Composition for co-administration of HIF-2Ɑ inhibitor and steroid, and method for preventing, alleviating, or treating asthma using same

Abstract

The present invention relates to a composition for co-administering Belzutifan, which is an HIF-2ɑ activity inhibitor having a steroid-resistant allergic airway inflammation reduction effect, and a steroid. The composition according to the present invention has the effect of alleviating inflammation and symptoms by co-administering an HIF-2ɑ inhibitor during the treatment of severe allergic asthma patients exhibiting steroid resistance. Thus, co-administering Belzutifan, which is an HIF-2ɑ inhibitor, and a steroid is a more effective treatment that can alleviate asthma and increase the quality of life of severe asthma patients.

Description

Composition for combined administration of HIF-2α inhibitor and steroid and method for preventing, improving or treating asthma using the same

[0001] The present invention relates to a composition for combined administration of Belzutifan, an HIF-2α inhibitor having a steroid-resistant allergic airway inflammation-reducing effect, and a steroid.

[0002]

[0003] The number of asthma sufferers, a type of allergic inflammatory disease, is estimated to reach 100 million worldwide, and the global market for atopic dermatitis treatment is known to be worth 2 trillion won. In Korea, the prevalence of asthma among elementary school students reached 10% in 2012 (Statistics Korea, 2012), and the prevalence of atopic dermatitis among children in Korea reached 20.6% in 2010 (Korea Centers for Disease Control and Prevention, 2012).

[0004] Currently, asthma treatments available include bronchodilators, inhaled steroids, and anti-inflammatory drugs. Steroid preparations are widely used to treat atopic dermatitis. However, these treatments only provide temporary symptom relief and cannot fundamentally control allergic diseases, failing to cure the underlying cause. Furthermore, they carry serious side effects.

[0005] Meanwhile, allergic inflammatory diseases such as asthma and atopy are known as immune diseases, and Th2 cells are thought to play a central role in causing allergic reactions. Th2 cells are produced by the differentiation of CD4 cells, and can differentiate into various types of Th cells depending on the type of cytokine that CD4 T cells recognize when stimulated by an antigen in lymphocytes. That is, when the cytokine recognized by CD4 T cells is IL-12, CD4 cells differentiate into Th1 cells, and when the cytokine recognized by CD4 T cells is a type 2 cytokine such as thymic stromal lymphoprotein (TSLP) or IL-4, CD4 cells differentiate into Th2 cells, causing allergic reactions. In addition, depending on the type of various cytokines recognized by CD4 T cells, other additional Th cells are produced.

[0006] These various cytokines include TSLP, IL-25, and IL-33, among which TSLP is expected to play the most effective role. For example, in animal models, it has been shown that suppressing TSLP secretion hinders the generation and activation of Th2 cells, preventing the animals from developing disease. Furthermore, it has also been reported that suppressing TSLP in animals with progressing disease can cure the disease. In summary, TSLP is a key cytokine that plays a role in both the differentiation and activation of Th2 cells, and its control is recognized as important for the treatment of allergic diseases.

[0007] Accordingly, various technologies for treating diseases targeting TSLP have been reported in the past, for example, antibodies that neutralize the activity of human TSLP and technologies for treating asthma, atopic dermatitis, allergic rhinitis, etc. using the same, antibodies specific to TSLP and technologies for treating inflammation and allergic inflammatory diseases using the same, etc. have been disclosed.

[0008] Meanwhile, 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (hereinafter referred to as Belzutifan or MK-6482), a novel HIF-2α inhibitor with excellent in vitro potency, pharmacokinetic profile, and in vivo efficacy in mouse models, has shown encouraging results in patients with advanced renal cell carcinoma (Xu, Rui, et al., J. Med. Chem. 62:6876-6893 (2019).

