT scans.
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[0057] This application also provides methods of lowering the serum uric acid
level, treating a
subject having a condition associated with an elevated serum uric acid level,
and treating
hyperuricemia in a subject with gout, in subjects with refractory gout. In
certain embodiments,
the subject is refractory to allopurinol, 2-((5-bromo-4-(4-
cyclopropylnaphthalen-1-y1)-4H-1,2,4-
triazol-3-yethio)acetic acid (RDEA594, lesinurad), 2-(3-cyano-4-
isobutoxypheny1)-4-methyl-
1,3-thiazole-5-carboxylic acid (febuxostat), or BCX4208. In some embodiments
the subject is
refractory to allopurinol. For example, in one embodiment, the subject is
refractory to
allopurinol administered at from 100 mg/day to 800 mg/day (e.g. from 100
mg/day to 300
mg/day) for about one month or longer, about three months or longer, about one
year or longer,
etc. In some embodiments the subject is refractory to febuxostat. For example,
in one
embodiment the subject is refractory to febuxostat administered at from 40
mg/day to 120
mg/day for about one month or longer, about three months or longer, about one
year or longer,
etc. In certain embodiments the subject has mild or moderate chronic kidney
disease (CKD2-3).
In other embodiments the subject has severe chronic kidney disease (CKD4). In
other
embodiments, the subject is on aspirin or diuretic therapy.
[0058] It will be recognized by persons with ordinary skill in the art that
patients with gout or
at risk of developing gout may be administered agents such as non-steroidal
anti-inflammatory
drugs (NSAIDS), colchicine, steroids, or similar medicaments to treat or
manage gout flares.
Accordingly, in certain embodiments of the methods described herein, the
subjects may also be
administered an agent such as an NSAID, colchicine or a steroid.
[0059] The methods described herein may be accomplished by the administration
of a
compound that generates the compound of Formula (IV) or a salt thereof via a
chemical reaction
after being administered. Such compounds include prodrugs of the compound of
Formula (IV).
Prodrugs of a compound are prepared by modifying functional groups present in
the compound
in such a way that the modifications may be cleaved in vivo to release the
parent compound, or
an active metabolite. For example, prodrugs include compounds wherein a
hydroxy, amino, or
sulfhydryl group in a compound is bonded to any group that may be cleaved in
vivo to
regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
Certain prodrugs may
increase the bioavailability of the compounds of the embodiments when such
compounds are
administered to a subject (e.g., by allowing an orally administered compound
to be more readily
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absorbed into the blood) or which enhance delivery of the parent compound to a
certain organ or
tissue (e.g., kidneys, adipose tissue, liver, muscles or joints) relative to
the parent species.
Prodrugs of the compound of Formula (IV) include esters, amides, and
carbamates (e.g., N, N-
dimethylaminocarbonyl) of the hydroxy functional group of the compound of
Formula (IV). The
compounds of Formulae (I), (II), and (III) are non-limiting examples of
prodrugs of the
compound of Formula (IV). Further examples of prodrugs can be found in J.
Rautio et al.
Prodrugs: design and clinical applications, Nat. Rev. Drug Discov., 7, 255-270
(2008); Edward
B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and
Pergamon Press, (1987); and T. Higuchi and V. Stella, Pro-drugs as Novel
Delivery Systems,
Vol. 14 of the A.C.S. Symposium Series (1975), each of which are hereby
incorporated by
reference herein.
[0060] In various embodiments, the compositions, methods, and kits described
herein lower
serum uric acid levels in a subject by about 5%, about 10%, about 15%, about
20%, about 25%,
about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,
about 65%,
about 70%, about 75%, about 80%, about 85%, about 90% or more, as compared to
serum uric
acid levels in the subject prior to administering the methods described
herein. In various
embodiments, serum uric acid levels are decreased about 5% to about 50%,
decreased by about
25% to about 75%, or decreased by about 50% to about 99%. Methods to determine
serum uric
acid levels are well known in the art and are often measured as part of a
standard chemistry panel
of blood serum samples.
