U.S. patent application number 14/930488 was filed with the patent office on 2018-03-01 for methods for treating gout flares.
This patent application is currently assigned to CymaBay Therapeutics, Inc.. The applicant listed for this patent is CymaBay Therapeutics, Inc.. Invention is credited to Brian Edward Lavan, Charles A. McWherter, Brian K. Roberts, Gopal Chandra Saha.
Application Number | 20180055803 14/930488 |
Document ID | / |
Family ID | 50622909 |
Filed Date | 2018-03-01 |
United States Patent
Application |
20180055803 |
Kind Code |
A1 |
Lavan; Brian Edward ; et
al. |
March 1, 2018 |
Methods for Treating Gout Flares
Abstract
Methods of treating gout flares comprising administering a
composition comprising a first urate-lowering agent are disclosed.
In some aspects, the first urate-lowering agent is (-)-halofenate,
(-)-halofenic acid, or a pharmaceutically acceptable salt thereof.
Other aspects provide for methods of reducing the number, duration,
frequency or intensity of gout flares experienced by a subject.
Inventors: |
Lavan; Brian Edward; (San
Francisco, CA) ; Saha; Gopal Chandra; (Dublin,
CA) ; Roberts; Brian K.; (Palo Alto, CA) ;
McWherter; Charles A.; (Oakland, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CymaBay Therapeutics, Inc. |
Newark |
CA |
US |
|
|
Assignee: |
CymaBay Therapeutics, Inc.
Newark
CA
|
Family ID: |
50622909 |
Appl. No.: |
14/930488 |
Filed: |
November 2, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13961848 |
Aug 7, 2013 |
|
|
|
14930488 |
|
|
|
|
13668003 |
Nov 2, 2012 |
9060987 |
|
|
13961848 |
|
|
|
|
61556052 |
Nov 4, 2011 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/426 20130101;
C07C 59/68 20130101; C07C 233/47 20130101; A61K 31/192 20130101;
A61K 31/216 20130101 |
International
Class: |
A61K 31/216 20060101
A61K031/216; A61K 31/426 20060101 A61K031/426; C07C 59/68 20060101
C07C059/68; C07C 233/47 20060101 C07C233/47; A61K 31/192 20060101
A61K031/192 |
Claims
1.-18. (canceled)
19. A method for decreasing the number, duration, frequency, or
intensity of gout flares experienced by a subject during initiation
or maintenance of therapy for the disappearance or reduction of
tophi, comprising administration to the subject of a
therapeutically effective amount of a flare decreasing agent that
is selected from the group consisting of (-)-halofenate and
(-)-halofenic acid, or a pharmaceutically acceptable salt thereof,
and substantially free from the corresponding (+)-enantiomer.
20. The method of claim 19 where the flare decreasing agent is
(-)-halofenate.
21. The method of claim 197 where the flare decreasing agent is
(-)-halofenic acid or a pharmaceutically acceptable salt
thereof.
22. The method of claim 19 where the therapeutically effective
amount of the flare decreasing agent is between about 50 mg/day and
about 1000 mg/day.
23. The method of claim 22 where the therapeutically effective
amount of the flare decreasing agent is between about 400 mg/day
and about 1000 mg/day.
24. The method of claim 23 where the therapeutically effective
amount of the flare decreasing agent is 400, 600, or 800
mg/day.
25. The method of claim 19 further comprising concomitant
administration to the subject of a therapeutically effective amount
of a flare prophylaxis agent or a pain management agent.
26. The method of claim 25, where the concomitant administration
comprises concurrent administration of the flare decreasing agent
and the flare prophylaxis agent or pain management agent.
27. The method of claim 25 where the concomitant administration
comprises sequential administration of the flare decreasing agent
and the flare prophylaxis agent or pain management agent.
28. The method of claim 25 where the flare decreasing agent is
(-)-halofenate.
29. The method of claim 25 where the flare decreasing agent is
(-)-halofenic acid or a pharmaceutically acceptable salt
thereof.
30. The method of claim 25 where the therapeutically effective
amount of the flare decreasing agent is between about 50 mg/day and
about 1000 mg/day.
31. The method of claim 30 where the therapeutically effective
amount of the flare decreasing agent is between about 400 mg/day
and about 1000 mg/day.
32. The method of claim 31 where the therapeutically effective
amount of the flare decreasing agent is 400, 600, or 800
mg/day.
33. The method of claim 25 where the flare prophylaxis agent or
pain management agent is an NSAID, an opiate, or colchicine.
34. The method of claim 33 where the flare prophylaxis agent or
pain management agent is colchicine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/556,052 filed on Nov. 4, 2011, the complete
disclosure of which is incorporated by reference herein.
BACKGROUND
[0002] This application relates to the treatment, including the
prevention, of gout flares.
SUMMARY
[0003] This application describes methods of treating a gout flare
experienced by a subject comprising administering to the subject a
compound of Formula (I)
##STR00001##
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.
[0004] Other aspects provide for methods of reducing the number,
duration, frequency or intensity of gout flares experienced by a
subject comprising administering a compound of Formula (I) or a
pharmaceutically acceptable salt thereof to the subject. Other
aspects provide for the treatment of hyperuricemia in a subject
with gout comprising administering to a subject in need thereof a
compound of Formula (I), wherein the dose, frequency, and duration
of administration are effective to reduce the number, duration,
frequency, or intensity of gout flares experienced by the subject
during the duration. Yet other aspects provide for methods of
providing to a subject (-)-halofenic acid with an intraday
peak-to-trough ratio of about 2.0 or less. Further aspects are
provided below.
[0005] Uric acid lowering agents such as allopurinol and febuxostat
generally increase the number, duration, frequency, or intensity of
gout flares upon initiation of therapy, and this exacerbation may
last for several weeks to months following initiation of such
therapy. Uric acid lowering agents often require a dose titration
strategy in which the dose is progressively increased to the
therapeutic dose in order to minimize the number, duration,
frequency, or intensity of flares. Flare treatment or prophylaxis
with an additional therapeutic agent such as a non-steroidal
anti-inflammatory agent (NSAID) or colchicine is often recommended
during this period. During longer term maintenance use of urate
lowering therapy, flares can also be precipitated by fluctuations
in uric acid levels caused by non-adherance with prescribing
instructions. Advantages of the current methods include decreasing
the number, duration, frequency, or intensity of flares experienced
by the patient (e.g. during initiation or maintenance of therapy
for uric acid lowering), decreasing the need for dose titration,
and reducing the amount or duration of additional anti-flare
medicaments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 is a graph showing the mean trough plasma
concentration values of (-)-halofenic acid during and following a
30-day dosing schedule of daily oral administration of 400 mg of
arhalofenate.
