WO2025165385A1

WO2025165385A1 - Use of cox-2 inhibitor and ivaltinostat combination therapy for treating rheumatoid arthritis

Info

Publication number: WO2025165385A1
Application number: PCT/US2024/022975
Authority: WO
Inventors: Sangsook CHO; Joong Myung Cho
Original assignee: CG Pharmaceuticals Inc
Current assignee: CG Pharmaceuticals Inc
Priority date: 2024-01-30
Filing date: 2024-04-04
Publication date: 2025-08-07
Anticipated expiration: 2026-07-30
Also published as: TW202529741A

Abstract

Embodiments of the present disclosure relate to methods of treating rheumatoid arthritis with a combination of a COX-2 inhibitor and ivaltinostat, or a pharmaceutically acceptable salt thereof.

Description

USE OF COX-2 INHIBITOR AND IVALTINOSTAT COMBINATION THERAPY FOR TREATING RHEUMATOID ARTHRITIS

BACKGROUND

[0001] Rheumatoid arthritis (RA) is a chronic, system autoimmune disease in which synovitis occurs as inflammation, infiltration of immune cells, and new blood vessels in the synovial membrane of peripheral joints. Damage from bone and joint cartilage destruction and weakening of tendons and ligaments can result to functional damage and joint deformities, resulting in significant pain. In addition to joint symptoms, RA is accompanied by extra- articular symptoms that may affect the lungs, kidney, and heart, in addition to osteoporosis and vasculitis. Recently, it was found that the risk of cardiovascular disease increases in patients with RA. RA can occur at any age and in any gender and it is estimated that there are about 260,000 patients currently being treated for RA.

[0002] The synovial membrane typically encases joints in a layer of synovial fluid that lubricates and protects joint tissues. However, in individuals suffering from RA, the immune system directs leukocytes to attack cells inside the synovium, wherein helper T-cells produce pro- inflammatory cytokines resulting in inflammation. The inflammation causes swelling and pain and results in the gradual destruction of collagen in the cartilage, which narrows the joint space and damages bone through erosion. The synovial membrane also expands due to increased cell division in the synovium causing joints to become swollen and puffy.

[0003] Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids and various antirheumatic drugs (DMARDs, disease modifying anti-rheumatic disease) are currently used to provide symptomatic relief or non-specific immunosuppressive action, which may cause side effects. However, these drugs do not seem to alter the long-term progression of RA. In addition, approximately 30-40% of patients do not appear to respond to these therapeutic agents. Bone damage can begin soon after the onset of RA and can worsen as the disease progresses as ligaments and tendons that stabilize the joint become weak due to bone damage. As such, the treatment of inflammation and pain associated with RA is important to slow disease progression. Cyclooxygenase-2 inhibitors (COX-2 inhibitors), also known as coxibs, are a type of NSAIDs that directly target cyclooxygenase-2 (COX-2), an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of this drug class.

[0004] Biologies targeting TNF-a have also been developed, but these therapies remain expensive and suffer from development problems due to the use of chimeric forms of mouse and human antibodies. About 10-20% of patients also do not respond to these therapies, which also have the side effect of increasing the frequency of infections. For at least the foregoing reasons, there is a need for improved therapies for RA.

SUMMARY

[0005] One aspect of the present application relates to a method of treating rheumatoid arthritis in a subject in need thereof that can include administering a COX-2 inhibitor such as polmacoxib in combination with a histone deacetylase (HD AC) inhibitor such as ivaltinostat to the subject. In some embodiments, the rheumatoid arthritis includes seropositive rheumatoid arthritis or seronegative rheumatoid arthritis.

