Use of inhibitors of receptor for advanced glycation endproducts (RAGE) for the treatment of inflammatory disorders

Abstract

Methods of using inhibitors of receptor for advanced glycation end products (RAGE) to treat a subject who has an inflammatory disorder are provided. The methods include use of the small molecule RAGE inhibitor azeliragon to reduce blood levels of cytokines including TNF-β, IL-6, IL-2, IL- 12 p70, IL-12 p40, IL-13 and IFNγ, thereby ameliorating the clinical manifestations of an inflammatory disorder.

Description

USE OF INHIBITORS OF RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS (RAGE) FOR THE TREATMENT OF INFLAMMATORY DISORDERS1. BACKGROUND

[0001] TH1 cytokines are known to play a role in the initiation and perpetuation of many inflammatory diseases. Among these diseases are autoimmune disorders, pulmonary inflammatory diseases including COPD and asthma, and complications of cancer. Azeliragon, an oral RAGE inhibitor, has been demonstrated to reduce blood levels of cytokines, including TNF-p, IL-6, IL-2, IL-12 p70, IL-12 p40, IL-13, and IFNy.

[0002] There is an urgent need for improved therapies to treat inflammatory diseases.2. SUMMARY

[0003] Disclosed herein are methods of treating inflammatory disorders. The methods comprise administering a RAGE inhibitor to a subject who has an inflammatory disorder.

[0004] In particular embodiments, the RAGE inhibitor is azeliragon ([3-(4-{2-butyl-1 -[4-(4-chloro- phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine) or a pharmaceutically acceptable salt thereof. In particular embodiments, the RAGE inhibitor is a polymorph of azeliragon ([3-(4-{2- butyl-1 -[4-(4-chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine), or a pharmaceutically acceptable salt thereof.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0006] FIG. 1 shows a histogram for baseline (day 0) measurements (pg / mL) for inflammatory biomarkers 1 -38 for azeliragon (AZL) or placebo (Placebo). TRT - treatment.

[0007] FIG. 2 shows a histogram for mean precent (%) change from baseline at month 18 for inflammatory biomarkers 1 -38 for azeliragon (AZL) or placebo (Placebo). TRT - treatment.

[0008] FIG. 3 shows a bar graph of mean % change from baseline at month 18 for inflammatory biomarkers 1 -38 (indicated by numbers and gene names) for Azeliragon 5 mg QD (left bar for each biomarker) and Placebo QD (right bar for each biomarker).

[0009] FIG. 4 shows a bar graph of mean % change from baseline at month 18 for the indicated inflammatory biomarkers for Azeliragon 5 mg QD (bottom bar for each biomarker) and Placebo QD (top bar for each biomarker).4. DETAILED DESCRIPTION4.1 Definitions

[0010] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described.

[0011] 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.

[0012] As used herein, the term “patient” refers to a human “subject.”

[0013] The terms "treat," "treated," "treating", or “treatment” as used herein have the meanings commonly understood in the medical arts, and therefore do not require cure or complete remission, and therefore include any beneficial or desired clinical results. A “therapeutically effective amount” of a composition is an amount sufficient to treat.

[0014] As used herein, the term “therapeutic” or "therapeutic agent” refers to any medicinal product that produces a therapeutic response in a subject.

[0015] The term “pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art that include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in Stahl and Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

[0016] As used herein, the term “antibody” refers to an immunoglobulin or a part thereof, and encompasses any polypeptide comprising an antigen-binding site regardless of the source, species of origin, method of production, and characteristics. Antibodies may be comprised of heavy and / or light chains or fragments thereof. Antibodies or antigen-binding fragments, variants, or derivatives thereof of the invention include, but are not limited to, polyclonal, monoclonal, multi-specific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab'), Fd. Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked FVs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-ld) antibodies. ScFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019. Immunoglobulin or antibody molecules of the invention can be of any type (e.g., IgG, IgE. IgM, Ig), IgA, and IgY), class (e.g., IgG 1 , lgG2, lgG3, lgG4, Ig A1 and lgA2) or subclass of immunoglobulin molecule.

[0017] The terms “co-administered” and “adjunctively administered” encompass any and all methods where the individual administrations of a first compound and a second compound to a subject overlap during any timeframe.

[0018] The terms “azeliragon,” “TTP448,” and “PF-04494700” refer to the small molecule N-[3-[4-[2- Butyl-1 -[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl]phenoxy]propyl]-N,N-diethylamine, or a pharmaceutically acceptable salt thereof.4.2 Methods of treating

[0019] In a first aspect, methods are provided for treating an inflammatory disorder in a subject in need thereof. The methods comprise administering a RAGE inhibitor to a subject who has an inflammatory disorder. In another aspect, the present disclosure provides for methods of treating an inflammatory disorder in a combination therapy with at least one or more other treatments.4.2.1 Subjects to be treated

[0020] In some embodiments, the subject to be treated has been diagnosed with an inflammatory disorder. In some embodiments, the subject is suspected of having an inflammatory disorder. In some embodiments, the subject is at risk of developing an inflammatory disorder.