[0007] FIG. 2 is a graph showing the mean and standard deviation
(SD) of (-)-halofenic acid plasma concentrations at Day 15 and Day
30 following daily oral administration of 400 mg of arhalofenate in
20 human subjects.
[0008] FIG. 3 is a graph showing reduction in serum uric acid in
subjects over time following once daily dosing with
arhalofenate.
[0009] FIG. 4 is a chart showing the effect of the administration
of (-)-halofenate on the incidence of gout flares in human
subjects. "Pbo" means placebo; dosage information refers to the
daily dosage of (-)-halofenate.
[0010] FIG. 5 is a chart showing the effect of the administration
of (-)-halofenate on flare duration in human subjects. "Pbo" means
placebo; dosage information refers to the daily dosage of
(-)-halofenate.
[0011] FIG. 6 is a chart showing the effect of febuxostat alone and
concomitant administration of febuxostat and (-)-halofenate on the
incidence of gout flares in human subjects presented as percentage
of patients experienced any flare per week.
[0012] FIG. 7 is a chart showing the effect of febuxostat alone and
concomitant administration of febuxostat and (-)-halofenate on
flare duration in human subjects.
DETAILED DESCRIPTION
[0013] As utilized in accordance with the present disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings:
[0014] "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.
[0015] "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.
[0016] "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).
[0017] "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).
[0018] "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.
[0019] The terms "combination therapy," "concomitantly
administering" and "concomitant administration" refer to the
administration of two or more agents in any manner in which the
pharmacological effects of those agents are manifested in the
subject at the same time. These terms encompass administering two
or more agents to a subject substantially concurrently, for example
in a single dosage form (e.g. a single capsule, pill, tablet,
etc.), administering at least one agent in one dosage form and the
other agent(s) in a separate dosage form, and administering each
agent in its own separate dosage form. The administration may be
performed sequentially or simultaneously. For example, for
sequential administration, the first agent may be administered
before or after the second agent.
[0020] The prefixes "d" and "l" 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 l-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
l-isomer). A specific optical isomer can also be referred to as an
"enantiomer," and a mixture of such isomers is often called an
"enantiomeric" or "racemic" mixture. See, e.g., A. Streitwiesser
& C. H. Heathcock, INTRODUCTION TO ORGANIC CHEMISTRY, 2.sup.nd
Edition, Chapter 7 (MacMillan Publishing Co., U.S.A. 1981). The
optical rotation [.alpha.].sub.D of (-)-halofenate was measured in
methyl alcohol.
[0021] "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.
[0022] "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.
[0023] "First urate-lowering agent" refers to a compound of any of
Formula (I), (II), (III) or (IV) or a therapeutically acceptable
salt or prodrug thereof. For clarity, this term implies no temporal
aspect or relationship, e.g. to a second urate-lowering agent.
[0024] "Flare" or "gout flare" refers to a symptom of gout
associated with a sudden onset of pain and inflammation, especially
in peripheral joints such as the toes or fingers.
[0025] "Gout" refers to a group of disorders or symptoms most often
associated with the accumulation 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.
[0026] "Gout-associated inflammation" refers to local or systemic
inflammation due to immune responses to the deposition of urate
crystals.
[0027] "Halofenate" refers to compounds of Formula (III) below,
i.e. (4-chlorophenyl)-(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.
[0028] "Halofenic acid" and "CPTA" refer to the compounds of
Formula (IV), i.e. 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetic
acid [also referred to as
2-(4-chlorophenyl)-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 (IV) as well as mixtures
thereof, unless otherwise specified.
[0029] "Hyperuricemia" refers to an elevated serum uric acid level
(see above).
[0030] "Impaired renal function" refers to a medical condition in
which the kidneys fail to adequately filter toxins and waste
products from the blood. Impaired renal function may take the form
or acute kidney injury or chronic kidney disease (i.e. CKD1-5).
[0031] "Moderate gout" refers to gout present in a subject having
at least two gout flares in the past 12 months.
[0032] "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.
[0033] "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.
[0034] "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
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.
[0035] "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.
[0036] "Refractory gout" refers to gout in patients who are
unresponsive or poorly responsive to one or more second
urate-lowering agents, or have experienced or are at an increased
risk of experiencing an adverse event therefrom. 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.
[0037] "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. For clarity, this
term implies no temporal aspect or relationship, e.g. to a first
urate-lowering agent.
[0038] "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.
[0039] "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.
[0040] "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.
[0041] "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.
[0042] "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, duration, frequency or intensity one or more
of its clinical symptoms (e.g. a gout flare). The term "management"
may be used synonymously.
[0043] "Urate" refers to uric acid
(7,9-dihydro-1H-purine-2,6,8(3H)-trione) and ions and salts
thereof.
[0044] This application describes methods of treating a gout flare
comprising administering to the subject a compound of Formula
(I)
##STR00002##
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.
[0045] In certain aspects, the compound is a compound of Formula
(II)
##STR00003##
wherein R.sup.2 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.
[0046] In other aspects, the compound is a compound of Formula
(III), also referred to as halofenate
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0047] In other aspects, the compound is a compound of Formula
(IV), also referred to as halofenic acid
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0048] It should 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.
[0049] 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.
[0050] In certain embodiments, the compound is the (-) enantiomer
of a compound of Formula (I), (II), (III) or (IV). In certain
embodiments, the compound is (-)-halofenate (i.e.
(-)-(R)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid
2-acetylamino-ethyl ester, also referred to as arhalofenate). In
other embodiments, the compound 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.
[0051] The enantiomers (stereoisomers) of compounds of Formula (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. Pat. No. 7,199,259 (Daugs),
U.S. Pat. Nos. 6,646,004; 6,624,194; 6,613,802; and 6,262,118 (each
to Luskey et al.), U.S. Pat. No. 7,714,131 (Zhu et al.), U.S. Pat.
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.
[0052] 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. Pat. 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., J.
Jaques 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, 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. Pat. 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, 1073-1077 (1997)).
[0053] FIGS. 1-2 show the pharmacokinetic profile of (-)-halofenic
acid. FIG. 1 shows the mean trough plasma concentration values of
(-)-halofenic acid during and following a 30-day dosing schedule of
daily oral administration of 400 mg of arhalofenate. FIG. 2 shows
the mean and standard deviation (SD) plasma concentration values of
(-)-halofenic acid at day 15 and day 30 following daily oral
administration of 400 mg of arhalofenate. These figures demonstrate
a long half-life with sustained drug levels present for several
days after the final dose, and a relatively constant intraday
plasma concentration. The plasma concentration of (-)-halofenic
acid is expected to correlate to the plasma concentration of uric
acid. Accordingly, the long half-life and low intraday
peak-to-trough ratio are expected to result in correspondingly
gradual changes in serum uric acid during the initiation of and
maintenance use of therapy. FIG. 3 demonstrates the reduction in
serum uric acid over time with several doses of arhalofenate, and
supports this theory. It is thought that large or rapid changes in
serum uric acid (resulting from, for example, the administration of
certain second urate-lowering agents, e.g. allopurinol, febuxostat,
and others when no first urate-lowering agent is administered) can
trigger gout flares or result in longer, more frequent, or more
intense flares, for example during and for the several weeks and
months after initiation of such agents, or with non-adherance to
daily use of such agents. Therefore, the pharmacokinetic profile of
(-)-halofenic acid should contribute to the successful use of
compounds of Formula (I), (II), (III) or (IV) and pharmaceutically
acceptable salts thereof in the prevention of gout flares (for
example, during certain durations such as the first several weeks
to month after initiation of administration), compared to other
urate lowering therapies.