[0061] In some embodiments, the compositions, methods, and kits of the present
disclosure
lower serum uric acid levels in a subject to about 7 mg/dL or less, to about
6.8 mg/dL or less, to
about 6 mg/dL or less, to about 5 mg/dL or less, to about 4 mg/dL or less, or
to about 3 mg/dL or
less as compared to serum uric acid levels in the subject prior to
administering the methods or
compositions described herein. In some embodiments, the methods of the present
disclosure
lower serum uric acid levels in a subject by 0.1, 0.2, 0.3, 0.4, 0.5, 1.0,
1.5, 2.0, 2.5, 3.0, 3.5, 4.0,
4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg/dL, or
greater, as compared to serum
uric acid levels in the subject prior to administering the methods or
compositions described
herein. In further embodiments, the methods described herein lower serum uric
acid levels by
between 0.1 and 10.0 mg/dL, between 0.5 and 6.0 mg/dL, between 1.0 and 4.0
mg/dL or between
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1.5 and 2.5 mg/dL. The appropriate serum uric acid level may vary depending on
the subject,
and may vary for a given subject over time, depending upon the subject's
overall medical
condition. Similarly, the appropriate serum uric acid level for one group of
subjects sharing a
common medical condition may be different from that which is appropriate for a
different group
of subjects sharing a different medical condition. Thus, it may be advisable
to reduce the serum
uric acid level of a given group of subjects to, for example, below about 5
mg/dL, and to reduce
the serum uric acid level of a different group of subjects to, for example,
below about 4 mg/dL.
In certain embodiments, the methods of the present disclosure decrease a serum
uric acid level in
the subject by an amount sufficient to result in the disappearance, reduction,
amelioration, or the
prevention of the onset, of one or more conditions associated with elevated
serum uric acid over
a certain timeframe, for example about four weeks or longer, about one month
or longer, about
three months or longer, about one year or longer, about two years or longer,
etc. For example, a
method can decrease the serum uric acid level in a subject by an amount
sufficient to result in the
disappearance or reduction of tophi over about four weeks or longer, about one
month or longer,
about three months or longer, about one year or longer, about two years or
longer, etc.
[0062] In further embodiments, the methods of the present disclosure comprise
administering a
pharmaceutical composition comprising a first urate-lowering agent and a
second therapeutic
agent, as described herein, to a subject whose serum uric acid level is at
least about 4 mg/dL, at
least about 5 mg/dL, at least about 6 mg/dL, at least about 6.8 mg/dL, at
least about 7 mg/dL, at
least about 8 mg/dL, at least about 9 mg/dL, at least about 10 mg/dL, or at
least about 11 mg/dL.
Again, the amount of decrease of serum uric acid level that is appropriate may
vary depending
on the subject, depending upon the subject's overall medical condition.
Similarly, the amount of
decrease of serum uric acid level that is appropriate for one group of
subjects sharing a common
medical condition may be different from that which is appropriate for a
different group of
subjects sharing a different medical condition.
[0063] The therapeutic agents and combinations thereof disclosed herein are
contemplated to
exhibit therapeutic activity when administered in an amount which can depend
on the particular
case. The variation in amount can depend, for example, on the subject being
treated and the
active ingredients chosen. A broad range of doses can be applicable. Dosage
regimes may be
adjusted to provide the optimum therapeutic response. For example, several
divided doses may
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be administered daily, weekly, monthly or other at suitable time intervals or
the dose may be
proportionally reduced as indicated by the exigencies of the situation. Such
dosages are
optionally altered depending on a number of variables, not limited to the
activity of the one or
more active ingredients used, the disease or condition to be treated, the mode
of administration,
the requirements of the individual subject, the severity of the disease or
condition being treated,
and the judgment of the practitioner.
[0064] As described throughout, the present disclosure contemplates
combination therapy and
methods of concomitant administration of a first and second urate-lowering
agent (wherein these
first and second urate-lowering agents are described above). Combination
therapy and
concomitant administration refer to the administration of the two agents
(i.e., a first agent and a
second urate-lowering agent, as described above) in any manner in which the
pharmacological
effects of both are manifested in the subject at the same time. Thus, such
administration does not
require that a single pharmaceutical composition, the same type of
formulation, the same dosage
form, or even the same route of administration be used for administration of
both the first and
second urate-lowering agents, or that the two agents be administered at the
same time. Such
administration may be accomplished most conveniently by the same dosage form
and the same
route of administration, at substantially the same time. For example, a first
urate-lowering agent,
e.g. halofenate, halofenic acid, or a pharmaceutically acceptable salt
thereof, and a second urate-
lowering agent, e.g. xanthine oxidase inhibitor (e.g., allopurinol or
febuxostat), can be
administered to the human subject together in a single oral dosage
composition, such as a tablet
or capsule, or each agent can be administered in separate oral dosage
formulations. One
advantage with separate formulations is an added flexibility in dosing, i.e.
