Method for treating or preventing asthma by administration of an IL-4R antagonist

Abstract

To provide methods for treating or preventing asthma and related conditions of patients.SOLUTION: Disclosed is a method for treating a subject having severe uncontrolled asthma, comprising administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof, where the plurality of maintenance doses are administered during a treatment phase comprising an induction phase, an oral corticosteroid (OCS) reduction phase and an OCS maintenance phase.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 579,120, filed Oct. 30, 2017; U.S. Provisional Patent Application No. 62 / 710,381, filed Feb. 16, 2018; U.S. Provisional Patent Application No. 62 / 647,368, filed Mar. 23, 2018; U.S. Provisional Patent Application No. 62 / 742,736, filed Oct. 8, 2018; and European Application No. EP18305566.4, filed May 4, 2018. The contents of the foregoing applications are hereby incorporated by reference in their entirety.

[0002] 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 in need thereof.

Background Art

[0003] Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugs. The inflammatory component of asthma is thought to include many cell types, including 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 adequate long-term control. Inhaled corticosteroids (ICS) are considered a “pyramidal presence” in managing asthma symptoms, and inhaled β2 agonists are the most effective bronchodilators currently available. Studies have demonstrated that combination therapy with ICS and inhaled long-acting β2 agonists (LABA) provides better asthma management than high doses of ICS alone. As a result, combination therapy has become the recommended treatment for patients not managed on low doses of ICS alone.

[0004] However, despite the maximum recommended treatment with a combination of anti-inflammatory and bronchodilator medications, 5% to 10% of the asthmatic population is estimated to have symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of total healthcare costs due to hospitalizations, use of emergency services, and unscheduled physician visits. Many of these patients are unresponsive to ICS due to multiple cellular and molecular mechanisms, so the need for new treatment approaches in this severe asthma population remains unaddressed. 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 currently managed to some extent with current treatments, but patients with severe uncontrolled asthma (e.g., severe corticosteroid-resistant asthma or steroid-intolerant asthma) have few treatment options that can adequately manage their disease. The consequence of non-response or lack of treatment compliance to treatment is loss of asthma control and ultimately, asthma exacerbation.

[0005] An estimated 45% of patients with severe asthma require systemic glucocorticoids to manage their disease and to prevent life-threatening exacerbations associated with an increased risk of permanent damage to lung tissue, progressive fixed airway obstruction, and accelerated decline in lung function. However, systemic glucocorticoids act non-selectively and are associated with significant multi-organ toxicity and broad immunosuppression. There is a need for safer and more effective targeted therapies that prevent exacerbations and lung function impairment, improve asthma symptoms and control, and reduce or eliminate the need for oral glucocorticoids.

[0006] Approximately 20% of patients with asthma are on long-term maintenance medications (controller) for maximum standard treatment Despite (the current) therapy, they have moderate to severe uncontrolled diseases with recurrent exacerbations and persistent symptoms. This population has an increased risk of morbidity (especially exacerbations) and consumes a significant amount of medical resources. Despite maximal treatment, these patients have a substantial decline in lung function and are doomed to further, relentless loss of lung function. There is no currently approved treatment shown to slow the inexorable decline or consistently and meaningfully increase lung function in these patients.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] Therefore, there is a need in the art for new targeted therapies for the treatment and / or prevention of asthma.

MEANS FOR SOLVING THE PROBLEMS

[0008] According to one aspect, there is provided a method for treating a subject having severe uncontrolled asthma (e.g., severe steroid-dependent asthma), the method comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, the plurality of maintenance doses being administered during a treatment period including an induction phase, an oral corticosteroid (OCS) reduction phase, and an OCS maintenance phase.

[0009] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w). In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0010] In certain embodiments, the subject is administered a loading dose and the subject is administered a maintenance dose having a dosing regimen of 500 mg q4w or 750 mg q4w.

[0011] In certain embodiments, the loading dose is removed. In certain embodiments, the subject is administered a dosing regimen of 500 mg q4w or 750 mg q4w.

[0012] In certain exemplary embodiments, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof, and / or each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

[0013] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks.

[0014] In certain exemplary embodiments, the first maintenance dose of the antibody or antigen-binding fragment thereof is administered 2 weeks after the loading dose of the antibody or antigen-binding fragment thereof.

[0015] In certain exemplary embodiments, the OCS reduction period is about 16 weeks in length.

[0016] In certain exemplary embodiments, the subject's OCS use is reduced during the OCS reduction period. In certain exemplary embodiments, the subject uses 50% or less, 75% or less, or 90% or less OCS in the maintenance period compared to the induction period. In certain exemplary embodiments, the subject's OCS use is reduced to about 5 mg / day or less in the maintenance period. In other exemplary embodiments, the OCS is reduced and / or removed, e.g., the subject is made to discontinue the previous OCS dose. In certain exemplary embodiments, the administration of OCS is completely removed from the treatment regimen.

[0017] In certain exemplary embodiments, the subject has a blood eosinophil count of about 150 cells / μl or less. In certain exemplary embodiments, the subject has a blood eosinophil count higher than about 150 cells / μl. In certain exemplary embodiments, the subject has a blood eosinophil count higher than about 300 cells / μl.

[0018] In certain exemplary embodiments, the subject experiences a reduction in exacerbations of severe asthma on an annualized basis. In certain exemplary embodiments, the subject experiences an improvement in lung function as measured by forced expiratory volume in one second (FEV1). In other embodiments, the subject demonstrates an improvement in peripheral airway lung function and / or a reduction in peripheral airway inflammation. In certain embodiments, the improvement in lung function and reduction in inflammation are measured by forced expiratory flow at 25-75% of lung volume (FEF25-75).

[0019] In certain exemplary embodiments, the use of OCS by the subject is optimized prior to treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the OCS is prednisone or prednisolone.

[0020] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0021] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0022] In another aspect, a method for treating a subject having severe uncontrolled asthma (e.g., severe steroid-dependent asthma), comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein the plurality of maintenance doses are administered during a treatment period including an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2, is provided.

[0023] In another aspect, a method for treating a subject having severe uncontrolled asthma, e.g., severe steroid-dependent asthma, comprising administering a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof, and the plurality of maintenance doses are administered during a treatment period including an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2, is provided.

[0024] In another aspect, a method for reducing the annualized rate of severe exacerbations in a subject having moderate to severe uncontrolled asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to IL-4R q2w or q4w.

[0025] In certain exemplary embodiments, the dosage is 200 mg q2w or 300 mg q2w.

[0026] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every 4 weeks (q4w).

[0027] In certain embodiments, the subject is administered a loading dose and a maintenance dose, and the subject is given a dosing regimen of 500 mg q4w or 750 mg q4w.

[0028] In certain embodiments, the loading dose is eliminated. In certain embodiments, the subject is given a dosing regimen of 500 mg q4w or 750 mg q4w.

[0029] In certain exemplary embodiments, the subject has a blood eosinophil count of less than about 150 cells / μl, of about 150 cells / μl or more, or higher than about 300 cells / μl.

[0030] In certain exemplary embodiments, the subject has an exhaled nitric oxide concentration (FeNO) level of about 25×10 -9 (25 ppb) or greater, of about 50 ppb or greater, or of about 25 ppb to about 50 ppb.

[0031] In another aspect, there is provided a method for improving the FEV1 score in a subject having moderate to severe uncontrolled asthma, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to IL-4R q2w or q4w.

[0032] In certain exemplary embodiments, the dosage is administered at 200 mg q2w or 300 mg q2w. In certain exemplary embodiments, the dosage is administered at 500 mg q4w or 750 mg q4w.

[0033] In certain exemplary embodiments, the subject has a blood eosinophil count of less than about 150 cells / μl, of about 150 cells / μl or more, or higher than about 300 cells / μl.

[0034] In certain exemplary embodiments, the subject has an exhaled nitric oxide concentration (FeNO) level of about 25×10 -9Having an exhaled nitric oxide concentration (FeNO) level above (25 ppb), having an FeNO level of about 50 ppb or above, or having an FeNO level between about 25 ppb and about 50 ppb.

[0035] In another embodiment, the subject shows at least a 10%, 15%, 20%, or 25% decrease in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC) at 4 weeks, 12 weeks, or 24 weeks after administration of an IL-4R antibody or a fragment thereof.

[0036] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0037] In another aspect, the present disclosure provides a method for improving the forced expiratory flow (FEF25-75) score at 25-75% of the lung volume in a subject having moderate to severe uncontrolled asthma, the method comprising administering to the subject an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof q2w or q4w.

[0038] In one embodiment, the dosage is 200 mg q2w or 300 mg q2w. In one embodiment, the dosage is 500 mg q4w or 750 mg q4w.

[0039] In one embodiment, the subject has a blood eosinophil count of less than about 150 cells / μl. In one embodiment, the subject has a blood eosinophil count of about 150 cells / μl or more. In one embodiment, the subject has a blood eosinophil count higher than about 300 cells / μl.

[0040] In another embodiment, the subject has a FeNO level of about 25 ppb or more. In another embodiment, the subject has a FeNO level of about 50 ppb or more. In another embodiment, the subject has a FeNO level between about 25 ppb and about 50 ppb.

[0041] In another embodiment, the subject shows at least a 10%, at least a 15%, at least a 20%, or at least a 25% reduction in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC) at week 4, week 12, or week 24 after administration of the IL-4R antibody or a fragment thereof.

[0042] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is a youth. In certain exemplary embodiments, the subject is an adult or a youth, e.g., 12 years of age or older.

[0043] In another aspect, the present disclosure provides a method of reducing or eliminating OCS use in a subject suffering from steroid-dependent severe asthma, the method comprising administering a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R to the subject; and administering a plurality of maintenance doses of the antibody or an antigen-binding fragment thereof to the subject, wherein at least a 50% or more, at least a 75% or more, or at least a 90% or more reduction in OCS use is achieved at week 24 after administration of the loading dose.

[0044] In one embodiment, OCS use is reduced to less than 5 mg per day at week 24 after administration of the loading dose. In another embodiment, the OCS is substantially eliminated after a predetermined period (e.g., 1 year) from administration of the loading dose. In certain embodiments, the OCS is substantially eliminated 40 weeks, 45 weeks, 50 weeks, 52 weeks or later after the first dose after administration of the loading dose.

[0045] In one embodiment, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w). In one embodiment, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof. In one embodiment, each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof. In another embodiment, the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks. In one embodiment, the first maintenance dose of the antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of the antibody or antigen-binding fragment thereof. In one embodiment, the OCS is prednisone or prednisolone.

[0046] In one embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining region (CDR) sequences from the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In one embodiment, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In one embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0047] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0048] In certain embodiments, a subject is administered a loading dose and the subject is subjected to dose regimens of 500 mg q4w and 750 mg q4w.

[0049] In certain embodiments, the loading dose is removed. In certain embodiments, the subject is subjected to dose regimens of 500 mg q4w and 750 mg q4w.

[0050] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is a youth. In certain exemplary embodiments, the subject is an adult or a youth, e.g., 12 years of age or older.

[0051] In another aspect, a method for treating a subject having moderate to severe oral corticosteroid (OCS)-dependent asthma, the method comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, is provided.

[0052] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences each comprising SEQ ID NOs: 3, 4, and 5, and three light chain CDR sequences each comprising SEQ ID NOs: 6, 7, and 8. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0053] In certain exemplary embodiments, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

[0054] In certain exemplary embodiments, the loading dose is about 400 mg of the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, each maintenance dose of the antibody or antigen-binding fragment thereof is about 200 mg of the antibody or antigen-binding fragment thereof.

[0055] In certain exemplary embodiments, the subject is 12 years of age or older.

[0056] In certain exemplary embodiments, the OCS is prednisone or prednisolone.

[0057] In another aspect, a method for treating a subject having moderate to severe asthma and co-existing moderate to severe atopic dermatitis, the method comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, is provided.

[0058] In another aspect, a method for treating a subject having moderate to severe uncontrolled asthma, wherein the onset of asthma occurred after the age of 40, the method comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, is provided.

[0059] In another aspect, a method for treating a subject having moderate to severe uncontrolled asthma and one or both of co-existing chronic rhinosinusitis and nasal polyposis, the method comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, is provided.

[0060] In another aspect, a method for treating a subject having moderate to severe uncontrolled asthma and co-existing allergic rhinitis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, the method is provided.

[0061] In another aspect, a method for improving the quality of life related to allergic rhinitis in a subject having moderate to severe uncontrolled asthma and co-existing allergic rhinitis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, the method is provided.

[0062] In another aspect, a method for improving the quality of life related to allergic rhinitis in a subject having oral corticosteroid-dependent asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy, the method is provided.

[0063] In certain exemplary embodiments, the asthma symptoms of the day are improved in the morning and evening.

[0064] In certain exemplary embodiments, the oral corticosteroid-dependent asthma is oral corticosteroid-dependent severe asthma.

[0065] In another aspect, there is provided a method for improving asthma management in a subject having oral corticosteroid-dependent asthma, the method comprising administering a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to the subject, and administering a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof to the subject, wherein the loading dose and the plurality of maintenance doses are administered as additional asthma maintenance therapy.

[0066] In certain exemplary embodiments, the quality of life related to health is improved.

[0067] In certain exemplary embodiments, the oral corticosteroid-dependent asthma is oral corticosteroid-dependent severe asthma.

[0068] Other embodiments will become apparent from a consideration of the ensuing detailed description, drawings, tables, and appended claims.

[0069] The above and other features and advantages of the present invention will be more fully understood from the following detailed description of embodiments taken in conjunction with the accompanying drawings. This patent file contains at least one drawing / photograph created in color. A copy of this application with color drawing / photograph(s) will be provided by the (United States Patent and Trademark) Office upon request and payment of the necessary fee.

Brief Description of the Drawings

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[0071] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described. 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 be limiting. The scope of the present invention is limited only by the appended claims.

[0072] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0073] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary by up to 1% from the recited 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.).

[0074] As used herein, the terms "treating," "treatment," or the like mean reducing a symptom, removing the cause of a symptom, either temporarily or permanently , or preventing or delaying the appearance of a symptom of a named disorder or condition.

[0075] Any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, but the typical methods and materials are described below. All publications mentioned herein are hereby incorporated by reference in their entirety.

[0076] A method for reducing the incidence of asthma exacerbation The present invention includes a method for reducing the incidence of asthma exacerbation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. According to certain embodiments, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R. Exemplary anti-IL-4R antibodies that can be used in connection with the methods of interest in the present invention are described elsewhere herein. As used herein, the expression "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" includes any worsening of the respiratory health of a subject that requires and / or is treatable by therapeutic intervention (such as steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.) for asthma. There are two types of asthma exacerbation events: loss of asthma control (LOAC) events and severe exacerbation events.

[0077] According to certain embodiments, a loss of asthma control (LOAC) event is defined as one or more of the following events: (a) additional rescue medication puff of salbutamol / albuterol or levalbuterol / levalbuterol more than 6 times in 24 hours for 2 consecutive days (compared to baseline); (b) more than a 4-fold increase in the dose of ICS at visit 2; and (c) use of systemic corticosteroids for more than 3 days; or (d) hospitalization or emergency department visit due to asthma requiring systemic corticosteroids.

[0078] In certain cases, asthma exacerbations may be categorized as "severe asthma exacerbation events." A severe asthma exacerbation event is an incident that requires immediate intervention, where the intervention is in the form of a treatment using either systemic corticosteroids or inhaled corticosteroids at 4 times the dose or more of the dose taken prior to the incident. According to certain embodiments, a severe asthma exacerbation event is defined as an asthma worsening that requires the following: use of systemic corticosteroids for 3 days or more; or hospitalization or emergency department visit due to asthma requiring systemic corticosteroids. Therefore, the general expression "asthma exacerbation" includes and encompasses the more specific subcategory of "severe asthma exacerbation." Thus, it includes methods for reducing the incidence of severe asthma exacerbation in patients in need thereof.

[0079] "Reduction in the incidence" of asthma exacerbation means that a subject who has received a pharmaceutical composition comprising an IL-4R antagonist experiences fewer asthma exacerbations (i.e., at least one fewer exacerbation) after treatment than before treatment, or does not experience an asthma exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14 weeks or more) after the start of treatment with the pharmaceutical composition. Alternatively, "reduction in the incidence" of asthma exacerbation means that after administration of the pharmaceutical composition, the likelihood that a subject experiences an asthma exacerbation is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more) compared to a subject who has not received the pharmaceutical composition.

