Combination therapies for treating asthma

Abstract

The disclosure relates to the treatment of allergic asthma using a combination therapy. Certain aspects relate to the treatment of a patient having allergic asthma by admininstering to the patient a combination therapy of a first therapeutic agent that is a wild-type KIT inhibitor, N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-( l-(2 -hydroxy-2 -methylpropyl)-3-methyl- lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide or a pharmaceutically acceptable salt thereof and a second therapeutic agent that is a glucocorticoid steroid, dexamethasone or a pharmaceutically acceptable salt thereof.

Description

Aty. Dkt. No.: 134108-863202025-8063PCT COMBINATION THERAPIES FOR TREATING ASTHMARELATED APPLICATION

[0001] This application claims the benefit of the filing date, under 35 U.S.C. § 119(e), of U.S. Provisional Application No. 63 / 765,240, filed on February 28, 2025, the entire contents of which are incorporated herein by reference.FIELD OF THE INVENTION

[0002] The disclosure relates to combination therapies useful for the treatment of allergic asthma. In particular, the invention relates to a combination therapy which comprises a wildtype KIT inhibitor, N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-(l-(2- hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof and a corticosteroid, e.g., dexamethasone.BACKGROUND OF THE INVENTION

[0003] Mast cells are a part of the immune system. They are a main driver of allergic inflammatory responses and are present throughout the body in connective and vascularized tissues, most prominently along surface boundaries with exposure to the external environment: in the skin, the respiratory tract and the gastrointestinal tract. Dysfunctional mast cell activity has been implicated in the pathophysiology of a broad range of allergic and other inflammatory disorders including urticaria, asthma and gastrointestinal disorders. For many who suffer from allergic conditions, inhibition of mast cell derived mediators, including histamines, leukotrienes, and prostaglandins, has resulted in insufficient therapeutic value to-date given that many mast cell-driven disorders involve multiple pro-inflammatory mediators. Asthma is one such allergic condition.

[0004] Asthma is a chronic airway disease affecting the lower respiratory tract, the symptoms of which are displayed by inflammation, recurrent wheezing, broncho-constriction and bronchial hypersecretion. It is estimated that more than 28 million people in the U.S. are considered to be asthmatic and of those ~2 million are active treated patients. Approximately 900K of actively treated patients suffer from allergic asthma.

[0005] Allergic asthma is the most common type of asthma and involves exaggerated bronchoconstriction in response to a specific aeroallergen. The most common allergens include pollen, dust mites, mold, pet dander, mold spores and cockroach residues among others. Allergic1ME1\6O112230. vlAtty. Dkt. No.: 134108-863202025-8063PCT asthma falls under the Type 2 (T2) endotype, which is marked by T2 inflammation with well- established involvement of mast cells in the early phase of the allergic asthma response. The early phase asthma reaction is mast cell-driven and involves smooth muscle response to mast cell mediators such as histamines and cytokines, leading to bronchoconstriction within minutes.

[0006] The traditional standard of care for controlling bronchial asthma has focused on the use of anti-inflammatory drugs, particularly steroid. Glucocorticosteroids are effective in most patients but do not provide prolonged relief without repeated administration and do not address the driver of the disease. In addition, long-term high-dose usage in moderate to severe asthma patients is generally linked to considerable side effects. Furthermore, glucosteroids fail to control disease symptoms in a significant number of asthma patients (corticosteroid-insensitive asthma or corticosteroid-reistant asthma). In many of these individuals, high doses of corticosteroids are frequently prescribed without pharmacological evidence for their utility and with increasing side effects. In many cases, the asthma remains uncontrolled and these patients are most at risk of hospitalization and asthma-related death. In addition to glucocorticoids, monoclonal antibody treatments are currently available for the treatment of severe allergic asthma patients, targeting IL-4, IL-5, or IgE. However, due to their mode of action in the downstream part of the inflammatory cascade, they are associated with side effects, including e.g., infections, eosinophilia, injection site reactions, and a significant portion of patients become refractory over time or some patients choose not to use these treatments due to inconvenience in mode of administration. Other monoclonal antibody treatments have been investigated and found to be not suitable. In spite of the research efforts conducted up to now, an urgent need still exists for new and more effective therapies with minimal side effects for treating allergic asthma.

[0007] One aspect of the disclosure is to provide a more effective, low dose treatment for allergic asthma with fewer short and long term side effects.SUMMARY OF THE INVENTION

[0008] This disclosure relates to combination therapies for the treatment of allergic asthma.The Applicant has now found that in an animal model of asthma, a low dose of the wild-type KIT inhibitor, N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-(l-(2-hydroxy- 2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide, was able to synergize with a low dose of the glucocorticoid steroid, dexamethasone. Specifically, a sub- efficacious dose of Compound 1 in combination with a sub-efficacious dose of dexamethasone in an ovalbumin (OVA)-induced model of asthma resulted in an unexpectedly significant reduction2ME1\6O112230. vlAtty. Dkt. No.: 134108-863202025-8063PCT in airway hyperresponsiveness. Provided herein are methods of treating allergic asthma in a subject by administering a combination therapy.