the dosage of the first
and second urate-lowering agents can be changed independently, quickly, and
easily. Where
separate dosage formulations are used, the first and second urate-lowering
agents can be
administered at essentially the same time (i.e., simultaneously or
concurrently), or at separately
staggered times (i.e., sequentially).
[0065] Depending on factors such as the diagnosis, symptoms, and therapeutic
goals of a
particular subject, a wide range of dosages of the first and second agent can
be contemplated. In
various embodiments, the first urate-lowering agents may be administered from
about 10 mg to
about 1000 mg per day and the second urate-lowering agent may be administered
from about 10
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mg to about 4000 mg per day. For example, halofenate, halofenic acid, or a
pharmaceutically
acceptable salt thereof may be administered at about 100 mg/day, about 200
mg/day, about 300
mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700
mg/day, about 800
mg/day, about 900 mg/day, or about 1000 mg/day.
[0066] As described above, in certain embodiments the second agent is
allopurinol. The
currently recommended daily dosage of allopurinol is from 100 mg/day to 800
mg/day in
increments of 100 mg/day. When administered as a second urate-lowering agent
as described
herein (i.e. when a first urate-lowering agent is also administered), the
dosage range of
allopurinol may be within, above, or below the currently recommended daily
dosage, as provided
above and as appropriate for the subject being treated. By way of non-limiting
example, in
certain embodiments wherein the first urate-lowering agent is arhalofenate
(i.e. (-)-halofenate)
and wherein the second urate-lowering agent is allopurinol, the following
daily dosages may be
administered: arhalofenate 100 mg/day, allopurinol 50 mg/day; arhalofenate 100
mg/day,
allopurinol 100 mg/day; arhalofenate 100 mg/day, allopurinol 200 mg/day;
arhalofenate 100
mg/day, allopurinol 300 mg/day; arhalofenate 100 mg/day, allopurinol 400
mg/day; arhalofenate
100 mg/day, allopurinol 600 mg/day; arhalofenate 100 mg/day, allopurinol 800
mg/day;
arhalofenate 200 mg/day, allopurinol 50 mg/day; arhalofenate 200 mg/day,
allopurinol 100
mg/day; arhalofenate 200 mg/day, allopurinol 200 mg/day; arhalofenate 200
mg/day, allopurinol
300 mg/day; arhalofenate 200 mg/day, allopurinol 400 mg/day; arhalofenate 200
mg/day,
allopurinol 600 mg/day; arhalofenate 200 mg/day, allopurinol 800 mg/day;
arhalofenate 300
mg/day, allopurinol 50 mg/day; arhalofenate 300 mg/day, allopurinol 100
mg/day; arhalofenate
300 mg/day, allopurinol 200 mg/day; arhalofenate 300 mg/day, allopurinol 300
mg/day;
arhalofenate 300 mg/day, allopurinol 400 mg/day; arhalofenate 300 mg/day,
allopurinol 600
mg/day; arhalofenate 300 mg/day, allopurinol 800 mg/day; arhalofenate 400
mg/day, allopurinol
50 mg/day; arhalofenate 400 mg/day, allopurinol 100 mg/day; arhalofenate 400
mg/day,
allopurinol 200 mg/day; arhalofenate 400 mg/day, allopurinol 300 mg/day;
arhalofenate 400
mg/day, allopurinol 400 mg/day; arhalofenate 400 mg/day, allopurinol 600
mg/day; arhalofenate
400 mg/day, allopurinol 800 mg/day; arhalofenate 600 mg/day, allopurinol 50
mg/day;
arhalofenate 600 mg/day, allopurinol 100 mg/day; arhalofenate 600 mg/day,
allopurinol 200
mg/day; arhalofenate 600 mg/day, allopurinol 300 mg/day; arhalofenate 600
mg/day, allopurinol
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400 mg/day; arhalofenate 600 mg/day, allopurinol 600 mg/day; arhalofenate 600
mg/day,
allopurinol 800 mg/day.