[0080] The present invention is a method for reducing the incidence of asthma exacerbation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, and a maintenance dose of one or more doses of inhaled corticosteroid (ICS) and / or a second long-term management drug 、including administering to the subject one or more maintenance doses of, for example, a long-acting β-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICSs include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., Flovent (trademark)), budesonide, mometasone (e.g., mometasone furoate, e.g., Asmanex (trademark)), flunisolide (e.g., Aerobid (trademark)), dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort (trademark)), beclomethasone dipropionate HFA (Qvar (trademark)), etc. Suitable LABAs include, but are not limited to, salmeterol (e.g., Serevent (trademark)), formoterol (e.g., Foradil (trademark)), etc. Suitable LTAs include, but are not limited to, montelukast (e.g., Singulaire (trademark)), zafirlukast (e.g., Accolate (trademark)), etc.

[0081] The present invention is a method for reducing the incidence of exacerbation of asthma in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, and administering to the subject one or more anti-attack drugs to eliminate or reduce one or more asthma-related symptoms. Suitable anti-attack drugs include, but are not limited to, immediate-acting β2-adrenergic receptor stimulants, such as albuterol (i.e., salbutamol, e.g., Proventil (trademark), Ventolin (trademark), Xopenex (trademark), etc.), pirbuterol (e.g., Maxair (trademark)), metaproterenol (e.g., Alupent (trademark)), etc.

[0082] Method for improving asthma-related parameters The present invention also includes a method for improving one or more asthma-related parameters in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbation (as described above) may be correlated with an improvement in one or more asthma-related parameters; however, such a correlation is not necessarily observed in all cases.

[0083] Examples of "asthma-related parameters" include: (1) the relative percent change from baseline of the forced expiratory volume in one second (FEV1) (e.g., at week 12); (2) the relative percent change from baseline when measured by the forced expiratory flow between 25 and 75% of lung volume (FEF25-75) (e.g., at week 12); (3) the annual rate of asthma management failure events during the treatment period; (4) the annual rate of severe exacerbation events during the treatment period; (5) the time to an asthma management failure event during the treatment period; (6) the time to a severe exacerbation event during the treatment period; (7) the time to an asthma management failure event during the entire study period; (8) the time to a severe exacerbation event during the entire study period; (9) healthcare resource utilization; (10) changes from baseline at week 12 regarding: i) morning and evening asthma symptom scores, ii) ACQ-5 scores, iii) AQLQ scores, iv) morning and evening PEF, v) the number of inhalations per day of salbutamol / albuterol or levalbuterol / levalbuterol for symptom relief, vi) nocturnal awakenings; (11) changes from baseline at week 12 and week 24 regarding: i) the 22-item Sinonasal Outcome Test (SNOT-22), ii) the Hospital Anxiety and Depression Score (HADS), iii) the EuroQol questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement of asthma-related parameters" means an increase in FEV1, AM PEF, or PM An increase from one or more baselines of PEF, and / or a decrease from one or more baselines of the daily albuterol / levalbuterol use, ACQ5 score, average number of nocturnal awakenings, or SNOT-22 score. As used herein, the term "baseline" with respect to a respiratory-related parameter means the numerical value of the respiratory-related parameter for a patient prior to or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0084] To determine whether a respiratory-related parameter has "improved", the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein. For example, the respiratory-related parameter may be measured after the first treatment with the pharmaceutical composition, on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or at more time points. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to confirm whether there has been an "improvement" (e.g., an increase or decrease depending on the specific parameter being measured) in the respiratory-related parameter.

[0085] As used herein, the term "obtain" or "obtaining" refers to obtaining a physical entity or value, such as a numerical value, either "directly obtaining" or "indirectly obtaining" a physical entity or value such as a respiratory-related parameter. "Directly obtaining" means performing a process for obtaining a physical entity or value (e.g., performing a synthesis or analytical method). "Indirectly obtaining" refers to receiving a physical entity or value from another entity or source (e.g., a research institute of a third entity that directly obtained the physical entity or value). Directly obtaining a physical entity includes performing a process that includes a physical change of a physical substance, such as a starting material. Exemplary changes include manufacturing a physical entity from two or more starting materials, sharing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, and performing a chemical reaction that includes breaking or forming covalent or non-covalent bonds. Directly obtaining a value includes performing a process that includes a physical change of a sample or another substance, such as performing an analytical process (sometimes referred to herein as a "physical analysis") that includes a physical change of a substance, such as a sample, analyte, or reagent.

[0086] Information obtained indirectly may be provided in the form of a report from an online database or application ("App"), for example, and may be provided in paper or electronic form. The report or information may be provided, for example, by a medical facility, such as a hospital or clinic; or by a healthcare provider, such as a doctor or nurse.

[0087] Forced expiratory volume in 1 second (FEV1). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from the baseline of the forced expiratory volume in 1 second (FEV1). Methods for measuring FEV1 are known in the art. For example, the FEV1 of a patient can be measured using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommended criteria. The ATS / ERS standardization of spirometry may be used as a guideline. Spirometry is generally performed between 6 and 10 am, after withholding albuterol for at least 6 hours. Pulmonary function tests are generally measured in the sitting position, and the highest measured value of FEV1 (in liters) is recorded.

[0088] The present invention includes a treatment method that results in an increase of at least 0.05 L from the baseline of FEV1 at week 12 after the start of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof results in an increase of about 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 the baseline of FEV1 at week 12.

[0089] FEF25-75%. According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in FEF25-75%. Methods for measuring FEF 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. FEF25-75 (forced expiratory flow between 25% and 75%) is the rate (liters per second) at which a person can empty half of the air in the middle of their maximum exhalation (i.e., forced vital capacity or FVC). That parameter relates to the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled. The subject's FEF25-75% provides information regarding the degree of peripheral airway disease and / or peripheral airway function such as inflammation. A change in FEF25-75 is an early indicator of obstructive lung disease. In certain embodiments, an improvement and / or increase in the FEF25-75% parameter is an improvement of at least 10%, 25%, 50% or more compared to baseline. In certain embodiments, the methods of the invention result in a normal FEF25-75% value (e.g., a value in the range from 50 to 60% to 130% of its average value) in a subject.

[0090] Morning and evening peak expiratory flow (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 the morning (AM) and / or evening (PM) peak expiratory flow (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 for recording the morning (AM) and evening (PM) PEF (as well as albuterol use per day, morning and evening asthma symptom scores, and the number of night-time awakenings due to asthma symptoms requiring rescue medication). The patient is instructed on the use of the device and is provided with written instructions regarding the use of the electronic PEF meter. Additionally, a medical professional may instruct the patient on how to record variables directly related to the patient using the electronic PEF meter. AM PEF is generally performed within 15 minutes after waking up (between 6 PM and 10 PM) and before any albuterol intake. PM PEF is generally performed in the evening (between 6 AM and 10 AM) and before any albuterol intake. The subject should attempt to refrain from albuterol for at least 6 hours prior to PEF measurement. Three PEF efforts are made by the patient and all three values are recorded by the electronic PEF meter. Usually the highest value is used for evaluation. Baseline AM PEF can be calculated as the average AM measurement recorded during the 7 days prior to the first dose administration of the pharmaceutical composition containing the IL-4R antagonist, and baseline PM PEF can be calculated as the average PM measurement recorded during the 7 days prior to the first dose administration of the pharmaceutical composition containing the IL-4R antagonist.

[0091] The present invention includes a treatment method that results in an increase of at least 1.0 L / min in AM PEF and / or PM PEF from the baseline at 12 weeks after the start of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, according to the present invention, the administration of an IL-4R antagonist to a subject in need thereof results in an increase of about 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 the baseline of PEF at 12 weeks.

[0092] Albuterol / levalbuterol use. According to certain embodiments, the administration of an IL-4R antagonist to a patient results in a decrease from the baseline of the daily use of albuterol or levalbuterol. The number of albuterol / levalbuterol inhalations is recorded daily by the patient in a diary, a PEF meter, or other recording device. The medicaments The use of albuterol / levalbuterol during treatment with the pharmaceutical composition described herein can typically be on an as-needed basis for symptoms rather than regularly and prophylactically. The baseline number of albuterol / levalbuterol inhalations per day can be calculated based on the average value over 7 days before the first dose administration of the pharmaceutical composition containing an IL-4R antagonist.

[0093] The present invention includes a treatment method that results in a decrease of at least 0.25 puffs per day from baseline in albuterol / levalbuterol use at week 12 after the start 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 thereof results in a decrease of about 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 in albuterol / levalbuterol use at week 12.

[0094] OCS use. According to certain embodiments, administration of an IL-4R antagonist to a patient can be combined with an OCS such as oral prednisone. The number of OCS administrations is recorded daily by the patient in a diary, a PEF meter, or other recording device. During treatment with the pharmaceutical composition described herein, short-term prednisone use can sometimes be used to manage acute asthma episodes, such as episodes that cannot be managed by bronchodilators and other anti-inflammatory drugs. In other aspects, prednisone is combined with an ICS or used as an alternative to an ICS. Oral prednisone may be administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. The OCS may optionally be administered once a day or multiple times a day (e.g., 2 times a day, 3 times a day, 4 times a day, etc.).

[0095] In certain exemplary embodiments, the present invention provides a method for reducing or eliminating dependence on OCS use in a subject. Reducing or eliminating steroid dependence is highly advantageous and desirable. In certain embodiments, a reduction of 50% or more (e.g., 50%, 60%, 70%, 80%, 90% or more) of the OCS dose is achieved after administration of the IL-4R antibody treatment over a given period (e.g., at week 24). In certain embodiments, the OCS is substantially eliminated 40 weeks, 45 weeks, 50 weeks, 52 weeks or later after the first dose following administration of the loading dose. In other embodiments, the level of OCS use is reduced to less than 5 mg per day (e.g., less than 5 mg per day, less than 4 mg per day, less than 3 mg per day, less than 2 mg per day, or less). In other embodiments, dependence on OCS use is substantially eliminated 3 months, 6 months, 9 months, or 1 year after treatment with an IL4R antibody or fragment thereof.

[0096] 5-item Asthma Control Questionnaire (ACQ) score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the 5-item Asthma Control Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[0097] The present invention includes a method of treatment that results in at least a 0.10 point decrease from baseline in the ACQ5 score 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 in need thereof results in a decrease of about 0.10 point, 0.15 point, 0.20 point, 0.25 point, 0.30 point, 0.35 point, 0.40 point, 0.45 point, 0.50 point, 0.55 point, 0.60 point, 0.65 point, 0.70 point, 0.75 point, 0.80 point, 0.85 point, or more from baseline in the ACQ score at week 12.

[0098] Nocturnal awakenings. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from the baseline average number of nocturnal awakenings.

[0099] In certain embodiments, the method decreases the average number of nocturnal awakenings by at least about 0.10 per night from baseline at week 12 after initiation of treatment. For example, administration of an IL-4R antagonist to a subject in need thereof results in a decrease 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 average number of nocturnal awakenings at week 12.

[0100] 22-item Sinonasal Outcome Test (SNOT-22) score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from the baseline 22-item Sinonasal Outcome Test (SNOT-22). The SNOT-22 is a validated questionnaire for assessing the impact of chronic rhinosinusitis on quality of life (Hopkins et al., 2009, Clin. Otolaryngol. 34:447-454).

[0101] The present invention includes a method of treatment that results in a decrease of at least 1 point from baseline in the SNOT-22 score 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 in need thereof can result in a decrease of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more from baseline in the SNOT-22 score at week 12.

[0102] Biomarker. In certain embodiments, a subject experiences an improvement in lung function as measured by a biomarker, e.g., a biomarker associated with severe steroid-dependent asthma or severe uncontrolled asthma. For example, the biomarker can be fractional exhaled nitric oxide concentration (FeNO), eotaxin-3, total IgE, periostin, or thymus and activation-regulated chemokine (TARC). In certain embodiments, the improvement in lung function is indicated by a decrease or increase (as appropriate) at week 4, week 12, or week 24 after treatment.

[0103] Method of treating asthma In some embodiments, the present invention provides a method of treating asthma (e.g., including moderate to severe uncontrolled asthma or inadequately controlled asthma) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. In certain embodiments, the method is useful for treating moderate to severe uncontrolled asthma in a subject.

[0104] As used herein, the term "asthma" can be used synonymously with "intermittent asthma" or "bronchial asthma". "Asthma", "bronchial asthma", and "intermittent asthma" refer to asthma in which one or any combination of the following applies: symptoms occur no more than 2 days per week; symptoms do not interfere with daily life; nocturnal symptoms occur no more than 2 days per month; or one or more pulmonary function tests (e.g., forced expiratory volume in 1 second (FEV1) higher than 80% and / or peak expiratory flow (PEF)) are normal when the subject is not experiencing an asthma attack.

[0105] As used herein, the term "persistent asthma" or "persistent bronchial asthma" refers to asthma that is more severe than (bronchial) asthma / intermittent (bronchial) asthma. A subject suffering from persistent asthma or persistent bronchial asthma experiences one or more of the following: symptoms more than 2 days per week; symptoms that interfere with daily life; nocturnal symptoms occurring more than 2 days per month; or one or more abnormal pulmonary function tests (e.g., forced expiratory volume in 1 second (FEV1) less than 80% and / or peak expiratory flow (PEF)) in a subject not experiencing an asthma attack; the subject is routinely dependent on asthma control medications; the subject has taken systemic steroids more than once after a severe asthma relapse in the past year; or use of short-acting beta2-agonists more than 2 days a week for asthma symptom relief.

[0106] Wheezing / intermittent wheezing, bronchial asthma / intermittent bronchial asthma, and persistent asthma / persistent bronchial asthma can be categorized as "mild", "moderate", "severe", or "moderate to severe". "Mild intermittent wheezing" or "mild intermittent bronchial asthma" is defined as having symptoms less than once a week and having a forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF) ≥ 80%. "Mild persistent wheezing" or "mild persistent bronchial asthma" differs in that the frequency of symptoms is more than once a week but less than once a day, and the variation in FEV1 or PEF is < 20% - 30%. "Moderate intermittent wheezing" or "moderate intermittent bronchial asthma" is defined as having symptoms less than once a week and having a FEV1 or PEF of 60 - 80%. "Moderate persistent wheezing" or "moderate persistent bronchial asthma" is defined as having exacerbations that may affect daily symptoms, activities, and / or sleep, nocturnal symptoms more than once a week, daily use of inhaled short-acting β2 agonists, and having a FEV1 or PEF of 60 - 80%. "Severe intermittent wheezing" or "severe intermittent bronchial asthma" is defined as having symptoms less than once a week and having a FEV1 or PEF of 60%. "Severe persistent wheezing" or "severe persistent bronchial asthma" is defined as having frequent exacerbations that may affect daily symptoms, activities, and / or sleep, frequent nocturnal symptoms, limitation of physical activity, daily use of inhaled short-acting β2 agonists, and having a FEV1 or PEF of 60%. "Moderate to severe intermittent wheezing" or "moderate to severe intermittent bronchial asthma" is defined as having symptoms between those of moderate intermittent wheezing / moderate intermittent bronchial asthma and severe intermittent wheezing / severe intermittent bronchial asthma. "Moderate to severe persistent wheezing" or "moderate to severe persistent bronchial asthma" is defined as having symptoms between those of moderate persistent wheezing / moderate persistent bronchial asthma and severe persistent wheezing / severe persistent bronchial asthma.

[0107] As used herein, the term "poorly controlled asthma" is either "poor control" or "very poorly controlled" as defined by the "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma", National Heart, Blood and Lung Institute, NIH, August 28, 2007. "Poorly controlled asthma" is defined as having symptoms more than 2 days a week, nocturnal awakenings 1 - 3 times a week, some limitation to daily activities, use of short-acting β2-agonists for symptom management more than 2 days a week, FEV1 of 60 - 80% of predicted and / or personal best, an ATAQ score of 1 - 2, an ACQ score of 1.5 or more, and an ACT score of 16 - 19. "Very poorly controlled asthma" is defined as having symptoms all day, nocturnal awakenings 4 or more times a week, extreme limitation to daily life, use of short-acting β2-agonists for symptom management several times a day, FEV1 less than 60% of predicted and / or personal best, an ATAQ score of 3 - 4, no applicable ACQ score, and an ACT score of 15 or less.

[0108] In some embodiments, the subject is based on the Global Initiative for Asthma (GINA) 2009 guidelines for asthma management and one or more of the following criteria: i) Medium or high dose ICS / LABA (2× fluticasone propionate Existing treatment using mometasone furoate 250 μg, twice daily, or the daily dose of an equivalent ICS, at a stable ICS / LABA dose; ii) FEV1 40-80% of predicted normal before loading dose administration of an IL-4R antagonist; iii) ACQ-5 score of 1.5 or more before loading dose administration of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 after 200 μg - 400 μg (inhaled 2 - 4 times) of salbutamol / albuterol before loading dose administration of an IL-4R antagonist; or v) Within 1 year before loading dose administration of an IL-4R antagonist, the following events: (a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, (b) Based on experiencing either hospitalization or emergency / urgent medical visit for asthma exacerbation, if diagnosed by a physician with moderate to severe uncontrolled asthma, is defined as having moderate to severe uncontrolled asthma.