[0009]

[0010] In a recent report, belzutipan demonstrated a favorable safety profile and promising antitumor activity in heavily pretreated ccRCC patients (Choueiri, TK et al. Nat Med 27, 802-805 (2021)). In the dose-escalation cohort of the reported study, no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached. The recommended dose for phase 2 was 120 mg once daily. The most common adverse events were anemia and hypoxia.

[0011] Accordingly, methods for treating cancer or von Hippel-Lindau (VHL) disease in patients requiring treatment using belzutipan have been known, and specifically, patents related to belzutipan have been known for use in the prevention or treatment of cancer or von Hippel-Lindau disease (KR Patent Publication No. 2023-0026492). However, the asthma-related activity of belzutipan has not been reported.

[0012] Accordingly, the inventors of the present invention conducted research to treat patients with severe allergic asthma who are resistant to steroids, and confirmed that when Belzutifan, an HIF-2a inhibitor, was used in combination with steroids, the eosinophilic airway inflammatory response that is resistant to steroids was reduced, thereby confirming that the combination was effective in treating patients with severe allergic asthma who are resistant to steroids, thereby completing the present invention.

[0013]

[0014] The present invention is the result of the support of the following research project.

[0015] [National Research and Development Project Supporting This Invention]

[0016] [Project ID]1345362117

[0017] [Assignment Number] 2019R1A6A1A03031807

[0018] [Ministry Name] Ministry of Education

[0019] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0020] [Research Project Name] Establishment of a Research Base for Science and Engineering

[0021] [Research Project Name] Pharmaceutical Science Research Institute

[0022] [Name of the project performing organization] Korea University Sejong Industry-Academic Cooperation Foundation

[0023] [Research Period] June 1, 2019 - February 29, 2028

[0024] [National Research and Development Project Supporting This Invention]

[0025] [Project ID]1711129073

[0026] [Assignment Number] 2021R1A2C2004279

[0027] [Ministry Name] Ministry of Science and ICT

[0028] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0029] [Research Project Name] Individual Basic Research (Ministry of Science and ICT) (R&D)

[0030] [Research Project Name] Study of cancer-specific viral transport and the anticancer mechanisms of memory T cells that recognize these viruses.

[0031] [Name of the project performing organization] Korea University Sejong Industry-Academic Cooperation Foundation

[0032] [Research Period] March 1, 2021 - February 28, 2026

[0033]

[0034] The technical problem to be achieved by the present invention is to provide a composition for preventing or treating steroid-resistant asthma, which can increase the therapeutic effect by co-administering Belzutifan, an HIF-2α inhibitor, in the treatment of patients with severe allergic asthma that exhibits steroid resistance.

[0035]

[0036] In order to achieve the above technical problem, the technical problem to be achieved by the present invention is to provide a pharmaceutical composition for combination administration for preventing or treating asthma, comprising as active ingredients a HIF-2α inhibitor or a pharmaceutically acceptable salt thereof and a steroid (Dexamethasone) or a pharmaceutically acceptable salt thereof.

[0037] In the present invention, the composition may be characterized by reducing allergic airway inflammation.

[0038] Another embodiment of the present invention provides a method for preventing or treating asthma, comprising administering to a human patient in need thereof (a) a HIF-2α inhibitor; and (b) a steroid or a pharmaceutically acceptable salt thereof.

[0039]

[0040] The composition according to the present invention has the effect of alleviating inflammation and symptoms by co-administering a HIF-2α inhibitor in the treatment of patients with severe allergic asthma who exhibit steroid resistance. Therefore, co-administration of Belzutifan, a HIF-2α inhibitor, and a steroid is a more effective treatment method that can alleviate asthma disease and increase the quality of life of patients with severe asthma.

[0041]

[0042] Figure 1 is a diagram of an experiment to confirm the role of HIF-2α in steroid-resistant inflammatory response.

[0043] Figure 2 confirms the reduction of steroid-resistant inflammatory response through HIF-2α removal.

[0044] Figure 3 is a diagram of an experiment to reduce steroid-resistant severe allergic inflammation by intraperitoneal administration of belzutiphan, an inhibitor of HIF-2α.

