Methods for treating or preventing asthma by administering IL-4R antagonists

Abstract

To provide methods for treating or preventing asthma and associated conditions in a patient.SOLUTION: The present invention provides methods that comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 61 / 943,019, filed Feb. 21, 2014, and U.S. Provisional Patent Application No. 62 / 077,669, filed Nov. 10, 2014. The contents of the foregoing applications are hereby incorporated by reference in their entirety for all purposes.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety. The ASCII copy created on Feb. 20, 2015 is named 565201 - SA9 - 134PC_SL.txt and is 4,279 bytes in size.

[0003] The present invention relates to the treatment and / or prevention of asthma and related conditions. More specifically, the present invention relates to the administration of an interleukin - 4 receptor (IL - 4R) antagonist for treating or preventing asthma in a patient who needs it.

Background Art

[0004] Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugs. The inflammatory components of asthma are thought to include many cell types, such as mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells, as well as their biological products. Asthma patients most often present with symptoms of wheezing, shortness of breath, cough, and chest tightness. For most asthma patients, long-term control medications and bronchodilator treatment regimens provide appropriate long-term control. Inhaled corticosteroids (ICS) are considered the "pyramid presence" in managing asthma symptoms, and inhaled β2 agonists are the most effective bronchodilators currently available. Studies have proven that combination therapy with ICS and inhaled long-acting β2 agonists (LABA) provides better asthma management than high-dose ICS alone. As a result, combination therapy has become the recommended treatment for patients not managed with low-dose ICS alone.

[0005] However, despite the maximum recommended treatment with a combination of anti-inflammatory and bronchodilator medications, 5% to 10% of the asthma population is estimated to have a symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of the total medical costs due to hospitalizations, use of emergency services, and unscheduled doctor visits. Many of these patients are poorly responsive to ICS due to multiple cell and molecular mechanisms, so the need for new treatment methods in this severe asthma population has not yet been addressed. In addition, attempts are made to minimize corticosteroid use due to the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and child growth. Most asthma patients are treated fairly well with current treatment agents, but there are few treatment options for corticosteroid-resistant severe asthma patients to appropriately manage the disease. The consequence of non-response or lack of treatment compliance to treatment is loss of asthma control and ultimately asthma exacerbation.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, there is a need in the art for novel targeted therapies for the treatment and / or prevention of asthma. [Means for solving the problem]

[0007] According to one embodiment, a method for treating asthma in a person requiring such treatment is provided.

[0008] In another embodiment, a method is provided for increasing the amount of energy per second (FEV1) in liters for an object that requires it.

[0009] In another embodiment, the present invention provides a method for reducing asthma-related exacerbations in individuals who require it.

[0010] In yet another embodiment, the present invention provides a method for improving one or more asthma-related parameters in a subject that requires it.

[0011] In a further embodiment, a method is provided for reducing or eliminating an asthma patient's dependence on inhaled corticosteroids and / or long-acting β-agonists for the treatment of one or more asthma exacerbations.

[0012] The method of interest in the present invention involves administering a therapeutically effective amount of a pharmaceutical composition containing an interleukin-4 receptor IL-4R antagonist to a target. According to certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. Exemplary anti-IL-4R antibodies that can be used in connection with the method of interest in the present invention are described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R and comprises heavy chain and light chain (complementarity-determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively.

[0013] The present invention also includes IL-4R antagonists disclosed herein for use in the manufacture of drugs for the treatment and / or prevention of asthma or for the treatment of any of the other indications or conditions disclosed herein.

[0014] The present invention also includes IL-4R antagonists disclosed herein for use in the treatment and / or prevention of asthma, and / or for the treatment and / or prevention of any of the other indications or conditions disclosed herein.

[0015] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring such treatment, comprising administering a combination therapy to the subject, the combination therapy comprising: i) one or more maintenance doses of inhaled corticosteroids (ICS), ii) one or more maintenance doses of long-acting β2-adrenergic agonists (LABAs), iii) a loading dose of approximately 400 to approximately 600 mg of an interleukin-4 receptor IL-4R antagonist, and iv) one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

[0016] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy-chain and light-chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three heavy-chain complementarity-determining region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three light-chain complementarity-determining (LCDR) sequences including SEQ ID NOs. 6, 7, and 8, respectively. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In a yet further specific embodiment, the antibody is dupilumab. In a yet further specific embodiment, the antibody is C It has AS number 1190264-60-8.

[0017] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0018] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0019] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0020] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0021] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0022] In certain embodiments, antibodies or their antigen-binding fragments are administered systemically, intradermally, intravenously, or intranasally to a subject.

[0023] In a particular embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0024] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In further embodiments, the ICS is mometasone furoate and the LABA is formoterol. In yet another embodiment, the ICS is budesonide and the LABA is formoterol. In yet yet another embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0025] In certain embodiments, subjects are selected from groups consisting of subjects aged 18 and over, subjects aged 12 to under 18, subjects aged 6 to under 12, and subjects aged 2 to under 6. It can be done.

[0026] In certain aspects, the subjects are those who meet the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatment using a stable ICS / LABA dose of moderate or high dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the administration of a loading dose of an IL-4R antagonist; ii) Forced expiratory volume (FEV1) 40-80% predicted normal value prior to the administration of a loading dose of an IL-4R antagonist; iii) IL-4R antagonist loading dose Prior to administration, Juniper Asthma Management Questionnaire, 5-question version (ACQ-5) score of 1.5 or higher; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) Within one year prior to administration of a loading dose of IL-4R antagonist, the following events occurred: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency medical visit for asthma exacerbation. Have you ever experienced any of the following? Having moderate to severe uncontrolled asthma for 12 months or more, based on one or more of the following criteria.

[0027] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 150 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0028] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 175 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 50 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0029] In a particular embodiment, the antibody or its antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.

[0030] One embodiment is a method for increasing the forced expiratory volume in one liter (FEV1) of a subject in need thereof, comprising administering a combination therapy to the subject, the combination therapy comprising: i) one or more maintenance doses of ICS, ii) one or more maintenance doses of LABA, iii) a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

[0031] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In even more specific embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In even more specific embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining (LCDR) sequences including SEQ ID NOs. 6, 7, and 8, respectively. In even more specific embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In even more specific embodiments, the antibody is dupilumab That is the case.

[0032] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0033] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0034] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0035] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0036] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0037] In certain embodiments, antibodies or their antigen-binding fragments are administered systemically, intradermally, intravenously, or intranasally to a subject.

[0038] In a particular embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0039] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In further embodiments, the ICS is mometasone furoate and the LABA is formoterol. In yet another embodiment, the ICS is budesonide and the LABA is formoterol. In yet another embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0040] In certain embodiments, subjects are selected from groups consisting of subjects aged 18 and over, subjects aged 12 to under 18, subjects aged 6 to under 12, and subjects aged 2 to under 6. It can be done.

[0041] In certain aspects, the subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatment using a stable ICS / LABA dose of moderate or high dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the loading dose administration of an IL-4R antagonist; ii) FEV1 prior to the loading dose administration of an IL-4R antagonist. iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) Having had moderate to severe uncontrolled asthma for 12 months or more, based on one or more of the following events within one year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations, or b) hospitalization or emergency medical visit for asthma exacerbations.

[0042] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 150 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0043] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 175 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 50 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0044] In a particular embodiment, the antibody or its antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.

[0045] One embodiment is a method for improving one or more asthma-related parameters in a subject requiring it, comprising administering to the subject a combination therapy comprising: i) one or more maintenance doses of ICS, ii) one or more maintenance doses of LABA, iii) a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist. The method includes administering ICS and LABA during the continuation of IL-4R antagonist administration.

[0046] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining (LCDR) sequences including SEQ ID NOs. 6, 7, and 8, respectively. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In a yet further specific embodiment, the antibody is dupilumab.

[0047] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0048] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0049] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0050] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0051] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0052] In certain embodiments, antibodies or their antigen-binding fragments are administered systemically, intradermally, intravenously, or intranasally to a subject.

[0053] In a particular embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0054] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In further embodiments, the ICS is mometasone furoate and the LABA is formoterol. In yet another embodiment, the ICS is budesonide and the LABA is formoterol. In yet yet another embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0055] In certain embodiments, subjects are selected from groups consisting of subjects aged 18 years or older, subjects aged 12 to under 18 years, subjects aged 6 to under 12 years, and subjects aged 2 to under 6 years.

[0056] In certain aspects, the subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatment using a stable ICS / LABA dose of moderate or high dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the loading dose administration of an IL-4R antagonist; ii) FEV1 prior to the loading dose administration of an IL-4R antagonist. iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) Having had moderate to severe uncontrolled asthma for 12 months or more, based on one or more of the following events within one year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations, or b) hospitalization or emergency medical visit for asthma exacerbations.

[0057] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 150 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0058] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 175 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 50 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0059] In a particular embodiment, the antibody or its antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.

[0060] In a particular embodiment, one or more asthma-related parameters are: (1) relative percentage change from baseline in forced expiratory volume in one second (FEV1) at week 12; (2) annual rate of asthma loss of control events during the treatment period; (3) annual rate of severe exacerbation events during the treatment period; (4) time to asthma loss of control event during the treatment period; (5) time to severe exacerbation event during the treatment period; (6) time to asthma loss of control event throughout the entire study period; (7) time to severe exacerbation event throughout the entire study period; (8) utilization of medical resources; (9) at week 12: i) morning and evening asthma symptom scores, ii) A (10) Select from groups consisting of: (i) CQ-5 score, (iii) AQLQ score, (iv) morning and evening PEF, (v) number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol per day for symptom relief, (iii) change from baseline in nocturnal awakenings; (10) at weeks 12 and 24: (i) 22-item sinus outcome test (SNOT-22), (ii) hospital anxiety and depression score (HADS), (iii) change from baseline in EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L).

[0061] In certain embodiments, a loss of asthma control (LOAC) event is defined as any of the following: i) six or more additional salbutamol / albuterol or levosalbutamol / levalbuterol rescue medication puffs over two consecutive 24-hour periods compared to baseline; ii) a four-fold or greater increase in corticosteroid dose during a second visit; iii) use of systemic corticosteroids for three or more days; or iv) the need for systemic corticosteroids. This is defined as hospitalization or emergency outpatient visit due to asthma.

[0062] In certain embodiments, a severe exacerbation event is defined as one of the following events: i) use of systemic corticosteroids for three days or more, or ii) hospitalization or emergency room visit due to asthma requiring systemic corticosteroids.

[0063] One embodiment includes a method for reducing the dependence of asthma patients on inhaled corticosteroids (ICS) and / or long-acting β-agonists (LABAs) for the treatment of one or more asthma exacerbations, the method comprising the steps of: (a) selecting patients having moderate to severe asthma that is not controlled with background asthma treatment including ICS, LABA or a combination thereof; and (b) administering to the patients a combination therapy comprising: i) one or more maintenance doses of ICS, ii) one or more maintenance doses of LABA, iii) a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

[0064] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining (LCDR) sequences including SEQ ID NOs. 6, 7, and 8, respectively. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In a yet further specific embodiment, the antibody is dupilumab.

[0065] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0066] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0067] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0068] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects are blood samples selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL. It has an eosinophil count.

[0069] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0070] In certain embodiments, antibodies or their antigen-binding fragments are administered systemically, intradermally, intravenously, or intranasally to a subject.

[0071] In a particular embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0072] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In further embodiments, the ICS is mometasone furoate and the LABA is formoterol. In yet another embodiment, the ICS is budesonide and the LABA is formoterol. In yet yet another embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0073] In certain embodiments, patients are selected from groups consisting of those aged 18 years or older, those aged 12 to under 18 years, those aged 6 to under 12 years, and those aged 2 to under 6 years.

[0074] In certain aspects, the patient meets the following criteria: i) existing treatment with a stable dose of moderate or high-dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the loading dose of an IL-4R antagonist; ii) FEV140-80% predicted normal value prior to the loading dose of an IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher prior to the loading dose of an IL-4R antagonist. iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) Having had moderate to severe uncontrolled asthma for 12 months or more, based on one or more of the following events within one year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations, or b) hospitalization or emergency medical visit for asthma exacerbations.

[0075] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 150 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0076] In a particular embodiment, the antibody or antigen-binding fragment that specifically binds to IL-4R is: i) approximately 175 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v The preparation is administered with a formulation containing (v) sucrose, (v) approximately 50 mM arginine hydrochloride, and (vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the preparation is approximately 8.5 centipoise.

[0077] In a particular embodiment, the antibody or its antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.

[0078] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring it, comprising administering to the subject a combination therapy comprising: i) one or more maintenance doses of ICS, ii) one or more maintenance doses of LABA, iii) a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist. The method involves administering ICS and LABA during the continuation of IL-4R antagonist administration, and the subjects having a blood eosinophil count selected from groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0079] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining (LCDR) sequences including SEQ ID NOs. 6, 7, and 8, respectively. In a further specific embodiment, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In a yet further specific embodiment, the antibody is dupilumab.

[0080] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0081] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0082] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0083] In a particular embodiment, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects are blood samples selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL. It has an eosinophil count.

[0084] In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks. In a further embodiment, one or more maintenance doses are administered for at least 24 weeks. In a still further embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0085] In certain embodiments, antibodies or their antigen-binding fragments are administered systemically, intradermally, intravenously, or intranasally to a subject.

[0086] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In further embodiments, the ICS is mometasone furoate and the LABA is formoterol. In yet another embodiment, the ICS is budesonide and the LABA is formoterol. In yet yet another embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0087] In certain embodiments, subjects are selected from groups consisting of subjects aged 18 years or older, subjects aged 12 to under 18 years, subjects aged 6 to under 12 years, and subjects aged 2 to under 6 years.

[0088] In certain aspects, the subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatment using a stable ICS / LABA dose of moderate or high dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the loading dose administration of an IL-4R antagonist; ii) FEV1 prior to the loading dose administration of an IL-4R antagonist. iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) Having had moderate to severe uncontrolled asthma for 12 months or more, based on one or more of the following events within one year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations, or b) hospitalization or emergency medical visit for asthma exacerbations.

[0089] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 150 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0090] In a particular embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R is administered in a formulation containing i) approximately 175 mg / mL of the antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 50 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, with a pH of approximately 5.9. In a further embodiment, the viscosity of the formulation is approximately 8.5 centipoise.

[0091] In a particular embodiment, the antibody or its antigen-binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.

[0092] One embodiment includes an IL-4R antagonist for use in the treatment and / or prevention of asthma and related conditions.

[0093] One embodiment includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or its antigen-binding fragment for use in the treatment and / or prevention of asthma and related conditions.

[0094] One embodiment comprises a formulation containing i) about 150 mg / mL of an antibody or antigen-binding fragment that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 25 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9. In a particular embodiment, the viscosity of the formulation is about 8.5 centipoise. In a particular embodiment, the antibody or antigen-binding fragment comprises HCVR containing the amino acid sequence of SEQ ID NO: 1 and LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0095] One embodiment comprises a formulation containing i) approximately 175 mg / mL of an antibody or antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) approximately 5% (w / v) sucrose, v) approximately 50 mM arginine hydrochloride, and vi) approximately 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is approximately 5.9. In a particular embodiment, the viscosity of the formulation is approximately 8.5 centipoise. In a particular embodiment, the antibody or antigen-binding fragment comprises HCVR containing the amino acid sequence of SEQ ID NO: 1 and LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0096] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject having low or moderate blood eosinophil levels, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0097] In a particular embodiment, the subjects have a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL, or the subjects have a blood eosinophil count of less than approximately 200 cells / μL.

[0098] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0099] In certain embodiments, one or more maintenance doses are administered q2w or q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered q2w. Contains 0 mg. In certain embodiments, the loading dose contains 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses contain 200 mg of the antibody or its antigen-binding fragment administered for q4w. In certain embodiments, the loading dose contains 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses contain 200 mg of the antibody or its antigen-binding fragment administered for q2w. In certain embodiments, one or more maintenance doses are administered for at least 24 weeks.

[0100] In certain embodiments, subjects have elevated levels of one or more biomarkers selected from the group consisting of: periostin, thymic and activating regulatory chemokines (TARCs), dipeptidyl peptidase 4 (DPP4), eosinophil cationic protein (ECP), eotaxin-3, total IgE, antigen-specific IgE, and exhaled nitric oxide concentration (FeNO).

[0101] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring it, the subject being between approximately 12 and approximately 75 years of age, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist and one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist.

[0102] In a particular embodiment, the subjects have a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL, or a blood eosinophil count of less than approximately 200 cells / μL.

[0103] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0104] In certain embodiments, one or more maintenance doses are administered for q2w or q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered for q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered for q2w. In certain embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered for q4w. In certain embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered for q2w. In certain embodiments, one or more maintenance doses are administered for at least 24 weeks.

[0105] In a particular embodiment, the subject has elevated levels of one or more biomarkers selected from the group consisting of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0106] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring it, comprising administering a combination therapy to the subject, the combination therapy being one or the other of prednisone. The method includes an oral dose of the above amount, a loading dose of approximately 400 to 600 mg of IL-4R antagonist, and a maintenance dose of 1 or more of approximately 200 to 300 mg of IL-4R antagonist.

[0107] In certain embodiments, one or more oral doses of prednisone of approximately 10 mg or less are administered. In certain embodiments, one or more oral doses of prednisone of approximately 5 mg or less are administered. In certain embodiments, one or more oral doses of prednisone is a daily dose. In certain embodiments, the subject has a blood eosinophil count between approximately 200 and approximately 299 cells / μL. In certain embodiments, the subject has a blood eosinophil count of less than approximately 200 cells / μL.

[0108] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0109] In certain embodiments, one or more maintenance doses are administered for q2w or q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered for q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered for q2w. In certain embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered for q4w. In certain embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered for q2w. In certain embodiments, one or more maintenance doses are administered for at least 24 weeks.

[0110] In a particular embodiment, the subject has elevated levels of one or more biomarkers selected from the group consisting of the following biomarkers: Eos, periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0111] One embodiment is a method for reducing the incidence of asthma exacerbations in one or more subjects requiring it, comprising administering a combination therapy to the subjects, the combination therapy comprising one or more maintenance doses of ICS, one or more maintenance doses of a second long-term control agent, a loading dose of approximately 400 to 600 mg of an IL-4R antagonist, and one or more maintenance doses of approximately 200 to 300 mg of an IL-4R antagonist, wherein the ICS and the second long-term asthma control agent are administered during the period of continued administration of the IL-4R antagonist.

[0112] In certain embodiments, an asthma exacerbation is selected from the group consisting of: an exacerbation of 30% or more of peak morning expiratory flow rate (PEF) from baseline over two consecutive days; six or more additional rescue medication puffs of albuterol or levalbuterol over a 24-hour period over two consecutive days (compared to baseline); and an asthma worsening requiring: systemic (oral and / or parenteral) steroid treatment, or an increase in inhaled corticosteroids to at least four times the last dose received prior to discontinuation, or hospitalization.

[0113] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0114] One embodiment is a method for improving the FEV1 of a subject requiring it, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject, wherein the therapeutically effective amount of the pharmaceutical composition comprises a pharmaceutical composition comprising a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist and a maintenance dose of approximately 200 to approximately 300 mg of an IL-4R antagonist, or one or more.

[0115] In certain embodiments, improvement in asthma-related parameters is defined as an increase of at least 0.10 L in FEV1 from baseline.

[0116] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0117] One embodiment is a method for reducing the incidence of asthma exacerbations in one or more subjects requiring it, wherein the subjects have low or moderate blood eosinophil levels and / or are between approximately 12 and approximately 75 years of age, and the method comprises administering a treatment to the subjects, the treatment comprising a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist and one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist.

[0118] In certain aspects, an asthma exacerbation is defined as an exacerbation in which the maximum morning expiratory flow rate (PEF) is reduced by more than 30% from baseline for two consecutive days. The group consists of six or more additional rescue medication puffs of albuterol or levalbuterol in 24 hours over two consecutive days (compared to baseline), systemic (oral and / or parenteral) steroid treatment, or an increase in inhaled corticosteroids to at least four times the last dose received before discontinuation, or an asthma exacerbation requiring hospitalization.