[0006] Another aspect of the present application relates to a method for treating rheumatoid arthritis, wherein the weight ratio of the COX-2 inhibitor to ivaltinostat can be from about 500: 1 to about 1 :500, or about 300: 1 to about 1 :300, or about 1 : 1 to about 1 :250. In further embodiments, the weight ratio of the COX-2 inhibitor to ivaltinostat can be from about 1 :25 to about 1 :100. In some embodiments, the COX-2 inhibitor is polmacoxib, celecoxib, rofecoxib, parecoxib or etoricoxib. In one embodiment, the COX-2 inhibitor is polmacoxib. In some embodiments, the COX-2 inhibitor is polmacoxib, which can be administered in a dose from about 0. 1 mg to about 5 mg. In further embodiments, polmacoxib can be administered in a dose from about 0.5 to about 4 mg, or from about 1 mg to about 2 mg. In some embodiments of the methods described herein, the COX-2 inhibitor can be administered at least once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or every 14 days. In other embodiments, the COX-2 inhibitor can be administered for at least 2 to 12 weeks. In some embodiments of the methods described herein, ivaltinostat can be administered in a dose from about 1 mg/m² to about 500 mg/m². In other embodiments, ivaltinostat can be administered in a dose from about 10 mg/m² to about 250 mg/m², or from about 50 mg/m² to about 125 mg/m². In some embodiments, ivaltinostat is administered at least once every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or every 14 days. In other embodiments, ivaltinostat can be administered for about or at least about 2 to 12 weeks. In some embodiments, both the COX-2 inhibitor and ivaltinostat can be administered orally. In other embodiments, ivaltinostat can be administered by intravenous infusion.

[0007] Another aspect of the present application relates to a method for treating rheumatoid arthritis, wherein a COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat can be administered in a single pharmaceutical formulation. In other embodiments, the COX-2 inhibitor and ivaltinostat can be administered in two separate pharmaceutical formulations. In still other embodiments, the COX-2 inhibitor can be administered orally and ivaltinostat can be administered by intravenous infusion. In some embodiments, the intravenous infusion can be over about 30 minutes to about 120 minutes, about 50 minutes to about 70 minutes, or about 60 minutes.

[0008] A further aspect of the present application relates to a method for treating rheumatoid arthritis, wherein the method can reduce one or more symptoms or conditions that can include joint inflammation, bone erosion, talus bone damage, or cartilage destruction. In other embodiments, the method can reduce expression of one or more inflammatory cytokines in the joint synovium. In some embodiments, the inflammatory cytokines include IL-ip, IL-6 and IL- 17.

[0009] Another aspect of the present application relates to a kit, comprising: a first pharmaceutical composition comprising a COX-2 inhibitor polmacoxib or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising ivaltinostat or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is polmacoxib, celecoxib, rofecoxib, parecoxib or etoricoxib. In one embodiment, the COX-2 inhibitor is polmacoxib. In some embodiments, both the first pharmaceutical composition and the second pharmaceutical composition can be oral formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGs. 1 A and IB shows the effect of treatment with polmacoxib in combination with ivaltinostat on rheumatoid arthritis compared to the vehicle control and positive controls methotrexate (MTX) and tofacitinib. FIG. 1A shows the effect of treatment as evaluated by an arthritis score. FIG. IB shows the effect of treatment based on the incidence of arthritis symptoms.

[0011] FIG. 2 shows the pain control effects of polmacoxib in combination with ivaltinostat as measured by a mechanical allodynia pain model, wherein the threshold for the pawwithdrawal reflex was measured after 11 weeks.

[0012] FIGs. 3A and 3B show the improved effect of controlling bone erosion with the combination of polmacoxib and ivaltinostat as compared to the vehicle control and positive controls MTX and tofacitinib. FIG. 3A shows the objective volume obtained by micro-CT. FIG. 3B shows the objective surface/objective volume ratio.

[0013] FIG. 4 shows the improved join inflammation control effect of the combination of polmacoxib and ivaltinostat as compared to the vehicle control and positive controls MTX and tofacitinib.

[0014] FIGs. 5A and 5B show the effect of modulating bone erosion and articular cartilage destruction using polmacoxib in combination with ivaltinostat as compared to the vehicle control and positive controls MTX and tofacitinib. [0015] FIG. 6 shows the improved effect of the combination polmacoxib and ivaltinostat of regulating cellular expression of IL-ip as compared to the vehicle control and positive controls MTX and tofacitinib.

[0016] FIG. 7 shows the improved effect of the combination polmacoxib and ivaltinostat of regulating cellular expression of IL-6 as compared to the vehicle control and positive controls MTX and tofacitinib.