[0021] As used herein, the term “an inflammatory disorder” refers to the broad class of disorders characterized by overactivity of the immune system. Examples of an inflammatory disorder include, but are not limited to rheumatoid arthritis, psoriatic arthritis, lupus, multiple sclerosis, inflammatory bowel disease, psoriasis, sinusitis, cystic fibrosis, inflammatory response to surgery, trauma or critical illness, gout, ankylosing spondylitis, pancreatitis, endometriosis, cystitis, atopic dermatitis, myositis, asthma, chronic obstructive pulmonary disease, sarcoidosis, myocarditis, vasculitis, scleroderma, Sjogren’s syndrome, Hashimoto’s Thyroiditis, Guillian Barre Syndrome, Graves’ Disease, Addison’s Disease, myasthenia gravis, celiac disease, pernicious anemia, localized cancer, cancer pain, cancer cachexia, cancer metastasis, type 1 diabetes, and primary sclerosing cholangitis.

[0022] In some embodiments, the present disclosure provides for methods wherein the subject is a mammal. In some embodiments, the present disclosure provides for methods wherein the subject is a human.4.2.2 Administration

[0023] The methods of the present disclosure include administration of a RAGE inhibitor to a subject who has an inflammatory disorder. In some embodiments, the RAGE inhibitor is administered to a subject who has received and / or is receiving an inflammatory disorder treatment. In some embodiments, the inflammatory disorder treatment comprises a glucocorticoid therapy, an immunosuppressive or immunomodulatory therapy, a genetic therapy, a cell-based therapy, and / or an antibody therapy. In some embodiments, the RAGE inhibitor is administered in combination with oneor more glucocorticoid or immunosuppressive or immunomodulatory agents. In some embodiments, the RAGE inhibitor and the glucocorticoid or immunosuppressive or immunomodulatory agent(s) is / are administered simultaneously. In some embodiments, the glucocorticoid or immunosuppressive or immunomodulatory agent(s) is / are administered prior to the RAGE inhibitor. In some embodiments, the RAGE inhibitor is administered prior to the one or more glucocorticoid or immunosuppressive or immunomodulatory agent(s). In some embodiments, either one of, or both of, the RAGE inhibitor and the glucocorticoid or immunosuppressive or immunomodulatory agent(s) is / are administered intermittently or continuously, or any combination of: simultaneously, sequentially, intermittently and / or continuously. The skilled artisan will recognize that intermittent administration is not necessarily the same as sequential because intermittent also includes a first administration of an agent and then another administration later in time of that very same agent. Moreover, the skilled artisan understands that intermittent administration also encompasses sequential administration in some aspects because intermittent administration does include interruption of the first administration of an agent with an administration of a different agent before the first agent is administered again. Further, the skilled artisan will also know that continuous administration can be accomplished by a number of routes including intravenous drip or feeding tubes, etc.

[0024] In some aspects, the present disclosure provides for methods where either one of, or both of, a RAGE inhibitor and an inflammatory disorder treatment (e.g., a glucocorticoid or a immunosuppressive or immunomodulatory agent(s)) is / are administered by a route selected from the group consisting of: oral, intravenous, subcutaneous, cutaneous, intramuscular, and intraperitoneal. In some aspects, the present disclosure provides for methods where either one of, or both of, or any combination thereof, a RAGE inhibitor, an inflammatory disorder treatment (e.g., a glucocorticoid or immunosuppressive or immunomodulatory agent(s)) is / are administered, and / or a further treatment are administered orally. In some aspects, the present disclosure provides for methods where either one of, or both of, or any combination thereof, a RAGE inhibitor, an inflammatory disorder treatment (e.g., glucocorticoid or an immunosuppressive or immunomodulatory agent(s)) and / or a further treatment are administered intravenously.

[0025] In some embodiments, the RAGE inhibitor is administered to a human subject who has received and / or is receiving treatment to reduce the clinical symptoms of an inflammatory disorder.4.2.3 Dosing

[0026] In some embodiments, azeliragon is administered at a dose of from about 0.05 to 3.0 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.05 to 2.5 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.05 to 2.0 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.05 to 1 .5 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.07 to 1 .0 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.1 to 1 .0 mg / kgof body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.2 to 1 .0 mg / kg of body weight per day. In some embodiments, azeliragon is administered at a dose of from about 0.2 to 0.9 mg / kg of body weight per day.

[0027] In some embodiments, azeliragon, is administered as a loading dose followed by a daily maintenance dose.

[0028] In some embodiments, the loading dose of azeliragon is between 10 and 100 mg per day. In some embodiments, the loading dose is between 10 and 90 mg per day. In some embodiments, the loading dose is between 15 and 80 mg per day. In some embodiments, the loading dose is between 20 and 75 mg per day. In some embodiments, the loading dose is between 30 and 65 mg per day. In some embodiments, the loading dose is between 45 and 65 mg per day. In particular embodiments, the loading dose is 60 mg per day.