[0045] Figure 4 shows that steroid-resistant severe allergic inflammation is reduced by intraperitoneal administration of belzutiphan, an HIF-2α inhibitor.

[0046]

[0047] Hereinafter, the present invention will be described in more detail. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

[0048] The terminology used in this specification is solely for the purpose of describing specific embodiments and is not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In the present specification, the term "comprising" or "including" a component does not exclude other components, but rather implies the inclusion of other components, unless otherwise specifically stated.

[0049] In the present invention, the term "prevention" may include, without limitation, any action that can block symptoms related to asthma disease or inhibit or delay progression using the composition of the present invention, and the term "treatment" refers to a series of activities performed to alleviate and improve the desired disease.

[0050] The “pharmaceutical composition” of the present invention may include a pharmaceutically acceptable carrier or diluent, and may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. In addition, it includes diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., and may include lubricants such as magnesium stearate, talc, etc. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, etc. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.

[0051] The pharmaceutical composition of the present invention can be administered to mammals such as livestock and humans by various routes, for example, orally, transdermally, subcutaneously, intramuscularly, intravenously, intraperitoneally, intrarectally, intrauterinely, intrathecally or intracerebrovascularly, intranasally, or topically. Accordingly, the composition of the present invention can be formulated in various forms, such as tablets, capsules, aqueous solutions, or suspensions. In the case of oral tablets, carriers such as lactose and corn starch and lubricants such as magnesium stearate can typically be added. In the case of oral capsules, lactose and / or dried corn starch can be used as diluents. If an oral aqueous suspension is required, the active ingredient can be combined with an emulsifier and / or suspending agent. If desired, specific sweeteners and / or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is typically prepared, with the pH of the solution appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute should be adjusted to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline with a pH of 7.4. The solution may be introduced into the patient's intramuscular bloodstream by local injection.

[0052] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route and period of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient may be administered at a dosage of 0.0001 to 300 mg / kg per day, preferably 50 to 300 mg / kg, and the administration may be administered once or twice a day. In addition, the pharmaceutical composition of the present invention may contain the active ingredient in a weight percentage of 0.001 to 90% based on the total weight of the composition.

[0053] The above “health functional food” refers to a food manufactured and processed using raw materials or ingredients with functionality useful to the human body according to the Health Functional Food Act, and “functionality” refers to consumption for the purpose of obtaining a useful effect for health purposes such as regulating nutrients for the structure and function of the human body or physiological action.

[0054] The health functional food of the present invention may contain conventional food additives, and its suitability as the "food additive" is determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified. Items listed in the "Food Additives Codex" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum; mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0055] The health functional food of the present invention, for the purpose of preventing or improving asthma, may contain the compound in a weight percentage of 0.01 to 95%, preferably 1 to 80%, based on the total weight of the composition. In addition, the health functional food of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc., for the purpose of preventing or improving asthma.

[0056] Hereinafter, the present invention will be described in detail by way of examples. However, the following examples specifically illustrate the present invention, and the content of the present invention is not limited by the following examples.

[0057]

[0058] Example 1. Experimental materials and preparation

[0059] 1. Laboratory mice

[0060] For all experiments, 5-week-old female wild-type BALB / c mice were purchased from OrientBio (Korea). BALB / c mice (DO11.10) transfected with the OVA-specific TCR gene were provided by the Korea Advanced Institute of Science and Technology (KAIST, Korea). All mice were raised and bred under specific pathogen-free conditions in the animal facility of the College of Pharmacy, Korea University. All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of Korea University.

[0061]

[0062] 2. Adoptive transfer of OVA-specific CD4 T cells

[0063] To generate naive (naive, never experienced with specific antigen) DO11.10 chimeric mice, 1.0 x 10 splenic CD4+KJ1-26+ cells were isolated from naive DO11.10 mice. 6 The dogs were intravenously injected into wild-type BALB / c mice. To obtain in vitroTh2 DO11.10 chimeric mice, 1.5 x 10 in vitro Th2-induced DO11.10 cells 6 The dogs were adoptively transferred into wild-type BALB / c mice.

