# Patent

## Title
Use of IL-1 antagonists to treat gout

## Abstract

Methods of treating, inhibiting, or ameliorating gout, including chronic acute (refractory) gout, pseudogout, or drug-induced gout, in a human subject in need thereof, comprising administering to a subject in need a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein the incidence of a gout flare is reduced or inhibited.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 12/200,681, filed on Aug. 28, 2008, now U.S. Pat. No. 7,632,490, which is a continuation-in-part of U.S. patent application Ser. No. 11/975,593 filed on Oct. 19, 2007, now abandoned, which claims the benefit under 35 USC §119(e) of U.S. Provisional 60/853,385 filed on Oct. 20, 2006, which applications are herein specifically incorporated by reference in their entireties.


BACKGROUND
1. Sequence Listing
An ASCII compliant text file of a sequence listing is filed concurrently with the present specification. The contents of the text file are herein incorporated by reference. The text file containing the sequence listing (as amended) is named “5060C-SeqList2,” was created on Jan. 4, 2010, and contains 136,960 bytes. The sequence information contained in the present text file is identical to the sequence information which was submitted in connection with the aforementioned related applications which are relied upon for an earlier filing date under 35 USC 120.
2. Field of the Invention
The invention relates to methods of using interleukin-1 (IL-1) antagonists to treat metabolic rheumatic disorders associated with hyperuricemia, including gout, and chronic active (refractory) gout. Further, the invention encompasses treatment of conditions such as pseudogout and drug-induced gout.
3. Description of Related Art
Metabolic rheumatic disorders associated with hyperuricemia, such as gout, are characterized by perversion of the purine metabolism resulting in hyperuricemia, i.e. an excess of uric acid in the blood, attacks of acute arthritis, and formation of chalky deposits in the cartilages of the joints. These deposits are made up chiefly of urates, or uric acid.
Known methods for treating gout include the use of uric acid synthesis inhibitors to inhibit the accumulation of uric acid in the body, and use of uric acid excretion promoters to accelerate the rapid excretion of uric acid accumulated in the body. Allopurinol is an example of a uric acid synthesis inhibitor. Probenecid, sulfinpyrazone and benzbromarone are examples of uric acid excretion promoters. Interleukin-6 (IL-6) has been proposed for use in the treatment of gout as a serum uric acid decreasing agent (see U.S. Pat. No. 6,007,804).
Pseudogout is not a hyperuremic disorder, and involves the deposition of calcium pyrophosphate.
BRIEF SUMMARY OF THE INVENTION
In a first aspect, the invention features a method of treating, inhibiting, or ameliorating metabolic rheumatic disorders associated with hyperuricemia comprising administering to a subject in need an interleukin 1 (IL-1) antagonist to a subject in need thereof. An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, including fusion proteins capable of trapping IL-1, such as an IL-1 “trap”. In a preferred embodiment, the IL-1 trap is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in U.S. Pat. No. 6,927,044, herein specifically incorporated by reference in its entirety. An IL-1 trap fusion protein comprises an IL-1 binding portion of the extracellular domain of human IL-1 RAcP, an IL-1 binding portion of the extracellular domain of human IL-1RI, and a multimerizing component. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO:10 (rilonacept) or a protein having at least 95% identity to the protein of SEQ ID NO:10 and capable of binding and inhibiting IL-1. Use of the IL-1 trap to treat gout offers unexpected advantages relative to the use of prior art IL-1 antagonists for several reasons, including allowing alleviation of gout symptoms with reduced frequency of administration, reduced side effects such as, for example, reduced injection site inflammation or reduced immunogenicity.
In a preferred embodiment, the metabolic rheumatic disorder associated with hyperuricemia is gout. The subject being treated is most preferably a human diagnosed as suffering from gout, for example, chronic acute gout. The method of the invention encompasses preventing or ameliorating gout or hyperuricemia in a human subject suffering therefrom.
In a more specific embodiment, the gout condition being treated is drug-induced gout flares, including flares induced by xanthine oxidase inhibitors such as allopurinol and febuxostat; flares induced by urate oxidase, for example, uricase, rasburicase and pegylated uricase; and flares induced by uricosuric agents, such as probenecid, sulfinpyrazone, benzbromarone, and fenofibrate.
In one example of drug-induced gout, patients treated with a xanthine oxidase inhibitor, a urate oxidase, or a uricosuric agent, are treated with an IL-1 antagonist to reduce the frequency and severity of acute gout flares associated with the initiation of the xanthine oxidase inhibitor, a urate oxidase, or a uricosuric agent therapy. In a specific embodiment, the IL-1 antagonist reduces, inhibits or prevents the occurrence of drug-induced flares by at least about 50%, more preferably 60%, 75% or 80%, relative to not receiving the IL-1 antagonist; in even more specific embodiments, the IL-1 antagonist reduces, inhibits or prevents drug-induced gout flares by about 80% relative to not receiving the IL-1 antagonist. In a specific embodiment, the drug-induced gout flare is associated with initiation of allupurinol or febuxostat therapy.
In a second aspect, the invention features a method of treating, inhibiting, or ameliorating pseudogout, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist to a subject in need thereof.
The methods of the invention includes administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intravenous, transdermal administration or oral routes of administration. Preferably, administration is by subcutaneous or intravenous injection or intravenous infusion.
In specific embodiments of the therapeutic method of the invention, the subject is treated with a combination of an IL-1 trap and a second therapeutic agent. The second therapeutic agent an additional IL-1 antagonist and/or co-therapies such as uric acid synthesis inhibitors to inhibit the accumulation of uric acid in the body, for example, allopurinol, uric acid excretion promoters to accelerate the rapid excretion of uric acid accumulated in the body, for example, probenecid, sulfinpyrazone and/or benzbromarone are examples of uric acid excretion promoters; corticosteroids; non-steroidal anti-inflammatory drugs (NSAIDs); and/or cholchicine. Administration of the first and second therapeutic agents may be separately, simultaneously, or sequentially.
Other objects and advantages will become apparent from a review of the ensuing detailed description.


