A method of treating chronic obstructive pulmonary disease (COPD) by administering IL-4R antagonists.

Abstract

A method for treating or preventing chronic obstructive pulmonary disease (COPD) in a subject is provided. The method includes administering a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or an antigen-binding fragment thereof, to a subject in need.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 453,786, filed on March 22, 2023; U.S. Provisional Patent Application No. 63 / 457,188, filed on April 5, 2023; U.S. Provisional Patent Application No. 63 / 460,981, filed on April 21, 2023; U.S. Provisional Patent Application No. 63 / 525,197, filed on July 6, 2023; U.S. Provisional Patent Application No. 63 / 602,616, filed on November 26, 2023; U.S. Provisional Patent Application No. 63 / 551,557, filed on February 9, 2024; European Patent Application No. 24315012.5, filed on January 12, 2024; and European Patent Application No. 24315047.1, filed on February 14, 2024. The entire disclosure of each of these applications is hereby incorporated by reference in its entirety for all purposes.

[0002] The present disclosure relates to the treatment and / or prevention of chronic obstructive pulmonary disease (COPD) in a subject that needs it. The present disclosure relates to the administration of an interleukin-4 receptor (IL-4R) antagonist for treating or preventing COPD in a subject that needs it.

Background Art

[0003] Chronic obstructive pulmonary disease (COPD) is a common heterogeneous disease associated with an abnormal inflammatory immune response of the lungs to harmful particles and gases. COPD results in a progressive airflow obstruction that is mainly irreversible or only partially reversible, and often results in loss of alveolar tissue and emphysema. The disease typically begins in the peripheral airways, where chronic inflammation causes structural changes including narrowing of the peripheral airways and destruction of the lung parenchyma, which results in loss of alveolar attachments to the peripheral airways and a decrease in lung elastic recoil.

[0004] COPD is most commonly caused by cigarette smoking but can also be caused by inhalation of particulate matter and noxious gases from outdoor or indoor air pollution, including occupational exposure to vapors, gases, dusts (including silica), and fumes. The most common clinical symptoms include chronic dyspnea, cough, shortness of breath, and / or sputum production.

[0005] Chronic obstructive pulmonary disease is a highly prevalent, severe, and progressive disease, resulting in significant morbidity, mortality, and economic burden. Based on the Burden of Obstructive Lung Disease (BOLD) and other large-scale epidemiological studies, the number of COPD cases worldwide was estimated to be 384 million in 2010, with a global prevalence of 11.7% (95% confidence interval: 8.4% - 15.0%). In the United States alone, over 12 million patients have been diagnosed, and the incidence of COPD is expected to increase rapidly with aging. COPD is a progressive and irreversible inflammatory lung disease that is periodically interrupted by exacerbations of the disease, which lead to long-term disability and death. In the United States, COPD is the third leading cause of death.

[0006] Standard treatment for moderate COPD starts with daily use of bronchodilators, mainly long-acting muscarinic antagonists (LAMA) and / or long-acting β2 agonists (LABA). As the disease progresses, particularly in patients with frequent exacerbations, bronchodilators are combined with anti-inflammatory drugs such as inhaled corticosteroids (ICS) and phosphodiesterase type 4 (PDE-4) inhibitors (roflumilast). The main limitations of existing drugs for COPD include moderate effectiveness and, particularly for inhaled corticosteroids, the increased risk of respiratory infections, including pneumonia, with high-dose potent molecules and in patients with severe COPD. Inhaled corticosteroids have a consistent effect in reducing the risk of moderate COPD exacerbations, defined by exacerbations of COPD that require the use of systemic corticosteroids and / or antibiotics, but there is no consistent benefit for severe exacerbations that require hospitalization.

[0007] Systemic, mostly oral, corticosteroids are used primarily to treat exacerbations, given their unacceptable safety profile and growing concerns in the COPD population. There are no approved treatments that halt the decline in FEV1 over time or alter the course of progressive COPD. [Overview of the project] [Problems that the invention aims to solve]

[0008] Therefore, significant unmet medical needs remain within the growing population of patients with COPD. Consequently, novel targeted therapies to further improve COPD symptoms and lung function, and prevent exacerbations, are needed in this field. [Means for solving the problem]

[0009] In one embodiment, the present disclosure provides a method for treating a subject having chronic obstructive pulmonary disease (COPD). In some embodiments, the method includes administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0010] In another embodiment, the disclosure also provides a method for treating subjects with moderate to severe COPD. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0011] In another embodiment, the disclosure also provides a method for treating subjects having COPD with type 2 inflammation. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0012] In another embodiment, the disclosure also provides a method for treating subjects with moderate to severe COPD accompanied by type 2 inflammation. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0013] In another embodiment, the disclosure also provides a method for treating subjects with COPD that is not adequately controlled with background therapy. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0014] In another embodiment, the disclosure also provides a method for treating subjects having COPD with unified airway disease (UAD). In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0015] In another embodiment, the disclosure further provides a method for treating a subject having COPD, wherein COPD coexists with at least one type 2 inflammatory disease. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to the subject.

[0016] In another embodiment, the disclosure further provides methods for improving one or more symptoms in subjects in need. In some embodiments, the methods include administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to a subject.

[0017] In another embodiment, the disclosure further provides methods for mitigating or preventing moderate to severe exacerbations in subjects requiring such methods. In some embodiments, the methods involve administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to a subject.

[0018] In another embodiment, the disclosure further provides a method for slowing the progression of lung function decline in subjects requiring it. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to a subject.

[0019] In another embodiment, the disclosure further provides methods for improving health-related quality of life in subjects where it is needed. In some embodiments, the methods include administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to a subject.

[0020] In another embodiment, the disclosure provides a method for delaying the time to the first moderate or severe exacerbation in subjects requiring it. In some embodiments, the method involves administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) to a subject.

[0021] In certain exemplary embodiments, the subject treated by the method described herein has a baseline blood eosinophil count of ≥300 cells / μL, ≥350 cells / μL, ≥400 cells / μL, ≥450 cells / μL, or ≥500 cells / μL.

[0022] In certain exemplary embodiments, the subjects treated by the method described herein have a baseline blood eosinophil count of less than 300 cells / μL.

[0023] In certain exemplary embodiments, the subjects treated by the method described herein have baseline exhaled nitric oxide (FeNO) levels of ≥20 ppb, ≥25 ppb, ≥30 ppb, ≥35 ppb, or ≥40 ppb.

[0024] In certain exemplary embodiments, the subjects treated by the method described herein have a baseline exhaled nitric oxide (FeNO) concentration level of less than 20 ppb.

[0025] In certain exemplary embodiments, the subject treated by the method described herein has a baseline immunoglobulin E level (IgE) of ≥100 kU / L.

[0026] In certain exemplary embodiments, the subjects treated by the method described herein have a baseline immunoglobulin E (IgE) level of less than 100 kU / L.

[0027] In certain exemplary embodiments, the COPD described herein is oxygen-dependent COPD.

[0028] In certain exemplary embodiments, COPD as described herein is not controlled at baseline despite standard treatment. In some embodiments, standard treatment includes LABA + LAMA + ICS or, if ICS is contraindicated, a combination of LABA + LAMA.

[0029] In certain exemplary embodiments, the subjects treated by the method described herein have acute or chronic bronchitis.

[0030] In certain exemplary embodiments, the subject treated by the method described herein has emphysema.

[0031] In certain exemplary embodiments, the subject treated by the method described herein has a pulmonary cyst.

[0032] In certain exemplary embodiments, the subjects treated by the method described herein have tracheobronchial COPD.

[0033] In certain exemplary embodiments, the subject treated by the method described herein is a current smoker.

[0034] In certain exemplary embodiments, the subjects treated by the method described herein are former smokers.

[0035] In certain exemplary embodiments, the subject treated by the method described herein is a human being.

[0036] In certain exemplary embodiments, the subjects treated by the method described herein are adult patients.

[0037] In certain exemplary embodiments, the methods described herein further include background therapy in addition to an antibody or its antigen-binding fragment.

[0038] In certain exemplary embodiments, background therapy includes inhaled corticosteroids (ICS), long-acting beta-agonists (LABAs), leukotriene receptor antagonists (LTRAs), long-acting muscarinic antagonists (LAMAs), methylxanthines, phosphodiesterase inhibitors (e.g., roflumilast or theophylline), or mixtures thereof.

[0039] In certain exemplary embodiments, background therapy includes LABA, LAMA, and ICS. In some embodiments, COPD is not controlled at baseline despite background therapy alone.

[0040] In certain exemplary embodiments, background therapy includes a high dose of ICS. In certain exemplary embodiments, the high dose ICS is beclomethasone dipropionate (chlorofluorocarbon, CFC) with a dose greater than 1000 mcg. In certain exemplary embodiments, the high dose ICS is beclomethasone dipropionate (hydrofluoroalkane, HFA) with a dose greater than 400 μg. In certain exemplary embodiments, the high dose ICS is budesonide (dry powder inhaler, DPI) with a dose greater than 800 mcg. In certain exemplary embodiments, the high dose ICS is ciclesonide (HFA) with a dose greater than 320 mcg. In certain exemplary embodiments, the high dose ICS is fluticasone propionate (DPI or HFA) with a dose greater than 500 μg. In certain exemplary embodiments, the high dose ICS is mometasone fluate with a dose greater than 440 μg. In certain exemplary embodiments, the high-dose ICS is triamcinolone acetonide, and the dose is greater than 2000 μg. In certain exemplary embodiments, the adult high dose of ICS relative to fluticasone propionate is >500 μg (DPI or HFA) or 401-800 μg (HFA) in the Japanese population.

[0041] In certain exemplary embodiments, background therapy includes a non-high dose ICS. In certain exemplary embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered with a non-high dose ICS, LAMA, and LABA. In certain exemplary embodiments, the non-high dose ICS is beclomethasone dipropionate or equivalent, with a dose of less than 1000 μg. In certain exemplary embodiments, the non-high dose ICS is fluticasone propionate (HFA), with a dose of less than 400 μg. In certain exemplary embodiments, the non-high dose ICS is budesonide (DPI), with a dose of less than 800 μg. In certain exemplary embodiments, the non-high dose ICS is ciclesonide (HFA), with a dose of less than 320 μg. In certain exemplary embodiments, the non-high dose ICS is fluticasone propionate (DPI or HFA), with a dose of less than 500 μg. In certain exemplary embodiments, the non-high-dose ICS is mometasone phlomate, with a dose of less than 440 μg. In certain exemplary embodiments, the non-high-dose ICS is triamcinolone acetonide, with a dose of less than 2000 μg. In certain exemplary embodiments, the adult non-high dose of ICS for fluticasone propionate is 500 μg or less (DPI or HFA) or 400 μg or less (HFA) for the Japanese population.

[0042] In certain exemplary embodiments, background therapy includes LABA and LAMA. In certain exemplary embodiments, COPD is not controlled at baseline despite background therapy alone.

[0043] In certain exemplary embodiments, inhaled corticosteroids (ICS) are contraindicated in the patient being treated.

[0044] In certain exemplary embodiments, background therapy includes roflumilast.

[0045] In certain exemplary embodiments, the background therapy includes theophylline.

[0046] In certain exemplary embodiments, one or more COPD-related parameters are improved in a subject after treatment according to the method herein, for example, over a specified period (e.g., 12 weeks, 24 weeks, 36 weeks, 52 weeks, or longer). In certain exemplary embodiments, one or more COPD-related parameters include: (1) annual rate of acute moderate or severe exacerbations of COPD (AECOPD), (2) annual rate of severe AECOPD, (3) time to first moderate or severe AECOPD, (4) forced expiratory volume in one second (FEV1) (before or after bronchodilator administration), (5) forced vital capacity (FVC), (6) forced expiratory flow rate (FEF) 25% to 75%, (7) exhaled nitric oxide concentration (FeNO), (8) Exacerbation Assistance Test (EXACT), (9) St. George's Respiratory Questionnaire (SGRQ) score, (10) Assessment of Respiratory Symptoms of COPD (E-RS:COPD) score, (11) Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index, and (12) Euro Quality of Life-5 Dimension (13) Questionnaire (EQ-5D) score, (14) Modified British Medical Research Council Questionnaire (mMRC) score, (15) Courses of steroids (e.g., systemic corticosteroids) in days, (16) Courses of antibiotics in days, (17) Resting respiratory rate, (18) FEV1 / FVC ratio, (19) Mucus plug, and (20) Any combination thereof, selected from the following groups.

[0047] In certain exemplary embodiments, the methods described herein reduce the level of one or more biomarkers in a subject. In certain exemplary embodiments, the biomarkers are selected from the group consisting of blood eosinophil (Eos) count, exhaled nitric oxide (FeNO) concentration level, immunoglobulin E level (IgE), eotaxin (e.g., eotaxin-3) level, lung and activated regulatory chemokine (PARC) levels.

[0048] In certain exemplary embodiments, the antibody or antigen-binding fragment used in the method described herein 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 comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0049] In certain exemplary embodiments, an antibody or its antigen-binding fragment is administered to the subject as an initial dose, followed by one or more secondary doses.

[0050] In certain exemplary embodiments, the initial dose is approximately 300 mg, and one or more secondary doses are each approximately 300 mg.

[0051] In certain exemplary embodiments, the secondary dose is administered every other week (q2w) or using an alternative dosing regimen.

[0052] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is at least 40 years old.

[0053] In certain exemplary embodiments, prior to the initiation of treatment, the subject has a Medical Research Council (MRC) dyspnea scale grade score of ≥2. In some embodiments, prior to the initiation of treatment, the subject has a baseline modified Medical Research Council (mMRC) dyspnea scale grade score of ≥2. mMRC is described in ATS (1982) Am Rev Respir Dis. No; 126(5):952-6.

[0054] In certain exemplary embodiments, the subjects have a history of high exacerbation risk.

[0055] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0056] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered using a pre-filled device.

[0057] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously.

[0058] In certain exemplary embodiments, the "subject requiring it" is a subject who is a current smoker. In certain exemplary embodiments, the subject is a current smoker who smokes cigarettes. In certain exemplary embodiments, the subject is a current smoker who has a history of smoking 10 packs or more of cigarettes per year. In certain exemplary embodiments, the subject is a current smoker who has smoked less than 10 packs of cigarettes per year. In certain exemplary embodiments, the subject is a current smoker who has a history of smoking 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs or more per year. In certain exemplary embodiments, the subject is a current smoker who has a history of smoking 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more.

[0059] In certain exemplary embodiments, the "subjects requiring it" are former smokers. In certain exemplary embodiments, the subjects are former smokers who have a history of smoking tobacco. In certain exemplary embodiments, the subjects are former smokers who have a history of smoking 10 packs or more per year. In certain exemplary embodiments, the subjects are former smokers who have a history of smoking less than 10 packs per year. In certain exemplary embodiments, the subjects are former smokers who have a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs per year. In certain exemplary embodiments, the subjects are former smokers who have a history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer.

[0060] In certain exemplary embodiments, the subjects are patients with a GOLD 1 severity level (mild COPD, FEV1 ≥ 80% predicted) according to the GOLD grading system. In certain exemplary embodiments, the subjects are patients with a GOLD 2 severity level (moderate COPD, 50% ≤ FEV1 ≤ 80% predicted) according to the GOLD grading system. In certain exemplary embodiments, the subjects are patients with a GOLD 3 severity level (severe COPD, 30% ≤ FEV1 ≤ 50% predicted) according to the GOLD grading system. In certain exemplary embodiments, the subjects are patients with a GOLD 4 severity level (very severe COPD, FEV1 < 30% predicted) according to the GOLD grading system.

[0061] In certain exemplary embodiments, subjects have (1) zero or one moderate exacerbation per year that does not lead to hospitalization, and (2) a modified Medical Research Council (mMRC) score of 0 to 1 or a COPD Assessment Test (CAT) score of less than 10. In certain exemplary embodiments, subjects have (1) zero or one moderate exacerbation per year that does not lead to hospitalization, and (2) an mMRC score of 2 or higher or a CAT score of 10 or higher. In certain exemplary embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization or at least one severe exacerbation per year that leads to hospitalization, and (2) an mMRC score of 0 to 1 or a CAT score of less than 10. In certain exemplary embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization or at least one severe exacerbation per year that leads to hospitalization, and (2) an mMRC score of 2 or higher or a CAT score of 10 or higher. In certain exemplary embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization, or at least one severe exacerbation per year that leads to hospitalization, regardless of mMRC score or CAT score. In certain exemplary embodiments, subjects have two or more severe exacerbations per year that lead to hospitalization.

[0062] In another embodiment, a method is provided for treating a subject with uncontrolled chronic obstructive pulmonary disease (COPD), comprising administering an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

[0063] In another embodiment, the Disclosure provides a method for treating uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in a subject, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) as an add-on maintenance therapy, in addition to COPD background therapy. In certain exemplary embodiments, the uncontrolled COPD is associated with a history of exacerbations. In certain exemplary embodiments, type 2 inflammation is led by, identified by, and / or determined by at least one biomarker (e.g., serum eosinophil levels).

[0064] In another aspect, the disclosure provides a method for reducing moderate to severe exacerbations and / or improving at least one COPD-related parameter selected from the group consisting of: (1) the annual rate of acute moderate or severe exacerbations (AECOPD) of COPD; (2) the annual rate of severe AECOPD; (3) the time to the first moderate or severe AECOPD; and (4) the forced expiratory volume in one second (FEV1) (before or after administration of a bronchodilator). (Post-administration), (5) Forced vital capacity (FVC), (6) Forced expiratory flow rate (FEF) 25%~75%, (7) Exhaled nitric oxide concentration (FeNO), (8) Chronic obstructive pulmonary disease exacerbation tool (EXACT), (9) St. George's Respiratory Questionnaire (SGRQ), (10) Assessment of respiratory symptoms of COPD (E-RS:COPD) or RS-total score, (11) Body mass index, airflow obstruction, dyspnea, exercise capacity (BODE) index, (12) Euro (13) Quality of Life-5 Dimension Questionnaire (EQ-5D), (14) Modified British Medical Research Council Questionnaire (mMRC), (15) Courses of steroids (e.g., systemic corticosteroids) in days, (16) Courses of antibiotics in days, (17) Resting respiratory rate, (18) FEV1 / FVC ratio, (19) Mucus plugs or any combination thereof.

[0065] Also provided are pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) as an add-on maintenance therapy, in addition to COPD background therapy, for use in the treatment of uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in the target population. In certain exemplary embodiments, the uncontrolled COPD is associated with a history of exacerbations.

[0066] The use of antibodies or antigen-binding fragments thereof that specifically bind to the interleukin-4 receptor (IL-4R) is also provided for the treatment of uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in subjects. In certain exemplary embodiments, uncontrolled COPD is associated with a history of exacerbations.

[0067] Also provided are combination therapies comprising an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) and a COPD background therapy, for use in a manner that reduces the subject's dependence on systemic corticosteroids (e.g., corticosteroids such as inhaled corticosteroids (ICS)) and / or LABAs for the treatment of uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in the subject. In certain exemplary embodiments, the uncontrolled COPD is associated with a history of exacerbations.

[0068] Also provided are kits comprising an antibody or its antigen-binding fragment that specifically binds to the interleukin-4 receptor (IL-4R) and one or more compounds for COPD background therapy. In certain exemplary embodiments, the kit is used to treat uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in a subject. In certain exemplary embodiments, the uncontrolled COPD is associated with a history of exacerbations.

[0069] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the COPD background therapy includes: (1) beta-2 agonists such as short-acting beta-2 agonists (SABA, e.g., fenoterol, revalbuterol, salbutamol, and terbutaline) or long-acting beta-2 agonists (LABA, e.g., alformoterol, formoterol, indacaterol, orodaterol, and salmeterol); (2) anticholinergics such as short-acting anticholinergics (SAMA, e.g., ipratropium bromide, oxytropium bromide) or long-acting anticholinergics (LAMA, e.g., acridinium bromide, glycopyrronium bromide, tiotropum, umeclidinium, glycopyrrolate, and rebefenacin); (3) combinations of SABA and SAMA (e.g., fenoterol + ipratropium or salbutamol + ipratropium); (4) combinations of LABA and LAMA (formoterol + acridinium, formoterol (6) Glycopyrronium, indacaterol + glycopyrronium, vilanterol + umeclidinium and orodaterol + tiotropium), (5) Methylxanthines (e.g., aminophylline and theophylline), (6) Combinations of LABA and corticosteroids (e.g., formoterol + beclomethasone, formoterol + budesonide, formoterol + mometasone, salmeterol + fluticasone propionate, vilanterol + fluticasone furoate), (6) Three agents The following are selected from the group consisting of (7) combinations (e.g., fluticasone + umeclidinium + vilanterol, beclomethasone + formoterol + glycopyrronium, budesodin + formoterol + glycopyrrolate, etc.), (8) phosphodiesterase inhibitors (e.g., phosphodiesterase-4 inhibitors such as roflumilast), (9) mucolytics (e.g., erdosteine, catobocisterine, and N-acetylcisterine), or any combination thereof. In certain exemplary embodiments, background therapy is a triple combination therapy, for example, a therapy involving the administration of an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) to the target.In certain exemplary embodiments, background therapy is a dual therapy that includes, for example, administering a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) to a patient when inhaled corticosteroids (ICS) are contraindicated.

[0070] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subjects are adults.