[0119] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair containing SEQ ID NOs. 1 / 2. 2. 3. The antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences containing SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences containing SEQ ID NOs. 6, 7, and 8, respectively. 4. The antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In this case, the antibody is dupilumab.

[0120] One embodiment is a method for improving the FEV1 of a subject in need thereof, the subject having low or moderate blood eosinophil levels and / or being between 12 and 75 years of age, and the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist and a maintenance dose of one or more of about 200 to about 300 mg of an IL-4R antagonist.

[0121] In certain embodiments, improvement in asthma-related parameters is defined as an increase of at least 0.10 L in FEV1 from baseline.

[0122] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. The antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair containing SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences containing SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences containing SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0123] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject having low or moderate serum eosinophil levels and / or being between 12 and 75 years of age, the method comprising administering a combination therapy to the subject, the combination therapy comprising one or more maintenance doses of ICS, one or more maintenance doses of a second long-term control agent, a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist, the ICS and the second long-term asthma control agent being administered during the period of continued administration of the IL-4R antagonist.

[0124] In certain embodiments, the maintenance dose of ICS 1 or more is a moderate to high dose. In certain embodiments, the subject has a blood eosinophil count between approximately 200 and approximately 299 cells / μL. In certain embodiments, the subject has a blood eosinophil count of less than approximately 200 cells / μL.

[0125] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0126] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring such treatment, comprising administering a combination therapy to the subject, the combination therapy comprising one or more oral doses of prednisone, one or more maintenance doses of an ICS, one or more maintenance doses of a second inhaled long-term asthma control agent, a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist, and one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist, wherein the ICS and the second inhaled long-term asthma control agent are administered during the period of continued administration of the IL-4R antagonist.

[0127] In certain embodiments, one or more maintenance doses of ICS are moderate to high doses. In certain embodiments, one or more oral doses of prednisone of approximately 10 mg or less are administered. In certain embodiments, one or more oral doses of prednisone of approximately 5 mg or less are administered. In certain embodiments, one or more oral doses of prednisone are daily doses.

[0128] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0129] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring it, the subject being between approximately 12 and approximately 17 years of age, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of approximately 400 to approximately 600 mg of an IL-4R antagonist and one or more maintenance doses of approximately 200 to approximately 300 mg of an IL-4R antagonist.

[0130] In a particular embodiment, the subjects have a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL, or a blood eosinophil count of less than approximately 200 cells / μL.

[0131] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0132] In certain embodiments, one or more maintenance doses are administered at q4w. In certain embodiments, one or more maintenance doses are administered for at least 24 weeks. In certain embodiments, the loading dose comprises 600 mg of antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of antibody or its antigen-binding fragment administered at q4w, and optionally, the one or more maintenance doses are administered for at least 24 weeks. In certain embodiments, the loading dose comprises 600 mg of antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of antibody or its antigen-binding fragment administered at q2w, and optionally, the one or more maintenance doses are administered for at least 24 weeks. In certain embodiments, the loading dose comprises 400 mg of antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of antibody or its antigen-binding fragment administered at q4w, and optionally, the one or more maintenance doses are administered for at least 24 weeks. In a particular embodiment, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered at q2w, and optionally, the one or more maintenance doses are administered for at least 24 weeks.

[0133] In a particular embodiment, the subject has elevated levels of one or more biomarkers selected from the group consisting of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0134] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject requiring such treatment, comprising administering a combination therapy to the subject, the combination therapy comprising one or more maintenance doses of inhaled corticosteroids (ICS), one or more maintenance doses of long-acting β2-adrenergic agonists (LABAs), a loading dose of approximately 4 mg / kg of an interleukin-4 receptor (IL-4R) antagonist, and one or more maintenance doses of approximately 2 mg / kg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

[0135] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair containing SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity-determining region (HCDR) sequences containing SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining region (LCDR) sequences containing SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0136] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w) or every four weeks (q4w).

[0137] One embodiment is a method for treating moderate to severe uncontrolled asthma in a subject having low or moderate blood eosinophil levels, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of approximately 4 mg / kg of IL-4R antagonist and one or more maintenance doses of approximately 2 mg / kg of IL-4R antagonist.

[0138] In certain embodiments, subjects have a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL. In certain embodiments, subjects have a blood eosinophil count of less than approximately 200 cells / μL.

[0139] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair including SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences including SEQ ID NOs. 3, 4, and 5, respectively, and three LCDR sequences including SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0140] In certain embodiments, one or more maintenance doses are administered q2w. In certain embodiments, one or more maintenance doses are administered q4w.

[0141] One embodiment is a method for treating persistent asthma in a subject requiring it, wherein the subject The method includes administering a combination therapy comprising one or more maintenance doses of inhaled corticosteroids (ICS), one or more maintenance doses of long-acting β2-adrenergic agonists (LABAs), a loading dose of approximately 400 to 600 mg of an interleukin-4 receptor (IL-4R) antagonist, and one or more maintenance doses of approximately 200 to 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

[0142] In certain embodiments, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair containing SEQ ID NOs. 1 / 2. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity-determining region (HCDR) sequences containing SEQ ID NOs. 3, 4, and 5, respectively, and three light chain complementarity-determining region (LCDR) sequences containing SEQ ID NOs. 6, 7, and 8, respectively. In certain embodiments, the antibody or its antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO. 1 and an LCVR containing the amino acid sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0143] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In certain embodiments, one or more maintenance doses are administered every four weeks (q4w). In certain embodiments, the antibody or its antigen-binding fragment is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0144] In a particular embodiment, the subjects have a blood eosinophil count selected from the groups consisting of ≥300 cells / μL, 200-299 cells / μL, and <200 cells / μL.

[0145] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In certain embodiments, the ICS is mometasone furoate and the LABA is formoterol. In certain embodiments, the ICS is budesonide and the LABA is formoterol. In certain embodiments, the ICS is fluticasone propionate and the LABA is salmeterol.

[0146] In a particular manner, subjects are selected from groups consisting of subjects aged approximately 18 years or older, subjects aged approximately 12 to 75 years, subjects aged approximately 12 to 18 years, subjects aged approximately 6 to 11 years, and subjects aged approximately 2 to 5 years.

[0147] In certain aspects, the subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: existing treatment using a stable ICS / LABA dose of moderate or high dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or a daily dose of an equivalent ICS) for at least one month prior to the administration of the loading dose of an IL-4R antagonist; 40-80% predicted normal value of forced expiratory volume (FEV1) prior to the administration of the loading dose of an IL-4R antagonist; and the 5-question version of the Juniper Asthma Management Questionnaire prior to the administration of the loading dose of an IL-4R antagonist. A (ACQ-5) score of 1.5 or higher; reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or having had persistent asthma for 12 months or more based on one or more of the following events within one year prior to administration of a loading dose of an IL-4R antagonist: treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations; or hospitalization or emergency medical visit for asthma exacerbations.

[0148] Other embodiments will become apparent from the detailed description, drawings, tables, and appended claims that follow.

[0149] The above-mentioned and other features and advantages of the present invention will be better understood from the following detailed description of embodiments useful in the description cited in relation to the accompanying drawings. The patent file includes at least one drawing / photograph made in color. A copy of this application with the color drawing / photograph will be provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fees. [Brief explanation of the drawing]

[0150] [Figure 1] This graph shows the mean serum functional mAb1 concentration over time for mAb1 administered at 300 mg once a week (qw). [Figure 2] This graph shows the mean serum concentrations over time for various studies in which mAb1 was administered at a dose of 300 mg once weekly. Asthma studies are represented by solid lines and circles. Multinational atopic dermatitis studies are represented by intermittent lines and rectangles. US atopic dermatitis studies are represented by intermittent lines and circles. [Figure 3] This graph shows the least-squares mean change in FEV1(L) from baseline over time in the hypereosinophil (HEos) intended-to-treat (ITT) population (analysis of repeated measures using a mixed-effects model (MMRM), including measurements up to week 12). Abbreviations: Dup = dupilumab; FEV1 = forced expiratory volume in 1 second; LS = least squares; q2w = once every 2 weeks; q4w = once every 4 weeks; SE = standard error of the mean. FEV1(L) collected from the start of systemic corticosteroids to 30 days after the end of systemic corticosteroid use for each severe exacerbation episode was excluded to reduce the confounding effect of systemic corticosteroids. [Figure 4] This graph shows the least squares mean change in FEV1(L) over time for the ITT group (MMRM including measurements up to week 12). FEV1(L) data collected from the start of systemic corticosteroid use to 30 days after the end of systemic corticosteroid use for each severe exacerbation episode are excluded to reduce the confounding effect of systemic corticosteroids. [Figure 5]This graph shows the least-squares mean change in FEV1(L) from baseline at week 12 for the ITT group, broken down by eosinophil category. FEV1(L) data collected from the start of systemic corticosteroid use to 30 days after the end of systemic corticosteroid use for each severe exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 6] This graph shows the cumulative mean fraction of the number of severe exacerbation events versus treatment duration for the HEos ITT population. For each severe exacerbation episode, FEV1(L) data collected from the start date of systemic corticosteroids to 30 days after the end date of systemic corticosteroids were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 7] This graph shows the cumulative mean fraction of the number of severe exacerbation events versus treatment duration for the ITT group. For each severe exacerbation episode, FEV1(L) collected from the start date of systemic corticosteroids to the end date of systemic corticosteroids + 30 days is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 8] This graph shows the annualized event rate of severe exacerbation events during the treatment period for the ITT population, broken down by baseline serum eosinophil (GIGA / L) category during the treatment period. Note: The SE of the estimated annualized event rate was calculated using the delta method from the SE of the estimated event rate compared to the annualized event rate. [Figure 9] This graph shows the least squares mean percentage change in FEV1(L) from baseline at week 12 for the HEos ITT group. To reduce the confounding effect of systemic corticosteroids, FEV1(L) data collected from the start of systemic corticosteroid use to 30 days after the end of systemic corticosteroid use were excluded for each severe exacerbation episode. [Figure 10] This graph shows the cumulative mean fraction of asthma management loss events during the treatment period for the HEos ITT group. [Figure 11] This figure shows a Kaplan-Meier plot of time to the first asthma management loss event during the treatment period for the HEos ITT population. [Figure 12]This figure shows Kaplan-Meier plots of the time to the first severe exacerbation event during the treatment period for the HEos ITT population. [Figure 13] This graph shows the mean percentage change from baseline TARC for the HEos ITT population. TARC = thymic and activating regulatory chemokines. [Figure 14] This graph shows the mean percentage change from baseline TARC for the ITT population. [Figure 15] This graph shows the mean percentage change from baseline eotaxin-3 in the HEos ITT population. [Figure 16] This graph shows the mean percentage change from baseline eotaxin-3 in the ITT population. [Figure 17] This graph shows the mean percentage change from baseline FeNO for the HEos ITT population. FeNO = exhaled nitric oxide concentration. [Figure 18] This graph shows the mean percentage change from baseline FeNO in the ITT population. [Figure 19] This graph shows the mean least-squares (LS) change in FEV1(L) from baseline over time (MMRM, including measurements up to week 12) for the ITT population with moderate serum eosinophil counts (0.2–0.299 GIGA / L). FEV1(L) data collected from the start of systemic corticosteroid use to 30 days after the end of systemic corticosteroid use for each severe exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 20] This graph shows the mean change in FEV1(L) from baseline to LS (including measurements up to week 12) over time for the ITT population with low blood eosinophil counts (<0.2 GIGA / L). FEV1(L) data collected from the start of systemic corticosteroid use to 30 days after the end of systemic corticosteroid use for each severe exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 21]This graph shows the cumulative mean fraction of severe exacerbation events over the treatment period in the ITT population with moderate serum eosinophil counts (0.2-0.299 GIGA / L). [Figure 22] This graph shows the cumulative mean fraction of severe exacerbation events in the ITT population with low blood eosinophil counts (<0.2 GIGA / L) over the treatment period. [Figure 23] This figure shows an overview of the asthma interim analysis disclosed herein. [Figure 24] This figure is a table showing demographic characteristics and disease baseline characteristics. [Figure 25] This graph shows the percentage of the ITT population for each subgroup defined by baseline blood eosinophil count. [Figure 26] This graph shows the mean percentage change in FEV1(L) from baseline LS during week 12, broken down by eosinophil subgroup defined by baseline blood eosinophil count (GIGA / L). [Figure 27] This graph shows the mean percentage change in FEV1 LS between the ITT group and the HEos group. [Figure 28] This graph shows the mean change in FEV1(L) from baseline over time (MMRM), including measurements up to week 12. [Figure 29] This graph shows the cumulative mean fraction of severe exacerbation events for available data. [Figure 30] This graph shows the mean change in AM asthma symptom score from baseline over time (MMRM, including measurements up to week 12). [Figure 31] This graph shows the mean percentage change in blood eosinophils from baseline over time. [Figure 32] This graph shows the mean percentage change from baseline in eosinophil cationic protein (ECP). [Figure 33] This graph shows that the suppression of total IgE is equivalent between the ITT population and the HEos ITT population. [Figure 34] This graph shows the average percentage change from baseline TARC. [Figure 35] This graph shows the average percentage change from baseline FeNO. [Figure 36] This graph shows the mean percentage change from baseline eotaxin-3. [Figure 37] This figure shows a scatter plot analysis illustrating the absolute FEV1. [Figure 38] This figure shows a scatter plot analysis illustrating the percentage change in FEV1. [Figure 39] This graph shows the cumulative mean fraction of LOAC events for available data. [Figure 40] This figure shows a Kaplan-Meier plot of the time to the first severe exacerbation event over the treatment period. [Figure 41] This graph shows the mean change in PM asthma symptoms from baseline (MMRM) over the scoring period, including measurements up to week 12. [Figure 42] This graph shows the mean change in AM PEF (L / min) from baseline over time (MMRM, including measurements up to week 12). [Figure 43] This graph shows the mean change in PM PEF (L / min) from baseline over time (MMRM, including measurements up to week 12). [Figure 44] This figure shows a graph of the mean change in LS (Life Cycle Management) over time from baseline (MMRM, including measurements up to week 12) in the number of daily inhalations of salbutamol / albuterol or levosalmola / levalbuterol for symptom relief. [Figure 45] This figure illustrates that the suppression of total IgE in the ITT population was similar between low Eos (<0.2 GI / L) and moderate Eos (0.200-0.299 GI / L). [Figure 46] This figure illustrates the average percentage change from baseline FeNO. [Figure 47]This figure illustrates periostin levels (pg / mL) in low Eos, moderate Eos, high Eos, and ITT populations. [Figure 48] This table shows that the magnitude of TARC and IgE suppression (mean % change) was greater with dupilumab (in patients with high Eos) than with leburikizumab after 12 weeks of treatment, even in patients retrospectively stratified by high periostin levels. [Figure 49] This figure shows that TARC and IgE suppression (mean percentage change) was greater with dupilumab than with lebrikizumab at week 12. [Figure 50] This figure shows important efficacy results for moderate to severe asthma and the hypereosinophil / periostin subgroup. Left column: Exacerbation. Right column: FEV1 score. [Figure 51-1] This diagram shows the description and breakdown of the subject. [Figure 51-2] Continuation of Figure 51-1. [Figure 52] This is a diagram showing the randomized population for the study. [Figure 53-1] This figure shows the target exposure to dupilumab. [Figure 53-2] Continuation of Figure 53-1. [Figure 54] This figure summarizes the change from baseline in FEV1(L) and the annual rate of severe exacerbations for each baseline serum Eos level. [Figure 55] This figure summarizes the percentage changes in week 12 among the ITT group, the high Eos (≥300) group, and the low Eos (<300) group. [Figure 56] This figure shows the mean baseline biomarkers for each eosinophil count subgroup. [Figure 57] This figure shows Asthma Management Questionnaire 5 (ACQ5) data for the Intent to Treat (ITT) population. [Figure 58] This figure shows the ACQ 5-item analysis for the ITT group. [Figure 59] This figure shows the Asthma Quality of Life Questionnaire (AQLQ) data for the ITT group. [Figure 60] This diagram shows AQLQ ITT data by domain. [Figure 61] This diagram shows the European Quality of Life - 5 items - 5L (EQ5D-5L) data. [Figure 62] This diagram shows the EQ5D-5L data item by item. [Figure 63] This figure shows Hospital Anxiety and Depression Score (HADS) data by domain. [Figure 64] This figure shows HADS data for the ITT population. [Figure 65] This figure shows HADS data for the ITT hypereosinophil (HEos) population. *The dependent variable was the change from baseline score up to week 24, and the covariates were factors (fixed effects) related to treatment, country / region of implementation, hospital visit, treatment / visit interaction, baseline score value, and baseline / visit interaction. The data was derived from an MMRM model using an unstructured correlation matrix. Scores collected from the start date of systemic corticosteroids to the end date of systemic corticosteroids + 30 days for each exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 66] This figure shows the HADS baseline data and the change from baseline at week 12 for the ITT population. *The change from baseline score up to week 24 was used as the dependent variable, and factors (fixed effects) for treatment, country / region of implementation, visit, treatment / visit interaction, baseline score value, and baseline / visit interaction were used as covariates. The data was derived from the MMRM model using an unstructured correlation matrix. Scores collected from the systemic corticosteroid initiation date to the systemic corticosteroid discontinuation date + 30 days for each exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids. [Figure 67] This figure shows the Sino Nasal Outcome Test 22 (SNOT 22) data for the ITT population. [Figure 68] This diagram shows SNOT22 data by domain. [Figure 69] This figure shows the results of the Numerical Rating Scale (NRS) for itching. [Modes for carrying out the invention]

[0151] Before describing the present invention, it should be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may change. It should also be understood that the technical terms used herein are for the purpose of describing specific embodiments only and are not intended to limit them, as the scope of the invention is limited only by the appended claims.

[0152] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0153] As used herein, the term “about” means that, when used in reference to a particular enumerated number, that value may vary by no more than 1% from the enumerated value. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0154] As used herein, the terms “to treat,” “to treat,” or similar terms mean to alleviate symptoms, to temporarily or permanently eliminate the cause of symptoms, or to prevent or delay the appearance of symptoms of the disorder or condition named.

[0155] Any method and materials similar to or equivalent to those described herein may be used in carrying out the present invention. While these may be used, typical methods and materials are described below. All publications referenced herein are incorporated herein by reference in their entirety.

[0156] Methods to reduce the incidence of asthma exacerbations The present invention relates to a method for reducing the incidence of asthma exacerbations in a subject requiring such reduction, comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. As used herein, the term “asthma exacerbation” means an increase in the severity and / or frequency and / or duration of one or more symptoms or signs of asthma. “Asthma exacerbation” also includes any deterioration of the subject’s respiratory health that requires and / or is treatable by therapeutic intervention for asthma (e.g., steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.). There are two types of asthma exacerbation events: loss of asthma control (LOAC) events and severe exacerbation events.

[0157] According to certain embodiments, a loss of asthma control (LOAC) event is defined as one or more of the following events: (a) six or more additional salbutamol / albuterol or levosalmola / levalbuterol rescue medication puffs in a 24-hour period over two consecutive days (compared to baseline); (b) a four-fold or greater dose increase of ICS at visit 2; and (c) use of systemic corticosteroids for three or more days; or (d) hospitalization or emergency department visit due to asthma requiring systemic corticosteroids.

[0158] In certain cases, asthma exacerbations may be categorized as “severe asthma exacerbation events.” A severe asthma exacerbation event means an incident requiring immediate intervention, wherein the intervention takes the form of treatment using either systemic or inhaled corticosteroids at four times or more the dose taken prior to the incident. According to certain embodiments, a severe asthma exacerbation event is defined as an asthma worsening requiring: the use of systemic corticosteroids for three days or more; or hospitalization or emergency room visit due to asthma requiring systemic corticosteroids. Thus, the general expression “asthma exacerbation” includes and encompasses the more specific subcategory of “severe asthma exacerbation.” Therefore, it includes methods for reducing the incidence of severe asthma exacerbations in patients who require it.