[0064]

[0065] 3. In vitro Th2 differentiation

[0066] OVA-specific naive CD4 T cells were isolated from the spleen of naive DO11.10 mice and cultured in RPMI 1640 medium (Hyclone, USA) supplemented with 10% fetal bovine serum (Hyclone, USA), 2 mM L-glutamine (Hyclone, USA), 50 μM β-mercaptoethanol, and penicillin / streptomycin solution (100 U / ml penicillin, 100 μg / ml streptomycin, Hyclone, USA) at 37°C and 5% CO2. To differentiate into Th2 cells, these cells (5 × 10 6cells / ml) were cultured for 3 days in the presence of 0.3 μM OVA peptide 323-339 (ISQAVHAAHAEINEAGR) (Sigma Aldrich, USA), 100 U / ml recombinant human IL-2 (PeproTech, USA), 40 ng / ml recombinant mouse IL-4 (PeproTech, USA), and 5 μg / ml anti-IFN-γ monoclonal antibody (BioLegend, USA). Then, these cells were seeded at 1 × 10 per well in a 24-well plate. 6 The cells were divided into individual cells and cultured in T cell culture medium containing 100 U / ml recombinant human IL-2 for an additional 4 days at 37°C and 5% CO2.

[0067]

[0068] 4. Genome editing using Cas9 / sgRNA RNP complex

[0069] To downregulate Epas1 expression in Th2 cells in vitro, Epas1-targeting sgRNA (5'-ACUGAUUGGUUACCACCCCGGUUUUAGAGCUAUGCU-3'), negative control sgRNA, Alt-R™ tracrRNA-5' ATTO™550, and Alt-R™ Sp Cas9 nuclease V3 were purchased from Integrated DNA Technologies (IDT, USA). 150 pmol of the synthesized sgRNA and Alt-R™ tracrRNA-5' ATTO™550 were incubated at 95°C for 5 min and then cooled to room temperature for at least 1 h to form a duplex. The preformed RNA duplex and 45 pmol of Cas9 nuclease V3 were further incubated at 37°C for 10 min to form a Cas9 / sgRNA RNP complex. To deliver this complex to Th2 cells in vitro, 6 × 10 6Cells were harvested on the third day. The harvested cells were resuspended in 20 μl of P4 Primary Cell 4D-Nucleofector™X Kit (Lonza, Switzerland), mixed with the Cas9 / sgRNA RNP complex, transferred to a Nucleocuvette™ strip, and electroporated using the Lonza 4D-Nucleofector system (CM137). To enhance the transfer efficiency of the complex to the cells, they were rested at room temperature for 30 min, suspended in T cell culture medium containing 100 U / ml recombinant human IL-2, and seeded at 1 x 10 per well in a 24-well culture plate. 6 Cells were transferred. Cells were cultured for an additional 4 days at 37°C and 5% CO2. Translocation efficiency was measured by ATTO™550 fluorescence corresponding to the PE channel using a flow cytometer at 2 and 4 days after electroporation.

[0070]

[0071] 5. Induction of lung allergic inflammation and mixtures

[0072] Mice were anesthetized with isoflurane and then intranasally treated with a mixture that induces lung inflammation. OVA (Sigma Aldrich, USA) was resuspended in PBS (Hyclone, USA), filtered, and stored at -80°C. HDM extract (GREER®USA) containing Dermatophagoides farinae (Der.f) and Dermatophagoides pteronyssinus (Der.p) was resuspended in distilled water and stored at -20°C. Recombinant human IL-33 was provided by the laboratory of Professor Young-Ho Jeon of Korea University and stored at -80°C. To induce HDM-induced allergic lung inflammation, mice were intranasally treated with 40 μl of a mixture of 100 μg OVA, 50 μg Der.f, and 50 μg Der.p. To induce IL-33-induced allergic lung inflammation, a 40 μl mixture was prepared using 25 μg OVA and 100 ng rhIL-33. To induce IL-33-induced eosinophilic pneumonia, 100 ng rhIL-33 was used, and all mixtures were prepared in PBS.