[0071] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subject receives triple therapy in addition to an antibody or its antigen-binding fragment. In certain exemplary embodiments, the triple therapy includes treatment with an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0072] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, ICS is contraindicated, and the subject receives dual therapy in addition to an antibody or its antigen-binding fragment. In certain exemplary embodiments, the dual therapy comprises LABA and LAMA.

[0073] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the antibody or its antigen-binding fragment is an add-on therapy. In certain exemplary embodiments, the antibody or its antigen-binding fragment is a maintenance therapy. In certain exemplary embodiments, the antibody or its antigen-binding fragment is an add-on maintenance therapy.

[0074] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subjects have a history of COPD exacerbations.

[0075] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subject has a biomarker of type 2 inflammation at an elevated level compared to a control. In certain exemplary embodiments, the biomarker may be selected from the group consisting of lung and activated regulatory chemokines (PARC), eotaxin-3, fibrinogen, IgE, sputum or blood eosinophils, sputum or blood neutrophils, exhaled nitric oxide concentration (FeNO), IL-4Rα, IL-4, IL-13, IL-33, serum periostin, calcium-activated chloride channel modulator (CLCA1), cystatin-SN (CST1), tumorigenesis inhibitor 2 (ST2), thymic stromal lymphocyte neoplasm (TSLP), or any combination thereof. In certain exemplary embodiments, the biomarker is blood eosinophil count. In certain exemplary embodiments, the biomarker is FeNO.

[0076] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subject has a baseline blood eosinophil count of ≥50 cells / μL, ≥100 cells / μL, ≥150 cells / μL, ≥200 cells / μL, ≥250 cells / μL, ≥300 cells / μL, ≥350 cells / μL, ≥400 cells / μL, ≥450 cells / μL, or ≥500 cells / μL. In certain exemplary embodiments, the subject has a baseline blood eosinophil count of less than 300 cells / μL.

[0077] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subject has a baseline FeNO level of ≥20 ppb, ≥22 ppb, ≥24 ppb, ≥26 ppb, ≥28 ppb, ≥30 ppb, ≥32 ppb, ≥34 ppb, ≥36 ppb, ≥38 ppb, ≥40 ppb, ≥42 ppb, ≥44 ppb, ≥46 ppb, ≥48 ppb, ≥50 ppb, or greater. In certain exemplary embodiments, the subject has a baseline FeNO level of ≥20 ppb.

[0078] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the subjects have baseline serum IgE levels of ≥100kU / L, ≥150kU / L, ≥200kU / L, ≥250kU / L, ≥300kU / L, ≥350kU / L, ≥400kU / L, ≥450kU / L, ≥500kU / L, ≥1000kU / L, ≥1500kU / L, ≥2000kU / L, ≥2500kU / L, ≥3000kU / L, ≥3500kU / L, ≥4000kU / L, ≥4500kU / L, ≥5000kU / L or higher (for example, when measured using the IMMUNOCAP® assay [Phadia, Inc., Portage, MI]).

[0079] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, consistent benefits are observed in subjects regardless of demographics, ICS dose (high / low), smoking status, GOLD severity of airflow limitation (baseline), and history of exacerbations.

[0080] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the antibody or its antigen-binding fragment comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0081] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, an antibody or its antigen-binding fragment is administered to a subject as an initial dose, followed by one or more secondary doses.

[0082] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the initial dose is about 300 mg, and one or more secondary doses are each about 300 mg.

[0083] In certain exemplary embodiments of the methods, pharmaceutical compositions, or combination therapies described herein, the secondary dose is administered every other week (q2w) or using an alternative dosing regimen.

[0084] Also provided are kits comprising an antibody or its antigen-binding fragment that specifically binds to the interleukin-4 receptor (IL-4R) and one or more compounds for COPD background therapy. In certain exemplary embodiments, the kit is used to treat uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation in a subject. In certain exemplary embodiments, the uncontrolled COPD is associated with a history of exacerbations.

[0085] The aforementioned and other features and advantages of this disclosure will be better understood from the following detailed description of exemplary embodiments in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0086] [Figure 1] The study designs of the BOREAS and NOTUS trials in Example 1 are outlined. These trials were multinational, randomized, double-blind, placebo-controlled, 52-week Phase 3 studies to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe type 2 inflammatory COPD, including those driven by IL-4, IL-5, and IL-13 activation with established LABA, LAMA, and / or ICS background therapy (triple therapy unless ICS is contraindicated). The investigational drug administered during the 52-week treatment period was either dupilumab 300 mg q2w or placebo q2w. [Figure 2A] The table shows the activity schedule for two randomized, placebo-controlled trials (Example 1) to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe type 2 inflammatory COPD. [Figure 2A-1] Same as above. [Figure 2B] The table shows the activity schedule for two randomized, placebo-controlled trials (Example 1) to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe type 2 inflammatory COPD. [Figure 2B-1] Same as above. [Figure 2C] The table shows the activity schedule for two randomized, placebo-controlled trials (Example 1) to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe type 2 inflammatory COPD. [Figure 2C-1] Same as above. [Figure 3] This demonstrates that dupilumab met all multiplicity-adjusted endpoints with high statistical significance. [Figure 4] This study demonstrates that dupilumab reduced the rate of moderate and severe exacerbations in patients. The 30% reduction in exacerbations was statistically significant and clinically meaningful. [Figure 5] The study demonstrates rapid and sustained improvement in lung function with dupilumab. The data show significant and clinically meaningful improvements in pre-BD FEV1 at weeks 12 and 52. [Figure 6] Higher efficacy was observed in a subgroup of COPD patients with baseline FeNO levels of ≥20 ppb. Exacerbations and improvements in lung function were increased along with markers of type 2 inflammation. [Figure 7] Dupilumab improved health status as measured by the St. George Respiratory Questionnaire (SGRQ). Improvements in the SGRQ were rapid and sustained throughout 52 weeks of treatment. [Figure 8] Dupilumab improved symptoms of COPD as measured by the E-RS COPD:RS-Total Score. The improvement was rapid and sustained throughout 52 weeks. [Figure 9] Higher efficacy was observed in the subgroup with baseline FeNO ≥ 20 ppb. Exacerbations and improvements in lung function were increased, along with markers of type 2 inflammation. [Figure 10] It demonstrates consistent efficacy observed in a subgroup of smokers. Improvements in exacerbations and lung function were similar in current and former smokers. [Figure 11] This shows that dupilumab reduced eosinophils and FeNO over time (after a transient increase). [Figure 12]This shows the adverse event profile of dupilumab during the BOREAS trial. [Figure 13A] This shows that baseline demographic characteristics were similar between the dupilumab group and the placebo group. [Figure 13B] This shows that baseline demographic characteristics were similar between the dupilumab group and the placebo group. [Figure 13C] This shows that baseline demographic characteristics were similar between the dupilumab group and the placebo group. [Figure 13D] This shows that baseline demographic characteristics were similar between the dupilumab group and the placebo group. [Figure 13E] This shows that baseline demographic characteristics were similar between the dupilumab group and the placebo group. [Figure 14] Dupilumab delays the time to the first moderate to severe exacerbation in patients, and separation can be seen as early as week 4. [Figure 15A] It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 15B] It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 15C] It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 15D] It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 15E] It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 15F]It demonstrates efficacy across multiple demographic subgroups. There was a consistent reduction in moderate to severe exacerbations across multiple demographic subgroups. [Figure 16A] The study demonstrates efficacy across multiple subgroups of type II biomarkers. Greater declines were associated with high levels of type II biomarkers. [Figure 16B] The study demonstrates efficacy across multiple subgroups of type II biomarkers. Greater declines were associated with high levels of type II biomarkers. [Figure 17] This shows a reduction in exacerbations in the GOLD airflow restriction subgroup. [Figure 18] This indicates that severe exacerbations were rare during the BOREAS trial. While there was a trend toward a decrease, no significant difference in severe exacerbations was observed between the dupilumab group and the placebo group. [Figure 19] The mean change in FEV1 from baseline during and after 52 weeks of treatment is shown. Dupilumab resulted in a rapid and sustained improvement in the mean change from baseline compared to placebo. [Figure 20A] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 20B] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 20C] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 20D] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 20E] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 20F] This shows consistent improvement in FEV1 at week 12 across subgroups. [Figure 21A] This shows consistent improvement in higher FEV1 levels in subgroups with higher levels of type 2 biomarkers. [Figure 21B] This shows consistent improvement in higher FEV1 levels in subgroups with higher levels of type 2 biomarkers. [Figure 24B-1] Same as above. [Figure 22] This shows that improvement in lung function was rapid and sustained, as indicated by FVC and FEV1 / FVC. [Figure 23] This shows that dupilumab resulted in a rapid and sustained improvement in FEV1 after bronchodilator administration (after BD administration). [Figure 24A] This study demonstrates that dupilumab improved symptoms in all domains of E-RS:COPD (shortness of breath, cough / sputum, and chest symptoms) at week 52. [Figure 24B] This study demonstrates that dupilumab improved symptoms in all domains of E-RS:COPD (shortness of breath, cough / sputum, and chest symptoms) at week 52. [Figure 25] This shows that dupilumab improved all domains of SGRQ at week 52. [Figure 25-1] Same as above. [Figure 26] This study demonstrates that dupilumab reduced exposure to systemic corticosteroid (SCS) and antibiotic treatment for exacerbations / respiratory conditions. [Figure 27] This shows the changes in serum eosinophils over time. In the dupilumab group, serum Eos levels decreased during the treatment period. A primary increase in mean Eos was observed at week 8, and it returned to baseline by week 24. No increase was observed in the median eosinophil count. [Figure 28] This shows the distribution of type 2 biomarkers in patients in the BOREAS trial. [Figure 29] The patient breakdown in the BOREAS trial is shown. *Note: The safety population is placebo (N=470) and dupilumab (N=469) because one patient assigned to placebo mistakenly received dupilumab; Covid-19 coronavirus disease 2019. [Figure 30] The St. George Respiratory Questionnaire (A) and E-RS COPD score (B) during the 52-week treatment period are shown. [Figure 31]The changes from baseline in FEF 25–75% before bronchodilator administration (A) and the changes from baseline in predicted FVC percentage before bronchodilator administration (B) are shown over the 52-week study period. [Figure 32] The hierarchical structure of the BOREAS and NOTUS trials is shown. [Figure 32-1] Same as above. [Figure 33] The NOTUS trial showed a 34% reduction in COPD exacerbations, which is statistically significant and clinically meaningful. [Figure 34] This study shows that dupilumab reduced the rate of moderate and severe COPD exacerbations. [Figure 35] This study shows that dupilumab shortened the time to the first moderate and severe exacerbation in patients who showed separation after week 4. [Figure 36] The NOTUS trial showed a larger, non-significant trend toward a reduction in severe exacerbations. [Figure 37] The study shows that dupilumab shortened the time to the first severe exacerbation of COPD. In NOTUS, dupilumab shortened the time to the first severe exacerbation with nominal significance. [Figure 38] This shows that dupilumab improved lung function as measured by pre-BD FEV1. The mean change in LS (Lung Span) of pre-BD FEV1 in both the BOREAS and NOTUS trials at weeks 12 and 52 is shown. Significant and clinically meaningful improvements in pre-BD FEV1 were observed at weeks 12 and 52 in both trials. [Figure 39] This study demonstrates that dupilumab improved lung function as measured by pre-BD FEV1. Both the BOREAS and NOTUS trials show the mean change in LS (Lung Sufficiency) from baseline to week 52 of pre-BD FEV1. Significant and clinically meaningful improvements in pre-BD FEV1 were observed immediately after treatment and maintained throughout the entire treatment period. [Figure 40]This shows the mean LS Δ from baseline in FEV1 after BD administration. Dupilumab improved lung function as measured by FEV1 after BD administration. The improvement was rapid and sustained. [Figure 41] Dupilumab improved health status as measured by the St. George Respiratory Questionnaire (SGRQ). In both trials, SGRQ improvements were observed by week 12 and persisted throughout 52 weeks of treatment. SGRQ: A measure of the impact on overall health status, daily living activities, and perceived well-being (health status). It consists of 50 items on a scale of 0 to 100, with higher scores indicating more limitations. MCID: 4 units. [Figure 42] Dupilumab improved health status as measured by the SGRQ. Significant improvements were observed in BOREAS and not in NOTUS, but the dupilumab response was consistent across both trials. The differential results were driven by a higher placebo response in NOTUS vs. BOREAS (47% vs. 43%). [Figure 43] This study shows that dupilumab improved COPD symptoms at week 52, as measured by the E-RS COPD:RS-Total Score. E-RS: Respiratory Symptoms in Stable COPD - A measure of the severity of overall shortness of breath, cough and sputum, and chest symptoms. Scale: 0-40, lower is better. Symptomatic improvement definition - 2.0. [Figure 44] This study shows that dupilumab improved COPD symptoms from baseline to week 52, as measured by the E-RS COPD:RS-Total Score. In BOREAS, a significant improvement in the E-RS Total Score was observed, and the improvement was rapid and sustained until week 52. In NOTUS, while the improvement in the E-RS Total Score at week 52 was not significant, there was a clear trend toward rapid and sustained symptom improvement after treatment. [Figure 45] The region / country of COPD patients in both trials is shown (BOREAS: 939 enrolled in 24 countries; NOTUS: 935 enrolled in 29 countries). [Figure 46]This shows the mean change in pulmonary function (LS) from baseline in pre-BD FEV1(L) for the subgroup with FeNO ≥ 20 ppb. Improvement in lung function increased with higher FeNO levels. NOTUS showed a clear improvement trend at week 52, although it was not statistically significant. [Figure 47] This shows the annualized rates of moderate to severe exacerbations in both trials in the subgroup with baseline FeNO ≥ 20 ppb. Dupilumab resulted in a 37% reduction over 52 weeks in BOREAS and a 53% reduction in NOTUS. [Figure 48] The pharmacokinetics of the BOREAS and NOTUS trials are shown. [Figure 49] This shows the time course of serum pharmacokinetics by ADA titer category. [Figure 49-1] Same as above. [Figure 50] This indicates that dupilumab reduced eosinophil levels over time (after a transient increase). There were no cases of symptomatic eosinophilia, EGPA, or eosinophilic pneumonia. [Figure 50-1] Same as above. [Figure 51] This shows that dupilumab reduced FeNO levels over time. [Figure 52] This shows the baseline demographic characteristics of the NOTUS trial and compares them with those of BOREAS. The baseline demographic characteristics of NOTUS were similar to those of BOREAS. [Figure 52-1] Same as above. [Figure 53] Based on the demographics of the NOTUS trial, efficacy is demonstrated across multiple subgroups. A consistent reduction in moderate to severe exacerbations was observed across all demographic subgroups. [Figure 54] The study demonstrated efficacy across multiple disease-based subgroups. A consistent reduction in moderate to severe exacerbations was observed across all disease-specific subgroups. [Figure 54-1] Same as above. [Figure 55]The study demonstrates efficacy across multiple subgroups based on type 2 biomarker subgroups. Greater reductions were observed at higher levels of type 2 biomarkers. [Figure 56] This shows FEV1 levels across multiple demographic subgroups. Improvement in FEV1 was observed at week 12 and was consistent across multiple demographic subgroups. [Figure 56-1] Same as above. [Figure 57] This shows FEV1 levels across multiple subgroups based on disease characteristics. Improvement in FEV1 was observed at week 12 and was consistent across the multiple disease characteristic subgroups. [Figure 57-1] Same as above. [Figure 58] This shows FEV1 levels across multiple subgroups based on biomarkers. Higher type 2 biomarkers were associated with greater improvement. [Figure 59] When measured by the mean change in LS from BL in FEV1 / FVC after BD administration, the improvement in lung function was consistent across multiple parameters. The improvement in lung function was rapid and sustained in FEV1 / FVC after BD administration. [Figure 60] When measured by the mean change in LS from BL in pre-BD FVC over time, improvements in lung function were consistent across multiple parameters. Improvements in lung function were observed in the dupilumab group in both trials, although to a smaller degree was observed in the NOTUS trial. [Figure 61] The results of the FEV1 gradient after BD administration are shown. No significant difference was observed in the FEV1 gradient after BD administration between dupilumab and placebo. [Figure 62] If dupilumab is evaluated by E-RS:COPD at week 52 in the NOTUS trial, it indicates improvement in dyspnea. [Figure 63] This shows that dupilumab improved all domains of SGRQ at week 52. [Figure 64]The pooled dupilumab adverse event profile is shown. Dupilumab demonstrated good tolerability with an acceptable safety profile in the pooled COPD safety population. No new safety concerns were identified. [Figure 65] This shows the health status and symptoms as assessed by E-RS and SGRQ. [Figure 66] The most common SOC (defined as an incidence of ≥5% and a difference of ≥1% between treatment arms) is shown. [Figure 67] The most common TEAEs (defined as an incidence rate of ≥5% and a difference of ≥1% between treated arms) are shown. [Figure 68] The most common SOC (defined as an incidence of ≥2% and a difference of ≥1% between treatment arms) is shown. [Figure 69] The most common TEAEs (defined as an incidence of ≥2% and a difference of ≥1% between treated arms) are shown. [Figure 70] This table shows COPD exacerbation events during the 52-week NOTUS trial period. Error bars indicate 95% confidence intervals. Participants include those who had the opportunity to reach week 52. (A) Cumulative moderate or severe COPD exacerbations. (B) Time to the first moderate or severe COPD exacerbation. q2w indicates every other week. [Figure 71] This chart shows the time course of pre-bronchodilator FEV1 in the NOTUS trial. Error bars indicate the 95% confidence interval. Participants include those who have the opportunity to reach week 52. LS represents least squares, and q2w represents every other week. [Figure 72]Baseline (This table shows the selected demographic and clinical characteristics of the patient at the treatment intention. *Plus-minus values ​​are mean ± SD. BD represents bronchodilators, COPD represents chronic obstructive pulmonary disease, E-RS:COPD represents the assessment of respiratory symptoms of COPD, FeNO represents exhaled nitric oxide concentration, FEV1 represents forced expiratory volume in one second, FVC represents forced vital capacity, ICS represents inhaled corticosteroids, LABA represents long-acting beta-agonists, LAMA represents long-acting muscarinic antagonists, ppb represents parts per billion, Q represents quartiles, and SERQ represents the St. George Respiratory Questionnaire. [Figure 72-1] Same as above. [Figure 73] This table summarizes the endpoints included in the hierarchical trial procedure (intent to treat population). *Endpoints are listed in the order in which they were tested hierarchically. †Only participants who had the opportunity to reach the 52-week evaluation were analyzed for the 52-week continuous and ratio endpoints. This included N=359 in the placebo group and N=362 in the dupilumab group (N=132 in the placebo group and N=132 in the dupilumab group in the subgroup with baseline FeNO levels ≥ 20 ppb). ‡P-values ​​after the trial hierarchy was broken were nominal. [Figure 73-1] Same as above. [Figure 73-2] Same as above. [Figure 74] Adverse events (safety population) are shown. Data are presented as n(%) of patients. *The safety population consisted of all patients who received at least one full or partial dose of dupilumab or placebo, and the analysis was performed according to the treatment each patient received. †The major cardiovascular adverse events (as determined) were cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. [Modes for carrying out the invention]

[0087] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, and such methods and conditions may vary. It should also be understood that the scope of the present invention is limited only by the appended claims, and therefore the terms used herein are intended solely to describe specific embodiments and are not intended to limit them.

[0088] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0089] As used herein, the term “about” means that, when used in reference to a particular enumerated number, that value may vary by no more than 1% from the enumerated value. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0090] As used herein, terms such as “to treat” and “to treat” mean to alleviate symptoms, to temporarily or permanently eliminate the cause of symptoms, or to prevent or delay the onset of symptoms of a specified disorder or condition (for example, to prevent an exacerbation of one or more symptoms of COPD).

[0091] Any methods and materials similar to or equivalent to those described herein may be used in carrying out the disclosures herein, but typical methods and materials are described here. All publications referenced herein are incorporated herein by reference in their entirety.

[0092] Methods to reduce the incidence of COPD exacerbations A method is provided for reducing the incidence of one or more COPD exacerbations (e.g., one or more chronic bronchitis exacerbations and / or emphysema exacerbations not adequately controlled with existing treatments) in a subject requiring such treatment, comprising administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist. According to a particular embodiment, 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 method, which is a major feature of this disclosure, are described herein.

[0093] In one embodiment, if a subject receives such a diagnosis from a physician based on the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) classification system, the subject is identified as having “mild,” “moderate,” “severe,” or “very severe” COPD. In these embodiments, the subject’s COPD is classified based on the severity of airway limitation tested using forced expiratory volume in one second (FEV1) after administration of a bronchodilator. The subject’s airflow limitation due to COPD is classified as “mild” using the GOLD classification system if the subject’s FEV1 is 80% or greater than the predicted FEV1. The predicted FEV1 is based on the average FEV1 value of a person of similar age, race, height, and sex with healthy lungs. The subject’s airflow limitation due to COPD is classified as “moderate” using the GOLD classification system if the subject’s FEV1 is 50% or greater than the predicted FEV1 but less than 80% of the predicted FEV1. For COPD-related airflow restrictions, if the target FEV1 is 30% or more of the predicted FEV1 but less than 50% of the predicted FEV1, it is classified as "severe" using the GOLD classification system. For COPD-related airflow restrictions, if the target FEV1 is less than 30% of the predicted FEV1, it is classified as "very severe" using the GOLD classification system.