[0029] In certain embodiments, the loading dose is administered daily. In particular embodiments, the loading dose is administered daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0030] In some embodiments, the daily maintenance dose of azeliragon is between 1 and 100 mg per day. In some embodiments, the daily maintenance dose is between 1 and 80 mg per day. In some embodiments, the daily maintenance dose is between 5 and 70 mg per day. In some embodiments, the daily maintenance dose is between 5 and 60 mg per day. In some embodiments, the daily maintenance dose is between 10 and 50 mg per day. In some embodiments, the daily maintenance dose is between 15 and 45 mg per day. In some embodiments, the daily maintenance dose is between 20 and 30 mg per day. In particular embodiments, the daily maintenance dose is 20 mg per day.4.2.4 Treatment results

[0031] The present disclosure is directed to methods using an effective amount of azeliragon to inhibit the progression of the clinical manifestations of an inflammatory disorder. In some embodiments, an effective amount of azeliragon is used to reduce the clinical symptoms of an inflammatory disorder.

[0032] In some aspects, provided for is a method of treating clinical manifestations of an inflammatory disorder including, but not limited to swelling, fatigue, weakness, weight loss, stiffness, shortness of breath, pain (e.g., acute and / or chronic pain), headache, paralysis, heart failure, myocarditis, pericarditis, pneumonitis, gastritis, colitis, kidney failure, cystitis, nephritis, arthritis, vasculitis, lung failure, liver failure, hypoglycemia, hyperglycemia, diarrhea, constipation, malabsorption, dysphagia, dermatitis, uveitis, conjunctivitis, myositis, and thyroiditis. In some aspects, provided for is a method of inhibiting and / or reducing clinical manifestations of an inflammatory disorder including, but not limited to swelling, fatigue, weakness, weight loss, stiffness,shortness of breath, pain (e.g., acute and / or chronic pain), headache, paralysis, heart failure, myocarditis, pericarditis, pneumonitis, gastritis, colitis, kidney failure, cystitis, nephritis, arthritis, vasculitis, lung failure, liver failure, hypoglycemia, hyperglycemia, diarrhea, constipation, malabsorption, dysphagia, dermatitis, uveitis, conjunctivitis, myositis, and thyroiditis.

[0033] In some aspects, provided for is a method of inhibiting the clinical manifestations of an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of azeliragon. In some aspects, the disclosure provides for a method of administering to the subject an effective amount of azeliragon to inhibit the clinical manifestations of an inflammatory disorder where the clinical manifestations of an inflammatory disorder are reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100% as measured by physical examination, including, but not limited to, assessment of swelling, flexibility, strength, pain, and manual muscle strength testing. In some aspects, the disclosure provides for a method of administering to the subject an effective amount of azeliragon to inhibit the clinical manifestations of an inflammatory disorder, wherein the clinical manifestations of an inflammatory disorder are reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100% as measured by the degree of the clinical manifestations of the inflammatory disorder (e.g., swelling, fatigue, weakness, weight loss, stiffness, and pain (e.g., acute and / or chronic pain)). In some aspects, the disclosure provides for a method of administering to the subject an effective amount of azeliragon to inhibit the clinical manifestations of an inflammatory disorder, wherein the clinical manifestations of an inflammatory disorder are reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100% as measured by the levels (e.g., blood levels) of markers of inflammatory disease (e.g., TNF-p, IL-6, IL-2, IL-12 p70, IL-12 p40, IL-13, and IFN-y), physical examination, patient’s symptoms, colonoscopy, sigmoidoscopy, bronchoscopy, gastroscopy, biopsies, or radiographic studies.

[0034] In some aspects, the disclosure provides for a method of administering a therapeutically effective amount of a compound that inhibits a receptor for advanced glycation end products (RAGE) (e.g., azeliragon) to a human subject in amount effective to reduce blood levels of at least one cytokine selected from TNF-p, IL-6, IL-2, IL-12 p70, IL-12 p40, IL-13 and IFN-y by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100%.

