WO2013066349A1 - Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent - Google Patents

Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent Download PDF

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Publication number
WO2013066349A1
WO2013066349A1 PCT/US2011/059394 US2011059394W WO2013066349A1 WO 2013066349 A1 WO2013066349 A1 WO 2013066349A1 US 2011059394 W US2011059394 W US 2011059394W WO 2013066349 A1 WO2013066349 A1 WO 2013066349A1
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Prior art keywords
urate
lowering agent
lower alkoxy
day
gout
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PCT/US2011/059394
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English (en)
French (fr)
Inventor
Brian K. Roberts
Gopal Chandra SAHA
Brian Edward LAVAN
Charles A. Mcwherter
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Metabolex, Inc.
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Priority to JP2014541011A priority Critical patent/JP6202633B2/ja
Priority to CN201910004813.0A priority patent/CN109908124A/zh
Priority to CA2859686A priority patent/CA2859686C/en
Priority to AU2011380507A priority patent/AU2011380507B2/en
Priority to MX2014005400A priority patent/MX357507B/es
Priority to KR1020147015169A priority patent/KR20140121383A/ko
Priority to NZ624708A priority patent/NZ624708A/en
Priority to PCT/US2011/059394 priority patent/WO2013066349A1/en
Application filed by Metabolex, Inc. filed Critical Metabolex, Inc.
Priority to SG11201402032RA priority patent/SG11201402032RA/en
Priority to EP11875114.8A priority patent/EP2773336A4/en
Priority to CN201180076191.4A priority patent/CN104066427A/zh
Publication of WO2013066349A1 publication Critical patent/WO2013066349A1/en
Priority to IL232386A priority patent/IL232386A0/en
Priority to CL2014001155A priority patent/CL2014001155A1/es
Priority to ZA2014/03575A priority patent/ZA201403575B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Hyperuricemia Conditions associated with elevated serum uric acid levels 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.
  • 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.
  • 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)
  • 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 carbonylamino; and each X is independently a halogen; or a pharmaceutically acceptable salt thereof.
  • 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).
  • 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).
  • 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).
  • the compound of Formula (I) is (-)-halofenate, (-)-halofenic acid, or a pharmaceutically acceptable salt thereof.
  • the second urate-lowering agent is a xanthine oxidase inhibitor, an inhibitor of uric acid production, a uricosuric agent or a uricase.
  • the second urate-lowering agent is allopurinol or febuxostat. Other aspects are provided below.
  • 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.
  • 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.
  • 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.
  • the synergistic effect allows dose reduction or dosing interval extension relative to a currently available uric acid lowering agent taken individually at prescribed doses.
  • administering refers to the act of giving a drug, prodrug, or therapeutic agent to a subject. Exemplary routes of administration are discussed below.
  • 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).
  • gouty symptom e.g., podagra or other gouty arthritis, gout flare, gouty attack.
  • Halofenate refers to (-)-halofenate, i.e. (-)-(R)-(4-chloro-phenyl)-(3- trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl ester.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Gout-associated inflammation refers to local or systemic inflammation due to immune responses to the deposition of urate crystals.
  • Halofenate refers to the compound of Formula (III), 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.
  • “Halofenic acid” and "CPTA” refer to the compound of Formula (IV), i.e.
  • Hyperuricemia refers to an elevated serum uric acid level (see above).
  • Moderate gout refers to gout present in a subject having at least two gout flares in the past 12 months.
  • “Pharmaceutically acceptable” refers to that which is useful in preparing a
  • composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that which is acceptable for veterinary or human
  • “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 ah, 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.
  • “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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxa
  • “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 dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • 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.
  • 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.
  • “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.
  • “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.
  • “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.
  • 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.
  • 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.
  • 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
  • pharmaceutically 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
  • 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.
  • management may be used synonymously.
  • Ultrasorbent refers to uric acid (7,9-dihydro-lH-purine-2,6,8(3H)-trione) and ions and salts thereof.
  • 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-lo ering agent is a compound of Formula (I)
  • 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.
  • the first urate-lowering agent is a compound of Formula (II)
  • R 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.
  • the first urate-lowering agent is a compound of Formula (III), also referred to as halofenate
  • the first urate-lowering agent is a compound of Formula (IV), also referred to as halofenic acid
  • 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.
  • 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 compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof; and a second urate-lowering agent.
  • 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.
  • 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.
  • 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.
  • the first urate-lowering agent is (-)-halofenate (i.e. (-)-(R)-(4- chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl ester, also referred to as arhalofenate).
  • the first urate-lowering agent is (-)-halofenic acid (i.e. (-)-4-chlorophenyl-(3-trifluoromethylphenoxy) acetic acid) or a pharmaceutically acceptable salt thereof.
  • the (-)-halofenate, (-)-halofenic acid, or pharmaceutically acceptable salt thereof is substantially free from the corresponding (+) enantiomer.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisopurine, inositol, phytic acid, myo-inositiol, kaempferol, myricetin4 and quercetin.
  • Allopurinol (l,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.
  • febuxostat Another xanthine oxidase inhibitor, febuxostat (2-(3-cyano-4- isobutoxyphenyl)-4-methyl-l,3-thiazole-5-carboxylic acid), was approved for treatment of gout in February 2009.
  • halofenate, halofenic acid or a pharmaceutically acceptable salt thereof is administered before, concurrently or subsequent to administration of allopurinol.
  • halofenate, halofenic acid or a pharmaceutically acceptable salt thereof is administered before, concurrently or subsequent to administration of febuxostat.
  • the second urate-lowering agent is a purine nucleoside phosphorylase (PNP) inhibitor.
  • PNP purine nucleoside phosphorylase
  • the PNP inhibitor is forodesine (BCX-1777) (BioCryst Pharmaceuticals, Inc.).
  • the PNP inhibitor is BCX-4208 (7-(((3R,4R)-3- hydroxy-4-(hydroxymethyl)pyrrolidin-l-yl)methyl)-3H-pyrrolo[3,2-d]pyrimidin-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.
  • 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, SLC22A12.