[0017] FIG. 8 shows the improved effect of the combination polmacoxib and ivaltinostat of regulating cellular expression of IL- 17 as compared to the vehicle control and positive controls MTX and tofacitinib.

DETAILED DESCRIPTION

[0018] Disclosed herein are methods for treating rheumatoid arthritis. In some embodiments, the methods include administration of a combination of a COX-2 inhibitor such as polmacoxib and a HD AC inhibitor such as ivaltinostat. Administration of the COX-2 inhibitor herein includes administering a pharmaceutically acceptable salt or solvate of the COX-2 inhibitor. Administration of ivaltinostat includes administering a pharmaceutically acceptable salt of ivaltinostat. In some embodiments, ivaltinostat is provided as the corresponding phosphoric acid salt.

Polmacoxib

[0019] Polmacoxib, 5-(4-(aminosulfonyl)-phenyl)-2,2,-dimethyl-4-(3-fluorophenyl)- 3 (2H) -furanone, is a nonsteroidal anti-inflammatory drug (NSAID).

[0020] Polmacoxib is also a selective COX-2 inhibitor and has reduced gastrointestinal toxicity compared to other NSAIDs. COX (cyclooxygenase) is responsible for the production of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX- 2 has been shown to be induced by pro-inflammatory stimuli and is an isoform of an enzyme that is suspected to be important in the synthesis of prostanoid regulators of pain, inflammation, and fever. Polmacoxib may be prepared in various crystalline forms as described in U.S. Patent No. 10,413,520, which is incorporated by reference in its entirety.

Ivaltinostat

[0021] Ivaltinostat, (E)-N 1 -(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen- 1 -yloxy)methyl)oct-2-enediamide phosphate, is an anticancer therapeutic candidate that inhibits enzymatic activity of histone deacetylase (HDAC).

[0022] Other useful pharmaceutical salts of ivaltinostat free base (E)-Nl-(3- (dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)oct-2-enediamide include other acid addition salts, such as the tartaric acid addition salt, which is disclosed in WO 2018/230829 and U.S. Publication No. 2020/0283371 Al, each of which is incorporated by reference in its entirety. In addition to the phosphate salt, other pharmaceutically acceptable salts of ivaltinostat free base may also be used in the methods described herein.

Definitions

[0023] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The use of the term “having” as well as other forms, such as “have”, “has,” and “had,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the above terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” For example, when used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, formulation, or device, the term “comprising” means that the compound, composition, formulation, or device includes at least the recited features or components, but may also include additional features or components. [0025] The terms “effective amount” and “therapeutically effective amount” are broad terms, and are to be given their ordinary and customary meaning to a person of ordinary skill in the art (and are not to be limited to a special or customized meaning), and refer without limitation to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. Where a drug has been approved by the U.S. Food and Drug Administration (FDA) or a counterpart foreign medicines agency, a “therapeutically effective amount” optionally refers to the dosage approved by the FDA or its counterpart foreign agency for treatment of the identified disease or condition.

[0026] “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition/formulation for prophylactic and/or therapeutic purposes. The term “prophylactic treatment” refers to treating a patient who is not yet suffering from a disease, but who is susceptible to, or otherwise at risk of, a particular disease, whereby the treatment reduces the likelihood that the patient will develop a disease. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease.

[0027] The terms “co-administration” or “combination therapy” as used herein means that the additional therapeutic agent(s) may be administered together with polmacoxib and/or ivaltinostat, as part of a single dosage form (such as a composition of this disclosure comprising a compound of the disclosure and additional therapeutic agent(s) or as separate, multiple dosage forms. Alternatively, the additional therapeutic agent(s) may be administered prior to, consecutively with, or following the administration of ivaltinostat.

[0028] The term “pharmaceutically acceptable salt” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and refers without limitation to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1 ,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a lithium, sodium or a potassium salt, an alkaline earth metal salt, such as a calcium, magnesium or aluminum salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, (Ci-Ce alkyl)amine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, and salts with amino acids such as arginine and lysine; or a salt of an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, or the like.

[0029] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0030] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,”

“less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0031] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

Pharmaceutical Compositions

[0032] Ivaltinostat, as described herein, may be provided for administration in the form of a pharmaceutical composition, including an effective amount of ivaltinostat or a pharmaceutically acceptable salt, such as the phosphate salt, and at least one pharmaceutically acceptable excipient or carrier.