[0094] In some embodiments, the subjects being treated are classified as “moderate,” “severe,” or “very severe” in the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) classification system. In some embodiments, the subjects being treated are classified as “severe” or “very severe” in the GOLD classification system. In some embodiments, the subjects being treated are classified as “moderate” in the GOLD classification system. In some embodiments, the subjects being treated are classified as “severe” in the GOLD classification system. In some embodiments, the subjects being treated are classified as “very severe” in the GOLD classification system. In some embodiments, the subjects are classified as (1) having 0 or 1 moderate exacerbations per year that do not lead to hospitalization, and (2) having a modified Medical Research Council (mMRC) score of 0 to 1 or a COPD Assessment Test (CAT) score of less than 10. In some embodiments, the subjects are (1) having 0 or 1 moderate exacerbations per year that do not lead to hospitalization, and (2) having an mMRC score of 2 or higher or a CAT score of less than 10. In some embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization, or at least one severe exacerbation per year that leads to hospitalization, and (2) an mMRC score of 0 to 1 or a CAT score of less than 10. In some embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization, or at least one severe exacerbation per year that leads to hospitalization, and (2) an mMRC score of 2 or higher or a CAT score of 10 or higher. In some embodiments, subjects have (1) two or more moderate exacerbations per year that do not lead to hospitalization, or at least one severe exacerbation per year that leads to hospitalization, regardless of mMRC score or CAT score. mMRC is described in ATS (1982) Am Rev Respir Dis. No; 126(5):952-6. The CAT score system is described in Jones et al. ERJ 2009; 34(3) 648-54. In some embodiments, subjects have two or more severe exacerbations per year that lead to hospitalization.

[0095] In another embodiment, a method is provided for reducing the incidence or relapse or exacerbation of COPD in subjects in need thereof, comprising administering a pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in reducing the incidence or relapse or exacerbation of COPD in subjects in need thereof. As used herein, the expression “exacerbation of COPD” means an increase in the severity and / or frequency and / or duration of one or more symptoms or indicators of COPD. “Exacerbation of COPD” also includes any deterioration in the respiratory health of subjects in need of and / or treatable therapeutic intervention for COPD (e.g., steroid therapy, antibiotic therapy, inhaled corticosteroid therapy, hospitalization, etc.).

[0096] In some embodiments, “moderate exacerbation” is defined as the annual rate of acute moderate or severe COPD exacerbations (AECOPD) requiring either systemic corticosteroids (such as intramuscular, intravenous, or oral) and / or antibiotics. In some embodiments, “severe exacerbation” is defined as an AECOPD requiring hospitalization, or requiring >24 hours of observation in an emergency / emergency medical facility, or resulting in death. In some embodiments, all other exacerbations are classified as “mild.” In some embodiments, moderate and severe events must be separated by at least 14 days in order to be counted as separate events.

[0097] A “reduction in incidence or recurrence” of COPD exacerbations means that subjects receiving the pharmaceutical composition of the Disclosure experience fewer COPD exacerbations after treatment than before treatment (i.e., at least one fewer exacerbation), or do not experience a COPD exacerbation for at least four weeks (e.g., 4, 6, 8, 12, 14 weeks or more) after the initiation of treatment with the pharmaceutical composition of the Disclosure. Alternatively, a “reduction in incidence or recurrence” of COPD exacerbations means that, after administration of the pharmaceutical composition of the Disclosure, the likelihood of a subject experiencing a COPD exacerbation is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) compared to subjects who do not receive the pharmaceutical composition of the Disclosure.

[0098] A method is provided for reducing the incidence of COPD exacerbations in subjects requiring it, comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject, as well as administering one or more maintenance doses of a second controller or second and third controllers, such as a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or inhaled corticosteroids (ICS), to the subject. In some embodiments, a pharmaceutical composition comprising an IL-4R antagonist is provided for use in combination with one or more maintenance doses of a second controller or second and third controllers, such as a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or inhaled corticosteroids (ICS), to reduce the incidence of COPD exacerbations in subjects requiring it.

[0099] In some embodiments, a combination of a pharmaceutical composition comprising an IL-4R antagonist and one or more maintenance doses of a second controller or second and third controllers, such as a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS), is provided for use in reducing the incidence of COPD exacerbations in subjects requiring it.

[0100] A method is provided for reducing the incidence of COPD exacerbations in subjects requiring it, comprising administering a pharmaceutical composition containing an IL-4R antagonist to a subject, as well as administering one or more palliative agents to a subject to eliminate or alleviate one or more COPD-related symptoms. The pharmaceutical composition containing an IL-4R antagonist is provided for use in combination with one or more palliative agents to eliminate or alleviate one or more COPD-related symptoms in subjects requiring it. A combination of a pharmaceutical composition containing an IL-4R antagonist and one or more palliative agents to eliminate or alleviate one or more COPD-related symptoms is provided for use in reducing the incidence of COPD exacerbations in subjects requiring it. Suitable palliative agents include, but are not limited to, rapid-acting β2-adrenergic receptor agonists such as albuterol / salbutamol or levalbuterol / levosalbutamol (including combinations of ipratropium or ipratropium / short-acting β-agonist (SABA)).

[0101] In some embodiments, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain CDR sequences, each containing SEQ ID NOs: 3, 4, and 5, and three light chain CDR sequences, each containing SEQ ID NOs: 6, 7, and 8.

[0102] A method for treating COPD is provided. In some embodiments, the COPD is uncontrolled COPD.

[0103] In some embodiments, subjects with COPD have chronic bronchitis and / or emphysema that is not adequately controlled with existing therapies.

[0104] In some embodiments, subjects with uncontrolled COPD have type 2 inflammation. In some embodiments, subjects with uncontrolled COPD are receiving triple therapy (e.g., LABA + LAMA + ICS). In some embodiments, subjects with uncontrolled COPD are receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated.

[0105] In some embodiments, subjects with uncontrolled COPD are adults. In some embodiments, subjects with uncontrolled COPD are adults receiving triple therapy (e.g., LABA + LAMA + ICS). In some embodiments, subjects with uncontrolled COPD are adults receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated.

[0106] In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and receiving triple therapy (e.g., LABA + LAMA + ICS). In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated.

[0107] In some embodiments, subjects with uncontrolled COPD are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD are treated with dupilumab as a maintenance treatment. In some embodiments, subjects with uncontrolled COPD are treated with dupilumab as an add-on maintenance treatment.

[0108] In some embodiments, subjects with uncontrolled COPD have type 2 inflammation and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as an add-on therapy.

[0109] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are adults receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as an add-on therapy.

[0110] In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD are subjects with type 2 inflammation and for whom ICS is contraindicated, and are therefore receiving double therapy (e.g., LABA + LAMA) and are treated with dupilumab as an add-on treatment.

[0111] In some embodiments, subjects with uncontrolled COPD have type 2 inflammation and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as maintenance therapy.

[0112] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as maintenance therapy.

[0113] In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and receiving triple therapy (e.g., LABA + LAMA + ICS), and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and for whom ICS is contraindicated, and are therefore receiving double therapy (e.g., LABA + LAMA), and are treated with dupilumab as maintenance therapy.

[0114] In some embodiments, subjects with uncontrolled COPD have type 2 inflammation and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as an add-on maintenance therapy.

[0115] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults receiving dual therapy (e.g., LABA + LAMA) because ICS is contraindicated and are treated with dupilumab as an add-on maintenance therapy.

[0116] In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and receiving triple therapy (e.g., LABA + LAMA + ICS) and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with type 2 inflammation and for whom ICS is contraindicated, and are therefore receiving double therapy (e.g., LABA + LAMA) and are treated with dupilumab as an add-on maintenance therapy.

[0117] In some embodiments, the subjects are adults receiving dupilumab as an add-on maintenance therapy for uncontrolled COPD with type 2 inflammation, either receiving triple therapy (e.g., LABA + LAMA + ICS) or, if ICS is contraindicated, receiving dual therapy (e.g., LABA + LAMA).

[0118] In some embodiments, dupilumab is indicated for adults receiving triple therapy or, if inhaled corticosteroids (ICS) are contraindicated, dual therapy, as an add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation.

[0119] In some embodiments, dupilumab is indicated as an add-on maintenance therapy in adult patients with uncontrolled chronic obstructive pulmonary disease (COPD) associated with a history of exacerbations and guided by biomarkers of type 2 inflammation (e.g., serum eosinophils).

[0120] In some embodiments, subjects with uncontrolled COPD are adults. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations. In some embodiments, subjects with uncontrolled COPD have elevated levels of at least one biomarker for type 2 inflammation compared to a control. In some embodiments, subjects with uncontrolled COPD have elevated levels of serum eosinophils compared to a control. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of at least one biomarker for type 2 inflammation compared to a control. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control.

[0121] In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of at least one biomarker for type 2 inflammation compared to a control. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of serum eosinophils compared to a control. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of at least one biomarker for type 2 inflammation compared to a control. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control.

[0122] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD have elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD have elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on treatment. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on treatment.

[0123] In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on therapy.

[0124] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD have elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD have elevated levels of serum eosinophils compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as maintenance therapy.

[0125] In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of serum eosinophils compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as maintenance therapy.

[0126] In some embodiments, subjects with uncontrolled COPD are adults and are treated with dupilumab as add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and are treated with dupilumab as add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD have elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD have elevated levels of serum eosinophils compared to a control and are treated with dupilumab as add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD have a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as add-on maintenance therapy.

[0127] In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of at least one biomarker of type 2 inflammation compared to a control and are treated with dupilumab as an add-on maintenance therapy. In some embodiments, subjects with uncontrolled COPD are adults with a history of COPD exacerbations and elevated levels of serum eosinophils compared to a control and are treated with dupilumab as an add-on maintenance therapy.

[0128] Methods to improve COPD-related parameters A method is provided for improving one or more COPD-related parameters in subjects requiring it (also referred to herein as “COPD-modifying” or “disease-modifying”), the method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in improving one or more COPD-related parameters in subjects requiring it. A reduction in the incidence of COPD exacerbations (as described above) may correlate with improvement in one or more COPD-related parameters, although such correlations are not necessarily observed in all cases.

[0129] Examples of "COPD-related parameters" include: (1) the annual rate of acute moderate or severe AECOPD, (2) the annual rate of severe AECOPD, (3) the relative absolute change from baseline in forced expiratory volume in one second (FEV1) before bronchodilator administration (e.g., at week 52), (4) the relative absolute change from baseline in forced expiratory volume in one second (FEV1) before bronchodilator administration (e.g., at week 24), (5) the relative absolute change from baseline in forced expiratory volume in one second (FEV1) after bronchodilator administration (e.g., at week 52), and (6) the relative change from baseline in forced expiratory volume in one second (FEV1) after bronchodilator administration. (7) Percentage change from baseline in forced expiratory volume in one second (FEV1) after administration of bronchodilators (e.g., at weeks 24 and 52), (8) Percentage decrease from baseline in forced expiratory volume in one second (FEV1) before and / or after administration of bronchodilators (e.g., gradient), (9) Time to first moderate or severe AECOPD, (10) Change from baseline in COPD Exacerbation Questionnaire (EXACT) score (e.g., at week 24), (11) Change from baseline in COPD Respiratory Symptom Assessment (E-RS:COPD) score (e.g., at week 24), (12) St.(13) Change from baseline in George Respiratory Questionnaire (SGRQ) score (e.g., at 24 weeks), (14) Change from baseline in Euro Quality of Life 5-Dimensional Questionnaire (EQ-5D) score (e.g., at 24 weeks), (15) Percentage of patients with moderate to severe AECOPD, (16) Change in forced vital capacity (FVC) from baseline to weeks 16-24, (17) Modified British Medical Research (17) Change from baseline in Council Questionnaire (mMRC) score (e.g., at 24 weeks), (18) Change from baseline in Health-Related Quality of Life (HRQoL) score (e.g., at 24 weeks), (19) Change from baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index score (e.g., at 24 weeks), (20) Change from baseline in daily steps (e.g., at 24 weeks), (21) Number of days receiving oral corticosteroids, (22) Number of days receiving antibiotics, (23) Change from baseline in resting oxygen saturation (e.g., at 24 weeks), (24) Change from baseline (e.g., at week 24), (25) Maintenance of lung function (e.g., compared to no treatment or placebo), (26) Reduction in lung function decline (e.g., compared to no treatment or placebo), (27) Relative absolute change from baseline in FEF 25%–75% (forced expiratory flow rate of 25%–75%) (e.g., at week 52), (28) Change from baseline in daily albuterol or revalbuterol use, (29) Change from baseline in COPD Assessment Test (CAT) score, and (20) One or any combination thereof of clinical symptoms of COPD exacerbation.

[0130] "Improvement in COPD-related parameters" means an increase from baseline in FEV1, FVC, FEF 25%–75%, resting oxygen saturation, EQ-5D score, or time to the first moderate or severe AECOPD. Improvement in COPD-related parameters also means a decrease from baseline in the percentage of AECOPD, daily use of albuterol or revalbuterol, days of antibiotic treatment, days of oral corticosteroid treatment, BODE index score, CAT score, SGRQ score, EXACT score, E-RS:COPD score, or clinical symptoms of COPD exacerbation. As used herein, with respect to COPD-related parameters, the term "baseline" means the numerical value of the COPD-related parameter for a patient before or at the time of administration of a pharmaceutical composition containing an IL-4R antagonist.

[0131] To determine whether COPD-related parameters have “improved,” the parameters are quantified at baseline and at points after administration of the pharmaceutical composition described herein. For example, COPD-related parameters may be measured on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 or week 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or beyond after initial treatment with the pharmaceutical composition. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to establish whether there has been “improvement” in the COPD-related parameters (e.g., an increase or decrease depending on the specific parameter being measured).

[0132] As used herein, the terms “obtain” or “to obtain” mean to acquire possession of a physical entity or value, such as a numerical value, by “directly obtaining” or “indirectly obtaining” a physical entity or value, such as COPD-related mg, about. “Directly obtaining” means to carry out a process (e.g., performing a synthesis or analytical method) to obtain the physical entity or value. “Indirectly obtaining” means to receive the physical entity or value from another entity or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a physical entity involves carrying out a process that includes a physical change of a physical substance, such as a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more distinct entities into a mixture, and carrying out a chemical reaction that includes breaking or forming covalent or non-covalent bonds. Obtaining a value directly involves performing a process that includes a physical change of the sample or another substance, such as performing an analytical process that includes a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”).

[0133] Information obtained indirectly may be provided, for example, in the form of reports supplied in paper or electronic format from online databases or applications ("Apps"). Reports or information may be provided, for example, by medical institutions such as hospitals or clinics, or by healthcare providers such as doctors or nurses.

[0134] Forced expiratory volume in one second (FEV1). According to certain embodiments, administration of IL-4R antagonists to patients results in an increase from baseline in forced expiratory volume in one second (FEV1). Methods for measuring FEV1 are known in the art. For example, a spirometer that meets the recommendations of the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005 can be used to measure FEV1 in patients (see Miller, et al. “ATS / ERS TASK FORCE: Standardization of Lung Function Testing” Eur Respir J. 2005 Aug;26(2):319-38). The ATS / ERS standardization of spirometry can be used as a guideline. Spirometry is generally performed between 6 AM and 10 AM, after at least 6 hours of albuterol retention. Pulmonary function tests are generally measured in a seated position, and the highest measurement is recorded for FEV1 (in liters).

[0135] This disclosure includes a therapeutic method that results in an increase of at least 0.01 L of FEV1 from baseline at week 24 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. This disclosure includes a pharmaceutical composition comprising an anti-IL-4R antagonist for use in increasing FEV1 from baseline by at least 0.01 L at week 24 after initiation of treatment with the pharmaceutical composition. For example, administration of IL-4R antagonists causes an increase of approximately 0.01L, 0.02L, 0.03L, 0.04L, 0.05L, 0.10L, 0.12L, 0.14L, 0.16L, 0.18L, 0.20L, 0.22L, 0.24L, 0.26L, 0.28L, 0.30L, 0.32L, 0.34L, 0.36L, 0.38L, 0.40L, 0.42L, 0.44L, 0.46L, 0.48L, 0.50L or more from baseline in FEV1 at week 24.

[0136] Forced vital capacity (FVC). According to certain embodiments, administration of IL-4R antagonists to patients results in an increase in FVC (forced vital capacity) from baseline. Methods for measuring FVC are known in the art. For example, a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations can be used to measure FVC in patients. Standardization of spirometry by ATS / ERS can be used as a guideline. Spirometry is generally performed between 6 AM and 10 AM, after at least 6 hours of albuterol retention. Pulmonary function tests are generally measured in a seated position, and the highest measurement is recorded for FVC (in liters).

[0137] FEF 25-75%. According to certain embodiments, administration of IL-4R antagonists to patients results in an increase from baseline in FEF 25-75% (25-75% forced expiratory flow rate). Methods for measuring FEF are known in the art. For example, a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations can be used to measure FEV1 in a patient. FEF 25-75% is the rate (liters / second) at which a person can empty exactly half of their exhaled air during maximal expiratory (i.e., forced vital capacity or FVC). The parameter relates to the mean flow rate from the point when 25 percent of FVC is exhaled to the point when 75 percent of FVC is exhaled. The FEF 25-75% of the subject provides information about peripheral airway function, such as the degree of peripheral airway disease and / or inflammation. A change in FEF 25-75% is an early indicator of obstructive pulmonary disease. In certain embodiments, improvements and / or increases in the FEF 25%–75% parameter are improvements of at least 10%, 25%, or 50% compared to the baseline. In certain embodiments, the method of the present disclosure results in a normal FEF 25%–75% value in the subject (e.g., a value ranging from 50%–60% to a maximum of 130% of the mean).

[0138] This disclosure includes a treatment method that results in at least a 5% reduction from baseline of AECOPD at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. This disclosure includes a pharmaceutical composition comprising an anti-IL-4R antagonist for use in reducing AECOPD by at least 5% from baseline at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 after initiation of treatment with the pharmaceutical composition. For example, according to this disclosure, administration of an IL-4R antagonist to a patient requiring it causes a reduction of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or more from baseline in AECOPD at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52.

[0139] This disclosure includes a treatment method that results in a reduction of at least 5% in the probability of first-time AECOPD at a particular time point, at 24 weeks after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist, compared to baseline. This disclosure includes a pharmaceutical composition containing an anti-IL-4R antagonist for use in reducing the probability of first-time AECOPD at a particular time point, at least 5% at 24 weeks after initiation of treatment with the pharmaceutical composition. For example, according to this disclosure, administration of an IL-4R antagonist to a subject in need thereof results in a reduction of approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, or more in the probability of first-time AECOPD at a particular time point, at 24 weeks, compared to baseline.

[0140] Use of albuterol / revalbuterol. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the daily use of albuterol or revalbuterol. The number of albuterol / revalbuterol inhalations may be recorded daily by the patient in a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, the use of albuterol / revalbuterol may typically be performed as needed for symptoms, rather than routinely or prophylactically. The baseline number of albuterol / revalbuterol inhalations / day may be calculated based on the average over the 7 days prior to the administration of the initial dose of the pharmaceutical composition containing the IL-4R antagonist.

[0141] This disclosure includes a therapeutic method that results in a reduction of at least 0.25 inhalations (puffs) per day of albuterol / revalterol use from baseline at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject requiring it results in a reduction of approximately 0.25 inhalations per day, 0.50 inhalations per day, 0.75 inhalations per day, 1.00 inhalation per day, 1.25 inhalations per day, 1.5 inhalations per day, 1.75 inhalations per day, 2.00 inhalations per day, 2.25 inhalations per day, 2.5 inhalations per day, 2.75 inhalations per day, 3.00 inhalations per day, or more of these from baseline at week 12.

[0142] Daily steps. According to a particular embodiment, administration of an IL-4R antagonist to a patient results in a change from baseline in daily steps, for example, an increase in daily steps over a specified period compared to daily steps over a specified period before administration of the IL-4R antagonist.

[0143] Corticosteroid / antibiotic use. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the number of days of oral corticosteroid use and / or a reduction in the required oral corticosteroid dose. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the number of days of antibiotic use over a specified period compared to the number of days the patient was receiving antibiotics over a specified period prior to the administration of the IL-4R antagonist.

[0144] Oxygen saturation. In some embodiments, administration of an IL-4R antagonist to a patient results in a change from baseline in resting oxygen saturation, for example, an increased resting oxygen saturation compared to that obtained before administration of the IL-4R antagonist.

[0145] Respiratory rate. In some embodiments, administration of an IL-4R antagonist to a patient results in a change from baseline in resting respiratory rate, e.g., a decrease or increase in respiratory rate. In certain exemplary embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in resting respiratory rate compared to the resting respiratory rate before administration of the IL-4R antagonist.

[0146] Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index (BODE) index. According to certain embodiments, administration of IL-4R antagonists to patients results in an improvement from baseline in the BODE index score, and this improvement from baseline is a decrease in the BODE index score. In some embodiments, administration of IL-4R antagonists to patients results in a decrease from baseline of more than 1 point in the BODE index score. The BODE index is a composite scale consisting of performance outcome measures, patient-reported outcome measures, and biomarkers. The BODE index is a multidimensional scoring system for assessing the respiratory and systemic manifestations of COPD (Celli et al. “The Body-mass Index, Airflow obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease” N Engl J Med. 2004 Mar 4;350(10):1005-12). This includes four domains: 1) the degree of lung damage (FEV1), 2) the patient's perception of symptoms (mMRC), and two independent domains: 6-minute walk distance (6MWD) and body mass index (BMI). Each domain can be scored independently, with a global score ranging from 0 to 10, where a higher score indicates a higher risk of death.