DETAILED DESCRIPTION
Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosures and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.
Metabolic Rheumatic Disorders Associated with Hyperuricemia
Gout is a group of metabolic rheumatic disorders associated with hyperuricemia and is the most common cause of an inflammatory arthropathy in middle-aged men. Gout is essentially a disorder of urate metabolism. Deposition of urate crystals in hyperuricemic individuals results in acute gout, characterized by agonizing pain and inflammation of rapid onset, most frequently affecting the first metatarsophalangeal joint. Hyperuricemia is associated with an increased risk of developing gout and this increases with the degree and duration of the hyperuricemia.
Treatment of gout aims to relieve pain and inflammation of the acute attack, and reduce the incidence of recurrent attacks. Dietary and pharmacological urate-lowering therapies principally aim to prevent clinical joint damage. Common approaches to the treatment of acute gout are corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and colchicine. The side effects of these drugs, particularly in the frail, elderly population who experience the highest incidence of acute gout, can be serious. An approach to the prevention of recurrent gout is the use of a xanthine oxidase inhibitor, allopurinol. However, allopurinol can have serious side effects such as allopurinol hypersensitivity syndrome (see, for example, Arellano et al. (1993) Ann Pharmacother 27:337-343).
Alternative drugs for preventing gout include the uricosuric agent sulphinpyrazone, limited by its side-effect profile, and benzbromarone and probenecid. Fenofibrate, a drug well known in the treatment of various forms of hyperlipidemia, has been proposed for the treatment of hyperuricemia.
Pseudogout
Pseudogout is a type of arthritis that, as the name implies, can cause symptoms similar to gout, but in reaction to a different type of crystal deposit. Pseudogout, sometimes referred to as calcium pyrophosphate deposition disease, can cause severe episodes of localized pain and swelling resulting in incapacitation for days or weeks. It also can cause more chronic arthritis that mimics osteoarthritis or rheumatoid arthritis. Knees are most often involved but wrists, shoulders, ankles, elbows or hands can be affected. Pseudogout is caused when deposits of calcium pyrophosphate crystals accumulate in a joint.
IL-1 Trap Antagonists
Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting with the multimerizing component present in another fusion protein to form a higher order structure, such as a dimer. Cytokine traps are a novel extension of the receptor-Fc fusion concept in that they include two distinct receptor components that bind a single cytokine, resulting in the generation of antagonists with dramatically increased affinity over that offered by single component reagents. In fact, the cytokine traps that are described herein are among the most potent cytokine blockers ever described. Briefly, the cytokine traps called IL-1 traps are comprised of the extracellular domain of human IL-1 R Type I (IL-1RI) or Type II (IL-1RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-1AcP), followed by a multimerizing component. In a preferred embodiment, the multimerizing component is an immunoglobulin-derived domain, such as, for example, the Fc region of human IgG, including part of the hinge region, the CH2 and CH3 domains. An immunoglobulin-derived domain may be selected from any of the major classes of immunoglobulins, including IgA, IgD, IgE, IgG and IgM, and any subclass or isotype, e.g. IgG1, IgG2, IgG3 and IgG4; IgA-1 and IgA-2. Alternatively, the IL-1 traps are comprised of the extracellular domain of human IL-1AcP, followed by the extracellular domain of human IL-1RI or IL-1RII, followed by a multimerizing component. For a more detailed description of the IL-1 traps, see WO 001 8932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1 traps have the amino acid sequence shown in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, or a substantially identical protein at least 95% identity to a sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26, and capable of binding and inhibiting IL1. Most preferably, the IL-1 antagonist is the protein of SEQ ID NO:10 (rilonacept).
In specific embodiments, the IL-1 antagonist comprises an antibody fragment capable of binding IL-1α, IL-1β, IL-1R1 and/or IL-1RAcp, or a fragment thereof. The preferred embodiment would be an antagonist of IL-1β. One embodiment of an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. Pat. No. 6,472,179, which publication is herein specifically incorporated by reference in its entirety. In all of the IL-1 antagonist embodiments comprising one or more antibody-derived components specific for IL-1 or an IL-1 receptor, the components may be arranged in a variety of configurations, e.g., a IL-1 receptor component(s)-scFv(s)-multimerizing component; IL-1 receptor component(s)-multimerizing component-scFv(s); scFv(s)-IL-1 receptor component(s)-multimerizing component, ScFv-ScFv-Fc, etc., so long as the molecule or multimer is capable of inhibiting the biological activity of IL-1.
Treatment Population
The method of the instant invention provides treatment of pseudogout and metabolic rheumatic disorders associated with hyperuricemia to human patients suffering therefrom. The treatment population is thus human subjects diagnosed as suffering from pseudogout, gout or hyperuricemia. The invention encompasses the treatment of a human subject at risk of suffering from a recurrent gout episode or for developing gout or pseudogout.