[0054] Methods described herein include reducing the number,
duration, frequency or intensity of one or more gout flares, the
methods comprising administering to a subject in need thereof a
compound of any of Formula (I), (II), (III) or (IV) or a
pharmaceutically acceptable salt thereof. In some embodiments the
compound is (-)-halofenate, (-)-halofenic acid or a
pharmaceutically acceptable salt thereof. In some embodiments, the
number, duration, frequency or intensity of gout flares experienced
by the subject is reduced relative to that experienced by the
subject before such administration is initiated. In other
embodiments, the number, duration, frequency or intensity of gout
flares experienced by the subject is reduced relative to the
number, duration, frequency or intensity of gout flares experienced
by the subject when the subject has previously undergone
urate-lowering therapy with a second urate-lowering agent. In some
embodiments, the methods described herein are for the prevention of
flares. In some embodiments, the methods described herein are for
the prophylaxis of flares.
[0055] In certain methods described herein, a compound of Formula
(I) and a flare prophylaxis or pain management agent (including,
but not limited to, a non-steroidal anti-inflammatory drug (NSAID),
an opiate, or colchicines, and wherein such agent is not a compound
of Formula (I)) can be concomitantly administered to the subject.
In certain methods, the amount or duration of administration of
such flare prophylaxis or pain management agent is reduced (as
compared to when no compound of Formula (I) is administered), and
in other methods no such flare prophylaxis or pain management agent
is administered.
[0056] The second urate-lowering agent may be any agent that lowers
serum uric acid levels that is not a first urate-lowering agent
(i.e. not a compound of any of Formula (I), (II), (III) or (IV) or
a pharmaceutically acceptable salt thereof). 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.
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, myricetin, and quercetin.
Allopurinol (1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-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-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic
acid), was approved for treatment of gout in February 2009. Purine
nucleoside phosphorylase (PNP) 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 (BCX1777) (BioCryst
Pharmaceuticals, Inc.). In other embodiments, the PNP inhibitor is
ulodesine (BCX4208;
7-(((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)methyl)-3H-pyrrolo-
[3,2-d]pyrimidin-4(5H)-one) (BioCryst Pharmaceuticals, Inc.).
Ulodesine 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. 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, SLC22A12. Uricosuric
agents include, but are not limited to, probenecid,
2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)a-
cetic acid (RDEA594, lesinurad), potassium
4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thi-
o)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,
levotofisopam, and cortisone also have uricosuric effects. Uricase
or urate oxidase enzymes are found in many mammals but not 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.RTM. (PURICASE.RTM.;
pegloticase) (Savient Pharmaceuticals, Inc.) which is approved in
the U.S. for the treatment of chronic gout in adult patients
refractory to conventional therapy.
[0057] In some embodiments, the number of gout flares experienced
by the subject is reduced relative to the number, duration,
frequency or intensity of gout flares experienced by the subject
when the subject has previously undergone urate-lowering therapy
with a second urate-lowering agent, wherein the second
urate-lowering agent is allopurinol, febuxostat, lesinurad or
BCX4208.
[0058] Certain methods provide for the treatment or management of
hyperuricemia in a subject with gout and reducing the number,
duration, frequency or intensity of gout flares experienced by the
subject. These methods comprise administering to a subject in need
thereof a compound of any of Formula (I), (II), (III) or (IV) or a
pharmaceutically acceptable salt thereof. In some embodiments the
compound is (-)-halofenate, (-)-halofenic acid or a
pharmaceutically acceptable salt thereof.
[0059] FIGS. 4-5 show the effect of (-)-halofenate monotherapy on
gout flares in human subjects. Referring to FIG. 4, the
administration of (-)-halofenate dose dependently reduced the
incidence of any flares (Total flare) and flares requiring
treatment compared to placebo (presented as percentage of patients
experienced any flares (total flare) and flares requiring treatment
by treatment arm). Referring to FIG. 5, the administration of
(-)-halofenate also reduced the duration of all flares (any flares
and flares requiring treatment). See Example below for more
details.
[0060] FIGS. 6-7 show the effect of concomitant administration of
(-)-halofenate with febuxostat (a second urate-lowering agent, as
described herein), compared to the administration of febuxostat
with no other urate-lowering agent ("Febuxostat Alone") on gout
flares in human subjects. Referring to FIG. 6, the concomitant
administration of (-)-halofenate and febuxostat reduced flare
incidence as compared to the administration of febuxostat without
(-)-halofenate. FIG. 7 shows that such concomitant administration
also reduced the duration of flares. See Example below for more
details.
[0061] In various embodiments, the methods 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.
[0062] In some embodiments, the methods of the present disclosure
lower serum uric acid levels in a subject to about 7 mg/dL or less,
to about 6.5 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 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 a week, about a month, about six
months, about one year, about two years, or for a longer duration.
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 one week, about one month, about six
months, about one year, about two years, or longer, e.g.
indefinitely, e.g. for the remainder of the lifetime of the
subject.
[0063] In further embodiments, the methods of the present
disclosure comprise administering a pharmaceutical composition
comprising a compound of Formula (I), (II), (III) or (IV) or a
pharmaceutically acceptable salt thereof 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.
[0064] The methods described herein (as well as the underlying
physiological mechanisms related to them) 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 absorbed into the blood) or which
enhance delivery of the parent compound to an organ or tissue
(e.g., adipose tissue, kidneys, liver, muscle, or joints) relative
to the parent species. More particularly, 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.
[0065] The compounds of Formulae (I), (II), (III) and (IV) and
pharmaceutically acceptable salts thereof 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 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.
[0066] Depending on factors such as the diagnosis, symptoms, and
therapeutic goals of a particular subject, a wide range of dosages
of the compound of Formula (I), (II), (III) or (IV) can be
contemplated. In various embodiments, the compound may be
administered from about 10 mg to about 1000 mg per day. For
example, halofenate, halofenic acid, or a pharmaceutically
acceptable salt thereof may be administered at about 50 mg/day,
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.