[0035] In some aspects, provided for is a method of treating an inflammatory disorder, comprising administering to a subject an effective amount of azeliragon, wherein the method results in a reduction in symptoms associated with an inflammatory disorder. The reduction in symptoms of an inflammatory disorder, in general, is determined relative to a baseline evaluation.4.3 Treatments

[0036] In one aspect, provided herein are methods for administering a RAGE inhibitor for the treatment of an inflammatory disorder. In some embodiments, provided herein are methods for administering a RAGE inhibitor as a monotherapy for an inflammatory disorder. In some embodiments, provided herein are methods for administering a RAGE inhibitor with at least one inflammatory disorder treatment (e.g., without limitation, a glucocorticoid therapy, an immunosuppressive or immunomodulatory therapy, a genetic therapy, a cell-based therapy, and / or an antibody therapy). In some embodiments, the methods include administering a RAGE inhibitor with at least one immunosuppressive or immunomodulatory agent. In some embodiments, provided herein are methods for administering a RAGE inhibitor with at least one glucocorticoid agent. In some embodiments, combining a RAGE inhibitor and at least one immunosuppressive or immunomodulatory agent reduces the symptoms or clinical manifestations of the inflammatory disorder relative to treatment with at least one immunosuppressive or immunomodulatory agent alone. In some embodiments, combining a RAGE inhibitor with a glucocorticoid agent that enhances a patient’s functional ability or quality of life relative to treatment with a glucocorticoid alone.4.3.1 RAGE inhibitor

[0037] A RAGE inhibitor interferes with RAGE signaling. In some embodiments, a RAGE inhibitor binds to RAGE, binds to a ligand of RAGE, and / or disrupts downstream signaling mediated by RAGE.

[0038] Ligands of RAGE include, but are not limited to: AGE, HMGB1 (Amphoterin), S100A12 (ENRAGE), S OB, SW0A7 (psoriasin), SWOP, SW0A8 / A9 (calprotectin), Amyloid-p-protein, Mac-1 , phosphatidylserine, and S10A4.

[0039] RAGE inhibitors include, but are not limited to, small molecules, antibodies, antibody fragments, aptamers, glycosaminoglycans, antisense RNA, soluble RAGE, and peptides.

[0040] Antibodies that can bind RAGE and / or interfere with RAGE signaling include Abeam EPR16849-75, EPR21171 , EPR12206, EPR12205, 1 C1 (mouse monoclonal), MM0520-8D11 , EPR12205, EPR16849-114, Chemicon International RAGE inhibitor, Santa Cruz antibodies: Anti- RAGE Antibody (A-9), Anti-RAGE Antibody (A11 ), Anti-RAGE Antibody (E-1 ), Anti-RAGE Antibody (RD9C2), Anti-RAGE Antibody (D-5), and Anti-RAGE Antibody (9A11 ).

[0041] Aptamers that can bind RAGE and / or interfere with RAGE signaling include 5’-CCGAAACCAGACCACCCCACCAAGGCCACTCGGTCGAACCGCCAACACTCACCCCA-3’, 5’-CATTCTTAGATTTTTGTCTCACTTAGGTGTAGATGGTGAT-3’, andccTgATATggTgTcAccgccgccTTAgTATTggTgTcTAc; phosphorothioate nucleotides are indicated as capital letters or one found in Diabetes, VOL. 62:3241 -3250 Sept 2013, Molecular Medicine 23:295- 306, 2017, or Scientific Reports 8:2686 1 -12, 2018 incorporated by reference herein.

[0042] Peptides that can bind RAGE and / or interfere with RAGE signaling include ELKVLMEKEL (RAP), KELPGFLQSGKDKD, GKDKDAVDKLLKD, APDTKTQ (RP1 ), a blocking peptide derived from a ligand of the RAGE receptor, or a peptide found in International Journal of Molecular Medicine 32: 938-944, 2013 or Clinical Cancer Research 18(16) 4356-4364, August 15, 2012, each of which is incorporated by reference herein.

[0043] Small molecules that can bind RAGE and / or interfere with RAGE signaling include FPS-ZM1 , azeliragon (TTP-488, PF-04494700), GM-1111 (a semi-synthetic glycosaminoglycan esther), alagebrium (ALT7-11 ), 4'-Methoxyresveratrol, chondroitin sulfate, heparan sulfate, and AEG 3482.4.3.1.1 Azeliragon

[0044] One specific example of a RAGE inhibitor is the small molecule N-[3-[4-[2-Butyl-1 -[4-(4- chlorophenoxy)phenyl]-1 H-imidazol-4-yl]phenoxy]propyl]-N,N-diethylamine, also referred to as azeliragon, TTP448, and PF-04494700.

[0045] U.S. Patents Nos. 7,361 ,678, 7,884,219, and 8,372,988, the disclosures of which are hereby incorporated by reference in their entirety, describe azole modulators or inhibitors of RAGE, including azeliragon, and methods of synthesizing azeliragon.

[0046] Azeliragon is found in at least four polymorphic forms.

[0047] Form I is characterized as having a solid state13C NMR spectrum comprising peaks at 149.7 and 141 .0 ppm, having X-ray powder diffraction peaks expressed in degrees-20 at 16.5 and 26.8, or having a Raman spectrum comprising peaks at 335 and 787 cm-1, as described in U.S. Patent No. 8,372,988 and incorporated herein.

