WO2013066352A1 - Methods for treating gout in patient subpopulations - Google Patents
Methods for treating gout in patient subpopulations Download PDFInfo
- Publication number
- WO2013066352A1 WO2013066352A1 PCT/US2011/059425 US2011059425W WO2013066352A1 WO 2013066352 A1 WO2013066352 A1 WO 2013066352A1 US 2011059425 W US2011059425 W US 2011059425W WO 2013066352 A1 WO2013066352 A1 WO 2013066352A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- subject
- gout
- uric acid
- halofenate
- Prior art date
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Classifications
-
- 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
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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.
- chronic hyperuricemia may lead to the deposition of uric acid crystals in the urinary tract, renal parenchyma, and soft tissues, resulting in urolithiasis, urate nephropathy with chronic kidney disease, and soft tissue tophi, respectively.
- This application is directed to methods of lowering the serum uric acid level in a subject, methods of treating a subject having a condition associated with an elevated serum uric acid levels, and methods for the treatment of hyperuricemia in a subject with gout, wherein the subject is a member of one or more subpopulations, the subpopulations comprising subjects with impaired renal function, subjects on aspirin therapy, and subjects on diuretic therapy.
- One aspect provides for a method of lowering serum uric acid level in a subject with impaired renal function, comprisin administering to the subject 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 alkoxycarbonylarnino; and each X is independently a halogen; or a pharmaceutically acceptable salt thereof.
- Other aspects provide methods for treating a subject having a condition associated with an elevated serum uric acid level and with impaired renal function comprising administering to the subject a compound of Formula (I).
- Other aspects provide methods for the treatment of hyperuricemia in a subject with gout and impaired renal function comprising administering to the subject in need thereof a compound of Formula (I).
- Other aspects provide methods for the treatment of hyperuricemia in a subject with gout comprising administering to the subject in need thereof a compound of Formula (I), wherein the subject is undergoing aspirin or a diuretic therapy.
- the compound of Formula (I) is (-)-halofenate, (-)-halofenic acid, or a pharmaceutically acceptable salt thereof.
- the impaired renal function is chronic kidney disease, and in further aspects the chronic kidney disease is mild or moderate. Further aspects are provided below.
- FIG. 1 is a chart showing the lowering of serum uric acid (sUA) in human subjects having (a) normal and stage 1 CKD, (b) stage 2 CKD, and (c) stage 3 CKD after treatment with (-)-halofenate at 600 mg per day.
- sUA serum uric acid
- FIG. 2 is a chart showing the lowering of serum uric acid in human subjects having stage 2 and 3 CKD after treatment with (-)-halofenate at dosages of at 200 mg, 400 mg, and 600 mg per day.
- FIG. 3 is a scatter plot of change in serum uric acid level in human subjects having stage 3, stage 2 and stage 1 CKD after treatment with (-)-halofenate.
- FIG. 4 is a chart showing the change in CrCL in human subjects after treatment with (-)-halofenate at dosages of at 200 mg, 400 mg, and 600 mg per day.
- FIG. 5 is a chart showing changes in HbAlc levels in human subjects having stage 2 and stage 3 CKD after treatment with (-)-halofenate.
- FIG. 6 is a chart showing changes in fasting plasma glucose (FPG) levels in human subjects having stage 2 and stage 3 CKD after treatment with (-)-halofenate.
- FIG. 7 is a chart showing changes in triglyceride (TG) levels in human subjects having stage 2 and stage 3 CKD after treatment with (-)-halofenate.
- FIG. 8 is a chart showing changes in serum uric acid levels in human subjects on low- or medium-dose aspirin therapy after treatment with (-)-halofenate.
- FIG. 9 is a chart showing changes in serum uric acid levels in human subjects on diuretic therapy after treatment with (-)-halofenate.
- 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.
- CKD Chironic kidney disease
- GFR glomerular filtration rate
- Cr or CrCl the volume of blood plasma that is cleared of creatinine per unit time
- CKD groups or stages of CKD, used herein are defined as follows: CKD0 (normal kidney function) - GFR greater than or equal to 120 mL/min; CKD1 - GFR of 90 tol 19 mL/min; CKD2 (mild CKD) - GFR of 60 to 89 mL/min; CKD3 (moderate CKD) - GFR of 30 to 59 mL/min; CKD4 (severe CKD) - GFR of 15 to 29 mL/min; CKD5 (kidney failure) - GFR less than 15 mL/min.