[0033] The term “pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as one or more excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0034] As used herein, an “excipient” refers to essentially inert substances that are added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as antioxidants and metal-chelating agents are excipients. Excipients also include ingredients in a pharmaceutical composition that lack appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. For example, a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0035] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or excipients, or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0036] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients (e.g., ivaltinostat and polmacoxib) are contained in an amount effective to achieve its intended purpose.

[0037] Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a pharmaceutical composition of ivaltinostat may be administered intravenously .In some other embodiments, a pharmaceutical composition of ivaltinostat may be administered orally. In some embodiments, a pharmaceutical composition of the COX-2 inhibitor (e.g., polmacoxib) can be administered orally. In some embodiments, both a pharmaceutical composition of the COX-2 inhibitor and a pharmaceutical composition of ivaltinostat can be administered orally. In other embodiments, a pharmaceutical composition of the COX-2 inhibitor can be administered orally and a pharmaceutical composition of ivaltinostat can be administered intravenously.

[0038] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical Compositions as described herein formulated in a compatible pharmaceutical excipient may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. The pharmaceutical composition comprising ivaltinostat may be separate from the pharmaceutical composition comprising the COX-2 inhibitor (e.g., polmacoxib). In some such embodiments, the pharmaceutical composition of ivaltinostat may be separately packaged from the COX-2 inhibitor in a kit or marketed separately as two individual products. In other embodiments, the pharmaceutical composition containing ivaltinostat is administered by the same route as that of the COX-2 inhibitor. As such, ivaltinostat and the COX-2 inhibitor may be in a single unit dosage form or may be adapted to be administered together. Methods of Treating Rheumatoid Arthritis

[0039] One aspect of the present application relates to a method of treating rheumatoid arthritis in a subject in need thereof, comprising administering a COX-2 inhibitor described herein (e.g., polmacoxib) in combination with ivaltinostat to the subject. In some embodiments, the rheumatoid arthritis can be seropositive rheumatoid arthritis. In other embodiments, the rheumatoid arthritis can be seronegative rheumatoid arthritis.

[0040] In some embodiments of the methods described herein, the weight ratio of the COX-2 inhibitor to ivaltinostat can be from about 500:1 to about 1:500, from about 300:1 to about 1:300, from about 1: 1 to about 1:500, or from about 1:1 to about 1 :250. In further embodiments, the weight ratio of the COX-2 inhibitor to ivaltinostat can be about 500:1, 475: 1, 450:1, 425: 1, 400:1, 375:1, 350: 1, 325:1, 300:1, 275:1, 250: 1, 225:1, 200: 1, 175:1, 150:1, 125:1, 100:1, 75: 1, 50:1, 25:1, 1:1, 1 :25, 1 :50, 1 :75, 1 :100, 1:125, 1 :150, 1 :175, 1:200, 1 :225, 1:250, 1:275, 1:300, 1:325, 1 :350, 1:375, 1 :400, 1 :425, 1:450, 1 :475, or 1:500, or a range defined by any two of the preceding values. In further embodiments, the weight ratio of the COX-2 inhibitor (e.g., polmacoxib) to ivaltinostat can be from about 1 : 1 to about 1:250, for example, about 1 : 1, 1 :5, 1:10, 1 :20, 1 :30, 1:40, 1 :50, 1:60, 1 :70, 1:80, 1 :90, 1 :100, 1 :110, 1 :120, 1: 130, 1 :140, 1 :150, 1:160, 1:170, 1 : 180, 1:190, 1:200, 1:210, 1 :220, 1:230, 1:240 or 1 :250, or a range defined by any two of the preceding values. In other embodiments, the weight ratio of the COX-2 inhibitor (e.g., polmacoxib) to ivaltinostat is from about 1 :10 to about 1:200. In still other embodiments, the weight ratio of the COX-2 inhibitor (e.g., polmacoxib) is from about 1 :20 to about 1 :150. In still other embodiments, the weight ratio of the COX-2 inhibitor (e.g., polmacoxib) is from about 1 :25 to about 1 : 100.

