US 2013 0059868A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0059868 A1 Miner et al. (43) Pub. Date: Mar. 7, 2013

(54) TREATMENT OF GOUT Publication Classification (75) Inventors: Jeffrey Miner, San Diego, CA (US); Jean-Luc Girardet, San Diego, CA (51) Int. Cl. (US); Barry D. Quart, Encinitas, CA A613 L/496 (2006.01) (US) A6IP 29/00 (2006.01) (73) Assignee: Ardea Biociences, Inc., San Diego, CA A6IP 9/06 (2006.01) (US) A613 L/426 (2006.01) A 6LX3/59 (2006.01) (21) Appl. No.: 13/637,343 (52) U.S. Cl...... 514/262.1: 514/384: 514/365 (22) PCT Fled: Mar. 29, 2011 (86) PCT NO.: PCT/US11A3O364 (57) ABSTRACT S371 (c)(1), (2), (4) Date: Oct. 24, 2012 Sodium 2-(5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H Related U.S. Application Data 1,2,4-triazol-3-ylthio)acetate is described. In addition, phar (60) Provisional application No. 61/319,014, filed on Mar. maceutical compositions and uses Such compositions for the 30, 2010. treatment of a variety of diseases and conditions. Patent Application Publication Mar. 7, 2013 Sheet 1 of 10 US 2013/00598.68A1

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TREATMENT OF GOUT wherein the mean duration of the gout flares in a patient undergoing uric acid level reduction is less than four days. CROSS-REFERENCE Another embodiment provides the method, wherein the mean 0001. This application claims priority to U.S. Provisional duration of the gout flares is less than three days. Another Application 61/319,014, filed Mar. 30, 2010, which is incor embodiment provides the method wherein the mean duration porated by reference in its entirety. of the gout flares is less than two days. 0010. One embodiment provides a method for treating FIELD OF THE INVENTION gout comprising administration to a patient in need a thera peutic agent that is a dual inhibitor of URAT1 and inflamma 0002 The present invention relates to the treatment of some. Another embodiment provides the method wherein the gout while Substantially reducing the duration and frequency dual inhibitor of URAT1 and inflammasome is 2-(5-bromo of gout flares associated with reductions of uric acid levels. 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- ylthio)acetate, or a polymorph thereof, or a pharmaceutically BACKGROUND OF THE INVENTION acceptable salt of 2-(5-bromo-4-(4-cyclopropylnaphthalen 0003 Gout is associated with elevated levels of uric acid 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate or a polymorph that crystallize and deposit in joints, tendons, and Surround thereof. ing tissues. Gout is marked by recurrent attacks of red, tender, 0011. One embodiment provides a method of reducing hot, and/or Swollen joints. monosodium urate induced inflammation comprising admin istering a pharmaceutical composition comprising a pharma SUMMARY OF THE INVENTION ceutical agent having both uricoSuric and anti-inflammatory activity. Another embodiment provides the method wherein 0004. The treatment of gout typically involves the reduc the pharmaceutical agent is a URAT1 inhibitor with anti tion of serum uric acid levels. However, gout flares are asso inflammatory activity. Another embodiment provides the ciated with the reduction of uric acid levels. Drugs such as method wherein the pharmaceutical agent is 2-(5-bromo-4- colchicine can reduce the pain associated with gout flares (4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) while a patient’s serum uric acid levels are being reduced, acetate, or a pharmaceutically acceptable salt thereof. however, colchicine is associated with several undesired side 0012. In another embodiment is provided the method effects, including gastrointestinal disorders. wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaph 0005 Accordingly, described herein are methods, compo thalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharma sitions and dosing regimens for reducing serum uric acid ceutically acceptable salt thereof, is about 750 mg. In another levels while providing for a concomitant reduction in the embodiment is provided the method wherein the daily dose of intensity and duration of gout flares associated with other 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- gout medications. Furthermore, described herein are meth triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt ods, compositions and dosing regimens for weaning a patient thereof, is about 600 mg. In another embodiment is provided off of co-administered colchicine; such weaning includes the method wherein the daily dose of 2-(5-bromo-4-(4-cyclo lower doses of colchicine and less time on colchicine relative propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or to other gout medications. a pharmaceutically acceptable salt thereof, is about 500 mg. 0006. One embodiment provides a method of treating gout In another embodiment is provided the method wherein the comprising co-administration of 2-(5-bromo-4-(4-cyclopro daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)- pylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a 4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically pharmaceutically acceptable salt thereof, and colchicine to a acceptable salt thereof, is about 400 mg. In another embodi Subject, wherein said method provides greater mean gout ment is provided the method wherein the daily dose of 2-(5- flare reduction than co-administration of colchicine and bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol therapeutic agent that is not a dual inhibitor of URAT1 and an 3-ylthio)acetate, or a pharmaceutically acceptable salt inflammasome. thereof, is about 200 mg. 0007 Another embodiment provides the method wherein 0013. In another embodiment is provided the method the total dosage of colchicine administered during co-admin wherein the daily dose is administered orally. In another istration with 2-(5-bromo-4-(4-cyclopropylnaphthalen-1- embodiment is provided the method wherein the daily dose is yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically administered in the morning. In another embodiment is pro acceptable salt thereof, is at least 50% less than the total vided the method wherein the daily dose is administered with dosage of colchicine co-administered with a therapeutic food. agent that is not a dual inhibitor of URAT1 and an inflamma SO. 0014) Another embodiment provides the above listed 0008 Another embodiment provides the method wherein methods of reducing the duration of gout flares further com the amount of time that colchicine is co-administered with prising administration of a second serum uric acid lowering 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- agent. In another embodiment is provided the method triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt wherein the second serum uric acid lowering agent is a Xan thereof, is at least one week less than when colchicine is thine oxidase inhibitor. In another embodiment is provided co-administered with a therapeutic agent that is not a dual the method wherein the Xanthine oxidase inhibitor is febux inhibitor of URAT1 and an inflammasome. ostat or allopurinol. 0009. One embodiment provides a method of reducing the duration of gout flares comprising administration of a phar INCORPORATION BY REFERENCE maceutical composition comprising 2-(5-bromo-4-(4-cyclo 00.15 All publications and patent applications mentioned propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or in this specification are herein incorporated by reference for a pharmaceutically acceptable salt thereof, to a subject, the purposes cited. US 2013/00598.68 A1 Mar. 7, 2013

BRIEF DESCRIPTION OF THE DRAWINGS 0028. The treatment of gout typically involves the reduc tion of serum uric acid levels. However, gout flares are asso 0016. The novel features of the invention are set forth with ciated with the reduction of uric acid levels. Drugs such as particularity in the appended claims. A better understanding colchicine can reduce the pain associated with gout flares of the features and advantages of the present invention will be while a patient’s serum uric acid levels are being reduced, obtained by reference to the following detailed description however, colchicine is associated with several undesired side that sets forth illustrative embodiments, in which the prin effects, including gastrointestinal disorders. ciples of the invention are utilized, and the accompanying 0029. Accordingly, described herein are methods, compo drawings of which: sitions and dosing regimens for reducing serum uric acid 0017 FIG. 1 illustrates the effect of Lesinurad on IL-1B levels while providing for a concomitant reduction in the release within 1 hour of stimulation with ATP (5 mM) or 1 lug intensity and duration of gout flares associated with other MSU (monosodium urate) crystals (compd1=Lesinurad; gout medications. Furthermore, described herein are meth C-1 inh-caspase-1 inhibitor). ods, compositions and dosing regimens for weaning a patient 0018 FIG. 2 illustrates the effect of rilonacept (IL-1 ra) on off of co-administered colchicine; such weaning includes TNF-C. (FIG. 2A) and IL-1 B production (FIG. 2B). lower doses of colchicine and less time on colchicine relative 0019 FIG. 3 illustrates the effect of Lesinurad on TNF-C. to other gout medications. (FIG. 3A) and IL-1 B (FIG. 3B) production in differentiated 0030. One embodiment provides a method of treating gout THP-1 cells comprising co-administration of 2-(5-bromo-4-(4-cyclopro 0020 FIG. 4 illustrates the effect of Lesinurad on IL-1B pylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a (FIG.4A) and the CLU countina CelTiter-Glo Rassay (FIG. pharmaceutically acceptable salt thereof, and a second thera 4B). peutic agent for the treatment of gout (and/or symptoms 0021 FIG.5 illustrates the effect of Lesinurad (Comp1) in thereof). In specific embodiments, the second therapeutic a rat model of inflammation in comparison with 1 mg/kg agent for the treatment of gout (and/or symptoms thereof) is colchicine (FIG. 5A) and 0.1 mg/kg colchicine (FIG. 5B). an NSAID, steroid, or colchicine. In other embodiments, the 0022 FIG. 6 illustrates in vivo MSU-induced inflamma second therapeutic agent for the treatment of gout (and/or tionina rat airpouch study for various doses of Lesinurad p.o. symptoms thereof) is any therapeutic agent described herein (0.1. 1, 10 mg/kg/day), colchicine S.c. (0.01, 0.1, 1 mg/kg), for the treatment of gout (and/or symptoms thereof). In some and Lesinurad and colchicine (* indicates p-0.05 versus embodiments, the second therapeutic agent for the treatment vehicle). FIG. 6A illustrates plasma extravasation value, FIG. of gout (and/or symptoms thereof) is an agent that treats, 6B exudate volume, and FIG. 6C total white blood cell count. reduces the intensity of, or reduces the duration of gout Symp 0023 FIG. 7 illustrates the average increase in knee diam toms (e.g., effects associated with gout other than uric acid eter (mm) in an in vivo MSU-induced rat knee joint study for concentrations). In specific embodiments, the second agent is various doses of colchicine S.c. (0.1.0.3, 1 mg/kg), Lesinurad colchicine. In certain embodiments, provided herein is a p.o. (60 mg/kg/day), and Lesinurad and colchicine (** indi method of treating gout in a Subject in need thereof, the cates p<0.01 versus vehicle: *** indicates p<0.001 versus method comprising co-administering 2-(5-bromo-4-(4-cy vehicle). clopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ac 0024 FIG. 8 illustrates the Phase II clinical study design etate, or a pharmaceutically acceptable salt thereof, and for Lesinurad treatment of gout patients with hyperuricemia. colchicine to a Subject. In specific embodiments, provided 0025 FIG.9 illustrates the time to first flare compared to a herein is a method that provides greater mean gout flare published colchicine control. The actual dose at the time of reduction (intensity, incidences and/or duration) than co-ad flare is shown and only flares requiring treatment were con ministration of colchicine (e.g., a similar amount of colchi sidered. cine) and therapeutic agent that is not a dual inhibitor of URAT1 and an inflammasome. In some embodiments, a therapy described herein is administered to a subject that has DETAILED DESCRIPTION OF THE INVENTION received previous gout therapy comprising the administration 0026. While preferred embodiments of the present inven of the second agent and a third therapeutic agent for the tion have been shown and described herein, it will be obvious treatment of gout (e.g., wherein the third therapeutic agent is to those skilled in the art that such embodiments are provided not an inhibitor of URAT1, is not an inflammasome, or both). by way of example only. Numerous variations, changes, and In specific embodiments, the amount of second agent is substitutions will now occur to those skilled in the art without reduced by at least 25%, at least 40%, at least 50%, at least departing from the invention. It should be understood that 60%, at least 75%, or any other suitable amount when com various alternatives to the embodiments of the invention pared to the amount of second agent that was administered described herein may be employed in practicing the inven with the third therapeutic agent. tion. It is intended that the following claims define the scope 0031. Another embodiment provides the method wherein of the invention and that methods and structures within the the total dosage of colchicine administered during co-admin Scope of these claims and their equivalents be covered istration with 2-(5-bromo-4-(4-cyclopropylnaphthalen-1- thereby. yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically 0027. The section headings used herein are for organiza acceptable salt thereof, is at least 50% less than the total tional purposes only and are not to be construed as limiting dosage of colchicine co-administered with a therapeutic the subject matter described. All documents, or portions of agent that is not a dual inhibitor of URAT1 and an inflamma documents, cited in the application including, without limi Some (e.g., at least 50% less than the total dosage of colchi tation, patents, patent applications, articles, books, manuals, cine that would be required to provide a similar or identical and treatises are hereby expressly incorporated by reference effect when co-administered with a therapeutic agent that is in their entirety for any purpose. not a dual inhibitor of URAT1 and an inflammasome; e.g., a US 2013/00598.68 A1 Mar. 7, 2013