[0048] Form II is characterized as having a solid state13C NMR spectrum comprising peaks at 153.6, 140.1 and 119.9 ppm, when the upfield resonance of crystalline adamantane is set to 29.5 ppm, having an X-ray powder diffraction comprising the following 20 values, measured using CuKa radiation having a wavelength of 1 .54056 A: 18.8 and 20.1 degrees, or having a Raman spectrum comprising Raman shifts of 300 and 1180 cm-1, as described in U.S. Patent No. 7,884,219 and incorporated herein.

[0049] Form III is characterized as having a solid state form is crystalline and is characterized by an XRPD pattern having peaks at 20 angles of 5.4°, 21 .5°, and 22.0°±0.2°, or an XRPD pattern characterized in FIG. 1 of U.S. publication 20210070714, as described in U.S. publication 20210070714 and incorporated herein.

[0050] Form IV is characterized as having a solid state form is crystalline and is characterized by an XRPD pattern having peaks at 20 angles of 19.7°, 22.0°, and 30.2°±0.2°, as described in U.S. publication 20210070714 and incorporated herein.

[0051] Azeliragon was used in at least the following clinical trials, the descriptions and protocols of which are incorporated herein in their entirety: NCT00141661 , NCT00287183, NCT00566397, NCT02080364, NCT02916056, and NCT03980730.4.3.2 An inflammatory disorder treatment

[0052] In various embodiments, an inflammatory disorder treatment comprises one or more therapies that enhances a patient’s functional ability or quality of life. In some embodiments, the inflammatory disorder treatment is immunosuppressive or immunomodulatory therapy. In some embodiments, the inflammatory disorder treatment is a form of glucocorticoid therapy. In some embodiments, the inflammatory disorder treatment is antibody therapy. In some embodiments, the inflammatory disorder treatment is cell-based therapy. In some embodiments, the inflammatory disorder treatment is genetic therapy.

[0053] In particular embodiments, the inflammatory disorder treatment comprises one or more glucocorticoid agents. In particular embodiments, the inflammatory disorder treatment comprises administration of one or more glucocorticoids in combination with a glucocorticoid-sparing agent including, but not limited to, methotrexate, mycophenolate, azathioprine, tacrolimus, cyclophosphamide, cyclosporine, intravenous immune globulin, and rituximab.

[0054] In various embodiments, an inflammatory disorder treatment comprises antibody therapy.4.3.3 Pharmaceutical compositions

[0055] Methods for treating an inflammatory disorder comprising administering effective amounts of a RAGE inhibitor are disclosed herein. The RAGE inhibitor can be formulated in pharmaceutical compositions. These pharmaceutical compositions may comprise, in addition to the active compound(s), a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.

[0056] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatin. Liquid pharmaceutical compositions generally include a liquid carrier such as water or oil, including oils of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Physiological salinesolution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.

[0057] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen- free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as required.

[0058] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

[0059] The present technology is not limited to any particular composition or pharmaceutical carrier, as such may vary. In general, compounds of the present technology will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another preferred manner for administering compounds of the present technology is inhalation.

[0060] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices- nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the subject’s respiratory tract. MDI’s typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the subject’s inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, therapeutic agent is formulated with an excipient such as lactose. A measured amount of therapeutic agent is stored in a capsule form and is dispensed with each actuation.

[0061] Pharmaceutical dosage forms of a compound of the present technology may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano / micro-) encapsulating, entrapping, or lyophilizationprocesses. As noted above, the compositions of the present technology can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0062] Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[0063] The compositions are comprised of in general, a compound of the present technology in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, aid administration, and do not adversely affect therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0064] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including oils of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0065] Compressed gases may be used to disperse a compound of the present technology in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0066] In some embodiments, the pharmaceutical compositions include a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art that include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.

[0067] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 -99.99 wt % of a compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 -80 wt %.4.4 Kits

[0068] The present disclosure also provides for a kit comprising the combination of a pharmaceutical composition comprising azeliragon and instructions for use. The present disclosure further provides for a kit comprising one or more pharmaceutical compositions where the pharmaceutical composition(s) comprise azeliragon and at least one further treatment, and instructions for use. Optionally the combination includes at least one pharmaceutically acceptable carrier or excipient.

[0069] Individual components of the kit can be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale. The kit may optionally contain instructions or directions outlining the method of use or administration regimen.5. EXAMPLES5.2 Example 1 : A Randomized Placed-Controlled Study to Evaluate the Safety andEfficacy of Azeliragon as a Treatment for Subjects with Mild Alzheimer’s Disease and Impaired Glucose Tolerance Revealed Significant Decreases in Inflammatory biomarkers.Study design

[0070] The study was a randomized placebo controlled phase 2 / 3 study to determine the safety and efficacy of azeliragon in subjects with mild Alzheimer’s disease and impaired glucose tolerance. A total of approximately 300 patients were administered a daily dose of azeliragon at a dose of 5 mg (capsule) administered orally, once daily for 6 months (Part 1 ) or 18 months (Part 2). Matching placebo capsules were administered orally for 6 months (Part 1 ) or 18 months (Part 2). At 18 months following the start of treatment, changes in inflammatory biomarker profiles were measured.Study Population