[0159] "Reduced incidence" of asthma exacerbations means that subjects who receive a pharmaceutical composition containing an IL-4R antagonist experience fewer asthma exacerbations after treatment than before treatment (i.e., at least one fewer exacerbation), or do not experience an asthma exacerbation for at least four weeks (e.g., 4, 6, 8, 12, 14 weeks, or more) after initiating treatment with the pharmaceutical composition. Alternatively, "reduced incidence" of asthma exacerbations means that the likelihood of a subject experiencing an asthma exacerbation after administration of the pharmaceutical composition is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) compared to subjects who do not receive the pharmaceutical composition.

[0160] The present invention relates to a method for reducing the incidence of asthma exacerbations in a subject requiring such reduction, comprising administering to the subject a pharmaceutical composition containing an IL-4R antagonist, and administering to the subject one or more maintenance doses of an inhaled corticosteroid (ICS) and / or a second long-term control agent, such as a long-acting β-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include fluticasone (e.g., fluticasone propionate, e.g., Flovent®), budesonide, momentum (e.g., mometasone furoate, e.g., Asmanex®), flunisolide (e.g., Aerobid®), dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort®), beclomethasone dipropionate HFA (Qvar®), etc. The following are examples of suitable LABAs, but are not limited to those listed above. Suitable LABAs include, but are not limited to, salmeterol (e.g., Serevent®) and formoterol (e.g., Foradil®). Suitable LTAs include, but are not limited to, montelukast (e.g., Singulaire®) and zafirlukast (e.g., Accolate®).

[0161] The present invention relates to a method for reducing the incidence of asthma exacerbations in a subject requiring such treatment, comprising administering a pharmaceutical composition containing an IL-4R antagonist to the subject, and administering one or more rescue medications to the subject to eliminate or reduce one or more asthma-related symptoms. Suitable rescue medications include, but are not limited to, fast-acting β2-adrenergic receptor agonists such as albuterol (i.e., salbutamol, e.g., Proventil®, Ventolin®, Xopenex®, etc.), pirbuterol (e.g., Maxair®), and metaproterenol (e.g., Alupent®).

[0162] Methods to improve asthma-related parameters The present invention relates to a method for improving one or more asthma-related parameters in a subject requiring such improvement, the method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. A reduction in the incidence of asthma exacerbations (as described above) may correlate with an improvement in one or more asthma-related parameters; however, such a correlation is not necessarily observed in all cases.

[0163] Examples of "asthma-related parameters" include: (1) relative percentage change from baseline in forced expiratory volume in one second (FEV1) at week 12; (2) annual rate of asthma loss of control events during the treatment period; (3) annual rate of severe exacerbation events during the treatment period; (4) time to asthma loss of control event during the treatment period; (5) time to severe exacerbation event during the treatment period; (6) time to asthma loss of control event throughout the entire study period; (7) time to severe exacerbation event throughout the entire study period. Time; (8) Utilization of medical resources; (9) In week 12: i) morning and evening asthma symptom scores, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations of salbutamol / albuterol or levosalmola / levalbuterol per day for symptom relief, vi) change from baseline in nocturnal awakenings; (10) In weeks 12 and 24: i) 22-item Sino Nasal Outcome Test (SNOT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) change from baseline in EuroQual Questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement in asthma-related parameters" means an increase from baseline in one or more of FEV1, AM PEF, or PM PEF, and / or a decrease from baseline in one or more of the following: daily albuterol / levalbuterol use, ACQ5 score, mean nocturnal awakenings, or SNOT-22 score. As used herein, the term "baseline" with respect to asthma-related parameters means the numerical value of the patient's asthma-related parameters before or at the time of administration of the pharmaceutical composition containing the IL-4R antagonist.

[0164] To determine whether asthma-related parameters have “improved,” the parameters are quantified at baseline and at points after administration of the pharmaceutical composition described herein. For example, asthma-related parameters may be measured on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 14 after the initial treatment with the pharmaceutical composition, or at weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, or at further points in time. Parameter values ​​at specific points in time after the start of treatment and parameters at baseline are also measured. The difference from the ter value is used to confirm whether there has been an "improvement" in asthma-related parameters (e.g., an increase or decrease depending on the specific parameter being measured).

[0165] As used herein, the terms “obtain” or “acquire” mean to obtain a physical entity or value, such as a numerical value, by “directly obtaining” or “indirectly obtaining” a physical entity or value, such as an asthma-related parameter. “Directly obtaining” means carrying out a process to obtain a physical entity or value (e.g., carrying out a synthesis or analytical method). “Indirectly obtaining” means receiving a physical entity or value from another entity or source (e.g., a laboratory of a third entity that directly obtained the physical entity or value). Directly obtaining a physical entity involves carrying out a process that involves a physical change of a physical substance, such as a starting material. Exemplary changes include producing a physical entity from two or more starting materials, sharing or fragmenting a substance, separating or purifying a substance, combining two or more distinct entities into a mixture, and carrying out a chemical reaction that involves the decomposition or formation of covalent or non-covalent bonds. Obtaining a value directly involves performing a process that includes a physical change of a sample or another substance, for example, performing an analytical process (which may also be referred to herein as “physical analysis”) that includes a physical change of a substance, such as a sample, analyte, or reagent.

[0166] Information obtained indirectly may be provided in the form of reports from online databases or applications ("Apps"), for example, in paper or electronic form. Reports or information may also be provided by, for example, healthcare facilities, such as hospitals or clinics; or by healthcare providers, such as doctors or nurses.

[0167] Forced expiratory volume in one second (FEV1). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase in FEV1 from baseline. Methods for measuring FEV1 are known in the art. For example, a patient's FEV1 can be measured using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommended criteria. ATS / ERS standardization of spirometry may be used as a guideline. Spirometry is generally performed between 6 and 10 a.m., at least 6 hours after abstaining from albuterol. Pulmonary function tests are generally performed in a seated position, and the highest FEV1 measurement (in liters) is recorded.

[0168] The present invention includes a therapeutic method that results in an increase of at least 0.05 L of FEV1 from baseline at 12 weeks after the initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject requiring it results in an increase of approximately 0.05 L, 0.10 L, 0.12 L, 0.14 L, 0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L, 0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L, 0.48 L, 0.50 L or more from baseline of FEV1 at 12 weeks.

[0169] Morning and evening maximum expiratory velocity (AM PEF and PM PEF). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in morning (AM) and / or evening (PM) maximum expiratory velocity (AM PEF and / or PM PEF). Methods for measuring PEF are known in the art. For example, according to one PEF measurement method, a patient is provided with an electronic PEF meter to record morning (AM) and evening (PM) PEF (as well as daily albuterol use, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring emergency medication). The patient receives instruction on the use of the device and is given written instructions on the use of the electronic PEF meter. In addition, a healthcare professional provides the electronic PEF meter with variables directly relevant to the patient. Instructions on how to record data using a monitor may also be provided. AM PEF is generally performed within 15 minutes of waking up (between 6 PM and 10 PM) and before any albuterol intake. PM PEF is generally performed in the evening (between 6:00 AM and 10:00 AM) before any albuterol intake. Subjects should attempt to refrain from albuterol for at least 6 hours prior to PEF measurement. Three PEF efforts are performed by the patient, and all three values ​​are recorded using an electronic PEF meter. The highest value is usually used for evaluation. Baseline AM PEF can be calculated as the mean AM measurement recorded over 7 days prior to the first dose of the pharmaceutical composition containing the IL-4R antagonist, and baseline PM PEF can be calculated as the mean PM measurement recorded over 7 days prior to the first dose of the pharmaceutical composition containing the IL-4R antagonist.

[0170] The present invention includes a therapeutic method that results in an increase from baseline of at least 1.0 L / min of AM PEF and / or PM PEF at 12 weeks after the initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, according to the present invention, administration of an IL-4R antagonist to a subject requiring it results in an increase of approximately 0.5 L / min, 1.0 L / min, 1.5 L / min, 2.0 L / min, 2.5 L / min, 3.0 L / min, 3.5 L / min, 4.0 L / min, 4.5 L / min, 5.0 L / min, 5.5 L / min, 6.0 L / min, 6.5 L / min, 7.0 L / min, 7.5 L / min, 8.0 L / min, 8.5 L / min, 9.0 L / min, 9.5 L / min, 10.0 L / min, 10.5 L / min, 11.0 L / min, 12.0 L / min, 15 L / min, 20 L / min, or more from baseline in PEF at week 12.

[0171] Albuterol / revalbuterol use. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in daily albuterol or revalbuterol use. The number of albuterol / revalbuterol inhalations is recorded daily by the patient using a diary, PEF meter, or other recording device. The use of albuterol / revalbuterol during treatment with the pharmaceutical compositions described herein may typically be used as needed for symptoms, rather than regularly and prophylactically. The baseline number of albuterol / revalbuterol inhalations / day can be calculated based on the average values ​​over the 7 days prior to the first dose administration of the pharmaceutical composition containing the IL-4R antagonist.

[0172] The present invention includes a therapeutic method that results in a reduction of at least 0.25 puffs per day from baseline albuterol / levalbuterol use at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject requiring it results in a reduction of approximately 0.25 puffs per day, 0.50 puffs per day, 0.75 puffs per day, 1.00 puffs per day, 1.25 puffs per day, 1.5 puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day, or more from baseline albuterol / levalbuterol use at week 12.

[0173] Prednisone use. According to certain embodiments, the administration of an IL-4R antagonist to the patient may be used in combination with oral prednisone. The number of prednisone doses is recorded daily by the patient using a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, short-term use of prednisone may be used occasionally to manage acute asthma episodes, such as episodes in which symptoms cannot be controlled by bronchodilators and other anti-inflammatory drugs. In other embodiments, prednisone is used in combination with or as an alternative to ICS. Oral prednisone may be administered in doses of approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. Oral prednisone may be administered once daily or multiple times daily (e.g., twice daily, three times daily, four times daily, etc.).

[0174] Five-item Asthma Management Questionnaire (ACQ) score. According to certain embodiments, administration of IL-4R antagonists to patients results in a decrease from baseline in the five-item Asthma Management Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma management.

[0175] The present invention includes a therapeutic method that results in a reduction of at least 0.10 points from baseline in the ACQ5 score at 12 weeks after the initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need of it results in a reduction of approximately 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, or more from baseline in the ACQ score at 12 weeks.

[0176] Nocturnal awakenings. According to certain embodiments, administration of IL-4R antagonists to patients results in a reduction from baseline in the mean number of nocturnal awakenings.

[0177] In a particular embodiment, the method reduces the mean number of nighttime awakenings from baseline by at least about 0.10 per night at week 12 after the start of treatment. For example, administration of an IL-4R antagonist to a subject in need may result in a reduction of about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 2.0, or more per night from baseline in the mean number of nighttime awakenings at week 12.

[0178] 22-item sinus outcome test (SNOT-22) score. According to certain embodiments, administration of IL-4R antagonists to patients results in a reduction from baseline in the 22-item sinus outcome test (SNOT-22). The SNOT-22 is a validated questionnaire for assessing the impact of chronic sinusitis on quality of life (Hopkins et al., 2009, Clin. Otolaryngol. 34: pp. 447-454).

[0179] The present invention includes a therapeutic method that results in a reduction of at least one point from baseline in the SNOT-22 score at 12 weeks after the initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need may result in a reduction of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points or more from baseline in the SNOT-22 score at 12 weeks.

[0180] How to treat asthma In some embodiments, the present invention provides a method for treating asthma in a subject requiring such treatment (including, for example, moderate to severe uncontrolled or poorly controlled asthma), comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. In certain embodiments, the method is useful for treating moderate to severe uncontrolled asthma in a subject.

[0181] As used herein, the term “asthma” may be used synonymously with “intermittent asthma.” “Asthma” and “intermittent asthma” refer to asthma that meets one or a combination of the following criteria: symptoms occur two days or less per week; symptoms do not interfere with daily life; nocturnal symptoms occur two days or less per month; or one or more pulmonary function tests (e.g., forced expiratory volume in one second (FEV1) and / or maximum expiratory flow rate (PEF) higher than 80%) are normal when the subject is not experiencing an asthma attack.

[0182] As used herein, the term “persistent asthma” refers to asthma that is more severe than asthma / intermittent asthma. Subjects with persistent asthma experience one or more of the following: symptoms more than two days a week; symptoms that interfere with daily life; nocturnal symptoms more than two days a month; or one or more abnormal pulmonary function tests (e.g., forced expiratory volume in one second (FEV1) and / or maximum expiratory flow rate (PEF)) when the subject is not experiencing an asthma attack; the subject routinely relies on asthma control medications; the subject has taken systemic steroids more than once last year after a severe asthma relapse; or uses short-acting β2-agonists more than two days a week for the relief of asthma symptoms.

[0183] Asthma / intermittent asthma and persistent asthma can be categorized as "mild," "moderate," "severe," or "moderate to severe." "Mild intermittent asthma" is defined as having symptoms less than once a week and having a forced expiratory volume in one second (FEV1) or maximum expiratory flow rate (PEF) of ≥80%. "Mild persistent asthma" differs in that symptoms occur more than once a week but less than once a day, and the variation in FEV1 or PEF is <20% to 30%. "Moderate intermittent asthma" is defined as having symptoms less than once a week and having a forced expiratory volume in one second (FEV1) or maximum expiratory flow rate (PEF) of 60-80%. "Moderate persistent asthma" is defined as having daily symptoms, exacerbations that affect activity and / or sleep, nocturnal symptoms more than once a week, daily use of inhaled short-acting β2-agonists, and 60-80% of forced expiratory volume in one second (FEV1) or maximum expiratory flow rate (PEF). "Severe intermittent asthma" is defined as having symptoms less than once a week and 60% of of forced expiratory volume in one second (FEV1) or maximum expiratory flow rate (PEF). "Severe persistent asthma" is defined as having frequent exacerbations that affect daily symptoms, activity and / or sleep, frequent nocturnal symptoms, limitation of physical activity, daily use of inhaled short-acting β2-agonists, and 60% of of of of of of of of "Moderate to severe persistent asthma" is defined as having symptoms that fall between those of moderate persistent asthma and severe persistent asthma.

[0184] As used herein, the term "improperly managed asthma" refers to "Expert Panel Report 3: Guidelines for the Diagnosis." As defined by "Uncontrolled Asthma and Management," National Heart, Blood and Lung Institute, NIH, August 28, 2007, as either "poorly controlled" or "very poorly controlled." "Poorly controlled asthma" is defined as having symptoms on more than two days per week, nocturnal awakenings 1 to 3 times per week, some limitation of daily activities, use of short-acting β2-agonists for symptom management on more than two days per week, an FEV1 of 60–80% of the predicted highest and / or personal highest, an ATAQ score of 1–2, an ACQ score of 1.5 or higher, and an ACT score of 16–19. "Very poorly managed asthma" is defined as having symptoms throughout the day, nocturnal awakenings four or more times per week, extreme limitations on daily life, several uses of short-acting β2-agonists for symptom management, an FEV1 less than 60% of the predicted highest and / or personal highest, an ATAQ score of 3-4, an ACQ score of not applicable, and an ACT score of 15 or less.

[0185] In some embodiments, the subjects meet the International Guidelines for Asthma Management (GINA) 2009 guidelines and one or more of the following criteria: i) stable ICSI / LABA (2 × fluticasone propionate 250 μg twice daily, or the daily dose of an equivalent ICS) for at least one month prior to loading dose administration of an IL-4R antagonist. A person is defined as having moderate to severe uncontrolled asthma if, based on the following events within one year prior to the administration of a loading dose of an IL-4R antagonist: ii) existing treatment using S / LAB doses; ii) FEV1 40-80% predicted normal value before administration of a loading dose of an IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) reversibility of at least 12% and 200 mL of FEV1 after 200 μg-400 μg (2-4 inhalations) of salbutamol / albuterol before administration of a loading dose of an IL-4R antagonist; or v) a diagnosis of moderate to severe uncontrolled asthma by a physician based on the following events: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation; or b) hospitalization or emergency medical visit for asthma exacerbation.

[0186] In one embodiment, a method for treating asthma is provided, comprising the steps of: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 cells per microliter; and (b) administering a pharmaceutical composition comprising an IL-4R antagonist to the patient.

[0187] In another embodiment, a method for treating asthma is provided, comprising the steps of: (a) selecting a patient having a blood eosinophil level of 200 to 299 cells per microliter; and (b) administering a pharmaceutical composition comprising an IL-4R antagonist to the patient.

[0188] In another embodiment, a method for treating asthma is provided, comprising the steps of: (a) selecting a patient having a blood eosinophil level of less than 200 cells per microliter; and (b) administering a pharmaceutical composition comprising an IL-4R antagonist to the patient.

[0189] In related embodiments, methods for treating asthma are provided, including additional treatment to background treatment. In certain embodiments, IL-4R antagonists are administered as additional treatment to asthma patients receiving background treatment for a specific period (e.g., one week, two weeks, three weeks, one month, two months, five months, twelve months, eighteen months, twenty-four months, or longer) (also known as the “stable period”). In some embodiments, the background treatment includes ICS and / or LABAs.

[0190] In some embodiments, the present invention provides a method for reducing the dependence of asthma patients on ICS and / or LABAs for the treatment of one or more asthma exacerbations, comprising: (a) selecting patients having moderate to severe asthma that is not controlled by background asthma treatment including ICS, LABA, or a combination thereof; and administering a pharmaceutical composition comprising an IL-4R antagonist to the patients.

[0191] In some embodiments, the present invention encompasses methods for treating or alleviating asthma-related conditions or complications, such as chronic sinusitis, allergic rhinitis, allergic fungal sinusitis, allergic bronchopulmonary aspergillosis, unified airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD), and exercise-induced bronchospasm.

[0192] The present invention also includes methods for treating persistent asthma. As used herein, the term “persistent asthma” means that the subject experiences symptoms at least once a week, during the day and / or at night, and that these symptoms last from several hours to several days. In certain alternative embodiments, persistent asthma is “mild persistent” (e.g., symptoms occur more than twice a week but less than daily, are severe enough to interfere with daily activities or sleep, and / or lung function normalizes or becomes reversible with inhalation of a bronchodilator), “moderate persistent” (e.g., symptoms occur daily, sleep is disturbed at least once a week, and / or lung function is moderately impaired), or “severe persistent” (e.g., symptoms persist despite correct use of approved medications, and / or lung function is severely impaired).

[0193] Interleukin-4 receptor antagonists A method of interest in the present invention involves administering a therapeutic composition containing an IL-4R antagonist to a subject requiring such treatment. As used herein, “IL-4R antagonist” is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed in cells, either in vitro or in vivo. Non-limiting examples of the category of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., “peptibody” molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R.

[0194] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4), such as IL-4Rα.

[0195] The term "antibody" refers to an immunoglobulin molecule containing four polypeptide chains (two heavy (H) chains and two light (L) chains linked together by disulfide bonds), and their polymers (e.g., IgM). Each heavy chain has a heavy chain variable region (HCVR or V in this specification). H(abbreviated as such) and a heavy chain constant region. The heavy chain constant region includes three domains, C H 1, C H 2 and C H 3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or V L as such) and a light chain constant region. The light chain constant region includes one domain (C L 1). V H and V L regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) in which more conserved regions called framework regions (FRs) are interspersed. Each V H and V L is composed of three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. Amino acid consensus sequences are defined based on the parallel analysis of two or more CDRs.

[0196] The term “antibody” also includes the antigen-binding fragment of a complete antibody molecule. Terms such as “antigen-binding portion” and “antigen-binding fragment” of an antibody, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained from a complete antibody molecule using any suitable standard technique, such as protein digestion or recombinant genetic modification methods, including manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is publicly known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated, for example, by chemical or molecular biological techniques, to position one or more variable and / or constant domains into suitable higher-order structures, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0197] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other modified molecules include, for example, domain-specific antibodies, single-domain antibodies, domain-deletion antibodies, chimeric antibodies, CDR graft antibodies, diabodies, triabodies, tetrabodies, minibodies, and nanobodies. The term "antigen-binding fragment" also encompasses bodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains.

[0198] The antigen-binding fragment of an antibody will generally contain at least one variable domain. The variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In the case of an antigen-binding fragment having a domain, V H and V L Domains can be positioned in any suitable arrangement relative to each other. For example, the variable region is a dimer, V H -V H , V H -V L or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may contain monomer V H or V L It may also contain a domain name.