- 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.
- this term implies no temporal aspect or relationship, e.g. to a second urate-lowering agent.
- 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).
- urate crystals uric acid or salts thereof, e.g. monosodium urate
- 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 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.
- 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.
- Hyperuricemia refers to an elevated serum uric acid level (see above).
- 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 includes acute kidney injury and chronic kidney disease (i.e. CKDl-5).
- 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 pharmaceutical use.
- “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, oxalic
- “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 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.
- 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.
- 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 one or more 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.
- This application describes methods for lowering the serum uric acid level in a subject comprising administering to a sub ect in need thereof 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, wherein the subject has impaired renal function.
- the compound is a compound of Formula (II)
- R is a member 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 compound is a compound of Formula (III), also referred to as halofenate
- the compound 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.
- the compound is the (-) enantiomer of a compound of
- the compound is (-)-halofenate (i.e. (-)- ( ?)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy)-acetic acid 2-acetylamino-ethyl ester, also referred to as arhalofenate).
- the compound 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, 1073-1077 (1997)).
- the present disclosure also provides for methods for treating one or more conditions associated with an elevated serum uric acid level, i.e. hyperuricemia, comprising administering to a subject in need thereof a compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof wherein the subject has impaired renal function.
- Conditions associated with hyperuricemia include, but are not limited to gout; acute gout; chronic gout; moderate gout; refractory gout; severe gout; deposition of uric acid crystals in the urinary tract, renal parenchyma, soft tissues, joints, cartilage or bones; urolithiasis; urate nephropathy; tophi;
- podagra podagra; acute inflammatory gouty arthritis; joint destruction; urinary tract infections; renal impairment; chronic kidney disease; kidney stones; local inflammation; systemic inflammation; immune-related disorders; cardiovascular disease including peripheral vascular disease, coronary artery disease and cerebrovascular disease; insulin resistance; diabetes; fatty liver disease;
- dementia including vascular dementia; dyslipidemia; preeclampsia; hypertension; obesity;
- these factors include obesity, diabetes, chronic kidney disease, 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 experienced one or more gout flares. In some
- 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.
- Certain methods provide for the treatment of hyperuricemia in a subject with gout.
- methods provide for the treatment of hyperuricemia in a subject with gout comprising administering a pharmaceutical composition comprising a first urate-lowering agent, wherein the subject has impaired renal function.
- the compound can be (-)-halofenate, (-)- halofenic acid, or a pharmaceutically acceptable salts thereof.
- the treatment can be for about four weeks or longer, for about one month or longer, for about 12 week 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, or for about 10 years or longer.
- the treatment can be indefinite, e.g. for the remainder of the lifetime of the subject.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 for about four weeks or longer, for about one month or longer, for about 12 week 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, or for about 10 years or longer.
- 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.
- the methods of the present disclosure comprise administering a pharmaceutical composition comprising a first urate-lowering agent 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.
- CKD chronic kidney disease
- subjects will have a certain non-normal stage of CKD as defined above, e.g. CKDl, CKD2 (mild), CKD3
- a subject's CKD stage may change over time.
- the subject has another type of impaired renal function, e.g. acute kidney injury.
- serum uric acid can be lowered in patients having (a) normal and stage 1 CKD, (b) stage 2 CKD, and (c) stage 3 CKD after treatment with (-)-halofenate at 600 mg per day.
- (-)-halofenate e.g. 600 mg day
- the compound is administered at a dose depending on the stage of CKD of the patient. For example, the dose of a compound described herein which is
- CKD3 a GFR between 30 and 59 mL/min
- CKD4-5 a GFR lower than 30 mL/min
- methods may comprise measuring the renal function of a subject.
- certain methods may comprise measuring the renal function of a subject before administering a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and certain methods may comprise measuring the renal function of the subject after a certain duration of treatment, e.g. after about 1 day, after about 1 week, after about 2 week, after about 1 month, after about 3 months, after about 6 months or after about 1 year.
- the renal function of the subject may be monitored by taking two or more successive renal function measurements.