[0073]

[0074] 6. Treatment with steroids (dexamethasone) or HIF-2α antagonists

[0075] Dexamethasone (Sigma, USA) was stored in 100% DMSO (BioShop, Canada) and was stored at -20°C. Belzutifan (MedChemExpress, USA), an HIF-2α antagonist, is an FDA-approved HIF-2α inhibitor, stored in 100% DMSO and stored at -20°C. Each compound was dissolved in phosphate-buffered saline (PBS) and injected intraperitoneally at a dose of 1 mg / kg.

[0076]

[0077] 7. Tissue processing to isolate leukocytes from mouse airways

[0078] To obtain leukocytes from the airway, a 22-gauge venous catheter was inserted into the exposed trachea and washed four times with 0.8 ml of PBS containing 0.5% FBS.

[0079]

[0080] 8. Evaluation of allergic airway inflammation

[0081] Bronchoalveolar lavage fluid (BALF) from mice was cultured at 5 x 10 in RPMI medium. 5 After diluting to 10 cells / ml, 200 μl of the suspension was loaded onto a cytospin clip, and the suspension was attached to a slide glass using a cytospin. The air-dried slides were stained with Diff-quik staining solution (Sysmex, Japan), and eosinophils in the stained slides were counted and analyzed under a microscope.

[0082]

[0083] 9. Statistical Analysis

[0084] Student's t-test was used for statistical analysis of cell frequency and count. All error bars in the bar graphs represent the mean ± SEM. A P value < 0.05 indicated a statistically significant difference in all experiments. (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ***, P < 0.0001; ns, not significant.)

[0085]

[0086] Example 2. Experimental Results

[0087] 1. Confirmation of a reduction in eosinophilic airway inflammation response exhibiting steroid resistance by knocking out (KO) Epas1 (HIF-2α encoding gene) in type 2 helper T cells.

[0088] The present inventors investigated whether Epas1 is involved in the development of steroid-resistant lung inflammation in allergen-specific Th2 cells. Therefore, the gene encoding HIF-2α (Epas1) was deleted in allergen-specific Th2 cells in vitro by electroporation of a Cas9 / Epas1-targeted RNP complex. The Epas1-deleted in vitro Th2 cells prepared as described above were injected into wild-type naive Balb / c mice. The following day, allergen and IL-33 were administered intranasally to the mice, followed by steroid injection (see Figure 1). Subsequently, the airway inflammatory response of the mice was examined, and it was confirmed that the number of eosinophils was significantly reduced in mice transplanted with Epas1-deleted in vitro Th2 cells, unlike mice transplanted with in vitro Th2 cells without Epas1 deletion (see Figure 2).

[0089] Through the above results, the inventors of the present invention confirmed that HIF-2α (especially in type 2 helper T cells) is important in inducing steroid-resistant inflammatory responses.

[0090]

[0091] 2. Confirmation of conversion of steroid-resistant inflammatory response to steroid-sensitive inflammatory response through administration of Belzutifan.

[0092] The present inventors investigated whether steroid-resistant severe allergic inflammatory responses could be modulated by steroids through inhibition of HIF-2α function. Belzutifan, an FDA-approved HIF-2α antagonist, was administered intraperitoneally to mice generating allergen-specific memory CD4 T cells, and allergens and IL-33 were administered intranasally and steroids were administered intraperitoneally (see Figure 3). Airway inflammatory responses in the mice were then examined, and it was confirmed that allergic airway inflammation was sensitively reduced in the belzutifan-treated group by steroids (see Figure 4).