[0199] In certain embodiments, the antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary higher-order structures of variable and constant domains that may be found within the antigen-binding fragment of an antibody described herein include: (i)V H -C H 1;(ii)V H -C H 2; (iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)VL -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C L In any of the variable and constant domain higher-order structures, including any of the exemplary higher-order structures listed above, the variable and constant domains may be directly linked to each other, or they may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which form a flexible or slightly flexible chain between adjacent variable and / or constant domains within a single polypeptide molecule, and generally, the hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Furthermore, the antigen-binding fragments of the antibodies described herein are linked to each other and / or one or more monomer V H Or V L The domain may contain homodimers or heterodimers (or other polymers) of any of the variable and constant domain higher-order structures listed above, which are associated with the domain non-covalently (e.g., by disulfide bonds).

[0200] Similar to fully antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally contain at least two distinct variable domains, each capable of specifically binding to a different antigen or to a different epitope on the same antigen. Any multispecific antibody form can be adapted for use in conjunction with the antibody antigen-binding fragments described herein using conventional techniques available in the art.

[0201] The constant region of an antibody is crucial to its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0202] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the human antibodies of interest in this invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations induced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo), for example, in CDRs, particularly CDR3. Furthermore, the term "human antibody" does not include antibodies in which CDR sequences derived from the germ cell line of another mammalian species, such as mice, are grafted onto a human framework sequence.

[0203] The term “recombinant human antibody” includes all human antibodies manufactured, expressed, generated or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (as described further below), antibodies isolated from recombinants, combinatorial human antibody libraries (as described further below), antibodies isolated from animals (e.g., mice) into which human immunoglobulin genes have been transfected (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20: pp. 6287-6295), or antibodies manufactured, expressed, generated or isolated by any other means, including splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if using animals into which human Ig sequences have been transfected), so the V of the recombinant antibody H and V L The amino acid sequence of the region is human germline V H and V L Derived from the sequence, human germline V H and V L Although it is a sequence related to the one in question, it is a sequence that cannot naturally exist in the human antibody germline repertoire in vivo.

[0204] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable 4-chain construct of approximately 150–160 kDa, where the dimers are held together by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, and the molecule consists of approximately 75–80 kDa molecules formed by covalently coupled light and heavy chains (half-antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0205] The frequency of occurrence of the second form in various intact IgG isotypes is attributable to, but is not limited to, structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form to the level generally observed using the human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention may be desirable, for example, during production to improve the yield of the desired antibody form, hinge, C H 2 or C H This includes antibodies that have one or more mutations in three regions.

[0206] "Isolated antibodies" means antibodies identified and separated and / or recovered from at least one component of their natural environment. For example, antibodies separated or removed from at least one component of an organism, or antibodies separated or removed from tissues or cells in which such antibodies are naturally present or naturally produced, are "isolated antibodies." Isolated antibodies also include antibodies in situ within recombinant cells. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to certain embodiments, isolated antibodies may be substantially free of other cellular material and / or chemical substances.

[0207] The term "specifically binds" or similar terms means that an antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, antibodies that "specifically bind" to IL-4R, as is the focus of this invention, can be measured by surface plasmon resonance assays in concentrations of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, and approximately K is less than 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or less than approximately 0.5 nM. D These include antibodies that bind to IL-4R or a portion thereof. However, isolated antibodies that specifically bind to human IL-4R may exhibit cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0208] Anti-IL-4R antibodies useful for this method may contain one or more amino acid substitutions, insertions, and / or deletions (e.g., substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and / or insertions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and / or deletions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) in the framework of the heavy and light chain variable domains and / or the CDR region, compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from publicly available antibody sequence databases. The present invention relates to a method comprising the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids (e.g., amino acids 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 in the case of trimer antibodies, or 1, 2, 3, 4, 5, or 6 in the case of HCVR and LCVR of antibodies) within the CDR region of one or more frameworks, comprising the method of mutating one or more amino acids (e.g., amino acids 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) within the CDR region of one or more frameworks and / or one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in the case of trimer antibodies, or 1, 2, 3, 4, 5, or 6) to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conserved amino acid substitution in the corresponding germline residue (such sequence exchanges are collectively referred to herein as “germline mutations”). Those skilled in the art can readily produce a very large number of antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof, starting from the heavy-chain and light-chain variable region sequences disclosed herein. In certain embodiments, VH and / also V L In other embodiments, all of the framework and / or CDR residues within the domain are reverse-mutated to residues found in the original germline sequence from which the antibody originated. In other embodiments, only specific residues, for example, only mutant residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutant residues found in CDR1, CDR2, or CDR3 are reverse-mutated to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are reverse-mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated). Furthermore, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, certain individual residues may be reverse-mutated to corresponding residues in a particular germline sequence, while certain other residues different from the original germline sequence are maintained or reverse-mutated to corresponding residues in a different germline sequence. Once antibodies and antigen-binding fragments containing one or more germline mutations are obtained, they can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, (optionally) improved or enhanced antagonistic or stimulant biological properties, or reduced immunogenicity. The use of antibodies and antigen-binding fragments obtained by this general method is encompassed in the present invention.

[0209] The present invention also includes methods comprising the use of an anti-IL-4R antibody comprising a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes the use of an anti-IL-4R antibody having an HCVR, LCVR, and / or CDR amino acid sequence having, for example, 10 or fewer, 8 or fewer, 6 or fewer, and 4 or fewer conservative amino acid substitutions compared to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0210] The term "surface plasmon resonance" refers to an optical phenomenon by which real-time interactions can be analyzed by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore (trademark) system (Biacore Life Sciences devision of GE Healthcare, Piscataway, NJ).

[0211] The term "K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0212] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Therefore, different antibodies can bind to different antigen regions and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes are generated by amino acids that are spatially adjacent and juxtaposed from different segments of a linear peptide chain. Linear epitopes are generated by adjacent amino acid residues within a polypeptide chain. In certain situations, an epitope may include a saccharide, phosphoryl group or sulfonyl group moiety on an antigen.

[0213] Production of human antibodies Methods for producing human antibodies in transgenic mice are known in the art. Using any such known method, human antibodies that specifically bind to human IL-4R can be produced.

[0214] First, a high-affinity chimeric antibody against IL-4R, having a human variable region and a mouse constant region, is isolated using VELOCIMMUNE® technology (see, for example, U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies. VELOCIMMUNE® technology involves the production of a transgenic mouse having a genome containing human heavy and light chain variable regions operably ligated to an endogenous mouse constant region locus, so that the mouse produces an antibody containing the human variable region and the mouse constant region in response to antigen stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably ligated to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0215] Generally, VELOCIMMUNE® mice are sensitized with the target antigen, and lymphocytes (e.g., B cells) are collected from mice expressing the antibody. These lymphocytes can be fused with myeloma cell lines to produce immortal hybridoma cell lines. Such hybridoma cell lines can be screened and selected to identify hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains can be isolated and ligated to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the heavy and light chains can be directly isolated from antigen-specific lymphocytes.

[0216] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized using standard procedures known to those skilled in the art, and selection is made for desired specifics, including affinity, selectivity, and epitope. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody of interest in this invention, such as wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the specific application, but the variable region possesses high-affinity antigen-binding properties and target specificity.

[0217] Generally, antibodies that can be used by this method have the high affinity described above when measured by binding to an antigen immobilized on a solid phase or an antigen in a solution phase. The mouse constant region is replaced with a desired human constant region to produce the fully human antibody of interest in this invention. The selected constant region may vary depending on the specific application, but the variable region possesses high affinity antigen-binding properties and target specificity.

[0218] In one embodiment, a human antibody or antigen-binding fragment that specifically binds to IL-4R and can be used in connection with the method of interest in the present invention comprises three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may also comprise three light-chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art, and such methods and techniques can be used to identify CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Cotia definition, and the AbM definition. Generally speaking, the Kabat definition is based on sequence diversity, the Cotia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Cotia approaches. For example, Kabat, "Sequences of Proteins See “of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J.Mol.Biol.273:927-948 (1997); and Martin et al., Proc.Natl.Acad.Sci.USA 86, pp.9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0219] In certain embodiments, the antibody or its antigen-binding fragment comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) derived from the heavy-chain variable region amino acid and light-chain variable region amino acid pair (HCVR / LCVR) of SEQ ID NO: 1 / 2.

[0220] In certain embodiments, the antibody or its antigen-binding fragment comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs. 3 / 4 / 5 / 6 / 7 / 8.

[0221] In certain embodiments, the antibody or its antigen-binding fragment comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2.

[0222] In one embodiment, the antibody is a dupilumab containing the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2.

[0223] Pharmaceutical composition The present invention includes a method comprising administering an IL-4R antagonist contained in a pharmaceutical composition to a patient. The pharmaceutical compositions of interest in the present invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, and tolerability. Many suitable formulations can be found in prescription collections known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, (cationic or anionic) lipid-containing vehicles (e.g., LIPOFECTIN®), DNA conjugates, and anhydrous absorption paces. This includes oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowaxes. See, for example, Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52: pp. 238-311.

[0224] The dose of antibody administered to a patient may vary depending on the patient's age and size, symptoms, condition, and route of administration. Dosage is generally calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically; for example, the patient's progress can be monitored through periodic assessments, and the dosage can be adjusted accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8: p. 1351).

[0225] Various delivery systems are known, such as liposomes, microparticles, encapsulation in microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262: pp. 4429-4432), and such delivery systems can be used to administer the pharmaceutical compositions of interest in this invention. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions may be administered by any convenient route, for example, by injection or bolus injection, by absorption through the endothelial or mucocutaneous layers (e.g., oral mucosa, rectal and intestinal mucosa), or together with other bioactive agents.

[0226] The pharmaceutical compositions of interest in this invention can be delivered subcutaneously or intravenously using standard injection needles and syringes. In addition, for subcutaneous delivery, pen-type delivery devices are readily available for delivering the pharmaceutical compositions of interest in this invention. Such pen-type delivery devices may be reusable or disposable. Reusable pen-type delivery devices generally utilize replaceable cartridges containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and easily replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. Disposable pen-type delivery devices do not have replaceable cartridges. More precisely, disposable pen-type delivery devices are pre-filled with the pharmaceutical composition, which is held in the device's reservoir. Once the pharmaceutical composition in the reservoir is empty, the entire device is discarded.

[0227] A great many reusable pen-type and auto-injector delivery devices are used for the subcutaneous delivery of pharmaceutical compositions. Examples include, to name just a few, AUTOPEN(trademark) (Owen Mumford, Inc. (Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25® pen, HUMALOG® pen, HUMALIN 70 / 30® pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN® I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR® (Novo Nordisk, Copenhagen, Denmark), BD® pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN®, OPTIPEN P Examples of disposable pen-type delivery devices used for subcutaneous delivery of pharmaceutical compositions of interest in this invention include, but are not limited to, RO(trademark), OPTIPEN STARLET(trademark), and OPTICLIK(trademark) (Sanofi-Aventis, Frankfurt, Germany). Examples of such devices include, but are not limited to, SOLOSTAR(trademark) pens (Sanofi-Aventis), FLEXPEN(trademark) (Novo Nordisk), KWIKPEN(trademark) (Eli Lilly), SURECLICK(trademark) auto-injectors (Amgen, Thousand Oaks, CA), PENLET(trademark) (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA(trademark) pens (Abbott Labs, Abbott Park, IL).

[0228] For direct administration into the sinuses, the pharmaceutical compositions of interest in this invention may be administered using, for example, a microcatheter (e.g., an endoscope and microcatheter), an aerozoizer, a powder dispenser, a sprayer, or an inhaler. The method involves administering an IL-4R antagonist in an aerosolized form to a subject requiring it. For example, a patient's asthma may be treated by administering an aerosolized antibody against IL-4R. The aerosolized antibody can be manufactured, for example, as described in U.S. Patent No. 8,178,098 (which is incorporated herein by reference in its entirety).

[0229] In certain circumstances, pharmaceutical compositions can be delivered using controlled-release systems. In one embodiment, a pump may be used (see Langer, cited above; Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201). In another embodiment, polymer materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, the controlled-release system may be placed immediately adjacent to the target of the composition, and therefore only a fraction of the systemic dose may be required (see, for example, Goodson, 1984, Medical Applications of Controlled Release, cited above, Vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0230] Injectable formulations include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, as well as intravenous infusion. These injectable formulations can be manufactured by known methods. For example, an injectable formulation can be manufactured by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injectable formulations. Examples of aqueous media for injectable formulations include physiological saline, isotonic solutions containing glucose and other adjuvants, which may be used in combination with appropriate solubilizers, such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), or nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which may be used in combination with solubilizers, such as benzyl benzoate or benzyl alcohol. Injectable formulations thus manufactured are generally filled into appropriate ampoules.

[0231] Advantageously, the oral or parenteral pharmaceutical compositions described above are manufactured in dosage forms of unit doses suitable for combining the dosages of the active ingredient. Such dosage forms of unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories and the like.

[0232] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the present invention are disclosed, for example, in US Patent Application Publication No. 2012 / 0097565.

[0233] Dosage The amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) administered to a subject according to the methods noted in the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means the amount of an IL-4R antagonist that brings about one or more of the following: (a) a reduction in the incidence of exacerbations of asthma; (b) an improvement in one or more asthma-related parameters (defined elsewhere in this specification), and / or (c) a detectable improvement in one or more symptoms or signs of an upper airway inflammatory condition. "Therapeutically effective amount" also includes the amount of an IL-4R antagonist that inhibits, prevents, alleviates, or delays the progression of asthma in a subject.

[0234] For anti-IL-4R antibodies, the effective therapeutic dose is approximately 0.05 mg to 700 mg of anti-IL-4R antibody, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3.0 mg, 5.0 mg, 7.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 1 90mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, About 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400 mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 5 The dosage can be 10 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, or approximately 700 mg. In certain embodiments, 300 mg of anti-IL-4R antibody is administered.

[0235] The amount of IL-4R antagonist contained in each dose may also be expressed in milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a patient at a dose of approximately 0.0001 to approximately 10 mg / (patient body weight / kg). For example, the IL-4R antagonist may be administered at doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0236] In some embodiments, the dose of the IL-4R antagonist may vary depending on the eosinophil count. For example, the subjects may have a blood eosinophil count ≥ 300 cells / μL (high blood eosinophil count) (HEos); a blood eosinophil count of 200-299 cells / μL; or a blood eosinophil count < 200 cells / μL (low blood eosinophil count).

[0237] In certain embodiments, the method includes a loading dose of approximately 400 to 600 mg of an IL-4R antagonist.

[0238] In certain embodiments, the method includes one or more maintenance doses of approximately 200 to 300 mg of an IL-4R antagonist.

[0239] In certain embodiments, ICS and LABA are administered during the administration period of an IL-4R antagonist.

[0240] In certain embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0241] In certain embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0242] In other embodiments, the loading dose comprises 600 mg of anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0243] In other embodiments, the loading dose comprises 400 mg of anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0244] In other embodiments, the loading dose comprises 600 mg of anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered once weekly.

[0245] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered once weekly.

[0246] In other embodiments, the loading dose comprises 600 mg of anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 300 mg of the antibody or its antigen-binding fragment administered every three weeks.

[0247] In other embodiments, the loading dose comprises 400 mg of anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses comprises 200 mg of the antibody or its antigen-binding fragment administered every three weeks.

[0248] In one embodiment, the subjects are between 6 and 18 years of age, and the IL-4R antibody or its antigen-binding fragment is administered at a dose of 2 mg / kg or 4 mg / kg.

[0249] In another embodiment, the subjects are between 2 and 6 years of age, and the IL-4R antibody or its antigen-binding fragment is administered at a dose of 2 mg / kg or 4 mg / kg.

[0250] In yet another embodiment, the subjects are under 2 years of age, and the IL-4R antibody or its antigen-binding fragment is administered at 2 mg / kg or 4 mg / kg.

[0251] Combination therapy Certain embodiments of the methods of focus in the present invention involve administering one or more additional therapeutic agents to a subject in combination with an IL-4R antagonist. As used herein, the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with a pharmaceutical composition containing an IL-4R antagonist. In some embodiments, the term “in combination with” includes sequential or concurrent administration of the IL-4R antagonist and the second therapeutic agent. The present invention includes methods for treating asthma or related conditions or complications or for reducing at least one exacerbation, comprising the administration of an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0252] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before the administration of the pharmaceutical composition containing the IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after the administration of the pharmaceutical composition containing the IL-4R antagonist. "Contemporary" administration of a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a different dosage form less than 5 minutes (before, after, or simultaneously with) the administration of the pharmaceutical composition containing the IL-4R antagonist, or that the additional therapeutic agent is administered to the subject as a single combination dose formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0253] Further therapeutic agents may include, for example, other IL-4R antagonists, IL-1 antagonists (including, for example, the IL-1 antagonist described in U.S. Patent No. 6,927,044), IL-6 antagonists, IL-6R antagonists (including, for example, the anti-IL-6R antibody described in U.S. Patent No. 7,582,298), TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists, IL-5 antagonists, IgE antagonists, CD48 antagonists, leukotriene inhibitors, antifungal agents, NSAIDs, long-acting β2-agonists (e.g., salmeterol or formoterol), inhaled corticosteroids (e.g., fluticasone or budesonide), systemic corticosteroids (e.g., oral or intravenous), methylxanthines, nedocromil sodium, sodium cromoglycate, or combinations thereof. For example, in certain embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered in combination with a combination of a long-acting β2-agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., SYMBICORT® (Astra Zeneca)]).

[0254] Administration regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined time period. Such a method includes sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, “sequentially administering” means administering each dose of the IL-4R antagonist to a subject at different times, for example, on different days separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). The present invention includes a method comprising sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more second doses of the IL-4R antagonist, and optionally, one or more third doses of the IL-4R antagonist.

[0255] The present invention includes a method for administering a pharmaceutical composition containing an IL-4R antagonist to a subject at a frequency of administration of approximately four times a week, twice a week, once a week, every two weeks (every other week), once every three weeks, once every four weeks (once a month), once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or at a frequency less frequent if a therapeutic response is obtained. In certain embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, weekly administrations of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used. In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, administrations of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used every two weeks (every other week). In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, doses of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be administered once every three weeks. A dose of 00 mg, 150 mg, 200 mg, or 300 mg can be administered once every four weeks (once a month). In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, a dose of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be administered once every five weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, a dose of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be administered once every six weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, a dose of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be administered once every eight weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, a dose of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be administered once every twelve weeks. In one embodiment, the route of administration is subcutaneous.

[0256] The term "week" refers to a period of (n × 7 days) ± 2 days, for example (n × 7 days) ± 1 day, or (n × 7 days), where "n" is the number of weeks, for example 1, 2, 3, 4, 5, 6, 8, 12, or more.

[0257] The terms “initial dose,” “second dose,” and “third dose” refer to the time series of IL-4R antagonist administrations. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. While the initial, second, and third doses may all contain the same amount of IL-4R antagonist, they will generally differ from one another in terms of administration frequency. However, in certain embodiments, the amounts of IL-4R antagonist contained in the initial, second, and / or third doses may differ from one another throughout the course of treatment (e.g., adjusted upward or downward as needed). In certain embodiments, two or more doses (e.g., 2, 3, 4, or 5) are administered as “loading doses” at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., “maintenance doses”). In one embodiment, the maintenance dose may be lower than the loading dose. For example, a loading dose of 600 mg or more of an IL-4R antagonist may be administered, followed by a maintenance dose of approximately 75 mg to 300 mg.

[0258] In certain embodiments, the loading dose is approximately 400 to 600 mg of IL-4R antagonist. In one embodiment, the loading dose is 400 mg of IL-4R antagonist. In another embodiment, the loading dose is 600 mg of IL-4R antagonist.

[0259] In certain embodiments, the maintenance dose is approximately 200 to 300 mg of IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of IL-4R antagonist. In another embodiment, the maintenance dose is 300 mg of IL-4R antagonist.

[0260] In certain embodiments, the load dose is twice the maintenance dose.

[0261] In some embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0262] In some embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0263] In some embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses are administered every four weeks. Contains 300 mg of fragments.

[0264] In some embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0265] In one exemplary embodiment, each second and / or third dose is administered 1 to 14 weeks after the immediately preceding dose (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks or more). The phrase “immediately preceding dose” means, with respect to a sequence of multiple doses, the dose of the anti-IL-4R antagonist administered to the patient immediately before the administration of the next dose in that sequence, without any intervening doses.