[0109] "Severe asthma" refers to asthma that cannot achieve adequate control with high-dose treatment with inhaled corticosteroids and additional long-term control medications (e.g., long-acting inhaled β2-agonists, montelukast, and / or theophylline), or with oral corticosteroid treatment (e.g., for at least 6 months per year), or when such treatment is reduced, adequate control is lost. In certain embodiments, severe asthma is asthma treated with high-dose ICS and at least one additional long-term control medication (e.g., LABA, montelukast, or theophylline) or oral corticosteroids for longer than 6 months / year, and when treatment is reduced, at least one of the following occurs or will occur, including: ACT < 20 or ACQ > 1.5; at least two exacerbations in the most recent 12 months; at least one exacerbation in the most recent 12 months that was treated in the hospital or required mechanical ventilation; or FEV1 < 80% (if FEV1 / FVC is below the normal lower limit).

[0110] "Steroid-dependent asthma" refers to asthma that requires one or more of the following treatments: frequent short-term oral corticosteroid treatment bursts within the past 12 months; regular use of high-dose inhaled corticosteroids within the past 12 months; regular use of long-acting injectable corticosteroids; daily use of oral corticosteroids; alternate-day oral corticosteroids; or long-term use of oral corticosteroids within the past year.

[0111] "Oral corticosteroid-dependent asthma" refers to subjects who have had three or more 30-day courses of oral corticosteroids (OCS) over a 12-month period and a primary asthma diagnosis within 12 months of the first OCS course. Subjects with OCS-dependent asthma may also experience one or any combination of the following: receiving prescribed LABA and high-dose IS (total daily dose > 500 μg fluticasone propionate dry powder formulation equivalent) by a physician for at least 3 months (ICS and LABA can be part of a combination product or administered by separate inhalers); receiving additional maintenance asthma long-term management medications according to standard treatment practice, such as leukotriene receptor antagonists (LTRA), theophylline, long-acting muscarinic antagonists (LAMA), secondary ICS, and cromones; receiving OCS for the treatment of asthma at a dose of 7.5 mg or more to 30 mg or less (prednisone or prednisolone equivalent); receiving alternate-day dosing (or different doses on alternate days) of OCS; FEV1 < 80% predicted normal value before morning bronchodilator (BD) use; having evidence of asthma as demonstrated by reversibility after BD (albuterol / salbutamol) use with FEV1 ≧ 12% and ≧ 200 mL (15 - 30 minutes after administration of 4 puffs of albuterol / salbutamol); or having a history of at least one asthma exacerbation event within 12 months.

[0112] In one aspect, there is provided a method of treating asthma, comprising: (a) selecting a patient having a blood eosinophil level of at least 300 per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0113] In another aspect, there is provided a method of treating asthma, comprising the following steps: (a) selecting a patient showing blood eosinophil levels of 200 to 299 per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0114] In another aspect, there is provided a method of treating asthma, comprising the following steps: (a) selecting a patient showing blood eosinophil levels of less than 200 per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0115] In related aspects, there is provided a method of treating asthma, including additional treatment to background treatment. In certain embodiments, the IL-4R antagonist is administered as additional treatment to asthmatic patients who have received background treatment for a specific period (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or more) (also referred to as the "stable period"). In some embodiments, the background treatment includes ICS and / or LABA.

[0116] In some embodiments, the present invention provides a method of reducing a patient's dependence on ICS and / or LABA for the treatment of one or more exacerbations of asthma, comprising the following steps: (a) selecting a patient with moderate to severe asthma not managed with background asthma treatment comprising ICS, LABA, or a combination thereof; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0117] In some embodiments, the present invention encompasses methods of treating or alleviating conditions or complications associated with asthma, such as chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, allergic bronchopulmonary aspergillosis, unified airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD), and exercise-induced bronchospasm.

[0118] The present invention also includes a method of treating persistent asthma. As used herein, the term "persistent asthma" means that the subject has symptoms during the day and / or at night at least once a week, and the symptoms persist for several hours to several days. In certain alternative embodiments, persistent asthma is "mild persistent" (e.g., more than twice a week but less than daily, with symptoms of a severity that interferes with normal activities or sleep, and / or the lung function is normal or reversible with the inhalation of a bronchodilator), "moderate persistent" (e.g., symptoms occur daily, sleep is disrupted at least once a week, and / or the lung function is moderately abnormal), or "severe persistent" (e.g., symptoms that persist despite the correct use of approved medications, and / or the lung function is severely impaired).

[0119] Interleukin-4 receptor antagonist The methods of interest in the present invention include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. As used herein, an "IL-4R antagonist" is any agent that binds or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed in cells in vitro or in vivo. Non-limiting examples of categories 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. According to certain embodiments, the IL-4R antagonist comprises an anti-IL-4R antibody that is constructed in the present invention and can be used in connection with the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R and comprises heavy and light chains from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively, and the complementarity-determining region (CDR) sequences.

[0120] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), such as IL-4Rα.

[0121] The term "antibody" refers to an immunoglobulin molecule containing four polypeptide chains (two heavy (H) chains and two light (L) chains linked to each other by disulfide bonds), and multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V H for short) and a heavy chain constant region. The heavy chain constant region contains three domains, C H 1, C H 2 and C H 3. Each light chain contains a light chain variable region (abbreviated herein as LCVR or V L for short) and a light chain constant region. The light chain constant region contains one domain (C L 1). V H and V L regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). 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 an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be modified naturally or artificially. Amino acid consensus sequences are defined based on the parallel analysis of two or more CDRs.

[0122] The term "antibody" includes antigen-binding fragments of a complete antibody molecule. Terms such as "antigen-binding portion of an antibody", "antigen-binding fragment of an antibody", as used herein, refer to 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 an antibody can be obtained from a complete antibody molecule using any suitable standard techniques, such as proteolytic digestion, or recombinant genetic modification methods including manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or can be readily obtained from, for example, commercial sources, DNA libraries (including phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated by chemical or use of molecular biology techniques to, for example, arrange one or more variable and / or constant domains in a suitable higher-order structure, or introduce codons, generate cysteine residues, modify, add or delete amino acids, and the like.

[0123] 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 regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other modified molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, mini-bodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed by the expression "antigen-binding fragment".

[0124] An antigen-binding fragment of an antibody will generally contain at least one variable domain. The variable domain can 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. V L domain that associates with the V H domain in the case of an antigen-binding fragment having a V H and a V L domain can be positioned in any suitable orientation relative to each other. For example, the variable regions can be dimers and contain V H -V H V H -V L or V L -V L dimers. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0125] In certain embodiments, the antigen-binding fragment of an antibody can 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 can be found within the antigen-binding fragments of the antibodies described herein include the following: (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 -CH 1; (ix) V L -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 higher-order structure of the variable and constant domains, including any of the exemplary higher-order structures listed above, the variable and constant domains may be directly linked to each other or 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 provide a flexible or somewhat flexible linkage between adjacent variable and / or constant domains within a single polypeptide molecule. 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 may non-covalently associate (e.g., by disulfide bonds) with each other and / or with one or more monomeric V H or V L domains and may include homodimers or heterodimers (or other multimers) of any of the variable and constant domain higher-order structures listed above.

[0126] Similar to full antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally include at least two different variable domains, each variable domain being capable of specifically binding to a distinct antigen or to different epitopes on the same antigen. Any multispecific antibody format can be adapted for use in connection with the antigen-binding fragments of the antibodies described herein using conventional techniques available in the art.

[0127] The constant region of an antibody is important for the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0128] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of interest in the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations induced by in vitro random or site-directed mutagenesis or by somatic mutations in vivo), for example, in the CDRs, particularly CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences.

[0129] The term "recombinant human antibody" refers to all human antibodies produced, expressed, generated or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from recombinants, combinatorial human antibody libraries (described further below), antibodies isolated from animals (e.g., mice) into which human immunoglobulin genes have been transduced (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295). ) or any other means including splicing to other DNA sequences of the human immunoglobulin gene sequence, including antibodies produced, expressed, generated or isolated by such means. Such recombinant human antibodies have variable and constant regions derived from the human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if animals into which the human Ig sequences have been transgenically introduced), so that the V H and V L region amino acid sequences are derived from the human germline V H and V L sequences and are sequences related to the human germline V H and V L sequences, but are sequences that cannot naturally exist in the human antibody germline repertoire in vivo.

[0130] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by inter-chain heavy chain disulfide bonds. In the second form, the dimers are not linked by inter-chain disulfide bonds, and molecules of approximately 75-80 kDa are formed and composed of covalently coupled light and heavy chains (half antibodies). These forms were extremely difficult to separate, even after affinity purification.

[0131] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences in the antibody hinge region isotypes. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form to levels generally observed using the human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention is, for example, desirable for improving the yield of the desired antibody form during production, hinge, C H 2 or C HComprises an antibody having one or more mutations in the 3 domain.

[0132] "Isolated antibody" means an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or an antibody that has been separated or removed from a tissue or cell in which the antibody naturally occurs or is naturally produced, is an "isolated antibody". Isolated antibodies also include antibodies in vivo in recombinant cells in situ. An isolated antibody is an antibody that has been subjected to at least one step of purification or isolation. According to certain embodiments, an isolated antibody may be substantially free of other cellular materials and / or chemical substances.

[0133] 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, surface plasmon resonance, etc. For example, an antibody that "specifically binds" to an IL-4R, as noted in the present invention, has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured by a surface plasmon resonance assay. D And includes an antibody that binds to an IL-4R or a portion thereof. However, an isolated antibody that specifically binds to human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0134] Anti-IL-4R antibodies useful in the method may have one or more amino acid substitutions, insertions and / or deletions (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9 or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention includes methods comprising the use of antibodies and their antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more frameworks and / or one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 for trimeric antibodies or 1, 2, 3, 4, 5 or 6 for the HCVR and LCVR of an antibody) CDR regions have one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids) mutated to the corresponding residues of the germline sequence from which the antibody is derived, or to the corresponding residues of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence exchanges are collectively referred to herein as "germline mutations"). One of ordinary skill in the art can readily produce a very large number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof starting from the heavy and light chain variable region sequences disclosed herein. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues within the domain are reverted to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues, for example, only the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3, are reverted to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Further, the antibody may contain some combination of two or more germline mutations within the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residues of a particular germline sequence, while certain other residues different from the original germline sequence are maintained or may be mutated to the corresponding residues of a different germline sequence. Once an antibody and antigen-binding fragment containing one or more germline mutations are obtained, they can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, (optionally) improved or enhanced antagonist or agonist biological properties, reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained by this general approach is encompassed by the present invention.

[0135] The present invention also includes methods that include the use of anti-IL-4R antibodies that include variants 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 anti-IL-4R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions as compared to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0136] The term "surface plasmon resonance" refers to an optical phenomenon by which real-time interactions can be analyzed, for example, using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ), by detecting changes in protein concentration within a biosensor matrix.

[0137] The term "K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0138] The term "epitope" refers to an antigenic determinant that interacts with the 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. Thus, different antibodies can bind to different antigen regions and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are generated by amino acids that are spatially adjacent and 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 carbohydrate, phosphoryl group, or sulfonyl group moiety on the antigen.

[0139] Production of Human Antibodies Methods for producing human antibodies in transgenic mice are known in the art. Using any such known method, a human antibody that specifically binds to human IL-4R can be made.

[0140] ​Using the VELOCIMMUNE® technology (see, e.g., U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals), or any other known method for producing monoclonal antibodies, a high-affinity chimeric antibody to IL-4R having human variable regions and murine constant regions is first isolated. The VELOCIMMUNE® technology involves the production of transgenic mice having a genome that includes human heavy and light chain variable regions operably linked to the endogenous murine constant region locus, such that the mice produce antibodies that include human variable regions and murine constant regions in response to antigen stimulation. DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0141] Generally, VELOCIMMUNE® mice are immunized with the antigen of interest, and lymphocytes (e.g., B cells) are recovered from the mice expressing the antibody. Those lymphocytes can be fused with a myeloma cell line to produce immortalized hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the variable regions of the heavy and light chains can be isolated and linked 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 isolated directly from antigen-specific lymphocytes.

[0142] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. Using standard procedures known to those skilled in the art, the antibody is characterized and selected for the desired specificity, such as affinity, selectivity, epitope, etc. The mouse constant region is replaced with the desired human constant region to produce the fully human antibodies of interest in the present invention, such as wild-type or modified IgG1 or IgG4. The constant region selected may vary depending on the specific application, but the variable region has high-affinity antigen-binding properties and target specificity.

[0143] Generally, the antibodies that can be used in the method have high affinity as described above when measured by binding to an antigen immobilized on a solid phase or an antigen in solution phase. The mouse constant region is replaced with the desired human constant region to produce the fully human antibodies of interest in the present invention. The constant region selected may vary depending on the specific application, but the variable region has high-affinity antigen-binding properties and target specificity.

[0144] In one embodiment, a human antibody or an antigen-binding fragment thereof that specifically binds to IL-4R and can be used in connection with the methods of interest in the present invention contains three heavy-chain CDRs (HCDs) contained within the heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1 It includes R1, HCDR2, and HCDR3. The antibody or antigen-binding fragment may also include three light-chain CDRs (LCVR1, LCVR2, LCVR3) contained within the light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within the HCVR and LCVR amino acid sequences are well known in the art, and such methods and techniques can be used to identify the CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally speaking, the Kabat definition is based on sequence diversity, the Chothia definition is based on the position of structural loop regions, and the AbM definition is a compromise between the Kabat approach and the Chothia approach. For example, see Kabat, "Sequences of Proteins 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, 9268-9272 (1989). Public databases are also available for the identification of CDR sequences within antibodies.

[0145] In certain embodiments, the antibody or antigen-binding fragment thereof includes six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the pair of heavy-chain variable region amino acids and light-chain variable region amino acids of SEQ ID NOs: 1 and 2 (HCVR / LCVR).

[0146] In certain embodiments, the antibody or antigen-binding fragment thereof includes six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0147] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0148] In one embodiment, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0149] Pharmaceutical composition The present invention includes a method comprising administering to a patient an IL-4R antagonist contained in a pharmaceutical composition. The pharmaceutical compositions of interest in the present invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, acceptability, etc. Many suitable formulations can be found in the formulary 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, anhydrous absorbent pastes, 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 52:238-311.

[0150] The dosage of the antibody administered to a patient may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. The dosage is generally calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Empirically determined dosages and schedules effective for administration of the pharmaceutical composition containing the anti-IL-4R antibody can be determined; for example, the patient's course can be monitored by periodic evaluation and the dosage adjusted accordingly. Further, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0151] Various delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432), and the pharmaceutical compositions of interest in the present invention can be administered using such delivery systems. Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelial or mucosa-lined internal surfaces (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents.

[0152] The pharmaceutical compositions of interest in the present invention can be delivered subcutaneously or intravenously with standard syringes and needles. In addition, with respect to subcutaneous delivery, pen-type delivery devices (e.g., autoinjector pens) are readily utilized for the delivery of the pharmaceutical compositions of interest in the present 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 replaced with a new cartridge containing the pharmaceutical composition. Thereafter, the pen-type delivery device can 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 a reservoir of the device. When the pharmaceutical composition in the reservoir is empty, the entire device is discarded.

[0153] A very large number of reusable pen-type and self-injector delivery devices are utilized for subcutaneous delivery of pharmaceutical compositions. By way of example, and only a few are mentioned, AUTOPEN™ (Owen) Examples include, but are not limited to, Mumford, Inc., Woodstock, UK), DISETRONIC (trademark) pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 (trademark) pen, HUMALOG (trademark) pen, HUMALIN 70 / 30 (trademark) pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN (trademark) I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (trademark) (Novo Nordisk, Copenhagen, Denmark), BD (trademark) pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN (trademark), OPTIPEN PRO (trademark), OPTIPEN STARLET (trademark), and OPTICLIK (trademark) (Sanofi - Aventis, Frankfurt, Germany). Examples of disposable pen - type delivery devices used for subcutaneous delivery of pharmaceutical compositions of interest in the present invention include, but are not limited to, just a few examples: SOLOSTAR (trademark) pen (Sanofi - Aventis), FLEXPEN (trademark) (Novo Nordisk) and KWIKPEN (trademark) (Eli Lilly), SURECLICK (trademark) auto - injector (Amgen, Thousand Oaks, CA), PENLET (trademark) (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA (trademark) pen ((A bbott Labs, Abbott Park IL), among others. Examples of large - volume delivery devices (e.g., large - volume syringes) include, but are not limited to, bolus syringes such as BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, etc.