[0071] The study population was adult patients diagnosed with probable Alzheimer Disease (AD) with documented evidence of progression of disease.Inclusion Criteria

[0072] Patients met all of the following criteria:1 . Diagnosis of probable Alzheimer Disease (AD) with documented evidence of progression of disease2. Mini Mental State Examination (MMSE) score of 21 -26, inclusive3. Clinical Dementia Rating global score of 0.5 or 14. Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog14) of 10 or more5. Brain magnetic resonance imaging (MRI) consistent with the diagnosis of probable AD6. Concurrent use of cholinesterase inhibitor or memantine with stable dose for at least 2 months prior to screening7. Hemoglobin A1c (HbA1c) 6.5% - 9.5%, inclusive8. Caregiver willing to participate and be able to attend clinic visits with patient9. Ability to ingest oral medicationsExclusion Criteria

[0073] Patients were not eligible to participate in the study if any of the following criteria applied:1 . Significant neurological or psychiatric disease other than Alzheimer's disease2. Previous clinical trial participation within 90 days of screening3. Previous exposure to putative disease modifying therapy for Alzheimer's disease within 1 year of screening4. History of cancer within the last 5 years except adequately treated cervical carcinoma in-situ, cutaneous basal cell or squamous cell cancer, or non-progressive prostate cancer not requiring current treatment5. Women of childbearing potential6. Uncontrolled blood pressure and / or blood pressure above 140 / 907. Participants receiving medications that may negatively impact cognitive function8. History of diabetic ketoacidosis within the past year9. History of chronic pancreatitis10. Stage 4 kidney disease11 . Use of insulin therapyResults

[0074] At 18 months following start of treatment, changes in inflammatory biomarker profiles in blood plasma were measured using the LincoPlex system and the human cytokine / chemokine full panel (Millipore, panel 1 , 38 analytes) according to the manufacturer’s instructions.

[0075] The results of the inflammatory biomarker measurements are shown in FIGS. 1-4. The numbers on the x-axis in FIG. 1 and FIG. 2 correspond to: 1 : EGF; 2: Eotaxin; 3: FGF-2; 4: Flt-3L; 5: Fractalkine; 6: G-C; 7: GM-CSF; 8: GRO; 9: IFNa2; 10: IFN y (IFNg); 11 : IL-10; 12: IL-12p40; 13: IL- 12p70; 14: IL-13; 15: IL-15; 16: IL-17A; 17: IL-1 a; 18: IL-1 b; 19: IL-1 Ra; 20: IL-2; 21 : IL-3; 22: IL-4; 23: IL-5; 24: IL-6; 25: IL-7 ; 26: IL-8; 27: IL-9 ; 28: IL-10; 29: MCP-1 ; 30: MCP-3; 31 : MDC; 32: MIP-1 a; 33: MIP-1 b; 34: sCD40L; 35: TGF-a; 36: TNFa; 37: TNFp; and 38 - VEGF.

[0076] FIG. 1 shows baseline measurements at day 0 for each of the analytes. FIGS. 2-4 show that a decrease in several inflammatory biomarkers was observed for patients treated with azeliragon as compared to patients receiving the placebo. In particular, the inflammatory biomarker panel showed statistically significant decreases from baseline (day 0) to Month 18 in the azeliragon-treated group for IL6, IL12, INFy, CD40L, MIP-1 b, IL2, TNFp, and FGF-2 (see FIGS. 2-4). Statistically significant differences between the means were determined by a Wilcoxon signed-rank test with P-values indicated with asterisks: * p <0.05. Additionally, FIGS. 2-4 show a trend toward a decrease in IL13, TGFa, MCP-3, MPC-1 , and CSF2.

[0077] In summary, the decrease in inflammatory biomarkers in the azeliragon-treated group provides biological evidence for using azeliragon to treat a human subject who has, is suspected of having, or is at risk of developing, an inflammatory disorder.5.1 Example 2: A Randomized Placebo-Controlled Phase ll / lll Study to Assess the Preliminary Evidence of an Effect of Azeliragon in Progressive Multiple SclerosisStudy design

[0078] This is a randomized placebo controlled phase 2 / 3 study to determine the safety and efficacy of azeliragon in progressive multiple sclerosis. A total of approximately 300 patients will selfadminister a daily dose of azeliragon at a dose of 60 mg daily or matching placebo for six days, followed by 20 mg daily or matching placebo for two years.Study population

[0079] The study population is adult patients diagnosed with multiple sclerosis.Inclusion Criteria