[0147] Treatment methods are provided that result in a reduction from baseline in the BODE score. For example, administration of an IL-4R antagonist to a patient requiring it results in a reduction of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points from baseline in the BODE score.

[0148] COPD Assessment Test (CAT) score. According to certain embodiments, administration of IL-4R antagonists to patients results in a decrease in the CAT score from baseline. Anti-IL-4R antagonists are provided for use in patients to reduce their CAT score from baseline. The CAT is a questionnaire designed to measure the impact of the disease on the quality of life in patients with COPD. The CAT is an eight-item self-administered questionnaire developed for use in routine clinical practice to measure the health status of patients with COPD. The CAT score ranges from 0 to 40, with higher scores indicating a greater impact on health status. The test concerns cough, sputum, chest tightness, dyspnea, activity limitations, confidence, sleep, and energy. Patients score the questions on a scale of 1 to 5 according to their own feelings about the disease (1 = I am very happy, 5 = I am very sad).

[0149] Treatment methods are provided that result in a decrease from baseline in the CAT score. For example, administration of an IL-4R antagonist to a subject requiring it results in a decrease of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 points from baseline in the CAT score.

[0150] The St. George's Respiratory Questionnaire (SGRQ). According to certain embodiments, administration of IL-4R antagonists to patients results in a reduction of the SGRQ score from baseline. Anti-IL-4R antagonists are provided for use in patients to reduce the SGRQ score from baseline. The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire designed to measure and quantify the health status of adult patients with chronic airflow limitation (see Jones et al. “The St George's Respiratory Questionnaire” Respir Med. 1991 Sep;85 Suppl B:25-31;discussion 33-7). The global score ranges from 0 to 100. Scores for each item (dimension) are calculated for three domains: symptoms, activities and impacts (psychosocial), and the total score. A lower score indicates a better quality of life (QoL).

[0151] The first part ("Symptoms") assesses relative symptoms, including the frequency and severity of cough, sputum production, wheezing, and shortness of breath, as well as the duration and frequency of shortness of breath or wheezing episodes. The second part has two components: "Activities" and "Impact." The "Activities" section addresses impairments to the patient's daily physical activity. The "Impact" section covers a wide range of impacts that the chest disease may have on the patient's daily living and psychosocial functioning (e.g., activities and functions of daily living, work, physical functioning, emotional impact, discrimination, and the patient's perception during treatment). The recall period for the questionnaire is the past four weeks.

[0152] The psychometric test has demonstrated reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. The minimum change in a 4-unit score has been established as clinically relevant after examination of both the patient and the clinician. The SGRQ is used in a variety of disease groups, including asthma, COPD, and bronchiectasis.

[0153] Treatment methods are provided that result in a reduction from baseline in the SGRQ score. For example, administration of an IL-4R antagonist to subjects requiring it results in a reduction of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 5 from baseline. Causes a decrease in the SGRQ score of 0, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0154] Chronic Obstructive Pulmonary Disease Exacerbation Tool (EXACT). According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the EXACT score from baseline. An IL-4R antagonist is provided for use in patients to reduce the EXACT score from baseline. The EXACT tool quantifies and measures COPD exacerbations and assesses the signs of symptoms of these COPD exacerbations. This means is a diary consisting of a total of 14 items representing the following domains: shortness of breath (5 items), cough and sputum (2 items), chest symptoms (3 items), difficulty in coughing (1 item), fatigue or weakness (1 item), sleep disturbance (1 item), and anxiety or worry (1 item). The development and validation history of the tool is consistent with the guidelines proposed by the FDA, EMA, and well-known measurement principles. The total EXACT score assesses COPD exacerbations. A higher score indicates more severe symptoms.

[0155] Assessment of respiratory symptoms in COPD (E-RS:COPD). According to certain embodiments, administration of IL-4R antagonists to patients results in a reduction of the E-RS:COPD score from baseline. IL-4R antagonists are provided for use in patients to reduce the E-RS:COPD score from baseline. The E-RS:COPD scale is part of the EXACT tool. It is a derivative used to measure the effect of treatment on the severity of respiratory symptoms in stable COPD. E-RS utilizes 11 respiratory symptom items included in the 14-item EXACT. The RS-Total score represents the overall severity of respiratory symptoms. Three subscales can be used to assess: 1) shortness of breath (RS-Shortness of Breath), 2) cough and sputum (RS-Cough and Sputum), and 3) chest-related symptoms (RS-Chest Symptoms). A higher score indicates more severe symptoms.

[0156] Euroqol-5 items (EQ-5D): According to certain embodiments, administration of IL-4R antagonists to patients results in an increase from baseline in the EQ-5D. IL-4R antagonists are provided for use in patients to increase their EQ-5D score from baseline. The Euroqol-5 items (EQ-5D) are a standardized PRO scale of health status developed by the EuroQol Group to provide a simple and common measure of health for clinical and economic assessment. The adult version of the questionnaire is adapted for patients aged 16 years and older. The EQ-5D consists of two parts: a descriptive questionnaire and the EQ Visual Analog Scale (EQ VAS). The EQ-5D 5L descriptive questionnaire consists of the following five dimensions: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each aspect has the following five levels of perceived problem: "no problem," "mild problem," "moderate problem," "severe problem," and "incapacitation." (See Herdman M, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual. Life Res. 2011;20(10):1727-36). Respondents are asked to indicate their health status by checking (or marking with an "X") the most appropriate statement for each of the five items. This yields a single-digit number representing the level of that item. The five numbers can be combined with a five-digit number describing the respondent's health status. The EQ VAS records the respondent's self-reported health status in a vertical VAS, in which case the endpoints are labeled "best possible health status (100)" and "worst possible health status (0)". This information can be used as a quantitative measure of health outcomes as judged by individual respondents.

[0157] Treatment methods are provided that result in an increase in EQ VAS score from baseline. For example, administration of an IL-4R antagonist to a subject requiring it is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 5 Causes an increase in the EQ VAS score from a baseline of 0, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0158] Medical Research Council (MRC) Dyspnea Scale. According to certain embodiments, administration of an IL-4R antagonist to a patient results in the patient reporting a better health status on the Medical Research Council (MRC) Dyspnea Scale. The IL-4R antagonist is provided for use in patients to enable them to report a better health status on the Medical Research Council (MRC) Dyspnea Scale. (See Bestall et al. “Usefulness of the Medical Research Council (MRC) Dyspnea Scale as a Measure of Disability in Patients with Chronic Obstructive Pulmonary Disease” Thorax 1999;54:581-586).

[0159] The Modified British Medical Research Council Questionnaire (mMRC). According to certain embodiments, administration of IL-4R antagonists to patients results in patients reporting improved health status on the Modified British Medical Research Council Questionnaire (mMRC). IL-4R antagonists are provided for use in patients to enable them to report better health status on the Modified British Medical Research Council Questionnaire (mMRC). The Modified British Medical Research Council Questionnaire (mMRC) is a questionnaire for assessing shortness of breath (Fletcher et al. Standardized questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960;2:1662).

[0160] Health-related quality of life (HRQoL) questionnaire. According to certain embodiments, administration of IL-4R antagonists to patients results in patients reporting better health status on the Health-Related Quality of Life (HRQoL) questionnaire. The Centers for Disease Control and Prevention (CDC) Healthy Days Measurement Program (Centers for Disease Control and Prevention, Atlanta, Georgia, November 2000) is available on the website: cdc.gov / hrqol / pdfs / mhd.pdf. IL-4R antagonists are provided for use in patients to enable them to report better health status on the HRQoL questionnaire.

[0161] Clinical symptoms of COPD exacerbations. According to certain embodiments, administration of IL-4R antagonists to patients results in a reduction of clinical symptoms of COPD exacerbations from baseline. IL-4R antagonists are provided for use in patients to reduce clinical symptoms of COPD exacerbations from baseline. Clinical symptoms of COPD exacerbations may include, but are not limited to, dyspnea, increased wheezing, increased cough, increased sputum volume, and / or increased purulent sputum.

[0162] Biomarkers. In certain embodiments, the subject experiences an improvement in lung function as measured by a biomarker. In certain exemplary embodiments, the subject experiences an increase in biomarker levels (compared to biomarker levels before administration of the IL-4R antagonist) after administration of an IL-4R antagonist. In certain exemplary embodiments, the subject experiences a decrease in biomarker levels (compared to biomarker levels before administration of an anti-IL-4R antagonist) after administration of an IL-4R antagonist. In certain exemplary embodiments, the subject experiences normalization of one or more biomarkers (compared to the expression levels of biomarkers before administration of an anti-IL-4R antagonist) after administration of an IL-4R antagonist. For example, biomarkers may be selected from the group consisting of lung and activation-regulated chemokines (PARCs), eotaxin-3, fibrinogen, IgE, sputum or blood eosinophils, sputum or blood neutrophils, exhaled nitric oxide concentration (FeNO), IL-4Rα, IL-4, IL-13, IL-33, serum periostin, calcium-activated chloride channel modulator (CLCA1), cystatin-SN (CST1), tumorigenesis inhibitor 2 (ST2), thymic stromal lymphocyte generating factor (TSLP), etc. In certain embodiments, whole blood mRNA samples are obtained for sequencing or whole transcriptome analysis. In certain embodiments, serum and / or plasma samples are obtained and optionally stored for exploratory biomarker studies of disease or drug effects. In certain embodiments, the samples are used in studies to develop methods, assays, prognoses, and / or companion diagnostics related to IL-4R, disease processes, disease state-related pathways, and / or the mechanism of action of the experimental intervention. In certain embodiments, improvement in lung function is indicated by a (reasonable) reduction or increase in biomarkers at 4, 12, or 24 weeks post-treatment.

[0163] In some embodiments, one or more conditions or complications associated with COPD, or comorbidities with COPD such as type 2 inflammatory conditions, e.g., asthma, chronic sinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), integrated airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), allergic conjunctivitis, atopic conjunctivitis, atopic dermatitis, vasculitis, cystic gland Methods are provided for treating or alleviating one or more of the following conditions: vascular disease (CF), chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), chronic sinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID hypersensitivity respiratory disease or NSAID-ERD), perennial allergic rhinitis (PAR), atopic dermatitis (AD), food allergies, hives or urticaria, chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm.

[0164] In some embodiments, methods are provided for treating or alleviating one or more conditions or complications associated with COPD, or comorbidities with COPD, such as pulmonary artery disease, coronary heart disease, heart failure, endothelial dysfunction, blood coagulation disorders, systemic thromboembolism, hypertension, metabolic syndrome, diabetes mellitus, dyslipidemia, anemia, arthritis, osteoporosis, muscle weakness (e.g., musculoskeletal dysfunction), gastroesophageal reflux, gastrointestinal disorders, sleep disorders, obstructive sleep apnea syndrome (OSAS), malnutrition, anemia, obesity, mental disturbances (e.g., anxiety, depression, cognitive impairment), malignant tumors (e.g., lung cancer), pulmonary fibrosis, pulmonary embolism, pneumonia, etc.

[0165] In some embodiments, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain CDR sequences, each containing SEQ ID NOs: 3, 4, and 5, and three light chain CDR sequences, each containing SEQ ID NOs: 6, 7, and 8.

[0166] Methods to treat COPD In some embodiments, methods are provided for treating COPD, including moderate to severe COPD and / or COPD with type 2 inflammation, in subjects requiring such treatment, the method comprising administering a pharmaceutical composition comprising an IL-4R antagonist. In certain embodiments, the method is useful for treating moderate to severe COPD in subjects. In certain embodiments, the method is useful for treating COPD with type 2 inflammation in subjects. In certain embodiments, the method is useful for treating moderate to severe COPD with type 2 inflammation in subjects. In certain embodiments, the method is useful for reducing one or more AECOPD events. Pharmaceutical compositions comprising an IL-4R antagonist are provided for treating COPD, including moderate to severe COPD and / or COPD with type 2 inflammation, in subjects requiring such treatment. Pharmaceutical compositions comprising an IL-4R antagonist are provided to reduce one or more AECOPD events in patients.

[0167] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting type 2 inflammation, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, type 2 inflammatory COPD is driven by activation of IL-4, IL-5, and / or IL-13. In some embodiments, type 2 inflammatory COPD is driven by elevated levels of eosinophils. In some embodiments, type 2 inflammatory COPD is driven by elevated levels of neutrophils. In some embodiments, patients with type 2 inflammation exhibit blood eosinophil levels of 300 cells or more per microliter.

[0168] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of 300 cells or more per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of 300 cells or more per microliter.

[0169] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of 250 cells or more per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of 250 cells or more per microliter.

[0170] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of 300 cells or more per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of 300 cells or more per microliter.

[0171] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of 500 cells or more per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of 500 cells or more per microliter.

[0172] In one embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of less than 300 cells per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of less than 300 cells per microliter.

[0173] In another embodiment, a method for treating COPD is provided, comprising (a) selecting a patient exhibiting a blood eosinophil level of 150 to 299 cells per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient exhibits a blood eosinophil level of 150 to 299 cells per microliter.

[0174] In another embodiment, a method is provided for treating COPD, comprising (a) selecting a patient having a blood eosinophil level of less than 150 cells per microliter, and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. In one embodiment of the composition for use, the patient has a blood eosinophil level of less than 150 cells per microliter.

[0175] In relevant embodiments, methods for treating COPD are provided, including add-on therapy to background therapy. In relevant embodiments, IL-4R antagonists are provided for use in treating COPD in patients, the IL-4R antagonists being used as add-on therapy to background therapy. In certain embodiments, the IL-4R antagonist is administered as add-on therapy to COPD patients who are receiving background therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months or more) (also called the “stable period”).

[0176] COPD background therapy includes: (1) short-acting beta-2 agonists such as SABAs (e.g., fenoterol, revalbuterol, salbutamol, and terbutaline) or long-acting beta-2 agonists such as LABAs (e.g., alformoterol, formoterol, indacaterol, olodaterol, and salmeterol); (2) anticholinergics such as short-acting anticholinergics (SAMAs, e.g., ipratropium bromide, oxytropium bromide) or long-acting anticholinergics (LAMAs, e.g., aclidinium bromide, glycopyrronium bromide, tiotropum, umeclidinium, glycopyrrolate, and rebefenacin); (3) combinations of SABA and SAMA (e.g., fenoterol + ipratropium or salbutamol + ipratropium); (4) combinations of LABA and LAMA (formoterol + aclidinium, formoterol + glycopyrronium, indacaterol + (5) Glycopyrronium, vilanterol + umeclidinium and orodaterol + tiotropium), (6) Methylxanthines (e.g., aminophylline and theophylline), (7) Combinations of LABA and corticosteroids (e.g., formoterol + beclomethasone, formoterol + budesonide, formoterol + mometasone, salmeterol + fluticasone propionate, vilanterol + fluticasone furoate), (8) Triple combination (e.g., flu (1) A combination of LABA+LAMA+ICS such as ticasone + umeclidinium + vilanterol, beclomethasone + formoterol + glycopyrronium, budesodin + formoterol + glycopyrrolate, (2) a phosphodiesterase inhibitor (e.g., a phosphodiesterase-4 inhibitor such as roflumilast), (3) a mucolytic agent (e.g., erdosteine, katobosisterin, and N-acetylcisterin), or any combination thereof, selected from the group.

[0177] In some embodiments, the subject receives at least one non-pharmacological therapy, including but not limited to cessation of smoking, lung rehabilitation, long-term oxygen therapy, non-invasive positive pressure ventilation, and lung volume reduction surgery.

[0178] In exemplary embodiments, background therapy includes LABA, LAMA, and ICS. In other exemplary embodiments, background therapy includes LABA and LAMA, and ICS is contraindicated.

[0179] In some embodiments, the present disclosure includes a method for reducing the dependence of a COPD patient on one or more LABAs, LAMAs, and ICSs for the treatment of one or more COPD exacerbations, comprising (a) selecting a patient having moderate to severe COPD that is not adequately controlled with background therapy including LABAs, LAMAs, and ICSs, and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients having moderate to severe COPD that is not adequately controlled with background COPD therapy including LABAs, LAMAs, and ICSs or a combination thereof, to reduce the dependence of a COPD patient on one or more ICSs, LAMAs, and LABAs for the treatment of one or more COPD exacerbations.

[0180] In some embodiments, the present disclosure includes a method for reducing the dependence of COPD patients on one or more LABAs, LAMAs, and ICS for the treatment of one or more COPD exacerbations, comprising (a) selecting patients with COPD with type 2 inflammation that is not adequately controlled with background therapy comprising LABAs, LAMAs, and ICS, and administering a pharmaceutical composition comprising an IL-4R antagonist to the patients. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients with COPD with type 2 inflammation that is not adequately controlled with background COPD therapy comprising LABAs, LAMAs, and ICS or a combination thereof, to reduce the dependence of COPD patients on one or more ICSs, LAMAs, and LABAs for the treatment of one or more COPD exacerbations.

[0181] In some embodiments, the present disclosure includes a method for reducing the dependence of COPD patients on one or more LABAs, LAMAs, and ICS for the treatment of one or more COPD exacerbations, comprising (a) selecting patients with moderate to severe COPD with type 2 inflammation that is not adequately controlled with background therapy including LABAs, LAMAs, and ICS, and administering a pharmaceutical composition comprising an IL-4R antagonist to the patients. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients with moderate to severe COPD with type 2 inflammation that is not adequately controlled with background COPD therapy including LABAs, LAMAs, and ICS or a combination thereof, to reduce the dependence of COPD patients on one or more ICSs, LAMAs, and LABAs for the treatment of one or more COPD exacerbations.

[0182] In some embodiments, the present disclosure includes a method for reducing a COPD patient's dependence on one or both LABAs and LAMAs for the treatment of one or more COPD exacerbations, comprising (a) selecting a patient having moderate to severe COPD that is not adequately controlled with background therapy including LABAs and LAMAs, and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients having moderate to severe COPD that is not adequately controlled with background COPD therapy including LABAs and LAMAs or a combination thereof, to reduce a COPD patient's dependence on one or both LAMAs and LABAs for the treatment of one or more COPD exacerbations.

[0183] In some embodiments, the present disclosure includes a method for reducing the dependence of COPD patients on one or both LABAs and LAMAs for the treatment of one or more COPD exacerbations, comprising (a) selecting patients with COPD with type 2 inflammation that is not adequately controlled with background therapy including LABAs and LAMAs, and administering a pharmaceutical composition comprising an IL-4R antagonist to the patients. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients with COPD with type 2 inflammation that is not adequately controlled with background COPD therapy including LABAs and LAMAs or a combination thereof, to reduce the dependence of COPD patients on one or both LAMAs and LABAs for the treatment of one or more COPD exacerbations.

[0184] In some embodiments, the present disclosure includes a method for reducing the dependence of a COPD patient on one or both LABAs and LAMAs for the treatment of one or more COPD exacerbations, comprising (a) selecting a patient having moderate to severe COPD with type 2 inflammation that is not adequately controlled with background therapy including LABAs and LAMAs, and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition comprising an IL-4R antagonist is provided for use in patients having moderate to severe COPD with type 2 inflammation that is not adequately controlled with background COPD therapy including LABAs and LAMAs or a combination thereof, to reduce the dependence of a COPD patient on one or both LAMAs and LABAs for the treatment of one or more COPD exacerbations.

[0185] In some embodiments, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain CDR sequences, each containing SEQ ID NOs: 3, 4, and 5, and three light chain CDR sequences, each containing SEQ ID NOs: 6, 7, and 8.

[0186] In some embodiments, the methods disclosed herein provide one or more of the following advantages to the treated object: (1) A statistically significant and clinically meaningful reduction in the annual rate of moderate to severe exacerbations, such as a relative risk reduction rate (RRR) of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%. (2) Rapid and sustained improvement in lung function, such as improvement at 2, 3, 5, 6, 7, 8, 9, 10, 11 or 12 weeks after the initial dose (this lasts for at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 104 weeks, at least 130 weeks, at least 156 weeks or more). In some embodiments, subjects have an improvement in FEV1 of at least +10 ml, at least +20 ml, at least +30 ml, at least +40 ml, at least +50 ml, at least +60 ml, at least +70 ml, at least +80 ml, at least +90 ml, at least +100 ml or more. (3) Consistently higher benefits in subjects with FeNO levels ≥ 20 ppb. Such benefits may include reduced exacerbations and improved FEV1. (4) Rapid and sustained improvement in health-related quality of life questionnaire scores. In some embodiments, improvement is measured by the SGRQ score. (In some embodiments, the SGRQ score in the treated subject is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or more lower than that of the placebo group. In some embodiments, the improvement in the SGRQ score in the treated subject is at least 1, at least 2, at least 3, at least 4, at least 5 or more compared to the untreated baseline.) (5) Rapid and sustained improvement of overall symptoms (shortness of breath, cough / sputum, chest). (In some embodiments, improvement is measured by the ERS-COPD score. In some embodiments, the ERS-COPD score in the treated subject is at least 0.2, at least 0.4, at least 0.6, at least 0.8, at least 1.0, at least 1.1, at least 1.2 lower than that of the placebo group), and (6) Benefits observed across multiple subgroups of demographic, clinical, and biomarker subgroups.

[0187] Interleukin-4 receptor antagonists The methods described herein involve administering a therapeutic composition comprising an IL-4R antagonist to a subject requiring such treatment. As used herein, “IL-4R antagonist” is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on cells in vitro or in vivo. Non-limiting examples of the category of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., “peptibody” molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, the IL-4R antagonist includes anti-IL-4R antibodies that may be used in connection with methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically binds to IL-4R, and includes heavy chain and light chain (complementarity-determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs. 1 and 2, respectively.