[0154] For direct administration into a cavity, the pharmaceutical composition of interest in the present invention may be administered, for example, using a microcatheter (e.g., an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer or an inhaler. The method includes administering an IL-4R antagonist in an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-4R may be administered to treat asthma in a patient. The aerosolized antibody can be produced as described, for example, in U.S. Patent No. 8,178,098, which is incorporated herein by reference in its entirety.

[0155] In certain situations, the pharmaceutical composition can be delivered by a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can 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 can be placed immediately adjacent to the target of the composition and thus requires only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in a review by Langer, 1990, Science 249:1527-1533.

[0156] Examples of injectable preparations include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, intravenous drip infusion, etc. These injectable preparations can be manufactured by known methods. For example, an injectable preparation can be manufactured by dissolving, suspending or emulsifying the above-mentioned antibody or its salt in a sterilized aqueous medium or an oily medium conventionally used for injections. Examples of the aqueous medium for injections include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, and these may be used in combination with appropriate solubilizing agents such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. As the oily medium, for example, sesame oil and soybean oil are used, and these may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. The injectable preparation thus manufactured is generally filled into appropriate ampoules.

[0157] Advantageously, the oral or parenteral pharmaceutical compositions described above are manufactured in dosage forms of unit doses suitable for adjusting the dosage of the active ingredient. Examples of such dosage forms of unit doses include, for example, tablets, pills, capsules, injectable preparations (ampoules), suppositories, etc.

[0158] 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.

[0159] Dosage An IL-4R antagonist administered to a subject according to the method noted in the present invention (for example, The amount of the anti-IL-4R antibody is generally a therapeutically effective amount. As used herein, the term "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 asthma exacerbation; (b) an improvement in one or more asthma-related parameters (defined elsewhere herein), and / or (c) a detectable improvement in one or more symptoms or signs of the 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.

[0160] In the case of an anti-IL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 700 mg of the anti-IL-4R antibody, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg or about 700 mg. In certain embodiments, 300 mg of the anti-IL-4R antibody is administered.

[0161] The amount of the IL-4R antagonist contained in each dose may 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 about 0.0001 to about 10 mg / (patient body weight kg). For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0162] In some embodiments, the dose of the IL-4R antagonist may vary depending on the eosinophil count. For example, the subject has a blood eosinophil count of ≧300 cells / μL or 300 - 499 cells / μL or ≧500 cells / μL (high blood eosinophils) (HEos); a blood eosinophil count of 200 - 299 cells / μL (moderate blood eosinophils); or a blood eosinophil count <200 cells / μL (low blood eosinophils).

[0163] In certain embodiments, the method includes a loading dose of about 400 to about 600 mg of the IL-4R antagonist.

[0164] In certain embodiments, the method includes one or more maintenance doses of about 200 to about 300 mg of the IL-4R antagonist.

[0165] In certain embodiments, the ICS and LABA are administered during the administration period of the IL-4R antagonist.

[0166] In certain embodiments, the loading dose includes 600 mg of the anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses include 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0167] In certain embodiments, the loading dose includes 400 mg of the anti-IL-4R antibody or its antigen-binding fragment, and one or more maintenance doses include 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

[0168] In certain embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks, which may be increased to 300 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0169] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0170] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0171] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered once a week.

[0172] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered once a week.

[0173] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0174] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0175] In one embodiment, the subject is from 6 to less than 18 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0176] In another embodiment, the subject is from 12 to less than 18 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0177] In another embodiment, the subject is from 6 to less than 12 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0178] In another embodiment, the subject is from 2 to less than 6 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0179] In yet another embodiment, the subject is less than 2 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0180] Combination therapy Certain embodiments of the methods of interest in the present invention involve administering to a subject one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of the IL-4R antagonist and a second therapeutic agent. The present invention includes methods of treating asthma or related conditions or complications or of reducing at least one exacerbation that include administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0181] ​For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, a further therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes before administration of the pharmaceutical composition comprising the IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, a further therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after administration of the pharmaceutical composition comprising the IL-4R antagonist. "Concurrent" administration with a pharmaceutical composition comprising an IL-4R antagonist means that a further therapeutic agent is administered to the subject in a different dosage form within less than 5 minutes (before, after, or concurrently) of administration of the pharmaceutical composition comprising the IL-4R antagonist, or that the subject is administered a single combined dosage formulation comprising both the further therapeutic agent and the IL-4R antagonist.

[0182] Additional therapeutic agents can be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Patent No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibodies described in U.S. Patent No. 7,582,298), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal agent, an NSAID, a long-acting β2 agonist (such as salmeterol or formoterol), an inhaled corticosteroid (such as fluticasone or budesonide), a systemic corticosteroid (such as oral or intravenous), a methylxanthine, nedocromil sodium, sodium cromoglycate, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered in combination with a combination agent comprising a long-acting β2 agonist and an inhaled corticosteroid (such as fluticasone + salmeterol [such as Advair® (GlaxoSmithKline)]; or budesonide + formoterol [such as SYMBICORT® (Astra Zeneca)]).

[0183] Dosing regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined period of time. Such methods include sequentially administering multiple doses of the 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 (such as several hours, several days, several weeks, or several months). The present invention includes methods comprising 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, optionally followed by one or more third doses of the IL-4R antagonist, sequentially.

[0184] The present invention provides a method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to a subject at a dosing frequency of about four times a week, twice a week, once a week (q1w), once every two weeks (bi-weekly or q2w), once every three weeks (every three weeks, or q3w), once every four weeks (once a month or q4w), once every five weeks (q5w), once every six weeks (q6w), once every eight weeks (q8w), once every twelve weeks (q12w), or at a lower frequency if a therapeutic response is obtained. In certain embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-weekly dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-two-weeks (bi-weekly) dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-three-weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-four-weeks (once-monthly) dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-five-weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-six-weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-eight-weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In other embodiments comprising administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once-every-twelve-weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In one embodiment, the route of administration is subcutaneous.

[0185] 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" in this case indicates the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0186] The terms "first dose", "second dose" and "third dose" refer to the time series of the administration of the IL-4R antagonist. Thus, the "first dose" is the dose administered at the start of the treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the first dose, and the "third dose" is the dose administered after the second dose. The first, second and third doses may all contain the same amount of the IL-4R antagonist, but will generally differ from each other in terms of the dosing frequency. However, in certain embodiments, the amounts of the IL-4R antagonist contained in the first, second and / or third doses may differ from each other during the course of the treatment (for example, adjusted upwards or downwards as necessary). In certain embodiments, two or more (for example, 2, 3, 4 or 5) doses are administered at the start of the treatment regimen as a "loading dose", and subsequent doses (for example, "maintenance doses") are then administered at a lower frequency. In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more loading doses of 600 mg of the IL-4R antagonist may be administered, and then a maintenance dose of about 75 mg to about 300 mg may be administered.

[0187] In certain embodiments, the loading dose is about 400 to about 600 mg of the IL-4R antagonist. In one embodiment, the loading dose is 400 mg of the IL-4R antagonist. In another embodiment, the loading dose is 600 mg of the IL-4R antagonist.

[0188] In certain embodiments, the maintenance dose is about 200 to about 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist. In another embodiment, the maintenance dose is 300 mg of the IL-4R antagonist.

[0189] In certain embodiments, the loading dose is twice the maintenance dose.

[0190] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0191] In some embodiments, the subject has OCS-dependent asthma, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0192] In some embodiments, the subject has co-existing moderate to severe atopic dermatitis, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0193] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0194] In some embodiments, the subject has OCS-dependent asthma, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0195] In some embodiments, the subject has co-existing moderate to severe atopic dermatitis, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[0196] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0197] In some embodiments, the subject has OCS-dependent asthma, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0198] In some embodiments, the subject has co-existing moderate to severe atopic dermatitis, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0199] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0200] In some embodiments, the subject has OCS-dependent asthma, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0201] In some embodiments, the subject has co-existing moderate to severe atopic dermatitis, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0202] In one exemplary embodiment, each second and / or third dose is 1 to 14 weeks (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 It is administered after 12, 12.5, 13, 13.5, 14, 14.5 weeks or more. The phrase "immediately preceding dose" means, with respect to the order of multiple administrations, the dose of the anti-IL-4R antagonist administered to the patient immediately prior to the administration of the very next dose in that order without intervening doses.

[0203] The method can include administering to the patient any number of second and / or third doses of the IL-4R antagonist. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 doses or more) second 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 (e.g., 2, 3, 4, 5, 6, 7, 8 doses or more) third doses are administered to the patient.

[0204] In embodiments comprising 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 immediately preceding dose. Similarly, in embodiments comprising 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 immediately preceding dose. Alternatively, the frequency at which the second and / or third doses are administered to the patient can vary throughout the course of the treatment regimen. The dosing frequency may also be adjusted by a physician during the course of treatment according to the needs of the individual patient in accordance with clinical tests.

[0205] The present invention includes a method comprising sequential administration to a patient of an IL-4R antagonist and a second therapeutic agent for treating asthma or a related condition. In some embodiments, the method includes administration of one or more doses of an IL-4R antagonist, followed by 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 an IL-4R antagonist of about 75 mg to about 300 mg 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 a β2 agonist or other therapeutic agent as described elsewhere herein) for treating, alleviating, reducing, or improving 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, and then a second therapeutic agent is administered to prevent recurrence of at least one symptom of asthma. Alternative embodiments relate to 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 at a different dosage and at a similar or different frequency compared to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0206] In certain embodiments, the IL-4R antagonist is administered every two weeks for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks, or more. In other embodiments, the IL-4R antagonist is administered every four weeks for 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or more. In specific embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0207] The present invention relates to a method for treating a subject having severe uncontrolled asthma (e.g., severe steroid-dependent asthma), the method comprising administering a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R to the subject. In certain embodiments, the method comprises administering a plurality of maintenance doses of the antibody or antigen-binding fragment thereof to the subject, the plurality of maintenance doses being administered during the treatment period. The treatment period includes an induction period, an OCS reduction period, and an OCS maintenance period. In certain exemplary embodiments, the induction period includes a period during which the subject receives their OCS dose continuously. In certain exemplary embodiments, the reduction period includes a period during which the subject receives a lower OCS dose compared to the dose received during the induction period. In certain exemplary embodiments, the maintenance period includes a period during which the subject receives a constant, stable amount or dose of OCS. Alternatively, the maintenance period includes a period during which OCS treatment / administration is reduced / removed. In certain embodiments, the use of OCS by the patient is completely removed and the patient is steroid-free within less than 1 year (e.g., within 1 year, 6 months, 3 months, or 1 month from the first treatment) from treatment with the IL4R antibody or fragment thereof.

[0208]

[0209] In another aspect, a method for treating a subject having severe steroid-dependent asthma and / or severe uncontrolled asthma comprises administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof. Each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof, the plurality of maintenance doses being administered during a treatment period that includes an induction period, an oral corticosteroid (OCS) reduction period, and a maintenance period, and the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

[0210] Treatment population The methods of interest in the present invention include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. The expression "subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or signs of asthma (e.g., moderate to severe uncontrolled asthma) or is diagnosed with asthma. For example, "subject in need thereof" can include, for example, a subject that exhibits (or exhibited) one or more asthma-related parameters, such as reduced FEV1 (e.g., less than 2.0 L), reduced FEF25-75%; reduced AM PEF (e.g., less than 400 L / min), reduced PM PEF (e.g., less than 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, etc., prior to treatment. In various embodiments, the method may be used to treat mild asthma, moderate to severe asthma, and severe asthma in a patient in need thereof. In certain embodiments, the method is used to treat mild, moderate to severe, and severe asthma in a patient in need thereof, and the patient further exhibits co-existing moderate to severe atopic dermatitis.

[0211] In related embodiments, the "subject in need thereof" may be a subject who has been prescribed or is currently taking a combination of ICS / LABA prior to receiving the IL-4R antagonist. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABA include formoterol and salmeterol. Examples of ICS / LABA therapy include fluticasone / salmeterol combination therapy, and budesonide / formoterol combination therapy. For example, the present invention includes methods that include administering an IL-4R antagonist to a patient who has received regular treatment with ICS / LABA for two weeks or more immediately prior to administration of the IL-4R antagonist (such previous treatment is referred to herein as "background treatment"). The present invention includes methods of treatment in which the background treatment is continued in combination with the administration of the IL-4R antagonist. In yet other embodiments, The amount of the ICS component, the LABA component, or both, is gradually decreased before or after the initiation of IL-4R antagonist administration. In some embodiments, the present invention includes a method of treating a patient having persistent asthma for at least 12 months or more. In one embodiment, a patient with persistent asthma may be resistant to treatment with a therapeutic agent such as a corticosteroid, and an IL-4R antagonist may be administered to such a patient according to the present method.

[0212] In some embodiments, the "subject in need thereof" may be a subject having elevated asthma-related biomarker levels. Examples of asthma-related biomarkers include, but are not limited to, IgE, thymus and activation-regulated chemokine (TARC), eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, the "subject in need thereof" may be a subject having blood eosinophils ≧ 300 cells / μL, 200 - 299 cells / μL, or < 200 cells / μL. In one embodiment, the "subject in need thereof" may be a subject having an elevated bronchial or airway inflammation level as measured by exhaled nitric oxide concentration (FeNO).

[0213] In some embodiments, the "subject in need thereof" is selected from the group consisting of subjects 18 years of age or older, subjects 12 years of age or older, subjects 12 - 17 years of age (12 years to less than 18 years), subjects 6 - 11 years of age (6 years to less than 12 years), and subjects 2 - 5 years of age (2 years to less than 6 years). In some embodiments, the "subject in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "subject in need thereof" is selected from the group consisting of adults 18 years of age or older, adolescents 12 - 17 years of age (12 years to less than 18 years), children 6 - 11 years of age (6 years to less than 12 years), and children 2 - 5 years of age (2 years to less than 6 years). The subject may be less than 2 years of age, for example, 12 - 23 months, or 6 - 11 months.

[0214] Normal IgE levels in healthy subjects are less than about 100 kU / L (measured, for example, using the IMMUNOCAP® assay [Phadia, Inc., Portage, MI]). Thus, the present invention includes a method comprising the step of selecting a subject exhibiting an elevated serum IgE level that is greater than about 100 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0215] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with an average value of about 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC quantitative ELISA kit provided by R&D Systems, Minneapolis, MN under catalog number DDN00). Thus, the present invention includes a method comprising the step of selecting a subject exhibiting an elevated TARC level that is greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0216] Eotaxin-3 belongs to a group of chemokines released by airway epithelial cells that are upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al., 1999, J. Allergy Clin. Immunol. 104:786-79 (page 0). The present invention includes a method comprising administering an IL-4R antagonist to treat a patient having an elevated eotaxin-3 level, such as an eotaxin-3 level higher than about 100 pg / ml, higher than about 150 pg / ml, higher than about 200 pg / ml, higher than about 300 pg / ml, or higher than about 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0217] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin levels have been found 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 a patient having an elevated periostin level.

[0218] Fractional exhaled nitric oxide (FeNO) 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 (Alving et al., 1993, Eur. Respir. J. 6:1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is by use of a NIOX instrument by Aerocrine AB, Solna, Sweden. The assessment can be performed before spirometry and after at least 1 hour of fasting. The present invention includes a method comprising administering an IL-4R antagonist to a patient having an elevated fractional exhaled nitric oxide (FeNO) level, such as an FeNO level higher than 30 ppb, higher than about 31 ppb, higher than about 32 ppb, higher than about 33 ppb, higher than about 34 ppb, or higher than about 35 ppb.

[0219] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker that has been found to be correlated with non-neoplastic diseases of the lung (Marechal et al., 1988, Anticancer Res. 8: 677-680). Serum CEA levels can be measured by ELISA. The present invention includes a method comprising administering an IL-4R antagonist to a patient having an elevated CEA level, for example, a CEA level 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.

[0220] YKL-40 (named after its N-terminal amino acids tyrosine (Y), lysine (K) and leucine (L), and having a molecular weight of 40 kD) is a chitinase-like protein that has been found to be upregulated and correlated with asthma exacerbation, 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 a patient having an elevated YKL-40 level, for example, a YKL-40 level 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.

[0221] Periostin is a secreted 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 are correlated with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Ibid. The present invention includes a method comprising administering an IL-4R antagonist to a patient having an elevated periostin level.

[0222] Induced sputum eosinophils and neutrophils are established direct markers for 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, for example, the guidelines of the European Respiratory Society.

[0223] In some embodiments, the subject is stratified into the following groups: blood eosinophil count ≥ 300 cells / μL (high blood eosinophils) (HEos) or 300 - 499 cells / μL or ≥ 500 cells / μL, blood eosinophil count 200 - 299 cells / μL (moderate blood eosinophils), or blood eosinophil count < 200 cells / μL (low blood eosinophils), and is administered an anti - IL - 4R antibody or an antigen - binding fragment thereof at a dose or dosing regimen based on the eosinophil level.