The invention also encompasses treating a population of patients with drug-induced gout flares, including flares induced by gout therapeutics such as xanthine oxidase inhibitors, such as allopurinol and febuxostat; flares induced by urate oxidase, for example, uricase, rasburicase and pegylated uricase; and flares induced by uricosuric agents, such as probenecid, sulfinpyrazone, benzbromarone, and fenofibrate. By “drug-induced” gout flare is meant occurrence of or increased incidence of a gout flare associated with initiation of therapy to treat gout and/or administration of a therapeutic agent for the treatment of gout, for example, initiation of therapy with a xanthine oxidase inhibitor, urate oxidase, or a uricosuric agent. A gout flare is “associated” with initiation of gout therapy when the flare occurs contemporaneously or following at least a first administration of a therapeutic agent for the treatment of gout.
Methods of Administration
The invention provides methods of treatment comprising administering to a subject an effective amount of an agent of the invention. In a preferred aspect, the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects).
Various delivery systems are known and can be used to administer an agent of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, fibers, commercial skin substitutes or angioplasty balloons or stents.
An initial dose may be followed by subsequent doses at a frequency of daily, weekly, biweekly, monthly or even less frequently. An initial dose, preferably administered subcutaneously or intravenously, may range from about 80 mg to about 500 mg of IL-1 antagonist, and subsequent doses may range from about 40 mg to about 250 mg of IL-1 antagonist.
Combination Therapies
In numerous embodiments, the IL-1 antagonists of the present invention may be administered in combination with one or more additional compounds or therapies. Combination therapy may be simultaneous or sequential. The IL-1 traps of the invention may be combined with, for example, TNF-inhibiting agents such as etanercept (ENBREL®, Amgen), infliximab (REMICADE®, Centocor), HUMIRA® (Abbott). Combination therapy may also include treatment with drugs currently used for the treatment or prevention of gout, including corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs); colchicine; xanthine oxidase inhibitors such as allopurinol and febuxostat; uricosuric agents such as sulphinpyrazone, benzbromarone and probenecid; and fenofibrate; and urate oxidase inhibitors such as uricase, rasburicase and pegylated uricase. Preferred co-therapeutics include NSAIDs, steroids and/or cholchicine.
Pharmaceutical Compositions
The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
The amount of the active agent of the invention which will be effective in the treatment of delayed-type hypersensitivity can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances.
For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.
EXAMPLES
The following example is put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
Example 1
A Phase I/II, Placebo Controlled Pilot Study of the Safety, Tolerability, and Clinical Activity of Rilonacept for the Treatment of Chronic Active Gout
Gout is a common disease with increasing incidence. There are approximately 5 MM Americans with gout. Medical needs are not fully met; a large number of individuals are either intolerant or not good candidates for current therapeutic or prophylactic strategies. This study explores the activity of rilonacept at one end of the gout spectrum: chronic active (refractory) gout. Results from this study may or may not be indicative of rilonacept's potential utility in acute active gout or in the prevention of gout flares; however, activity in this situation suggests potential benefit. The chronic active (refractory) gout population, while small, represents a true situation of medical need.
Primary Objective: To assess the safety of rilonacept in subjects with chronic, active gout, having at least one joint continuously inflamed.
Secondary Objectives: (1) To compare within subject changes in self-reported pain score (VAS) during the placebo run-in phase with the active treatment phase; (2) to assess the changes in the Subject and Physician Global Assessments during the placebo run-in and active treatment phases; (3) to assess the effect of rilonacept on C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in subjects with chronic active gout.
Study Arms and Cohorts: Subjects are screened at Day-7; a two-week single blind placebo run-in begins at the Baseline visit (2×2 ml of placebo for rilonacept SQ); Single blind rilonacept 320 mg is administered subcutaneously at the Week 2 visit and then subjects self-inject 160 mg/week at home. Visits occur every two weeks through Week 8. PPD skin test, CXR, and inclusion/exclusion criteria are assessed at the Screening visit. Self-injection technique is taught at Screening and Baseline. Laboratory sample collections occur at Screening, Baseline, Weeks 2, 4, and 8. A follow-up visit occurs at Week 14.
Sample Size and Number of Sites: N=5 from up to 5 sites in the U.S.
Drug Supply: Placebo: 5 subjects×2 vials=10 vials+30% overage=13 vials; Rilonacept: 5 subjects×8 vials=48 vials+30% overage=66 vials, 3 vials per kit.
Subject Eligibility Criteria. Inclusion Criteria: (1) Male or female ≧21 years; (2) Chronis, active monoarticular or polyarticular gout (≧1 continuously inflamed joint due to gout, ±tophi); (3) VAS 10-point pain scale score of ≧3 (i.e., moderate or greater) due to joint pain/inflammation; (4) subjects for whom standard therapies are ineffective or associated with risks related to side effects.