[0067] 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 decreased 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.
[0068] Compounds of Formula (I), (II), (III) or (IV) can be
incorporated into a variety of formulations and medicaments for
therapeutic administration. More particularly, these compounds can
be formulated into pharmaceutical compositions or formulations by
combination with appropriate, pharmaceutically acceptable carriers
or diluents, and can be formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
pills, powders, granules, dragees, gels, slurries, ointments,
solutions, suppositories, injections, inhalants and aerosols. As
such, administration of the compounds can be achieved in various
ways, including oral, buccal, rectal, parenteral, intraperitoneal,
intradermal, transdermal, or intratracheal administration.
Moreover, the compound can be administered in a local rather than
systemic manner, in a depot or sustained release formulation. In
addition, the compounds can be administered in a liposome.
[0069] Compounds of Formula (I), (II), (III) or (IV) or a
pharmaceutically acceptable salt thereof can also be formulated
with common excipients, diluents or carriers and compressed into
tablets, or formulated as elixirs or solutions for convenient oral
administration, or administered by the intramuscular or intravenous
routes. The compounds can be administered transdermally, and can be
formulated as sustained release dosage forms and the like. In one
embodiment, the above methods may further comprise the
administration of a second urate-lowering agent selected from the
group consisting of a xanthine oxidase inhibitor, an inhibitor of
uric acid production, a uricosuric agent and a uricase. In one
embodiment, the method 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. 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.
[0070] In other embodiments, a first and a second urate-lowering
agent (wherein these first and second urate-lowering agents are
described herein) can be concomitantly administered. 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 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 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 different
times (i.e., sequentially). In various embodiments, the second
urate-lowering agent can be administered at from about 10 mg to
about 4000 mg per day. In certain embodiments, the second
urate-lowering agent is a xanthine oxidase inhibitor, preferably
selected from the group consisting of allopurinol, febuxostat,
oxypurinol, tisopurine, inositol, phytic acid, myo-inositiol,
kaempferol, myricetin, and quercetin, especially allopurinol or
febuxostat. In certain embodiments, the second urate-lowering agent
is allopurinol and is administered at from about 50 mg to about 800
mg per day. In other embodiments, the second urate-lowering agent
is febuxostat and is administered at from about 40 mg to about 120
mg per day. For example, in certain embodiments, the first
urate-lowering agent is (-)-halofenate and is administered at from
about 100 mg to about 1000 mg per day, and the second
urate-lowering agent is febuxostat and is administered at from
about 40 mg to about 120 mg per day. By way of further non-limiting
examples wherein the first urate-lowering agent is (-)-halofenate
and wherein the second urate-lowering agent is febuxostat, the
following daily dosages may be administered: 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 40 mg/day; arhalofenate 800
mg/day, febuxostat 80 mg/day; arhalofenate 800 mg/day, febuxostat
120 mg/day. In another embodiment, the second urate-lowering agent
is a uricosuric agent, preferably selected from the group
consisting of probenecid,
2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)a-
cetic acid, potassium
4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thi-
o)acetamido)-3-chlorobenzoate, RDEA684, benzbromarone,
sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin,
losartan, adrenocorticotropic hormone and cortisone, especially
probenecid.
[0071] 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 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.
[0072] In various embodiments, compounds of Formula (I), (II),
(III) or (IV) or a pharmaceutically acceptable salt thereof can be
administered over a broad frequency range. For example, in various
embodiments the compounds may be administered once daily (QD),
twice daily (BID), three times daily (TID) or four times per day
(QID). In one embodiment, the compound is administered once daily
(QD). In another embodiment, the compound is administered twice
daily (BID). In other embodiments, administration of the compound
can be skipped without having deleterious effect, that is, the
compound can be administered over (i.e. before and after) a "drug
holiday" where the drug holiday is the period of the skipped dose.
For example, in a daily dosing regimen, the compound can be
administered over a drug holiday of one day, (i.e. administered on
day N and day N+2 but not on day N+1, where day N is any arbitrary
day) without the subject experiencing any substantially or
materially adverse effect from the skipped administration. In
certain embodiments the drug holiday can be two days. In other
embodiments the drug holiday can be more than two days.
[0073] In various embodiments, compounds of Formula (I), (II),
(III) or (IV) or a pharmaceutically acceptable salt thereof can be
administered over a broad duration. For example, in various
embodiments the compounds may be administered for about 10 days or
longer, about four weeks or longer, about one month or longer,
about 12 weeks or longer, about three months or longer, about six
months or longer, about one year or longer, about two years or
longer, about five years or longer, or about 10 years or longer. In
some embodiments the administration may be indefinite, e.g. for the
remainder of the lifetime of the subject.
[0074] The pharmacokinetic profile of (-)-halofenic acid can be
modulated by the dose, frequency, and duration of administration of
the compound or a prodrug thereof. One measure of the
pharmacokinetic profile is the peak-to-trough ratio, defined as the
highest blood plasma concentration divided by the lowest blood
plasma concentration of a compound or agent within a certain time
interval (e.g. within the interval corresponding to the frequency
of administration). For example, certain methods include providing
to a subject an intraday peak-to-trough ratio of (-)-halofenic acid
of about 2.0 or less, comprising administering to the subject a
compound of Formula (I), (II), (III) or (IV) or pharmaceutically
acceptable salts thereof at a dose of about 100 to about 1000 mg
per day. In various embodiments, the intraday peak-to-trough ratio
is about 1.7 or less, about 1.5 or less, about 1.4 or less, or
about 1.3 or less. In embodiments, the intraday peak-to-trough
ratio is provided after administering the compound daily for at
least about 10 days, e.g. at least about 12 days. The
pharmacokinetic profile can also depend on the route of
administration, as well as by the compound and formulation
administered to the subject. For example, one method includes
providing to a subject an intraday peak-to-trough ratio of
(-)-halofenic acid of about 2.0 or less, comprising administering
to the subject arhalofenate (i.e. (-)-halofenate) by mouth in an
oral formulation (e.g. a tablet, capsule, pill, etc. as described
above) at a dose of 100 to 1000 mg per day.
[0075] Certain methods described herein may be accomplished by
administering a compound of Formula (I), (II), (III) or (IV) or
pharmaceutically acceptable salts thereof at a certain dose,
frequency, and duration of administration, as provided herein. For
example, certain methods provide for the treatment of hyperuricemia
in a subject with gout comprising administering to a subject in
need thereof a compound of Formula (I), (II), (III) or (IV) or
pharmaceutically acceptable salts thereof wherein the dose,
frequency, and duration of administration are effective to reduce
the number, duration, frequency, or intensity of gout flares
experienced by the subject during the duration of administration.