[0224] In some embodiments, the subject is stratified into the following groups: blood eosinophil count ≥ 300 cells / μL, 300 - 499 cells / μL, or ≥ 500 cells / μL (high blood eosinophils); blood eosinophil count ≥ 150 cells / μL (moderate blood eosinophils); or blood eosinophil count < 150 cells / μL (low blood eosinophils), and is administered an anti - IL - 4R antibody or an antigen - binding fragment thereof at a dose or dosing regimen based on the eosinophil level.

[0225] In some embodiments, the subject has "eosinophilic phenotype" asthma defined by blood eosinophil count ≥ 150 cells / μL, blood eosinophil count ≥ 300 cells / μL, blood eosinophil count 300 - 499 cells / μL, or blood eosinophil count ≥ 500 cells / μL, and is administered an anti - IL - 4R antibody or an antigen - binding fragment thereof.

[0226] Method for evaluating pharmacodynamic asthma - related parameters The present invention also includes a method for evaluating one or more pharmacodynamic asthma-related parameters in a subject in need thereof, resulting from administration of a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbation (as described above), or an improvement in one or more asthma-related parameters (as described above), may be correlated with an improvement in one or more pharmacodynamic asthma-related parameters, but such a correlation is not necessarily observed in all cases.

[0227] Examples of "pharmacodynamic asthma-related parameters" include, for example, the following: (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) fractional exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement in pharmacodynamic asthma-related parameters" means, for example, a decrease from baseline of one or more biomarkers such as TARC, eotaxin-3 or IgE, a decrease in sputum eosinophils or neutrophils, FeNO, periostin or blood eosinophil count. As used herein, the term "baseline" with respect to a pharmacodynamic asthma-related parameter means the value of the subject's pharmacodynamic asthma-related parameter before or at the time of administration of the pharmaceutical composition described herein.

[0228] To evaluate the pharmacodynamic asthma-related parameters, the parameters are quantified at baseline and at a time point after administration of the pharmaceutical composition. For example, the pharmacodynamic asthma-related parameters may be measured after the first treatment with the pharmaceutical composition, on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or at one or more additional time points. Using the difference between the value of the parameter at a specific time point after the start of treatment and the value of the parameter at baseline, a change (e.g., as measured by the specific depending on the parameters, and in some cases, to confirm whether there was an increase or decrease).

[0229] In certain embodiments, administration of an IL-4R antagonist to a patient results in a change in the expression of certain biomarkers, such as a decrease or increase. Asthma-related biomarkers include, but are not limited to: (a) total IgE; (b) thymus and activation-regulated chemokine (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 asthmatic patient may result in a decrease in TARC or eotaxin-3 levels or a decrease in total IgE levels in serum. Said decrease can be detected at the 1st week, 2nd week, 3rd week, 4th week, 5th week or later 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).

[0230] Biomarker expression as discussed above can be assayed by detection of proteins or RNAs in serum. Serum samples can be used to monitor additional protein or RNA biomarkers related to the response to treatment with an IL-4R antagonist, IL-4 / IL-13 signaling, asthma, atopy or eosinophilic diseases (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, periostin). In some embodiments, RNA samples are used for determination of RNA levels (non-gene analysis), e.g., determination of the RNA levels of biomarkers; in other embodiments, RNA samples are used for transcriptome sequencing (e.g., gene analysis).

[0231] Formulation In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 150 mg / mL of an antibody or antigen-binding fragment thereof 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, vi) about 0.2% (w / v) polysorbate 80. In this case, the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 centipoises.

[0232] In alternative embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of an antibody or antigen-binding fragment thereof 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 50 mM arginine hydrochloride, vi) about 0.2% (w / v) polysorbate 80. In this case, the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 centipoises.

[0233] In specific embodiments, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0234] The invention is further illustrated by the following examples, which should not be construed as further limitations. The content of all figures and all references, patents and published patent applications cited throughout this application are hereby expressly incorporated by reference for all purposes.

[0235] Furthermore, in accordance with the present invention, conventional molecular biology, microbiology and recombinant DNA techniques within the skill of the art may be utilized. Such techniques are well described in the literature See, for example, 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 (D.N. Glover ed., 1985); Oligonucleotide Synthesis (M.J. Gait ed., 1984); Nucleic Acid Hybridization [B.D. Hames and S.J. Higgins eds. (1985)]; Transcription And Translation [B.D. Hames and S.J. Higgins eds., (1984)]; Animal Cell Culture [R.I. Freshney ed. (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

Example

[0236] The following examples are presented to give those skilled in the art a complete disclosure and description of how to make and use the methods and compositions of interest in the present invention and are not intended to limit the scope that the inventors regard as their invention. Efforts have been made to be accurate with respect to the numerical values used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0237] The exemplary IL-4R antagonist used in the following examples is the human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1").

Example

[0238] VENTURE Phase III Trial (NCT02528214) Severe uncontrolled asthma can lead to dependence on oral corticosteroids with systemic steroid exposure. This can result in serious short - and long - term adverse effects including weight gain, diabetes, osteoporosis, glaucoma, anxiety, depression, cardiovascular disease, and immunosuppression. Patients with severe chronic asthma live with a profound reduction in lung function, approximately 52 percent of the predicted normal value for patients in this study at baseline. The reduction in lung function affects the ability to breathe normally and can cause frequent exacerbations requiring acute treatment and hospitalization. These problems occur even in patients being treated with long - term OCS.

[0239] A Phase 3 trial / study was conducted to evaluate dupilumab in adults and adolescents with severe steroid - dependent asthma without defining a minimum blood eosinophil requirement, where they received additional dupilumab 300 mg or placebo every 2 weeks for 24 weeks. The Phase 3 trial (VENTURE) enrolled 210 patients (101 in the dupilumab group and 102 in the placebo group, 203 completed the randomization period) with severe asthma and regular use of maintenance OCS in the 6 months prior to this study (Figure 1). In this study, the OCS prescribed was prednisone or prednisolone. Patients were randomized using a 1:1 randomization ratio and treated with either 300 mg every 2 weeks along with a dupilumab loading dose of 600 mg or placebo (Figure 2). The median baseline eosinophil count in this study was 260 eosinophils / microliter. The primary endpoint was the reduction in glucocorticoid dose at Week 24. Key secondary endpoints included the proportion of patients who achieved a ≥50% reduction in glucocorticoid dose and a reduction in glucocorticoid dose to <5 mg / day at Week 24. Severe exacerbation rate and forced expiratory volume in 1 second before bronchodilator use (FEV 1) was evaluated in the overall population and in patients with blood eosinophils ≥ 300 cells / μL. Safety was evaluated overall.

[0240] The inclusion criteria for this study are shown in Table 1 below. The baseline demographics of this study are shown in Figure 3.

[0241]

Table 1

[0242] The primary outcome analyzed was the percent reduction in OCS dose at week 24. Key secondary outcomes analyzed included a reduction of 50% or more in OCS dose and a reduction in OCS dose to < 5 mg / day. Other secondary outcomes examined included achieving the maximum possible reduction per protocol in patients and patients no longer requiring OCS. Disease-specific efficacy scales were used. The scales were a reduction in annualized severe exacerbations and an improvement in lung function (FEV1). Figure 2 shows the overall breakdown of patients in this study.

[0243] Primary Outcome In the intention-to-treat (ITT) population, dupilumab treatment significantly reduced the oral glucocorticoid dose compared to placebo while maintaining asthma management: least-squares (LS) mean (standard error [SE]) percentage change from baseline to week 24 (-70.1% (4.90) vs -41.9% (4.57) from baseline, respectively; P < 0.001; Figure 4A; Table 2). The median observed change from baseline to week 24 in dupilumab-treated patients was 100% (interquartile range (IQR), 62.5% - 100%) compared to 50% (IQR, 0% - 100%) in the placebo group.

[0244]

Table 2

Table 3

[0245] Secondary Outcome Outcome of Glucocorticoid Reduction For the primary evaluation item, at week 24 in the entire population, dupilumab added to standard treatment significantly reduced the use of maintenance oral corticosteroids (OCS) to 70.1% (median 100%) compared with 41.9% (median 50%) with placebo (p < 0.001).

[0246] In a pre-specified analysis of patients with a baseline eosinophil count of 300 cells / microliter or more, adding dupilumab significantly reduced OCS use to an average of 80% (median 100%) compared with 43% (median 50%) for placebo.

[0247] The proportion of patients who achieved a ≥50% reduction in the oral corticosteroid dose relative to baseline at week 24 was significantly higher for dupilumab compared with placebo (80% vs 50%; P < 0.001; observed values: 80% for dupilumab, 53% for placebo) (Figure 4A; Table 2). Sensitivity analysis also demonstrated a higher proportion of patients with 50%, 75%, and 90% reductions in oral corticosteroids for dupilumab (Table 3). Significantly more patients treated with dupilumab compared with placebo achieved a reduction in the oral corticosteroid dose to <5 mg / day (69% vs 33%; P < 0.001; observed values: 72% for dupilumab, 37% for placebo) (Figure 4A; Table 2).

[0248]

Table 4

[0249] Notably, 48% of dupilumab-treated patients achieved a reduction in their maximum possible glucocorticoid dose at week 24, compared with 26% of placebo-treated patients (P = 0.002; observed values: 52% for dupilumab and 30% for placebo) (Figure 4A; Table 2). Similarly, 48% of dupilumab-treated patients no longer required oral corticosteroids at week 24, compared with 25% of placebo-treated patients (P = 0.002; observed values: 52% for dupilumab and 29% for placebo) (Figure 4A; Table 2). Dupilumab consistently reduced oral corticosteroid outcome measures regardless of baseline blood eosinophil counts (Figures 5A and 5B; Table 4).

[0250]

Table 5

Table 6

[0251] Improvement was observed in all baseline blood eosinophil subgroups, but the magnitude of the treatment effect was greatest in subgroups with higher baseline eosinophil counts (e.g., the odds ratio for dupilumab versus placebo in patients with ≥50% reduction in oral glucocorticoid dose was 6.59 (95% CI, 2.1–20.4) for patients with ≥300 cells / μL at baseline and 2.91 (95% CI, 1.3–6.6) for patients with <300 cells / μL at baseline). Across the overall population, 69 percent of patients who received dupilumab reduced their OCS dose to <5 mg per day while maintaining asthma control, compared with 33 percent of patients who received placebo It was achievable (p-value < 0.0001); in the high EOS group, 84 percent of dupilumab patients were able to reduce their OCS dose to less than 5 mg per day compared to 40 percent on placebo (p-value equal to 0.0002). Half of the patients completely discontinued oral glucocorticoid use. Despite glucocorticoid reduction, dupilumab versus placebo in the overall population and the ≥ 300 cells / μL Eos subgroup reduced severe exacerbations by 59.3% (P<0.001) and 71.1%, respectively, and improved FEV1 by 0.22 L (P<0.001) and 0.32 L, respectively.

[0252] Exacerbation and FEV1 In addition to the significant reduction in oral glucocorticoid use during the 24-week treatment period, dupilumab significantly (P<0.001) reduced severe asthma exacerbations by 59.3% in the overall population compared to placebo (Figure 4B and Table 7), and also improved FEV1 by 0.22 L (0.05) at week 24 in the overall population (P<0.001 compared to 0.01 L [0.05] with placebo). Dupilumab reduced the annual rate of severe asthma exacerbations and improved FEV1 compared to placebo regardless of baseline eosinophil count (Figure 6A and Figure 6B, Table 5), but these benefits were more pronounced in patients with higher baseline blood eosinophil counts. For example, dupilumab reduced severe exacerbations by 71.1% and improved FEV1 by LS mean (SE) 0.32 L (95% CI 0.10 to 0.54) in patients with baseline blood eosinophils ≥ 300 cells / μL (both P<0.001 compared to placebo).

[0253]

Table 7

Table 8

[0254] The improvement in FEV1 was rapid and sustained, being present as early as week 2 (LS mean change 0.15 L; 95% CI 0.04 to 0.26) and increasing further by week 24 (P<0.05 at all time points) (Figure 4C and Table 2). At week 24, dupilumab improved lung function as assessed by forced expiratory volume in 1 second (FEV1) by 220 mL (15 percent) compared with a 10 mL difference for placebo in the overall population (p equal to 0.0007), and by 320 mL (25 percent) compared with a 120 mL difference for placebo in patients with eosinophil counts of 300 cells / microlitre or more (p equal to 0.0049).

[0255] Other secondary and exploratory outcomes The phase 3 study enrolled patients with steroid-dependent severe asthma regardless of eosinophil levels or other biomarkers, and the results showed improvement in lung function and exacerbations compared with placebo across the following patient subgroups: baseline blood eosinophil counts above 300 cells / microlitre; above 150 cells / microlitre; and below 150 cells / microlitre. Dupilumab demonstrated consistent improvement in lung function across the asthma programme in patients with severe asthma suffering from daily deterioration in respiratory capacity.

[0256] The ACQ-5 score at week 24 showed a significant improvement (P = 0.002) with dupilumab in asthma management compared with placebo (LS mean difference in change from baseline: -0.47 [95% CI, -0.76 to -0.18]). For dupilumab, the LS mean improvement from baseline at week 24 (-1.05) was twice the minimum important difference of 0.5 in clinical terms for the ACQ-5 instrument.

[0257] Dupilumab treatment suppressed FeNO by week 2, which was maintained throughout the 24-week treatment period (P < 0.001 vs placebo at all time points; Figure 4D). The percentage of patients with FeNO < 25 ppb (upper limit of normal) (Table 6) increased from 43.6% at baseline to 84.4% in the dupilumab group, while in the placebo group, no change was observed (from 44.7% to 45.1%).

[0258]

Table 9

[0259] Morning and evening daily asthma symptoms in patients with oral corticosteroid-dependent severe asthma Patients' asthma symptoms were scored for their severity 0 (mildest) - 4 (most severe) in the morning for night-time symptoms (AM symptoms) and in the evening for daytime symptoms (PM symptoms) and recorded as scores in an electronic diary. Changes from baseline in asthma symptom scores during the 24-week treatment period were analyzed by using a mixed-effects model with repeated measures.

[0260] The mean baseline AM / PM symptom scores in the dupilumab and placebo groups were 1.37 / 1.37 and 1.50 / 1.52, respectively, in the ITT population (n = 210), and 1.45 / 1.49 and 1.50 / 1.52, respectively, in patients who had reduced OCS use by 100% by week 24 (40.5%). In the dupilumab group, symptoms improved rapidly (LS mean change from baseline in AM / PM symptom scores at week 2, -0.18 / -0.23; P < 0.05 for both compared with placebo), continued to improve until week 16 (-0.47 / -0.47; P < 0.05 for both compared with placebo), and maintained a positive effect until week 24 (Figures 25A and 25C). Patients in the dupilumab group who had reduced OCS use by 100% by week 24 showed a similar pattern of response and had greater symptom improvement (Figures 25B and 25D). Overall, the most frequently occurring treatment-emergent adverse event in dupilumab-treated patients compared with placebo-treated patients was eosinophilia (14% vs 1%). Injection site reactions occurred in 9% of dupilumab-treated patients compared with 4% of placebo-treated patients.

[0261] Dupilumab improved morning and evening asthma symptoms in a rapid and sustained manner in patients with OCS-dependent severe asthma, despite OCS withdrawal. Symptom improvement was greatest in patients who had reduced OCS use by 100% by week 24. Dupilumab was generally well tolerated.

[0262] Population: ITT; subgroup of 100% OCS reduction. Assessment: LS mean change from baseline in AM / PM asthma symptoms during treatment. Treatment arm: dupilumab 300mg q2w; placebo.

[0263] Asthma management and quality of life related to health status Asthma management was evaluated by weekly recording in an electronic diary of the validated 5-item Asthma Control Questionnaire (ACQ-5), with higher scores (range 0–6) indicating poorer control for the ACQ-5. Health-related quality of life (HRQoL) was evaluated by using the self-administered 7-item Asthma Quality of Life Questionnaire (AQLQ), with higher total scores (range 0–7) indicating better HRQoL for the AQLQ. Changes from baseline in ACQ-5 and AQLQ scores during the 24-week treatment period were analyzed using a mixed-effects model with repeated measures.