[0067] Also as described above, in certain embodiments the second agent is
febuxostat. The
currently recommended daily dosage of febuxostat is 40 mg/day or 80 mg/day in
the United
States, and 40 mg/day, 80 mg/day or 120 mg/day in certain other countries.
When administered
as a second urate-lowering agent as described herein (i.e. when a first urate-
lowering agent is
also administered), the dosage range of febuxostat may be within, above, or
below the currently
recommended daily dosage, as provided above and as appropriate for the subject
being treated.
By way of non-limiting example, in certain embodiments wherein the first urate-
lowering agent
is arhalofenate (i.e. (-)-halofenate) and wherein the second urate-lowering
agent is febuxostat,
the following daily dosages may be administered: arhalofenate 100 mg/day,
febuxostat 20
mg/day; arhalofenate 100 mg/day, febuxostat 40 mg/day; arhalofenate 100
mg/day, febuxostat
80 mg/day; arhalofenate 100 mg/day, febuxostat 120 mg/day; arhalofenate 200
mg/day,
febuxostat 20 mg/day; arhalofenate 200 mg/day, febuxostat 40 mg/day;
arhalofenate 200
mg/day, febuxostat 80 mg/day; arhalofenate 200 mg/day, febuxostat 120 mg/day;
arhalofenate
300 mg/day, febuxostat 20 mg/day; arhalofenate 300 mg/day, febuxostat 40
mg/day;
arhalofenate 300 mg/day, febuxostat 80 mg/day; arhalofenate 300 mg/day,
febuxostat 120
mg/day; arhalofenate 400 mg/day, febuxostat 20 mg/day; arhalofenate 400
mg/day, febuxostat
40 mg/day; arhalofenate 400 mg/day, febuxostat 80 mg/day; arhalofenate 400
mg/day,
febuxostat 120 mg/day; arhalofenate 600 mg/day, febuxostat 20 mg/day;
arhalofenate 600
mg/day, febuxostat 40 mg/day; arhalofenate 600 mg/day, febuxostat 80 mg/day;
arhalofenate
600 mg/day, febuxostat 120 mg/day; arhalofenate 800 mg/day, febuxostat 20
mg/day;
arhalofenate 800 mg/day, febuxostat 40 mg/day; arhalofenate 800 mg/day,
febuxostat 80
mg/day; arhalofenate 800 mg/day, febuxostat 120 mg/day.
[0068] Other dose ranges within the ranges described above for each of the
first urate-lowering
agent and the second urate-lowering agent may be readily envisaged. One of
skill in the art will
appreciate that the dose and dosing regimen may be adjusted when therapeutic
agents are used in
combination. When such combinations are used, the dose of one or more of the
agents may be
reduced to a level below the level required for a desired efficacy when the
one or more agents are
used alone. Similarly, the dosing regimen may be modified, e.g., to
synchronize the dosing of
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the one or more therapeutic agents to facilitate improved patient ease of use
and compliance.
Alternately, the dosing regimen of the one or more therapeutic agents can be
sequential, e.g., to
reduce the combined load of the agents at a given time. For example, in
certain embodiments,
the dose of the second urate-lowering agent (e.g. allopurinol, febuxostat, or
the other second
urate-lowering agents described herein) can be adjusted to a lower level than
that currently
recommended when the first urate-lowering agent is and second urate-lowering
agents are
administered.
[0069] Dose titration or dose escalation protocols may be employed to
determine the proper or
optimal dose to administer to a subject. For example, dose titration or
escalation studies may
select for doses that improve efficacy or tolerability. Dose titration or
escalation allows for the
gradual adjusting of the dose administered until the desired effect is
achieved. Dose titration
gradually decreases the dosage administered while dose escalation gradually
increases the dose
administered. Methods of dose titration and escalation are well known in the
art. As a non-
limiting example, a subject may be administered 200 mg/day halofenate,
halofenic acid, or a
pharmaceutically acceptable salt thereof every day and measured for serum uric
acid levels on a
daily basis. The dosage may be increased or decreased, for example, on a
weekly basis. The
subject may be monitored for a period of, for example, 2 to 12 weeks to find
the desired dose.