[0080] Patients must meet all of the following criteria to be eligible to participate:1 . Patient must fulfill the McDonald diagnostic criteria for multiple sclerosis.2. Patient must have non-relapsing, progressive disease.3. Male or non-pregnant and non-lactating female and > 18 to < 80 years of age.4. Patient has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained < 14 days prior to enrollment) and at Baseline-Day 0: Absolute neutrophil count (ANC) > 1.0 x 109 / L; Platelet count > 75,000 / mm3(75 x 109 / L); Hemoglobin (Hgb) > 9 g / dL.5. Patient has the following blood chemistry levels at Screening (obtained < 14 days prior to enrollment) and at Baseline-Day 0:• AST (SGOT), ALT (SGPT) < 3 x upper limit of normal range (ULN), unless liver metastases are present, then < 5 x ULN is allowed. Total bilirubin < 1 .5 x ULN.• Serum creatinine < 1 .5X ULN or estimated creatinine clearance of > 60 mL / min (per Cockroft-Gault formula).6. Patient has been informed about the nature of the study and has agreed to participate in the study. Patient has signed the Informed Consent Form (ICF) prior to participation in any study-related activities.Exclusion Criteria

[0081] Patients will not be eligible to participate in the study if any of the following criteria apply:1 . Patient is currently receiving another pharmaceutical treatment for multiple sclerosis such as immunosuppressive or immunomodulatory treatment. Non-pharmaceutical treatments, such as physical therapy or cognitive therapy are permitted.2. Patient has a concomitant serious medical or psychiatric illness that, in the opinion of the investigator, could compromise the patient's safety or the study data integrity.3. Patient is unwilling or unable to comply with study procedures.Treatment planDosage and Administration

[0082] The study drug, azeliragon, is provided in 5 mg gelatin capsules.

[0083] 30 mg of azeliragon is administered orally twice daily (total of 60 mg daily) for six days as a loading dose, followed by 20 mg once daily thereafter as a maintenance dose.Concomitant Medication and Treatment

[0084] Concomitant medications and over the counter medications and supplements taken during the study must be recorded with indication, daily dose, and start and stop dates of administration. All participants will be questioned about concomitant medication and supplements at each clinic visit.

[0085] The following medications are prohibited as concomitant medications during the study:

[0086] Drugs known to be strong CYP 2C8 inhibitors: gemfibrozil, monteleukast, and pioglitazone.

[0087] All treatments that the investigator considers necessary for a subject’s welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medication will be recorded on the case report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, and date will also be included on the CRF.Duration of Study Participation

[0088] The study duration per subject two years.Study assessments and schedule

[0089] Patients will be seen approximately every 3 months for assessment of safety and tolerability of azeliragon.

[0090] The primary efficacy endpoint will be the Expanded Disability Status Scale (EDSS) at 1 and 2 years.Results

[0091] Administration of azeliragon to subjects with multiple sclerosis results in less decline of the EDSS at 2 years.EQUIVALENTS AND INCORPORATION BY REFERENCE

[0092] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0093] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

CLAIMS1 . A method of treating a human subject who has an inflammatory disorder, the method comprising: administering a therapeutically effective amount of a compound that inhibits receptor for advanced glycation end products (RAGE) to a human subject in amount effective to reduce blood levels of at least one cytokine selected from TNF-p, IL-6, IL-2, IL-12 p70, IL-12 p40, IL-13 and IFN-y.

2. The method of claim 1 , wherein the inflammatory disorder is rheumatoid arthritis, psoriatic arthritis, lupus, multiple sclerosis, inflammatory bowel disease, psoriasis, sinusitis, cystic fibrosis, inflammatory response to surgery, trauma or critical illness, gout, ankylosing spondylitis, pancreatitis, endometriosis, cystitis, atopic dermatitis, myositis, asthma, chronic obstructive pulmonary disease, sarcoidosis, myocarditis, vasculitis, scleroderma, Sjogren’s syndrome, Hashimoto’s Thyroiditis, Guillian Barre Syndrome, Graves’ Disease, Addison’s Disease, myasthenia gravis, celiac disease, pernicious anemia, localized cancer, cancer pain, cancer cachexia, cancer metastasis, type 1 diabetes, or primary sclerosing cholangitis.

3. The method of any one of the preceding claims, wherein the RAGE inhibitor disrupts signaling via RAGE.

4. The method of any one of the preceding claims, wherein the RAGE inhibitor binds to RAGE, binds to a ligand of RAGE, and / or disrupts downstream signaling mediated by RAGE.

5. The method of any one of the preceding claims, wherein the RAGE inhibitor is a RAGE antagonist.

6. The method of any one of the preceding claims, wherein the RAGE inhibitor is selected from the group consisting of a small molecule, antibody, antibody fragment, aptamers, glycosaminoglycans, antisense RNA, peptides, and soluble RAGE (sRAGE).

7. The method of any one of the preceding claims, wherein the RAGE inhibitor is a small molecule.

8. The method of claim 7, wherein the RAGE inhibitor is selected from the group consisting of FPS- ZM1 , azeliragon (TTP-488, PF-04494700), GM-1111 , alagebrium (ALT7-11 ), 4'-Methoxyresveratrol, chondroitin sulfate, heparan sulfate, and AEG 3482.