similar effect being one wherein the effect is at least 80% acceptable salt of 2-(5-bromo-4-(4-cyclopropylnaphthalen similar, at least 90% similar, or the like). In certain embodi 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate or a polymorph ments, the daily dosage of colchicine is less than 3 mg, less thereof. than 1.5 mg, less than 1.2 mg, less than 1 mg, less than 0.7 mg, 0036. One embodiment provides a method of reducing less than 0.5 mg, less than 0.3 mg, or the like. In some monosodium urate induced inflammation comprising admin embodiments, the initial dosage of colchicine is less than 1.2 istering a pharmaceutical composition comprising a pharma mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less ceutical agent having both uricoSuric and anti-inflammatory activity. Another embodiment provides the method wherein than 0.3 mg, or the like. In certain embodiments, the dosage of the pharmaceutical agent is a URAT1 inhibitor with anti colchicine Subsequent to the initial dose is less than 0.6 mg, inflammatory activity. Another embodiment provides the less than 0.5 mg, less than 0.3 mg, less than 0.15 mg, or the method wherein the pharmaceutical agent is 2-(5-bromo-4- like. (4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) 0032. Another embodiment provides the method wherein acetate, or a pharmaceutically acceptable salt thereof. the amount of time that colchicine is co-administered with 0037. In some embodiments a method described herein 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- provides a daily dose of 2-(5-bromo-4-(4-cyclopropylnaph triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharma thereof, is at least one week less than when colchicine is ceutically acceptable salt thereof, is about 10 mg to about 2 g, co-administered with a therapeutic agent that is not a dual about 50 mg to about 1 g, about 200 mg to about 800 mg. inhibitor of URAT1 and an inflammasome (e.g., at least one about 200 mg to about 600 mg. or any other suitable thera week less than the total dosage of colchicine that would be peutically effective amount. In another embodiment is pro required to provide a similar or identical effect when co vided the method wherein the daily dose of 2-(5-bromo-4-(4- administered with atherapeutic agent that is not a dual inhibi cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) tor of URAT1 and an inflammasome; e.g., a similar effect acetate, or a pharmaceutically acceptable salt thereof, is about being one wherein the effect is at least 80% similar, at least 750 mg. In another embodiment is provided the method 90% similar, or the like). wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaph thalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharma 0033. In some embodiments, provided herein is a method ceutically acceptable salt thereof, is about 600 mg. In another of treating gout comprising administering to an individual in embodiment is provided the method wherein the daily dose of need thereof a therapeutically effective amount of 2-(5- 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt 3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 500 mg. In another embodiment is provided thereof. In specific embodiments, the therapeutically effec the method wherein the daily dose of 2-(5-bromo-4-(4-cyclo tive amount of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1- propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically a pharmaceutically acceptable salt thereof, is about 400 mg. acceptable salt thereof is sufficient to reduce the incidences In another embodiment is provided the method wherein the of reduce the duration of, and/or reduce the severity or inten daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)- sity of the gout symptoms (e.g., flares). In some embodi 4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically ments, the method further comprises reducing the amount of acceptable salt thereof, is about 200 mg. a second therapeutic agent for the treatment of gout, (and/or 0038. In another embodiment is provided the method symptoms thereof), administered to the Subject. In some wherein the daily dose is administered orally. In another embodiments, the second therapeutic agent is an NSAID, embodiment is provided the method wherein the daily dose is steroid, or colchicine. In specific embodiments, the second administered in the morning. In another embodiment is pro agent is colchicine. In specific embodiments, the amount of vided the method wherein the daily dose is administered with second agent is reduced by at least 25%, at least 40%, at least food. 50%, at least 60%, at least 75%, or any other amount to 0039. Another embodiment provides the above listed provide efficacious gout (and/or gout symptom) therapy. methods of reducing the duration of gout flares further com 0034. One embodiment provides a method of reducing the prising administration of a second serum uric acid lowering duration of gout flares comprising administration of a phar agent. In another embodiment is provided the method maceutical composition comprising 2-(5-bromo-4-(4-cyclo wherein the second serum uric acid lowering agent is a Xan propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or thine oxidase inhibitor. In another embodiment is provided a pharmaceutically acceptable salt thereof, to a subject, the method wherein the Xanthine oxidase inhibitor is febux wherein the mean duration of the gout flares in a patient ostat or allopurinol. undergoing uric acid level reduction is less than four days. Another embodiment provides the method, wherein the mean Gout duration of the gout flares is less than three days. Another 0040 Gout is a painful form of arthritis caused by high embodiment provides the method wherein the mean duration uric acid in the blood (hyperuricemia). As serum uric acid of the gout flares is less than two days. (SUA) levels increase, so does the risk of having gout and 0035. One embodiment provides a method for treating painful flares. Decreasing uric acid to a level of less than 6 gout comprising administration to a patient in need a thera mg/dL has been shown to be effective for managment of gout peutic agent that is a dual inhibitor of URAT1 and inflamma over the long-term. some. Another embodiment provides the method wherein the 0041 According to the National Health and Nutrition dual inhibitor of URAT1 and inflammasome is 2-(5-bromo Examination Survey III, 1988-1994, an estimated 5.1 million 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- people in the United States suffer from gout. Gout is the most ylthio)acetate, or a polymorph thereof, or a pharmaceutically common form of inflammatory arthritis in men. Gout affects US 2013/00598.68 A1 Mar. 7, 2013 approximately 3 times as many men as women, and men are for the development of gout symptoms increases steadily at more likely than women to have gout at all ages. Racial and concentrations higher than 6 mg/dL. In a patient with hype ethnic differences are not as distinct among patients in the US, ruricemia, urate can crystallize as monosodium urate mono though African Americans aged 45 years or older are more hydrate (MSUM) and may form deposits in the synovial likely to have gout than Caucasians in the same age group. membrane. An acute gout attack can occur when there is a 0042 Gout flares occur when excess uric acid forms crys marked inflammatory response to these crystal deposits. tals, causing inflammation in the joints that leads to Swelling 0051. In broad terms, gout attacks are symptoms of the and pain. Flares happen most often in the toes, but can happen inflammatory response to monosodium urate crystal deposi in hands, elbows, and knees. Gout flares often occur without tion. Supersaturation of serum urate is the underlying cause, warning and can cause joint Swelling, severe pain, tenderness, but not sufficient in and of itself to cause precipitation. Simi redness, and heat. Over time, gout flares become more fre larly, the presence of crystals alone may be insufficient to quent and of greater duration. elicit an inflammatory response. 0043 Acute gout is caused by an inflammatory response 0.052 Asymptomatic patients may have crystals in the to monosodium urate monohydrate (MSUM) crystal forma synovial fluid and neutrophils within the synovium-diag tion—a temperature-dependent phenomenon, which can nostic clinical signs of gout. Additionally, microtophi have occur under conditions of elevated serumurate concentration. been identified in areas of the synovium during the early Gout flare is known as one of the most painful conditions in stages of gout attacks. These observations are consistent with rheumatology, with pain intensity comparable to childbirth or a continuum of inflammatory response between intercritical long bone fractures. The condition regularly interrupts sleep, periods and acute attacks in chronic gout. inhibits walking, and interferes with work and leisure activi 0053. The inflammatory response may be initiated when ties. microcrystals shed from microtophi adjacent to the joint 0044 Serum urate, produced when purines are metabo space and enter the synovial fluid. In addition to their loca lized, is eliminated from the body in the form of uric acid. tion, the size of the crystals may be a significant factor. New Uric acid may have a significant physiological function, act microcrystals that form and those that break off from larger ing as an antioxidant, a role in which it is as effective as crystals appear to be essential to the process. This observation ascorbate. However, when the balance of purine nucleotide may also explain why aggressive antihyperuricemic therapy synthesis, breakdown and recycling, and elimination may triggera mobilization flare: it can cause larger crystals to becomes unbalanced, hyperuricemia may result. dissolve and release microcrystals. Thus, prophylactic treat 0045. The development of hyperuricemia is straightfor ment with anti-inflammatory drugs has been recommended ward: uric acid builds up in the blood when the body increases for 6 months or longer after the start of antihyperuricemic its production ofuric acid, or the kidneys do not eliminate it therapy, while urate levels are in flux. efficiently, or both. Overproduction is responsible for 10% of 0054 Many biochemical mediators are involved in the cases of primary gout; underexcretion for 90%. inflammatory response. Monocytes play a large role, releas 0046 Production may increase through endogenous (cell ing proinflammatory cytokines and attracting neutrophils to turnover and metabolism) and/or exogenous (dietary) factors. the site, thus amplifying the response. Phagocytes resident 0047 Reduced elimination suggests a renal cause because within the synovium may be insufficient to triggeran immune most uric acid is eliminated via the kidneys. (Enteric elimi response to microcrystals. However, the entry of new mono nation is the next most significant means of elimination, and cytes and neutrophils may shift the immune balance, leading it can increase in response to hyperuricemia.) Genetic factors to the gout flare. may play a role for individuals with hyperuricemia and reduced renal clearance of uric acid. Most Subjects with gout Treatment of Gout have lower clearance rates for uric acid, which may be mea Sured directly or as a ratio ofurate to inulin clearance (Curate/ NSAIDS Cinulin ratio). However, most gout and hyperuricemia patients show no other renal function abnormality. 0055 NSAIDS are the usual first line treatment for gout with no significant difference between agents in effective 0048 Though 90% of primary gout cases are triggered by ness. Improvement may be seen within 4 hours. They how difficulties in urate elimination, the exact mechanism behind ever are not recommended in those with certain other health lower uric acid clearance rates has not been established. problems such as gastrointestinal bleeding, renal failure, or Known factors that may affect urate clearance include the heart failure. While indomethacin is historically the most volume of urine flow (excretion is increased by >25% if urine commonly used NSAID, due to concerns of side effects and flow is doubled), the level of estrogens (as evidenced by lower no evidence of greater benefit, an alternative like ibuprofen serum uric acid concentrations in women before menopause may be preferred. For those at risk of gastric irritation from and in children), Surgery, and autonomic nervous system NSAIDs, an additional proton pump inhibitor may be given. function. NSAIDs include but are not limited to aminoarylcarboxylic 0049 Secondary gout can also be attributed to a reduction acid derivatives such as enfenamic acid, etofenamate, flufe in the glomerular filtration rate causing a decrease in the namic acid, isonixin, meclofenamic acid, mefenamic acid, excretion of uric acid by the kidney. This can be seen in niflumic acid, talniflumate, terofenamate, and tolfenamic certain kidney disorders or with medications such as diuretics acid; arylacetic acid derivatives Such as aceclofenac, acem that interfere with urate excretion. etacin, alclofenac, amfenac, amtolimetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etod Gout Flares olac, felbinac, fenclozic acid, fentiazac, glucametacin, 0050. The serum urate saturation point is approximately ibufenac, indomethacin, isofeZolac isoxepac, lonazolac, 6.8 mg/dL. Although several biochemical factors impact metiazinic acid, mofeZolac, oxametacine, piraZolac, proglu whether an individual experiences a flare at this point. Risk metacin, Sulindac, tiaramide, tolmetin, tropesin, and Zomepi US 2013/00598.68 A1 Mar. 7, 2013