  • Uricosuric agents include, but are not limited to, probenecid, 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetic acid (RDEA594, lesinurad), potassium 4-(2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3- yl)thio)acetamido)-3-chlorobenzoate (RDEA806), RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropic hormone, and cortisone.
  • probenecid 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l
  • 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.
  • a first urate-lowering agent e.g.
  • a first urate-lowering agent e.g. (-)-halofenate, (-)-halofenic acid or a pharmaceutically acceptable salt thereof
  • probenecid e.g. benzbromarone or sulfinpyrazone.
  • 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 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).
  • the pegylated uricase enzyme is Krystexxa® (PURICASE®; pegloticase) (Savers Pharmaceuticals, Inc.) which is approved in the U.S. for the treatment of chronic gout in adult patients refractory to conventional therapy.
  • 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 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;
  • 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.
  • these factors include obesity, diabetes, chronic kidney failure, hypertension, use of diuretic drugs and certain other drugs (e.g.
  • 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.
  • 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.
  • the first urate-lowering agent is (-)-halofenate, (-)-halofenic acid or a
  • 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.
  • the treatment can be indefinite, e.g. for the remainder of the lifetime of the subject.
  • 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.
  • the second agent may be allopurinol or febuxostat.
  • the methods comprise treating gout.
  • the methods comprise treating gout by preventing gout flares.
  • the method comprises reducing the number, frequency, duration or severity of one of more gout flares.
  • the method comprises preventing, reducing or reversing uric acid crystal formation.
  • the uric acid crystal formation is in one or more of the joints, under skin, and kidney.
  • the formations include tophaceous deposits.
  • the subject has uric acid crystal formation determined by aspiration of tophi or by aspiration of synovial fluid of an inflamed joint.
  • 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.
  • 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.
  • the subject is refractory to allopurinol, 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4- triazol-3-yl)thio)acetic acid (RDEA594, lesinurad), 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid (febuxostat), or BCX4208.
  • the subject is refractory to allopurinol.
  • the subject is refractory to allopurinol administered at from 100 mg/day to 800 mg/day (e.g.
  • the subject is refractory to febuxostat.
  • 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.
  • the subject has mild or moderate chronic kidney disease (CKD2-3).
  • the subject has severe chronic kidney disease (CKD4).
  • the subject is on aspirin or diuretic therapy.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • colchicine colchicine
  • steroids or similar medicaments to treat or manage gout flares.
  • the subjects may also be administered an agent such as an NSAID, colchicine or a steroid.
  • 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.
  • 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 a certain organ or tissue (e.g., kidneys, adipose tissue, liver, muscles or joints) relative to the parent species.
  • a subject e.g., by allowing an orally administered compound to be more readily absorbed into the blood
  • a certain organ or tissue e.g., kidneys, adipose tissue, liver, muscles or joints
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • a first urate-lowering agent e.g. halofenate, halofenic acid, or a pharmaceutically acceptable salt thereof
  • a second urate- lowering agent e.g. xanthine oxidase inhibitor (e.g., allopurinol or febuxostat)
  • a single oral dosage composition such as a tablet or capsule
  • 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.
  • 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).
  • 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 mg to about 4000 mg per day.
  • 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.
  • 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.
  • 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.
  • the first urate-lowering agent is arhalofenate (i.e.
  • 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.
  • 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.
  • the first urate-lowering agent is arhalofenate (i.e.
  • 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.
  • 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.
  • the dose of the second urate-lowering agent e.g. allopurinol, febuxostat, or the other second urate-lowering agents described herein
  • the dose of the second urate-lowering agent 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.
  • 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.
  • 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.
  • 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.
  • 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 dosage form (e.g. a single tablet or capsule) may include 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.
  • the pharmaceutical composition described herein can be in a single tablet comprising 200 mg of arhalofenate and 150 mg of allopurinol.
  • 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.
  • the formulation may be divided into unit doses containing appropriate quantities of the one or more active ingredients.
  • 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.
  • aqueous suspension compositions are packaged in single-dose non- reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • 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.
  • 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
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, oil of wintergreen, or
  • 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.
  • 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.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the one or more active ingredients may be incorporated into sustained-release preparations and formulations as described herein.
  • 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).
  • kits comprising a composition comprising a first and second urate-lowering agent (wherein these first and second urate-lowering agents are described above).
  • the first urate-lowering agent in the kit is (-)-halofenate (i.e. arhalofenate).
  • the second urate-lowering agent in the kit is allopurinol.
  • 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.
  • a kit may comprise dosage forms of a first urate-lowering agent and a second urate-lowering agent described herein, and instructions for prescribing,
  • kits is for a subject with hyperuricemia or a condition associated with
  • kits comprising a container housing a plurality of dosage forms containing a first and second urate-lowering agent described herein and instructions for carrying out drug
  • 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 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).
  • 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.
  • a condition associated with hyperuricemia e.g., gout
  • the kit comprises a container housing a plurality of said oral agents and instructions for carrying out drug administration therewith.
  • 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.
  • the randomized treatment regimens will be the following (Day 1 through Week 4):
  • Treatment Group #1 Arhalofenate 400 mg (plus allopurinol)
  • 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.
  • 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.
  • 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).
  • Arhalofenate 400 mg/oral daily from Day 8 through Day 21; 600 mg/oral/daily from Day 22 through Day 35
  • Phase 1 Screening Phase: 1 to 4 weeks
  • 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 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.
  • CRF case report form