[0070] In accordance with the compositions, methods and kits described herein,
the first urate-
lowering agent and second urate-lowering agent may be administered in any
manner in which the
pharmacological effects of both are likely to be manifested in the subject at
approximately the
same time. Such administration does not require that a single pharmaceutical
composition, the
same type of formulation, the same dosage form, or even the same route of
administration be
used for administration of both the first and second urate-lowering agents, or
that the two agents
be administered at the same time. That is, in various embodiments, the first
urate-lowering agent
and the second urate-lowering agent described herein may be present in a
single dosage form
(e.g. a single tablet or capsule for oral administration), and in other
embodiments the first urate-
lowering agent may be present in a first dosage form (e.g. a first tablet or
capsule) and the second
urate-lowering agent may be present in a second dosage form (e.g. a second
tablet or capsule).
The dosage forms may include the first and second urate-lowering agents in
doses according to
the examples provided above. A single dosage form (e.g a single tablet or
capsule) may include
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a single daily supply of the first and second urate-lowering agent, or a
fraction thereof, e.g. one-
half of a daily supply, one-third a daily supply, one-fourth a daily supply,
etc. For example, the
pharmaceutical composition described herein can be in a single tablet
comprising 200 mg of
arhalofenate and 150 mg of allopurinol. By way of further example, the
pharmaceutical
composition described herein can be in a single tablet comprising 200 mg of
arhalofenate and 40
mg of febuxostat. Other dosage forms within the scope of this disclosure may
be readily
envisaged.
[0071] In unit dosage form, the formulation may be divided into unit doses
containing
appropriate quantities of the one or more active ingredients. In some
embodiments, the unit
dosage is in the form of a package containing discrete quantities of the
formulation. Non-
limiting examples include packaged tablets or capsules, and powders in vials
or ampoules. In
some embodiments, aqueous suspension compositions are packaged in single-dose
non-
reclosable containers. Alternatively, multiple-dose reclosable containers are
used, in which case
it is typical to include a preservative in the composition. By way of example
only, formulations
for parenteral injection are presented in unit dosage form, which include, but
are not limited to
ampoules, or in multi dose containers, with an added preservative. Tablets,
troches, pills,
capsules and the like may also contain the components as listed hereafter: a
binder such as gum,
acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such
as corn starch, potato starch, alginic acid and the like; a lubricant such as
magnesium stearate;
and a sweetening agent such as sucrose, lactose or saccharin may be added or a
flavoring agent
such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage
unit form is a
capsule, it may contain, in addition to materials of the above type, a liquid
carrier. Various other
materials may be present as coatings or to otherwise modify the physical form
of the dosage unit.
For instance, tablets, pills, or capsules may be coated with shellac, sugar or
both. A syrup or
elixir may contain one or more active ingredients, sucrose as a sweetening
agent, methyl and
propylparabens as preservatives, a dye and flavoring such as cherry or orange
flavor. In some
embodiments, additional ingredients, for example, nonsteroidal anti-
inflammatory drugs or
colchicine, ingredients for treating other related indications, or inert
substances such as artificial
coloring agents are added. Of course, any material used in preparing any
dosage unit form
should be pharmaceutically pure and substantially non-toxic in the amounts
employed. In
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addition, the one or more active ingredients may be incorporated into
sustained-release
preparations and formulations as described herein.
[0072] The pharmaceutical compositions of the present disclosure may be
administered once
daily (QD), twice daily (BID), three times daily (TID) or four times per day
(QID). In one
embodiment, the pharmaceutical composition of the present disclosure is
administered once daily
(QD). In another embodiment, the pharmaceutical composition of the present
disclosure is
administered twice daily (BID).