rac; arylbutyric acid derivatives such as bumadizon, buti recommended dose is 1.2 mg at first indication of a flare bufen, fenbufen, Xenbucin: arylcarboxylic acids such as followed by 0.6 mg one hour later. clidanac, ketorolac, tinoridine: arylpropionic acid derivatives 0.058 Agents which have found use in the treatment of Such as alminoprofen, benoxaprofin, bermoprofen, bucloxic gout are P2X receptor inhibitors, reactive oxygen species acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibu inhibitors, toll like receptor antagonists, IL.1 inhibitors— profen, ibuproxam, indoprofen, ketoprofen, loxoprofen, anakinra, rilonacept, TNF blockers—embrel etc., glucocorti naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, coids prednisone, prednisolone, triamcinolone, dexametha protizinic acid, Suprofen, tiaprofenic acid, Ximoprofen, and Sone, inflammasome inhibitors, caspase inhibitors, Zaltoprofen; pyrazoles such as difenamizole, and epirozole; NSAIDS—celecoxib, Ibuprofen, naproxen, fenbufen, feno pyrazolones Such as apaZone, benzpiperylon, feprazone, profen, flur-biprofen, ketoprofen, tiaprofenic acid, azapropa mofebutaZone, moraZone, oxyphenbutaZone, phenylbuta Zone, diclofenac, diflunisal, etodolac, indomethacin (in Zone, pipebuZone, propyphenaZone, prostaglandins, ram dometacin), ketorolac, mefenamic, meloxicam, nabumetone, ifenaZone, SuXibuZone, and thiazolinobutaZone; salicylic acid phenylbutaZone, piroXicam, Sulindac, tenoxicam, tolfenamic derivatives such as acetaminosalol, aspirin, benorylate, bro acid, hydroxychloroquine (Plaquenil) or chloroquine mosaligenin, calcium acetylsalicylate, diflunisal, etersalate, (Aralen), leflunomide (Arava), methotrexate, SulfaSalazine fendosal, gentisic acid, glycol salicylate, imidazole salicy aZulfidine, Abatacept (Orencia), Adalimumab (Humira), late, lysine acetylsalicylate, mesalamine, morpholine salicy Anakinra (Kineret), Etanercept (Enbrel), Infliximab (Remi late, 1-naphtyl salicylate, olsalazine, parsalmide, phenylace cade), Rituximab (Rituxan). tylsalicylate, phenyl salicylate, Salacetamide, Salicylamide o-acetic acid, salicylsulfuric acid, Salsalate, Sulfasalazine; thi URAT1 azinecarboxamides Such as ampiroXicam, droxicam, isoxi cam, lomoxicam, piroXicam, and tenoxicam, cyclooxyge 0059 URAT1 is a urate transporter and urate-anion nase-II inhibitors (''COX-II") such as Celebrex (Celecoxib), exchanger which regulates the levelofurate in the blood. This Vioxx, Relafen, Lodine, and Voltaren and others, such as protein is an integral membrane protein primarily found in epsilon-acetamidocaproic acid, S-adenosylmethionine, kidney. 3-amino-4-hydroxybutytic acid, amiXetrine, bendazac, ben Zydamine, C.-bisabolol, bucololome, difenpiramide, ditaZol. Inflammasome emorfaZone, fepradinol, guaiaZulene, nabumetone, nime 0060. The inflammasome is responsible for activation of Sulide, oxaceprol, paranyline, perisoxal, produaZone, tenidap inflammatory processes, and has been shown to induce cell and Zilenton; sleep aids including but not limited to a benzo pyroptosis, a process of programmed cell death distinct from diazepine hypnotic, non-benzodiazepine hypnotic, antihista apoptosis. The inflammasome is a multiprotein complex con mine hypnotic, antidepressant hypnotic, herbal extract, bar sisting of caspase 1, PYCARD, a NALP and sometimes biturate, peptide hypnotic, triazolam, brotizolam, caspase 5 or caspase 11. The exact composition of an inflam loprazolam, lormetazepam, flunitrazepam, flurazepam, masome depends on the activator which initiates inflamma nitrazepam, quaZepam, estaZolam, temazepam, lorazepam, Some assembly i.e. dsRNA will trigger one inflammasome oxazepam, diazepam, halazepam, prazepam, alprazolam, composition whereas asbestos will assembly a different vari chlordiazepoxide, cloraZepate, an imidazopyridine or pyra ant. The inflammasome promotes the maturation of inflam Zolopyrimidine hypnotic, Zolpidem or Zolpidem tartarate, matory cytokines interleukin 1-B and interleukin 18. Zopiclone, esZopiclone, Zaleplon, indiplone, diphenhy 0061 The present invention relates to methods for treating dramine, doxylamine, phenyltoloxamine, pyrilamine, dox or preventing diseases, comprising administering an effective epin, amtriptyline, trimipramine, traZodon, nefazodone, amount of Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen buproprion, bupramityiptyline, an herbal extract such as Vale 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate. rian extract or amentoflavone, a hormone Such as melatonin, or gabapeptin. Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1- yl)-4H-1,2,4-triazol-3-ylthio)acetate Steroids 0062 Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen 0056 Glucocorticoids have been found to be equally 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate is known to decrease effective to NSAIDs and may be used if contraindications uric acid levels, (see for example US 2009-0197825, U.S. exist for NSAIDs. Intra-articular steroids have also been patent application Ser. No. 12/553,844 and U.S. patent appli found to be effective however the risk of concurrent joint cation Ser. No. 12/554,719). Details of clinical studies involv infection must be ruled out. ing sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)- 4H-1,2,4-triazol-3-ylthio)acetate have been described in U.S. Colchicine provisional patent application 61/252,530, U.S. provisional patent application 61/252,537 and U.S. provisional patent 0057 Colchicine is an alternative for those unable to tol application 61/265.240. erate NSAIDs. Its side effects (primarily gastrointestinal 0063 Uric acid is the result of the oxidation of Xanthine. upset) has decreased its usage. Gastrointestinal upset how Disorders ofuric acid metabolism include, but are not limited ever depends on the dose and the risk can be decreased by to, polycythemia, myeloid metaplasia, gout, a recurrent gout using Smalleryet still effective doses. Colchicine may interact attack, gouty arthritis, hyperuricaemia, hypertension, a car with other commonly prescribed drugs such as atorvastatin diovascular disease, coronary heart disease, Lesch-Nyhan and erythromycin among others. When administered in the syndrome, Kelley-Seegmiller syndrome, kidney disease, kid formulation marketed as COLCRYS (cholchicine, USP), the ney Stones, kidney failure, joint inflammation, arthritis, uroli recommended dose for the prophylaxis of gout flares is 0.6 thiasis, plumbism, hyperparathyroidism, psoriasis or sarcoi mg once or twice daily. For the treatment of gout flares the dosis. US 2013/00598.68 A1 Mar. 7, 2013