[0009] US2024 / 0262826, the entire teachings of which are incorporated herein by reference, discloses potent, highly selective wild-type KIT inhibitors. The structure of one of the inhibitors disclosed in US2024 / 026826, N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)- 5-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3- carboxamide is referred to herein as “Compound 1”. The structure of Compound 1 is shown below:Compound 1 is a potent, selective, small molecule inhibitor of wild-type KIT. Its potency has been demonstrated in vitro in a cellular phosphoylation c-KIT inhibition assay (IC500.3 nM) and its advantageous low CNS brain penetration is supported by its Pgp efflux ratio of 13.2 at 1 mM. Compound 1 has been shown to reduce mast cell activation and eliminate mast cells in preclinical models. A single dose of Compound 1 was shown to inhibit SCF-induced histamine release in mice and a single dose of Compound 1 inhibited asthma-like phenotypes in a rodent induced asthma model. Compound 1 reduced activation and degranulation of human derived mast cells in culture and decreased mast cell numbers in an in vivo rodent model. (American Academy Allergy, Asthma, and Immunology (AAAAI) 2024, February 23-26).

[0010] Dexamethasone is a fluorinated glucocorticoid steroid used to treat asthma, allergies, a number of skin diseases, chronic obstructive pulmonary disease (COPD) as well as other rheumatic problems. The structure of dexamethasone is shown as Compound B:(B).3ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT Dexamethasone is also available as a pharmaceutically acceptable salt. In one aspect, the salt is dexamethasone sodium phosphate. Dexamethasone is available in tablet, soluble tablet, liquid, injection, eye drop and spray form.

[0011] In some aspects, the disclosure provides a method of treating allergic asthma in a subject in need thereof comprising administering to the subject a combination therapy which comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of dexamethasone or a pharmaceutically acceptable salt thereof. In some aspects, the disclosure provides a method as described above, wherein each therapeutic agent of the combination therapy is administered simultaneously or separately.BRIEF DESCRIPTION OF THE FIGURES

[0012] Figure 1 is a bar graph which shows airway hyperresponsiveness in units of enhanced pause (Penh) measured 2 hours after challenge with an aerosol formulation of OVA. Treatment is administered 3 hours prior to challenge with an aerosol formulation of OVA or 5 hours before measurement of airway hyperresponsievess.DETAILED DESCRIPTION

[0013] The disclosure relates to the treatment of allergic asthma. In some embodiments, the combination of Compound 1 or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt thereof disclosed here can provide a synergistic effect in treating allergic asthma. In some embodiments, a low dose of Compound 1 or a pharmaceutically acceptable salt thereof and / or a low dose of a corticosteroid or a pharmaceutically acceptable salt thereof disclosed here can be used in the treatment of allegic asthma.

[0014] [ Embodiment 1] A method of treating allergic asthma in a subject in need thereof comprising administering to the subject a combination therapy which comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of corticosteroid or a pharmaceutically acceptable salt thereof.

[0015] [ Embodiment 2] The method of embodiment 1, wherein the corticosteroid is selected from dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone,4ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT beclomethasone, budesonide, ciclesonide, fluticasone, and mometasone, or a pharmaceutically acceptable salt of any one of foregoing.

[0016] [ Embodiment 3] The method of embodiment 1, wherein the corticosteroid is selected from dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, and mometasone furoate.

[0017] [ Embodiment 4] The method of embodiment 1, wherein the corticosteroid is prednisone or a pharmaceutically acceptable salt thereof.

[0018] [ Embodiment 5] The method of embodiment 1, wherein the corticosteroid is prednisolone or a pharmaceutically acceptable salt thereof.

[0019] [ Embodiment 6] The method of embodiment 1, wherein the corticosteroid is methylprednisolone or a pharmaceutically acceptable salt thereof.

[0020] [ Embodiment 7] The method of embodiment 1, wherein the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt thereof.

[0021] [ Embodiment 8] The method of embodiment 1, wherein the corticosteroid is beclomethasone or a pharmaceutically acceptable salt thereof.

[0022] [ Embodiment 9] The method of embodiment 8, wherein the corticosteroid is beclomethasone dipropionate.

[0023] [ Embodiment 10] The method of embodiment 1, wherein the corticosteroid is budesonide or a pharmaceutically acceptable salt thereof.

[0024] [ Embodiment 11] The method of embodiment 1, wherein the corticosteroid is ciclesonide or a pharmaceutically acceptable salt thereof.