[0041] In some embodiments of the methods described herein, the COX-2 inhibitor is polmacoxib, which can be administered in a dose from about 0.1 mg to about 4 mg, from about 0.5 mg to about 3 mg, from about 0.75 mg to about 2.5 mg, or from about 1 mg to about 2 mg. For example, polmacoxib can be administered in a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 mg. In other embodiments, the COX-2 inhibitor is celecoxib, which can be administered in a dose from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, or from about 200 mg to about 300 mg. In some embodiments, the COX-2 inhibitor can be administered at least once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, or every 14 days. In some embodiments, the COX-2 inhibitor is administered for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks. [0042] In some embodiments of the methods described herein, ivaltinostat can be administered in a dose from about 1 mg/m² to about 500 mg/m². In other embodiments, ivaltinostat can be administered in a dose from about 10 mg/m² to about 250 mg/m², for example about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, or 250 mg/m². In further embodiments, ivaltinostat can be administered in a dose from about 50 mg/m² to about 125 mg/m² or from about 75 mg/m² to about 100 mg/m². In some embodiments, ivaltinostat can be administered at least once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, or every 14 days. In some embodiments, ivaltinostat is administered for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0043] In some embodiments of the methods described herein, the COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat both can be administered orally. In some embodiments, the COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat can be administered in a single pharmaceutical formulation. In other embodiments, the COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat can be administered in two separate pharmaceutical formulations. In some embodiments, the COX-2 inhibitor (e.g., polmacoxib) can be administered orally and ivaltinostat can be administered by intravenous infusion. In some embodiments the intravenous infusion of ivaltinostat can be over about 30 minutes to about 120 minutes, about 50 minutes to about 70 minutes, or about 60 minutes.

[0044] In some embodiments of the methods described herein, the COX-2 inhibitor (e.g., polmacoxib) can be administered after administration of ivaltinostat. In other embodiments, the COX-2 inhibitor can be administered before or simultaneously with ivaltinostat. In some embodiments, the COX-2 inhibitor can be administered from 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour or about 2 hours after ivaltinostat. In some embodiments, the COX-2 inhibitor is administered from 1 minute to 5 hours, 5 minutes to 4 hours, 10 minutes to 3.5 hours, 30 minutes to 3 hours, 30 minutes to 2 hours, 30 minutes to 1.5 hours, 1 hour to 2.5 hours, about 1 hour or about 2 hours before ivaltinostat.

[0045] In some embodiments of the methods described herein, the COX-2 inhibitor (e.g., polmacoxib) can be administered on the same day that ivaltinostat is administered. In other embodiments, the COX-2 inhibitor (e.g., polmacoxib) can be administered on the day after, two days after, three days after, four days after, five days after, six days after, seven days after, eight days after, nine days after, and/or ten days after the start of therapy with ivaltinostat. [0046] In some embodiments of the methods described herein, the method can reduce and/or ameliorate symptoms or conditions resulting due to RA. In some embodiments, the method can reduce and/or ameliorate joint inflammation due to RA. In some embodiments, the reduction of joint inflammation due to RA can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than the reduction of joint inflammation due to RA with tofacitinib and/or methotrexate. In other embodiments, the method can reduce and/or ameliorate bone erosion due to RA. In some embodiments, the reduction of bone erosion due to RA can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than the reduction of bone erosion due to RA with tofacitinib and/or methotrexate. In still other embodiments, the method can reduce and/or ameliorate talus bone damage due to RA. In some embodiments, the reduction of joint inflammation due to RA can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than the reduction of talus bone damage due to RA with tofacitinib and/or methotrexate. In still yet other embodiments, the method can reduce and/or ameliorate cartilage destruction due to RA. In some embodiments, the reduction of joint inflammation due to RA can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than the reduction of cartilage destruction due to RA with tofacitinib and/or methotrexate.

[0047] In some embodiments of the methods described herein, the method can reduce expression of inflammatory cytokines in the joint synovium. In some embodiments, the method can reduce expression of IL-ip. In some embodiments, the reduction of IL-ip expression can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than reduction of IL- 1 P expression with tofacitinib and/or methotrexate. In other embodiments, the method can reduce expression of IL-6. In some embodiments, the reduction of IL-6 expression can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than reduction of IL-6 expression with tofacitinib and/or methotrexate. In other embodiments, the method can reduce expression of IL- 17. In some embodiments, the reduction of IL-17 expression can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150% or 200% more than reduction of IL- 17 expression with tofacitinib and/or methotrexate.