- a first renal function measurement can be taken at or shortly before a compound of the present disclosure is first administered (e.g.
- a second renal function measurement can be taken after a certain duration of treatment as above (e.g. after about 1 week, after about 1 month, etc.).
- the subject will have the same degree of renal impairment (e.g. have the same stage of CKD, i.e. CKDl, CKD2, etc.) from the first renal function measurement to the second renal function measurement.
- the subject's renal impairment will have improved from the first renal function measurement to the second renal function measurement (e.g. the subject can have CKD3 at the first measurement and CKD2 at the second measurement, etc.).
- Renal function may be measured by GFR or by other methods known to those with ordinary skill in the art.
- FIG. 2 shows a dose-dependent lowering of serum uric acid in subjects with stage 2 and stage 3 CKD after treatment with (-)-halofenate at dosages of at 200 mg, 400 mg, and 600 mg per day.
- the compound is administered at a dose that is independent of the stage of chronic kidney disease.
- the dose of compounds described herein is not adjusted or does not have to be adjusted when administered to patients having mild, moderate, or severe CKD if comparable serum-acid lowering is desired.
- FIG. 3 shows lowering of serum uric acid levels in human subjects having stage 3, stage 2 and stage 1 CKD after treatment with (-)-halofenate.
- the administration of a first urate-lowering agent may comprise the resulting in no significant adverse effect on kidney function.
- methods include a method for the treatment of hyperuricemia in a subject with gout, the method comprising administering a pharmaceutical composition comprising a first urate-lowering agent, wherein the subject has impaired renal function and wherein the administration results in no significant adverse effect on kidney function.
- FIG. 4 shows changes in CrCL in human subjects after treatment with (-)-halofenate at dosages of at 200 mg, 400 mg, and 600 mg per day. As described above, creatinine clearance can be used to measure kidney function. As shown in FIG. 4, the administration of (-)-halofenate resulted in no significant change in CrCL as compared to placebo, indicating that (-)-halofenate does not worsen kidney function at the tested doses and durations of administration.
- This application also provides for methods of treating hyperuricemia or a condition associated with hyperuricemia comprising administering a first urate-lowering agent (i.e. a compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof) wherein the subject has impaired renal function (e.g. chronic kidney disease) and wherein the administration results in a lowering of HbAlc or plasma glucose levels.
- a first urate-lowering agent i.e. a compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof
- HbAlc or hemoglobin Ale comprises the main portion of glycosylated hemoglobin in the blood.
- the ratio of glycosylated hemoglobin to total hemoglobin is proportional to blood glucose levels.
- levels of HbAlc serve as markers of blood glucose.
- FIG. 5 shows changes in HbAlc levels in human subjects having stage 2 and stage 3 CKD after treatment with (-)-halofenate
- FIG. 6 shows similar changes in fasting plasma glucose.
- the compound is (-)- halofenate.
- the condition associated with hyperuricemia is gout.
- the subject has an elevated fasting plasma glucose level (i.e. a level above 100 mg/dL; see, e.g., A. Tirosh et al., N. Engl. J. Med., 353, 1454-62 (2005)).
- the administration of the compound results in a lowering of HbAlc levels by at least about 0.8%, e.g. by at least about 1%.
- the administration of the compound results in a lowering of fasting plasma glucose levels by at least about 10%, e.g. by at least about 15%.
- the compound is administered to the subject once per day for about four weeks or longer, for about one month or longer, etc.
- This application also provides for methods of treating hyperuricemia or a condition associated with hyperuricemia comprising administering to a subject in need thereof a first urate- lowering agent, wherein the subject has impaired renal function and wherein the administration results in a lowering of triglyceride levels.
- FIG. 7 shows changes in triglyceride levels in human subjects having stage 2 and stage 3 CKD after treatment with (-)-halofenate.
- the compound is (-)-halofenate.
- the condition associated with hyperuricemia is gout.
- the subject has an elevated triglyceride level (i.e. a level above 150 mg/dL; see, e.g., A. Tirosh et al.
- the administration of the compound results in a lowering of triglyceride levels by at least about 20%, e.g. by at least about 30%.
- the compound is administered to the subject once per day for about four weeks or longer, for about one month or longer, etc.