[0188] The term "human IL4R" (hIL-4R) refers to human cytokine receptors that specifically bind to interleukin-4 (IL-4), such as IL-4Rα.

[0189] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains, and two light (L) chains interconnected by disulfide bonds, and their polymers (e.g., IgM). Each heavy chain has a heavy chain variable region (HCVR or V in this specification). H It includes the heavy chain constant region (abbreviated as C). The heavy chain constant region consists of three domains, C H 1. C H 2 and C H Includes 3. Each light chain has a light chain variable region (LCVR or V in this specification). L(abbreviated as) 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) in which more conserved regions called framework regions (FRs) are interspersed. Each V H and V L is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) can be identical to the human germline sequence or can be naturally or artificially modified. The amino acid consensus sequence can be defined based on the parallel analysis of two or more CDRs.

[0190] The term "antibody" also includes antigen-binding fragments of a complete antibody molecule. As used herein, terms such as "antigen-binding portion of an antibody", "antigen-binding fragment of an antibody", etc. include any naturally occurring, enzymatically obtained, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived from a complete antibody molecule using any suitable standard technique such as proteolytic digestion or recombinant genetic engineering techniques including, for example, the manipulation and expression of DNA encoding the antibody variable domain and optionally the constant domain. Such DNA is known and / or can be readily obtained, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries) or can be synthesized. The DNA can be sequenced and manipulated using chemical or molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains in a suitable configuration or for the introduction of codons, creation of cysteine residues, modification, addition or deletion of amino acids.

[0191] 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) the hypervariable regions of antibodies (e.g., minimal recognition units consisting of amino acid residues mimicking isolated complementarity-determining regions (CDRs) such as the CDR3 peptide or restrictive FR3-CDR3-FR4 peptides). Other manipulated molecules such as domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small module immunotherapies (SMIPs), and shark variable IgNAR domains are also included in the expression “antigen-binding fragment.”

[0192] The antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. L V bound to the domain H In antigen-binding fragments having a domain, V H Domain and V L Domains can be located relative to each other in any suitable arrangement. For example, a variable region can be a dimer, V H -V H , V H -V L or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may contain monomer V H or V L It may contain a domain.

[0193] In certain embodiments, the antigen-binding fragment of an antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of an antibody described herein include: (i)V H -CH 1. (ii)V H -C H 2, (iii)V H -C H 3, (iv)V H -C H 1-C H 2. (v)V H -C H 1-C H 2-C H 3. (vi)V H -C H 2-C H 3. (vii)V H -C L (viii)V L -C H 1. (ix)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 configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or 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, resulting in a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule, and typically the hinge region may consist of 2 to 60 amino acids, typically 5 to 50, or typically 10 to 40 amino acids. Furthermore, the antigen-binding fragments of the antibodies described herein may be linked to each other and / or one or more monomers V H or V LIt may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above, associated non-covalently with a domain (e.g., by a disulfide bond).

[0194] Similar to full antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each of which can specifically bind to a distinct antigen or a different epitope 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 routine techniques available in the art.

[0195] The constant region of an antibody is important in 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.

[0196] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies described herein may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or somatic mutations in vivo), for example, in the CDRs, particularly in 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.

[0197] The term "recombinant human antibody" includes all human antibodies prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (as further described below), antibodies isolated from a recombinant combinatorial human antibody library (as further described below), antibodies isolated from animals transgenic for human immunoglobulin genes (e.g., mice) (see, e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created or isolated by any other means, including splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if transgenic animals for human Ig sequences are used), and therefore the V of the recombinant antibody H Region and V L The amino acid sequence of the region is human germline V H Array and V L This sequence is derived from a sequence that cannot naturally exist in the human antibody germline repertoire in vivo.

[0198] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable quad-chain construct of approximately 150–160 kDa, where the dimers are held together by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, and the molecule of approximately 75–80 kDa consists of covalently bonded light and heavy chains (half-antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0199] The frequency of occurrence of the second form in various intact IgG isotypes is attributed, to a limited extent, to structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level typically observed using the human IgG1 hinge. H 2 or C H Antibodies having one or more mutations in three regions are provided, which may be desirable, for example, in manufacturing to improve the yield of the desired antibody form.

[0200] "Isolated antibody" means an antibody identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody isolated or removed from tissue or cells in which at least one component of an organism or antibody is naturally present or naturally produced is an "isolated antibody." Isolated antibodies also include in situ antibodies within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody may substantially contain no other cellular material and / or chemical substances.

[0201] Terms such as "specifically bind" mean that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, antibodies that "specifically bind" to IL-4R may have K levels less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or less than approximately 0.5 nM when measured by a surface plasmon resonance assay. DThis includes antibodies that bind to IL-4R or a portion thereof. However, isolated antibodies that specifically bind to human IL-4R may exhibit cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0202] Anti-IL-4R antibodies useful for this method may contain 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 region and / or CDR region of the heavy chain variable domain and light chain variable domain, compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be easily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from publicly available antibody sequence databases. A method is provided comprising the use of antibodies and antigen-binding fragments derived from any of the amino acid sequences disclosed herein, in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 with respect to a tetrameric antibody, or 1, 2, 3, 4, 5, or 6 with respect to the HCVR and LCVR of the antibody) within the CDR region are mutated to a corresponding residue in the germline sequence from which the antibody is derived, or a corresponding residue in another human germline sequence, or a conserved amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as “germline mutations”). Those skilled in the art can readily produce a number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof, starting from the heavy chain variable region sequences and light chain variable region sequences disclosed herein. In certain embodiments, V H and / or V LIn other embodiments, all of the framework and / or CDR residues within the domain are mutated back to residues found in the original germline sequence from which the antibody originated. In other embodiments, only specific residues, for example, only mutant residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutant residues found in CDR1, CDR2, or CDR3 are mutated back to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody originally originated). Furthermore, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, certain individual residues are mutated to corresponding residues in a particular germline sequence, while certain other residues different from the original germline sequence are maintained or mutated to corresponding residues in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, (optionally) improved or enhanced biological properties of an antagonist or agonist, or decreased immunogenicity. The use of antibodies and antigen-binding fragments obtained in this general manner is encompassed in this disclosure.

[0203] Methods involving the use of anti-IL-4R antibodies 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 use of anti-IL-4R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, or 4 or fewer conservative amino acid substitutions compared to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein is provided.

[0204] The term "surface plasmon resonance" refers to an optical phenomenon that enables real-time interaction analysis by detecting changes in protein concentration within a biosensor matrix, for example, using the BIAcore® system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0205] "K D The term "equilibrium dissociation constant" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0206] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule, known as a paratope. A single antigen may have two or more epitopes. Therefore, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes can be either conformal or linear. Conformal epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include sugar, phosphoryl, or sulfonyl groups on an antigen.

[0207] The terms “substantially identical” or “substantially identical” when referring to nucleic acids or fragments thereof indicate that, when optimally aligned with another nucleic acid (or its complementary strand) with appropriate nucleotide insertions or deletions, there is nucleotide sequence identity in at least about 95% or at least about 96%, 97%, 98%, or 99% of the nucleotide bases, as measured by any well-known sequence identity algorithm such as FASTA, BLAST, or Gap, as discussed below.

[0208] When applied to polypeptides, the terms “substantial similarity” or “substantially identical” mean that two peptide sequences share at least 95% sequence identity or at least 98% or 99% sequence identity when optimally aligned by a program such as GAP or BESTFIT using default gap weights. In exemplary embodiments, non-identical residue positions differ due to conservative amino acid substitutions. A “conservative amino acid substitution” is when one amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of the protein. If two or more amino acid sequences differ from each other due to conservative substitutions, the degree of percent sequence identity or similarity can be adjusted upward to compensate for the conservative nature of the substitutions. Means for making this adjustment are well known to those skilled in the art. (See, for example, Pearson (1994) Methods Mol. Biol. 24:307-331, incorporated herein by reference). Examples of amino acids with side chains having similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains: cysteine ​​and methionine. Exemplary conserved amino acid substituents are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Instead, a conservative permutation is any change that has a positive value in the PAM250 log-likelihood matrix, as disclosed in Gonnet et al. (1992) Science 256:1443 45, which is incorporated herein by reference. A “moderately conservative” permutation is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0209] Sequence similarity of polypeptides, also known as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using similarity measures assigned to various substitutions, deletions, and other modifications, including conserved amino acid substitutions. For example, GCG software includes programs such as Gap and Bestfit, which, along with default parameters, can be used to determine sequence homology or sequence identity between closely related polypeptides, e.g., homologous polypeptides from different species or between a wild-type protein and its mutaine. (See, e.g., GCG version 6.1). Polypeptide sequences can also be compared using FASTA, a program in GCG version 6.1, with default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignment and percent sequence identity of the best overlap region between the query sequence and the search sequence (Pearson (2000), cited above). Another exemplary algorithm for comparing the sequences of this disclosure with a database containing numerous sequences from different organisms is the computer program BLAST, in particular BLASTP or TBLASTN, using default parameters. (For example, see Altschul et al. (1990) J.Mol.Biol.215:403-410 and Altschul et al. (1997) Nucleic Acids Res.25:3389-402, each of which is incorporated herein by reference.)

[0210] Preparation of human antibodies Methods for producing human antibodies in transgenic mice are known in the art. Using any such known method, human antibodies that specifically bind to human IL-4R can be produced.

[0211] A high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region is initially isolated using VELOCIMMUNE® technology (see, for example, U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies. VELOCIMMUNE® technology involves the creation of a transgenic mouse having a genome containing a human heavy chain variable region and a human light chain variable region operably ligated to an endogenous mouse constant region locus, so that the mouse produces an antibody containing the human variable region and the mouse constant region in response to antigen stimulation. The DNA encoding the variable regions of the antibody's heavy chain and light chain is isolated and operably ligated to the DNA encoding the human heavy chain and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0212] Generally, VELOCIMMUNE® mice are loaded with the target antigen, and lymphocytes (such as B cells) are collected from mice that express the antibody. Immortal hybridoma cell lines can be prepared by fusing these lymphocytes with myeloma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains can be isolated and ligated to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced intracellularly, such as in CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0213] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for desirable features, including affinity, selectivity, and epitope, using standard procedures known to those skilled in the art. The mouse constant region is replaced with a desired human constant region to produce the fully human antibody described herein, e.g., wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the specific application, but the high-affinity antigen-binding and target specificity features reside in the variable region.

[0214] Generally, antibodies that can be used in the methods described herein have high affinity, as described above, when measured by binding to an antigen immobilized on either a solid or solution phase. The mouse constant region is replaced with a desired human constant region to produce the fully human antibodies described herein. The selected constant region may vary depending on the specific application, but the high affinity antigen binding and target specificity characteristics reside in the variable region.

[0215] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the context of the method described herein comprises three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may also comprise three light-chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that may be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. 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 identifying CDR sequences within antibodies.

[0216] In certain embodiments, the antibody or its antigen-binding fragment comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain variable region amino acid sequence pair and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs. 1 and 2.

[0217] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NO: 3 / 4 / 5 / 6 / 7 / 8.

[0218] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pairs of SEQ ID NO: 1 and 2.

[0219] In certain embodiments, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pairs of SEQ ID NO: 1 and 2.

[0220] In certain embodiments, the antibody sequence is dupilumab, which comprises the heavy chain / light chain amino acid sequence pairs of SEQ ID NO: 9 and 10.

[0221] Dupilumab HCVR amino acid sequence:

Chemical Structure

Chemical Structure

Chemical Structure

[0222] In a specific embodiment, the antibody of the disclosure or the antigen binding fragment is the SCB-VL-39 / SCB-VH-92、SCB-VL-40 / SCB-VH-92、SCB-VL-41 / SCB-VH-92、SCB-VL-42 / SCB-VH-92、SCB-VL-43 / SCB-V H-92、SCB-VL-44 / SCB-VH-92、SCB-VL-44 / SCB-VH-62、SCB-VL-44 / SCB-VH-68、SCB-VL-44 / SCB-VH-72、SCB-VL-44 / SCB-VH-82、SCB-VL-44 / SCB-VH-85 、SCB-VL-44 / SCB-VH-91、SCB-VL-44 / SCB-VH-93、SCB-VL-45 / SCB-VH-92、SCB-VL-46 / SCB-VH-92、SCB-VL-47 / SCB-VH-92、SCB-VL-48 / SCB-VH-92、SCB-VL-48 / SCB-VH-92 B-VL-49 / SCB-VH-92、SCB-VL-50 / SCB-VH-92、SCB-VL-51 / SCB-VH-92、SCB-VL-51 / SCB-VH-93、SCB-VL-52 / SCB-VH-92、SCB-VL-52 / SCB-VH-62、SCB-VL -52 / SCB-VH-91、SCB-VL-53 / SCB-VH-92、SCB-VL-54 / SCB-VH-92、SCB-VL-54 / SCB-VH-62、SCB-VL-54 / SCB-VH-68、SCB-VL-54 / SCB-VH-72、SCB-VL-54 / SCB-VH-82、SCB-VL-54 / SCB-VH-85、SCB-VL-54 / SCB-VH-91、SCB-VL-55 / SCB-VH-92、SCB-VL-55 / SCB-VH-62、SCB-VL-55 / SCB-VH-68、SCB-VL-55 / SCB -VH-72、SCB-VL-55 / SCB-VH-82、SCB-VL-55 / SCB-VH-85、SCB-VL-55 / SCB-VH-91、SCB-VL-56 / SCB-VH-92、SCB-VL-57 / SCB-VH-92、SCB-VL-57 / SCB-VH-92 -93、SCB-VL-57 / SCB-VH-59、SCB-VL-57 / SCB-VH-60、SCB-VL-57 / SCB-VH-61、SCB-VL-57 / SCB-VH-62、SCB-VL-57 / SCB-VH-63、SCB-VL-57 / SCB-VH-64、SCB-VL-57 / SCB-VH-65, SCB-VL-57 / SCB-VH-66, SCB-VL-57 / SCB-VH-67, SCB-VL-57 / SCB-VH-68, SC B-VL-57 / SCB-VH-69, SCB-VL-57 / SCB-VH-70, SCB-VL-57 / SCB-VH-71, SCB-VL-57 / SCB-VH-72, SCB- VL-57 / SCB-VH-73, SCB-VL-57 / SCB-VH-74, SCB-VL-57 / SCB-VH-75, SCB-VL-57 / SCB-VH-76, SCB-VL -57 / SCB-VH-77, SCB-VL-57 / SCB-VH-78, SCB-VL-57 / SCB-VH-79, SCB-VL-57 / SCB-VH-80, SCB-VL-5 7 / SCB-VH-81, SCB-VL-57 / SCB-VH-82, SCB-VL-57 / SCB-VH-83, SCB-VL-57 / SCB-VH-84, SCB-VL-57 / SCB-VH-85, SCB-VL-57 / SCB-VH-86, SCB-VL-57 / SCB-VH-87, SCB-VL-57 / SCB-VH-88, SCB-VL-57 / SC It includes a light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of B-VH-89, SCB-VL-57 / SCB-VH-90, SCB-VL-57 / SCB-VH-91, SCB-VL-58 / SCB-VH-91, SCB-VL-58 / SCB-VH-92, and SCB-VL-58 / SCB-VH-93.

[0223] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-44 / SCB-VH-92.

[0224] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-54 / SCB-VH-92.

[0225] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-55 / SCB-VH-92.

[0226] In certain embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR including the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR including the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-55-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0227] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises an HCVR including the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR including the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0228] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises an HCVR including the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR including the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-44-LCDR3.

[0229] The antibodies listed in Table 1 below are described in detail in U.S. Patent No. 10,774,141, which is incorporated herein by reference in its entirety for all purposes.

[0230] [Table 1]

[0231] [Table 2]

[0232] [Table 3]

[0233] [Table 4]

[0234] [Table 5]

[0235] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises a light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of MEDI-1-VL / MEDI-1-VH to MEDI-42-VL / MEDI-42-VH.

[0236] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the LCVR / HCVR sequence pair of MEDI-37GL-VL / MEDI-37GL-VH.

[0237] In certain embodiments, the antibody or antigen-binding fragment of the Disclosure comprises an HCVR including the HCDR1 sequence of MEDI-37GL-HCDR1, the HCDR2 sequence of MEDI-37GL-HCDR2, and the HCDR3 sequence of MEDI-37GL-HCDR3, and an LCVR including the LCDR1 of MEDI-37GL-LCDR1, the LCDR2 of MEDI-37GL-LCDR2, and the LCDR3 of MEDI-37GL-LCDR3.

[0238] The antibodies listed in Table 2 below are described in detail in U.S. Patent No. 8,877,189, which is incorporated herein by reference in its entirety for all purposes.

[0239] [Table 6]

[0240] [Table 7]

[0241] [Table 8]

[0242] [Table 9]

[0243] [Table 10]

[0244] [Table 11]

[0245] [Table 12]

[0246] In certain embodiments, the antibody or antigen-binding fragment of the present disclosure comprises the LCVR / HCVR sequence pair AJOU-90-VL / AJOU-83-VH.

[0247] In certain embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR including the HCDR1 sequence of AJOU-84-HCDR1, the CHDR2 sequence of AJOU-85-HCDR2, and the HCDR3 sequence of AJOU-32-HCDR3, and an LCVR including the LCDR1 of AJOU-96-LCDR1, the LCDR2 of AJOU-60-LCDR2, and the LCDR3 of AJOU-68-LCDR3.

[0248] The antibodies listed below in Table 3 are described in more detail in International Publication No. 2020 / 096381 and Kim et al. (Scientific Reports. 9:7772. 2019), which are incorporated herein by reference in their entirety for all purposes.

[0249] [Table 13]

[0250] [Table 14]

[0251] [Table 15]

[0252] [Table 16]

[0253] In certain embodiments, the antibody or antigen-binding fragment of the Disclosure comprises a light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of 11 / 3, 27 / 19, 43 / 35, 59 / 51, 75 / 67, 91 / 83, 107 / 99, 123 / 115, 155 / 147, and 171 / 163.

[0254] The antibodies listed in Table 4 below are described in more detail in U.S. Patent No. 7,605,237 and U.S. Patent No. 7,608,693, which are incorporated herein by reference in their entirety for all purposes.

[0255] [Table 17]

[0256] [Table 18]

[0257] The antibodies listed in Table 5 below are described in more detail in International Publication No. 2022 / 052974, which is incorporated herein by reference in its entirety for all purposes.

[0258] Table 19

[0259] Table 20

[0260] Table 21

[0261] Table 22

[0262] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure are: Y0188-1 / Y0188-1, Y0188-2 / Y0188-2, Y0188-3 / Y0188-3, Y0188-4 / Y0188-4, Y0188-6 / Y0188-6, Y0188-8 / Y0188-8, Y0188-9 / Y0188-9, Y0188-10 / Y0188-10, Y0188-14 / Y0188-14, HV3-15-14 / Y01-14, HV3-15-14 / 164-14, HV3-15-14 / KV4-14, HV3-15-14 / KV1-27-14 , HV3-15-14 / KV1-9-14, HV3-15-14 / KV1-NL1-14, HV3-15-14 / KV1D-43-14, HV3-48-14 / Y01-14, HV3-48-14 / 164-14, HV3-48-14 / KV4-14, HV3-48-14 / KV1-27-14, HV3-48-14 / KV1-9-14, HV3-48-14 / KV1-NL1-14, HV3-48-14 / KV1D-43-14, HV3-73*2-14 / Y01-14, HV3-73*2-14 / 164-14, HV3-73*2-14 / KV 4-14, HV3-73*2-14 / KV1-27-14, HV3-73*2-14 / KV1-9-14, HV3-73*2-14 / K V1-NL1-14, HV3-73*2-14 / KV1D-43-14, HV3-72-14 / Y01-14, HV3-72-14 / 16 4-14, HV3-72-14 / KV4-14, HV3-72-14 / KV1-27-14, HV3-72-14 / KV1-9-14, HV3-72-14 / KV1-NL1-14, HV3-72-14 / KV1D-43-14, Y01-14 / Y01-14, Y01-14 / 164-14, Y01-14 / KV4-14, Y01-14 / KV1-27-14, Y01-14 / KV1-9-14, Y01-14 / KV1-NL1-14, Y01-14 / KV1D-43-14, 162-14 / Y01-14, 162-14 / 164-14, 162- 14 / KV4-14, 162-14 / KV1-27-14, 162-14 / KV1-9-14, 162-14 / KV1-NL1-14, 1 62-14 / KV1D-43-1L, VH73-14 / Y01-14, VH73-14 / 164-14, VH73-14 / KV4-14,It includes heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs (HCVR / LCVR) selected from the group consisting of VH73-14 / KV1-27-14, VH73-14 / KV1-9-14, VH73-14 / KV1-NL1-14, and VH73-14 / KV1D-43-14.

[0263] The antibodies listed in Table 6 below are described in detail in International Publication No. 2021 / 213329, which is incorporated herein by reference in its entirety for all purposes.