Exclusion Criteria: (1) Organ transplant recipient; (2) current active infection; (3) serum creatinine<2.5 mg/dL; (4) other arthritic condition that could interfere with evaluations.
Primary Endpoint: Tolerability and safety profile of rilonacept.
Secondary Endpoints: (1) The change from Baseline to Week 8 in subject's pain score (10 cm VAS scale); (2) the change from Baseline to Week 8 in the Subject's Global Assessment; (3) the change from Baseline to Week 8 in the Physician's Global Assessment; (4) the change from Baseline to Week 8 in ESR and CRP.
Example 2
Safety of Rilonacept in Subjects with Chronic Active Gouty Arthritis
A 14 week, multi-center, non-randomized, single-blind, placebo-controlled, monosequence crossover study of rilonacept in subjects with chronic, active monoarticular or polyarticular gouty arthritis. Subjects receive 2 weeks of single-blind placebo followed by a loading dose of subcutaneous injections of 320 mg rilonacept, followed by weekly subcutaneous injections for 5 weeks of 160 mg rilonacept Study Population. The study population included adult subjects (at least 18 years of age, male or female) with chronic, active monoarticular or polyarticular gouty arthritis diagnosed by a physician for at least 6 months with at least one continuously inflamed joint (self-reported or otherwise) for ≧4 weeks, a diagnosis of gout based on a history of the presence of crystals in the synovial fluid analysis, chronically elevated serum uric acid, and/or tophi; a visual analogue scale increment pain scale score of at least 3 due to joint pain/inflammation at both the Screening and Baseline Visits, and subjects for whom standard therapies for gout are less than effective or are associated with risks related to side effects.
Study Design. This study was a 14-week, multi-center, non-randomized, single-blind, placebo-controlled, monosequence crossover study of IL-1 trap (rilonacept) in subjects with chronic, active monoarticular or polyarticular gouty arthritis. Subjects received 2 weeks of single-blind placebo followed by a loading dose of subcutaneous injections of 320 mg rilonacept, followed by weekly subcutaneous injections for 5 weeks of 160 mg rilonacept. The study was conducted in approximately 12 sites in the U.S. This study includes a monosequence crossover design for the enrolled subjects: Treatment 1: Placebo injections for two weeks; Treatment 2: Injections of rilonacept for six weeks. Descriptive statistics was used to evaluate safety and efficacy of rilonacept in gout. Approximately 10 subjects were enrolled to receive placebo (2 weeks) and rilonacept (6 weeks) administered subcutaneously. Subjects received a total of two doses of placebo (on study days 0 and 7) and six doses of rilonacept on Days 14, 21, 28, 35, 42, and 49 during the study. Dose escalation was not allowed. Subjects were evaluated for efficacy and safety on a regular basis with clinical observations and laboratory measurements including anti-rilonacept antibodies, hs-CRP and ESR. The overall structure of the study included the following periods: Screening period: Screening procedures occurred within 7 days of start of study and included obtaining informed consent and evaluations to determine eligibility for study participation. Baseline: At the baseline visit (day 0), eligibility was confirmed, and the subject enrolled. Baseline assessments were made. The first injection of placebo was administered, and a vial of placebo dispensed. Placebo Treatment period: During the treatment period (Day 0 through Week 2), patients received placebo study medication, efficacy assessments were taken; safety and tolerability assessments were taken, including urine and blood samples for clinical laboratory testing. Active Treatment period: During the treatment period (Week 2 through Week 8), patients received active study medication, efficacy assessments were taken; safety and tolerability assessments were taken, including urine and blood samples for clinical laboratory testing. Blood samples were collected for biomarkers, IL-1 trap (rilonacept) plasma levels, and rilonacept antibodies. Follow-up: At Week 14, vital signs, bodyweight, adverse events, and concomitant medications assessments were taken. Blood samples were collected for biomarkers, rilonacept plasma levels, and rilonacept antibodies. The results are shown in Table 1. The first column lists the parameters assessed; column 2 (placebo response) compares the parameter measurements obtained at Week 2 with those measured at Day 0; column 3 (response of rilonacept) compares the parameter measurements obtained at Week 8 with those of Week 2; and column 4 (effect of withdrawal from treatment with rilonacept) compares the parameter measurements obtained at Week 14 with those obtained at Week 2.
Results. During treatment with placebo, there was no apparent trend toward improvement in any clinical parameter nor in CRP. Also, during treatment with placebo, there is no evidence of improvement. At the end of treatment with rilonacept, the proportion of responders is significantly better than a placebo response of 10%, regardless of how response was defined (p<0.01). Also, there was a significant reduction in patient's self-reported pain (p=0.02). When treatment with rilonacept was withdrawn, the trends toward efficacy waned and pain returned. These results suggest that placebo response is minimal, and reduction in pain is not observed until treatment with rilonacept is administered.