- This application also provides for methods of (1) lowering the serum uric acid level in a subject; (2) treating a subject having a condition associated with an elevated serum uric acid levels; and (3) treating hyperuricemia in a subject with gout, the methods comprising
- a compound of Formulae (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof wherein the subject is a member of one or more subpopulations, the subpopulations comprising subjects on aspirin therapy and subjects on diuretic therapy (i.e. receiving or being administered aspirin or a diuretic).
- the subject is a member of one or more subpopulations, the subpopulations comprising subjects on aspirin therapy and subjects on diuretic therapy (i.e. receiving or being administered aspirin or a diuretic).
- the subject is on aspirin therapy at a low or medium dose (e.g. at or less than 325 mg/day).
- exemplary diuretics include, but are not limited to high-ceiling or loop diuretics such as ethacrynic acid, torsemide and bumetanide, low-ceiling diuretics, thiazides such as hydrochlorothiazide, carbonic anhydrase inhibitors such as acetazolamide and methazolamide, potassium-sparing diuretics such as spironolactone, potassium canreonate, amiloride and triamterene, calcium-sparing diuretics, and osmotic diuretics such as mannitol.
- FIG. 8 is a chart showing lowering of serum uric acid levels in human subjects on low- or medium-dose aspirin therapy.
- FIG. 9 is a chart showing lowering of serum uric acid levels in human subjects on diuretic therapy.
- the methods described herein may be useful in subjects with refractory gout.
- Subjects with refractory gout 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 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 Formulae (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.
- the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisopurine, inositol, phytic acid, myo-inositiol, kaempferol, myricetin 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.
- 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.
- Purine nucleoside phosphorylase (PNP) inhibitors represent a relatively new approach to lowering serum uric acid levels in patient with hyperuricemia, gout, and related conditions.
- 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.
- 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- 1,2,4- 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)acetarnido)-3-chlorobenzoate
- RDEA806 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.
- 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®
- 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.
- 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., adipose tissue, kidney, liver, muscle or joints) relative to the parent species.
- prodrugs of the compound of Formula (IV) include esters, amides and carbamates (e.g., N, N-dimethylaminocarbonyl) of the hydroxy functional group of the compound of Formula (IV).
- the compounds of Formulae (I), (II), and (III) are non-limiting examples of prodrugs of the compound of Formula (IV).
- 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.
- the compounds 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.
- the compound of Formulae (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof can be contemplated.
- the compound may be administered from about 10 mg to about 1000 mg per day.
- (-)- 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.
- 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.
- Compounds of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can be incorporated into a variety of formulations and medicaments for therapeutic administration. More particularly, these compounds can be formulated into pharmaceutical compositions 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.
- administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, or intratracheal administration.
- the compound can be administered in a local rather than systemic manner, in a depot or sustained release formulation.
- the compounds can be administered in a liposome.
- 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.
- 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.
- the method comprise administering a pharmaceutical composition comprising a first urate-lowering agent and a second therpapeutic 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 may vary depending on the subject, depending upon the subject's overall medical condition.
- the application discloses combination therapy and methods of concomitant administration of a first and second urate-lowering agent (wherein these first and second urate-lowering agents are described herein). Combination therapy and concomitant administration refer to the
- compositions 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
- 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 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.
- the second urate-lowering agent is allopurinol and is administered at from about 50 mg to about 800 mg per day.
- the first urate-lowering agent is (-)-halofenate and is administered at from about 100 mg to about 600 mg per day
- the second urate-lowering agent is febuxostat and is administered at from about 40 mg to about 120 mg per day.
- the second urate-lowering agent is a uricosuric agent, preferably selected from the group consisting of probenecid, 2-((5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetic acid, potassium 4-(2-((5-bromo-4- (4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetamido)-3-chlorobenzoate, RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropic hormone and cortisone, especially probenecid.
- probenecid 2-((5-bromo-4-(4- cyclopropylnaphthalen-l-yl)
- compositions of the present disclosure may be administered once daily (QD), twice daily (BID), three times daily (TID) or four times per day (QID).
- the composition of the present disclosure is administered once daily (QD).
- the composition of the present disclosure is administered twice daily (BID).