Definitions described herein, sufficient to inhibit the activity of URAT-1 in blood. In some embodiments, the invention provides meth 0064. The term “subject', as used herein in reference to ods of inhibiting URAT-1 activity in plasma by contacting the individuals suffering from a disorder, and the like, encom plasma with an amount of a polymorphic, crystalline or passes mammals and non-mammals. Examples of mammals mesophase form of sodium 2-(5-bromo-4-(4-cyclopropyl include, but are not limited to, any member of the Mammalian naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS class: humans, non-human primates Such as chimpanzees, described herein, sufficient to inhibit the activity of URAT-1 and other apes and monkey species; farm animals such as in plasma. In some embodiments, the invention provides cattle, horses, sheep, goats, Swine; domestic animals such as methods of inhibiting URAT-1 activity in an animal by con rabbits, dogs, and cats; laboratory animals including rodents, tacting said animal with an amount of a polymorphic, crys Such as rats, mice and guinea pigs, and the like. Examples of talline or mesophase form of sodium 2-(5-bromo-4-(4-cyclo non-mammals include, but are not limited to, birds, fish and propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, as the like. In one embodiment of the methods and compositions described herein sufficient to inhibit the activity of URAT-1 in provided herein, the mammal is a human. said animal. In some embodiments, the invention provides 0065. The terms “effective amount”, “therapeutically methods of inhibiting URAT-1 activity in a mammal by con effective amount” or “pharmaceutically effective amount’ as tacting said mammal with an amount of a polymorphic, crys used herein, refer to an amount of at least one agent or com talline or mesophase form of sodium 2-(5-bromo-4-(4-cyclo pound being administered that is Sufficient to treat or prevent propylnaphthalen- 1 -yl)-4H-1,2,4-triazol-3-ylthio)acetate, the particular disease or condition. The result can be reduc as described herein sufficient to inhibit the activity of URAT-1 tion and/or alleviation of the signs, symptoms, or causes of a in said mammal. In some embodiments, the invention pro disease, or any other desired alteration of a biological system. vides methods of inhibiting URAT-1 activity in a human by For example, an “effective amount for therapeutic uses is the contacting said human with an amount of a polymorphic, amount of the composition comprising a compound as dis crystalline or mesophase form of sodium 2-(5-bromo-4-(4- closed herein required to provide a clinically significant cyclopropylnaphthalen- 1 -yl)-4H-1,2,4-triazol-3-ylthio)ac decrease in a disease. An appropriate 'effective' amount in etate, as described herein, sufficient to inhibit the activity of any individual case may be determined using techniques, URAT-1 in said human. Such as a dose escalation study. Pharmaceutical Compositions Modulating URAT-1 Activity 0067. Described herein are pharmaceutical compositions 0066. The invention also relates to methods of modulating comprising an effective amount of a polymorphic, crystalline URAT-1 activity by contacting URAT-1 with an amount of a or mesophase form of sodium 2-(5-bromo-4-(4-cyclopropyl polymorphic, crystalline or mesophase form of sodium 2-(5- naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol described herein. In some embodiments, the pharmaceutical 3-ylthio)acetate, as described herein, sufficient to modulate compositions comprise an effective amount of a polymor the activity of URAT-1. Modulate can be inhibiting or acti phic, crystalline or mesophase form of sodium 2-(5-bromo vating URAT-1 activity. In some embodiments, the invention 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- provides methods of inhibiting URAT-1 activity by contact ylthio)acetate, as described herein, and at least one ing URAT-1 with an amount of a polymorphic, crystalline or pharmaceutically acceptable carrier. In some embodiments mesophase form of Sodium 2-(5-bromo-4-(4-cyclopropyl the pharmaceutical compositions are for the treatment of naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS disorders. In some embodiments the pharmaceutical compo described herein, sufficient to inhibit the activity of URAT-1. sitions are for the treatment of disorders in a mammal. In In some embodiments, the invention provides methods of Some embodiments the pharmaceutical compositions are for inhibiting URAT-1 activity in a solution by contacting said the treatment of disorders in a human. In some embodiments Solution with an amount of a polymorphic, crystalline or the pharmaceutical compositions are for the treatment or mesophase form of Sodium 2-(5-bromo-4-(4-cyclopropyl prophylaxis of disorders of uric acid metabolism. In some naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS embodiments the pharmaceutical compositions are for the described herein sufficient to inhibit the activity of URAT-1 in treatment or prophylaxis of hyperuricemia. In some embodi said solution. In some embodiments, the invention provides ments the pharmaceutical compositions are for the treatment methods of inhibiting URAT-1 activity in a cell by contacting or prophylaxis of gout. said cell with an amount of a polymorphic, crystalline or mesophase form of Sodium 2-(5-bromo-4-(4-cyclopropyl Modes of Administration, Formulations and Dosage Forms naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS described herein, sufficient to inhibit the activity of URAT-1 0068. Described herein are pharmaceutical compositions in said cell. In some embodiments, the invention provides comprising a polymorphic, crystalline or mesophase form of methods of inhibiting URAT-1 activity in a tissue by contact Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H ing said tissue with an amount of a polymorphic, crystalline 1,2,4-triazol-3-ylthio)acetate, as described herein. The com or mesophase form of sodium 2-(5-bromo-4-(4-cyclopropyl pound, compound forms and compositions described herein naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS may be administered either alone or in combination with described herein, sufficient to inhibit the activity of URAT-1 pharmaceutically acceptable carriers, excipients or diluents, in said tissue. In some embodiments, the invention provides in a pharmaceutical composition, according to standard phar methods of inhibiting URAT-1 activity in blood by contacting maceutical practice. Administration can be effected by any the blood with an amount of a polymorphic, crystalline or method that enables delivery of the compounds to the site of mesophase form of Sodium 2-(5-bromo-4-(4-cyclopropyl action. These methods include, though are not limited to naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, aS delivery via enteral routes (including oral, gastric or duodenal US 2013/00598.68 A1 Mar. 7, 2013 feeding tube, rectal Suppository and rectal enema), parenteral depending on the condition and its severity. The pharmaceu routes (injection or infusion, including intraarterial, intracar tical composition may be in unit dosage form. In such form, diac, intradermal, intraduodenal, intramedullary, intramuscu the preparation is Subdivided into unit doses containing lar, intraosseous, intraperitoneal, intrathecal, intravascular, appropriate quantities of the active component, e.g., an effec intravenous, intravitreal, epidural and Subcutaneous), inhala tive amount to achieve the desired purpose. Determination of tional, transdermal, transmucosal, Sublingual, buccal and the proper dosage for a particular situation is within the skill topical (including epicutaneous, dermal, enema, eye drops, of the art. For convenience, the total daily dosage may be ear drops, intranasal, vaginal) administration, although the divided and administered in portions during the day if most Suitable route may depend upon for example the condi desired. The amount and frequency of administration will be tion and disorder of the recipient. Those of skill in the art will regulated according to the judgment of the attending clinician be familiar with administration techniques that can be (physician) considering such factors as described above. employed with the compounds and methods of the invention. Thus the amount of pharmaceutical composition to be admin By way of example only, the compounds, compound forms istered may vary widely. When referring to a dosage amount, and compositions described herein can be administered the quantity stated is of the active pharmaceutical ingredient. locally to the area in need of treatment, by for example, local Administration may occur in an amount of between about infusion during Surgery, topical application Such as creams or 0.001 mg/kg of body weight to about 100 mg/kg of body ointments, injection, catheter, or implant, said implant made weight per day (administered in single or divided doses), or at for example, out of a porous, non-porous, or gelatinous mate least about 0.1 mg/kg of body weight per day. A particular rial, including membranes, such as Sialastic membranes, or therapeutic dosage can include, e.g., from about 0.01 mg to fibers. The administration can also be by direct injection at the about 7000 mg of compound, or, e.g., from about 0.05 mg to site of a diseased tissue or organ. about 2500 mg. The quantity of active compound in a unit 0069. The pharmaceutical compositions described herein dose of preparation may be varied or adjusted from about 0.1 may, for example, beinaform Suitable for oral administration mg to 1000 mg, from about 1 mg to 300 mg. or 10 mg to 200 as a tablet, capsule, pill, powder, Sustained release formula mg, according to the particular application. In some tions, Solution, Suspension, for parenteral injection as a sterile instances, dosage levels below the lower limit of the aforesaid Solution, Suspension or emulsion, for topical administration range may be more than adequate, while in other cases still as an ointment or cream or for rectal administration as a larger doses may be employed without causing any harmful Suppository. The pharmaceutical composition may be in unit side effect, e.g. by dividing Such larger doses into several dosage forms suitable for single administration of precise Small doses for administration throughout the day. In combi dosages. The pharmaceutical composition will include a con national applications in which the compound is not the sole ventional pharmaceutical carrier or excipient and a com therapy, it may be possible to administer lesser amounts of pound according to the invention as an active ingredient. In compound and still have therapeutic or prophylactic effect. addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Combination Therapies 0070 The formulations may conveniently be presented in 0072 The compounds and compound forms described unit dosage form and may be prepared by any of the methods herein may be administered as a sole therapy or in combina well known in the art of pharmacy. All methods include the tion with another therapy or therapies. step of bringing into association a compound or compound 0073. By way of example only, if one of the side effects form of the Subject invention or a pharmaceutically accept experienced by a patient upon receiving a compound or com able salt, ester, prodrug or Solvate thereof (“active ingredi pound form as described herein is hypertension, then it may ent') with the carrier which constitutes one or more accessory be appropriate to administer an anti-hypertensive agent in ingredients. In general, the formulations are prepared by uni combination with the compound. Or, by way of example only, formly and intimately bringing into association the active the therapeutic effectiveness of a compound or compound ingredient with liquid carriers or finely divided solid carriers form as described herein may be enhanced by administration or both and then, if necessary, shaping the product into the of an adjuvant (i.e., by itself the adjuvant may only have desired formulation. Methods of preparing various pharma minimal therapeutic benefit, but in combination with another ceutical compositions with a specific amount of active com therapeutic agent, the overall therapeutic benefit to the patient pound are known, or will be apparent, to those skilled in this is enhanced). Or, by way of example only, the benefit expe art. rienced by a patient may be increased by administering a compound or compound form as described herein with Doses another therapeutic agent (which also includes a therapeutic 0071. The amount of pharmaceutical compositions regimen) that also has therapeutic benefit. Regardless of the administered will firstly be dependent on the mammal being disease, disorder or condition being treated, the overall ben treated. In the instances where pharmaceutical compositions efit experienced by the patient may simply be additive of the are administered to a human Subject, the daily dosage will two therapeutic agents or the patient may experience a syn normally be determined by the prescribing physician with the ergistic benefit. dosage generally varying according to the age, sex, diet, 0074. In the instances where the compounds or compound weight, general health and response of the individual patient, forms as described herein are administered with other thera the severity of the patient’s symptoms, the precise indication peutic agents, they need not be administered in the same or condition being treated, the severity of the indication or pharmaceutical composition as other therapeutic agents, and condition being treated, time of administration, route of may, because of different physical and chemical characteris administration, the disposition of the composition, rate of tics, be administered by a different route. For example, the excretion, drug combination, and the discretion of the pre compound or compound form as described herein may be scribing physician. Also, the route of administration may vary administered orally to generate and maintain good blood US 2013/00598.68 A1 Mar. 7, 2013 levels thereof, while the other therapeutic agent may be disorder comprising administering to said individual an effec administered intravenously. The determination of the mode tive amount of a polymorph, crystalline form or mesophase as of administration and the advisability of administration, described herein of sodium 2-(5-bromo-4-(4-cyclopropyl where possible, in the same pharmaceutical composition, is naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate. well within the knowledge of the skilled clinician. The initial 0078. The invention extends to the use of the compounds administration can be made according to established proto and compound forms described herein in the manufacture of cols known in the art, and then, based upon the observed a medicament for treating a disease or disorder. effects, the dosage, modes of administration and times of 0079. In some embodiments, the disease or disorder is administration can be modified by the skilled clinician. hyperuricemia. In certain instances, hyperuricemia is charac 0075. The compounds, compound forms and composi terized by higher than normal blood levels of uric acid, sus tions described herein (and where appropriate other chemo tained over long periods of time. In certain instances, therapeutic agent) may be administered concurrently (e.g., increased blood urate levels may be due to enhanced uric acid simultaneously, essentially simultaneously or within the production (~10-20%) and/or reduced renal excretion (-80 same treatment protocol) sequentially or separately, depend 90%) of uric acid. In certain instances, causes of hyperurice ing upon the nature of the disease, the condition of the patient, mia may include obesity/weight gain, excessive alcohol use, and the actual choice of other chemotherapeutic agent to be excessive dietary purine intake (foods such as shellfish, fish administered. For combinational applications and uses, the roe, Scallops, peas lentils, beans and red meat, particularly compounds, compound forms and compositions described offal—brains, kidneys, tripe, liver), certain medications, herein and the chemotherapeutic agent need not be adminis including low-dose aspirin, diuretics, niacin, cyclosporine, tered simultaneously or essentially simultaneously. Thus, the pyrazinamide, ethambutol. Some high blood pressure drugs compounds, compound forms and compositions as described and some cancer chemotherapeutics, immunosuppressive herein may be administered first followed by the administra and cytotoxic agents, specific disease states, particularly tion of the chemotherapeutic agent; or the chemotherapeutic those associated with a high cell turnover rate (such as malig agent may be administered first followed by the administra nancy, leukemia, lymphoma or psoriasis), and also including tion of the compounds, compound forms and compositions as high blood pressure, hemoglobin diseases, hemolytic anemia, described herein. This alternate administration may be sickle cell anemia, various nephropathies, myeloproliferative repeated during a single treatment protocol. The determina and lymphoproliferative diseases, hyperparathyroidism, tion of the order of administration, and the number of repeti renal disease, conditions associated with insulin resistance tions of administration of each therapeutic agent during a and diabetes mellitus, and in transplant recipients, and pos treatment protocol, is well within the knowledge of the skilled sibly heart disease, inherited enzyme defects, abnormal kid physician after evaluation of the disease being treated and the ney function (e.g. increased ATP turn over, reduced glomeru condition of the patient. For example, the chemotherapeutic lar urate filtration) and exposure to lead (plumbism or agent may be administered first, especially if it is a cytotoxic “saturnine gout”). agent, and then the treatment continued with the administra 0080. In certain instances, hyperuricemia may be asymp tion of the compounds, compound forms and compositions as tomatic, though is associated with the following conditions: described herein followed, where determined advantageous, gout, gouty arthritis, uric acid stones in the urinary tract by the administration of the chemotherapeutic agent, and so (urolithiasis), deposits of uric acid in the soft tissue (tophi), on until the treatment protocol is complete. Thus, in accor deposits of uric acid in the kidneys (uric acid nephropathy), dance with experience and knowledge, the practicing physi and impaired kidney function, possibly leading to chronic and cian can modify each administration protocol for treatment acute renal failure. according to the individual patient’s needs, as the treatment 0081. In further or additional embodiments, the disease or proceeds. The attending clinician, in judging whether treat disorder is gout, which is a condition that results from uric ment is effective at the dosage administered, will consider the acid crystals depositing in tissues of the body. It is often general well-being of the patient as well as more definite signs related to an inherited abnormality in the body’s ability to such as relief of disease-related symptoms. Relief of disease process uric acid, but may also be exacerbated by a diet high related symptoms such as pain, and improvement in overall in purines. Defective uric acid processing may lead to condition can also be used to help judge effectiveness of elevated levels of uric acid in the blood causing recurring treatment. attacks of joint inflammation (arthritis), uric acid deposits in 0076 Specific, non-limiting examples of possible combi and around the joints, tophaceous gout, the formation of nation therapies include use of the compounds and composi tophi, decreased kidney function, and kidney Stones. tions described herein with Febuxostat, Allopurinol, Approximately 3-5 million people in the United States suffer Probenacid, Sulfinpyrazone, Losartan, Fenofibrate, BenZbro from attacks of gout with attacks 6 to 9 times more common marone or PNP-inhibitors (such as, but not limited to Forode in men than in women (see Sanders and Wortmann, “Harri sine, BCX-1777 or BCX-4208). This list should not be con son's Principles of Internal Medicine”, 16th Edition: 2005; strued to be closed, but should instead serve as an illustrative Food and Drug Administration (FDA) Advisory Committee example common to the relevant therapeutic area at present. Meeting, Terkeltaub presentation, June 2004; Terkeltaub, Moreover, combination regimens may include a variety of “Gout', N Engl J Med., 349, 1647-55, 2003). In certain routes of administration, including but not limited to oral, instances, gout is one of the most common forms of arthritis, intravenous, intraocular, Subcutaneous, dermal, and inhaled accounting for approximately 5% of all arthritis cases. In topical. certain instances, kidney failure and urolithiasis occur in 10-18% of individuals with gout and are common sources of Diseases morbidity and mortality from the disease. 0077. Described herein are methods of treating a disease I0082 Gout is associated with hyperuricemia. In certain or disorder in an individual Suffering from said disease or instances, individuals suffering from gout excrete approxi US 2013/00598.68 A1 Mar. 7, 2013