In some embodiments, the compound is arhalofenate. In some
embodiments the dose is from about 100 mg to about 1000 mg. In some
embodiments the frequency is daily. In some embodiments the
duration of administration is about 10 days or longer, about four
weeks or longer, about one month or longer, about 12 weeks or
longer, about three months or longer, about six months or longer,
about one year or longer, about two years or longer, about five
years or longer, or about 10 years or longer. In some embodiments
the administration may be indefinite, e.g. for the remainder of the
lifetime of the subject. In some embodiments the administration
daily and over a drug holiday of one day. In some embodiments
further comprise administering to the subject arhalofenate by mouth
in an oral formulation. Particular embodiments covering
compositions, formulations and their method of uses are disclosed
in a PCT Patent Application No. PCT/US11/59394 entitled "Methods
for Treating Hyperuricemia in Patients with Gout Using Halofenate
or Halofenic Acid and a Second Urate-Lowering Agent" filed Nov. 4,
2011, and the PCT Application is incorporated herein in its
entirety.
[0076] In other aspects, the compounds and methods described herein
may be used to treat or prevent familial Mediterranean fever;
thrombocytopenic purpura; pericarditis; scleroderma; Behcet's
disease; rheumatoid arthritis; familial cold autoinflammatory
syndrome; Muckle-Wells syndrome; chronic infantile neurologic,
cutaneous and articular syndrome/neonatal onset multisystem
inflammatory disease (CINCA/NOMID); pyogenic arthritis, pyoderma
gangrenosum and acne (PAPA), and related disorders.
Methods
[0077] Methods used in relation to FIGS. 1-2 showing the
pharmacokinetic profile of (-)-halofenic acid were as follows:
[0078] Plasma proteins in human plasma samples containing of
(-)-halofenic acid, an internal standard (I.S.) and heparin as the
anticoagulant were precipitated with acetonitrile. The samples were
vortex mixed, centrifuged and an aliquot was analyzed by reversed
phase high performance liquid chromatography using a Phenomenex
Polar RP column maintained at 45.degree. C. The mobile phase was
nebulized using heated nitrogen in a Z-spray source/interface and
the ionized compounds were detected using a tandem quadrupole mass
spectrometer.
[0079] The plasma concentrations were rounded to the nearest
one-tenth g/mL before the calculations. Plasma samples with
concentrations below the quantifiable limit of 1.0 .mu.g/mL (BQL)
were assigned values of zero.
[0080] Methods used in relation to FIG. 3 showing reduction in
serum uric acid in subjects over time following once daily dosing
with arhalofenate were as follows.
[0081] A single centre Phase 1, placebo- and positive-controlled,
double-blind, randomized, dose escalation study was conducted to
evaluate the multiple-dose pharmacokinetics (PK) of (-)-halofenate
administered as a daily dose orally for 10 days, at the
protocol-specified doses in healthy adult subjects. A total of 119
subjects completed study treatment according to protocol: 6
subjects received (-)-halofenate 100 mg/day for 10 days; 6 subjects
received (-)-halofenate 200 mg/day for 10 days; 9 subjects received
(-)-halofenate 400 mg/day for 10 days; 20 subjects received
(-)-halofenate 600 mg/day for 10 days; 10 subjects received
(-)-halofenate 600 mg Enteric Coated (EC)/day for 10 days; 9
subjects received (-)-halofenate 800 mg EC/day for 10 days; 10
subjects received (-)-halofenate 1000 mg EC/day for 10 days; 24
subjects received placebo treatment daily for 10 days; and 25
subjects received naproxen 500 mg b.i.d. monotherapy for 7 days. In
this study, serum uric acid was measured at screening and on Days
1, 3, 5, 7, 9, 14 and 21.
TABLE-US-00001 TABLE 1 Mean uric Mean uric Mean acid at acid at
change at Mean Treatment baseline Day 9 Day 9 % group N (mg/dL)
(mg/dL) (mg/dL) change Placebo 23 4.70 4.66 -0.04 -1 400 mg 10 4.91
3.89 -1.02 -21 600 mg 20 5.04 3.40 -1.65 -33 600 mg EC 10 5.61 3.92
-1.69 -30 800 mg EC 9 5.60 3.83 -1.77 -32 1000 mg EC 10 5.48 3.04
-2.44 -45
[0082] As shown in FIG. 3 and Table 1, data from this study
demonstrates that the treatment with (-)-halofenate resulted in
gradual reduction in serum uric acid over a period of time at all
dose levels tested, and in a dose dependent manner.
Examples
Example 1: Suppression of Uric-Acid Induced Inflammation In
Vitro
[0083] Differentiated murine 3T3-L1 adipocytes are cultured in
vitro in 24 well plates. To the culture medium (-)-halofenic acid
is added at a final concentration of 50-150 .mu.M prior to the
addition of uric acid at 5 mg/dL or 15 mg/dL and the culture
continued for 3 or 7 days. A parallel culture of cells is conducted
in the presence of a vehicle such as dimethylsulfoxide (DMSO). At
the end of the culture period media is removed, cells are isolated
and messenger RNA prepared. The levels of secreted cytokines
representing a panel of pro-inflammatory cytokines including but
not restricted to monocyte chemoatractant protein-1 (MCP-1), tumor
necrosis factor .alpha. (TNF-.alpha.), interlekin-1.beta.,
(IL-1.beta.), interleukin-6 (IL-6) and interleukin-12 (Il-12) are
determined in the media isolated from the cells using commercially
available cytokine assay kits. The levels of gene expression for
the mRNAs for a panel of pro-inflammatory cytokines including but
not restricted to monocyte chemoatractant protein-1 (MCP-1), tumor
necrosis factor .alpha. (TNF-.alpha.), interlekin-1.beta.,
(IL-1.beta.), interleukin-6 (IL-6) and interleukin-12 (Il-12) are
determined using real-time PCR. The addition of (-)-halofenate
prevents the uptake of uric acid into 3T3-L1 adipocytes and thereby
suppresses the uric acid induced inflammatory response resulting in
a reduced level of expression and consequently secretion of this
panel of pro-inflammatory cytokines. A similar study is also
conducted in primary mouse macrophages and human umbilical vein
endothelial cells.
Example 2: Animal Gout Flare Model
[0084] The models described in R. Torres et al., Ann. Rheum. Dis.
68, 1602-08 (2009) (available at
http://ard.bmj.com/content/68/10/1602.long), which is herein
incorporated by reference in its entirety, is used. Briefly, twenty
C57BL6 mice are obtained from Jackson Laboratories (Bar Harbor Me.