- Particular embodiments covering compositions, formulations and their method of uses are disclosed in a PCT Patent Application entitled “Methods for Treating Hyperuricemia in Patents with Gout Using Halofenate or Halofenic Acid and a Second Urate-Lowering Agent" filed concurrently with the present application, and the PCT Application is incorporated herein in its entirety.
- the embodiments of this application are characterized by the specification and by the features of the Claims of this application as filed, and of corresponding pharmaceutical compositions, methods and uses of these compounds.
- FIGS. 1-4 were generated based on the pooled analysis of four phase 2 studies conducted with (-)-halofenate in type 2 diabetic patients. In these studies a total of 955 patients were enrolled. In the Ml 02-20303 study, two dose levels of (-)-halofenate (200 mg and 400 mg) or placebo were given orally daily to a total of 217 patients for 12 weeks. In the M102-20405 study, (-)-halofenate at a dose of 600 mg or placebo was given daily to a total of 100 patients for 12 weeks.
- FIGS. 5-7 were generated based on a randomized, double-blind, placebo-controlled phase 2 study, Ml 02-20303.
- two dose levels of (-)-halofenate (200 mg and 400 mg) or placebo were given orally daily for 12 weeks to a total of 217 type 2 diabetes patients who were inadequately controlled on existing insulin therapy.
- these patients received the study drug for 12 weeks, and followed up for an additional four weeks.
- change in HbAlc from baseline at week 16 was the primary endpoint and changes in fasting plasma glucose and triglyceride from baseline at Week 12 were secondary endpoints.
- FIGS. 7-8 were generated based on the pooled analysis described in Example 1.
- the changes in uric acid between the aspirin treated and aspirin un-treated groups at the 200 mg, 400 mg, and 600 mg groups were not statistically different.
- the changes in uric acid between the diuretic treated and diuretic un-treated groups at the 200 mg, 400 mg, and 600 mg groups were not statistically different.
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Abstract
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Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020147015209A KR101848122B1 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
MX2014005399A MX354846B (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations. |
PCT/US2011/059425 WO2013066352A1 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
EP11875027.2A EP2775835A4 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
SG11201402027PA SG11201402027PA (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
CA2859689A CA2859689C (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
NZ624714A NZ624714A (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
AU2011380509A AU2011380509B2 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
JP2014541012A JP6047172B2 (en) | 2011-11-04 | 2011-11-04 | How to treat gout in a patient subgroup |
BR112014010693-2A BR112014010693A2 (en) | 2011-11-04 | 2011-11-04 | use of a compound for the preparation of a pharmaceutical composition for the treatment of gout in subpopulations of patients |
CN201180076189.7A CN104066323A (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
IL232385A IL232385A (en) | 2011-11-04 | 2014-04-30 | Use of the compounds halofenate or halofenic acid in the manufacture of medicaments for treating hyperuricemia in patients with gout, hyperuricemia or impaired renal function |
CL2014001156A CL2014001156A1 (en) | 2011-11-04 | 2014-05-02 | Method to reduce the level of uric acid in a subject with impaired renal function by administering a compound of formula (i). |
ZA2014/03574A ZA201403574B (en) | 2011-11-04 | 2014-05-16 | Methods for treating gout in patient subpopulations |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/US2011/059425 WO2013066352A1 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
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PCT/US2011/059425 WO2013066352A1 (en) | 2011-11-04 | 2011-11-04 | Methods for treating gout in patient subpopulations |
Country Status (14)
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EP (1) | EP2775835A4 (en) |
JP (1) | JP6047172B2 (en) |
KR (1) | KR101848122B1 (en) |