mately 40% less uric acid than nongouty individuals for any births. In certain instances, LNS is caused by a genetic defi given plasma urate concentration. In certain instances, urate ciency of the enzyme hypoxanthine-guanine phosphoribosyl levels increase until the Saturation point is reached. In certain transferase (HGPRT). In certain instances, LNS is an instances, precipitation ofurate crystals occurs when the Satu X-linked recessive disease. In certain instances, LNS is ration point is reached. In certain instances, these hardened, present at birth in baby boys. In certain instances, the disease crystallized deposits (tophi) form in the joints and skin, caus leads to severe gout, poor muscle control, and moderate men ing joint inflammation (arthritis). In certain instances, depos tal retardation, which appear in the first year of life. In certain its are be made in the joint fluid (synovial fluid) and/or joint instances, the disease also results in self-mutilating behaviors lining (synovial lining). Common areas for these deposits are (e.g., lip and finger biting, head banging) beginning in the the large toe, feet, ankles and hands (less common areas include the ears and eyes). In certain instances, the skin second year of life. In certain instances, the disease also around an affected joint becomes red and shiny with the results in gout-like Swelling in the joints and severe kidney affected area being tender and painful to touch. In certain problems. In certain instances, the disease leads neurological instances, gout attacks increase in frequency. In certain symptoms include facial grimacing, involuntary writhing, instances, untreated acute gout attacks lead to permanent joint and repetitive movements of the arms and legs similar to those damage and disability. In certain instances, tissue deposition seen in Huntington's disease. The prognosis for individuals ofurate leads to: acute inflammatory arthritis, chronic arthri with LNS is poor. In certain instances, the life expectancy of tis, deposition ofurate crystals in renal parenchyma and uroli an untreated individual with LNS is less than about 5 years. In thiasis. In certain instances, the incidence of gouty arthritis certain instances, the life expectancy of a treated individual increases 5 fold in individuals with serumurate levels of 7 to with LNS is greater than about 40 years of age. 8.9 mg/dL and up to 50 fold in individuals with levels >9mg/ dL (530 Lumol/L). In certain instances, individuals with gout I0087. In certain instances, hyperuricemia is found in indi develop renal insufficiency and end stage renal disease (i.e., viduals with cardiovascular disease (CVD) and/or renal dis 'gouty nephropathy'). In certain instances, gouty nephropa ease. In certain instances, hyperuricemia is found in individu thy is characterized by a chronic interstitial nephropathy, als with prehypertension, hypertension, increased proximal which is promoted by medullary deposition of monosodium Sodium reabsorption, microalbuminuria, proteinuria, kidney urate. disease, obesity, hypertriglyceridemia, low high-density lipo 0083. In certain instances, gout includes painful attacks of protein cholesterol, hyperinsulinemia, hyperleptinemia, acute, monarticular, inflammatory arthritis, deposition of hypoadiponectinemia, peripheral, carotid and coronary urate crystals in joints, deposition of urate crystals in renal artery disease, atherosclerosis, congestive heart failure, parenchyma, urolithiasis (formation of calculus in the urinary stroke, tumor lysis syndrome, endothelial dysfunction, oxi tract), and nephrolithiasis (formation of kidney Stones). In dative stress, elevated renin levels, elevated endothelin levels, certain instances, secondary gout occurs in individuals with and/or elevated C-reactive protein levels. In certain instances, cancer, particularly leukemia, and those with other blood hyperuricemia is found in individuals with obesity (e.g., cen diseases (e.g. polycythemia, myeloid metaplasia, etc). tral obesity), high blood pressure, hyperlipidemia, and/or 0084. In certain instances, attacks of gout develop very impaired fasting glucose. In certain instances, hyperuricemia quickly, frequently the first attack occurring at night. In cer is found in individuals with metabolic syndrome. In certain tain instances, symptoms include Sudden, severe joint pain instances, gouty arthritis is indicative of an increased risk of and extreme tenderness in the joint area, joint Swelling and acute myocardial infarction. In some embodiments, adminis shiny red or purple skin around the joint. In certain instances, tration of a compound described herein to an individual are the attacks are infrequent lasting 5-10 days, with no symp useful for decreasing the likelihood of a clinical event asso toms between episodes. In certain instances, attacks become ciated with a disease or condition linked to hyperuricemia, more frequent and last longer, especially if the disease is not including, but not limited to, prehypertension, hypertension, controlled. In certain instances, episodes damage the affected increased proximal Sodium reabsorption, microalbuminuria, joint(s) resulting in stiffness, Swelling, limited motion and/or proteinuria, kidney disease, obesity, hypertriglyceridemia, persistent mild to moderate pain. low high-density lipoprotein cholesterol, hyperinsulinemia, 0085 Plumbism or “saturnine gout, is a lead-induced hyperleptinemia, hypoadiponectinemia, peripheral, carotid hyperuricemia that results from lead inhibition of tubular and coronary artery disease, atherosclerosis, congestive heart urate transport causing decreased renal excretion ofuric acid. failure, stroke, tumor lysis syndrome, endothelial dysfunc In certain instances, more than 50% of individuals suffering tion, oxidative stress, elevated renin levels, elevated endothe from lead nephropathy Suffer from gout. In certain instances, lin levels, and/or elevated C-reactive protein levels. acute attacks of Saturnine gout occur in the knee more fre quently than the big toe. In certain instances, renal disease is I0088. In some embodiments, a compound or compound more frequent and more severe in Saturnine gout than in form as described herein is administered to an individual primary gout. In certain instances, treatment consists of Suffering from a disease or condition requiring treatment with excluding the individual from further exposure to lead, the a diuretic. In some embodiments, a compound or compound use of chelating agents to remove lead, and control of acute form as described herein is administered to an individual gouty arthritis and hyperuricaemia. In certain instances, sat Suffering from a disease or condition requiring treatment with urnine gout is characterized by less frequent attacks than a diuretic, wherein the diuretic causes renal retention ofurate. primary gout. In certain instances, lead-associated gout In some embodiments, the disease or condition is congestive occurs in pre-menopausal women, an uncommon occurrence heart failure or essential hypertension. in non lead-associated gout. 0089. In some embodiments, administration of a com I0086. In certain instances, Lesch-Nyhan syndrome (LNS pound or compound form as described herein to an individual or Nyhan's syndrome) affects about one in 100,000 live is useful for improving motility or improving quality of life. US 2013/00598.68 A1 Mar. 7, 2013

0090. In some embodiments, administration of a com iting Xanthine oxidase, is less pharmaceutically acceptable pound or compound form as described herein to an individual due to low oral bioavailability. In certain instances, fatal reac is useful for treating or decreasing the side effects of cancer tions due to hypersensitivity, bone marrow Suppression, hepa treatment. titis, and vasculitis have been reported with Allopurinol. In 0091. In some embodiments, administration of a com certain instances, the incidence of side effects may total 20% pound or compound form as described herein to an individual ofall individuals treated with the drug. Treatment for diseases is useful for decreasing kidney toxicity of cis-platin. of uric acid metabolism has not evolved significantly in the 0092. In certain instances, gout is treated by lowering the following two decades since the introduction of allopurinol. production ofuric acid. In certain instances, gout is treated by 0097. In certain instances, uricoSuric agents (e.g., increasing the excretion ofuric acid. In certain instances, gout probenecid, Sulfinpyrazone, and benzbromarone) increase is treated by URAT 1, xanthine oxidase, Xanthine dehydro uric acid excretion. In certain instances, probenecid causes an genase, Xanthine oxidoreductase, a purine nucleoside phos increase in uric acid secretion by the renal tubules and, when phorylase (PNP) inhibitor, a uric acid transporter (URAT) used chronically, mobilizes body stores of urate. In certain inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 instances, 25-50% of individuals treated with probenecid fail inhibitor, a solute carrier family 2 (facilitated glucose trans to achieve reduction of serum uric acid levels <6 mg/dL. In porter), member 9 (SLC2A9) inhibitor, an organic anion certain instances, insensitivity to probenecid results from transporter (OAT) inhibitor, an OAT-4 inhibitor, or combina drug intolerance, concomitant Salicylate ingestion, and renal tions thereof. In general, the goals of gout treatment are to i) impairment. In certain instances, one-third of the individuals reduce the pain, Swelling and duration of an acute attack, and develop intolerance to probenecid. In certain instances, ii) prevent future attacks and joint damage. In certain administration of uricoSuric agents also results in urinary instances, gout attacks are treated Successfully using a com calculus, gastrointestinal obstruction, jaundice and anemia. bination of treatments. In certain instances, gout is one of the 0098. Successful treatment aims to reduce both the pain most treatable forms of arthritis. associated with acute gout flare and long-term damage to the 0093 i) Treating the gout attack. In certain instances, the affected joints (Emerson, “The Management of Gout', N pain and Swelling associated with an acute attack of gout can Engl J Med., 334(7), 445-451, 1996). Therapeutic goals be addressed with medications such as acetaminophen, Ste include providing rapid and safe pain relief, preventing fur roids, nonsteroidal anti-inflammatory drugs (NSAIDs), ther attacks, preventing the formation oftophiand Subsequent adrenocorticotropic hormone (ACTH) or colchicine. In cer arthritis, and avoiding exacerbating other medical conditions. tain instances, proper medication controls gout within 12 to Initiation of treatment depends upon the underlying causes of 24 hours and treatment is stopped after a few days. In certain hyperuricemia, Such as renal function, diet, and medications. instances, medication is used in conjunction with rest, While gout is a treatable condition, there are limited treat increased fluid intake, ice-packs, elevation and/or protection ments available for managing acute and chronic gout and a of the affected area/s. In certain instances, the aforementioned number of adverse effects are associated with current thera treatments do not prevent recurrent attacks and they do not pies. Medication treatment of gout includes pain manage affect the underlying diseases of abnormal uric acid metabo ment, prevention or decrease in joint inflammation during an lism. acute gouty attack, and chronic long-term therapy to maintain 0094) ii) Preventing future attacks. In certain instances, decreased serum uric acid levels. reducing serum uric acid levels below the saturation level is 0099 Nonsteroidal anti-inflammatory drugs (NSAIDs) the goal for preventing further gout attacks. In some cases, are effective anti-inflammatory medications for acute gout this is achieved by decreasing uric acid production (e.g. but are frequently associated with irritation of the gastrointes allopurinol), or increasing uric acid excretion with uricoSuric tinal (GI) system, ulceration of the stomach and intestines, agents (e.g. probenecid, Sulfinpyrazone, benzbromarone). and occasionally intestinal bleeding (Schlesinger, “Manage 0095. In certain instances, allopurinol inhibits uric acid ment of Acute and Chronic Gouty Arthritis Present State-of formation, resulting in a reduction in both the serum and the-Art': Medications, 64 (21), 2399-2416, 2004: Pascual urinary uric acid levels and becomes fully effective after 2 to and Sivera, “Therapeutic advances in gout: Curr Opin Rheu 3 months. matoll., March, 19(2), 122-7, 2007). Colchicine for acute gout O O Guanine N Xanthine -H- Urate " ls YN^ " ls )/ Hypoxanthine !- N H N N- Inhibited - Allopurinol Hypoxanthine by Allopurinol

0096. In certain instances, allopurinol is a structural ana is most commonly administered orally as tablets (every 1-2 logue of hypoxanthine, (differing only in the transposition of hours until there is significant improvement in pain or the the carbon and nitrogen atoms at positions 7 and 8), which patient develops GI side effects such as severe diarrhea, nau inhibits the action of Xanthine oxidase, the enzyme respon sea and vomiting), or intravenously. Corticosteroids, given in sible for the conversion of hypoxanthine to xanthine, and short courses, can be administered orally or injected directly Xanthine to uric acid. In certain instances, it is metabolized to into the inflamed joint. the corresponding Xanthine analogue, alloxanthine (oxypu 0100 Medications are available for reducing blood uric rinol), which is also an inhibitor of Xanthine oxidase. In acid levels that either increase renal excretion ofuric acid by certain instances, alloxanthine, though more potent in inhib inhibiting re-uptake or reduce production of uric acid by US 2013/00598.68 A1 Mar. 7, 2013

blockade of Xanthine oxidase. These medicines are generally EXAMPLES not initiated until after the inflammation from acute gouty arthritis has subsided because they may intensify the attack. If Lesinurad they are already being taken prior to the attack, they are 0105 Lesinurad is the generic name for 2-(5-bromo-4-(4- continued and only adjusted after the attack has resolved. cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace Since many subjects with elevated blood uric acid levels may tic acid, whose chemical structure is: not develop gouty attacks or kidney Stones, the decision for prolonged treatment with uric acid-lowering medications is individualized.