[0048] A potential advantage of utilizing a method of administering a combination of a COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat, or a pharmaceutically acceptable salt thereof, may be a reduction in the required amount(s) of the COX-2 inhibitor and/or ivaltinostat, or a pharmaceutically acceptable salt thereof, that is effective in treating RA, as compared to the amount required to achieve the same therapeutic result when the COX-2 inhibitor or ivaltinostat, or a pharmaceutically acceptable salt thereof, are administered alone. Another potential advantage of utilizing a method of administering a combination of a COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat, or a pharmaceutically acceptable salt thereof, is that the use of two or more compounds having different mechanisms of action may result in little to no pharmacokinetic interactions and little to no overlapping toxicities between the COX-2 inhibitor and ivaltinostat. A further potential advantage of utilizing a method of administering a combination of a COX-2 inhibitor (e.g., polmacoxib) and ivaltinostat, or a pharmaceutically acceptable salt thereof, is that the combination may produce a synergistic therapeutic effect, wherein the therapeutic effect achieved is greater than the additive effect of the potencies of the individual therapeutic agents.

Kits

[0049] Another aspect of the present disclosure relates to a kit for treating RA. In some embodiments, the kit can include a first pharmaceutical composition comprising a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising ivaltinostat, or a pharmaceutically acceptable salt thereof. In some embodiments, the COX-2 inhibitor is polmacoxib, celecoxib, rofecoxib, parecoxib or etoricoxib. In one embodiment, the COX-2 inhibitor is polmacoxib. In some embodiments, both the first and second pharmaceutical formulations are in oral formulations. In other embodiments, the first pharmaceutical composition is in an oral formulation and the second pharmaceutical composition is in an intravenous formulation. The amount of the COX-2 inhibitor and ivaltinostat in the kit are described above.

[0050] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the invention, as it is described herein above and in the claims.

EXAMPLES

[0051] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the invention, as it is described herein above and in the claims.

Study Design

[0052] One study disclosed herein was a preclinical study of a mouse model designed to investigate the therapeutic efficacy of polmacoxib and ivaltinostat, alone or in combination, on rheumatoid arthritis. The rheumatoid arthritis model was induced through injection of type II collagen (collagen-induced arthritis) and exhibited immune and pathological characteristics similar to those of human rheumatoid arthritis. After 3 weeks of primary immunization with type II collagen, mice were orally administered polmacoxib (1 mg/kg), ivaltinostat (25 mg/kg or 100 mg/kg), polmacoxib (1 mg/kg) with ivaltinostat (25 mg/kg), or polmacoxib (1 mg/kg) with ivaltinostat (100 mg/kg) for 8 weeks and the efficacy of the drugs were evaluated. As a vehicle control, PBS (phosphate-buffered saline) was used. MTX (methotrexate) and tofacitinib mixed in PBS were used as positive controls.

Results

[0053] FIG. 1A presents an evaluation of the progression of arthritis in the mice over the course of 11 weeks from the onset of arthritis as evaluated by an arthritis score. Mice were scored using the arthritis index, indicating the onset and severity of joint inflammation, twice weekly for up to 1 1 weeks after the primary immunization. There severity of the arthritis was assessed on a scale of 0-4 for each leg according to the following criteria in Table 1 :

Table 1.

[0054] The arthritis score for each mouse was expressed as the sum of the scores of the four limbs. As shown in FIG. 1A, the arthritis score was the lowest in the polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) groups after 11 weeks. The arthritis score was lower in the polmacoxib combined with ivaltinostat groups compared to the positive controls tofacitinib (30 mg/kg) and MTX (0.5 mg/kg). FIG. IB shows that the incidence percentage of arthritis also was lowest in the polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg) group compared to the vehicle control group 11 weeks after primary immunization. The incidence percentage was evaluated according to the observation of arthritis in each limb as detailed in Table 2.

Table 2.