[0025] [ Embodiment 12] The method of embodiment 1, wherein the corticosteroid is fluticasone or a pharmaceutically acceptable salt thereof.

[0026] [ Embodiment 13] The method of embodiment 12, wherein the corticosteroid is fluticasone furoate.

[0027] [ Embodiment 14] The method of embodiment 12, wherein the corticosteroid is fluticasone propionate.

[0028] [ Embodiment 12] The method of embodiment 1, wherein the corticosteroid is mometasone or a pharmaceutically acceptable salt thereof.5ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT

[0029] [ Embodiment 13] The method of embodiment 12, wherein the corticosteroid is mometasone furoate.

[0030] [Embodiment 14] A method of treating allergic asthma in a subject in need thereof comprising administering to the subject a combination therapy which comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of dexamethasone or a pharmaceutically acceptable salt thereof.

[0031] [Embodiment 15] The method of embodiment 1, wherein each therapeutic agent of the combination therapy is administered simultaneously or separately.Definitions:

[0032] Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art.

[0033] The term “allergic asthma” (sometimes also known as allergy-induced asthma) is asthma caused by an allergic reaction to an allergen. Common allergies are pollen, dust mites, animal fur or feathers.

[0034] As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit / risk ratio.

[0035] Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0036] “Therapeutic agent” is a compound or pharmaceutically acceptable salt thereof useful in the treatment allergic asthma. In one aspect, the therapeutic agents are Compound 1 and6ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT dexamethasone or pharmaceutically acceptable salts thereof. In another aspect, the therapeutic agents are Compound 1 and a corticosteroid. Examplary corticosteroids include, but are not limited, to dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone, budesonide, ciclesonide, fluticasone, and mometasone, or a pharmaceutically acceptable salt of any one of foregoing. In one aspect, the corticosteroid is dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate.

[0037] “Therapy” as used herein, refers to a therapeutic agent, as defined above.“Combination therapy” as used herein, refers to a combination of two therapeutic agents for the treatment of allergic asthma. When a therapy has more than one therapeutic agent, the therapeutic agents can be part of the same or different routes of administration and on the same of different administration schedules.

[0038] ‘Patient” or “subject” refers to any living organism suffering from or prone to a condition that can be prevented or treated by administration of a therapeutic agent or composition or combination as provided herein. In one aspect, the patient is a human.

[0039] As used herein, “administering” refers to the delivery of a therapeutic agent to a subject using any of the various methods and delivery systems known to those skilled in the art. In one aspect, the route of administration for Compound 1 may include oral. Routes of administration for dexamethasone may include oral, intravenous, intramuscular, aerol, ophthalmic, and otic. Routes of administration for prednisone, prednisolone, methylprednisolone, and hydrocortisone may include oral, intravenous, and intramuscular. Beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate may be administered through the use of an inhaler. In some aspects, a therapeutic agent is administered to a subject in need thereof. In some aspects, a therapeutic agent is administered as a pharmaceutical formulation, wherein the therapeutic agent is combined with one or more pharmaceutically acceptable excipients or carriers. Thus, in some aspects, disclosed herein are compositions comprising at least a therapeutic agent optionally further comprising at least one pharmaceutically acceptable excipient or carrier.

[0040] The therapeutic agent thereof may be formulated for administration in any convenient way for use in human or veterinary medicine.

[0041] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals7ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0042] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa buter and suppository waxes; (9) oils, such as peanut oil, cotonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0043] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0044] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) weting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0045] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol,8ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cotonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and faty acid esters of sorbitan, and mixtures thereof.

[0046] Suspensions, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0047] Powders and sprays can contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0048] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of compound or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0049] Dosage forms for the topical or transdermal administration of a compound of this disclosure or pharmaceutically acceptable salts thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0050] When the compounds or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0051] The formulations can be administered orally, transdermally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

[0052] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective 9ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0053] The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of allergic asthma in the subject as compared to a control. An effective amount of Compound 1 as a monotherapy can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day). The effective amount of dexamethasone as a monotherapy for adults may vary from doses of 0.75 to 9 mg once daily. In another aspect, the effective amount of dexamethasone is 0.3 to 0.6 mg / kg daily once daily for 1 to 5 days. In another aspect, the effective amount of dexamethasone is 0.5 mg to 16 mg, 0.5 mg to 10 mg once daily. In pediatric patients, the effective amount of dexamethasone may vary with a range of initial doses that is 0.02 to 0.3 mg / kg / day in three or four divided doses (0.6 to 9 mg / m2bsa / day).

[0054] In one aspect, the patient may receive a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as a monotherapy, e.g., smaller doses, less frequent doses, and / or shorter treatment duration. In one aspect, when Compound 1 is administered as a therapeutic agent in a combination therapy, the effective amount of Compound 1 is a dose that is less than the effective amount administered for a monotherapy. Said another way the effective amount of Compound 1 that is administered in a combination therapy is an effective amount that is sub-efficacious when administered as a monotherapy.