Kits ------O 0101 The compounds, compound forms, compositions and methods described herein provide kits for the treatment of diseases and disorders, such as the ones described herein. These kits comprise a compound, compound form, com pounds, compound forms or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches 0106. In some instances, the term Lesinurad also includes described herein. Such kits may also include information, the Sodium salt of Lesinurad, i.e. sodium 2-(5-bromo-4-(4- Such as scientific literature references, package insert mate cyclopropylnaphthalen-1-yl)- 4H-1,2,4-triazol-3-ylthio)ac rials, clinical trial results, and/or Summaries of these and the etate. In the examples described herein, the compound like, which indicate or establish the activities and/or advan administered may be Lesinurad, or its sodium salt, in an tages of the composition, and/or which describe dosing, amorphous or polymorph form thereof. In instances where administration, side effects, drug interactions, or other infor the sodium salt is used, the amounts quoted herein may in fact mation useful to the health care provider. Such information be lower than the actual amounts of the sodium salt of may be based on the results of various studies, for example, Lesinurad used in the experiment, but were calculated to studies using experimental animals involving in vivo models provide an effective amount of the free acid compound. and studies based on human clinical trials. Kits described herein can be provided, marketed and/or promoted to health I. In Vitro Experiments providers, including physicians, nurses, pharmacists, formu lary officials, and the like. Kits may also, in Some embodi Example 1 ments, be marketed directly to the consumer. Comparison of Lesinurad to Other Gout Therapies 0102 The compounds, compound forms and pharmaceu tical compositions described herein may be utilized for diag 0.107 Activation of the inflammasome results in the nostics and as research reagents. For example, the com release of preformed IL-1, which goes on to activate other pounds, compound forms and pharmaceutical compositions, targets as well as increase the production of IL-1 itself. either alone or in combination with other compounds, can be Lesinurad blocks IL-1 release very early, within 1 hour of used as tools in differential and/or combinatorial analyses to stimulation, as illustrated in FIG. 1. This activity may be elucidate expression patterns of genes expressed within cells compared with rilonacept which only inhibits the production and tissues. As one non-limiting example, expression patterns of TNF-C. (as expected since TNF-C. production is down within cells or tissues treated with one or more compounds stream of IL-1B action) as illustrated in FIG. 2A (6 hour time are compared to control cells or tissues not treated with com point). However, rilonacept does not reduce IL-1 production pounds and the patterns produced are analyzed for differential as illustrated in FIG. 2B. levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, Example 2 expression level, size, structure or function of the genes In Vitro MSU-Induced Inflammation to Assess the examined. These analyses can be performed on stimulated or Effect of Lesinurad on Human Cells unstimulated cells and in the presence or absence of other compounds which affect expression patterns. Example 2A 0103 Besides being useful for human treatment, the com pounds, compound forms and pharmaceutical compositions In Vitro THP-1 (Human Cell) Assay described herein are also useful for veterinary treatment of companion animals (e.g. dogs, cats), exotic animals and farm STEPA: Preparation of MSU Crystals animals (e.g. horses), including mammals, rodents, and the (0.108 Uric acid (2g, Sigma, Cat #U0881, Log S89329 like. 419) was heated in a flask at 200° C. for 2 hours. Endotoxin 0104. The examples and preparations provided below fur free water (396 mL) followed by aqueous sodium hydroxide ther illustrate and exemplify the compounds of the present solution (2.375 mL of 5N or 1.19 mL 10N) were added and invention and methods of preparing such compounds. It is to heated on a stir plate until the uric acid dissolved. It was then be understood that the scope of the present invention is not cooled, filtered (stericup filter), and the pH measured (pH limited in any way by the scope of the following examples and 7.9). The solution was stirred at room temperature for 24 preparations. hours and then centrifuged at 1000 g for 10 min. The super US 2013/00598.68 A1 Mar. 7, 2013 natant was discarded and resuspended in PBS and centrifuged 0120 DMSO Opti-Freeze DMSO Cryopreservation at 1000 g for 10 min; this step was repeated twice. The washed Medium, Fisher BioReagents, Cat NO BP2652-50 crystals were heated at 60°C. until dry and then autoclaved at 0121 Freezing media 50% FBS+40% RPMI-10% 200° C. for 2 hours. The crystals were then weighed and DMSO resuspended in PBS at a concentration of 26 mg/ml. STEP B: Isolation of Monocytes STEP B: Assay Details 0.122 The hPBM cells isolated in step A were counted, centrifuged (300 g; 10 min) and the Supernatant aspirated. 0109 THP-1 cells were differentiated with 0.5 uM of The cell pellet was resuspended in 80 ul of buffer per 107 phorbol myristate acetate (PMA) incubated for 3 hours. Cells total cells, and 20 ul of CD14 Microbeads per 107 cells were then spun down and washed once with HBSS. 1.25x10/ added and after mixing incubated on ice 15 mins. The cells mL cells were plated in white clear bottom white 96 well plate were washed by adding 5 ml of MACs buffer and centrifuged in 100 uL volume and incubated overnight. The next day the (300 g; 10 mins). media was aspirated from the wells. 100 u, of 1 x Optimem (0123. While the cells were being centrifuged, the MACS along with the compounds were added. The cells and MS column was equilibrated by placing the column onto the Lesinurad were incubated at 37° C. for 6 hours. 75ul of the magnet. 15 ml conical tube was placed below the column to supernatant was collected and frozen to -20°C. for cytokine/ collect the flow through. 3 ml of MACS buffer was added to chemokine analysis by MSD. 10 uL of CelTiter-Glo the column to equilibrate it; flow through was discarded and (Promega) was added to the assay plate and incubated at R.T a new 15 ml tube placed under the column. for 15 mins and then read on analyst. 0.124. The centrifuged cells were then resuspended in 5 ml of MACS buffer and applied to the column. The flow through STEPC: IL-1B and TNF-C. was discarded. The column was then removed from the mag 0110 FIG. 3A shows a plot of Lesinurad concentration net and placed on a new 15 ml tube. 3 ml of MACS buffer was (log) Versus TNF-C. concentration (pg/ml), generating a added to the column and the flow through containing the Lesinurad TNF-C. ICso-52 uM. FIG. 3B shows a plot of monocytes collected. Cells were spun down (300 g, 5 min: Lesinurad concentration (log) versus IL-1B concentration supernatant discarded), resuspended in RPMI complete (pg/ml), generating a Lesinurad IL-1B ICso-30 uM. media and counted. 0.125 Materials and Reagents: Example 2B 0.126 Miltenyi Bio's Monocyte Isolation kit II Cat No. 130-050-201 0127. MACS buffer: PBS pH 7.2 100 ml: 0.5% FBS; In Vitro Primary Human Monocyte Assay 2 mM EDTA 0111 STEP A: Isolation of human Peripheral Blood 0128 RPMI complete media recipe: 10% heat inacti Mononuclear Cells (hPBMCs) vated fetal bovine serum 0112 Blood (50-60 ml) was collected in Heparin vac 0129 RPMI 1640: 1% PenStrepGlut; 1% Non-Essen cutainers (BD vaccutainer, Cat No-367874, Sodium Heparin, tial Amino Acid; 1%. Hepes; 1% Na-pyruvate; BME 10 ml tube; each holding -8-10 ml blood), which was imme 0130 GPCR study performed by Life Technologies diately mixed to prevent coagulation. Accuspin-Histopaque 0131 Chemotaxis assay performed by Bio-quant (in 1077 (Sigma Aldrich cat no-A7054) was allowed to reach primary human monocytes, neutrophils and T cells). room temperature and diluted blood 1:1 in DPBS (Dulbec co's Phosphate-Buffered Saline (1X), liquid Invitrogen, STEPC: IL-1B and CLU 14040-133), mixed by pipetting. The tubes were centrifuged I0132 FIG. 4A shows a plot of IL-1B (pg/ml) for varying (800 g; 30 seconds; room temp) to ensure all the Histopaque concentrations of Lesinurad (100 uM, 50 uM and 25 uM), 1077 was below the high density polyethylene barrier. indicating dose dependent IL-1B inhibition with a Lesinurad 0113 Diluted blood (50 ml) was added to the upper cham an IL-1 B ICs-50 uM. FIG. 4B shows a plot of CLU for ber of each ACCUSPIN tube and centrifuged at room temp varying concentrations of Lesinurad (100 uM, 50 uM and 25 for 10 minutes at 1000xg or 15 minutes at 800xg, (brakes uM). were off for this step; acc=1, dcl=1). PBMCs were collected from the PBS/Ficoll interphase with a transfer pipette and II In Vivo Rat Studies transferred to a new 50 mL tube. 10%RPMI was added to Example 3 bring the volume to 40 ml and the cells spun down at 240xg (1000 rpm), 8 min at room temp. Effect of Orally Administered Lesinurad on 0114 Supernatant was decanted and 5 mL of RBC lysis Monosodium Urate (MSU) Crystal-Induced solution added to the pellet and mixed well. The tubes were Inflammation in Rats incubated at room temp for 5 mins, diluted to 10 mL with DPBS and spun down at 240xg (1000 rpm), 8 min, room Example 3A temp. The supernatant was discarded, resuspended in RPMI complete media, and the cells counted. Effects of Lesinurad in a Rat Air Pouch Model of 0115 Materials and Reagents: Crystal-Induced Arthropathy 0116 RBC lysis buffer Miltenyi Biotec Red Blood 0.133 Procedure Cell Lysis Solution (#130-094-183) 0134) 1. Preparation of monosodium urate (MSU) crys tals. 0117 RPMI RPMI Medium 1640 (1x), liquid Cat. I0135 a. 1.68 guric acid was dissolved in 500 ml 0.01 No. 11875-135 NaOH and heated to 70° C. NaOH was added as 0118 FBS Fetal Bovine Serum, Qualified, Heat-In required to maintain pH 8-9. The solution was filtered activated Cat. No. 16140-071 and incubated at ambient with slow stirring continu 0119) 10% RPMI RPMI-10% FBS ously for 24 hours. US 2013/00598.68 A1 Mar. 7, 2013

0.136 b. Crystals were washed, dried and sterilized TABLE 1-continued by autoclaving. 0.137 c. Crystals were suspended in sterile saline at Group Treatment Schedule 0.67 mg/ml, 2.67 mg/ml and 10 mg/ml just prior to No. Dose SC. 0.138 2. 110 Sprague-Dawley rats (male, 160-180 g) Group Rats Treatment (mg/kg) ROA Timing MSU (mg) were quarantined for 3 days; rats were accepted for the 5 10 Colchicine O.O1 SC -30 min 150 Study if no signs of clinical distress were noted during 6 10 Colchicine O.1 SC -30 min 150 7 10 Colchicine 1 SC -30 min 150 the quarantine period. The rats were maintained oncer 8 10 Lesinurad 10 PO -30 min 150 tified laboratory diet and water ad libitum. 9 10 Lesinurad 30 PO -30 min 150 0.139. 3. The rats were ear-notched for individual iden 10 10 Lesinurad 100 PO -30 min 150 tification and rat weights were recorded. 11 10 Allopurinol 10 PO -30 min 150 0140 4. The rats were distributed randomly to 11 groups of 10 rats per group based upon average weight. 0141 5. The rats were anesthetized and bled for sample 0158 11. Thirty minutes after treatment, the rats were from retro-orbital sinus into microtainer tubes. anesthetized and injected into the air pouch with 15 ml 0.142 a. The blood was processed to serum; MSU suspension. 0.143 b. The serum was transferred to labeled Eppen 0159) 12. Four (4) hours after MSU injection, the rats dorf tubes (T=0) and stored at -80° C. 014.4 c. Minimum serum volume of 100 ul (or 200 ul were anesthetized and bled for sample from retro-orbital blood) was collected from each rat. sinus into microtainer tubes. (0145 6. DAY 0: The rats are anesthetized. (0160 a. The blood was processed to serum 0146 a. The nape of the neck was shaved, cleansed 0.161 b. The serum was transferred to labeled Eppen with 70% isopropanol followed by cleansing with Povidone. dorf tubes (T=0) and stored at -80° C. 0147 b. A 23-gauge needle was attached to a 30 ml 0162 c. Minimum serum volume of 100 ul (or 200 ul syringe fitted with an air filter. blood) was collected from each rat. 0148 c. 30 ml of sterile air was injected subcutane (0163 d. 5 ml sterile PBS containing 10 U/ml heparin ously and the rat returned to routine maintenance. injected into the air pouch of anesthetized rats. 0149 7. DAY 3: Steps 6a) through 6c) were repeated. 0.164 13. The pouch was gently massaged and the exu O150 8. DAYS 4 and 5: 0151 a. Rats in test compound groups were dosed date was immediately removed from the air pouch. Exu once daily by Subcutaneous injection or oral dosing as dates Volume was measured and recorded for each ani in the treatment table below. mal. 0152 b. 24 hours after dosing on DAY 4 (DAY 5), 0.165 a. Exudate cells were collected by centrifuga sample bleeds are collected from each rat immedi tion at 2,000 rpm for 5 minutes at room temperature. ately prior to dosing on DAY 5, processed to serum The Supernatants were aliquoted to two portions and and stored at -80°C. A minimum of 0.100 ml serum Stored at -80° C. was collected for each bleed. 0166 b. Cells were re-suspended in 0.5 ml heparin 0153. 9. DAY 6: TIME=0 HOUR: Rats were injected subcutaneously with Colchicine or dosed orally with ized saline for neutrophil cell counts. Vehicle, Lesinurad or Allopurinol. 0.167 c. Plasma extravasation was measured by opti 0154 Lesinurad formulation: Lesinurad was dis cal absorbance at 620 nm for each exudate sample. solved in distilled water (dHO) to preparea20 mg/ml 0.168. 14. Exudate from each animal was assayed for dosing solution (Group 10). The 20 mg/ml stock was TNF-alpha and IL-1. diluted in dHO to prepare a 6 mg/ml solution (Group 9) and a 2 mg/ml solution (Group 8). (0169 15. Data treatments: 0155 Allopurinol formulation: Allopurinol was dis (0170 a. Mean cell counts and standard deviations solved in distilled water (dELO) to prepare a 2 mg/ml were determined for each group. dosing solution (Group 11). 0156 Immediately following SC injections, each 0171 b. Mean optical absorbance measurements and animal was injected intravenously with Evans blue standard deviations were determined for each group. dye (2.5% w/vol; 2.0 ml/kg). Evans blue binds to 0172 c. Group means and standard deviations for albumin and acts as a marker for plasma extravasa TNF-alpha and IL-1 were determined for each group. tion. 0173 d. Statistical significance of treatments on (O157 10. Group Treatments are shown in Table 1. mean cell counts, mean optical absorbance measure ments and mean cytokine measurements were deter TABLE 1. mined by comparison of means for treatment and Group Treatment Schedule positive control groups with vehicle group. 0.174 Results No. Dose Group Rats Treatment (mg/kg) ROA Timing MSU (mg) (0175. As shown in FIG. 5, (total white blood cell counts for 10 mg/kg, 30 mg/kg and 100 mg/kg. Lesinurad) monoso 1 10 Vehicle NA PO -30 min None 2 10 Vehicle NA PO -30 min 10 dium urate crystal-induced inflammatory response was 3 10 Vehicle NA PO -30 min 40 blocked by Lesinurad. FIG. 5A provides the comparison with 4 10 Vehicle NA PO -30 min 150 1 mg/kg colchicine. FIG. 5B provides the comparison with 0.1 mg/kg colchicine. US 2013/00598.68 A1 Mar. 7, 2013 14