[0266] The method may include administering any number of second and / or third doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more second doses (e.g., two, three, four, five, six, seven, eight or more doses) are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more third doses (e.g., two, three, four, five, six, seven, eight or more doses) are administered to the patient.

[0267] In embodiments including multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments including multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency at which second and / or third doses are administered to the patient may vary throughout the course of the treatment regimen. The administration frequency may also be adjusted by the physician during the course of treatment according to the individual patient's needs based on clinical examinations.

[0268] The present invention includes a method comprising sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient for the treatment of asthma or a related condition. In some embodiments, the method comprises the administration of one or more doses of an IL-4R antagonist, followed by the administration of one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) of a second therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-4R antagonist may be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) of a second therapeutic agent (e.g., an inhaled corticosteroid or β2-agonist or other therapeutic agent, as described elsewhere herein) for the treatment, relief, reduction, or improvement of one or more symptoms of asthma. In some embodiments, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) of an IL-4R antagonist are administered, resulting in improvement of one or more asthma-related parameters, after which a second therapeutic agent is administered to prevent recurrence of at least one symptom of asthma. Alternative embodiments relate to the combined administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) of an IL-4R antagonist are administered, and the second therapeutic agent is administered in a different dosage, at a similar or different frequency compared to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or concurrently with the IL-4R antagonist.

[0269] In certain embodiments, the IL-4R antagonist is administered every two weeks for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks, or longer. In other embodiments, the IL-4R antagonist is administered every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In specific embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0270] Treatment group A method of interest in the present invention involves administering a therapeutic composition containing an IL-4R antagonist to a subject in need of it. The expression “subject in need” means a human or non-human animal exhibiting one or more symptoms or signs of asthma (e.g., moderate to severe uncontrolled asthma), or being diagnosed with asthma. For example, a “subject in need” could be a subject that exhibits (or has exhibited) one or more asthma-related parameters prior to treatment, such as decreased FEV1 (e.g., <2.0 L), decreased AM PEF (e.g., <400 L / min), decreased PM PEF (e.g., <400 L / min), an ACQ5 score of at least 2.5, at least one nocturnal awakening per night, and / or an SNOT-22 score of at least 20. In various embodiments, the method may be used to treat mild, moderate to severe, and severe asthma in patients in need of it.

[0271] In related embodiments, “subjects requiring it” may be subjects who have been prescribed or are currently taking an ICS / LABA combination prior to receiving an IL-4R antagonist. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABAs include formoterol and salmeterol. Examples of ICS / LABA therapies include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. For example, the present invention includes a method comprising administering an IL-4R antagonist to a patient who has been receiving regular ICS / LABA therapy for two weeks or more immediately prior to the administration of the IL-4R antagonist (such prior treatment is referred to herein as “background treatment”). The present invention also includes a treatment method in which the background treatment is continued in conjunction with the administration of the IL-4R antagonist. In yet another embodiment, the amounts of the ICS component, the LABA component, or both are gradually reduced before or after the initiation of IL-4R antagonist administration. In some embodiments, the present invention includes a method for treating patients who have had persistent asthma for at least 12 months. In one embodiment, patients with persistent asthma may be resistant to treatment with therapeutic agents such as corticosteroids, and such patients may be administered an IL-4R antagonist according to the present method.

[0272] In some embodiments, “subjects requiring it” may be subjects having elevated levels of asthma-related biomarkers. Examples of asthma-related biomarkers include, but are not limited to, IgE, thymic and activating regulatory chemokines (TARCs), eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, “subjects requiring it” may be subjects with blood eosinophil counts of ≥300, 200-299 / μL, or <200 / μL. In one embodiment, “subjects requiring it” may be subjects having elevated levels of bronchial or airway inflammation, as measured by exhaled nitric oxide concentration (FeNO).

[0273] In some embodiments, “the subjects who need it” are selected from the group consisting of subjects aged 18 years or older, subjects aged 12 to 17 years (12 to under 18 years), subjects aged 6 to 11 years (6 to under 12 years), and subjects aged 2 to 5 years (2 to under 6 years). In some embodiments, “the subjects who need it” consist of adults, adolescents, and children. A group is selected. In some embodiments, “the subject requiring it” is selected from the group consisting of adults aged 18 years or older, adolescents aged 12–17 years (12–18 years), children aged 6–11 years (6–12 years), and children aged 2–5 years (2–6 years). The subject may also be under 2 years of age, for example, 12–23 months or 6–11 months.

[0274] Normal IgE levels in healthy subjects are less than approximately 100 kU / L (measured, for example, using the IMMUNOCAP® assay [Phadia, Inc., Portage, MI]). Therefore, the present invention includes a method comprising the steps of selecting a subject exhibiting elevated serum IgE levels, which are serum IgE levels higher than approximately 100 kU / L, higher than approximately 150 kU / L, higher than approximately 500 kU / L, higher than approximately 1000 kU / L, higher than approximately 1500 kU / L, higher than approximately 2000 kU / L, higher than approximately 2500 kU / L, higher than approximately 3000 kU / L, higher than approximately 3500 kU / L, higher than approximately 4000 kU / L, higher than approximately 4500 kU / L, or higher than approximately 5000 kU / L, and administering a pharmaceutical composition containing a therapeutically effective amount of an IL-4R antagonist to the subject.

[0275] In healthy subjects, TARC levels range from 106 ng / L to 431 ng / L, with an average value of approximately 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC Quantitative ELISA Kit, available from R&D Systems, Minneapolis, MN, under catalog number DDN00). Accordingly, the present invention includes a method comprising the steps of selecting a subject exhibiting elevated TARC levels, which are serum TARC levels higher than approximately 431 ng / L, higher than approximately 500 ng / L, higher than approximately 1000 ng / L, higher than approximately 1500 ng / L, higher than approximately 2000 ng / L, higher than approximately 2500 ng / L, higher than approximately 3000 ng / L, higher than approximately 3500 ng / L, higher than approximately 4000 ng / L, higher than approximately 4500 ng / L, or higher than approximately 5000 ng / L; and administering to the subject a pharmaceutical composition containing a therapeutically effective dose of an IL-4R antagonist.

[0276] Eotaxin-3 belongs to the group of chemokines released by airway epithelial cells that are upregulated by Th2 cytokines IL-4 and IL-13 (Lilly et al., 1999, J. Allergy Clin. Immunol. 104: pp. 786-790). The present invention includes a method comprising administering an IL-4R antagonist to treat patients having elevated eotaxin-3 levels, for example, higher than approximately 100 pg / ml, higher than approximately 150 pg / ml, higher than approximately 200 pg / ml, higher than approximately 300 pg / ml, or higher than approximately 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0277] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin levels have been shown to be upregulated in patients with asthma (Jia et al., 2012, J Allergy Clin Immunol. 130:647-654.e10.doi:10.1016:j.jaci.2012.06.025.Epub, August 1, 2012). The present invention includes a method comprising administering an IL-4R antagonist to treat patients with elevated periostin levels.

[0278] Exhaled nitric oxide (FeNO) concentration is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines, including IL-4 and IL-13 (Alwing et al., 1993, Eur.Respir.J.6: pp. 1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is performed using the NIOX instrument by Aerocrine AB, Solna, Sweden. Evaluation should be performed before vital capacity measurement and with minimal effort. Both can be performed after a one-hour fast. The present invention includes a method comprising administering an IL-4R antagonist to a patient having elevated exhaled NO (FeNO) levels, for example, FeNO levels higher than 30 ppb, about 31 ppb, about 32 ppb, about 33 ppb, about 34 ppb, or about 35 ppb.

[0279] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker known to correlate with non-neoplastic lung diseases (Marechal et al., 1988, Anticancer Res. 8: pp. 677-680). Serum CEA levels can be measured by ELISA. The present invention includes a method comprising administering an IL-4R antagonist to patients having elevated CEA levels, for example, higher than about 1.0 ng / ml, higher than about 1.5 ng / ml, higher than about 2.0 ng / ml, higher than about 2.5 ng / ml, higher than about 3.0 ng / ml, higher than about 4.0 ng / ml, or higher than about 5.0 ng / ml.

[0280] YKL-40 [named after its N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L), with a molecular weight of 40 kD] is a chitinase-like protein known to be upregulated and correlated with asthma exacerbations, IgE, and eosinophils (Tang et al., 2010, Eur.Respir.J.35:757-760). Serum YKL-40 levels are measured, for example, by ELISA. The present invention includes a method comprising administering an IL-4R antagonist to patients having elevated YKL-40 levels, for example, higher than about 40 ng / ml, higher than about 50 ng / ml, higher than about 100 ng / ml, higher than about 150 ng / ml, higher than about 200 ng / ml, or higher than about 250 ng / ml.

[0281] Periostin is a secretory matrix cell protein associated with fibrosis, and its expression is upregulated by recombinant IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial fibroblasts (Jia et al., (2012) J. Allergy Clin. Immunol. 130:647). In human asthma patients, periostin expression levels correlate with reticular basement thickness, an indicator of subepithelial fibrosis. (Same literature). The present invention includes a method comprising administering an IL-4R antagonist to a patient having elevated periostin levels.

[0282] Induced sputum eosinophils and neutrophils are established direct markers of airway inflammation (Djukanovic et al., 2002, Eur. Respire. J. 37:1S-2S). Sputum is induced by inhalation of hypertonic saline and processed for cell counting according to methods known in the art, e.g., the European Respiratory Society guidelines.

[0283] In some embodiments, subjects are stratified into the following groups: blood eosinophil count ≥ 300 cells / μL (high blood eosinophil count) (HEos), blood eosinophil count 200-299 cells / μL (moderate blood eosinophil count), or blood eosinophil count < 200 cells / μL (low blood eosinophil count), and receive administration of an anti-IL-4R antibody or its antigen-binding fragment at a dose or administration regimen based on eosinophil level.

[0284] Methods for evaluating pharmacodynamic asthma-related parameters The present invention also includes a method for evaluating one or more pharmacodynamic asthma-related parameters in subjects requiring administration of a pharmaceutical composition containing an IL-4R antagonist. A reduction in the incidence of asthma exacerbations (as described above) or an improvement in one or more asthma-related parameters (as described above) may correlate with an improvement in one or more pharmacodynamic asthma-related parameters, although such correlations are not necessarily observed in all cases.

[0285] Examples of "pharmacodynamic asthma-related parameters" include, for example, (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement of pharmacodynamic asthma-related parameters" means, for example, a decrease from baseline in one or more biomarkers such as TARC, eotaxin-3, or IgE; a decrease in sputum eosinophil or neutrophil count; FeNO; periostin; or blood eosinophil count. As used herein, the term "baseline" with respect to pharmacodynamic asthma-related parameters means the numerical value of the patient's pharmacodynamic asthma-related parameters before or at the time of administration of the pharmaceutical composition described herein.

[0286] To evaluate pharmacodynamic asthma-related parameters, these parameters are quantified at baseline and at points after administration of the pharmaceutical composition. For example, pharmacodynamic asthma-related parameters may be measured on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 14 after the initial treatment with the pharmaceutical composition, or at weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, or at further points in time. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to confirm whether there has been a change (e.g., an increase or decrease, depending on the specific parameter being measured), such as an "improvement," in the pharmacodynamic asthma-related parameter.

[0287] In certain embodiments, administration of an IL-4R antagonist to a patient may cause changes in the expression of certain biomarkers, e.g., decreases or increases. Asthma-related biomarkers include, but are not limited to, (a) total IgE; (b) thymic and activating regulatory chemokines (TARC); (c) YKL-40; (d) carcinoembryonic antigen in serum; (e) eotaxin-3 in plasma; and (f) periostin in serum. For example, administration of an IL-4R antagonist to an asthma patient may cause one or more of the following: a decrease in TARC or eotaxin-3 levels, or a decrease in serum total IgE levels. Such decreases can be detected at week 1, 2, 3, 4, 5, or thereafter after administration of the IL-4R antagonist. Biomarker expression can be assayed by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured, for example, by reverse transcription-linked polymerase chain reaction (RT-PCR).

[0288] The biomarker expression discussed above can be assayed by detecting proteins or RNA in serum. Serum samples can also be used to monitor further protein or RNA biomarkers related to responses to treatment with IL-4R antagonists, IL-4 / IL-13 signaling, asthma, atopic dermatitis, or eosinophilic diseases (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, and periostin). In some embodiments, RNA samples are used for RNA level determination (non-genetic analysis), e.g., determination of RNA levels of biomarkers; in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0289] formulation In some embodiments, the antibody or its antigen-binding fragment is formulated with a composition comprising: i) approximately 150 mg / mL of the antibody or its antigen-binding fragment that specifically binds to IL-4R, ii) approximately 20 mM histidine, iii) approximately 12.5 mM acetate, iv) Approximately 5% (w / v) sucrose, v) approximately 25 mM arginine hydrochloride, vi) approximately 0.2% (w / v) polysorbate 80. In this case, the pH of the formulation is approximately 5.9, and the viscosity of the formulation is approximately 8.5 centipoise.

[0290] In an alternative embodiment, the antibody or its antigen-binding fragment is formulated with a composition comprising: i) approximately 175 mg / mL of the antibody or its antigen-binding fragment that specifically binds to IL-4R; ii) approximately 20 mM histidine; iii) approximately 12.5 mM acetate; iv) approximately 5% (w / v) sucrose; v) approximately 50 mM arginine hydrochloride; vi) approximately 0.2% (w / v) polysorbate 80. In this case, the pH of the formulation is approximately 5.9, and the viscosity of the formulation is approximately 8.5 centipoise.

[0291] In a specific embodiment, the antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0292] The present invention is further illustrated by the following embodiments, which should not be considered as further limitations. All figures and references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0293] Furthermore, conventional molecular biology, microbiology, and recombinant DNA techniques within the scope of the skills of the art may be utilized in accordance with the present invention. Such techniques are well described in the literature. For example, see Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th edition (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (edited by DNGlover, 1985); Oligonucleotide Synthesis (edited by MJ Gait, 1984); Nucleic Acid Hybridization (edited by B.D. Hames and S.J. Higgins, 1985); Transcription and Translation (edited by B.D. Hames and S.J. Higgins, 1984); Animal Cell Culture (edited by R.R. Freshney, 1986); Immobilized Cells and Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Usubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). [Examples]

[0294] The following examples are provided to give a complete disclosure and explanation of the methods and compositions of interest in the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. While efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), some experimental error and deviation should be taken into consideration. Unless otherwise indicated, parts are parts by weight, molecular weight is the average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or approximately atmospheric pressure.

[0295] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1").

[0296] [Example 1] Pharmacokinetics of mAb1 in asthma patients A pharmacokinetic study was conducted in asthma patients. mAb1 300 mg was administered to each patient once a week for 12 weeks. max , AUC, t last , C last and t 1 / 2 Various drugs including The bodily dynamics parameters were measured. The results are shown in Table 1 below.

[0297] [Table 1]

[0298] 458 hours (19.1 days) average t 1 / 2 This is consistent with the half-life of the IgG molecule, further supporting the idea that target-mediated clearance was not the primary efflux pathway for mAb1 at the concentrations observed during this study.

[0299] Figure 1 shows a graph of the mean serum functional mAb1 concentration over time. As shown in Figure 1, after administering a dose of 300 mg / week of mAb1 to asthma patients once a week for 12 weeks, C trough The concentration appeared to plateau between weeks 10 and 12. Compared to after the first dose, C after the 12th dose... trough The cumulative effect assessed by this method was 5.88 with a 300 mg once-weekly dose. In most patients, serum mAb1 levels were still detectable at the time of the final PK sample (7-9 weeks after the last drug administration). These findings suggest the potential benefits of a loading dose.

[0300] Serum concentrations of mAb1 were measured in patients with atopic dermatitis or asthma during a 300 mg once-weekly administration regimen. As shown in Figure 2, systemic exposure to mAb1 was similar in patients with atopic dermatitis and asthma during the first four weeks of 300 mg once-weekly administration.

[0301] [Example 2] A randomized, double-blind, placebo-controlled dose-determination study to evaluate the anti-IL-4R antibody dupilumab in patients with moderate to severe uncontrolled asthma. A. Research Objectives and Overview A randomized, double-blind, placebo-controlled, dose-determining trial was conducted to evaluate mAb1 (dupilumab) in patients with moderate to severe uncontrolled asthma. The primary objective of this study was to evaluate the efficacy of various doses and regimens of mAb1 in patients with moderate to severe uncontrolled asthma. A secondary objective of this study was to evaluate the efficacy of mAb1 in patients with moderate to severe uncontrolled asthma. The evaluation of various doses and regimens of mAb1 was to assess the following: safety and tolerability, systemic exposure to mAb1 and anti-drug antibodies, and patient-reported outcomes (PROs); baseline biomarkers for their potential value to predict treatment response; on-treatment biomarkers for their potential value to associate with treatment response; and genetic profiles for their potential value to predict treatment response.

[0302] B. Research Design This study is a multinational, multicenter, randomized, double-blind, placebo-controlled, dose-determining, parallel-group study comparing various doses and regimens of subcutaneously administered mAb1 over 24 weeks in patients with moderate to severe uncontrolled asthma. Approximately 770 patients were randomly assigned to one of five treatment groups of 150 patients each.

[0303] This clinical trial, using an add-on treatment approach to inhaled corticosteroid / long-acting beta-agonist combination therapy (ICS / LABA), consisted of three periods: a screening period (14-21 days) to determine if patients met the inclusion criteria and to confirm the level of asthma control before the randomization treatment period; a randomization treatment period (24 weeks); and a post-treatment period (16 weeks) to monitor patients after treatment.

[0304] C. Patient Selection Patients aged 18–65 years diagnosed by a physician with moderate to severe uncontrolled asthma for 12 months or longer, based on the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria, were eligible for inclusion in this study: (1) Existing treatment using a stable ICS / LABA dose of moderate or high-dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or an equivalent daily dose of ICS) for at least one month prior to visit 1; (2) FEV1 before the first dose of the investigational drug at visits 1 and 2. (3) ACQ-5 score ≥ 1.5 at visit 1 and visit 2; (4) Reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations) at visit 1; and (5) Any of the following events experienced within one year prior to visit 1: treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, or hospitalization or emergency medical visit for asthma exacerbation.