TABLE 1











Effects of





Withdrawal from



Placebo

Treatment with



Response
Rilonacept Response
Rilonacept













Change
Change
Change
Change
Change


Assessment
Day 0-week 2
Week 2-4
week 2-4
week 2-8
week 8-14















Subject's
0.96
0.046
0.07
0.02
0.07


Assessment of Pain


Physician's Global
0.09
0.4
0.8
0.2
0.02


Assessment


Subject's Global
1.0
0.07
0.14
0.06
0.02


Assessment


Number of
0.3
0.7
0.9
0.099
0.95


Affected Joints


Symptom-Adjusted
0.2
0.7
0.8
0.04
0.3


Scores for Affected


Joints (maximum


of 3 per joint)


Severity-and-
0.2
0.2
0.8
0.04
0.14


Symptom-Adjusted


Scores for Affected


Joints (maximum


of 9 per joint)


Change from
0.5
0.002
0.004
0.004
0.04


Baseline CRP









Example 3
Effectiveness of IL-1 Antagonist for Prevention of Gout Flares During Initiation of Allopurinol Therapy
A multi-center, randomized, double-blind, placebo-controlled study in subjects with intercritical gout was conducted. 83 subjects were enrolled and treated with allopurinol orally once a day beginning on Day 1. Subjects were randomized in a 1:1 ratio to receive 160 mg rilonacept subcutaneously once a week or a placebo subcutaneously once a week for 16 weeks. Subjects received a loading dose on Day 1 (Baseline Visit) of rilonacept (320 mg given as two vials of 160 mg) or placebo (given in two equal volumes)(volumes 2 ml each) administered as subcutaneous injections.
Subjects in both treatment arms were started on a daily dose of 300 mg allopurinol on Day 1. The allopurinol dose was adjusted by 100 mg increments monthly to titrate subjects until they attained a serum uric acid level of less than 6 mg/dL. The maximum dose of allopurinol was 800 mg per day. For subjects with impaired renal function, the initial dose of allopurinol was adjusted based on the estimated creatinine clearance according to the Cockroft-Gault formula for estimating creatinine clearance.
Subjects would return to the clinic every 4 weeks for 16 weeks for study related procedures. Sites would call subjects every 2 weeks between visits for a brief review of their clinical status. A Safety Follow-up visit would occur 42 days after the last dose of study drug.
Subjects were instructed to call the study site upon first symptoms of a self-reported gout flare. A daily diary capturing pain, global well-being and symptoms of gout was completed by the subject starting on Day 1 of the flare until the resolution of all flare symptoms. Day 1 of the flare was defined as the onset of pain in any gouty joint and the end of the flare was defined as the day all pain in all joints resolved. All gout flares that occurred during the study from Baseline through the Terminal Visit (Visit 6) were followed to completion.
Screening period. Screening procedures occurred within 2 weeks of start of study and included obtaining informed consent and evaluations to determine eligibility for study participation.
Baseline. At the baseline visit (day 1), eligibility was confirmed, and the subject randomized. Baseline assessments were made. The first administration (2 injections) of either 160 mg rilonacept (total loading dose of 320 mg rilonacept) or placebo was administered, and vials of the study medication dispensed. Subjects also received 300 mg allopurinol.