USA) and used between the ages of 12 and 16 weeks. The mice are
housed singly at least a week before study and allowed access to
regular chow and water ad libitum. Arhalofenate is administered
orally to half (ten) of the mice (test mice) daily at a dose of 125
mg/kg for periods of time including for example 1 day, 5 days and 2
weeks prior to induction of inflammation by uric acid. The
remaining ten mice (control mice) are administered a vehicle
consisting of 1% Carboxymethyl Cellulose//2% Tween-80. In another
treatment modality, arhalofenate is co-administered at the time of
uric acid treatment.
[0085] Crystals of monosodium urate (MSU) are prepared as described
in R. Liu-Bryan et al., Arthritis Rheum. 52, 2936-46 (2005). In one
model, MSU crystals (0.5 mg) suspended in 20 microliters of
endotoxin-free PBS are injected intro-articularly into the
tibio-tarsal joint (ankle) of the mice anaesthetized with 2.5%
isoflurane. Thermal hyperalgesia, weight bearing ability, angle
joint diameter, and histological analyses are performed according
to Torres et al, supra. The level of secretion of a panel of
pro-inflammatory cytokines including but not restricted to monocyte
chemoatractant protein-1 (MCP-1), tumor necrosis factor .alpha.
(TNF-.alpha.), interlekin-1.beta., (IL-1.beta.), interleukin-6
(IL-6) and interleukin-12 (Il-12) are measured in fluid isolated
from the injected joints. Joints are dissected and homogenized to
allow preparation of mRNA and the level of gene expression of the
same panel of pro-inflammatory cytokines determined. In another
model, mice are injected intraperitoneally with 1 mg of MSU
suspended in 0.5 ml of endotoxin free PBS. After 6 h, mice are
killed and their peritoneal cavities washed and harvested for
measurement of neutrophil influx by staining with a neutrophil
specific antibody R-phycoerythrin conjugated rat anti mouse Ly-6G
monoclonal antibody. In another model, an air pouch is introduced
subcutaneously and 1 mg of MSU is injected into the pouch. Six
hours after crystal injection the cells resident in the pouch are
collected by lavaging with 5 ml of buffer. Neutrophil infiltatation
is measured by staining as above. The levels of monocyte
chemoatractant protein-1 (MCP-1), tumor necrosis factor .alpha.
(TNF-.alpha.), interlekin-1.beta., (IL-1.beta.), interleukin-6
(IL-6) and interleukin-12 (Il-12) are also measured in the lavaged
fluid isolated from the urate injected air pouch.
Example 3
[0086] Clinical trial evaluating the effectiveness of arhalofenate
at the doses of 400 mg and 600 mg compared to Placebo in serum uric
acid reduction and flare prevention in gout patients with
hyperuricemia.
[0087] Study Design: This was a randomized, double-blind,
placebo-controlled study of 400 mg and 600 mg arhalofenate
administered daily for 4 weeks as monotherapy in patients with gout
(per criteria of the American Rheumatism Association) with
hyperuricemia. Patients using urate lowering therapy (ULT) must
have been willing to discontinue treatment for the duration of the
study. Patients with a recent history of an acute gout flare must
have been symptom free for at least 1 week prior to screening.
[0088] Upon successful completion of screening, patients entered
into a minimum 3-week Run-in/Stabilization Phase. During this
phase, patients on existing ULT were asked to temporarily
discontinue their current therapy. Patients also started colchicine
0.6 mg once daily until the final study visit as prophylaxis to
prevent potential gout flares. Patient who met final eligibility
criteria were randomized (1:1:1) into the Treatment Phase to
receive Placebo, arhalofenate 400 mg, or arhalofenate 600 mg. Each
randomized patient took double-blind study medication daily for a
period of four weeks beginning at Day 1 (Visit 3). Patients
returned to the study site after 2 weeks at Visit 4 and then weekly
at Visits 5 and 6 (Weeks 3 and 4). A Follow-up Visit (Visit 7) took
place 2 weeks after the last dose of study medication.
[0089] Diagnosis and Main Criteria for Inclusion: Male or female
patients aged 18 to 75 years, inclusive who had been diagnosed with
gout and had an sUA .gtoreq.8.0 mg/dL and .ltoreq.12.0 mg/dL were
eligible to participate in this study. Patients with a recent
history of an acute gout flare must have been symptom free for at
least 1 week prior to both screening and randomization.
Criteria for Evaluation:
[0090] The primary efficacy analysis compared the percentage change
in sUA from baseline to end of treatment between the treatment
groups. In addition, gout flares were captured as special interest
event and the incidence of gout flares (all flares and flares that
required treatment), severity (as assessed either mild, moderate,
or severe by the Principal Investigator), and duration (days) were
compared between treatment groups.
Results:
[0091] All randomized patients in this study were male; mean ages
ranged from 50.9 years in the 400 mg arhalofenate group to 54.5
years in the placebo group. The mean (.+-.SD) time since the
initial gout diagnosis was 7.1 years [.+-.6.7] in Placebo groups
and 12.0 years [.+-.8.2] in the 600 mg arhalofenate group. The mean
(.+-.SD) number of gout flares in the preceding 3 months were 2.5
(.+-.2.2), 1.4 (.+-.1.2), and 2.1 (.+-.2.4) for the placebo, 400 mg
arhalofenate, and 600 mg arhalofenate groups, respectively. The
mean (.+-.SD) sUA values at baseline (Day 1) were 9.7 mg/dL
(.+-.1.6) in the placebo group, 9.4 mg/dL (.+-.1.1) in the 400 mg
arhalofenate group and 9.8 mg/dL (.+-.1.3) in the 600 mg
arhalofenate group. A total of 67 (72.0%) patients were randomized
to receive double-blind treatment: 23 patients received Placebo, 21
arhalofenate 400 mg, and 23 arhalofenate 600 mg. A total of 64
patients completed the study: 22 patients in Placebo group, 20
patients in arhalofenate 400 mg group, and 22 patients in
arhalofenate 600 mg group. After 4 weeks of daily treatment with
double-blind study medication, the mean sUA percent (and absolute)
changes from baseline (Day 1) in the PP population were: 4.1% (0.2
mg/dL) in the placebo group, -15.4% (1.4 mg/dL) in the 400 mg
arhalofenate group and -23% (-2.3 mg/dL) in the 600 mg arhalofenate
group. When compared with placebo, the sUA reduction in both of the
arhalofenate treatment groups was statistically significant
(p<0.0001). A total of 10 patients reported flare during the
Treatment Phase: 5 patients (21.7%) in the placebo group, 4
patients (19.0%) in the 400 mg arhalofenate group, and 1 patient
(4.3%) in the 600 mg arhalofenate group [FIG. 4]. Of these, 3
patients (13.0%) in the placebo group, 1 patient (4.8%) in the 400
mg arhalofenate group, and 1 patient (4.3%) in the 600 mg
arhalofenate group required medication (additional colchicine
and/or NSAIDs) [FIG. 4]. The mean duration of Total flares was
longer in the placebo group (5.2 days) than in either the 400 mg
arhalofenate group (1.3 days) or the 600 mg arhalofenate group (1.0
days) [FIG. 5]. The mean (.+-.SD) duration of Flares Requiring
Treatment was also longer in the placebo group (4.7 days) than in
either the 400 mg arhalofenate group (2.0) or the 600 mg
arhalofenate group (1.0 day) [FIG. 5]. No severe gout flare was
reported during the double-blind period. Flares were less severe in
the arhalofenate 600 mg group compared to other groups (3 of 5
flares in placebo group, 2 of 4 flares in 400 mg arhalofenate group
and 0 of 2 flares in 600 mg arhalofenate group were considered
moderate in severity by the investigator).