[0305] Patients who met all of the above inclusion criteria were screened for the following exclusion criteria: (1) Patient < 18 years of age; (2) Chronic obstructive pulmonary disease (COPD) or other lung disease that impairs pulmonary function tests (e.g., emphysema, idiopathic pulmonary fibrosis, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis); (3) Clinically significant findings of lung disease other than asthma, on chest X-ray within 12 months prior to screening or at the time of screening; (4) Current smoker or quit smoking within 6 months prior to the visit; (5) Ex-smoker with a smoking history of > 10 packs / year; (6) Comorbidities that may interfere with the evaluation of IMP (mAb1); (7) Illegibility, alcohol abuse or drug use (8) Abuse is present or suspected; (9) Inability to follow study procedures (e.g., due to language problems or psychological disorders); (10) Reversal of sleep patterns (e.g., night shift workers); (11) Patients requiring beta-adrenergic receptor blockers (beta-blockers) for any reason; (12) Immunoglobulin E (IgE) treatment (omalizumab) within 130 days prior to visit 1; Biological treatment within 6 months prior to visit 1; (13) Initiation of allergen immunotherapy within 3 months prior to visit 1, or planned initiation or dose change of treatment during the screening period or randomization treatment period; (14) Exposure to another investigational antibody within a time period prior to visit 1 when the antibody's half-life (if known) is less than 5. If the half-life is unknown, the minimum interval from previous exposure to the investigational antibody is 6 months. (14) Patients receiving any other (non-antibody) investigational drug within 30 days prior to hospital visit; (15) Patients with a history of participation in this study or other mAb1 studies. (16) The patient is the principal investigator or any assistant investigator, research assistant, pharmacist, clinical trial coordinator, other staff, or a relative of the patient, who is directly involved in the implementation of the protocol; (17) Non-compliance with the use of essential background treatments and ICS / LABA complex products during the screening period (this non-compliance is defined as: less than 80% of the total prescribed “stable dose” puffs were taken during the screening period. Compliance will be verified based on ICS / LABA use recorded in the patient’s electronic diary during the screening period); ( 18) Diagnosis of a history of serious concomitant illnesses or conditions that make the use of ICS contraindicated (e.g., active and inactive pulmonary tuberculosis) or conditions that make the use of LABA contraindicated (e.g., significant cardiovascular disease, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, hyperthyroidism, pheochromocytoma, hypokalemia, corrected QT interval prolongation (male >450 ms, female >470 ms), or tachyarrhythmia); (19) Treatment with medications associated with clinically significant corrected QT interval prolongation / Torsades de Pointes ventricular tachycardia; (20) Women of childbearing potential (live Women who are premenopausal and physically capable of becoming pregnant, and who meet any of the following criteria: women who do not have a confirmed negative serum β-hCG test at visit 1, or women who are not protected by one of the following acceptable forms of effective contraception during this study: establishment of oral, injectable, or implantable hormonal contraceptives; copper-containing intrauterine devices (IUDs) or progestogen-containing intrauterine systems (IUSs); or barrier contraceptives (condoms, pessaries, or cervical / vaginal rings) used in conjunction with spermicides (foams, gels, films, creams, or suppositories). (21) Diagnosed with active parasitic infection; (21) Diagnosed with active parasitic infection; (22) Diagnosed with active parasitic infection; (23) Diagnosed with active parasitic infection; (24) Diagnosed with active parasitic infection; (25) Diagnosed with active parasitic infection; (26(22) Suspected or high risk of parasitic infection (except in cases where active infection is ruled out by clinical and (if necessary) experimental evaluation prior to randomization); (23) History of human immunodeficiency virus (HIV) infection or positive HIV test (anti-HIV-1 and HIV-2 antibodies) on visit 1; (24) History of invasive, opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), even if the infection has been resolved. (24) A history or suspected immunosuppression; or, in the judgment of the principal investigator, an unusually high frequency, recurrent, or prolonged infection; (25) Evidence of an acute or chronic infection requiring treatment with antibiotics, antivirals, antifungals, antiparasitic agents or antiprotozoal agents within 4 weeks prior to the visit; a significant viral infection within 4 weeks prior to the visit that could not be treated with antiviral agents (e.g., influenza that was only treated symptomatically); (26) Attenuated live vaccine within 12 weeks prior to the visit, or during the study There is a plan for attenuated live vaccination - Prohibited attenuated live vaccines are Calmette-Guérin bacillus (BCG) anti-tuberculosis vaccine; varicella (chickenpox / varicella); intranasal influenza (flumist influenza); inactivated influenza vaccine delivered by injection is acceptable; measles (measles / rubeola); measles-mumps-rubella (MMR) combined; measles-mumps-rubella-varicella (MMRV) combined; mumps; oral polio (Sebin); Oral typhoid fever; rotavirus; rubella; smallpox (vaccinia); varicella-zoster virus (herpes zoster); and yellow fever; (26) patients with active autoimmune diseases or patients using immunosuppressive therapy for autoimmune diseases (e.g., Hashimoto's thyroiditis, Braves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris); and (27) patients who are positive or unconfirmed for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at visit 1.

[0306] Only patients who met all inclusion criteria and none of the exclusion criteria were included in this study.

[0307] D. Research Procedures Sterile mAb1 at various concentrations was supplied to 5 mL glass vials; each vial had a dispensable capacity of 2 mL: 150 mg / mL solution (300 mg dose / 2 mL) or 100 mg / mL solution (200 mg dose / mL).

[0308] Patients were randomly assigned to one of the following 24-week treatments, receiving either mAb1 or placebo subcutaneously (SC) every two weeks (q2w) according to one of the following doses and regimens: ● 600 mg loading dose (LD) followed by mAb1 300 mg every two weeks (D); ● 400 mg loading dose (LD) followed by mAb1 200 mg every two weeks (D); ● 600 mg loading dose (LD) followed by mAb1 300 mg every 4 weeks (D); ● 400 mg loading dose (LD) followed by mAb1 200 mg every 4 weeks (D); or ● Placebo loading dose, placebo every two weeks (P).

[0309] Dosing the drug every two weeks is also known as dosing it every other week. Dosing the drug every four weeks is also known as dosing it once a month.

[0310] Prior to screening, patients had received a stable dose of moderate or high-dose ICS / LABA (≥250 μg fluticasone propionate twice daily, or an equivalent dose of ICS) for at least one month prior to visit 1. In this study, the acceptable combination products during the treatment period were: mometasone furoate / formoterol; budesonide / formoterol; and fluticasone propionate / salmeterol. If a patient was using an alternative combination product (e.g., fluticasone / formoterol) prior to the randomization visit, the investigator switched the patient to one of the three acceptable treatment-period combination products at an equivalent dose at randomization visit 2 (day 1).

[0311] During the randomization treatment period, patients continued a stable dose of ICS / LABA equivalent to that used during the screening period. See Table 2 for acceptable ICS / LABA combination products, dosage forms, strengths, and schedules required during the treatment period to meet background treatment requirements for medium-to-high daily doses of ICS.

[0312] [Table 2]

[0313] Upon completion of the randomization treatment period (or after early discontinuation of the investigational drug), patients continued treatment with the stable dose of ICS / LABA maintained throughout the randomization treatment period (or their treatment was modified based on medical judgment).

[0314] During this study, patients were permitted to receive salbutamol / albuterol hydrofluoroalkane pressurized MDI or levosalbutamol / levalbuterol hydrofluoroalkane pressurized MDI as a treatment for seizures, as needed. Sprays were also sometimes used as an alternative delivery method.

[0315] During the screening or randomization treatment period, the following concomitant treatments were not permitted: systemic (oral or injectable) corticosteroids (except when used to treat asthma exacerbations); methylxanthines (e.g., theophylline, aminophylline); lipoxygenase inhibitors (e.g., azelastine, dilauton); chromone; anti-immunoglobulin E (IgE) therapy (e.g., omalizumab); biological therapies; methotrexate; initiation of allergen immunotherapy (allergen immunotherapy at a designated site for 3 months or more prior to visit 1 was permitted); and intravenous immunoglobulin (IVIG) therapy.

[0316] The permitted concomitant medications included: leukotriene antagonists / modifiers were permitted during this study, but patients had to have been using a stable dose 30 days or more prior to visit 1; allergen immunotherapy at a designated site for 3 months or more prior to visit 1 was permitted; antihistamines were permitted as concomitant medications; ophthalmic or intranasal corticosteroids were permitted during this study, but patients had not been using a stable dose 30 days or more prior to visit 1. It had to be that way.

[0317] Patients were randomized to receive mAb1 300 mg every two weeks, mAb1 200 mg every two weeks, mAb1 300 mg every four weeks, mAb1 200 mg every four weeks, or placebo, using a randomization ratio of 1:1:1:1:1. Randomization was stratified by hospital visit, central laboratory serum eosinophil count (high serum eosinophils ≥ 300 cells / μL (HEos); serum eosinophils ≥ 200-299 cells / μL; serum eosinophils < 200 cells / μL) and country.

[0318] Approximately 40 percent of patients had high eosinophil levels across all dose groups, and approximately 77 percent of randomized patients had a history of atopic conditions, including atopic dermatitis, allergic conjunctivitis, allergic rhinitis, chronic sinusitis, nasal polyposis, food allergies, and / or urticaria.

[0319] E. Efficacy of the treatment The primary endpoint of this study was the change in FEV1 from baseline at week 12. Such measurements were performed using a spirometer. Spirometry was performed between 6:00 AM and 10:00 AM, 6 hours after the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol, and 12 hours after the final dose of ICS / LABA. Pulmonary function tests were performed in a seated position, and the highest FEV1 measurement was recorded in liters.

[0320] Secondary efficacy endpoints evaluated: (1) Relative change (%) of FEV1 from baseline at week 12; (2) Annual rate of asthma loss of control events during the treatment period; (3) Annual rate of severe exacerbation events during the treatment period; (4) Time to asthma loss of control event during the treatment period; (5) Time to severe exacerbation event during the treatment period; (6) Time to asthma loss of control event throughout the entire study period; (7) Time to severe exacerbation event throughout the entire study period; (8) Utilization of medical resources; (9) Baseline of the following at week 12 Changes from baseline: morning and evening asthma symptom scores, ACQ-5, AQLQ scores, morning and evening PEF, number of salbutamol / albuterol or levosalmola / levalbuterol inhalations per day for symptom relief, and nocturnal awakenings; (10) Changes from baseline in weeks 12 and 24 regarding: SNOT-22, Hospital Anxiety and Depression Scale (HADS), and EuroQual Questionnaire (EQ-5D-3L or EQ-5D-5L). Changes from baseline at other time points (e.g., 24 weeks) were also analyzed for the above measurements.

[0321] Two types of asthma exacerbation events were defined: loss of control (LOAC) events and severe exacerbation events. A loss of control (LOAC) event in this study was defined as any of the following: six or more additional salbutamol / albuterol or levosalbutamol / levalbuterol rescue medication puffs (compared to baseline) in a 24-hour period over two consecutive days; or a four-fold or greater dose increase of ICS at visit 2; or the use of systemic corticosteroids for three or more days; or hospitalization or emergency department visit due to asthma requiring systemic corticosteroids. A severe exacerbation event in this study was defined as an asthma worsening requiring the use of systemic corticosteroids for three or more days; or hospitalization or emergency department visit due to asthma requiring systemic corticosteroids.

[0322] Three disease-specific efficacy scales were used in this study: ACQ-5 (Asthma Management Questionnaire, 5-question version), AQLQ (Asthma Quality of Life Questionnaire), and a 22-item sinus outcome test.

[0323] The ACQ-5 is designed to measure both the adequacy of asthma management and changes in asthma management that occur spontaneously or as a result of treatment. The ACQ-5 is used to measure the following top 5 scores. The ACQ-5 has five questions that reflect asthma symptoms: nocturnal awakenings due to symptoms, morning awakenings due to symptoms, limitation of daily activities, shortness of breath, and wheezing. Patients are asked to recall how their asthma was during the previous week and to rate their symptoms on a 7-point scale (0 = no impairment, 6 = maximum impairment). A comprehensive score is calculated: the questions are evenly weighted, and the ACQ-5 score is the average of the five questions, and therefore between 0 (fully controlled) and 6 (severely uncontrolled). A higher score indicates lower asthma control. Patients with a score below 1.0 have well-controlled asthma, while patients with a score above 1.0 have poorly controlled asthma. On the 7-point scale of the ACQ-5, a change or difference of 0.5 in the score is the minimum value that can be considered clinically significant.

[0324] The AQLQ is designed to measure the most troublesome functional impairments for adults (17–70 years old) as a result of asthma. This measure consists of 32 items, each rated on a 7-point Likert scale from 1 to 7. The AQLQ has four domains. These domains, and the number of items within each domain, are as follows: Symptoms (12 items), Activity Limitations (11 items), Emotional Functioning (5 items), and Environmental Stimuli (4 items). An overall score on a scale of 0 to 7 and individual domain scores are calculated. A higher score indicates a better quality of life.

[0325] SNOT-22 is a validated questionnaire for assessing the impact of chronic sinusitis on quality of life.

[0326] This study used the following three disease-specific routine efficacy assessments: maximum expiratory velocity, asthma symptom score, and rescue medication use. Throughout the study, patients routinely used an electronic diary / PEF meter to: measure PEF in the morning and evening, answer morning and evening asthma symptom scale questionnaires, record the number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol per day for symptom relief, record the number of inhalations of background composite ICS / LABA products used per day, and record the number of nocturnal awakenings.

[0327] At screening (visit 1), patients were provided with an electronic PEF meter to record morning (AM) and evening (PM) PEFs, daily salbutamol / albuterol or levosalmole / levalbuterol scores, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring rescue medication. In addition, the principal investigator instructed patients on how to record the following variables using the electronic PEF meter: AM PEF to be performed within 15 minutes of waking (between 6am and 10am) before any albuterol or levalbuterol intake; PM PEF to be performed in the evening (between 6pm and 10pm) before any albuterol or levalbuterol intake; patients should attempt to refrain from albuterol or levalbuterol for at least 6 hours prior to PEF measurement; three PEF efforts will be performed by the patient; all three values ​​will be recorded by the electronic PEF meter, and the highest value will be used for evaluation. Baseline AM PEF is the average AM measurement recorded during the 7 days prior to the first dose of the investigational drug, and baseline PM PEF is the average PM measurement recorded during the 7 days prior to the first dose of the investigational drug.

[0328] Patients recorded their full symptom score twice the day before measuring PEF. All asthma symptoms experienced by the patient during waking hours were recorded in the evening (PM symptom score). Symptoms experienced during the night were recorded as soon as the patient woke up (AM symptom score). Baseline symptom scores were the mean AM and mean PM scores recorded over the 7 days prior to randomization. Patients were instructed to record the severity of their symptoms as follows: AM symptom score: 0 = No asthma symptoms, slept through the night; 1 = Slept soundly but reported some symptoms in the morning, no nighttime awakenings; 2 = Awakened once due to asthma (including early morning awakening); 3 = Awakened several times due to asthma (including early morning awakening), and 4 = Did not sleep well due to asthma, awake for most of the night. PM symptom score: 0 = Very good, no asthma symptoms; 1 = Wheezing, cough or 1 = 1 episode of shortness of breath; 2 = 1 or more episodes of wheezing, coughing, or shortness of breath that do not interfere with daily life; 3 = wheezing, coughing, or shortness of breath that interfere with daily life to some extent, mostly throughout the day; and 4 = worst asthma, unable to perform normal daily activities.

[0329] The number of salbutamol / albuterol or levosalbutamol / levalbuterol inhalations was recorded daily by patients in an electronic diary / PEF meter. Each patient was reminded that salbutamol / albuterol or levosalbutamol / levalbuterol should only be used when necessary for symptoms and not regularly or prophylactically. Baseline salbutamol / albuterol or levosalbutamol / levalbuterol inhalations per day were based on the 7-day mean prior to randomization.

[0330] The same safety assessments, including adverse events, vital signs, physical examinations, electrocardiogram variables, laboratory safety variables, and pregnancy tests, will be applied across all arms.

[0331] Adverse events for each patient were monitored and documented from the time the subject gave informed consent at visit 1 until the end of the study visit, except for the following: SAEs and AEs that were ongoing when the database was locked. Adverse events (Ae), particularly noteworthy adverse events (AESI), and serious adverse events (SAE) were reported.

[0332] Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (respiratory rate per minute), body temperature (degrees Celsius), and weight (kg), were measured at each visit. Height (cm) was measured only at the screening (visit 1). Vital signs were measured in a seated position using the same arm at each visit, and were measured before receiving the investigational drug at each visit.

[0333] Pharmacokinetic and anti-drug antibody endpoints were tested. Pre-administration blood samples were collected to determine serum functional dupilumab and anti-dupilumab antibodies. Pre-administration serum mAb1 concentration was obtained on visit 2 (day 1), mAb1 trough levels were obtained at weeks 2, 4, 8, 12, 16, 20, and 24, and follow-up serum mAb1 was obtained at weeks 28, 32, 36, and 40. Anti-mAb1 antibody status (negative or potency) was obtained on visit 2 (day 1), weeks 2, 4, 8, 12, 16, 20, 24, and 40. Patients with an ADA titer of ≥240 at the end of the study were scheduled to return approximately 6 months later for further evaluation of their ADA titer. Further follow-up was considered based on a comprehensive assessment of antibody titers and clinical symptoms.

[0334] Several biomarkers related to asthmatic inflammation and Th2 polarization (whole blood biomarkers, plasma biomarkers, serum biomarkers, and exhaled nitric oxide) were evaluated for their value in predicting treatment response and / or demonstrating the time course of drug response.

[0335] The blood eosinophil count was measured as part of a standard 5-part leukocyte count using an automated blood analyzer.

[0336] Eotaxin-3 is a valid enzyme immunoassay (human eotaxin-3) Measurements were taken using the Quantikine ELISA kit (R&D Systems) in heparinized plasma.

[0337] The concentrations of eosinophil cationic protein (ECP) and Staphylococcus aureus enterotoxin IgE were measured using a quantitative immunoCAP assay (Phadia). Antigen-specific IgE was detected using an antigen panel appropriate for the clinical trial site (Phadiatop test; Phadia). Approved quantitative methods for diagnostic testing (e.g.) Total IgE was measured using ImmunoCAP. Thymic and activating regulatory chemokines (TARCs) were assayed using a validated enzyme immunoassay (Human TARC Quantikine ELISA Kit; R&D Systems). Periostin was measured using a validated immunoassay (Human Periostin DuoSet ELISA Development Kit; R&D Systems).

[0338] Exhaled nitric oxide was analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden) or similar analyzer at a flow rate of 50 mL / second and reported in parts per billion (ppb). This assessment was performed before vital capacity measurement and after at least one hour of fasting.

[0339] Genetic pharmacological testing was optional and voluntary. Participants provided blood samples upon visiting the study, and these samples were stored for future analysis. Blood was collected for DNA and RNA. Using DNA and RNA samples, it is possible to determine the potential relationship between genes and their response to treatment with mAb1 and potential side effects of mAb1. Genes that can be studied include those related to the IL4R receptor, IL-4, IL-13, and STAT6, as well as further genes that may be components of the IL4R signaling pathway or asthma.

[0340] Patient-reported outcomes and resource utilization were assessed using the HADS (Hospital Anxiety and Depression Scale), EQ-5D-3L or EQ-5D-5L, and resource utilization.

[0341] The HADS is a standardized scale for detecting anxiety and depression, already used and validated in relation to asthma. This scale consists of 14 items: 7 related to anxiety and 7 related to depression. Each item on the questionnaire is scored from 0 to 3; for either anxiety or depression, a score between 0 and 21 is possible. A score of 11 or higher on either subscale is considered a significant "case" of psychopathic state, while scores between 8 and 10 represent the "borderline" and scores between 0 and 7 represent "normal."

[0342] The EQ-5D-3L or EQ-5D-5L is a standardized questionnaire of health-related quality of life developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic assessment. The EQ-5D is designed for patient self-administration. The EQ-5D essentially consists of two pages (EQ-5D Descriptive System and EQ VAS). The EQ-5D Descriptive System includes five items: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each item has three levels: no problem, some problem, and severe problem. The EQ Visual Analog Scale (VAS) uses a vertical visual analog scale to record the responder's self-assessed health status. The VAS "Thermometer" has evaluation items ranging from 100 (the best possible health condition) to 0 (the worst possible health condition).

[0343] Questionnaires regarding the use of medical resources (such as medication for seizures, consultations with specialists, hospitalization, visits to emergency or critical care facilities, outcomes, and sick leave) were administered on the second visit and then monthly thereafter.

[0344] F. Research Procedure This clinical trial utilizes an add-on treatment approach to inhaled corticosteroid / long-acting β-agonist combination therapy (ICS / LABA) and consists of three periods: a screening period (14-21 days; visit 1), a randomization treatment period (24 weeks; visits 2-11), and a post-treatment period (16 weeks; visits 12-15).