[0073] This disclosure also describes articles of manufacture such as kits
comprising a
composition comprising a first and second urate-lowering agent (wherein these
first and second
urate-lowering agents are described above). In some embodiments the first
urate-lowering agent
in the kit is (-)-halofenate (i.e. arhalofenate). In some embodiments the
second urate-lowering
agent in the kit is allopurinol. In other embodiments the second urate-
lowering agent in the kit is
febuxostat. The kits can include the compositions packaged for distribution
and in quantities
sufficient to carry out the methods described herein. Kits may also include
instructions (e.g. a
package insert, package label, etc.) for using the kit components in one or
more methods
described herein. For example, a kit may comprise dosage forms of a first
urate-lowering agent
and a second urate-lowering agent described herein, and instructions for
prescribing,
administering or otherwise using the dosage forms to lower serum uric acid
levels. In some
embodiments a kit is for a subject with hyperuricemia or a condition
associated with
hyperuricemia (e.g., gout) to use in the self-administration of the
pharmaceutical composition,
wherein the kit comprises a container housing a plurality of dosage forms
containing a first and
second urate-lowering agent described herein and instructions for carrying out
drug
administration therewith. In one embodiment, a kit comprises a first dosage
form comprising
halofenate, halofenic acid, or a pharmaceutically acceptable salt thereof in
one or more of the
forms identified above and at least a second dosage form comprising one or
more of the forms
identified above, in quantities sufficient to carry out the methods of the
present disclosure. The
second dosage form, and any additional dosage forms (e.g., a third, fourth of
fifth dosage form)
can comprise any active ingredient disclosed herein for the treatment of a
hyperuricemic disorder
(e.g., gout). All dosage forms together can comprise a therapeutically
effective amount of each
compound for the treatment of a condition associated with hyperuricemia (e.g.,
gout). In some
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embodiments a kit is for a subject with a condition associated with
hyperuricemia (e.g., gout) to
use in the self-administration of at least one oral agent, wherein the kit
comprises a container
housing a plurality of said oral agents and instructions for carrying out drug
administration
therewith. The embodiments of this application are characterized by the
specification and by the
features of the Claims of this application as filed, and of corresponding
pharmaceutical
compositions, methods and uses of these compounds.
Examples
Example 1: Clinical Trial
[0074] This is a randomized, double-blind, placebo-controlled study to
evaluate the safety and
efficacy of daily oral doses of between 400 to 600 mg of arhalofenate (i.e., (-
)-halofenate) in
combination with 300 mg oral doses of allopurinol will be conducted in
approximately 90 gout
patients with inadequate hypouricemic (uric acid lowering) response to
allopurinol alone.
Approximately 45 of these 90 patients will participate in a
allopurinol/oxypurinol serial PK
sample collection sub-study.
[0075] The 90 patients will be randomized in total; approximately 30 to each
of 3 study arms
in the following manner (1:1:1):
1) Arhalofenate 400 mg (plus allopurinol 300 mg)
2) Arhalofenate 600 mg (plus allopurinol 300 mg)
3) Placebo (plus allopurinol 300 mg)
[0076] Dose/Route/Regimen
[0077] Patients in all treatment groups will take colchicine 0.6 mg once daily
by mouth starting
at Week -3 through the final study follow-up visit, as background therapy for
prophylaxis of gout
flares. Patients in all treatment groups will also take allopurinol 300 mg
once daily by mouth
starting at Week -3 during the run-in and continuing through Week 4. Patients
who fail to
achieve target serum uric acid lowering on allopurinol alone will be
randomized into the study.
[0078] The randomized treatment regimens will be the following (Day 1 through
Week 4):
= Treatment Group #1: Arhalofenate 400 mg (plus allopurinol)
= Treatment Group #2: Arhalofenate 600 mg (plus allopurinol)
= Treatment Group #3: Placebo (plus allopurinol)
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[0079] Analysis
[0080] All participating patients who will have received treatment in any dose
group and for
whom the primary PK data are considered to be sufficient and interpretable
will be analyzed in
the PK analyses. For patients included in the serial PK subset, allopurinol
and oxypurinol
pharmacokinetics in the presence and absence of arhalofenate at both doses
will be determined
from the repeat dose (Week 3, Visit 5) plasma concentrations, including the
following PK
parameters, as appropriate:
= Exposure, or area under the concentration-time curve (AUC0-24, AUCO-
last,AUCO-inf)
= Maximum concentration (Cmax)
= Time to reach maximum concentration (Tmax)
= Terminal elimination half-life (t1/2)
[0081] Safety
[0082] The interpretation of the safety and tolerability will be made based on
the assessment of
safety parameters evaluated throughout the study, including clinical
laboratory tests, 12-lead
ECGs, vital signs, physical examination, concomitant medication review, and
AEs (excluding
medical events, which are "AEs" captured before dosing on Day 1). The
reporting of the safety
data is descriptive, and will include all patients receiving at least one dose
of arhalofenate or
allopurinol. Descriptive analysis will include the incidence and type of AEs
by treatment group
including tabulation by severity, as well as actual data and changes in
laboratory, vital signs, and
12-lead ECG measurements from pre-dosing to all post-dosing time points.