[0055] In one aspect, the effective amount of the combination therapy comprises an amount of Compound 1 that is an amount that is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% less than the effective amount administered for monotherapy and an amount of corticosteroid (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate) that is the effective amount administered for a monotherapy. In one aspect, the effective amount of the combination therapy comprises an amount of Compound 1 that is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% less than the effective amount administered for monotherapy and an amount of corticosteroid (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate) that is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% less than the effective amount administered for monotherapy.10ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT

[0056] In one aspect, the effective amount of the combination therapy comprises 4-5 mg once daily of Compound 1 and an amount of corticosteroid (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate) that is the effective amount administered for a monotherapy. In one aspect, the effective amount of the combination therapy comprises 4-5 mg of Compound 1 and an amount of corticosteroid (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, or mometasone furoate) that is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% less than the effective amount administered for monotherapy.

[0057] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, faty acid esters, hydroxymethy cellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, weting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.Example 1 - Inhibition of OVA-induced airway hyperresponsiveness in rodents as measured by penh with a single dose

[0058] Brown Norway rats (male, 140-180 g) were acclimatized for 1 week prior to the experiment. Animals were housed in enriched and ventilated housing cages throughout the experimental phase. Animals’ cages’ liters were changed at least once a week. Animals were housed in groups of 5 - 6 animals on a normal 12 hour light cycle (at 08:00 pm lights off), 22 ± 2 °C and 50 ± 10 % relative humidity. Chow and water were available ad libitum.

[0059] After animal acclimation, on Day 0, 1 mb of 2 mg / mL of ovalbumin (OVA) in sterile PBS was mixed with 1 mb of 10 mg / mL Alum Adjuvant in sterile PBS. The solution was 11ME1\6O112230. vlAty. Dkt. No.: 134108-863202025-8063PCT shaken for 20 minutes at room temperature and then 1 mL was injected i.p. into each rat. On Day 7, the mixing of OVA and Alum Adjuvant was repeated and the rats were again i.p. injected with 1 mL per rat. Rats in the control group were injected i.p. with PBS only on Day 0 and Day 7.

[0060] On Day 14, rats were dosed orally with Compound 1 and / or dexamethasone at specified concentrations.

[0061] The vehicle for Compound 1 was prepared as follows: Vitamin E TPGS (semi solid at room temperature) was heated between 40°C and 50°C until fully molten / in liquid form, approximately 15 minutes. Next, 425.0 mL of PEG 400, 25.0 mL of Ethanol, and 50.0 mL of molten Vitamin E TPGS were combined within a 500 mL container, which was then vortexed for 2 minutes. The solution was then heated to between 40°C and 50°C for 15 minutes and stored at room temperature for 1-2 hours. For storage at 4°C, the solution was reheated to 40°C for 5-10 minutes until the solution became clear.

[0062] For oral administration, Compound 1 powder was combined with the prepared vehicle to achieve a specified concentration. The Compound 1 containing solution was sonicated for 15-20 minutes and then vortexed fully. Before dosing, the Compound 1 containing solution was heated to 40 °C until the solution became completely homogenous. Oral dosing was performed at 10 mL / kg.

[0063] Dexamethasone was prepared at specified concentrations for oral administration in saline and stored at 4°C in the dark.

[0064] Three hours post-dosing with Compound 1 and / or dexamethasone, rats were challenged with 2% -6% OVA (w / v) aerosol. The aerosol was prepared using an ultrasonic nebulizer for 30 minutes on fresh solutions containing either 20 mg / mL or 60 mg / mL of OVA in sterile PBS. Rats in the control group were challenged with PBS aerosol only.

[0065] Two hours-post OVA aerosol challenge, Penh levels were measured using an appropriate unrestrained, whole body plethysmography chamber and FinePointe software.

[0066] On Day 15, rats were again orally dosed with Compound 1 and / or dexamethasone as described above. Two hours post-dosing with Compound 1 and / or dexamethasone, rats are euthanized by CO2 and secondary measurements are conducted- Pharmacokinetics from plasma, analysis by flow cytometry of immune cell infiltration into the bronchial alveolar lavage fluid (BALF), airway immunohistochemistry, etc.12ME1\6O112230. vl

Claims

Atty. Dkt. No.: 134108-863202025-8063PCT CLAIMSWhat is claimed is:

1. A method of treating allergic asthma in a subject in need thereof comprising administering to the subject a combination therapy which comprises an effective amount of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide or a pharmaceutically acceptable salt thereof and an effective amount of dexamethasone or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein each therapeutic agent of the combination therapy is administered simultaneously or separately.ME1\6O112230. vl

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