Example 3B re-suspended in 0.5 ml heparinized saline for neutrophil cell counts. Plasma extravasation was measured by optical absor In Vivo MSU-Induced Inflammation Rat Air Pouch bance at 620 nm for each exudate sample. Blood sample Study bleeds were collected from each animal to provide 0.5 ml 0176 The objective of this study was to assess the effect of minimum Volume of serum per rat. Lesinurad (dosed orally, 0.1-60 mg/kg QD) in monosodium STEPC: Extravasation (Optical Absorbance at 620 nm) urate (MSU) crystal injection-induced inflammation in rats. 0.179 Extravasation values for various doses of Lesinurad and/or colchicine are shown in Table 2 below and in FIG. 6A, STEPA: Animals and Animal Care demonstrating: 0177. Male Sprague-Dawley rats weighing 130-200 g 0180 Saline injection (no MSU) produces no detect from Harlan, Indianapolis, Ind. (Air Pouch studies) were able extravasation; unpacked, placed in cages, a health inspection performed and 0181. MSU crystal injection induces extravasation; a number assigned. Rats were caged in groups of 3-5 with free 0182 Colchicine (0.01, 0.1 and 1 mg/kg) showed a access to certified laboratory rodent chow and drinking water, dose-dependent decrease in extravasation; in environmentally-controlled rooms (20-26° C.; 40-70% 0183 Lesinurad (10 mg/kg) reduced extravasation. TABLE 2

Extravasation Values for Various Doses of Lesinurad and or Colchicine

Dose Regimen mg/kg 1. 2 3 4 5 6 7 8 9 10 Aw

"Control O.OO -O.O1 O.OO O.OO -0.01 -0.01 -0.02 -O.O1 O.OO -0.01 -0.01 Vehicle 2.16 1.42 1.68 1.94 1.66 180 1.76 1.89 2.11 1.62 18O Colchicine O.O1 1.46 1.67 1.63 1.74 2.62 2.39 1.99 1.42 1.34 153 1.78 O.1 1.31 1.74 O.68 1.7S 1.72 O.98 0.83 1.22 1.2S 1.41 1.29 1 1.17 119 1.24 1.24 1.12 O.S2 0.73 O.S9 O.75 0.36 0.89 Lesinurad O.1 1.89 2.19 154 2.14 194 1.61 1.90 1.88 1.84 1.83 1.87 1 2.27 1.36 1.94 1.67 1.79 1.98 2.04 1.83 1.79 2.01 1.87 10 O.89 0.77 O.71 0.97 0.82 1.94 0.82 1.2S 1.2O O.93 1.03 Lesinurad 10.0.01 O.71 1.24 1.04 1.08 O.78 O.7O 1.23 O.7O O.84 1.51 0.98 Colchicine 10.0.1 O.82 1.06 1.07 111 121 136 1.31 1.35 1.63 0.43 1.13

Control = no MSU; *Vehicle = sterile saline relative humidity), with time-controlled fluorescent lighting STEP D: Exudate Volume systems providing 12/12 dark light cycle. 0.184 Exudate volume values (mL) for various doses of STEP B: Method Lesinurad and/or colchicine are shown in Table 3 below and in FIG. 6B, demonstrating: 0.178 Under anesthesia, 30 mL sterile air was injected 0185. In vehicle-treated rats, the amount of exudate subcutaneously on day 0 and day 3. Vehicle (water) or more than doubles Lesinurad were administered orally. On the day of the experi ment, rats were dosed with Vehicle, Lesinurad p.o., and/or 0186. At 0.01 and 0.1 mg/kg doses colchicine did not colchicine s.c. (Sigma, Cat.#C9754, Lot.il 188K1131). significantly reduce exudate Volume. Immediately following administrations, each animal was 0187. At 1 mg/kg colchicine significantly reduced exu injected i.v. with Evans blue dye (2.5% w/vol; 2.0 ml/kg), date Volume. which binds to albumin and acts as a plasma extravasation marker. 30 min post drug administration, the rats were anes 0188 At 0.1 and 1 mg/kg/day doses Lesinurad 1 did not thetized and the air pouch injected with 15 ml of either saline significantly reduce exudate Volume. or MSU suspension (10 mg/mL). Four (4) hours after MSU 0189 At 10 mg/kg/day Lesinurad significantly reduced injection, 5 ml of sterile PBS containing 10U/ml heparin was exudate Volume. injected into the airpouch of anesthetized rats. The pouch was gently massaged and the exudate was immediately removed 0.190 Lesinurad 10 mg/kg/day co-administered with from the air pouch. The exudate Volume was measured and colchicine (0.01 and 0.1 mg/kg), did not significantly recorded for each animal. Cells in the exudate were collected reduce exudate volume better than either therapy alone. by centrifugation (2,000 rpm; 5 mins; rt). The supernatants 0191) A number of cytokines in the exudates were mea were stored at -20° C. for cytokine analysis. Cells were Sured; Lesinurad significantly reduced IL-4 levels. US 2013/00598.68 A1 Mar. 7, 2013 15

TABLE 3

Exudate Volume Values for Various Doses of Lesinurad and or Colchicine

Dose Regimen mg/kg 1 2 3 4 5 6 7 8 10 Aw

Control 4.6 4.6 5 4.9 5 4.2 4.6 4.9 48 4.6 4.72 Vehicle 12 9 14 10.8 10 12 11 10 12 8 1088 Colchicine O.O1 10 9 9 12 8 11 11 8 12 8 9.8 O.1 10 7.8 8 9.8 11 11 15 9 9 8 9.86 1 7 S.9 8 8.6 5.6 4.6 4 5.2 8 4.4 6.13 Lesinurad O.1 11 8 10 9.6 9.2 7 8 12 8 9 9.18 1 13 5 10 12 14 7.8 11.4 7 9.6 7 9.68 10 6 8 6 9 12 8.4 9 7.5 7 1O 8.29 Lesinurad 100.01 11 9 8 9 5 5 7 4.9 6 8.8 7.37 Colchicine 10.0.1 7.8 8 5 8 10 7 11 9 9.6 S 8.04

Control = no MSU; *Vehicle = sterile saline

STEP E: White Blood Cell (WBC) Count Example 3C In Vivo MSU-Induced Inflammation—Rat Knee 0192 Total numbers of white blood cells are shown in the Joint Study 0197) The objective of this study was to assess the effect of table below (x10) for various doses of Lesinurad and/or Lesinurad (dosed orally, 0.1-60 mg/kg QD) in monosodium colchicine are shown in Table 4 and graphically in FIG. 6C, urate (MSU) crystal injection-induced inflammation in rats. demonstrating: STEPA: Animals and Animal Care 0198 Male Sprague-Dawley rats weighing 130-200 g 0193 Four hours after MSU injection, there are signifi from Shanghai SLAC Laboratory Animal Co., Ltd., China cant amounts of white blood cells in the air pouch; were unpacked, placed in cages, a health inspection per 0194 Colchicine dose-dependently lowered the num formed and a number assigned. Rats were caged in groups of 3-5 with free access to certified laboratory rodent chow and ber of white blood cells; drinking water, in environmentally-controlled rooms (20-26° 0.195 Lesinurad (0.1, 1 and 10 mg/kg/day) significantly C.; 40-70% relative humidity), with time-controlled fluores lowered the number of white blood cells; cent lighting systems providing 12/12 dark light cycle. 0196) Lesinurad (10 mg/kg/day) co-administered with STEP B: Method colchicine (0.01 or 0.1 mg/kg), did not significantly 0199 Rats were randomized into 7 groups on the basis of reduce the number of white blood cells better than either body weight on Day 1 and treated according to the Table 5 therapy alone. below. TABLE 4

White Blood Cell Count for Various Doses of Lesinurad and for Colchicine

Dose Regimen mg/kg 1 2 3 4 5 6 7 8 9 10 Av

Control O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.OO O.O1 O.OO O.OO Vehicle 1.98 1.49 5.88 3.02 4.OS 3.24 O.74 O.33 0.18 240 2.33 Colchicine O.O1 340 O.63 2.27 O.90 2.22 2.42 O.69 O.34 0.87 2.72 1.65 O.1 2.6O 1.21 O.32 1.27 151 O.O3 OO6 O27 O.41 0.14 O.78 1 3.43 O.32 O.S2 O.26 O.3S O.O3 O.O9 O.26 O.36 O.O1 O.S6 Lesinurad O.1 O.14 2.28 2.75 0.48 0.92 O.O3 2.OO O.39 O.14 O.O7 O.92 1 O.68 O.O1 O.48 O54 O.26 1.17 O.34 O.O2 O.19 O.44 0.41 10 O.O8 0.16 O.S.S 1.01 1.02 O.95 0.29 O.90 O.6O 0.15 0.57 Lesinurad 10.0.01 0.06 0.03 0.08 1.53 0.09 0.05 0.02 0.25 0.20 0.13 0.24 Colchicine 100.1 0.21 1.24 0.18 0.50 0.65 0.35 0.41 0.47 0.03 0.04 0.41 US 2013/00598.68 A1 Mar. 7, 2013 16

TABLE 5 Group Treatment Schedule Dose Knee joint Gp in Treatment mL/kg mg/kg Route Dose/Day injection 1 10 Vehicle 10 — p.o. Day1-Day 7 Saline (Once daily) 2 15 "Vehicle 10 — p.o. Day1-Day 7 2MSU (Once daily) 3 10 Colchicine 1 0.1 p.o. (Vehicle); Day1-Day6 (Vehicle); 2MSU s.c. (Colchicine) Day7 (Colchicine) 4 10 Colchicine 1 0.3 p.o. (Vehicle); Day1-Day6 (Vehicle); 2MSU s.c. (Colchicine) Day7 (Colchicine) 5 15 Colchicine 1 1 p.o. (Vehicle); Day1-Day6 (Vehicle); 2MSU S.c. (Colchicine) Day7 (Colchicine) 6 15 Lesinurad 10 60 p.O. Day1-Day 7 2MSU (Once daily) 7 10 Lesinurad & 10 60 p.o. (Lesinurad); Day1-Day7 (Lesinurad); MSU Colchicine S.c. (Colchicine) Day7(Colchicine) (0.1 mg/kg) Vehicle = sterile water; *MSU = monosodium urate