Example 4
[0092] Clinical trial evaluating the effectiveness of Arhalofenate
in combination with Febuxostat compared to Febuxostat alone in
serum uric acid reduction and flare prevention in gout patients
with hyperuricemia.
[0093] Study Design: This was an open-label study to determine the
sUA reduction and flare prevention with arhalofenate in combination
with febuxostat and compared that with febuxostat alone in gout
patients (per criteria of the American Rheumatism Association) with
hyperuricemia when arhalofenate administered at 400 mg once daily
orally for 2 weeks (Weeks 2-3) and then increased to 600 mg once
daily orally for an additional 2 weeks (Weeks 4-5) in addition to
80 mg febuxostat once daily orally (Weeks 1-5). Patients with a
recent history of an acute gout flare must have been symptom free
for at least 1 week prior to screening.
[0094] All patients who met the screening criteria started a 2-week
Run-in/Stabilization Phase at the same time as out-patient basis.
During this phase, patients on existing urate lowering therapy were
asked to discontinue their current therapy for the duration of the
study. At the same time, patients also started colchicine 0.6 mg
once daily as prophylaxis to prevent potential gout flares. Upon
completing the Run-in/Stabilization Phase, patients were reassessed
at Day -2 (Visit 2) to confirm the final eligibility for the
Treatment Phase. The sUA at this visit must have been .gtoreq.8.0
mg/dL and .ltoreq.10 mg/dL to qualify for the Treatment Phase. In
addition, all safety lab values must have met the eligibility
criteria at this visit. Patients successfully meeting the
eligibility criteria entered the study site for an in-clinic stay
for a total of 37 consecutive days.
[0095] The Treatment Phase began on Day 1 and continued for 5 weeks
until Day 35. The Treatment Phase consisted of 3 sequential drug
dosing periods:
[0096] 80 mg febuxostat orally once daily from Days 1 through 7
(Febuxostat Period).
[0097] 80 mg febuxostat plus 400 mg arhalofenate orally once daily
from Days 8 through 21 (Febuxostat plus 400 mg arhalofenate
Period).
[0098] 80 mg febuxostat plus 600 mg arhalofenate orally once daily
from Days 22 through 35 (Febuxostat plus 600 mg arhalofenate
Period).
[0099] In addition, all patients continued to receive 0.6 mg
colchicine daily for gout flare prophylaxis.
Criteria for Evaluation:
[0100] Efficacy of febuxostat plus arhalofenate combination
treatment was assessed by the proportion of patients achieving a
sUA <6 mg/dL, <5 mg/dL, <4 mg/dL, and <3 mg/dL at Day
22 and Day 36. In addition, absolute and percent changes in sUA at
Day 22 and Day 36 from baseline (Day 1) were also evaluated. Gout
flares were captured as special interest event in this study. The
incidence of gout flares, severity (as assessed either mild,
moderate, or severe by the Principal Investigator), and duration
(days) were compared between treatment periods.
Results:
[0101] A total of 12 patients met the final eligibility criteria at
Visit 2 (Day -2) and entered into the in-patient Treatment Phase of
the study as a single cohort. On Day 1, after receiving the first
dose of febuxostat, 1 patient withdrew consent to continue study
participation for personal reason (got a permanent job); the
remaining 11 patients completed the study including Follow-up
phase. The mean (.+-.SD) time since the initial gout diagnosis was
12.6 years (.+-.7.2). The mean (.+-.SD) number of gout flares in
the preceding 3 months was 0.9 (.+-.1.2). The mean (.+-.SD) sUA at
baseline was 9.0 mg/dL (.+-.0.8). At Day 8, after one week of daily
treatment with 80 mg febuxostat, 11 patients (100%) reached sUA
target of <6 mg/dL, 6 patients (55%) reached <5 mg/dL, and 1
patient (9%) reached <4 mg/dL. At Day 22, after 2 weeks of daily
treatment with 80 mg febuxostat plus 400 mg arhalofenate (preceded
by 80 mg febuxostat daily for 1 week), statistically significantly
higher proportion of patients achieved sUA target of <5 mg/dL
compared with Day 8 (sUA <5.0 mg/dL in 10 patients, p=0.0455).
By Day 36, after 2 weeks of daily treatment with 80 mg febuxostat
plus 600 mg arhalofenate (preceded by 80 mg febuxostat daily for 1
week and 80 mg febuxostat plus 400 mg arhalofenate for 2 weeks),
statistically significantly higher proportion of patients achieved
sUA targets of <5 mg/dL and <4 mg/dL compared with Day 8 (sUA
<5.0 mg/dL in 11 patients, p=0.0253; sUA <4.0 mg/dL in 7
patients, p=0.0143).
[0102] In this study, gout flare was considered as a special
interest event. All patients were taking 0.6 mg colchicine daily as
flare prophylaxis for the entire duration of the study. Overall, 4
patients experienced gout flares during the study--2 patients
during 1 week of febuxostat only period, 2 patients during 2 weeks
of 400 mg arhalofenate plus febuxostat period. No patient reported
flare during 2 weeks of 600 mg arhalofenate plus febuxostat period.
When adjusted by duration of treatment, 18.2% patients/week during
febuxostat only period, and 9.1% patients/week during 400 mg
arhalofenate plus febuxostat period reported flare [FIG. 6]. Mean
duration of the gout flares during the Treatment Phase was 6.5 days
for the febuxostat only period and 4.0 days for the 400 mg
arhalofenate plus febuxostat period [FIG. 7]. All of the flares
were mild or moderate in severity.
Example 5
[0103] Clinical Trial to evaluate the role of arhalofenate
monotherapy (600 mg and 800 mg) in preventing gout flare and
reducing sUA in gout patients when used as a urate lowering agent
and compare that with allopurinol 300 mg.
[0104] Study Design: This is a multi-center, randomized,
double-blind, active and placebo-controlled, parallel group study
in gout patients with sUA of .gtoreq.7.5 mg/dL and .ltoreq.12 mg/dL
who experienced at least 3 flares during the past 12 months.