Treatment period. During the treatment period (Day 1 through Week 16), subjects received study medication (including daily allopurinol, adjusted as appropriate), efficacy assessments were taken; safety and tolerability assessments were taken, including urine and blood samples for clinical laboratory testing. Primary and secondary efficacy endpoints were measured at Week 12, but treatment continued through Week 16. All safety variables were summarized with time periods from Day 1 of study medicine to last dose date plus 42 days.
Follow-up. At Week 22, subject diaries were reviewed; vital signs, adverse events, and concomitant medications assessments were taken. Blood samples were collected for clinical laboratory assessments, rilonacept plasma levels and rilonacept antibodies assessments.
Primary efficacy variables. The primary efficacy variable was the mean number of gout flares from Day 1 to Week 12. The variable was calculated for each subject as number of flares observed from Day 1 to Week 12. For dropouts, only numbers of flares that occurred during the treatment period (defined as termination date-randomization date +1) were counted.
Secondary efficacy variables. (1). The proportion of subjects with one or more gout flares from Day 1 to Week 12. (2). The mean number of gout flares per month from Day 1 to Week 12. The variable was calculated for each subject as: Mean number of flares per month=(number of flares observed from Day 1 to Week 12)/(number of days subject was in study/28 days). (3). The mean number of gout flare days from Day 1 to Week 12. The variable for each subject was calculated as number of gout flares days from Day 1 to Week 12. Subjects with flares that started before the Week 12 visit and ended after the Week 12 visit included only days up to the Week 12 visit. (4). The mean number of gout flare days per month from Day 1 to Week 12. The mean number of gout flare days per month was calculated for each subject: Mean number of gout flares days per month from Day 1 to Week 12=(Number of flares days from Day 1 to Week 12)/(Number of days subject was in the study/28 days). Subjects with flares that started before the Week 12 visit and ended after the Week 12 visit included only days up to the Week 12 visit. (5). The mean number of days with the subject's pain score of 5 or more (from daily dairy) from Day 1 to Week 12. This was calculated for each subject as number of days with the subject's pain score 5 or more observed from Day 1 to Week 12. (6). The mean number of days per month with the subject's pain score of 5 or more (from daily dairy) from Day 1 to Week 12. This was calculated for each subject as: mean number of days per month with the subject's pain score 5 or more from Day 1 to Week 12=(Number of days with the subject's pain score of 5 or more observed)/(Number of days subject was in the study/28 days).
Exploratory Efficacy Variables. Exploratory variables included time to first gout flare, percentage of subjects with usage, and duration of NSAIDS and glucocorticoids during study, proportion of subjects with uric acid levels less than 6 mg/dL by visit, and percentage of total gout flares by number of visits. The time period for all these variables was from Day 1 to Week 12.
Results are shown in Tables 2 and 3. Rilonacept achieved a dramatic 81% reduction in gout flares, from 0.79 to 0.15 (Table 2; p=0.0006). [1]P-value is based on the two-sample t-test; [2]Gout-Free-Flare: no gout flare during time interval; [3]P-value based on Fisher's exact test.