[0264] In the dupilumab and placebo groups, mean baseline ACQ-5 scores were 2.42 and 2.58, and mean baseline AQLQ scores were 4.38 and 4.31, respectively. In the dupilumab group, asthma control improved rapidly (week 2, least squares (LS) mean change from baseline in ACQ-5 score, 0.57; P = 0.002 vs placebo), further improved by week 12 (1.01; P = 0.001 vs placebo), and remained stable through week 24 (1.05; P = 0.002 vs placebo) (Figure 26A). In patients receiving dupilumab treatment, an LS mean improvement from baseline in AQLQ score of 0.76 was observed at week 12 (P = 0.14 vs placebo), which further improved to 0.89 at week 24 (P = 0.008 vs placebo) (Figure 26B). Overall, the most frequent treatment-emergent adverse event occurring in dupilumab-treated patients compared with placebo-treated patients was eosinophilia (14% vs 1%). Injection-site reactions occurred in 9% of dupilumab-treated patients versus 4% of placebo-treated patients.

[0265] Additional dupilumab compared with placebo significantly improved asthma management and HRQoL in patients with OCS-dependent severe asthma. Improvement in asthma management occurred as early as week 2 and was maintained over 24 weeks. Dupilumab was generally well tolerated.

[0266] Population: ITT. Evaluation items: LS mean change from baseline of ACQ-5 at Week 2, Week 12, and Week 24; LS mean change from baseline of AQLQ at Week 12 and Week 24; safety during the treatment period. Treatment arms: dupilumab 300 mg q2w; placebo.

[0267] Safety The incidence of TEAE was similar across treatment groups in the safety population (62.1% vs 64.5% for dupilumab vs placebo). The TEAE occurring most frequently in ≥5% of patients treated with dupilumab vs patients treated with placebo according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms were viral upper respiratory tract infection (8.7% vs 17.8%), bronchitis (6.8% vs 5.6%), rhinitis (6.8% vs 3.7%), influenza (2.9% vs 5.6%), injection site reaction (8.7% vs 3.7%), and laboratory measurement of eosinophilia (grouping the preferred terms "increased eosinophil count" and "eosinophilia") (13.6% vs 0.9%). According to the study protocol, all cases of eosinophil count > 3,000 cells / μL with treatment were to be reported as AEs, which occurred in 12.6% of dupilumab-treated patients vs 0.9% in the placebo group. All reported TEAE of eosinophilia were solely laboratory findings without any clinical outcome or related AE.

[0268] Serious TEAE were reported in 9 (8.7%) dupilumab-treated patients and 6 (5.6%) placebo-treated patients; serious TEAE were not related to the investigational medicinal product. There were no deaths in this study. Treatment-emergent anti-drug antibody responses were observed in 5 patients (5.0% for dupilumab; 4.7% for placebo) in each group, and there was no significant impact on efficacy or safety. There were no deaths in this study. Treatment-emergent anti-drug antibody responses were observed in 5 patients (5.0% for dupilumab; 4.7% for placebo) in each group, and there was no significant impact on efficacy or safety.

[0269]

Table 10

[0270] Methods Study Design and Monitoring This multinational, randomized, double-blind, placebo-controlled study in the third phase evaluated the efficacy and safety of dupilumab in patients with oral glucocorticoid-dependent severe asthma. Patients completed an 8- to 10-week oral glucocorticoid dose optimization period, followed by a 1:1 randomization to dupilumab or placebo for a 24-week treatment period. This treatment period consisted of a 4-week induction period during which the optimized oral glucocorticoid dose was continued; a 16-week oral glucocorticoid reduction period (weeks 4 to 20) during which the glucocorticoid dose was tapered every 4 weeks according to a pre-specified algorithm in the protocol; a 4-week maintenance period during which patients continued the glucocorticoid dose established at week 20; and a 12-week post-treatment evaluation period. Eligible patients who completed the treatment were permitted to enter a long-term open-label extension study.

[0271] This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, and applicable regulatory requirements. An independent Data Safety Monitoring Committee conducted blinded monitoring of patient safety data. Local institutional review boards or ethics committees at each study site monitored the conduct of the trial and the documentation. All patients provided written informed consent before participating in the trial.

[0272] Patients Based on the 2014 International Guidelines for Asthma Management, patients 12 years of age and older with asthma diagnosed by a physician for over 12 months were eligible to participate. Patients were required to have received regular systemic glucocorticoids (prednisone or prednisolone or equivalent 5 - 35 mg / day) for the past 6 months during the 4 weeks prior to screening, and high - dose inhaled glucocorticoids (fluticasone propionate > 500 μg total daily dose or equivalent of equal potency) in combination with up to 2 long - term control medications (e.g., long - acting β2 - agonists or leukotriene receptor antagonists) for up to 3 months. Eligible patients had to have a forced expiratory volume in 1 second (FEV1) ≤ 80% of predicted normal (≤ 90% for adolescents) before bronchodilator use, an FEV1 reversibility of 12% or more and 200 mL or more, or airway hyperresponsiveness, demonstrated during the 12 months prior to screening visit 1. There were no minimum requirements for baseline blood or sputum eosinophil counts or any other type 2 biomarkers (e.g., FeNO or IgE), and patients were recruited. Important exclusion criteria included lung diseases other than asthma, exacerbations of asthma requiring emergency treatment or hospitalization within 4 weeks after visit 1, and current smokers, or smokers who had quit within 6 months prior to screening or had a smoking history longer than 10 pack - years.

[0273] Treatment and Procedures Patients were randomized (1:1) to receive subcutaneous dupilumab 300 mg every 2 weeks (q2W) as additional treatment (after a loading dose of 600 mg on day 1), or corresponding placebo. Randomization was performed by two - way voice / web - response technology and stratified by optimal oral glucocorticoid dose (prednisone / prednisolone ≤ 10 mg / day or > 10 mg / day) and country. Patients using other oral glucocorticoids were switched to clinically equivalent doses of prednisone or prednisolone during the screening period.

[0274] The optimized oral glucocorticoid dose was defined as the lowest dose that patients could tolerate without experiencing an increase of ≥ 0.5 in the 5-item Asthma Control Questionnaire (ACQ-5) score, a severe exacerbation, or any clinically significant event that would require adjustment of the oral glucocorticoid dose. During the dose reduction period, the oral glucocorticoid dose was reduced every 4 weeks to minimize the risk of clinically significant events and carryover effects from the previous dose. After week 20, dose adjustments were not permitted, except for safety reasons. Background maintenance medications for asthma were continued at stable doses, and use of short-acting β2-agonists was permitted when required for asthma symptoms.

[0275] Evaluation items The primary efficacy evaluation item was the percentage reduction in the oral glucocorticoid dose from baseline to week 24 while maintaining asthma control. Patients were considered to have maintained asthma control between weeks 20 and 24 if there were no clinically significant events (as determined by the investigator in charge of the study) that would require adjustment of the oral glucocorticoid dose. For patients who experienced an exacerbation, the final oral glucocorticoid dose was considered to be one step higher than the dose they were receiving at the time of the exacerbation.

[0276] Important secondary efficacy evaluation items evaluated in patients who maintained asthma control were the percentage of patients who achieved a ≥ 50% reduction from baseline in the oral glucocorticoid dose and the percentage of patients who achieved a reduction in the oral glucocorticoid dose to < 5 mg / day. Other secondary evaluation items included the absolute reduction in the oral glucocorticoid dose, the percentage of patients who achieved the maximum possible reduction in the oral glucocorticoid dose, and the percentage of patients who no longer required oral glucocorticoids.

[0277] Additional efficacy evaluation items included the annual rate of severe exacerbation events (defined as hospitalization, emergency department visit, or treatment with systemic glucocorticoids at at least twice the current dose for 3 or more days) during the treatment period; the absolute change from baseline in FEV1 before bronchodilator use at week 2, week 4, week 8, week 12, week 16, week 20, and week 24; and the change from baseline in the ACQ-5 score at week 24.

[0278] Preliminary evaluation items for the absolute change from baseline in FeNO (ppb) were evaluated at week 2, week 4, week 8, week 12, week 16, week 20, and week 24 using the NIOX device (Aerocrine AB, Solna, Sweden).

[0279] Statistical Analysis It was estimated that 90 randomized patients per treatment group would provide 94% power (two-sided test at α = 0.05) to detect a 27% treatment difference in the daily glucocorticoid dose assuming a common standard deviation of 50%.

[0280] The primary evaluation item was analyzed using an analysis of covariance (ANCOVA) model. The model included, as the response variable, the percentage reduction in the oral glucocorticoid dose at week 24, and, as covariates, the treatment group, the optimized oral glucocorticoid dose at baseline, the region (country of implementation), and the baseline eosinophil subgroup (≥ 150 cells / μL, < 150 cells / μL). The treatment difference was tested at a two-sided significance level of α = 0.05. For patients who discontinued the study or lost oral glucocorticoid dose data at week 24 (2 patients in the dupilumab group and 1 in the placebo group), the main method for handling missing data was the pattern mixture model by multiple imputation (PMM by MI).

[0281] Important secondary and other binary secondary evaluation items were analyzed using a logistic regression model. The annual rate of severe exacerbation events during the 24-week treatment period was analyzed using a negative binomial regression model. Using a mixed effects model with a repeated measures approach, the change in FEV1 before bronchodilator use from baseline and the change in the 5-item asthma control questionnaire (ACQ-5) from baseline at week 24 were analyzed at various time points during the 24-week treatment period.

[0282] Regardless of the treatment received, an efficacy analysis was performed in the intention-to-treat (ITT) population defined as all randomized patients analyzed according to the assigned treatment. The primary evaluation item and important secondary evaluation items, FEV1, and the severe asthma exacerbation rate were also analyzed in subgroups of patients defined by baseline blood eosinophil levels (≥ 300 cells / μL, < 300 cells / μL, ≥ 150 cells / μL, and < 150 cells / μL). The safety population included all patients who received one or more doses or partial doses of the study treatment and was analyzed according to the treatment received.

[0283] All analyses were performed using SAS software, version 9.4 (SAS Institute).

[0284] Conclusion This study demonstrated that dupilumab as add-on therapy significantly reduced oral glucocorticoid use in patients with oral glucocorticoid-dependent severe asthma, reduced severe asthma exacerbation by 59.3% and improved FEV1 by 0.22 L in the overall population, and in "eosinophilic" patients with baseline blood eosinophils ≥ 300 cells / μL, a 71% reduction in exacerbation and a 0.32 L improvement in FEV1. Dupilumab treatment also improved asthma control and reduced FeNO levels, a marker of airway type 2 inflammation.

[0285] The additional dupilumab 300 mg every two weeks (q2w) (versus placebo) significantly reduced oral corticosteroid (OCS) use at week 24 (70.1% versus 41.9% least squares [LS] mean, 100% versus 50% median), while simultaneously reducing the rate of severe asthma exacerbations during the 24-week treatment period (59%) and improving forced expiratory volume in 1 second (FEV1) at week 24 (LS mean difference 0.22 L), and was generally well tolerated in patients with OCS-dependent severe asthma.

[0286] Dupilumab is the first biologic to demonstrate positive efficacy based on multiple asthma outcome measures in the overall study population regardless of baseline blood eosinophil count (i.e., ≥300, <300, ≥150, and <150 cells / μL). In fact, 28.6% of the enrolled patients had baseline blood eosinophils of <150 cells / μL. In this subgroup, 75% of dupilumab-treated patients had a 50% reduction in oral glucocorticoid dose and 62% of patients had a reduction in oral glucocorticoid dose to <5 mg / day. These data contrast with previous studies on anti-interleukin-5 monoclonal antibodies, including mepolizumab and benralizumab, which showed treatment effects only in patients with predominantly high baseline blood eosinophils.

[0287] In this study, placebo-treated patients also showed a 41.9% reduction in oral glucocorticoid dependence. Better adherence to the drug regimen in the clinical study setting may have contributed to this observation. However, towards the end of the study, these placebo-treated patients showed a mild deterioration in lung function (FEV1), highlighting the need for treatment to improve lung function in patients with OCS-dependent severe asthma. Dupilumab's ability to increase lung function as significantly even at the time of glucocorticoid withdrawal as it did in this study suggests that it is inhibiting a major driver of lung inflammation that results in the decline in lung function.

[0288] Dupilumab reduced FeNO levels in a setting of significant oral glucocorticoid withdrawal in a study population with persistent type 2 inflammation (as determined by an increase in FeNO), despite chronic glucocorticoid use.

[0289] Dupilumab reduced the oral glucocorticoid dose by an observed mean of 74% (observed median 100%) in a broader population without requiring a minimum baseline blood eosinophil count. While not intending to be bound by scientific theory, these findings suggest that dupilumab, which dual-blocks the interleukin-4 and interleukin-13 signaling pathways through interleukin-4 receptor-α blockade, inhibits type 2 inflammation more broadly than targeting eosinophils alone. Interleukin-4 is central to the differentiation and proliferation of type 2 helper T cells, induction of cytokine production, and IgE synthesis, while interleukin-13 plays a central role in the pathological features of diseases such as goblet cell hyperplasia, mucus production, smooth muscle contractility, and airway hyperresponsiveness.

[0290] In patients with glucocorticoid-dependent severe asthma, dupilumab was generally well tolerated, and the safety profile was consistent with previous studies in asthma and other indications such as eosinophilic esophagitis, nasal polyposis, and atopic dermatitis. Dupilumab-treated patients showed a greater mean transient increase from baseline in blood eosinophil counts compared to placebo, and the proportion of patients with eosinophil counts > 3,000 cells / μL increased (12.6%). Patients with a transient increase in blood eosinophils did not experience concurrent clinical AEs or outcomes. The increase in blood eosinophil counts is consistent with the hypothesis that dupilumab blocks interleukin-4 and interleukin-13 functions in eosinophil survival, activation, and tissue recruitment, but does not deplete eosinophils from the bone marrow, resulting in a transient increase in circulating eosinophil counts. Since glucocorticoids suppress circulating eosinophils, a greater reduction in oral glucocorticoids in the dupilumab group may also contribute to the eosinophil increase. Treatment-related conjunctivitis AEs were not observed between the dupilumab and placebo groups, in contrast to the atopic dermatitis study of dupilumab.

[0291] In conclusion, add-on therapy with dupilumab significantly reduced the need for oral glucocorticoids in patients with glucocorticoid-dependent severe asthma, regardless of baseline blood eosinophil counts, while simultaneously reducing severe exacerbations and improving lung function (FEV1), and was generally well tolerated.

Example

[0292] QUEST Phase III trial study (NCT02414854) Method Patients 12 years of age and older with moderate to severe asthma not adequately controlled with ICS and one or two long-term controller medications were randomized 2:1 to receive additional subcutaneous dupilumab 200 mg or 300 mg every 2 weeks (q2w) for 52 weeks or matching placebo in a double-blind, placebo-controlled phase 3 study (NCT02414854). The primary endpoints were the annualized rate of severe asthma exacerbations in the full analysis set and the absolute change in forced expiratory volume in 1 second (FEV1) from baseline to week 12 before bronchodilator use. Secondary endpoints included exacerbations and FEV1 in patients with ≥300 neutrophils / μL. Asthma control and dupilumab safety were also evaluated. The co-primary endpoints were the annualized rate of severe exacerbations over 52 weeks and the change in FEV1 (L) from baseline to week 12.

[0293] Specific details of this study are described below. This randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy of dupilumab in patients with moderate to severe uncontrolled asthma. Patients completed a 4 ± 1-week screening period, followed by randomization to dupilumab and matching placebo, a 52-week randomized treatment period, and a 12-week follow-up period after treatment (see Figure 7).

[0294] Patients Patients 12 years of age and older with persistent asthma for ≥12 months and physician-diagnosed asthma were eligible to participate based on the 2014 Global Initiative for Asthma (GINA) guidelines for asthma management and met the following important criteria: Treated with: medium to high-dose inhaled glucocorticoids (fluticasone propionate > 500 μg total daily dose or equivalent of equal potency), in addition to current treatment with up to two additional long-term control medications (e.g., long-acting β2-agonists or leukotriene receptor antagonists); forced expiratory volume in 1 second (FEV1) ≤ 80% of predicted normal value before bronchodilator use (≤ 90% for patients aged 12 - 17 years); FEV1 reversibility of ≥ 12% and ≥ 200 mL; Asthma Control Questionnaire-5 (ACQ-5) score ≥ 1.5; exacerbation of asthma in the previous year requiring hospitalization, emergency medical care, or treatment with systemic glucocorticoids for more than 3 days. Patients were recruited regardless of baseline blood eosinophil count or type 2 biomarkers (see Figure 8).

[0295] Treatment and Procedures Patients were randomized (2:2:1:1) to receive 52 weeks of additional treatment with subcutaneous dupilumab 200 mg (loading dose 400 mg) or 300 mg (loading dose 600 mg) every 2 weeks (q2w), or placebo in an amount corresponding to each active dose (supplied as prefilled syringes, 1.14 ml for dupilumab 200 mg and 2.0 ml for dupilumab 300 mg). Randomization was performed by two-way voice / web response technology and stratified by age (< 18 years, ≥ 18 years), peripheral blood eosinophil count at screening (< 300 cells / μL, ≥ 300 cells / μL), inhaled glucocorticoid dose level (medium / high), and country. Background long-term asthma control medications were continued at stable doses throughout the study and recorded daily by the patients in an electronic diary. Use of inhaled glucocorticoids, long-acting β2-agonists, long-acting muscarinic antagonists, anti-leukotrienes, and methylxanthines was permitted. Throughout the study, patients were permitted to use short-acting β2-adrenergic receptor stimulants as needed for symptom relief. Type 2 biomarkers were measured; biomarkers included blood eosinophils, FeNO, serum IgE, periostin, TARC, and plasma eotaxin-3.