[0264] [Table 23]

[0265] [Table 24]

[0266] [Table 25]

[0267] In certain embodiments, the antibodies or antigen-binding fragments of the present disclosure are: 1A6 VH, 1D8 VH, 1H9 VH, 2H1 VH, 2F8 VH, 9B4 VH, 9E7 VH, 24G10 VH, 25D6 VH, 25G9 VH, 31B9 VH, 34A2 VH, 34H11 VH, 35D5 VH, 35A7-1 VH, 35A7-2 VH, 36F4 VH, 1A6 VL, 1D8 VL, 1H9 VL, 2H1 VL, 2F8 VL, 9B4 VL, 9E7 VL, 24G10 VL, 25D6 VL, 25G9 VL, 31B9 VL, 34A2 VL, 34H11 VL, 35D5 VL, 35A7-1 VL, 35A7-2 It includes heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs (HCVR / LCVR) selected from the group consisting of VL, 36F4 VL, VH1021, VH1022, VH1023, VH1024, VH1025, VH1026, VH1027, VH1028, VL1011, VL1012, VL1013, and VL1014.

[0268] The antibodies listed in Table 7 below are described in more detail in U.S. Patent No. 11,725,057 B2, which is incorporated herein by reference in its entirety for all purposes.

[0269] [Table 26]

[0270] [Table 27]

[0271] [Table 28]

[0272] [Table 29]

[0273] [Table 30]

[0274] [Table 31]

[0275] Pharmaceutical composition A method is provided comprising administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained in a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other agents that provide appropriate impregnation, delivery, resistance, etc. Numerous suitable formulations can be found in the prescription book known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowaxes. See Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol. 52:238-311.

[0276] The dose of antibody administered to a patient may vary depending on the patient's age and size, symptoms, disease state, and route of administration. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted according to the severity of the disease. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically, for example, by monitoring the patient's progression through periodic assessments and adjusting the dose accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0277] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, for example, liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption via epithelial or mucosal linings (e.g., oral mucosa, rectal and intestinal mucosa), and may be administered together with other bioactive agents.

[0278] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously using standard needles and syringes. Furthermore, with respect to subcutaneous delivery, pen delivery devices (e.g., auto-injector pens) readily provide a suitable application for delivering the pharmaceutical compositions described herein. Such pen delivery devices may be reusable or disposable. Reusable pen 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. The pen delivery device can then be reused. Disposable pen delivery devices do not have replaceable cartridges. Rather, disposable pen delivery devices are pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition is depleted from the reservoir, the entire device is discarded.

[0279] Numerous reusable pen and auto-injector delivery devices have applications for subcutaneous delivery of pharmaceutical compositions. Examples include, to name a few, AUTOPEN® (Owen Mumford, Inc. (Woodstock, UK)), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25® pen, HUMALOG® pen, HUMALIN 70 / 30® pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN® I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR® (Novo Nordisk, Copenhagen, Denmark), BD® pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN®, OPTIPEN PRO®, and OPTIPEN®. Examples of disposable pen delivery devices for use in subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, STARLET® and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany).Examples of high-volume delivery devices (e.g., high-volume injectors) include, but are not limited to, bolus syringes such as BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, Ypsomed YpsoDose, and Bespak Lapas.

[0280] Exemplary drug delivery devices may include needle-based infusion systems, such as those described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based infusion systems can be broadly classified into multi-dose container systems and single-dose (with partial or total dispensing) container systems. Containers may be replaceable or integrated non-replaceable containers.

[0281] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based infusion device with replaceable containers. In such a system, each container holds multiple doses, and its size may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based infusion device with an integrated non-replaceable container. In such a system, each container holds multiple doses, and its size may be fixed or variable (pre-set by the user).

[0282] As further described in ISO 11608-1:2014(E), a single-dose container system may involve a needle-based infusion device with replaceable containers. In one example of such a system, each container holds a single dose, and the entire deliverable volume is dispensed (total discharge). In a further example, each container holds a single dose, and a portion of the deliverable volume is dispensed (partial discharge). As also described in ISO 11608-1:2014(E), a single-dose container system may include a needle-based infusion device with an integrated, non-replaceable container. In one example of such a system, each container holds a single dose, and the entire deliverable volume is dispensed (total discharge). In a further example, each container holds a single dose, and a portion of the deliverable volume is dispensed (partial discharge).

[0283] An exemplary sleeve-trigger autoinjector with manual needle insertion is described in International Publication No. 2015 / 004052. An exemplary audible end-of-administration feedback mechanism is described in International Publication Nos. 2016 / 193346 and International Publication Nos. 2016 / 193348. An exemplary needle safety mechanism after use of an autoinjector is described in International Publication No. 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in International Publication No. 2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication No. 2016 / 193355.

[0284] For direct administration into the sinuses, the pharmaceutical compositions described herein may be administered using, for example, a microcatheter (e.g., endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. This method includes the administration of an IL-4R antagonist in an aerosolized form to a subject requiring such an aerosol. For example, a patient's COPD can be treated by administering an aerosolized antibody against IL-4R. The aerosolized antibody may be prepared, for example, as described in U.S. Patent No. 8,178,098, which is incorporated herein in its entirety by reference.

[0285] In certain circumstances, pharmaceutical compositions may be delivered by controlled-release systems. In one embodiment, a pump may be used (see Langer; Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201). In another embodiment, polymer materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, the controlled-release system may be positioned near the target of the composition, thus requiring only a portion of the systemic dose (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, vol.2, pp.115-138). For other controlled-release systems, see the review Langer, 1990, Science 249:1527-1533.

[0286] Injectable formulations may include dosage forms for intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and intravenous infusion. These injectable formulations can be prepared by known methods. For example, an injectable formulation may be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous media for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, and can be used in combination with appropriate solubilizers such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)). Examples of oily media include sesame oil and soybean oil, and can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. Injectable formulations thus prepared are typically filled into appropriate ampoules.

[0287] Advantageously, the above-mentioned pharmaceutical compositions for oral or parenteral use are prepared into dosage forms of unit doses suitable for the dosage of the active ingredient. Such dosage forms of unit doses include, for example, tablets, pills, capsules, injections (ampoules), and suppositories.

[0288] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that may be used as described herein are disclosed, for example, in U.S. Patent No. 8,945,559.

[0289] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4R antibody or its antigen-binding fragment) administered to a subject according to the methods characterized in the present invention or for use according to the present invention is generally a therapeutically effective dose. As used herein, the term “therapeutically effective dose” means an amount of IL-4R antagonist that results in one or more of the following: (a) a reduction in the incidence of COPD exacerbations, (b) improvement in one or more COPD-related parameters (as defined elsewhere herein), and / or (c) a detectable improvement in one or more symptoms or signs of upper respiratory tract inflammatory conditions. “Therapeuticly effective dose” also includes an amount of IL-4R antagonist that inhibits, prevents, mitigates or delays the progression of COPD in a subject.

[0290] For anti-IL-4R antibodies, the effective therapeutic dose is approximately 0.05 mg to 700 mg, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3.0 mg, 5.0 mg, 7.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 90 mg. , about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 20 0mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, About 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 41 0mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, The anti-IL-4R antibody may be approximately 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, or 700 mg. In certain embodiments, approximately 300 mg of anti-IL-4R antibody is administered.

[0291] The amount of IL-4R antagonist contained in each dose may be expressed in milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, an IL-4R antagonist may be administered to a patient in doses ranging from approximately 0.0001 to approximately 10 mg / kg of the subject's body weight. For instance, an IL-4R antagonist may be administered in doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0292] In certain embodiments, the initial dose is approximately the same as the loading dose. In certain embodiments, the initial dose is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.5 times, or 3.0 times or more of the loading dose.

[0293] In certain embodiments, two or more doses (e.g., 2, 3, 4, or 5 or more) are administered as an "initial dose" or "loading dose" at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., "secondary dose" or "maintenance dose"). In one embodiment, the maintenance dose may be lower than the loading dose or initial dose. For example, after administering one or more loading doses of 600 mg of IL-4R antagonist, a maintenance dose of about 75 mg to about 300 mg may be administered. In certain embodiments, the method includes an initial dose or loading dose of about 400 mg or about 600 mg of IL-4R antagonist. In certain embodiments, the method includes one or more secondary doses or maintenance doses of about 200 mg or about 300 mg of IL-4R antagonist.

[0294] In one embodiment, the maintenance dose is the same as the loading dose or initial dose. For example, both the loading dose and maintenance dose of the IL-4R antagonist may be administered in doses of approximately 75 mg to approximately 300 mg. In a particular embodiment, the method includes an initial dose and a maintenance dose of approximately 300 mg of the IL-4R antagonist.

[0295] In certain exemplary embodiments, the subjects are children weighing over 30 kg, and the IL-4R antagonist is administered in doses of approximately 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In some embodiments, the subjects are children weighing over 30 kg, and the IL-4R antagonist is administered in an initial dose or loading dose of approximately 400 mg and one or more secondary doses or maintenance doses of approximately 200 mg, with the secondary dose administered every other week (q2w). In some embodiments, the subjects are children weighing over 30 kg, and the IL-4R antagonist is administered in an initial dose and a maintenance dose of approximately 200 mg, with the maintenance dose administered every other week (q2w).

[0296] In certain exemplary embodiments, the subjects are children weighing 30 kg or less and having a body weight of at least 15 kg, and the IL-4R antagonist is administered in doses of approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, or approximately 600 mg. In some embodiments, the subjects are children weighing 30 kg or less and having a body weight of at least 15 kg, and the IL-4R antagonist is administered in an initial dose of approximately 600 mg and one or more secondary or maintenance doses of approximately 300 mg, with the secondary doses administered every four weeks (q4w). In some embodiments, the subjects are children weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered in an initial dose of approximately 300 mg and a maintenance dose, with the maintenance dose administered every four weeks (q4w).

[0297] In certain exemplary embodiments, the subjects are adolescents weighing less than 60 kg, and the IL-4R antagonist is administered in doses of approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In some embodiments, the subjects are adolescents weighing less than 60 kg, and the IL-4R antagonist is administered in an initial dose of approximately 400 mg and one or more secondary or maintenance doses of approximately 200 mg, with the secondary dose administered every other week (q2w). In other embodiments, the subjects are adolescents weighing less than 60 kg, and the IL-4R antagonist is administered in an initial dose and maintenance dose of approximately 200 mg, with the maintenance dose administered every other week (q2w). In certain embodiments, the subjects are adolescents weighing 30 kg or more and less than 60 kg, and the IL-4R antagonist is administered in doses of approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, or approximately 600 mg. In some embodiments, the subjects are adolescents weighing 30 kg or more and less than 60 kg, and the IL-4R antagonist is administered in an initial dose of approximately 400 mg and one or more secondary or maintenance doses of approximately 200 mg, with the secondary dose administered every other week (q2w). In other embodiments, the subjects are adolescents weighing 30 kg or more and less than 60 kg, and the IL-4R antagonist is administered in an initial dose and a maintenance dose of approximately 200 mg, with the maintenance dose administered every other week (q2w).

[0298] In certain exemplary embodiments, the subjects are adolescent subjects weighing at least 60 kg, and the IL-4R antagonist is administered in doses of approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, or approximately 600 mg. In exemplary embodiments, the subjects are adolescent subjects weighing at least 60 kg, and the IL-4R antagonist is administered in an initial dose of approximately 600 mg and one or more secondary or maintenance doses of approximately 300 mg, with the secondary doses administered every other week (q2w). In other embodiments, the subjects are adolescent subjects weighing at least 60 kg, and the IL-4R antagonist is administered in an initial dose and maintenance dose of approximately 300 mg, with the maintenance doses administered every other week (q2w).

[0299] In certain exemplary embodiments, the subjects are adults, and the IL-4R antagonist is administered in doses of approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In other exemplary embodiments, the subjects are adults, and the IL-4R antagonist is administered in an initial dose of approximately 600 mg and one or more secondary or maintenance doses of approximately 300 mg, with the secondary doses administered every other week (q2w). In other exemplary embodiments, the subjects are adults, and the IL-4R antagonist is administered in an initial dose of approximately 400 mg and one or more secondary or maintenance doses of approximately 200 mg, with the secondary doses administered every other week (q2w). In certain embodiments, the subjects are adults, and the initial dose comprises approximately 300 mg of IL-4R antagonist, with one or more subsequent doses comprising approximately 300 mg of IL-4R antagonist administered every other week (q2w). In certain exemplary embodiments, the subjects are between 40 and 85 years of age.

[0300] In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 150 mg / mL using a pre-filled device. In some embodiments, a 150 mg / mL IL-4R antagonist solution in a pre-filled device is used to deliver approximately 300 mg of the IL-4R antagonist in a 2 mL injection. In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 175 mg / mL using a pre-filled device. In some embodiments, a 175 mg / mL IL-4R antagonist solution in a pre-filled device is used to deliver approximately 200 mg of the IL-4R antagonist in a 1.14 mL injection.

[0301] Combination therapy Certain embodiments of the methods described herein involve administering one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition containing the IL-4R antagonist. In some embodiments, the term “in combination with” includes sequential or simultaneous administration of the IL-4R antagonist and the second therapeutic agent. Methods are provided for treating COPD or related conditions or complications, or for reducing at least one COPD exacerbation, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0302] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before the administration of the pharmaceutical composition containing the IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after the administration of the pharmaceutical composition containing the IL-4R antagonist. "Concurrent" administration with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within 5 minutes (before, after, or simultaneously) of the administration of the pharmaceutical composition containing the IL-4R antagonist, or that it is administered to the subject as a single combination formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0303] Additional therapeutic agents may include, for example, another IL-4R antagonist, IL-33 antagonist, IL-1 antagonist (including the IL-1 antagonist described in U.S. Patent No. 6,927,044), IL-6 antagonist, IL-6R antagonist (including the anti-IL-6R antibody described in U.S. Patent No. 7,582,298), TNF antagonist, IL-8 antagonist, IL-9 antagonist, IL-17 antagonist, IL-5 antagonist, IgE antagonist, CD48 antagonist, leukotriene inhibitor, antifungal agents, NSAIDs, long-acting muscarinic antagonists (LAMAs), long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICS), systemic corticosteroids (e.g., oral or intravenous), methylxanthines, nedocromil sodium, cromolyn sodium, or combinations thereof. In exemplary embodiments, additional therapeutic agents administered in combination with the IL-4R antagonist constitute background therapy.

[0304] In certain embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered together with a combination of LABA, LAMA, and ICS. In other embodiments, ICS is contraindicated, and the pharmaceutical composition containing an IL-4R antagonist is administered together with a combination of LABA and LAMA.

[0305] In certain embodiments, the pharmaceutical composition containing the IL-4R antagonist is administered in conjunction with background therapy including LABA, LAMA, and ICS. In other embodiments, ICS is contraindicated, and the pharmaceutical composition containing the IL-4R antagonist is administered in conjunction with background therapy including LABA and LAMA.

[0306] In certain embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered together with a high dose of an ICS. In some embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered together with a high dose of an ICS, a LAMA, and a LABA. In some embodiments, the high dose of an ICS is beclomethasone dipropionate (CFC) in doses greater than 1000 mcg. In some embodiments, the high dose of an ICS is beclomethasone dipropionate (HFA) in doses greater than 400 μg. In some embodiments, the high dose of an ICS is budesonide (DPI) in doses greater than 800 mcg. In some embodiments, the high dose of an ICS is ciclesonide (HFA) in doses greater than 320 mcg. In some embodiments, the high dose of an ICS is fluticasone propionate (DPI or HFA) in doses greater than 500 μg. In some embodiments, the high dose of an ICS is mometasone fluate in doses greater than 440 μg. In some embodiments, the high-dose ICS is triamcinolone acetonide, with a dose greater than 2000 μg.

[0307] In certain embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered together with a non-high-dose ICS. In some embodiments, a pharmaceutical composition containing an IL-4R antagonist is administered together with a non-high-dose ICS, LAMA, and LABA. In some embodiments, the non-high-dose ICS is beclomethasone dipropionate (CFC) with a dose of 1000 mcg or less. In some embodiments, the non-high-dose ICS is beclomethasone dipropionate (HFA) with a dose of 400 μg or less. In some embodiments, the non-high-dose ICS is budesonide (DPI) with a dose of 800 mcg or less. In some embodiments, the non-high-dose ICS is ciclesonide (HFA) with a dose of 320 mcg or less. In some embodiments, the non-high-dose ICS is fluticasone propionate (DPI or HFA) with a dose of 500 μg or less. In some embodiments, the non-high-dose ICS is mometasone fluate with a dose of 440 μg or less. In some embodiments, the non-high-dose ICS is triamcinolone acetonide, with a dose of 2000 μg or less.

[0308] Suitable LABAs include, but are not limited to, salmeterol (e.g., SEREVENT®), formoterol (e.g., FORADIL®, PERFOROMIST®), indacaterol (e.g., ARCAPTA®), alformoterol (e.g., BROVANA®), and orodaterol (e.g., STIVERDI®).

[0309] Suitable ICSs include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., FLOVENT®), budesonide, mometasone (e.g., mometasone furoate, e.g., ASMANEX®), flunisolide (e.g., AEROBID®), dexamethasone acetate / phenobarbital / theophylline (e.g., AZMACORT®), beclomethasone dipropionate HFA (QVAR®), beclomethasone dipropionate (CFC), ciclesonide (HFA), and triamcinolone acetonide.

[0310] Suitable LAMAs include, but are not limited to, tiotropium bromide (e.g., SPIRIVA®), acridinium bromide (e.g., EKLIRA®, TUDORZA®), glycopyrronium bromide (e.g., SEEBRI®), and umeclidinium (e.g., INCRUSE®).

[0311] Suitable LAMA and LABA combinations include, but are not limited to, umeclidinium and vilanterol (e.g., Anoro), orodaterol and tiotropium (e.g., Stiolto), indacaterol and glycopyrrolate (e.g., Utibron), and glycopyrrolate and formoterol (e.g., Bevespi).

[0312] Suitable oral corticosteroids include, but are not limited to, prednisone, prednisolone, methylprednisolone, hydrocortisone, dexamethasone, and cortisone acetate.

[0313] Administration regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined time course. Such a method includes sequential administration of multiple doses of the IL-4R antagonist to a subject. As used herein, “sequential administration” means that each dose of the IL-4R antagonist is administered to the subject at different points in time, for example, on different days separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). A method is provided which includes sequentially administering a single initial dose of the IL-4R antagonist to a patient, followed by one or more secondary doses of the IL-4R antagonist, and optionally, followed by one or more tertiary doses of the IL-4R antagonist.

[0314] A method is provided for administering a pharmaceutical composition containing an IL-4R antagonist to a target at a frequency of administration of approximately four times a week, twice a week, once a week (qw or q1w), once every two weeks (every two weeks is used interchangeably with every other week, once every two weeks or q2w), once every three weeks (every three weeks or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or at a frequency of administration as low as possible as long as a therapeutic response is achieved.

[0315] In certain embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, weekly doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be used. In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be used every two weeks (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be used every three weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be administered once every four weeks (monthly). In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be administered once every five weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be administered once every six weeks. In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be administered once every 8 weeks. In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, doses of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg may be administered once every 12 weeks. In certain exemplary embodiments, the route of administration is subcutaneous.

[0316] The term “week” refers to a period of (n × 7 days) ± 3 days, for example (n × 7 days) ± 2 days, (n × 7 days) ± 1 day, or (n × 7 days), where “n” is the number of weeks, for example 1, 2, 3, 4, 5, 6, 812, or more.

[0317] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of administration of the IL-4R antagonist. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “baseline dose” or “loading dose”), the “secondary dose” is the dose administered after the initial dose, and the “tertiary dose” is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, or they may differ from each other in terms of administration frequency. However, in certain embodiments, the amounts of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses may differ from each other over the course of treatment (e.g., adjusted up or down as needed). In certain embodiments, two or more doses (e.g., 2, 3, 4, or 5) are administered as a “loading dose” at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., “maintenance doses”). In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more initial doses or loading doses of 600 mg or 400 mg of an IL-4R antagonist may be administered, followed by secondary doses or maintenance doses of approximately 75 mg to approximately 400 mg. In one embodiment, the secondary dose / maintenance dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of 300 mg or 200 mg of an IL-4R antagonist may be administered, followed by secondary doses / maintenance doses of approximately 300 mg or approximately 200 mg, respectively. In one embodiment, the loading dose may be divided, for example, two or more doses administered at different time points, such as two loading doses where the second loading dose is administered two weeks after the first loading dose.

[0318] In certain embodiments, the initial dose is approximately 50 mg to 600 mg of IL-4R antagonist. In one embodiment, the initial dose is approximately 600 mg of IL-4R antagonist. In another embodiment, the initial dose is approximately 400 mg of IL-4R antagonist. In yet another embodiment, the initial dose is approximately 300 mg of IL-4R antagonist.

[0319] In certain embodiments, the secondary dose is approximately 50 mg to 600 mg of IL-4R antagonist. In one embodiment, the maintenance dose is approximately 300 mg of IL-4R antagonist. In another embodiment, the maintenance dose is approximately 200 mg of IL-4R antagonist.

[0320] In certain embodiments, the initial dose is three times the maintenance dose. In certain embodiments, the initial dose is twice the maintenance dose. In certain embodiments, the initial dose is equal to the maintenance dose. In exemplary embodiments, the initial dose is approximately 300 mg and the maintenance dose is approximately 300 mg.

[0321] In some embodiments, the initial dose comprises 600 mg of antibody or its antigen-binding fragment, and one or more secondary doses comprises 300 mg of antibody or its antigen-binding fragment administered every other week (every other week is used interchangeably with every two weeks, every two weeks, or q2w). In other embodiments, the subject is an adult, and the initial dose comprises approximately 300 mg of antibody or its antigen-binding fragment, and one or more secondary doses comprises approximately 300 mg of antibody or its antigen-binding fragment administered every other week (every other week is used interchangeably with every two weeks, every other week, or q2w).