[0093]

[0094] As discussed above, the inventors of the present invention have confirmed that co-administration of a HIF-2α inhibitor in the treatment of patients with severe allergic asthma who are resistant to steroids alleviates inflammation and symptoms. Therefore, the combination of the HIF-2α inhibitor belzutifan and steroids is expected to be a more effective treatment, alleviating asthma symptoms and improving the quality of life of patients with severe asthma.

[0095]

[0096] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0097] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

[0098]

[0099] The present invention relates to a composition for combination administration comprising Belzutifan, a HIF-2α inhibitor, and a steroid, and a method for preventing, improving, or treating asthma using the same. The composition presented in the present invention has been confirmed to have the effect of significantly reducing eosinophilic airway inflammatory response when administered in combination with a steroid in patients with severe allergic asthma who are difficult to treat with steroid monotherapy. Specifically, the composition according to the present invention can increase the therapeutic efficacy of patients who exhibit steroid resistance, thereby overcoming the limitations of existing asthma therapeutics and increasing the therapeutic efficiency, thereby significantly improving the quality of life of patients. In addition, the composition of the present invention can be easily manufactured into various pharmaceutical formulations, and thus has a high possibility of being applied in actual medical settings, and can be utilized as a new treatment strategy in the field of asthma therapeutics.

[0100] Therefore, the composition for combined administration of a HIF-2α inhibitor and a steroid according to one embodiment of the present invention can be considered to have industrial applicability.

Claims

1. A pharmaceutical composition for combination administration for preventing or treating asthma, comprising an HIF-2α inhibitor or a pharmaceutically acceptable salt thereof and a steroid (Dexamethasone) or a pharmaceutically acceptable salt thereof as active ingredients.

2. In paragraph 1, A pharmaceutical composition for combination administration for preventing or treating asthma, characterized in that the HIF-2α inhibitor is Belzutifan or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, A pharmaceutical composition for combination administration for preventing or treating asthma, characterized in that the pharmaceutical composition for combination administration is in the form of a mixture in which a HIF-2α inhibitor or a pharmaceutically acceptable salt thereof and a steroid or a pharmaceutically acceptable salt thereof are mixed.

4. In paragraph 1, A pharmaceutical composition for combination administration for the prevention or treatment of asthma, characterized in that the pharmaceutical composition for combination administration is in a form in which a HIF-2α inhibitor or a pharmaceutically acceptable salt thereof and a steroid or a pharmaceutically acceptable salt thereof are each formulated and administered simultaneously or sequentially.

5. In paragraph 1, A pharmaceutical composition for combination administration for preventing or treating asthma, characterized in that the asthma is at least one selected from the group consisting of allergic asthma and steroid-resistant asthma.

6. In paragraph 1, The above pharmaceutical composition is a pharmaceutical composition for combination administration for preventing or treating asthma, characterized in that it reduces allergic airway inflammation.

7. In paragraph 1, A pharmaceutical composition for combination administration for preventing or treating asthma, characterized in that the HIF-2α inhibitor and the steroid are included in a ratio of 1:1 to 1.

5.

8. A method for preventing or treating asthma, comprising administering to a subject other than a human in need of treatment for asthma a HIF-2α inhibitor; and a steroid or a pharmaceutically acceptable salt thereof.

9. In paragraph 8, A method for preventing or treating asthma, characterized in that the HIF-2α inhibitor is Belzutifan or a pharmaceutically acceptable salt thereof.

10. In paragraph 8, A method for preventing or treating asthma, characterized in that the asthma is at least one selected from the group consisting of allergic asthma and steroid-resistant asthma.

11. In paragraph 8, The above method is a method for preventing or treating asthma, which converts the steroid resistance of a subject into steroid sensitivity. 12.a) Step of treating the candidate drug with HIF-2α protein; b) a step of measuring the amount or biological activity of the HIF-2α protein; and c) a step of determining that the candidate drug is a drug for preventing or treating asthma when the amount or biological activity of the HIF-2α protein is measured to be reduced; A method for screening a pharmaceutical composition for preventing or treating asthma comprising:

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