[0296] Evaluation Items The primary efficacy evaluation items were the annual rate of severe exacerbation events during the 52-week treatment period in the entire study population and the absolute change from baseline in FEV1 before BD use at week 12. These evaluation items were also included as secondary study evaluation items for patients with blood eosinophil count ≥ 300 eosinophils / μL. Additional secondary study evaluation items are summarized in Table 8. Severe asthma exacerbation was defined as an exacerbation of asthma requiring treatment with systemic glucocorticoids for more than 3 days or hospitalization or emergency department visit requiring systemic glucocorticoids. Safety and tolerability were reported by the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs.

[0297]

Table 11

[0298] Statistical Analysis A sample size of approximately 1,638 patients was estimated to provide 99% power (two-sided test at α = 0.05) to detect a 55% relative risk reduction in the annual rate of severe exacerbation (i.e., annual rates of 0.6 and 0.27 for the placebo and dupilumab groups, respectively) in this study. This sample size was also expected to provide 98% power to detect a 0.15 L treatment difference in the change in FEV1 before BD use from baseline to week 12. Efficacy analysis was performed in the intention-to-treat (ITT) population defined as all randomized patients by the assigned treatment, regardless of whether the treatment was received. Covariate The annual rate of severe exacerbations was analyzed using a negative binomial regression model that included four treatment groups, age, region, baseline eosinophil count, baseline inhaled corticosteroid dose level, and exacerbations 1 year prior. Changes from baseline in continuous assessment items such as FEV1 and patient-reported outcomes were analyzed using a mixed-effects model for repeated measures (MMRM), which included treatment, age, baseline eosinophil count, baseline inhaled corticosteroid dose level, visit, treatment / visit interaction, baseline value, and baseline / visit interaction as covariates. Gender and baseline height were included as covariates only in the model for spirometry parameters.

[0299] Results The baseline demographics and clinical characteristics of the ITT population are shown in Table 4 and were generally similar across the four treatment groups (Table 10). In 1,902 patients, dupilumab 200 / 300 mg q2w reduced the annualized rate of severe exacerbations by 48% / 46% (both P<0.0001) compared to placebo during the 52-week treatment period (Figure 9A). Improvement in FEV1 was observed at Week 12 in the overall population (LS mean difference 0.14 L / 0.13 L vs placebo; both P<0.0001).

[0300] Pre-specified subgroup analyses by baseline blood eosinophil count showed a significant reduction in the exacerbation rate (P<0.001) for dupilumab 200 mg and 300 mg compared to placebo in corresponding amounts in patients with ≥300 eosinophils / μL (65.8% and 67.4% reduction vs placebo) and patients with ≥150 eosinophils / μL (55.8% and 59.8% reduction vs placebo). There was a consistent trend but no significance in exacerbations and FEV1 outcomes in patients with <300 eosinophils / μL. Pre-specified subgroup analyses by baseline FeNO level showed similar effects (P<0.001). (See Figure 9B and Table 9).

[0301] [Table 12]

Table 13

[0302] In the entire study population, dupilumab 200 mg and 300 mg q2w improved the pre-BD FEV1 by 0.32 L and 0.34 L, respectively, at week 12 (differences of 0.14 L and 0.13 L compared with the corresponding placebo, P<0.001) (Figure 10A). In patients with ≥300 eosinophils / μL, the FEV improvement was greater, and dupilumab improved the FEV1 at week 12 by 0.43 L and 0.47 L, respectively (differences of 0.21 - 0.24 L compared with the corresponding placebo, P<0.001). (See Figure 10B.) The improvement in FEV1 was rapid (significant difference compared with placebo, evident by the first assessment at week 2 for both regimens) and persisted throughout the 52-week treatment period (P<0.001 for both regimens at week 52). In addition, the FEV1 slope analysis after bronchodilator use between week 8 and week 52 showed a loss of lung function of 0.04 L / year for placebo and no loss for either dupilumab dose (P<0.05).

[0303] The improvement in FEV1 at week 12 (P<0.05) with both dose regimens was higher in a subgroup of patients with higher baseline FeNO levels (0.19 L and 0.12 L for 25 ppb ≤ FeNO < 50 ppb; 0.30 L and 0.39 L for FeNO ≥ 50 ppb). (See Figure 10C and Table 8.)

[0304] In addition, dupilumab 200 mg and 300 mg significantly improved the percentage change from baseline in pre-bronchodilator FEV1 from week 1 to week 12 compared to placebo: 21.34% versus 12.11%, and 23.08% versus 13.67% respectively (P<0.001). The rate of severe exacerbation events resulting in hospitalization or emergency department visits during the 52-week treatment period was 0.035 versus 0.065 in combined dupilumab-treated patients compared to combined placebo-treated patients (P=0.004). This represented a 46.8% relative risk reduction for dupilumab compared to placebo. (See Table 9.)

[0305] Dupilumab significantly improved ACQ-5 as early as week 2, and its effect persisted throughout the treatment course (P<0.01). Similarly, the Asthma Quality of Life Questionnaire, standardized version score, AM and PM asthma symptom scores, and AM and PM peak expiratory flow rates were improved at week 24 and week 52. (See Table 9.)

[0306] Patients treated with dupilumab showed a greater decrease from baseline over the course of treatment in FeNO, total IgE, periostin, eotaxin-3, and TARC compared to placebo (Table 13). A transient increase in blood eosinophil count was observed in both treatment groups and decreased to near baseline levels by week 52.

[0307] To better understand the effect of dupilumab in patients with evidence of type 2 inflammation, an analysis evaluating biomarker efficacy associations was conducted. Each biomarker was tested in an un-penalized spline model for biomarker / treatment interaction with respect to exacerbation and FEV1. In these analyses, eosin The interaction between the sphere and FeNO was significant when exacerbation was the outcome measure (P<0.005), but eosinophils, FeNO, periostin, ECP, IgE, and eotaxin-3 were significant for FEV1 at week 12 (Table 11). The dupilumab effect on exacerbation was similar for IgE levels above and below the baseline median (167 IU / mL), and the improvement in FEV1 was greater for IgE levels above the median.

[0308] Dupilumab-treated patients with baseline blood eosinophils ≥150 cells / μL and FeNO ≥25 ppb (type 2 - high) experienced a greater treatment benefit compared to placebo for both reduced severe exacerbation rate and improved FEV1. (See Figures 11A and 11B.) No treatment effect was observed in patients with baseline eosinophils <150 cells / μL and FeNO <25 ppb (type 2 - low). However, dupilumab-treated patients with either baseline blood eosinophils <150 cells / μL and FeNO ≥25 ppb or baseline blood eosinophils ≥150 cells / μL and FeNO <25 ppb experienced a numerical reduction in the severe exacerbation rate.

[0309] The most frequent adverse event in the dupilumab-treated patient treatment group compared to the placebo group was injection site reaction (15% / 18% vs. 5% / 10% respectively). In contrast to the dupilumab study in atopic dermatitis, the rate of conjunctivitis was similar between dupilumab and placebo.

[0310]

Table 14

Table 15

Table 16

Table 17

[0311]

Table 18

Table 19

Table 20

Table 21

[0312]

Table 22

Table 23

Table 24

Table 25

[0313]

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

[0314]

Table 33

Table 34

[0315] Investigation Dupilumab significantly reduced the annualized rate of severe exacerbation in the ITT population, and a greater treatment effect was observed with increases in the baseline levels of blood eosinophils and FeNO. Dupilumab also significantly decreased the rate of those requiring the most severe asthma exacerbations, hospitalizations, or emergency department visits. The evaluation of FEV1 and asthma management over time showed that the efficacy of dupilumab was rapid, with a significant difference from placebo evident at the first evaluation in week 2 for both dosing regimens and maintained throughout the 52-week treatment period. A significant and clinically meaningful improvement in FEV1 of 0.32 - 0.34 L was observed at week 12, regardless of the baseline blood eosinophil count, with an even greater increase of 0.43 - 0.47 L in patients with baseline blood eosinophils ≥ 300 / μL.

[0316] Furthermore, the post-bronchodilator FEV1 slope analysis showed no loss of lung function observed in dupilumab-treated patients compared to the loss observed in placebo patients, suggesting a potential effect of dupilumab on airway tissue repair. The slope analysis showed that placebo patients lost an average of approximately 40 mL per year, which is consistent with data from other asthma cohorts. Additionally, since IL-4Rα is expressed on smooth muscle cells, in addition to the anti-type 2 inflammatory effect, there may be a direct bronchodilator effect of this drug.

[0317] The consistent and significant improvements seen with dupilumab are likely due to its unique mechanism of action. With the recent increase in focus on exacerbations in the asthma community driven by concerns about payor cost - effectiveness, there has been a shift away from the significant morbidity and quality - of - life issues associated with substantial loss of lung function seen in moderate - to - severe asthmatic patients. Despite current treatments, these moderate - to - severe asthmatic patients are still at risk of further loss of lung function and continued decline over time. Therefore, the possibility that a new treatment could provide a clinically meaningful substantial recovery of lung function and potentially halt further future deterioration could be of great benefit to these patients.

[0318] The results of this study confirm that interleukin - 4 and interleukin - 13 are important proximal drivers of type 2 inflammation in asthma. Dupilumab is the first biologic agent to significantly reduce FeNO levels, in addition to other systemic type 2 biomarkers such as IgE, confirming its biologic activity on airway inflammation. Without being bound by scientific theory, the unique mechanism of action of dupilumab, which has dual blockade of interleukin - 4 and interleukin - 13 signaling, can explain why dupilumab shows significant treatment effects in a broader patient population and an unprecedented effect on improvement of lung function, suggesting a potential direct bronchodilatory effect in addition to its anti - inflammatory effect. It is notable that this study shows the most significant association of benefit with baseline levels of blood eosinophils compared to two other important studies on dupilumab. Although it is not clear why the association is more prominent in this study, it suggests that blood eosinophils may be an inadequate measure of type 2 inflammation and that other biomarkers of type 2 inflammation such as FeNO may be important. Nevertheless, generally across all three studies, dupilumab appears to address a broader population of asthmatics than those defined only by an increase in either blood eosinophil levels or IgE levels, which are required for other approved biologic agents.

[0319] Dupilumab activity has been demonstrated against several atopic / allergic conditions, which often coexist in asthma patients. In this study, more than 80% of the patients had coexisting atopic or allergic conditions, including atopic dermatitis (about 10% of the cohort), nasal polyposis (about 20% of the cohort), and allergic rhinitis (more than 65% of the cohort). The high rate of coexisting atopic / allergic conditions suggests that these patients have systemic hyperactivity of the type 2 inflammation axis and, thus, that treatment with dupilumab for asthma may help to simultaneously reduce these related conditions.

[0320] Dupilumab was generally well tolerated and had an acceptable safety profile. With the exception of injection site reactions, the incidence of TEAE was similar across treatment groups. Consistent with the mechanism of action and as observed in atopic dermatitis trials, dupilumab-treated patients showed a greater mean transient increase from baseline in blood eosinophil counts compared to placebo. For each study protocol, all cases with eosinophil counts > 3,000 cells / μL on treatment were to be reported as AEs in this study. The majority of the observed increases in eosinophil counts were laboratory findings not associated with clinical outcomes or related AEs. The increase in blood eosinophil counts is consistent with the hypothesis that dupilumab blocks the functions of interleukin-4 and interleukin-13 in eosinophil survival, activation, and recruitment to tissues but does not deplete eosinophils from the bone marrow, which is affected by IL-5. As a result, the first treatment with dupilumab can result in a transient increase in circulating blood eosinophil counts. Treatment-related conjunctivitis AEs were not observed between the dupilumab and placebo groups, in contrast to the dupilumab atopic dermatitis studies.

[0321] In conclusion, in the largest study to date of dupilumab in patients with moderate to severe uncontrolled asthma, dual blockade of interleukin-4 and interleukin-13 with dupilumab effectively treats a broad asthma population, resulting in a significant reduction in the rate of severe exacerbations, rapid and sustained improvement in lung function and asthma control, and symptom relief, as demonstrated here. The most robust results were observed in patients with elevated type 2 immune features, including eosinophil counts and FeNO. Dupilumab is the only biologic shown to be effective in multiple studies of moderate to severe asthma patients, regardless of baseline type 2 biomarker levels. Dupilumab was generally well tolerated and had an acceptable safety profile. These data support the use of dupilumab as an effective additional treatment for this asthma patient population with a highly unmet need.

Example

[0322] QUEST Phase III Trial Study - Dupilumab reduces the rate of severe exacerbations and improves lung function in adolescent patients with moderate to severe uncontrolled asthma The prevalence of asthma in children and adolescents has been increasing over the past 30 years (Asher (2014) Int. J. Tuberc. Lung Dis.). In 2011, approximately 11.4% of adolescents (12 - 17 years) in the USA were reported to currently have asthma (Bloom (2011) Vital and Health Statistics Series).

[0323] The prevalence of asthma is as high (or often higher) in adolescents as in younger children, but adolescents are less likely to seek medical relief (Couriel (2003) J.Paediatric Resp.Rev.). Many adolescents underestimate the severity of their asthma and overestimate their response to bronchodilators (Rhee (2008) J.Asthma; Andersson (2013) Pediatrics). Asthma has a profound impact on the physical, psychological, and social health of adolescents and negatively affects their health-related quality of life (Cui (2016) J.Pediatrics).

[0324] This study evaluated the efficacy and safety of dupilumab in subgroups of adolescents (12 - 17 years) and adults (≥18 years) with moderate - severe uncontrolled asthma. The endpoints evaluated during the 52 - week treatment period were the annual rate of severe exacerbations and the change from baseline in pre - bronchodilator FEV1 (L). Baseline demographics and clinical characteristics are shown in Figure 12.

[0325] Inclusion criteria: 12 years or older diagnosed by a physician with uncontrolled asthma for at least 12 months (Global Initiative for Asthma (GINA) 2014); treated with medium - high dose ICS (inhaled corticosteroids) + up to two additional long - term controller medications; pre - bronchodilator FEV1 (forced expiratory volume in 1 second) ≤80% (adults) and ≤90% (adolescents) of predicted normal value at screening and baseline; bronchodilator reversibility ≥12% and ≥200 mL; ACQ - 5 (Asthma Control Questionnaire - 5) score ≥1.5 at screening and baseline; ≥1 exacerbation in the previous year; no minimum requirement for baseline blood eosinophil count or any other type 2 biomarker.

[0326] Exclusion criteria: Chronic obstructive pulmonary disease, or other lung diseases that may impair lung function; Severe asthma exacerbation within 1 month from the date of registration or during the screening period; Current smokers, or smokers who quit within 6 months before screening, or smokers with a smoking history longer than 10 pack-years; Concurrent diseases that may interfere with the evaluation of the investigational drug.

[0327] Statistical analysis: Efficacy analysis was performed on the ITT population defined as all randomized patients by the assigned treatment, regardless of whether they received treatment.

[0328] The annual rate of severe asthma exacerbation during the 52-week treatment period was analyzed using a negative binomial regression model. The change from baseline of FEV1 at various time points during the 52-week treatment period was analyzed using a mixed effects model with repeated measures.

[0329] The primary endpoints, the severe asthma exacerbation rate and FEV1, were also analyzed in subgroups of patients defined by age (<18 years and >18 years). The safety population included all patients who received ≥1 dose or part of a dose of the investigational treatment and was analyzed according to the treatment received.

[0330] Dupilumab reduced severe exacerbations and improved FEV1 in the overall ITT population (Figures 13A and 13B), reduced the severe exacerbation rate in adolescents and adults (Figures 14A and 14B), and improved FEV1 in adolescents and adults at Week 12 (Figure 15A) and Week 52 (Figure 15B), and in addition throughout the 52-week treatment period (Figures 16A and 16B).

[0331] Dupilumab improved percent predicted FEV1 in adolescents and adults during the 52-week treatment period (Figures 18A and 18B). FeNO levels (Figures 19A and 19B), ACQ-5 scores (Figures 20A and 20B), and AQLQ scores (Figures 21A and 21B) were evaluated.