[0322] In some embodiments, the subject has moderate to severe COPD, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent secondary doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week.

[0323] In some embodiments, the subject has COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent secondary doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week.

[0324] In some embodiments, the subjects have moderate to severe COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent secondary doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week.

[0325] In one exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 weeks after the previous dose (for example, 1 week, 1 1 / 2 weeks, 2 weeks, 2 1 / 2 weeks, 3 weeks, 3 1 / 2 weeks, 4 weeks, 4 1 / 2 weeks, 5 weeks, 5 1 / 2 weeks, 6 weeks, 6 1 / 2 weeks, 7 weeks, 7 1 / 2 weeks, 8 weeks, 8 1 / 2 weeks, 9 weeks, 9 1 / 2 weeks, 10 weeks, 10 1 / 2 weeks, 11 weeks, 11 1 / 2 weeks, 12 weeks, 12 1 / 2 weeks, 13 weeks, 13 1 / 2 weeks, 14 weeks, 14 1 / 2 weeks, or beyond). The phrase "immediately preceding dose" refers to the dose of IL-4R antagonist administered to the patient immediately before the next dose in a series of multiple doses, without any intervening doses.

[0326] This method may involve administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more secondary doses (e.g., two, three, four, five, six, seven, eight, or more) are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more tertiary doses (e.g., two, three, four, five, six, seven, eight, or more) are administered to the patient.

[0327] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency at which secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The administration frequency may also be adjusted by the physician during the course of treatment based on the results of clinical examinations and the individual patient's needs.

[0328] A method is provided for the sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient for the treatment of COPD or a related condition. In some embodiments, the method includes the step of administering one or more doses of an IL-4R antagonist, followed by the administration of one or more doses of a second therapeutic agent (e.g., 2, 3, 4, 5, 6, 7, 8 or more). For example, one or more doses of an IL-4R antagonist ranging from about 75 mg to about 600 mg may be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of a second therapeutic agent (e.g., TCS or TCI) to treat, alleviate, reduce or improve one or more symptoms of COPD. In some embodiments, the IL-4R antagonist is administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) resulting in improvement of one or more COPD-related parameters, followed by the administration of a second therapeutic agent to prevent relapse of at least one symptom of COPD. Alternative embodiments relate to the co-administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses of the IL-4R antagonist (e.g., 2, 3, 4, 5, 6, 7, 8 or more) are administered, and the second therapeutic agent is administered in separate doses at the same or different frequencies as the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or concurrently with the IL-4R antagonist.

[0329] In some embodiments, the subjects have moderate to severe COPD, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, wherein the antibody or its antigen-binding fragment is administered in combination with LAMA, LABA, and ICS.

[0330] In some embodiments, the subjects have COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, the antibody or its antigen-binding fragment being administered in combination with LAMA, LABA, and ICS.

[0331] In some embodiments, the subjects have moderate to severe COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, wherein the antibody or its antigen-binding fragment is administered in combination with LAMA, LABA, and ICS.

[0332] In some embodiments, the subjects have moderate to severe COPD, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, wherein the antibody or its antigen-binding fragment is administered in combination with LAMA and LABA.

[0333] In some embodiments, the subject has COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, wherein the antibody or its antigen-binding fragment is administered in combination with LAMA and LABA.

[0334] In some embodiments, the subjects have moderate to severe COPD with type 2 inflammation, and the initial dose comprises 300 mg of antibody or its antigen-binding fragment, with one or more subsequent doses comprising 300 mg of antibody or its antigen-binding fragment administered every other week, wherein the antibody or its antigen-binding fragment is administered in combination with LAMA and LABA.

[0335] In certain embodiments, the IL-4R antagonist is administered every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks or longer. In other embodiments, the IL-4R antagonist is administered every 4 weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks or longer. In specific embodiments, the IL-4R antagonist is administered for at least 52 weeks.

[0336] In certain embodiments, a kit is provided comprising a dosage form of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment 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, for the treatment of COPD. In certain embodiments, the antibody or antigen-binding fragment comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO. 1 and the light chain variable region (LCVR) sequence of SEQ ID NO. 2. In certain embodiments, the antibody is dupilumab.

[0337] The kit may include a label or package insert, which may include instructions for administering dosage forms for the treatment of COPD. The instructions may enumerate the medication regimens further described herein for the treatment of COPD.

[0338] Treatment group The methods (or uses) characterized in this disclosure 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 exhibiting one or more symptoms or signs of COPD (e.g., moderate to severe COPD and / or COPD with type 2 inflammation) or diagnosed with COPD. For example, “subject in need thereof” may include, for example, a subject exhibiting (or having exhibited) one or more COPD parameters prior to treatment, e.g., decreased FEV1 (e.g., less than 2.0 L) and / or a subject experiencing one or more exacerbations of a COPD event, e.g., an acute exacerbation of COPD (AECOPD) event.

[0339] In some embodiments, the “subjects requiring it” have a Unified Airway Disease (UAD). UAD is a concept based on common pathophysiological and immunological mechanisms underlying certain respiratory diseases. Based on this concept, upper and lower airway diseases often coexist because they reflect symptoms of a single underlying disease in different parts of the airway (see Kanda et al. “Regulation of Interaction Between the Upper and Lower Airways in United Airway Disease” Med Sci(Basel)2019;7(2) and Yii et al. “Precision Medicine in United Airways Disease: A Treatable Traits Approach” Allergy 2018;73(10):1964-1978). For example, UAD may be associated with eosinophilic airway inflammation related to Th2 cytokines (IL-4, IL-5, and IL-13) and / or IgE (see Laidlaw, et al. “Chronic Rhinosinusitis with Nasal Polyps and Asthma” Journal of Allergy and Clinical Immunology: In Practice 2021;9(3):1133-1141 and Fokkens et al. “EUFOREA Consensus on Biologics for CRSwNP with or without Asthma” Allergy 2018;73(10):1964-1978).The concept of UAD is associated with the co-occurrence or multiple occurrence of diseases related to type 2 inflammation, which may include, for example, asthma, chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps, rhinitis, and COPD (see Kanda et al. "Regulation of Interaction Between the Upper and Lower Airways in United Airway Disease" Med Sci (Basel) 2019;7(2) and Yii et al. "Precision Medicine in United Airways Disease: A Treatable Traits Approach" Allergy 2018;73(10):1964-1978). In certain exemplary embodiments, the subjects to be treated have UAD (e.g., asthma, chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps, bronchiectasis or rhinitis, e.g., allergic rhinitis, allergic asthmatic rhinitis, focal allergic rhinitis-non-allergic asthma, non-allergic eosinophilic rhinitis syndrome-non-allergic eosinophilic asthma, asthma-chronic sinusitis, COPD-chronic sinusitis, etc.). In exemplary embodiments, the subjects to be treated have UAD with COPD. In additional exemplary embodiments, the subjects have UAD with COPD and one or more additional comorbid type 2 inflammatory diseases (i.e., asthma, chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), or rhinitis).

[0340] In relevant embodiments, “subjects requiring it” may be subjects who have been prescribed or are currently taking LAMA, LABA, and ICS prior to the administration of the IL-4R antagonist. In some embodiments, subjects have been prescribed or are currently taking high-dose ICS, LAMA, and LABA.

[0341] In other embodiments, “subjects requiring it” may be subjects who have been prescribed or are currently taking LAMAs and LABAs prior to the administration of the IL-4R antagonist. In some embodiments, ICS is contraindicated for the subject.

[0342] In some embodiments, “subjects requiring it” are subjects with moderate to severe COPD. In some embodiments, subjects with moderate to severe COPD have a post-bronchodilator FEV1 / FVC ratio of <0.70 and a post-bronchodilator FEV1% of >30% and ≤70%. In some embodiments, subjects with moderate to severe COPD have a post-bronchodilator FEV1 / FVC ratio of <0.70 and a post-bronchodilator FEV1% of less than 30%, less than 25%, or less than 20%.

[0343] In some embodiments, “subjects requiring it” are subjects having COPD with type 2 inflammation (i.e., COPD coexisting with at least one type 2 inflammatory disease). In some embodiments, subjects with type 2 inflammation have a blood eosinophil level of ≥300 cells / microliter. Examples of type 2 inflammatory diseases include, but are not limited to, atopic dermatitis (AD), asthma, chronic sinusitis with nasal polyps (CRSwNP), chronic sinusitis without nasal polyps (CRSsNP), eosinophilic esophagitis, chronic induced urticaria, and nodular prurigo.

[0344] In some embodiments, the "subjects requiring it" are subjects with moderate to severe COPD accompanied by type 2 inflammation.

[0345] In some embodiments, “the subject requiring it” is a subject having a Medical Research Council (MRC) Dyspnea Scale grade of ≥2 (see Bestall, et al. “Usefulness of the Medical Research Council (MRC) Dyspnea Scale as a Measure of Disability in Patients with Chronic Obstructive Pulmonary Disease” Thorax 1999;54:581-586). In certain exemplary embodiments, prior to the initiation of treatment, the subject has a baseline modified Medical Research Council (mMRC) dyspnea scale grade score of ≥2. mMRC is described in ATS (1982) Am Rev Respir Dis. No;126(5):952-6.

[0346] In some embodiments, the "subjects requiring it" are subjects with a history of signs and symptoms of chronic bronchitis (chronic wet cough). In some embodiments, the subjects have had signs and symptoms of chronic bronchitis for at least three months within the past year, or have experienced a wet cough lasting more than three months within a two-year period.

[0347] In some embodiments, “the subject requiring it” is a subject with a history of high exacerbation risk. In some embodiments, high exacerbation risk is defined as a history of exacerbations of two or more moderate exacerbations or one or more severe exacerbations within the past year. In some embodiments, the subject experienced at least one moderate or severe exacerbation while taking ICS / LAMA / LABA or LAMA / LABA.

[0348] In some embodiments, the "subject requiring it" is a human being. In some embodiments, the subject is a human adult. In some embodiments, the subject is between 40 and 80 years old. In some embodiments, the "subject requiring it" is between 40 and 85 years old. In some embodiments, the subject is 40 years of age or older. In some embodiments, the subject is 65 years of age or older. In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject is under 40 years of age. In some embodiments, the subject is under 80 years of age. In some embodiments, the subject is under 85 years of age. In some embodiments, the subject is 18 years of age or older.

[0349] In some embodiments, the "subjects who need it" are current smokers. In some embodiments, the subjects are current smokers who smoke cigarettes. In some embodiments, the subjects are current smokers who have a history of smoking 10 packs or more of cigarettes per year. In some embodiments, the subjects are current smokers who have a history of smoking less than 10 packs of cigarettes per year. In some embodiments, the subjects are current smokers who have a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs of cigarettes per year. In some embodiments, the subjects are current smokers who have a history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer.

[0350] In some embodiments, the "subjects who need it" are former smokers. In some embodiments, the subjects are former smokers who have a history of smoking tobacco. In some embodiments, the subjects are former smokers who have a history of smoking 10 packs or more of tobacco per year. In some embodiments, the subjects are former smokers who have a history of smoking less than 10 packs of tobacco per year. In some embodiments, the subjects are former smokers who have a history of smoking 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs or more of tobacco per year. In some embodiments, the subjects are former smokers who have a history of smoking approximately 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs or more of tobacco per year. In some embodiments, the subjects are former smokers who have a history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more. In some embodiments, the subjects are former smokers who have quit smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the subjects are former smokers who have abstained from smoking for at least six months. In some embodiments, the subjects are former smokers who intend to quit smoking permanently.

[0351] In some embodiments, “the subject requiring it” may be a subject having a tested FEV1 value that is 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 20%, 15%, or 10% lower than the predicted FEV1.

[0352] Normal IgE levels in healthy subjects are less than approximately 100 kU / L (for example, when measured using the IMMUNOCAP® assay [Phadia, Inc., Portage, MI]). In some embodiments, “subjects requiring it” may be subjects exhibiting elevated serum IgE levels, which are greater than approximately 100 kU / L, greater than approximately 150 kU / L, greater than approximately 500 kU / L, greater than approximately 1000 kU / L, greater than approximately 1500 kU / L, greater than approximately 2000 kU / L, greater than approximately 2500 kU / L, greater than approximately 3000 kU / L, greater than approximately 3500 kU / L, greater than approximately 4000 kU / L, greater than approximately 4500 kU / L, or greater than approximately 5000 kU / L.

[0353] In some embodiments, “subjects requiring it” may be subjects having elevated eotaxin-3 levels, such as above approximately 100 pg / ml, above approximately 150 pg / ml, above approximately 200 pg / ml, above approximately 300 pg / ml, or above approximately 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0354] In some embodiments, “the subject requiring it” may be a subject having elevated exhaled NO (FeNO) levels, such as above approximately 30 ppb, above approximately 31 ppb, above approximately 32 ppb, above approximately 33 ppb, above approximately 34 ppb, or above approximately 35 ppb.

[0355] In some embodiments, the target group is: ≥300 cells / μL (or cells / mm²). 3 ) or ≥250 cells / μL (or cells / mm²) 3 ) blood eosinophil count (high blood eosinophil count), 299-150 cells / μL (or cells / mm³) 3 ) blood eosinophil count (moderate blood eosinophils), <150 cells / μL (or cells / mm³) 3 ) blood eosinophil count (low blood eosinophil count) or <300 cells / μL (or cells / mm³) 3 The patient is stratified by the number of eosinophils in their blood, and an IL-4R antagonist is administered selectively at a dose or regimen based on the eosinophil level.

[0356] In some embodiments, “subjects requiring it” are subjects with COPD accompanied by mucus plugging in the lungs. In some embodiments, “subjects requiring it” are subjects with COPD accompanied by ventilation deficit. In some embodiments, subjects treated by the method of the present disclosure have an improved mucus score. In some embodiments, subjects treated by the method of the present disclosure have improved ventilation. The mucus score can be assessed by CT (J Clin Invest 2018;128:997-1009;Chest 2019;155:1178-1189). Ventilation can be assessed by MRI, measured by the MRI ventilation deficit rate (VDP) which is generated as a ventilation deficit amount normalized to thoracic volume (Acad.Radiol.2012;19:141-152).

[0357] Evaluation methods for pharmacodynamic COPD-related parameters A method is provided for evaluating one or more pharmacodynamic COPD-related parameters in subjects requiring such treatment, as induced by the administration of a pharmaceutical composition containing an IL-4R antagonist. A reduction in the incidence of COPD symptoms or improvement in COPD-related parameters may correlate with improvements in one or more pharmacodynamic COPD-related parameters, although such correlations are not necessarily observed in all cases.

[0358] Examples of “pharmacodynamic COPD-related parameters” include, for example, (a) biomarker expression levels and (b) serum protein and RNA analysis. “Improvement in pharmacodynamic COPD-related parameters” means, for example, a decrease from baseline in one or more biomarkers such as lung and activation-controlled chemokines (PARCs), eotaxin-3, fibrinogen, IgE, blood or sputum eosinophils, blood or sputum neutrophils, or FeNO. As used herein, the term “baseline” with respect to pharmacodynamic COPD-related parameters means the numerical value of the pharmacodynamic COPD-related parameter for a patient before or at the time of administration of the pharmaceutical composition described herein.

[0359] To evaluate pharmacodynamic COPD-related parameters, the parameters are quantified at baseline and at time points after administration of the pharmaceutical composition. For example, pharmacodynamic COPD-related parameters may be measured approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, or approximately 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or beyond. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to establish whether there has been a change, such as "improvement," in the pharmacodynamic COPD-related parameter (e.g., an increase or decrease depending on the specific parameter being measured).

[0360] In certain embodiments, administration of IL-4R antagonists to patients can cause changes in the expression of specific biomarkers, such as a decrease or increase. COPD-related biomarkers include, but are not limited to, lung and activated regulatory chemokines (PARCs), eotaxin-3, fibrinogen, IgE, blood or sputum eosinophils, blood or sputum neutrophils, or FeNO. For example, administration of IL-4R antagonists to COPD patients can cause a decrease in total serum IgE levels. Such decreases can be detected approximately 1, 2, 3, 4, 5 weeks, or beyond, 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 polymerase-coupled reverse transcription (RT-PCR).

[0361] As described above, biomarker expression can be assayed by detecting proteins or RNA in serum. Serum samples may also be used to monitor further protein or RNA biomarkers related to responses to treatment with IL-4R antagonists or IL-4 / IL-13 signaling (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, etc.). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., the RNA level of a biomarker, while in other embodiments, RNA samples are used for transcriptome sequencing (e.g., gene analysis).

[0362] formulation In some embodiments, the antibody or its antigen-binding fragment is formulated in a composition comprising: i) about 150 mg / mL of an antibody or its antigen-binding fragment that specifically binds to IL-4R; ii) about 20 mM histidine; iii) about 12.5 mM acetate; iv) about 5% (w / v) sucrose; v) about 25 mM arginine hydrochloride; vi) about 0.2% (w / v) polysorbate 80, where the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 cpoise.

[0363] In an alternative embodiment, the antibody or its antigen-binding fragment is formulated in a composition comprising: i) about 175 mg / mL of an antibody or its antigen-binding fragment that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 50 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80, where the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 cpoise.

[0364] In a specific embodiment, the antibody or its antigen-binding fragment includes an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0365] In specific embodiments, the antibody comprises dupilumab. Unless otherwise specified, the term “dupilumab” also includes any biosimilar thereof.

[0366] Suitable stabilization formulations are also described in U.S. Patent No. 8,945,559, which is incorporated in its entirety herein by reference for all purposes.

[0367] This disclosure is further illustrated by the following examples, which should not be construed as further limitations. All drawings, tables, and references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0368] Furthermore, according to this disclosure, conventional molecular biology, microbiology, and recombinant DNA technologies can be used within the scope of the art in this field. Such technologies are well described in the literature. For example, Green & Sambrook, Molecular Cloning: A Laboratory Manual, Fourth Edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (DNGlover ed.1985); Oligonucleotide Synthesis (MJ Gait ed.1984); eds.(1985)];Transcription And Translation[BDHames&S.J.Higgins,eds.(1984)];Animal Cell Culture[RIFreshney,ed.(1986)];Immobilized Cells And Enzymes[IRL Press,(1986)];B.Perbal,A Practical Guide To Molecular Cloning(1984);FMAusubel et al.(eds.),Current Protocols in Molecular Biology,John See Wiley & Sons, Inc. (1994). [Examples]

[0369] The following examples are provided to those skilled in the art to provide a complete disclosure and explanation of how the methods and compositions featured in this disclosure are prepared and used, and are not intended to limit the scope of what the inventors consider to be such disclosures. While attempts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), some experimental error and deviation should be taken into consideration. Unless otherwise specified, parts are parts by weight, molecular weight is the average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or near atmospheric pressure.

[0370] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody called dupilumab (also known herein as "mAb 1" or DUPIXENT®).

[0371] Example 1. A randomized, double-blind, placebo-controlled, parallel-group, 52-week pivotal trial to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe chronic obstructive pulmonary disease (COPD) with type 2 inflammation (two phase 3 trials with similar design and population - NCT03930732 / EFC15804 (BOREAS) and NCT04456673 / EFC15805 (NOTUS)). theory Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease with significant economic burdens, and available standard treatments are inadequate for managing symptoms, lung function, exacerbations, and long-term disease progression. This trial was designed to investigate the efficacy and safety profile of dupilumab over one year in patients with COPD who required additional treatment to their current management. The presence of a placebo arm was appropriate for the purpose of the trial as it provided the most robust assessment of the efficacy and safety of dupilumab. All patients received standard treatment background medication throughout the trial. This trial design provided an opportunity to investigate the efficacy of dupilumab across multiple COPD domains, including lung function, prevention of moderate and severe exacerbations, and symptom management. The effects on lung function and symptom management were evaluated over the short and long term.

[0372] the purpose Main purpose: The objective is to evaluate the efficacy of dupilumab 300 mg q2w in patients with moderate or severe COPD, as measured by the annual rate of acute moderate or severe COPD exacerbations (AECOPD).

[0373] Secondary purpose: The objectives are to evaluate the effect of dupilumab 300 mg q2w on pre-bronchodilator forced expiratory volume in one second (FEV1) over 12 weeks compared to placebo, the effect on health-related quality of life as assessed by changes from baseline to week 52 on the St. George Respiratory Questionnaire (SGRQ), and the effect on pre-bronchodilator FEV1 over 52 weeks compared to placebo.

[0374] This study evaluates the effect of dupilumab 300 mg q2w on lung function assessment.

[0375] This study evaluates the efficacy of dupilumab in moderate and severe COPD exacerbations.

[0376] The purpose is to evaluate safety and tolerability.

[0377] The objective is to evaluate the incidence of systemic exposure to dupilumab and anti-drug antibodies (ADAs).

[0378] This involves evaluating the drug concentration of dupilumab in the serum over time.

[0379] The goal is to investigate the relationship between biomarkers and treatment response.

[0380] The objective is to evaluate the effects of dupilumab compared to placebo on FEV1 and FVC.

[0381] The objective is to evaluate the effect of dupilumab compared to placebo on the annual rate of moderate to severe COPD exacerbations using the Exacerbation Response Tool for Chronic Lung Disease (EXACT).

[0382] The objective is to evaluate the efficacy of dupilumab compared to placebo for treatment failure requiring a change in background medication.