Approximately 225 eligible patients will be randomized in a
2:2:2:2:1 ratio into one of the following five treatment
groups:
[0105] 1) Arhalofenate (600 mg) once daily.
[0106] 2) Arhalofenate (800 mg) once daily.
[0107] 3) Allopurinol (300 mg) plus colchicine (0.6 mg) once
daily.
[0108] 4) Allopurinol (300 mg) once daily.
[0109] 5) Placebo once daily.
[0110] Study Objectives:
[0111] Primary:
[0112] To evaluate the efficacy of each of two dose levels of
arhalofenate dosed once daily for the prevention of flares in adult
gout patients with hyperuricemia.
[0113] Secondary:
[0114] To evaluate the efficacy of each of two dose levels of
arhalofenate in reducing serum uric acid (sUA).
[0115] To evaluate whether arhalofenate can effectively reduce
acute gout flares without colchicine prophylaxis.
[0116] To evaluate the safety and tolerability of each of two dose
levels of arhalofenate in this study population.
[0117] To select an appropriate dose level of arhalofenate dosed
once daily for future trials
[0118] To measure steady-state arhalofenate concentrations at each
of two dose levels of arhalofenate dosed once daily.
[0119] To evaluate changes in metabolic parameters of interest in
selected patients.
[0120] Study Endpoints:
[0121] Primary
[0122] The incidence of gout flares (mean number of flares per
patient) from baseline through Week 12.
[0123] In this study, a gout flare is defined as a patient-reported
acute articular or bursal pain at rest (exceeding 3.0 cm on a 10.0
cm VAS) typical of a gout attack and deemed (by patient and/or
investigator) to require treatment with an anti-inflammatory
therapeutic agent, and the presence of at least 2 of the following
3 signs or symptoms: joint swelling, warmth, and tenderness; and at
least one of the following: rapid onset of pain, decreased range of
motion, redness, or other symptoms similar to a prior gout
flare.
[0124] Secondary
[0125] Key Secondary endpoints:
[0126] Percent sUA reduction from baseline in arhalofenate 800 mg
group compared to Placebo group.
[0127] Percent sUA reduction from baseline in arhalofenate 600 mg
group compared to Placebo group.
[0128] Proportion of patients with sUA <6 mg/dL at Week 12 in
arhalofenate 800 mg group compared to Placebo group.
[0129] The incidence of gout flares from baseline through Week 12
in arhalofenate 600 mg group compared to allopurinol 300 mg
group.
[0130] Proportion of patients with sUA <6 mg/dL at Week 12 in
arhalofenate 600 mg group compared to Placebo group.
[0131] Proportion of patients experiencing at least one flare from
baseline through week 12.
[0132] Proportion of patients experiencing multiple flares from
baseline through week 12.
[0133] Time from baseline to first flare.
[0134] The incidence of flares from baseline through Week 4, Week 5
through Week 8 and Week 9 through Week 12.
[0135] Flare composite score (summation of the daily maximum pain
severity on VAS during the duration of the flare).
[0136] Evaluation of activity limitation during flare via
HAQ-II.
[0137] Changes from baseline through week 12 in HbA1c and fasting
TG in patients with HbA1c >7.0% and TG >150 mg/dL at
baseline, respectively.
[0138] Adverse events, and changes in vital signs and safety
laboratory tests.
[0139] Safety-related study drug discontinuations.
[0140] Flare-related study drug discontinuations.
[0141] Flares that occur during the study will be managed with oral
NSAIDs (as 1.sup.st line therapy) or oral steroids (as 2.sup.nd
line therapy) if the patient cannot tolerate or has an inadequate
response to NSAIDs. The patient will be allowed to take other
analgesics, according to investigator judgment (e.g. acetaminophen
with codeine), as 3.sup.rd line therapy if the patient cannot
tolerate or has an inadequate response to NSAIDs and oral steroids.
Colchicine will be prohibited as treatment for flares during the
randomized treatment phase.
[0142] All patients will be instructed to maintain their current
diet and lifestyle, including drinking habits (alcoholic and sugary
beverages), throughout the entire study. Patients will be asked to
defer initiating any weight loss diets or meaningfully changing
their activity level and lifestyle, as such a change may influence
sUA levels and potentially trigger a flare, thus confounding a
trial of this nature.
[0143] Once randomized (entered) into the study, patients will
return to the clinic within 7 days to receive study drug supplies
and begin dosing (Day 1). Subsequent study visits will occur at the
end of week 2, week 4, week 8, and week 12 of dosing.
[0144] The patient will be required to report a flare via an
electronic device as soon as conveniently possible and preferably
before taking pain medication. Flare-related data, such as date and
time of onset, pain severity (VAS), and medication taken will be
reported by the patient. Once flare data has been entered by the
patient, the device will send an alert to the investigator or
his/her designee to contact the patient in order to facilitate
additional therapy or data entry, as needed.
[0145] Sample Size:
[0146] This study is powered to detect a treatment group difference
in flare rate (flares per patient) of 50% versus the control group
(group 4, allopurinol 300 mg). Power calculations (using
methodology for comparisons of incidence rates) indicate that a
sample size of 50 patients per treatment group should provide 80%
power, based on the use of a two-sided, two-sample test at the 5%
level of significance, to detect a 50% treatment group difference,
which is a conservative estimate of the expected treatment
effect.
[0147] In this study, the placebo control group will be used for
sUA comparisons (percent reduction and proportion of patients
achieving sUA <6 mg/dL) only. Power calculations indicate that a
sample size of 25 patients in this arm should provide 80% power,
based on the use of a two-sided, two-sample test at the 5% level of
significance, to detect a 50% treatment group difference.
[0148] Efficacy Analyses:
[0149] For the efficacy endpoint of flare rate (mean flare per
patient from Day 1 through week 12), the primary analysis will
compare the arhalofenate 800 mg group to the allopurinol 300 mg
group using a two-sided test at the 5% level of significance.
[0150] The following key secondary analyses will be conducted using
a hierarchical procedure (Westfall and Krishen 2001) to control the
overall level of significance, in the order shown below:
[0151] Arhalofenate 800 mg group vs Placebo for percent sUA
reduction.
[0152] Arhalofenate 600 mg group vs Placebo for percent sUA
reduction.
[0153] Arhalofenate 800 mg group vs Placebo for proportion of
patients with sUA <6 mg/dL.
[0154] Arhalofenate 600 mg group vs Allopurinol 300 mg for flare
rate.
[0155] Arhalofenate 600 mg group vs Placebo for proportion of
patients with sUA <6 mg/dL.
[0156] The above hypotheses will be tested using two-sided tests at
the 5% level of significance, but a specified comparison will only
be tested if the primary efficacy analysis and all previously
conducted key analyses are statistically significant
(p<0.05).
[0157] 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.
* * * * *
References