[0332] Adolescents were 107 / 1,902 registered patients (34 in the dupilumab group, 21 / 18 in the matching placebo group); 35.5% were female, mean baseline FEV1 was 2.33 L, mean % predicted FEV1 was 70.45%, and mean number of severe exacerbations in the previous year was 1.91. Adolescents who received placebo experienced fewer severe exacerbations (0.36 / 0.33) than adults (0.89 / 1.00). In adolescents, dupilumab 200 mg reduced the rate of exacerbations by 46.4% per year, while dupilumab 300 mg did not produce a treatment effect compared to placebo (not bound by scientific theory, but this was likely due to small sample size and unequal numbers of pre-events (mean 1.53 vs 2.22, respectively)). Unadjusted rates of exacerbation were 0.46 (dupilumab 300 mg) and 0.76 (placebo). A significant improvement in the change in FEV1 (L) from baseline compared to placebo was seen in adolescents (dupilumab 200 mg: least-squares mean 0.36 [95% CI 0.12 to 0.61]; 300 mg: 0.27 [0.02 to 0.52]) (P<0.05), numerically higher than in adults (200 mg and 300 mg: 0.12 [0.07 to 0.18]).

[0333] The adverse event profile was equivalent between subgroups (Figures 17, 22, 23, and 24). The most commonly seen treatment-emergent adverse events (TEAEs) that occurred more frequently in the combined dupilumab group were as follows: Adolescents - viral airway infection (2 in placebo [5.1%]; 7 in dupilumab [10.3%]); Adults - injection site erythema (34 in placebo [5.7%]; 168 in dupilumab [14.1%]). Eosinophilia was observed only in the adult population.

[0334] Dupilumab significantly reduced the annual rate of severe exacerbations and improved lung function in adults with moderate to severe uncontrolled asthma. The improvement in FEV1 was rapid and sustained throughout the 52-week treatment period. Dupilumab also significantly improved lung function in adolescents with moderate to severe uncontrolled asthma, and a numerical decrease in severe exacerbations was observed.

[0335] As in adults, the improvement in FEV1 in adolescents was rapid and persisted throughout the 52-week treatment period. The magnitude of the improvement in FEV1 was greater in adolescents. Dupilumab was generally well tolerated.

Example

[0336] QUEST Phase III trial study - Dupilumab improved the quality of life related to health in patients with moderate to severe asthma, improved lung function, and reduced the rate of severe exacerbations. Quality of life related to health in patients with coexisting allergic rhinitis Allergic rhinitis (AR), a common type 2 comorbidity in asthma patients, contributes to an increase in the overall disease burden. Phase 3 LIBERTY in patients with moderate to severe uncontrolled asthma This analysis of the ASTHMA QUEST study (NCT02414854) evaluated the effect of dupilumab on the validated Rhinitis Quality of Life Questionnaire [RQLQ(S)+12] in patients with self-reported coexisting AR.

[0337] Asthma patients 12 years of age and older, not controlled with medium to high-dose ICS plus two or fewer additional long-term controller medications, received additional dupilumab 200 / 300 mg or matching placebo every 2 weeks (q2w) for 52 weeks. Patients with a self-reported history of AR (63.5%; n / N = 1,207 / 1,902) completed the validated RQLQ(S)+12 at Week 12 and Week 25. Clinical AR diagnosis was not recorded.

[0338] The overall RQLQ(S)+12 score (baseline mean [SD] 1.90 [1.12] - 2.01 [1.16]) was significantly improved with dupilumab 200 / 300 mg q2w compared to placebo at week 52 (least-squares mean difference [95% CI] -0.42 [-0.61, -0.24] / -0.39 [-0.56, -0.21]; P < 0.0001). Dupilumab 200 / 300 mg significantly (P < 0.001) improved the domain scores for activity (0.44 [0.68, 0.21] / 0.39 [0.61, 0.16]), sleep (0.47 [0.69, 0.25] / 0.38 [0.59, 0.17]), and eye symptoms (0.37 [0.58, 0.16] / 0.39 [0.59, 0.19]) from baseline to week 52 compared to placebo; and for dupilumab 300 mg by week 12 (0.23 [0.42, 0.04], 0.26 [0.45, 0.07], 0.26 [0.45, 0.08]; P < 0.05). The nasal symptom domain score was significantly improved with dupilumab 200 / 300 mg compared to placebo at week 12 (0.36 [0.56, 0.16] / 0.32 [0.51, 0.13]; P < 0.001) and week 52 (0.61 [0.84, 0.39] / 0.55 [0.76, 0.33]; P < 0.0001). The adverse events most commonly seen more frequently with dupilumab compared to placebo were injection site reactions (15% / 18% vs 5% / 10%).

[0339] Dupilumab significantly improved nasal-conjunctivitis specific health-related quality of life and was generally well tolerated in patients with moderate-to-severe uncontrolled asthma and concomitant AR.

[0340] Population: Patients with concomitant AR. Assessment item / visit: LS mean change from baseline during 52-week treatment period for RQLQ domains (nasal symptoms, eye symptoms, activity, sleep); safety (ITT). Treatment arms: Dupilumab 200 mg and 300 mg q2w and matching placebo.

[0341] Improvement in Lung Function and Reduction in Severe Exacerbations in Patients With or Without Concurrent Allergic Rhinitis A post hoc analysis of the Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients with asthma (aged 12 years and older, not controlled on medium to high doses of ICS + 2 or fewer additional long-term controller medications) with a self-reported history of concurrent AR (63.5%; n / N = 1,207 / 1,902) or without concurrent AR evaluated the effect of dupilumab 200 mg or 300 mg or matching placebo, administered every 2 weeks (q2w), on the annual rate of severe exacerbations and forced expiratory volume in 1 second (FEV1). Clinical diagnosis of AR was not recorded.

[0342] Baseline characteristics of patients with or without AR were generally similar. The annual rate of severe exacerbations decreased with dupilumab 200 mg q2w compared with placebo (relative risk with AR: 0.606 [95% CI, 0.451–0.814]; P = 0.0009; without AR: 0.406 [95% CI, 0.273–0.605]; P < 0.0001), and similar results were seen for 300 mg q2w. FEV1 improved at week 12 with dupilumab 200 mg q2w (LS mean difference with AR compared with placebo: 0.14 L [95% CI, 0.07–0.21]; P < 0.0001; without AR: 0.13 L [95% CI, 0.05–0.22]; P = 0.0023), persisted through week 52 (both with and without AR: P < 0.0001), and similar results were seen at week 52 for 300 mg q2w. The most commonly observed adverse events in the dupilumab treatment groups (compared with the placebo group) were injection site reactions (200 mg / 300 mg vs matching placebo: 15% / 18% vs 5% / 10%).

[0343] In this difficult-to-treat asthma population with concurrent AR, and also in patients without concurrent AR, dupilumab significantly improved FEV1 and reduced the rate of severe exacerbations per year.

[0344] Population: Patients with and without co - existing AR (AR defined according to CSR). Assessment items: LS mean change from baseline in FEV1 at Week 12 and Week 52; Severe exacerbations during the 52 - week treatment period. Safety: ITT.

Example

[0345] QUEST Phase III trial study - In patients with moderate - to - severe asthma, dupilumab suppresses type 2 biomarkers in patients with asthma with and without co - existing chronic rhinosinusitis with nasal polyps (CRS + NP) or without nasal polyps (CRS - NP). In the Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200 / 300 mg every two weeks compared to matching placebo suppressed type 2 biomarkers in patients with moderate - to - severe uncontrolled asthma and improved health - related quality of life as evaluated by SNOT - 22 in treatment - resistant subgroups with co - existing chronic rhinosinusitis with nasal polyps (CRS + NP) or (CRSwNP) and in treatment - resistant subgroups with chronic rhinosinusitis without nasal polyps (CRS - NP). This post - hoc analysis evaluated the effect of dupilumab on type 2 biomarkers in this subgroup.

[0346] Changes from baseline by baseline / time course were evaluated for fractional exhaled nitric oxide concentration (FeNO), total IgE, and eotaxin - 3. CRS with or without NP was self - reported by 20.1% (n / N = 382 / 1,897) of patients. Baseline FeNO and eosinophil-3 levels were numerically higher in patients with CRS-NP or CRS+NP than in those without it. Biomarker suppression was evident by week 12 in all dupilumab-treated patients. At week 52, significant biomarker suppression was observed in patients with and without CRS-NP or CRS+NP, as indicated by the median percentage change from baseline as follows (dupilumab 200 / 300 mg vs matching placebo): With CRS-NP or CRS+NP: FeNO 46.2 / 37.7 vs 5.5 / 6.4, IgE 74.8 / 76.8 vs 0.0 / 2.0, eosinophil-3 47.7 / 50.9 vs 1.5 / 5.4 (all, P≤0.0001); Without CRS-NP or CRS+NP: FeNO 31.0 / 35.9 vs 5.9 / 10.1, IgE 67.3 / 67.7 vs 3.3 / 6.6, eosinophil-3 31.8 / 37.2 vs 0.0 / 0.8 (all, P<0.0001). The adverse event most commonly seen more frequently with dupilumab than placebo was injection site reaction (15% / 18% vs 5% / 10%).

[0347] Dupilumab suppressed local and systemic type 2 biomarkers in patients with and without CRS+ / -NP.

[0348] Population: Patients with and without co-existing CRS or NP. Assessment items: Percent change from baseline serum total IgE, plasma eosinophil-3, and FeNO over a 52-week treatment period. Safety: ITT. Treatment arms: Dupilumab 200 mg and 300 mg q2w and matching placebo.

Example

[0349] QUEST Phase III trial study - In patients with moderate to severe late-onset uncontrolled asthma, dupilumab reduces severe exacerbations and improves lung function In the 3rd LIBERTY ASTHMA QUEST study (NCT02414854), this post hoc analysis evaluated the efficacy of dupilumab in patients with late-onset asthma (>40 years of age), and an FEV1 / forced vital capacity [FVC] ratio <0.7 (suggestive of fixed airway obstruction) or ≥0.7 before baseline bronchodilator use.

[0350] The annual rate of severe exacerbations during the 52-week treatment period was evaluated using a negative binomial regression model. Changes from baseline in FEV1 (L) before and after bronchodilator use and the FEV1 / FVC ratio before bronchodilator use at Week 12 and Week 52 were analyzed using a mixed effects model for repeated measures.

[0351] Dupilumab 200 mg and 300 mg q2w significantly reduced the annual rate of severe exacerbations compared with placebo in patients with late-onset asthma and fixed airway obstruction (68.8% and 75.7%, respectively, both P<0.0001), and in patients without fixed airway obstruction (55.1% and 50.7%, respectively, both P<0.05) (Figure 27). At Week 12, FEV1 before and after bronchodilator use and the FEV1 / FVC ratio improved in dupilumab-treated patients with late-onset asthma and fixed airway obstruction (P<0.05 vs placebo for either or both doses). Similar improvements were observed at Week 52 (P<0.05 for FEV1 before and after bronchodilator use with dupilumab 200 mg q2w; P=0.09 for FEV1 before bronchodilator use and P=0.06 for FEV1 after bronchodilator use with dupilumab 300 mg q2w). Patients with late-onset asthma without fixed airway obstruction had a more modest improvement in FEV1 before bronchodilator use vs placebo at Week 12 and Week 52 compared with patients with late-onset asthma with fixed airway obstruction (P≥0.05). The most frequent adverse events in the dupilumab treatment group compared with the corresponding placebo were injection site reactions (15% / 18% vs 5% / 10%). For late-onset asthma patients without fixed airway obstruction, there was a more modest improvement in FEV1 before bronchodilator use compared to placebo at Week 12 and Week 52 compared to patients with late-onset asthma with fixed airway obstruction (P≥0.05). The most frequent adverse events in the dupilumab treatment group compared to the corresponding placebo were injection site reactions (15% / 18% vs 5% / 10%).

[0352] In patients with or without fixed airway obstruction and having late-onset asthma, dupilumab significantly reduced the rate of severe exacerbations. Furthermore, improvement in lung function was observed at week 12 and week 52 in patients with late-onset asthma and fixed airway obstruction, who typically experienced worse asthma outcomes than those experienced by patients with late-onset asthma without fixed airway obstruction.

[0353] Population: ITT population with age of asthma onset > 40 years and FEV1 / FVC < 0.7 after BD use; ITT population with age of asthma onset > 40 years and FEV1 / FVC ≥ 0.7 after BD use.

[0354] Evaluation items / visits (data included in summary): Severe exacerbations during 52-week treatment period; LS mean change from baseline of pre-BD FEV1 (L) at week 12 and week 52; LS mean change from baseline of post-BD FEV1 (L) at week 12 and week 52; LS mean change from baseline of FEV1 / FVC ratio at week 12 and week 52; Safety.

[0355] Treatment arms: Dupilumab 200 mg q2w, dupilumab 300 mg q2w, and corresponding placebo group.

Claims

1. A pharmaceutical composition for use in the treatment of a subject suffering from OCS-dependent severe asthma, comprising an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), whereby the use of OCS is reduced, and the treatment comprises: Subcutaneously administering an initial dose of the pharmaceutical composition comprising about 600 mg of the antibody or an antigen-binding fragment thereof to the subject; and Subcutaneously administering a plurality of maintenance doses of the pharmaceutical composition once every two weeks (q2w) to the subject once every two weeks (q2w), wherein each maintenance dose of the pharmaceutical composition comprises about 300 mg of the antibody or an antigen-binding fragment thereof, comprising, here, The plurality of maintenance doses are administered during a treatment period comprising an induction period, an OCS reduction period, and an OCS maintenance period; and The antibody or an antigen-binding fragment thereof comprises three heavy-chain complementarity-determining region (CDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light-chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, the pharmaceutical composition.

2. The antibody or an antigen-binding fragment thereof comprises a heavy-chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light-chain variable region comprising the amino acid sequence of SEQ ID NO: 2, The pharmaceutical composition according to claim 1.

3. The first maintenance dose is administered two weeks after the initial dose, The pharmaceutical composition according to claim 1 or 2.

4. The maintenance dose is administered for at least 24 weeks, The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein one or more asthma-related parameters are improved, and the one or more asthma-related parameters are selected from the group consisting of: (1) Forced expiratory volume in one second (FEV 1 (1) Percentage change relative to the baseline of (2) Percentage change relative to the baseline when measured by forced expiratory flow (FEF25-75) at 25-75% of the lung volume; (3) Annual rate of asthma management failure events during the treatment period; (4) Annual rate of severe exacerbation events during the treatment period; (5) Time to asthma management failure events during the treatment period; (6) Time to severe exacerbation events during the treatment period; (7) Changes from the baseline at week 12 regarding the following: (i) Morning and evening asthma symptom scores, (ii) Five-item asthma control questionnaire (ACQ-5) scores, (iii) Asthma quality of life questionnaire (AQLQ) scores, (iv) Morning and evening PEF (peak expiratory flow), (v) Number of inhalations per day of salbutamol / albuterol, or levalbuterol / levalbuterol for symptom relief, (vi) Nocturnal awakenings, and (8) Changes from the baseline at week 12 and week 24 regarding the following: (i) 22-item sinus outcome test (SNOT-22), (ii) Hospital anxiety and depression scores (HADS), or (iii) EuroQol questionnaire (EQ-5D-3L or EQ-5D-5L), The pharmaceutical composition.

6. The initial dose and the plurality of maintenance doses are additional asthma maintenance treatments, The pharmaceutical composition according to any one of claims 1 to 4.

7. OCS use is reduced at week 24 after administration of the initial dose, and in some cases, OCS is substantially eliminated 40 weeks after the first dose after administration of the initial dose, The pharmaceutical composition according to any one of claims 1 to 4 and 6.

8. The OCS is prednisone or prednisolone, The pharmaceutical composition according to any one of claims 1 to 7.

9. Before its use, the subject has an FEV of less than 2.0 L, 1 , an AM PEF of less than 400 L / min, a PM PEF of less than 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, The pharmaceutical composition according to any one of claims 1 to 8.

10. Before its use, the subject has a blood eosinophil count of less than 150 cells / μl, 150 cells / μl or more, or higher than 300 cells / μl, The pharmaceutical composition according to any one of claims 1 to 9.

11. The subject is an adult, adolescent, or 12 years of age or older, The pharmaceutical composition according to any one of claims 1 to 10.

12. The pharmaceutical composition is administered by intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes, The pharmaceutical composition according to claim 11.

13. The pharmaceutical composition is administered subcutaneously using a pen-type delivery device The pharmaceutical composition according to claim 12.

14. The pen-type delivery device is a reusable pen-type delivery device including an exchangeable cartridge containing the pharmaceutical composition, or the pen-type delivery device is a disposable refillable pen-type delivery device containing the pharmaceutical composition held in a reservoir of the device, The pharmaceutical composition according to claim 13.

15. The pharmaceutical composition includes dupilumab, The pharmaceutical composition according to any one of claims 1 to 14.

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