[0083] Pharmacodynamics
[0084] The effects of each of the three treatment groups will be assessed as
the absolute and
percent change from baseline to each of the selected post-dosing time points
for the following
endpoints:
= sUA at Week 4 of treatment
= The proportion of patients achieving a sUA < 6 mg/dL
= The proportion of patients achieving a sUA < 5 mg/dL
= The proportion of patients achieving a sUA < 4 mg/dL
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Example 2: Clinical Trial
[0085] This study evaluates the safety and efficacy of single oral doses of
between 400 to 600
mg of arhalofenate in combination with 80 mg oral doses of febuxostat in
approximately 10 to 15
gout patients for the treatment of hyperuricemia in patients with gout.
[0086] In addition to colchicine 0.6 mg daily for flare prophylaxis, all
patients will receive
febuxostat and arhalofenate in the following order during the Treatment Phase:
= Days 1 through 7: febuxostat 80 mg orally once daily (febuxostat only
period)
= Days 8 through 21: febuxostat 80 mg plus arhalofenate 400 mg orally once
daily
(febuxostat plus arhalofenate 400 mg period)
= Days 22 through 35: febuxostat 80 mg plus arhalofenate 600 mg orally once
daily
(febuxostat plus arhalofenate 600 mg period)
[0087] The sUA level will be assessed on the last day of each treatment period
(Day 7, Day 21,
and Day 35); on these days, sUA samples will be collected at four different
time points: pre-
dose (fasting), 2 hours post-dose, 6 hours post-dose, and 10 hours post-dose
(prior to evening
meal).
[0088] Dose/Route/Regimen
= Colchicine: 0.6 mg /oral/daily from Day -16 through Day 49
= febuxostat: 80 mg/oral/daily from Day 1 through Day 35
= Arhalofenate: 400 mg/oral daily from Day 8 through Day 21; 600
mg/oral/daily from
Day 22 through Day 35
[0089] Duration of Treatment
= Phase 1: Screening Phase: 1 to 4 weeks
= Phase 2: Run-in/Stabilization Phase: > 2 weeks
= Phase 3: Treatment Phase: 5 weeks
= Phase 4: Follow-up Phase: 2 weeks
[0090] Analysis
[0091] Safety
[0092] The interpretation of the safety and tolerability will be made based on
the assessment of
safety parameters evaluated throughout the study, including clinical
laboratory tests, 12-lead
ECGs, vital signs, physical examination, concomitant medication review, and
AEs. The
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reporting of the safety data is descriptive, and will include all patients
receiving at least one dose
of arhalofenate. Descriptive analysis will include the incidence and type of
AEs including
tabulation by severity, as well as actual data and changes in laboratory,
vital signs, and 12-lead
ECG measurements. Listings of clinically significant abnormal laboratory data
will be
presented. The case report form (CRF)-captured ECG and physical exam will be
summarized
using categorical statistical method.
[0093] Pharmacodynamics
[0094] The effects of each of the febuxostat plus arhalofenate combination
treatment periods
will be assessed as the change from baseline (Day 1) to end of treatment
period for the following
endpoints:
= The proportion of patients achieving a sUA < 6 mg/dL
= The proportion of patients achieving a sUA < 5 mg/dL
= The proportion of patients achieving a sUA < 4 mg/dL
= The proportion of patients achieving a sUA < 3 mg/dL
= Absolute and percent change in sUA
[0095] While the foregoing description describes specific embodiments, those
with ordinary
skill in the art will appreciate that various modifications and alternatives
can be developed.
Accordingly, the particular embodiments and examples described above are meant
to be
illustrative only, and not to limit the scope of the invention, which is to be
given the full breadth
of the appended claims, and any and all equivalents thereof.
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