TABLE 2





Time Interval
Rilonacept
Placebo
P-value







Day 1 to Week 12





Mean Number of Gout Flares
0.15 ± 0.358
0.79 ± 1.071
0.0006[1]



(n = 41)
(n = 42)



















TABLE 3





Time Interval
Rilonacept
Placebo
P-value[3]







Day 1 to Week 12





Subjects Gout-Flare-Free[2]
85.4% (n = 35)
54.8% (n = 23)
0.0037


Subjects with ≧ Gout Flare
14.6% (n = 6)
45.2% (n = 19)

## Claims

1. A method of reducing the occurrence of gout flares in a subject, said method comprising administering to the subject a therapeutic agent for the treatment of gout and an interleukin-1 (IL-1) antagonist.

2. The method of claim 1, wherein said therapeutic agent for the treatment of gout and said IL-1 antagonist are administered simultaneously.

3. The method of claim 1, wherein said therapeutic agent for the treatment of gout and said IL-1 antagonist are administered sequentially.

4. The method of claim 1, wherein said IL-1 antagonist is an IL-1 trap.

5. The method of claim 4, wherein said IL-1 trap is rilonacept.

6. The method of claim 1, wherein said therapeutic agent for the treatment of gout is a xanthine oxidase inhibitor, a urate oxidase, or a uricosuric agent.

7. The method of claim 6, wherein said therapeutic agent for the treatment of gout is a xanthine oxidase inhibitor.

8. The method of claim 7, wherein said xanthine oxidase inhibitor is allopurinol.

9. The method of claim 7, wherein said xanthine oxidase inhibitor is febuxostat.

10. The method of claim 6, wherein said therapeutic agent for the treatment of gout is a urate oxidase.

11. The method of claim 10, wherein said urate oxidase is uricase, pegylated uricase, or rasburicase.

12. The method of claim 6, wherein said therapeutic agent for the treatment of gout is a uricosuric agent.

13. The method of claim 12, wherein said uricosuric agent is probenecid, sulfinpyrazone, benzbromarone, or fenofibrate.