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NZ624708A NZ624708A (en) 2011-11-04 2011-11-04 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent
CA2859686A CA2859686C (en) 2011-11-04 2011-11-04 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent
AU2011380507A AU2011380507B2 (en) 2011-11-04 2011-11-04 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent
MX2014005400A MX357507B (es) 2011-11-04 2011-11-04 Metodos para tratar hiperucemia en pacientes con gota utilizando halofenato o acido halofenico y un segundo agente de reduccion de urato.
KR1020147015169A KR20140121383A (ko) 2011-11-04 2011-11-04 통풍 환자에서 할로페네이트 또는 할로펜산 및 제 2 요산염-저하제를 사용하여 고요산혈증을 치료하는 방법
PCT/US2011/059394 WO2013066349A1 (en) 2011-11-04 2011-11-04 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent
SG11201402032RA SG11201402032RA (en) 2011-11-04 2011-11-04 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent
JP2014541011A JP6202633B2 (ja) 2011-11-04 2011-11-04 ハロフェナートまたはハロフェン酸および第２の尿酸低下薬を用いる痛風に罹っている患者の高尿酸血症の治療方法
CN201910004813.0A CN109908124A (zh) 2011-11-04 2011-11-04 利用卤芬酯或卤芬酸以及第二尿酸降低剂治疗痛风患者中高尿酸血症的方法
EP11875114.8A EP2773336A4 (en) 2011-11-04 2011-11-04 METHODS OF TREATING HYPERURICEMIA IN DROPPING PATIENTS USING HALOFENATE OR HALOFENIC ACID AND SECOND URATIC REDUCING AGENT
CN201180076191.4A CN104066427A (zh) 2011-11-04 2011-11-04 利用卤芬酯或卤芬酸以及第二尿酸降低剂治疗痛风患者中高尿酸血症的方法
IL232386A IL232386A0 (en) 2011-11-04 2014-04-30 Preparations containing halophanate or halophanic acid and a substance that lowers urate and their uses
CL2014001155A CL2014001155A1 (es) 2011-11-04 2014-05-02 Metodo para reducir el acido urico en el suero de un sujeto con hiperuricemia, administrando un primer agente reductor de urato y un segundo agente reductor de urato; composicion farmaceutica; kit farmaceutico; uso en el tratamiento de gota aguda, cronica, moderada, refractaria o severa.
ZA2014/03575A ZA201403575B (en) 2011-11-04 2014-05-16 Methods for treating hyperuricemia in patients with gout using halofenate or halofenic acid and a second urate-lowering agent

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US11446317B2 (en) 2017-10-26 2022-09-20 Otsuka Pharmaceutical Co., Ltd. Inositol phosphate-containing composition
JP2022145809A (ja) * 2014-12-01 2022-10-04 オメロス コーポレーション 術後眼炎症状態を阻害するための抗炎症性かつ散瞳性前房内溶液

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EP2773336A4 (en) 2015-06-03
JP6202633B2 (ja) 2017-09-27
MX357507B (es) 2018-07-12
AU2011380507A1 (en) 2014-05-29
EP2773336A1 (en) 2014-09-10
JP2014532758A (ja) 2014-12-08
CN104066427A (zh) 2014-09-24
IL232386A0 (en) 2014-06-30
ZA201403575B (en) 2015-11-25
SG11201402032RA (en) 2014-09-26
CL2014001155A1 (es) 2015-01-16
AU2011380507B2 (en) 2017-06-15
KR20140121383A (ko) 2014-10-15
NZ624708A (en) 2015-11-27
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