[0345] The following steps were taken on visit 1: (1) A medical history was taken to collect the patient's demographic information, asthma history (including smoking habits), other medical and surgical history, and prior and concomitant medications; (2) The eligibility criteria were reviewed and eligibility assessed, with particular attention paid to verifying the following: (a) The prescribed combination product ICS / LABA dosage was prepreto-call definition of the medium-to-high dose ICS requirement at a stable dose of ICS / LABA in the month prior to visit 1 (i.e., fluticasone propionate 250 μg twice daily, or equivalent-potency ICS). (b) The patient has met the daily medication requirement; and (b) within one year prior to visit 1, the patient has experienced: 1) a single systemic (oral or parenteral) steroid burst treatment for asthma exacerbation and / or 2) hospitalization or emergency medical visit for asthma exacerbation; (3) vital signs [blood pressure, heart rate, respiratory rate, body temperature, weight (kg), height (cm)] have been measured; (4) a physical examination has been performed; (5) the ACQ-5 has been administered and an ACQ-5 score of 1.5 has been verified; (6) exhaled nitric oxide has been measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after 1 hour of fasting; (7) vital capacity measurement has been performed. Inclusion criteria at visit 1 included demonstrating specific FEV1 requirements and reversibility. After withholding the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol for 6 hours and the final dose of ICS / LABA for 12 hours, vital capacity was first measured between 6 and 10 a.m. FEV1 must be within the 40-80% predicted normal range and must meet the eligibility criteria for vital capacity measurement, which should be attempted three times during the screening period; (8) Reversibility was confirmed.Reversibility must be at least 12% and 200 mL in terms of FEV1 after salbutamol / albuterol 200 μg-400 μg (2-4 inhalations); (9) 12-lead electrocardiogram (ECG) was performed; (10) Chest X-ray was performed if none were available within the past 12 months; (11) Blood samples were taken (fasting) to screen for the following clinical laboratory determinations: a) Hematology: this included hemoglobin, hematocrit, platelet count, total white blood cell count (including 5-element percentage counts) and total red blood cell count; b) Separate blood samples for local analysis. (12) A medical sample was taken, and (c) serological chemistry: this included: creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate and creatine phosphokinase; (12) hepatitis tests (hepatitis B surface antigen (HBsAg), hepatitis B IgM core antigen (HBcAb-IgM), hepatitis C antibody (HC (ab) Blood samples were taken for HIV testing (anti-HIV-1 and HIV-2 antibodies) and antinuclear antibody (ANA)); (13) Blood samples were taken for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM and IgA); (14) For women of possible pregnancy, serum β-HCG pregnancy test results were obtained; (15) Urine samples were taken for urinalysis (urine test strips); (16) Blood samples were taken for biomarker set A and serum total IgE; (17) Certain informed consent For patients who signed the form; optional blood RNA samples were collected; (18) electronic diaries / PEF meters were distributed, diary usage instructions were provided, and patients were reminded to bring the device to their next visit; (19) patients were reminded to continue with a stable dose of ICS / LABA and instructed to record their daily usage in the electronic diary; (20) salbutamol / albuterol or levosalbutamol / levalbuterol were dispensed and resupplied for use as a treatment for seizures throughout this study. Patients were instructed to record their usage in the electronic diary.(21) The patient was advised to refrain from taking the final dose of salbutamol / albuterol or levosalmola / levalbuterol for 6 hours prior to the next visit, and to refrain from taking the final dose of ICS / LABA for 12 hours; and (22) AE reporting was initiated.

[0346] The following steps were taken on visit 2 (Week 0): (1) All medication use was recorded in the eCRF along with the start date and dosage; AE / SAE and background asthma treatment tolerance were recorded. (1) The patients were asked; (2) Based on a review of the inclusion / exclusion criteria, the participation criteria were reviewed and eligibility was reconfirmed; (3) The ACQ-5 and AQLQ were administered; (4) The following was verified: a) the ACQ-5 score at visit 2 was 21.5, and b) adherence to essential background treatment and use of ICS / LABA complex products (this adherence was defined as follows: 80% of the total number of prescribed “stable dose” puffs were taken during the screening period; and this was recorded in the patients’ electronic diaries during the screening period). (5) Compliance was verified based on the use of ICS / LABA; (6) Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight) were measured; (7) Spirometry was performed: Inclusion criteria at visit 1 included demonstrating specific FEV1 requirements and reversibility, and spirometry was performed between 6 and 10 a.m., 6 hours after the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug. FEV1 had to be 40-80% normal, and patients had to meet the criteria for spirometry before randomization at visit 2.

[0347] If a patient met all inclusion criteria and none of the exclusion criteria, the following steps were also taken at visit 2: (1) The visit was registered by calling IVRS / IWRS, and if the participation criteria were met, the patient was randomized and assigned a first treatment kit number. (1) Referencing the central laboratory blood eosinophil count at visit 1, the patient was stratified to the correct high blood eosinophil count (>300 cells / μL), moderate blood eosinophil count (200-299 cells / μL), or low blood eosinophil count (<200 cells / μL) at the time of this IVRS / IWRS call; (2) If the patient's background ICS / LABA conjugate prior to visit 2 was an alternative conjugate (e.g., fluticasone / formoterol), the patient was switched to an equivalent dose of one of the three acceptable treatment period conjugates listed below: fluticasone / salmeterol propionate, budesonide / formoterol, or mometasone / formoterol furoate. Note that the acceptable ICS / LABA conjugates, as well as acceptable dosage forms, strengths, and schedules required during the treatment period to meet the background treatment requirements for the daily dose of moderate to high dose ICS, have been discussed above. (3) SNOT-22 was administered; (4) HADS and EQ-5D-3L or EQ-5D-5L questionnaires were administered; (5) A medical resource utilization questionnaire was administered; (6) (for women of possible pregnancy) a urine pregnancy test was performed; (7) Blood samples were taken for the clinical laboratory (before administration of IMP(mAb1)).Please note that the clinical laboratory tests at visit 2 were limited to hematology (including separate hematological samples taken for local analysis), pharmacokinetics, anti-drug antibodies, biomarker set A, periostin, total serum IgE, biomarker set B, and archived serum samples; (8) For patients who signed certain informed consent forms, blood samples were collected for DNA and RNA sampling (during the randomization treatment period and before administration of the investigational drug); (9) Downloaded an electronic diary / PEF meter, The patient was instructed to bring the device to the next visit; (10) IMP(mAb1) was dispensed and administered; (11) The patient was instructed to continue with a stable dose of ICS / LABA and to record daily usage in an electronic diary; and (12) the next visit was scheduled and the patient was instructed to refrain from taking the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit.

[0348] The following procedures were performed on visit 3 (week 2): (1) All concomitant medications used were recorded; patients were asked about AE / SAE and treatment tolerance for background asthma; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) ACQ-5 was administered; (4) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (5) Vital capacity was measured, and the measurement was performed between 6 and 10 a.m., 6 hours after the final dose of salbutamol / albuterol or levosalmola / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug. (6) Performed a 12-lead electrocardiogram (ECG); (7) Performed blood sampling (before administration of IMP(mAb1)) for pharmacokinetics, anti-drug antibodies, and biomarker set A; (8) Performed optional blood RNA sampling; (9) Instructed the patient to download an electronic diary / PEF meter and bring the device to the next visit; (10) Prepared and administered IMP(mAb1); and (11) Scheduled the next visit and instructed the patient to refrain from the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and from the final dose of ICS / LABA for 6 hours prior to the next visit.

[0349] These same procedures were performed on the fourth visit (week 4). In addition, the patient was given a questionnaire on the use of medical resources.

[0350] The following steps were taken on visit 5 (week 6): (1) Recorded all concomitant medications used; asked about AE / SAE and tolerance to treatment for background asthma; (2) Measured vital signs (blood pressure, heart rate, respiratory rate, temperature, weight); (3) Instructed the patient to download an electronic diary / PEF meter and bring the device to the next visit; (4) Dispensed and administered IMP (mAb1); (5) Instructed the patient to continue a stable dose of ICS / LABA and record daily usage in the electronic diary; and (6) Scheduled the next visit and instructed the patient to refrain from the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit.

[0351] The following steps were taken on visit 6 (week 8): (1) All concomitant medications were recorded; AE / SAE and background asthma treatment tolerance were inquired about; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) ACQ-5 was administered; (4) A medical resource utilization questionnaire was administered; (5) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (6) Vital capacity measurement was performed, and the vital capacity measurement was performed, Between 6 and 10 a.m., after a 12-hour delay from the final dose of ICS / LABA, the following was performed before administration of the investigational drug: (7) Blood samples were taken for clinical laboratory, pharmacokinetic, anti-drug antibody, biomarker set A, and serum total IgE; (8) Patients were instructed to download an electronic diary / PEF meter, bring the device to their next visit, and record their daily usage in the electronic diary; and (9) IMP(mAb1) was dispensed and administered.

[0352] The following steps were taken on visit 7 (week 10): (1) Recorded all concomitant medications; asked about AE / SAE and background asthma treatment tolerance; (2) Measured vital signs (blood pressure, heart rate, respiratory rate, temperature, weight); (3) Instructed the patient to download an electronic diary / PEF meter and bring the device to the next visit; (4) Dispensed and administered IMP (mAb1); (5) Scheduled the next visit and instructed the patient to: continue with a stable dose of ICS / LABA and record the daily dose in the electronic diary; come to the next visit on an empty stomach; and withhold the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the last dose of ICS / LABA for 6 hours prior to the next visit.

[0353] The following steps were taken on visit 8 (week 12): (1) All concomitant medications used were recorded; AE / SAE and background asthma treatment tolerance were inquired about; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) Physical examination was performed; (4) ACQ-5 and AQLQ were administered; (5) SNOT-22 was administered; (6) HADS and EQ-5D-3L or EQ-5D-5L questionnaires were administered; (7) A medical resource utilization questionnaire was administered; (8) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed on the lungs. (9) Spirometry was performed before vitality measurement and after fasting for at least one hour; (10) Spirometry was performed between 6:00 AM and 10:00 AM, 6 hours after the final dose of salbutamol / albuterol or levosalmola / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug; (11) 12-lead electrocardiogram (ECG) was performed; (12) Blood was collected (on an empty stomach) for clinical laboratory, pharmacokinetic, anti-drug antibody, biomarker set A, periostin, archive serum samples, and total serum IgE; (13) Blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM and IgA); (14) Urinalysis (urine test strips) (14) A urine sample was collected for this purpose; (15) The patient was instructed to download an electronic diary / PEF meter and bring the device to the next visit and to record daily usage in the electronic diary; (16) IMP (mAb1) was dispensed and administered; (17) A home administration diary (for self-injection) was distributed to the patient; (18) The patient was instructed to continue with a stable dose of ICS / LABA and to record daily usage in the electronic diary; and (18) The next visit was scheduled and the patient was instructed to refrain from taking the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit.

[0354] The following procedures were performed on visit 9 (week 16): (1) Adherence to IMP (mAb1) was checked; all concomitant medication use was recorded; AE / SAE and background asthma treatment tolerance were inquired about; (2) The patient's home administration diary was reviewed for content and completeness; (3) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (4) ACQ-5 was administered; (5) A medical resource utilization questionnaire was administered; (6) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (7) Vital capacity was measured, and the vital capacity measurement was performed between 6 a.m., 6 hours after the final dose of salbutamol / albuterol or levosalmola / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug; (8) Blood samples were taken for clinical laboratory, pharmacokinetic, anti-drug antibody, biomarker set A, and serum total IgE; (9) The patient was instructed to download an electronic diary / PEF meter and bring the device to the next visit; (10) Instructions for self-injection and administration were outlined and a home administration diary was distributed to the patient; (11) IMP (mAb1) was dispensed and administered; (12) The patient was instructed to continue a stable dose of ICS / LABA and to record the daily dose in the electronic diary; and (13) The next visit was scheduled and the patient was instructed to refrain from taking the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit.

[0355] The same procedure was performed on visit 10 (week 20), however, the patient was reminded to continue the stable dose of ICS / LABA used during the screening period for the next visit, to come to the next visit on an empty stomach, and to refrain from the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol for 6 hours and the final dose of ICS / LABA for 12 hours before the next visit.

[0356] The following steps were taken on visit 11 (Week 24 / completion of treatment): (1) Checked adherence to IMP (mAb1); recorded all concomitant medication use; asked about AE / SAE and background asthma treatment tolerance; (2) reviewed the patient's home administration diary for content and completeness; (3) measured vital signs (blood pressure, heart rate, respiratory rate, temperature, weight); (4) performed physical examination; (5) administered ACQ-5 and AQLQ; (6) administered SNOT-22; (7) administered HADS and EQ-5D-3L or EQ-5D-5L questionnaires; (8) administered a medical resource utilization questionnaire; (9) measured exhaled nitric oxide, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (1 0) Spirometry was performed between 6:00 AM and 10:00 AM, 6 hours after the final dose of salbutamol / albuterol or levosalmola / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug; (11) 12-lead electrocardiogram (ECG) was performed; (13) Blood was collected (on an empty stomach) for clinical laboratory tests, pharmacokinetics, anti-drug antibodies, biomarker set A, periostin, biomarker set B, archive serum samples, and total serum IgE; (14) Blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM and IgA); (15) Urinalysis (urine test strips) (16) A urine sample was collected for this purpose; (17) The patient was instructed to download an electronic diary / PEF meter and bring the device to the next visit and to record daily usage in the electronic diary; (18) The patient was instructed to continue with a stable dose of ICS / LABA and to record daily usage in the electronic diary; (19) The next visit was scheduled and the patient was instructed to refrain from taking the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit; and (16) The IVRS / IWRS was called and the End of Treatment (EOT) date was registered.

[0357] At each of the 12th, 13th, and 14th visits (post-treatment periods of weeks 28, 32, and 36), the following was performed: (1) All concomitant medication use was recorded; AE / SAE and background asthma treatment tolerance were inquired about; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) ACQ-5 was administered; (4) A medical resource utilization questionnaire was administered; (5) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (6) Vital capacity was measured, and the vital capacity measurement was performed between 6:00 AM and 10:00 AM, 6 hours after the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after the final dose of ICS / LABA, and before administration of the investigational drug; (7) Pharmacokinetics and biomarker set A were measured. (8) For visit 13, total serum IgE was measured; (9) Patients were instructed to download an electronic diary / PEF meter and bring the device to their next visit; (10) Patients were instructed to continue the stable dose of ICS / LABA maintained throughout the randomization treatment period (unless the treatment is changed based on medical judgment) and to record the daily dose in an electronic diary; (11) Appointment schedules were made for the next visit, and patients were instructed to refrain from the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol and the final dose of ICS / LABA for 6 hours prior to the next visit; and (12) For visit 14, patients were instructed to come to the clinic on an empty stomach.

[0358] The following procedures were performed on visit 15 (end of study visit in week 40): (1) All concomitant medication use was recorded; AE / SAE and background asthma treatment tolerance were inquired about; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) Physical examination was performed; (4) ACQ-5 was administered; (5) SNOT-22 was administered; (6) A medical resource utilization questionnaire was administered; (7) Exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed before vital capacity measurement and after fasting for at least 1 hour; (8) Vital capacity was measured, and the vital capacity measurement was performed between 6:00 AM and 10:00 AM using salbutamol / albuterol or levosalmole / levosalmole. (9) A 12-lead electrocardiogram (ECG) was performed 6 hours before the final dose of albuterol and 12 hours before the final dose of ICS / LABA, and before administration of the investigational drug; (10) Blood samples were taken (on an empty stomach) for clinical laboratory, pharmacokinetics, anti-drug antibodies, biomarker set A, serum total IgE, periostin, and biomarker set B; (11) Blood samples were taken for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM, and IgA); (12) An electronic diary / PEF meter was downloaded; and (13) IVRS / IWRS was called to register the EOS (end of study) date.

[0359] The baseline biomarker values ​​of the study participants were as follows (Table 3):

[0360] [Table 3]

[0361] [Table 4]

[0362] G. Dosage and duration of medication A summary of treatment exposures is provided in Table 4. Cumulative treatment exposure to the treatments ranged from 61.4 to 65.3 patient-years across the placebo and dupilumab treatment arms. The mean duration of the study treatments ranged from 146.4 to 151.7 days across the five treatment groups.

[0363] [Table 5]

[0364] [Table 6]

[0365] H. Efficacy Main efficacy evaluation items The primary analysis compared the dupilumab treatment group with the placebo group. The primary efficacy endpoint was the change in FEV1 from baseline to week 12 in the HEos ITT population. The primary efficacy variable was analyzed using a mixed-effects model with repeated measures (MMRM) approach. The final analysis of the primary endpoint was an assessment of the absolute change in FEV1 from baseline at week 12, conducted during the interim analysis.

[0366] Figure 3 shows the mean least squares (LS) change in FEV1 over time for the HEos ITT population. The mean change in FEV1 LS from baseline at week 12 was 0.18 L in the placebo group and ranged from 0.26 L (200 mg q4w dose) to 0.43 L (200 mg q2w dose) in the four dupilumab-treated arms (Table 5). The mean LS differences between dupilumab and placebo were 0.08 L (200 mg q4w), 0.017 L (300 mg q4w), 0.25 L (200 mg q2w), and 0.20 L (300 mg The q2w dose was used. The mean difference in life expectancy (LS) compared to placebo was statistically significant for the 300mg q4w (p=0.024), 200mg q2w (p=0.0009), and 300mg q2w dose (p=0.0073). Statistical significance was not achieved for the lowest dose (200mg q4w; p=0.2966). The change in FEV1 from baseline to week 12 in the ITT population was analyzed to determine the effect of dupilumab on FEV1 in the entire study population.

[0367] Figure 4 shows the mean change in FEV1 LS over time for the ITT population. The mean change in FEV1 LS from baseline to week 12 for the ITT population was 0.12 L in the placebo group and ranged from 0.21 L (200 mg q4w dose) to 0.31 L (200 mg q2w dose) in the four dupilumab-treated arms (Table 6). The mean difference in LS between dupilumab and placebo was 0.09 L (200 mg q4w), 0.012 L (300 mg q4w), 0.19 L (200 mg q2w), and 0.16 L (300 mg q2w). The mean difference in LS compared to placebo was statistically significant for all dupilumab doses.

[0368] [Table 7]

[0369] [Table 8]

[0370] Two sets of sensitivity analyses were performed for the primary endpoint, namely the change in FEV1 from baseline to week 12 in the HEos ITT population: 1) Sensitivity analysis 1 was identical to the primary statistical model but included all FEV1 measurements (i.e., no FEV1 measurements were censored from the start of systemic corticosteroids to 30 days prior, as was done for the primary endpoint analysis); 2) Sensitivity analysis 2 was identical to the primary statistical model but excluded all FEV1 measurements collected after the first day of systemic corticosteroid use. Both sensitivity analyses (Tables 7 and 8) were suitably comparable to the primary endpoint analysis provided above.

[0371] [Table 9]

[0372] [Table 10]

[0373] The change in FEV1 from baseline to week 12 was analyzed by eosinophil category in the ITT population, showing that patients with low baseline peripheral blood eosinophil counts were able to increase their baseline eosinophil counts. The efficacy of dupilumab on FEV1 was assessed across a range of patients, including those with peripheral blood eosinophil counts (Table 9). As the patient category of peripheral blood eosinophil count increased from ≥0 to ≥0.300, the change from baseline in FEV1 response generally increased slightly in all treatment groups, including placebo (Figure 5).

[0374] [Table 11]

[0375] [Table 12]

[0376] [Table 13]

[0377] [Table 14]

[0378] [Table 15]

[0379] [Table 16]

[0380] [Table 17]

[0381] I. Annual rate of severe exacerbation events during the treatment period Figure 6 shows the cumulative number of severe exacerbation events (including all events up to the data cutoff date) for the HEos ITT population during the treatment period, broken down by treatment arm. The annual rate of severe asthma exacerbation events was analyzed using a negative binomial regression model. During the 24-week treatment period, the number of patients in the HEos ITT population with ≥1 severe exacerbation event was 16 in the placebo group, and 5, 5, 7, and 10 in the dupilumab 200 mg q4w, 200 mg q2w, 300 mg q2w, and 300 mg q2w groups, respectively (Table 10). The relative risk of severe asthma exacerbation compared to placebo, based on the adjusted annualized rate of severe exacerbation events, was 0.257 (200 mg q4w), 0.739 (300 mg q4w), 0.356 (200 mg q2w), and 0.254 (300 mg q2w). Statistical significance (unadjusted for multiplicity) was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0382] The annual rate of severe asthma exacerbations in the ITT population was analyzed. The cumulative number of severe exacerbations in the ITT population during the treatment period is shown for each treatment arm in Figure 7. Similar to the HEos ITT population analysis, patients using dupilumab experienced fewer severe exacerbations during the 24-week treatment period (Table 11), and the relative risk of severe asthma exacerbations compared to placebo, based on the adjusted annualized severe exacerbation rate, was reduced. Statistical significance was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0383] The annual rate of severe asthma exacerbations was analyzed by eosinophil category in the ITT population to assess the effect of dupilumab on the rate of severe exacerbations across a range of patients, from those with low baseline peripheral blood eosinophil counts to those with high baseline peripheral blood eosinophil counts (Table 12). As shown in Figure 8, the adjusted annual rate of severe picture events compared to placebo decreased in dupilumab-treated patients, regardless of eosinophil category, as the patient category of peripheral blood eosinophil count increased from ≥0 to ≥300. In the placebo group, patients with eosinophil counts <0.250 experienced a higher rate of severe exacerbations compared to placebo patients with eosinophil counts ≥0.250.