0200 Groups 1 and 2 were orally dosed with Vehicle (ster- 0208 Lesinurad (60 mg/kg/day) co-administered with ile water) once daily for seven days from Day 1. Groups 3, 4 colchicine (0.1 mg/kg), did not significantly produce and 5 were orally dosed with Vehicle from Day 1 to Day 6, on better efficacy than either therapy alone. Day 7 they received colchicine administered subcutaneously. Groups 6 and 7 were orally dosed with Lesinurad once daily TABLE 6 for seven days from Day 1: Group 7 also received colchicine administered subcutaneously on Day 7. Increase in Rat Knee Diameter 0201 Thirty minutes post dosing on Day 7, rats were Dose anesthetized and the diameter and Surface temperature of Regimen mg/kg l Aw right knee joints were measured. Sterilized MSU crystals (6 Control 10 O.11 mg) suspended in sterile saline (0.05 mL) were injected into Vehicle 15 O.91 a knee joint cavity of the right hind limb of each rat in Group Colchicine O.1 10 O.71 Colchicine ** O.3 10 O.S3 2-Group 7. The injection was performed from the anterior Colchicine ** 1 15 O41 aspect of the knee joint, which was slightly extended and Lesinurad.** 60 15 O46 flexed. Sterile saline (0.05 mL) alone was injected into Group Lesinuradicolchicine 60.0.1 10 O.S3 1 rats. **p < 0.01 vs Vehicle; 0202 Four hours after MSU administration, the rats were ***p < 0.001 vs Vehicle anesthetized, the diameter of right knee joints were measured with calipers; surface temperature for right knees were mea sured. Synovial lavage fluid from the knee was collected by III. Human Clinical Trials injecting phosphate buffered saline with 1% BSA (0.2 mL) into the joint cavity, the fluid then collected, centrifuged and Example 4 the supernatants stored at -80°C. Phase II Clinical Trial Gout Dose Response Study STEPC: Increase in Knee Diameter (mm) 0209 Purpose: To compare the proportion of subjects whose serumurate (suA) level is <6.0 mg/dL after 28 days of 0203 The average increase in knee diameter (mm), which dosing by treatment group. is used as a marker for MSU-induced knee joint swelling, is 0210 Official Title: Randomized, Double-Blind, Multi shown in Table 6 below for various doses of Lesinurad and/or center, Placebo-Controlled, Safety and Efficacy Study of colchicine and graphically in FIG.7 (statistical analysis: One Lesinurad Versus Placebo in the Treatment of Hyperuricemia way ANOVA followed by Dunnett's test), demonstrating in Patients. With Gout 0204 Four hours post saline injection there was little 0211 Experimental dosage form: 200 mg capsule of Lesinurad, with appropriate pharmaceutically acceptable change in the knee diameter from the pre-injection time; excipients 0205 Increase in knee diameter after MSU injection 0212 Condition: Hyperuricemia was about nine fold compared to saline; 0213 Intervention: Lesinurad or Placebo 0206 Colchicine (0.1, 0.3 and lmg/kg) dose-depen 0214 Study Type: Interventional dently decreased the MSU-induced increase in knee 0215 Study: Allocation: Randomized diameter; 0216 Design: 0207 Lesinurad significantly decreased the MSU-in 0217 Control: Placebo Control duced increase in knee diameter; 0218 Endpoint Classification: Safety/Efficacy Study US 2013/00598.68 A1 Mar. 7, 2013

0219 Intervention Model: Parallel Assignment 0246 History of malignancy, except treated non-mela 0220 Masking: Double Blind (Subject, Caregiver, nomatous skin cancer or cervical dysplasia. Investigator, Outcomes Assessor) 0247. History of cardiac abnormalities, including 0221 Primary Purpose: Treatment abnormal and clinically relevant ECG changes such as 0222 Primary Outcome Measures: Compare the propor bradycardia (sinus rate <45bpm), complete left bundle tion of subjects whose serumurate (suA) level is <6.0 mg/dL branch block (LBBB), second or third degree heart after 28 days of dosing by treatment group. block, intraventricular conduction delay with QRS dura 0223 Secondary Outcome Measures: tion >120 msec, symptomatic or asymptomatic arrhyth 0224 Evaluate the proportion of subjects with sUA lev mias with the exception of sinus arrhythmia, evidence of els <6.0 mg/dL at each weekly study visit. Ventricular pre-excitation, frequent palpitations or syn 0225 Evaluate absolute and percent reduction from copal episodes, heart failure, hypokalemia, family his baseline in suA levels at each weekly study visit. tory of Long QT Syndrome, and/or family history of 0226 Evaluate the percent change in 24-hr urine urate sudden death in anotherwise healthy individual between level (excretion) from baseline to Day 28. the ages of 1 and 30 years. 0227 Evaluate the incidence of gout flares. 0248. Any condition predisposing them to QT prolon 0228 Evaluate the safety and tolerability of Lesinurad gation including pathological Q-wave (defined as in Subjects with gout. Q-wave >40 msec or depth >0.4-0.5 mV). 0249. Any use of a concomitant medication that pro long the QT/QTc interval within the 14 days prior to TABLE 7 Baseline (Day 0). Clinical Study Design 0250 QT interval corrected for heart rate according to Fridericia (QTcF)>450 msec at Screening or pre-dose at Arm Intervention Baseline (Day 0). 1 Lesinurad 0251 Uncontrolled hypertension (above 150/95). 200 mg qd for 28 days 0252) Inadequate renal function serum creatinine-1.5 2 Lesinurad 200 mg qd for 7 days followed by mg/dL or creatinine clearance.<60 mL/min (by Cock 400 mg qd for 21 days roft-Gault formula). 3 Lesinurad 0253 Hemoglobin-10 g/dL (males) or <9 g/dL (fe 200 mg qd for 7 days, followed by males). 400 mg qd for 7 days, followed by 600 mg qd for 14 days 0254 Alanine aminotransferase (ALT) or aspartate 4 Matching placebo aminotransferase (AST)>2.5xupper limit of normal qd for 28 days (ULN). 0255 Gamma glutamyl transferase (GGT)>3xULN. 0256 Active peptic ulcer disease requiring treatment. 0229. Eligibility 0257. History of xanthinuria, active liver disease, or 0230 Ages Eligible for Study: 18-75 Years hepatic dysfunction. 0231 Genders Eligible for Study: Both 0258 Requires therapy with any other urate-lowering 0232. Accepts Healthy Volunteers: No medication, other than the study medication. 0233. Inclusion Criteria: 0259 Requires long-term use of salicylates: diuretics: 0234 Male or post-menopausal or surgically sterile azathioprine; mercaptopurine; theophylline; intrave female. nous colchicine; cyclosporine; cyclophosphamide; 0235 Hyperuricemic (i.e., screening sUA28 mg/dL). pyrazinamide: Sulfamethoxazole; or trimethoprim. 0236 Meets criteria for the diagnosis of gout as per the 0260 Taking medications known as enzyme inducers. American Rheumatism Association (ARA) Criteria for 0261 Gout flare at screening that is resolved for less the Classification of Acute Arthritis of Primary Gout than one week prior to the first treatment with study (see Appendix B). medication (exclusive of chronic synovitisfarthritis). 0237 Willing and able to give informed consent and 0262 Pregnant or breast feeding. adhere to visit/protocol schedules (informed consent 0263. Received an investigational medication within 4 must be given before the first study procedure is per weeks prior to study medication administration. formed). 0264 Known hypersensitivity or allergy to colchicine 0238 Exclusion Criteria: or any components in their formulations. 0239 Classified as an overproducer of urine urate 0265 Body mass index (BMI) >40 kg/m. (CurdG.0 ml/min/1.73 m 24-hour urine). 0266 Taking greater than 1000 mg/day of Vitamin C. 0240 Consumes more than 14 drinks of alcohol per 0267 Any other medical or psychological condition, week (e.g., 1 drink=5 oz. 150 ml ofwine, 12 oz. 360 ml which in the opinion of the Investigator and/or Medical of beer, or 1.5 oz 45 ml of hard liquor). Monitor, might create undue risk to the subject or inter 0241 History or suspicion of drug abuse. fere with the subjects ability to comply with the proto 0242 Documented history of, or suspicion of kidney col requirements, or to complete the study. StOneS. 0268 Results: Incidence of gout flares are presented in 0243 History of rheumatoid arthritis or other autoim Table 8 below indicating the majority of flares occurred in the mune disease. first week when patients were receiving 200 mg QD (6/10 0244 Confirmed (positive serology to HIV1 and HIV2) total flares on drug). Few additional flares occurred as dose or suspected HIV infection. increased, even with greater decrease in SUA. Duration of 0245 Positive serology to HCV antibodies (Abs), and/ flares is shorter at higher doses, the opposite of what would be or hepatitis B Surface antigen (HBSAg). expected with greater reduction in SUA. US 2013/00598.68 A1 Mar. 7, 2013 18

TABLE 8 TABLE 11-continued Incidence of Gout Flares Percent of Patient Experiencing at Least One Gout Flare by Week Four % Patients Mean % of patients with Mean ARM 4Wk% Flare Randomized with Duration Flares by Dose at Duration Dose Group N Flares of Flares Time of Flare of Flares Placebo? 12-223 Placebo 34 600 mg 32 13% 1.5 days 9% (3/32) 1.7 days 400 mg 33 12% 3.8 days 2% (1/65) 2 days 'Data from clinical studies APEX (Phase III) and TMX-00-004 (Phase II). 200 mg 31 6% 4 days 6% (6/96) 4 days *Colchicine 0.6 mg qd, bid, or naproxen 250 mg qd administered prophylactically, Placebo 27 4% 1 day 4% 1 day Projected based on two times the 2 week flare data from TMX-00-004. TMX-0-004 study had 2 weeks on colchicine 0.6 mg bid, 2 weeks off during treatment period, (0273 FIG. 9 shows a plot of the cumulative flare rate for Example 5 flares from days 0-35. In a separate study (see Schlesinger et at EULAR, 2010, Abstract OP 0198, “Efficacy of Canaki Lesinurad Treatment of Gout Patients with numab (ACZ885) in the Prevention of Flares in Gout Patients Hyperuricemia initiating Allopurinol Therapy') allopurinol dosed with 0269. A phase II clinical trial including 123 gout patients colchicine (0.5 mg QD) resulted in 28% of patients experi with hyperuricemia (serum uric acid D.8 mg/dL) in 4 treat encing flares. ment arms was conducted. The trail lasted 8 weeks, compris 1. A method of treating gout comprising co-administration ing a 2 week run in period, 4 week treatment period and 2 of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- week follow-up. triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt 0270 Patients were randomly assigned to arms 1, 2, 3 or 4 thereof, and colchicine to a Subject. and orally administered Lesinurad according to Table 9 below 2. The method of claim 1, wherein said method provides and FIG. 8; all received colchicine prophylaxis (0.5-0.6 mg greater mean gout flare reduction than co-administration of QD) for 2 weeks prior to Lesinuraddosing and throughout the colchicine and a therapeutic agent that is not a dual inhibitor 4 week treatment period. of URAT1 and an inflammasome. 3. The method of claim 1, wherein the total dosage of TABLE 9 colchicine administered during co-administration with 2-(5- bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol Clinical Study Design 3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is at least 50% less than the total dosage of colchicine Lesinurad dose (ng that would be required for a similar effect when co-adminis Arm l Week 1 Week 2 Week 3 Week 4 tered with a therapeutic agent that is not a dual inhibitor of URAT1 and an inflammasome. 1 31 200 2OO 2OO 200 2 33 200 400 400 400 4. The method of claim 1, wherein the amount of time that 3 32 200 400 600 600 colchicine is co-administered with 2-(5-bromo-4-(4-cyclo 4 27 O (placebo) () (placebo) 0 (placebo) 0 (placebo) propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is at least one week less than would be required for a similar effect when 0271 Time to first flare for each arm is given in Table 10 colchicine is co-administered with a therapeutic agent that is below (indicating cumulative flare rate). not a dual inhibitor of URAT1 and an inflammasome. 5. A method of reducing monosodium urate induced TABLE 10 inflammation in a Subject in need thereof, the method com Time to First Flare prising administering a pharmaceutical composition com prising a pharmaceutical agent having both uricoSuric and Arm Day 0 Day 7 Day 14 Day 21 Day 28 anti-inflammatory activity. 1 27 27 26 25 25 6. The method of claim 5, wherein the pharmaceutical 2 31 31 30 28 26 agent is a URAT1 inhibitor with anti-inflammatory activity. 3 33 31 31 29 29 7. The method of claim 5, wherein the pharmaceutical 4 (placebo) 32 32 32 29 29 agent is 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H 1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically accept 0272 Table 11 below shows the percent of patients expe able salt thereof. riencing at least one gout flare by week 4 of treatment, cal 8. (canceled) culated based on ITT patient number. 9. (canceled) 10. (canceled) TABLE 11 11. The method of claim 1, wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- Percent of Patient Experiencing at Least One Gout Flare by Week Four triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt ARM 4Wk% Flare thereof, is about 400 mg. 1 10 12. The method of claim 1, wherein the daily dose of 2 12 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- 3 13 triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 200 mg. US 2013/00598.68 A1 Mar. 7, 2013

13. The method of claim 11, wherein the daily dose is 19. The method of claim 12, wherein the daily dose is administered orally. administered orally. 14. The method of claim 11, wherein the daily dose is 20. The method of claim 12, wherein the daily dose is administered in the morning. administered in the morning. 15. The method of claim 11, wherein the daily dose is 21. The method of claim 12, wherein the daily dose is administered with food. administered with food. 16. The method of claim 11, further comprising adminis 22. The method of claim 12, further comprising adminis tration of a second serum uric acid lowering agent. tration of a second serum uric acid lowering agent. 17. The method of claim 16, wherein the second serumuric 23. The method of claim 22, wherein second serum uric acid lowering agent is a Xanthine oxidase inhibitor. acid lowering agent is febuXostat or allopurinol. 18. The method of claim 17, wherein the Xanthine oxidase inhibitor is febuxostat or allopurinol. k k k k k