CN (1) | CN104066323A (en) |
AU (1) | AU2011380509B2 (en) |
BR (1) | BR112014010693A2 (en) |
CA (1) | CA2859689C (en) |
CL (1) | CL2014001156A1 (en) |
IL (1) | IL232385A (en) |
MX (1) | MX354846B (en) |
NZ (1) | NZ624714A (en) |
SG (1) | SG11201402027PA (en) |
WO (1) | WO2013066352A1 (en) |
ZA (1) | ZA201403574B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2836209A4 (en) * | 2012-04-13 | 2015-11-25 | Cymabay Therapeutics Inc | Method for treating hyperuricemia in patients with gout using halofenate or halofenic acid and an anti-inflammatory agent |
CN105851522A (en) * | 2014-07-25 | 2016-08-17 | 许伟琦 | Feed for preventing lithangiuria |
US11446317B2 (en) * | 2017-10-26 | 2022-09-20 | Otsuka Pharmaceutical Co., Ltd. | Inositol phosphate-containing composition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105920022A (en) * | 2016-05-12 | 2016-09-07 | 成都易创思生物科技有限公司 | Anti-gout medicinal compound preparation |
Citations (2)
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US6613802B1 (en) * | 1999-06-04 | 2003-09-02 | Metabolex, Inc. | Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia |
US20110268801A1 (en) * | 2007-11-27 | 2011-11-03 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4250191A (en) * | 1978-11-30 | 1981-02-10 | Edwards K David | Preventing renal failure |
-
2011
- 2011-11-04 AU AU2011380509A patent/AU2011380509B2/en not_active Ceased
- 2011-11-04 KR KR1020147015209A patent/KR101848122B1/en active IP Right Grant
- 2011-11-04 CA CA2859689A patent/CA2859689C/en not_active Expired - Fee Related
- 2011-11-04 MX MX2014005399A patent/MX354846B/en active IP Right Grant
- 2011-11-04 NZ NZ624714A patent/NZ624714A/en not_active IP Right Cessation
- 2011-11-04 CN CN201180076189.7A patent/CN104066323A/en active Pending
- 2011-11-04 EP EP11875027.2A patent/EP2775835A4/en not_active Withdrawn
- 2011-11-04 WO PCT/US2011/059425 patent/WO2013066352A1/en active Application Filing
- 2011-11-04 JP JP2014541012A patent/JP6047172B2/en not_active Expired - Fee Related
- 2011-11-04 SG SG11201402027PA patent/SG11201402027PA/en unknown
- 2011-11-04 BR BR112014010693-2A patent/BR112014010693A2/en not_active IP Right Cessation
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2014
- 2014-04-30 IL IL232385A patent/IL232385A/en active IP Right Grant
- 2014-05-02 CL CL2014001156A patent/CL2014001156A1/en unknown
- 2014-05-16 ZA ZA2014/03574A patent/ZA201403574B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6613802B1 (en) * | 1999-06-04 | 2003-09-02 | Metabolex, Inc. | Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes, hyperlipidemia and hyperuricemia |
US20110268801A1 (en) * | 2007-11-27 | 2011-11-03 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
Non-Patent Citations (1)
Title |
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See also references of EP2775835A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2836209A4 (en) * | 2012-04-13 | 2015-11-25 | Cymabay Therapeutics Inc | Method for treating hyperuricemia in patients with gout using halofenate or halofenic acid and an anti-inflammatory agent |
CN105851522A (en) * | 2014-07-25 | 2016-08-17 | 许伟琦 | Feed for preventing lithangiuria |
CN106036135A (en) * | 2014-07-25 | 2016-10-26 | 许伟琦 | Medicine, composition and veterinary medicine for preventing calculus and fast discharging calculus |
US11446317B2 (en) * | 2017-10-26 | 2022-09-20 | Otsuka Pharmaceutical Co., Ltd. | Inositol phosphate-containing composition |
Also Published As
Publication number | Publication date |
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CA2859689A1 (en) | 2013-05-10 |
AU2011380509A1 (en) | 2014-05-29 |
CN104066323A (en) | 2014-09-24 |
KR101848122B1 (en) | 2018-04-11 |
ZA201403574B (en) | 2015-11-25 |
MX2014005399A (en) | 2015-04-08 |
JP2014532759A (en) | 2014-12-08 |
EP2775835A4 (en) | 2015-07-29 |
IL232385A (en) | 2017-10-31 |
IL232385A0 (en) | 2014-06-30 |
CL2014001156A1 (en) | 2015-01-16 |
BR112014010693A2 (en) | 2020-11-10 |
EP2775835A1 (en) | 2014-09-17 |
KR20140123927A (en) | 2014-10-23 |
AU2011380509B2 (en) | 2016-05-19 |
SG11201402027PA (en) | 2014-09-26 |
MX354846B (en) | 2018-03-22 |
JP6047172B2 (en) | 2016-12-21 |
CA2859689C (en) | 2018-05-22 |
NZ624714A (en) | 2016-01-29 |
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