[0384] [Table 18]

[0385] [Table 19]

[0386] [Table 20]

[0387] [Table 21]

[0388] [Table 22]

[0389] [Table 23]

[0390] [Table 24]

[0391] [Table 25]

[0392] [Table 26]

[0393] [Table 27]

[0394] J. Relative change in FEV1 from baseline to week 12 (%) The percentage change in FEV1 from baseline in the HEos ITT population was analyzed at week 12. Figure 9 shows the mean percentage change in LS from baseline to week 12 of FEV1. The mean percentage change in LS of FEV1 from baseline to week 12 was 10.44% in the placebo group and ranged from 17.98% (200 mg q4w dose) to 25.92% (200 mg q2w dose) in the four dupilumab-treated arms (Table 13). The mean difference in LS between dupilumab and placebo was 7.54% (200 mg q4w), 11.14% (300 mg q4w), 15.48% (200 mg q2w), and 15.37% (300 mg q2w). The mean difference in life expectancy (LS) compared to placebo was statistically significant for the 300 mg q4w, 200 mg q2w, and 300 mg q2w doses. Statistical significance was not shown for the lowest dose (200 mg q4w).

[0395] [Table 28]

[0396] FEV1 values ​​collected from the start date of systemic corticosteroids to 30 days after the end date of systemic corticosteroids for each exacerbation episode were excluded to reduce the confounding effect of systemic corticosteroids.

[0397] K. Annual rate of loss of asthma control (LOAC) events during the treatment period Figure 10 shows the change in the cumulative mean fraction of LOAC events over 24 weeks for each treatment arm. During the 24-week treatment period, the number of patients in the HEos ITT population with LOAC events ≥ 1 was 23 in the placebo group, and 6, 12, 7, and 10 in the dupilumab 200 mg q4w, 300 mg q4w, 200 mg q2w, and 300 mg q2w groups, respectively (Table 14). The relative risk of LOACs compared to placebo, based on the adjusted annualized LOAC prevalence, was 0.232 (200 mg q4w) and 0.626 (3 0.00mg q4w), 0.413 (200mg q2w), and 0.311 (300mg The q2w dose was observed. Statistical significance was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0398] [Table 29]

[0399] L. Time to asthma management loss and severe exacerbation events during the treatment period. Time to first LOAC event and first severity of first LOAC event in the HEos ITT population during the treatment period The time to a major exacerbation event is shown for each treatment arm in Figures 11 and 12. These two Kaplan-Meier plots show comparable results for the time to the first major exacerbation event and the time to the first LOAC event. All dupilumab groups demonstrated a delay in event occurrence.

[0400] M. Serum thymus and activated regulatory chemokines Dupilumab treatment was associated with a significant decrease in mean serum TARC concentration (compared to baseline) (Figures 13 and 14). Near maximum effect was reached by week 4, and this effect was similar for all four dose regimens. This effect was maintained, except for a partial loss of effect in the HEos ITT population treated with two q4w regimens. Serum TARC gradually increased over time in the placebo group.

[0401] N. Plasma Eotaxin-3 Mean plasma eotaxin-3 concentrations decreased for all four dupilma regimens, with the near-maximum effect observed by 4–8 weeks of treatment, although an increase in plasma eotaxin-3 was observed in patients receiving placebo (Figures 15 and 16). The mean percentage increase in plasma eotaxin-3 was dose-dependent, with the effect being smaller in the 200 mg q4w group. The distinctions between the three higher-dose regimens were not very clear. The mean percentage decrease in eotaxin-3 was generally greater in the HEos ITT population than in the ITT population.

[0402] O. Exhaled nitric oxide concentration Exhaled nitric oxide (FNO) levels were assessed at baseline in approximately half of the patients (median 28 ppb compared to the upper norm of 25 ppb in healthy individuals), and FNO levels were higher in the HEos ITT population (median 40 ppb). Group-mean FeNO levels decreased in a nearly dose-dependent manner for all dupilumab dose regimens, with the maximum effect achieved after 4 weeks of treatment (Figures 17 and 18). The greater effects observed with the two q2w dose regimens were maintained throughout dupilumab treatment.

[0403] [Example 3] Subgroup Analysis FEV1 values ​​were determined for the group with moderate blood Eos levels (Table 15). Figure 19 shows these results graphically.

[0404] [Table 30]

[0405] FEV1 values ​​were determined for the group with low blood Eos (Table 16). Figure 20 shows these results graphically.

[0406] [Table 31]

[0407] The temporal changes in baseline FEV1 were analyzed for the ITT population (Table 17).

[0408] [Table 32]

[0409] We analyzed the number of severe exacerbation events in the ITT population with moderate serum Eos (Table 18). Figure 21 shows these results graphically.

[0410] [Table 33]

[0411] We analyzed the number of severe exacerbation events in the ITT population with low serum Eos (Table 19). Figure 22 shows these results graphically.

[0412] [Table 34]

[0413] The most common adverse event was injection site reactions, which were more frequent in the four dupilumab dose groups (13–25 percent) compared to placebo (12 percent). Other common adverse events in this study included upper respiratory tract infections (dupilumab 10–13 percent; placebo 13 percent), headache (dupilumab 5–10 percent; placebo 8 percent), nasopharyngitis (dupilumab 3–10 percent; placebo 6 percent), and bronchitis (dupilumab 5–8 percent; placebo 8 percent). The incidence of infections was balanced across all treatment groups (dupilumab 42–45 percent; placebo 46 percent), and the incidence of serious adverse events was similar (dupilumab 3–7 percent; placebo 5 percent).

[0414] P. Patient-reported outcome interim analysis ACQ Patient-reported outcome (PRO) data were obtained. Figures 57 and 58 show the results of the Asthma Management Questionnaire (ACQ). The effect was not stabilized at 12 weeks. A higher treatment effect was observed in the hypereosinophil (HEos) population compared to the ITT population (-0.46 (-0.79, -0.12)) (Figure 57). The first two domains (awakening, morning symptoms) were considerably more significant than placebo (PBO).

[0415] AQLQ Asthma Quality of Life Questionnaire (AQLQ) data were obtained (Figures 59 and 60). The results showed that dupilumab (DUPI) was superior to placebo (PBO) in all domains.

[0416] EQ5D-5L European Quality of Life 5-Item-5L (EQ5D-5L) data were obtained (Figures 61 and 62). A significant effect was observed in the HEos population (0.10 (0.04, 0.16)).

[0417] HADS Hospital Anxiety and Depression Scores (HADS) data were obtained (Figures 63-66). Statistically significant effects were observed in the HEos group for both anxiety (-1.54 (-2.58, -0.50)) and depression (-1.88 (-2.88, -0.88)). At baseline, anxiety was more affected than depression. Higher treatment efficacy was observed for depression compared to anxiety. A significant improvement in the overall HADS was observed in the HEos group (-3.47 (-5.29, -1.65)).

[0418] At baseline, the 300 mg q2w arm was significantly worse compared to the other treatment arms.

[0419] Patients worsened more significantly in the depressive environment than in the anxiety domain. At week 12, the 200 mg q4w, 200 mg q2w, and 300 mg q2w arms demonstrated high significance compared to placebo and improved across different treatment arms. The same trend was observed in each subscore. HADS anxiety demonstrated the same trend for change, but arm 1 demonstrated the highest response risk compared to placebo (based on responder profile analysis). HADS depression demonstrated the same trend for change, but arm 1 demonstrated the highest response risk compared to placebo (based on responder profile analysis). Responder:OR demonstrated a significant risk of treatment compared to placebo in terms of response (arms 1, 3, and 4). This risk improved in arm 3 (OR 200 mg q2w = 4.61). Responder (%): Placebo (39.7%) vs. 200 mg q2w (66.2%) (Figure 65).

[0420] At baseline, the 300 mg q2w arm was significantly worsened compared to the other treatment arms (except for depression). Patients worsened more significantly in the anxiety domain in a depressive environment. At week 12, only the 200 mg q2w arm demonstrated a significant effect compared to placebo, and this effect improved across different treatment arms. Different trends were observed in each subscore. No significant effect was observed for HADS anxiety compared to placebo; HADS depression was significant for arms 3 and 4 (Figure 66).

[0421] SNOT-22 Sinus Outcome Test-22 (SNOT-22) data were obtained (Figures 67 and 68). The results showed that dupilumab (DUPI) was superior to placebo (PBO) (Figure 67), that nasal scores drove the treatment effect, and that DUPI was superior to PBO in terms of nasal scores, sleep scores, and general scores.

[0422] NRS Numerical Rating Scale (NRS) data for itching was obtained (Figure 69).

[0423] [Example 3] Summary of Results Overall, dupilumab demonstrated high efficacy, resulting in reduced exacerbations, improved lung function, and improved asthma management. Dupilumab was very well tolerated (Table 20). Dupilumab was superior to placebo in terms of nasal score, sleep score, and general score. The safety profile was consistent with observations in previous studies. A dose-response was observed, and the bi-weekly regimen was superior. There was a dose-dependent imbalance between dupilumab and placebo for injection site reactions, but no imbalance for nasopharyngitis, as previously observed with other treatments. Efficacy was observed across the entire population. This indicates that it is possible to distinguish between one or more subpopulations that will respond to treatment without the need for biomarkers. Importantly, significant efficacy was demonstrated in the ITT population compared to the efficacy of other treatments known in the art at the time of filing. Comparable or superior efficacy was observed in the biomarker-rich population compared to the efficacy of other treatments known in the art at the time of filing.

[0424] [Table 35]

[0425] The top three doses of dupilumab in combination with standard therapy met the primary endpoint of statistically significant improvement in FEV1 from baseline at week 12 compared to placebo in combination with standard therapy in patients with hypereosinophilia (≥300 cells / μL). In addition, the two highest dupilumab doses demonstrated statistically significant improvements in mean percentage change in FEV1, as well as a reduction in severe exacerbations, both in the hypereosinophilic eosinophilic population and in the overall study population.

[0426] Regarding the group of patients with hypereosinophilia: The primary (and secondary) endpoints of this study, the mean improvement in FEV1 from baseline (and mean percentage change in FEV1) at week 12, were as follows: 390 ml (26 percent) dupilumab 300 mg Q2W; 430 ml (26 percent) dupilumab 200 mg Q2W; 180 ml (10 percent) placebo. (p < 0.01).

[0427] Regarding the entire group: The mean improvement in FEV1 from baseline (and mean percentage change in FEV1) at week 12 was as follows: 280 ml (18 percent) dupilumab 300 mg Q2W; 310 ml (18 percent) dupilumab 200 mg Q2W; 120 ml (6 percent) placebo. (p < 0.001).

[0428] Regarding both the hypereosinophilic patient group and the overall patient group: Dupilumab demonstrated a reduction in the adjusted annual rate of severe exacerbations compared to placebo (64–75 percent reduction, p < 0.05 in the hypereosinophil group and p < 0.01 in the overall population).

[0429] These results are based on a pre-specified interim analysis conducted when all patients reached week 12 of the 24-week treatment period. The mean duration of treatment at this point in time was 21.5 weeks.

[0430] label Dupilumab is prescribed to adults and adolescents (age 12 and older) as an add-on treatment to moderate-to-high dose inhaled corticosteroids (ICS) and a second long-term control medication for the treatment of sustained-release asthma.

Claims

1. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 600 mg of antibody that specifically binds to IL-4R, and A method comprising administering to a subject one or more maintenance doses of approximately 300 mg of an antibody that specifically binds to IL-4R, wherein the pharmaceutical composition comprises an antibody that specifically binds to the interleukin-4 receptor (IL-4R) for use in the treatment of severe, uncontrolled asthma in a subject requiring such treatment, The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an additional treatment.

3. The pharmaceutical composition according to claim 1, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

4. The pharmaceutical composition according to claim 3, wherein the antibody that specifically binds to IL-4R is dupilumab.

5. The pharmaceutical composition according to claim 1, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

6. One or more maintenance doses of the antibody that specifically binds to IL-4R are at least The pharmaceutical composition according to claim 5, administered for 24 weeks.

7. The pharmaceutical composition according to claim 1, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

8. The pharmaceutical composition according to claim 7, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

9. The pharmaceutical composition according to claim 1, wherein the subject has an eosinophilic phenotype.

10. The pharmaceutical composition according to claim 1, wherein the subject is at least 12 years old.

11. The pharmaceutical composition according to claim 1, wherein the subject had been treated with a medium- or high-dose ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

12. The pharmaceutical composition according to claim 1, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

13. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 400 mg of an antibody that specifically binds to IL-4R, and A method comprising administering to a subject one or more maintenance doses of approximately 200 mg of an antibody that specifically binds to IL-4R, wherein the pharmaceutical composition comprises an antibody that specifically binds to the interleukin-4 receptor (IL-4R) for use in the treatment of severe, uncontrolled asthma in a subject requiring such treatment, The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is an additional treatment.

15. The pharmaceutical composition according to claim 13, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

16. The pharmaceutical composition according to claim 15, wherein the antibody that specifically binds to IL-4R is dupilumab.

17. The pharmaceutical composition according to claim 13, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

18. The pharmaceutical composition according to claim 17, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

19. The pharmaceutical composition according to claim 13, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

20. The pharmaceutical composition according to claim 19, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

21. The pharmaceutical composition according to claim 13, wherein the subject has an eosinophilic phenotype.

22. The pharmaceutical composition according to claim 13, wherein the subject is at least 12 years old.

23. The pharmaceutical composition according to claim 13, wherein the subject had been treated with a medium- or high-dose ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

24. The pharmaceutical composition according to claim 13, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

25. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 600 mg of antibody that specifically binds to IL-4R, and A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R), for use in a subject having severe, uncontrolled asthma, comprising administering a maintenance dose of approximately 300 mg or more of an antibody that specifically binds to IL-4R to a subject, wherein the antibody is used to increase the forced expiratory volume in one liter (FEV1), The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

26. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an additional treatment.

27. The pharmaceutical composition according to claim 25, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

28. The pharmaceutical composition according to claim 27, wherein the antibody that specifically binds to IL-4R is dupilumab.

29. The pharmaceutical composition according to claim 25, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

30. The pharmaceutical composition according to claim 29, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

31. The pharmaceutical composition according to claim 25, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

32. The pharmaceutical composition according to claim 31, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

33. The pharmaceutical composition according to claim 25, wherein the subject has an eosinophilic phenotype.

34. The pharmaceutical composition according to claim 25, wherein the subject is at least 12 years old.

35. The pharmaceutical composition according to claim 25, wherein the subject had been treated with a medium- or high-dose ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

36. The pharmaceutical composition according to claim 25, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

37. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 400 mg of an antibody that specifically binds to IL-4R, and A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R), for use in increasing the forced expiratory volume in one liter (FEV1) in a subject having severe, uncontrolled asthma, comprising administering a maintenance dose of approximately 200 mg or more of an antibody that specifically binds to IL-4R to a subject, The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

38. The pharmaceutical composition according to claim 37, wherein the pharmaceutical composition is an additional treatment.

39. The pharmaceutical composition according to claim 38, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

40. The pharmaceutical composition according to claim 39, wherein the antibody that specifically binds to IL-4R is dupilumab.

41. The pharmaceutical composition according to claim 37, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

42. The pharmaceutical composition according to claim 41, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

43. The pharmaceutical composition according to claim 37, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

44. The pharmaceutical composition according to claim 43, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

45. The pharmaceutical composition according to claim 37, wherein the subject has an eosinophilic phenotype.

46. The pharmaceutical composition according to claim 37, wherein the subject is at least 12 years old.

47. The pharmaceutical composition according to claim 37, wherein the subject had been treated with a medium or high dose of ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

48. The pharmaceutical composition according to claim 37, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

49. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 600 mg of antibody that specifically binds to IL-4R, and A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R), for use in a subject having severe, uncontrolled asthma, comprising administering a maintenance dose of approximately 300 mg or more of an antibody that specifically binds to IL-4R to a subject, wherein the antibody is used to reduce the annual rate of severe asthma exacerbations in a subject having severe, uncontrolled asthma. The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

50. The pharmaceutical composition according to claim 49, wherein the pharmaceutical composition is an additional treatment.

51. The pharmaceutical composition according to claim 49, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

52. The pharmaceutical composition according to claim 51, wherein the antibody that specifically binds to IL-4R is dupilumab.

53. The pharmaceutical composition according to claim 49, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

54. The pharmaceutical composition according to claim 53, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

55. The pharmaceutical composition according to claim 49, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

56. The pharmaceutical composition according to claim 55, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

57. The pharmaceutical composition according to claim 49, wherein the subject has an eosinophilic phenotype.

58. The pharmaceutical composition according to claim 49, wherein the subject is at least 12 years old.

59. The pharmaceutical composition according to claim 49, wherein the subject had been treated with a medium or high dose of ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

60. The pharmaceutical composition according to claim 49, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

61. One or more maintenance doses of inhaled corticosteroids (ICS), long-acting β 2 One or more maintenance doses of an adrenaline stimulant (LABA), An initial dose of approximately 400 mg of an antibody that specifically binds to IL-4R, and A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R), for use in a subject having severe, uncontrolled asthma, comprising administering a maintenance dose of approximately 200 mg or more of an antibody that specifically binds to IL-4R to a subject, wherein the antibody is used to reduce the annual rate of severe asthma exacerbations in a subject having severe, uncontrolled asthma. The pharmaceutical composition comprises an antibody that specifically binds to IL-4R, each comprising three heavy chain complementarity determination region (HCDR) sequences including SEQ ID NOs. 3, 4, and 5, and three light chain complementarity determination (LCDR) sequences including SEQ ID NOs. 6, 7, and 8.

62. The pharmaceutical composition according to claim 61, wherein the pharmaceutical composition is an additional treatment.

63. The pharmaceutical composition according to claim 62, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

64. The pharmaceutical composition according to claim 63, wherein the antibody that specifically binds to IL-4R is dupilumab.

65. The pharmaceutical composition according to claim 61, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

66. The pharmaceutical composition according to claim 65, wherein one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

67. The pharmaceutical composition according to claim 61, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

68. The pharmaceutical composition according to claim 67, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen-type delivery device.

69. The pharmaceutical composition according to claim 61, wherein the subject has an eosinophilic phenotype.

70. The pharmaceutical composition according to claim 61, wherein the subject is at least 12 years old.

71. The pharmaceutical composition according to claim 61, wherein the subject had been treated with a medium- or high-dose ICs / LABA prior to treatment with an antibody that specifically binds to IL-4R, and required one or more systemic steroids for asthma exacerbation.

72. The pharmaceutical composition according to claim 61, wherein treatment with an antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in one liter (FEV1) at 12 weeks of treatment.

73. A pharmaceutical composition comprising administering to a subject by subcutaneous injection an initial dose of approximately 600 mg of dupilumab and a maintenance dose of approximately 300 mg or more of dupilumab, for use in the treatment of severe uncontrolled asthma in the subject, wherein the subject is at least 12 years old, has an eosinophilic phenotype, and the pharmaceutical composition comprises dupilumab, wherein the subject is at least 12 years old, has an eosinophilic phenotype, and the pharmaceutical composition comprises dupilumab, a method comprising administering to a subject by subcutaneous injection an initial dose of approximately 600 mg of dupilumab and a maintenance dose of approximately 300 mg or more of The composition further includes one or more maintenance doses of inhaled corticosteroids (ICS) and long-acting β 2 The pharmaceutical composition comprising one or more maintenance doses of an adrenaline stimulant (LABA).

74. The pharmaceutical composition according to claim 73, wherein one or more maintenance doses of dupilumab are administered every two weeks (q2w).

75. A pharmaceutical composition comprising dupilumab for use in the treatment of severe, uncontrolled asthma in a subject requiring such treatment, comprising administering to the subject by subcutaneous injection an initial dose of approximately 400 mg of dupilumab and one or more maintenance doses of approximately 200 mg of dupilumab, wherein the subject is at least 12 years old, has an eosinophilic phenotype, and the pharmaceutical composition further comprises one or more maintenance doses of inhaled corticosteroids (ICS) and long-acting β 2 The pharmaceutical composition comprising one or more maintenance doses of an adrenaline stimulant (LABA).

76. The pharmaceutical composition according to claim 75, wherein one or more maintenance doses of dupilumab are administered every two weeks (q2w).

Images