[0055] FIG. 2 shows a scatter plot demonstrating the pain control effects of polmacoxib and ivaltinostat after 10 and 11 weeks, respectively. To investigate the pain control effect, hind paws of mice were stimulated with an electronic von Frey analgesiometer to assess mechanical allodynia. The pain control effect was evaluated by measuring the threshold (g) required to elicit a paw-withdrawal reflex. At 11 weeks, pain was statistically significantly suppressed in the polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg) group compared to the vehicle control group (vehicle vs. *P <0.05).

[0056] FIGs. 3 A and 3B show the effect of controlling the degree of damage to the talus bone by a combination of polmacoxib and ivaltinostat in a mouse model. A micro-CT analysis was performed on the talus bone 11 weeks after primary immunization. As shown in FIG. 3A, compared with the vehicle control group, the objective volume was statistically significantly increased in the groups administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) (vehicle vs. **P<0.01). The objective surface/objective volume ratio (FIG. 3B) was also statistically significantly reduced in the groups administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) (vehicle vs. *P < 0.05, **P<0.01). It was also observed that the combination of polmacoxib with ivaltinostat produces a synergistic effect for the control of talus bone damage.

[0057] FIG. 4 presents a plot showing the effect of polmacoxib and ivaltinostat on joint inflammation. Mouse joint tissues were fixed in 10% neutral-buffered formalin, decalcified in decalcifying agent, embedded in paraffin, and cut into sections 5 pm thick. The sections were stained with hematoxylin and eosin (H&E) and Safranin O and scored using the following criteria in Table 3:

Table 3. [0058] Compared to the vehicle control group, the infiltration of inflammatory cells was statistically significantly reduced in the groups administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg (vehicle vs. **P<0.01, ***P<0.001). It is also seen from FIG. 4 that the combination of polmacoxib produces a synergistic effect in the control of inflammation that is greater than the expected additive effect of combining polmacoxib with ivaltinostat for the control of inflammation.

[0059] FIGs. 5(A) and 5(B) shown the effect of polmacoxib and ivaltinostat on bone erosion articular cartilage destruction. Safranin O staining was performed on joint tissues obtained 1 1 weeks after primary immunization and analyzed according to the bone damage and erosion of articular cartilage evaluation criteria presented in Tables 4 and 5, respectively.

Table 4.

Table 5.

[0060] As shown in FIG. 5A, bone erosion was statistically significantly reduced in the groups administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) (vehicle vs. ***P<0.001). Cartilage destruction was also statistically significantly reduced in the groups administered with polmacoxib ( 1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) (vehicle vs. *P<0.05, ***P<0.001) as shown in FIG. 5B. The combination of polmacoxib and ivaltinostat also produces a synergistic effect in reducing bone erosion and cartilage destruction. The combination of polmacoxib and ivaltinostat produces a significant reduction in both bone erosion and cartilage destruction in comparison to polmacoxib and ivaltinostat alone.

[0061] To investigate the effect of polmacoxib and ivaltinostat on the regulation of inflammatory cytokines in joints, immunohistochemical staining was performed on joint tissues obtained 11 weeks after primary immunization. In particular, sections were treated with 3% (v/v) H2O2 in methanol to block endogenous peroxidase activity. Immunohistochemistry was performed using the Envision Detection™ kit. Tissue sections were incubated with primary antibodies against IL-ip, IL-6 and IL-7 for 2 hours at room temperature. Sections were then incubated with a biotinylated secondary antibody and streptavidin-peroxidase complex for 30 min. The final colored products were developed using chromogen diaminobenzidine and the sections were examined under a photomicroscope (magnifications x 400). ImageJ software (Wayne Rasband, NIH, USA) was used to analyze the area of cells expressing each cytokine in the synovial membrane as a percentage.

[0062] FIG. 6 shows that the positive areas of cells expressing IL- 1 [I were statistically significantly reduced in the groups administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg) (vehicle vs. *P<0.05). Compared with the vehicle group, positive areas of cells expressing IL-6 were also statistically significantly reduced in the group administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg) (vehicle vs. *P<0.05) as can be seen in FIG. 7. In addition, FIG. 8 shows that positive areas of cells expressing IL- 17 showed a tendency to decrease when administered with polmacoxib (1 mg/kg) combined with ivaltinostat (25 mg/kg or 100 mg/kg).