9. The method of claim 8, wherein the RAGE inhibitor is azeliragon, which is [3-(4-[2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl]-phenoxy)-propyl]-diethyl-amine, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the RAGE inhibitor is a polymorph of [3-(4-{2-butyl-1 -[4-(4-chloro- phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having a solid state13C NMRspectrum comprising peaks at 153.6, 140.1 and 119.9 ppm, when the upfield resonance of crystalline adamantane is set to 29.5 ppm, or a pharmaceutically acceptable salt thereof.11 . The method of claim 9, wherein the RAGE inhibitor is a polymorph of of [3-(4-{2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having an X-ray powder diffraction comprising the following 20 values, measured using CuKa radiation having a wavelength of 1 .54056 A: 18.8 and 20.1 degrees, or a pharmaceutically acceptable salt thereof.

12. The method of claim 9, wherein the RAGE inhibitor is a polymorph of [3-(4-{2-butyl-1 -[4-(4-chloro- phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having a Raman spectrum comprising Raman shifts of 300 and 1180 cm-1, or a pharmaceutically acceptable salt thereof.

13. The method of any one of the preceding claims, further comprising administering the therapeutically effective amount of the RAGE inhibitor to a human subject who has received and / or is receiving an inflammatory disorder treatment.

14. The method of claim 13, wherein the inflammatory disorder treatment comprises glucocorticoid therapy, immunosuppressive or immunomodulatory therapy, genetic therapy, cell-based therapy, and / or antibody therapy.

15. The method of claim 14, wherein the inflammatory disorder treatment comprises one or more glucocorticoids.

16. The method of claim 15, wherein the one or more glucocorticoids is selected from dexamethasone, prednisone, and methylprednisolone.

17. The method of claim 15 or 16, wherein the inflammatory disorder treatment further comprises a glucocorticoid-sparing agent.

18. The method of claim 17, wherein the glucocorticoid-sparing agent is selected from methotrexate, mycophenolate, azathioprine, tacrolimus, cyclophosphamide, cyclosporine, intravenous immune globulin, and rituximab.

19. The method of any one of the preceding claims, further comprising administering the therapeutically effective amount of the RAGE inhibitor to a human subject who has received and / or is receiving treatment to reduce the clinical symptoms of an inflammatory disorder.

20. The method of any one of the preceding claims, wherein the RAGE inhibitor is administered orally.21 . The method of any one of the preceding claims, wherein the RAGE inhibitor is administered in multiple doses.

22. The method of any one of the preceding claims, wherein the RAGE inhibitor is administered as a loading dose followed by a daily dose.

23. The method of claim 23, wherein the RAGE inhibitor is administered as a loading dose of 60 mg daily for at least three days.

24. The method of claim 23, wherein the RAGE inhibitor is administered as a loading dose of 60 mg daily for six days.

25. The method of any one of claims 22-24, wherein the daily dose is 20 mg.

26. The method of any one of claims 22-24, wherein the daily dose is 10 mg.

27. The method of any one of claims 22-24, wherein the daily dose is 5 mg.

28. The method of any one of claims 13-27, wherein the RAGE inhibitor is administered concurrently with the inflammatory disorder treatment.

29. The method of any one of claims 13-27, wherein the RAGE inhibitor is administered sequentially or separately with the inflammatory disorder treatment.

30. The method of claim 29, wherein the RAGE inhibitor is administered sequentially before, after, or both before and after the inflammatory disorder treatment.31 . The method of claim 29, wherein the RAGE inhibitor is administered separately before, after, or both before and after the inflammatory disorder treatment.

32. A method of treating clinical manifestations of an inflammatory disorder in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a compound that inhibits receptor for advanced glycation end products (RAGE) to a subject who has clinical manifestations of an inflammatory disorder.

33. The method of claim 32, wherein the RAGE inhibitor is azeliragon, which is [3-(4-[2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl]-phenoxy)-propyl]-diethyl-amine, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the RAGE inhibitor is a polymorph of [3-(4-{2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having a solid state13C NMR spectrum comprising peaks at 153.6, 140.1 and 1 19.9 ppm, when the upfield resonance of crystalline adamantane is set to 29.5 ppm, or a pharmaceutically acceptable salt thereof.

35. The method of claim 33, wherein the RAGE inhibitor is a polymorph of of [3-(4-{2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having an X-ray powder diffraction comprising the following 20 values, measured using CuKa radiation having a wavelength of 1 .54056 A: 18.8 and 20.1 degrees, or a pharmaceutically acceptable salt thereof.

36. The method of claim 33, wherein the RAGE inhibitor is a polymorph of [3-(4-{2-butyl-1 -[4-(4- chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine, having a Raman spectrum comprising Raman shifts of 300 and 1 180 cm-1, or a pharmaceutically acceptable salt thereof.