[0063] In summary, polmacoxib in combination with ivaltinostat decreased the rheumatoid arthritis score, pain and talus bond damage, and reduced inflammation, bone erosion, cartilage destruction and expression of inflammatory cytokines in the joint synovium. The combination demonstrated synergistic effect and was more effective than the two active agents when administered alone.

[0064] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modifications and alternatives coming within the true scope and spirit of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering a COX-2 inhibitor in combination with ivaltinostat to the subject.

2. The method of claim 1, wherein the rheumatoid arthritis is seropositive rheumatoid arthritis or seronegative rheumatoid arthritis.

3. The method of claim 1 or 2, wherein the weight ratio of the COX-2 inhibitor to ivaltinostat is from about 300: 1 to about 1 :300 or from about 1 : 1 to about 1 :250.

4. The method of claim 3, wherein the weight ratio of the COX-2 inhibitor to ivaltinostat is from about 1:25 to about 1: 100.

5. The method of any one of claims 1 to 4, wherein the COX-2 inhibitor is polmacoxib, celecoxib, rofecoxib, parecoxib or etoricoxib.

6. The method of claim 5, wherein the COX-2 inhibitor is polmacoxib.

7. The method of claim 6, wherein polmacoxib is administered in a dose from about 0.1 mg to about 5 mg.

8. The method of claim 7, wherein polmacoxib is administered in a dose from about 0.5 mg to about 4 mg, or from about 1 mg to about 2 mg.

9. The method of any one of claims 1 to 8, wherein the COX-2 inhibitor is administered at least once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or every 14 days.

10. The method of any one of claims 1 to 9, wherein the COX-2 inhibitor is administered for at least 2 to 12 weeks.

11. The method of any one of claims 1 to 10, wherein ivaltinostat is administered in a dose from about 1 mg/m² to about 500 mg/m².

12. The method of claim 11, wherein ivaltinostat is administered in a dose from about 10 mg/m² to about 250 mg/m², or from about 50 mg/m² to about 125 mg/m².

13. The method of any one of claims 1 to 12, wherein ivaltinostat is administered at least once every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or every 14 days.

14. The method of any one of claims 1 to 13, wherein ivaltinostat is administered for at least 2 to 12 weeks.

15. The method of any one of claims 1 to 14, wherein both the COX-2 inhibitor and ivaltinostat are administered orally.

16. The method of claim 15, wherein the COX-2 inhibitor and ivaltinostat are administered in a single pharmaceutical formulation.

17. The method of claim 16, wherein the COX-2 inhibitor and ivaltinostat are administered in two separate pharmaceutical formulations.

18. The method of any one of claims 1 to 14, wherein the COX-2 inhibitor is administered orally and ivaltinostat is administered by intravenous infusion.

19. The method of claim 18, wherein the intravenous infusion is over about 30 minutes to about 120 minutes, about 50 minutes to about 70 minutes, or about 60 minutes.

20. The method of any one of claims 1 to 19, wherein the method reduces one or more symptoms or conditions selected from joint inflammation, bone erosion, talus bone damage, or cartilage destruction.

21. The method of claims 1 to 20, wherein the method reduces expression of one or more inflammatory cytokines in the joint synovium.

22. The method of claim 21, wherein the inflammatory cytokines are selected from the group consisting of: IL- 1 , IL-6 and IL- 17.

23. A kit, comprising: a first pharmaceutical composition comprising a COX-2 inhibitor; and a second pharmaceutical composition comprising ivaltinostat.

24. The kit of claim 23, wherein the COX-2 inhibitor is polmacoxib, celecoxib, rofecoxib, parecoxib or etoricoxib.

25. The kit of claim 24, wherein the COX-2 inhibitor is polmacoxib.

26. The kit of any one of claims 23 to 25, wherein both the first pharmaceutical composition and the second pharmaceutical composition are oral formulations.

27. The kit of any one of claims 23 to 25, wherein the first pharmaceutical composition is an oral formulation, and the second pharmaceutical composition is an intravenous formulation.