[0383] endpoint Primary endpoints: Annual rate of moderate or severe COPD exacerbations over a 52-week treatment period compared to placebo. Moderate exacerbations were recorded by the investigator and defined as AECOPD requiring either systemic corticosteroids (intramuscular, intravenous, or oral, etc.) and / or antibiotics. Severe exacerbations were recorded by the investigator and defined as AECOPD requiring hospitalization, or requiring >24 hours of observation in an emergency / critical care facility, or resulting in death. For both moderate and severe events to be counted as separate events, they had to be separated by at least 14 days.

[0384] Secondary endpoints: Period of exacerbation-related systemic corticosteroid (SCS) intake.

[0385] Course with adjusted annual total SCS.

[0386] The change in pre-bronchodilator FEV1 from baseline at weeks 12 and 52 compared to placebo, and the change in pre-bronchodilator FEV1 from baseline at weeks 12 and 52 in patients with baseline exhaled nitric oxide (FeNO) levels of ≥20 parts per billion (ppb).

[0387] Change in SGRQ total score from baseline to week 52 compared to placebo (scores range from 0 to 100, with lower scores indicating better quality of life; minimum clinically important difference (MCID) of 4 points).

[0388] Percentage of patients with an SGRQ improvement of ≥4 points at week 52.

[0389] Changes in pre-bronchodilator FEV1 from baseline to week 52, compared to placebo.

[0390] Changes in pre-bronchodilator FEV1 from baseline to weeks other than weeks 12 and 52 (i.e., weeks 2, 4, 8, 24, 36, and 44), compared to placebo.

[0391] Changes in FEV1 after bronchodilator administration from baseline to weeks 2, 4, 8, 12, 24, 36, and 52, compared to placebo.

[0392] Changes in forced expiratory flow rate (FEF) from 25% to 75% from baseline to weeks 2, 4, 8, 12, 24, 36, 44, and 52.

[0393] Annual rate of severe COPD exacerbations compared to placebo over a 52-week treatment period.

[0394] Time to the first moderate or severe COPD exacerbation compared to placebo during a 52-week treatment period.

[0395] Adverse events (AEs) / Adverse events that occur during treatment (TEAEs).

[0396] Clinically significant abnormalities in hematological, biochemical, and urinalysis tests.

[0397] ADA for dupilumab.

[0398] Blood eosinophil levels over time.

[0399] Tertiary / exploratory endpoints: Serum functional dupilumab concentrations and PK profiles.

[0400] Pharmacodynamic responses to selected biomarkers: lung and activation control chemokines (PARCs), eotaxin-3, exhaled nitric oxide concentration (FeNO after bronchodilator administration), and total IgE.

[0401] Fibrinogen.

[0402] Sputum induction related to RNA expression.

[0403] Messenger ribonucleic acid (mRNA) sequencing or whole transcriptome analysis from blood and sputum.

[0404] Deoxyribonucleic acid (DNA) for evaluating the effects of pharmacogenomics.

[0405] Predictive effect of selected biomarkers on treatment response.

[0406] Annual loss of lung function as assessed by FEV1 gradient analysis.

[0407] Change from baseline in FVC at weeks 12, 24, and 52 (percentage predicted value and absolute value in mL).

[0408] Clinical assessment of COPD symptoms using the COPD respiratory symptom assessment tool (E-RS:COPD) included in the EXACT tool.

[0409] Annual rate of COPD exacerbations assessed by EXACT over 52 weeks (score ranges from 0 to 40, with lower scores indicating fewer severe respiratory symptoms).

[0410] Increased frequency of controller drug use after disease exacerbation.

[0411] Increased total daily dose of controller medication in patients after exacerbation.

[0412] Test design The BOREAS (NCT03930732 / EFC15804) and NOTUS (NCT04456673 / EFC15805) trials were multinational, randomized, double-blind, placebo-controlled, 52-week phase 3 studies to evaluate the efficacy, safety, and tolerability of dupilumab in patients with moderate to severe type 2 inflammatory COPD, including those driven by IL-4, IL-5, and IL-13 activation, against established LABA, LAMA, and / or ICS background therapy (triple therapy unless ICS is contraindicated). The investigational drug was dupilumab 300 mg q2w or placebo q2w administered during the 52-week treatment period. A summary of the study design is shown in Figure 1.

[0413] The trial consisted of three study periods. The screening period was 4 weeks ± 1 week. The randomized investigational drug (IMP) treatment period was 52 weeks ± 3 days. The post-IMP treatment period was 12 weeks ± 5 days.

[0414] Patients who met the inclusion and exclusion criteria were randomized (1:1) to one of the following IMP treatment duration groups for 52 weeks: dupilumab 300 mg administered as a single subcutaneous (SC) injection q2w or placebo administered as a single SC injection. The study activity schedule is shown in Figures 2A-C.

[0415] Each trial planned for approximately 924 patients (actually 939 participants), and an estimated total of 462 evaluable patients per intervention group were randomly assigned to the trial intervention.

[0416] Randomization was stratified by country and by baseline ICS dose (high-dose ICS). For example, in the Japanese population, the high-dose ICS for adults is >500mcg (DPI or HFA) or 401-800mcg (HFA). Enrollment was planned to be capped at 30% of current smokers (defined by smoking status at the time of screening).

[0417] Post-IMP treatment follow-up: Upon completion of the 52-week randomized IMP treatment period, patients continued triple-combination background ICS / LABA / LAMA therapy (unless ICS was contraindicated) and entered a 12-week safety follow-up period. Adjustments to background medications were permitted at the discretion of the principal investigator if deemed clinically necessary during the post-treatment period. The use of e-cigarettes was not permitted during the study.

[0418] Inclusion Criteria Participants were only eligible to take the exam if all of the following criteria were met.

[0419] age For the BOREAS trial, participants must be between 40 and 80 years old at the time they sign the informed consent form. For the NOTUS trial, participants must be between 40 and 85 years old at the time they sign the informed consent form.

[0420] Participant types and disease characteristics: Participants diagnosed by a physician with COPD who met the following criteria at the time of screening: Current or former smokers with a smoking history of ≥10 pack years. Current smokers are defined as patients who are active smokers with a smoking history of ≥10 pack years (active smoking includes cigarettes, e-cigarettes, cigars, pipes, etc.). Former smokers are defined as active smokers who had a smoking history of ≥10 pack years (active smoking includes cigarettes, e-cigarettes, cigars, pipes, etc.) and who have stopped smoking for at least 6 months prior to their first visit to the hospital.

[0421] Moderate to severe COPD (FEV1 / FVC ratio <0.70 after bronchodilator administration, and FEV1% >30% and ≤70% after bronchodilator administration).

[0422] Medical Research Council (MRC) Dyspnea Scale Grade ≥ 2.

[0423] Patient reports of signs and symptoms of chronic bronchitis (chronic wet cough) over a 3-month period per year, up to screening in the absence of other known causes of chronic cough.

[0424] A documented history of high exacerbation risk, defined as a history of ≥2 moderate or ≥1 severe exacerbations within the year prior to enrollment. The patient should have experienced at least one exacerbation while taking ICS / LAMA / LABA (or LAMA / LABA if ICS is contraindicated). Moderate exacerbations were documented by the investigator and defined as AECOPD requiring either systemic corticosteroids (intramuscular (IM), intravenous or oral) and / or antibiotics. One of the two moderate exacerbations required had to necessitate the use of systemic corticosteroids. Severe exacerbations were documented by the investigator and defined as AECOPD requiring hospitalization or >24 hours of observation in an emergency / emergency medical facility.

[0425] Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization, and stable dose pharmacotherapy for ≥1 month prior to visit: (Dual therapy: LABA + LAMA is acceptable if ICS is contraindicated).

[0426] Evidence of type 2 inflammation: The patient has a blood eosinophil count of ≥300 cells / microliter at the time of first visit (screening).

[0427] Body Mass Index (BMI) ≥ 16 kg / m² 2 .

[0428] Participants had to be male or female. Female participants were eligible to participate if they were not pregnant, not of childbearing potential, or agreed to follow contraception instructions during the intervention period and for at least 12 weeks after the last dose of the study intervention.

[0429] They have the ability to provide informed consent through signatures.

[0430] Exclusion criteria Participants were excluded from the study if any of the following criteria applied: Patients must have been diagnosed with COPD within 12 months prior to randomization.

[0431] Patients who are currently diagnosed with asthma or have a history of asthma according to the International Guidelines for Asthma Management (GINA) or other accepted guidelines.

[0432] Other serious lung diseases besides COPD (e.g., pulmonary fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss syndrome, etc.) or other diagnosed lung or systemic diseases associated with elevated peripheral blood eosinophil counts.

[0433] Cor pulmonale, evidence of right heart failure.

[0434] Oxygen administration for more than 12 hours per day. Prolonged oxygen administration at >4.0 L / min or when the participant requires more than 2.0 L / min of oxygen to maintain an oxygen saturation of >88%.

[0435] Hypercapnia requiring biphasic positive pressure ventilation (BiPAP).

[0436] Acute exacerbation of COPD (AECOPD) within 4 weeks prior to or during the screening period.

[0437] Respiratory tract infection within four weeks prior to or during the screening period.

[0438] A history of or planned lung resection or lung volume reduction surgery. Patients who participated in the acute phase of a lung rehabilitation program, i.e., patients who started rehabilitation < 4 weeks prior to screening (Note: This may include patients in the maintenance phase of a rehabilitation program).

[0439] They have been diagnosed with alpha-1 antitrypsin deficiency.

[0440] You are unable to follow the examination procedures (for example, due to language difficulties, psychological disorders), or you are unable to read, understand, or complete the questionnaire, or you are unable to use the e-Diary without assistance.

[0441] Immunoglobulin E (IgE) therapy (omalizumab) or any other biological agent therapy (including anti-IL5 mAbs) or immunosuppressant within 130 days prior to a visit, for the treatment of inflammatory or autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) and other diseases within two months prior to a visit or within five half-lives, whichever is longer.

[0442] Exposure to other investigational drugs (small molecules and monoclonal antibodies) within 6 months prior to visit 1. The minimum interval from exposure to any other (non-antibody) investigational drug is 30 days prior to visit 1.

[0443] A history of systemic hypersensitivity or anaphylaxis to any biological agent therapy, including any excipients.

[0444] Patients receiving drug therapy or treatment that is prohibited as a combination therapy.

[0445] If the patient is the principal investigator or any co-principal investigator, research assistant, pharmacist, or study coordinator, or a relative of any other staff member directly involved in conducting the study.

[0446] Clinically significant abnormal electrocardiogram (ECG) findings at randomization that may affect the conduct of the trial at the discretion of the principal investigator, such as prolonged QTc intervals [males > 450 msec, females > 470 msec, Fredericia corrected].

[0447] Patients with a history or current condition of clinically significant renal, hepatic, cardiovascular, metabolic, neurological, hematological, ophthalmic, respiratory (excluding COPD), gastrointestinal, or cerebrovascular disease / condition, drug and / or alcohol abuse disorder, or other serious medical condition or disorder that may have interfered with the study or may require treatment that may have interfered with the study, in the judgment of the principal investigator. Specific examples include, but are not limited to, poorly controlled insulin-dependent diabetes mellitus and uncontrolled hypertension.

[0448] A history of malignant or active malignant tumors, including lymphoproliferative disorders, within the five years prior to baseline (excluding successfully treated cervical intraepithelial neoplasia, non-metastatic squamous cell carcinoma of the skin, or basal cell carcinoma).

[0449] Patients with a history of active tuberculosis or non-tuberculous mycobacterial infection, untreated latent tuberculosis, or incompletely treated tuberculosis were excluded from the study unless the patient was adequately treated and it was sufficiently demonstrated by experts, in the medical judgment of the principal investigator and / or infectious disease specialist, that treatment with biological agents could be initiated. Tuberculosis testing was conducted country by country in accordance with local guidelines, where required by regulatory authorities or ethics committees.

[0450] Acute myocardial infarction occurring within 6 months of the initial screening visit.

[0451] TIA or stroke within 6 months of the screening visit.

[0452] Hospitalization due to any CV or cerebrovascular event within 6 months of the screening visit.

[0453] New York Heart Association Functional Classification (NYHA) Class III or IV.

[0454] Patients who have been taking cardiac medications (such as antiarrhythmics, antihypertensives, and antidiuretics) at unstable doses for the past six months. Dosage changes for cholesterol modifiers and anticoagulants are permitted.

[0455] Cardiac arrhythmias, including paroxysmal (e.g., intermittent) atrial fibrillation, were excluded. Patients with persistent atrial fibrillation defined as having persisted for at least 6 months, managed with a heart rate control strategy (i.e., selective beta-blockers, calcium channel blockers, pacemaker placement, digoxin, or ablation therapy), and managed with a stable, appropriate level of anticoagulation therapy for at least 6 months may be considered for inclusion.

[0456] In the judgment of the principal investigator, any unstable ischemic heart disease or other related cardiovascular disorder, such as pulmonary embolism or deep vein thrombosis, occurring within ≤6 months of enrollment, that may have put the patient at risk of or adversely affected the trial outcome.

[0457] Patients who are <80% compliant with controller therapy during screening.

[0458] Previous use of dupilumab.

[0459] Women who are breastfeeding, breastfeeding, or pregnant.

[0460] Women of childbearing potential (biologically fertile women before menopause): Women who did not confirm a negative serum beta-hCG test at visit 1 or a negative urine pregnancy test at visit 2, and / or who were unwilling to use any acceptable form of effective contraception during the trial period. Postmenopausal women (defined as having been menstruating for at least 12 consecutive months) were not required to use additional contraception.

[0461] If diagnosed with an active parasitic infection (helminthiasis), the patient is suspected of having a parasitic infection or is at high risk of having one, unless active infection has been ruled out by clinical examination and (if necessary) laboratory evaluation prior to randomization.

[0462] History of HIV infection or positive HIV 1 / 2 serological test at the time of the first visit to the hospital.

[0463] Despite having resolved the infection, the patient has a known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), or, in the judgment of the principal investigator, has an unusually frequent recurrent or prolonged infection.

[0464] Evidence of an acute or chronic infection requiring treatment with antibiotics, antivirals, antifungals, antiparasitic drugs, or antiprotozoal drugs within four weeks prior to the visit, or evidence of a serious viral infection within four weeks prior to the visit that may not have received antiviral treatment (e.g., influenza, for which only symptomatic treatment has been received).

[0465] Vaccination with a live attenuated vaccine within four weeks prior to the visit, or vaccination with a live attenuated vaccine planned during the trial.

[0466] Patients with active autoimmune disease or patients who have been using immunosuppressive therapy for an autoimmune disease (e.g., inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.).

[0467] Patients who have any of the following results at the time of screening: positive (or inconclusive) HBsAg, positive IgM HBc Ab, positive total HBc Ab confirmed by positive HBV DNA, or positive HCV Ab confirmed by positive HCV RNA.

[0468] Clinically significant laboratory tests at the time of screening include any of the following values: alanine transaminase (ALT) >3 times the upper limit of the normal range (ULN), hemoglobin <10 g / 100 mL in men and <9 g / 100 mL in women, or <100,000 / mm³. 3 Platelets or creatinine ≥ 150 μmol / L.

[0469] Patients receiving macrolide therapy (e.g., azithromycin), except those who have not received stable therapy for >12 months.

[0470] Patients who withdrew their consent before registration / randomization.

[0471] If, despite patients being screened, enrollment / randomization is stopped at the trial stage.

[0472] Trial intervention The trial class was defined as any trial intervention, marketed product, placebo, or medical device intended to be administered to trial participants in accordance with the trial protocol. A summary of the trial interventions administered is shown in Table 8 below.

[0473] [Table 32]

[0474] Investigational drug The investigational drug (IMP) was administered every 14 ± 3 days (q2w) during the 52-week treatment period.

[0475] The investigational drug (IMP) was administered by the principal investigator / healthcare worker or a person designated by them after clinic procedures and blood collection. Patients were monitored for at least 30 minutes after the administration of all IMP injections. The monitoring period may be extended in accordance with country-specific or local requirements.

[0476] Subcutaneous injection sites were alternated between the upper thigh, the four quadrants of the abdomen, or the upper arm, and care was taken to avoid injecting into the same site twice during a continuous administration.

[0477] The initial IMP administration was performed by the principal investigator or co-investigator. Patients were permitted to self-inject IMP at home after at least one injection at the investigational site supervised by the principal investigator or co-investigator. To train patients in how to prepare and inject IMP, the principal investigator initially trained patients upon their first visit to the site during the treatment period. During this visit, patients administered the injection under the supervision of the principal investigator or co-investigator. This training was documented in the patient's study file. Patient injections were administered only in the abdomen or upper thigh. Patients were also instructed to monitor for any reactions for at least 30 minutes (or longer, according to country- or region-specific requirements) after injection.

[0478] Non-investigational drugs At screening visit 1, all patients must have received triple combination background therapy, including triple combination therapy: LABA + LAMA + ICS (if ICA is contraindicated, dual combination therapy: LABA + LAMA is acceptable), for at least three months prior to visit 2 / randomization and at least one month prior to screening / visit 1. The preparations were administered in dry powder inhalers (DPIs), medium-dose inhalers (MDIs), or pocket nebulizers. The route of administration was oral inhalation. The administration regimen was as prescribed.

[0479] Throughout the trial, patients continued with established background therapy for COPD, including dosage and regimen.

[0480] Patients were required to willingly continue their established background medications for COPD throughout the treatment period. After successful management of acute exacerbations of COPD (e.g., with oral corticosteroids and / or antibiotics), all efforts were made to restart the initial background COPD treatment regimen if, in the opinion of the investigator, this was medically acceptable. Background medications should not have been adjusted during screening. After one severe or two moderate exacerbations of COPD, dose adjustments in background therapy were permitted as needed for symptom control and for the remainder of the study period. Adjustments to background medications were permitted at the discretion of the investigator if deemed clinically necessary during the post-treatment period.

[0481] Palliative care Pain relievers were supplied by the facility and reimbursed by the sponsor's local affiliates in accordance with national regulations or as required locally. Patients were permitted to receive albuterol / salbutamol or levalbuterol / levosalbutamol or ipratropium or ipratropium / short-acting β-agonist [SABA] combination or terbutaline as needed during the study. Spray solutions were permitted as an alternative method of delivery. Formulations were MDI, spray solution or DPI. The route of administration was oral inhalation. The administration regimen was as prescribed.

[0482] The testers converted the use of salbutamol / albuterol sprayers and levosalmolamol / levalbuterol sprayers as shown in the table below.

[0483] [Table 33]

[0484] Example of conversion from salbutamol / albuterol nebulizer to inhalation (puff): The patient received three salbutamol / albuterol nebulizer treatments (2.5 mg / treatment) between 7:00 AM and 11:00 AM. The total daily dose was 7.5 mg or 12 inhalations.

[0485] [Table 34]

[0486] Example of conversion from levosalbutamol / levalbuterol nebulizer to inhalation: The patient received three levosalbutamol / levalbuterol nebulizer treatments (1.25 mg / treatment) between 7:00 AM and 11:00 AM. The total daily dose was 3.75 mg or 12 inhalations.

[0487] [Table 35]

[0488] Example of conversion from ipratropium or ipratropium / SABA nebulizer to inhalation: The patient received three ipratropium or ipratropium / SABA nebulizer treatments (0.5 mg ipratropium / treatment) between 7:00 AM and 11:00 AM. The total for the day was 1.5 mg or 12 inhalations.

[0489] Storage and handling IMP adjustment Patients were provided with either dupilumab or a corresponding placebo in a glass pre-filled syringe.

[0490] Method for assigning patients to treatment groups Patients were randomized in a 1:1 ratio to receive one of the following SC regimens: dupilumab 300 mg q2w or placebo corresponding to dupilumab q2w.

[0491] Randomization was stratified at baseline by country and ICS dose (high-dose ICS [yes / no]). For example, in the Japanese population, the high dose of fluticasone propionate as an ICS for adults is >500mcg (DPI or HFA) or 401–800mcg (HFA). Warnings were incorporated into the IVRS / IWRS, and enrollment of patients who were current smokers (defined by smoking status at screening) was limited to 30% or less of all enrolled patients or 278 patients or less.

[0492] The investigational drug was provided at the time of the trial visit when the trial activities were summarized (Figures 2A-C). IMP returned from the patient's home was not provided again to the participant.

[0493] Methods of blinding Dupilumab and placebo were provided in identical 2 mL pre-filled syringes. To ensure blinding, each 2 mL (dupilumab / placebo) glass pre-filled syringe treatment kit was prepared so that the treatment (dupilumab and its corresponding placebo) was identical and indistinguishable, and labeled with the treatment kit number.

[0494] In a double-blind design, study patients, principal investigators, and site personnel remained blinded to the study treatment and did not have access to the randomized arm or IMP contents (dupilumab or placebo).

[0495] Combination therapy The following concomitant medications are not permitted during the trial after screening: Use of any biological agent with a half-life of 5 or less of the compound before participating in the study (6 months if the half-life is unknown) and during the course of the study.

[0496] Use of PDE4 inhibitors (roflumilast) and theophylline during the course of the trial is prohibited unless the patient has been stable for more than 6 months prior to the screening visit.

[0497] Except for AECOPD, in new chronic use of macrolide antibiotics (e.g., azithromycin), the macrolide may be used for up to 28 days.

[0498] Systemic immunosuppressants, including the chronic use of systemic corticosteroids (e.g., methotrexate, any anti-TNF mAb, B-cell and / or T-cell targeted immunosuppressive therapies).

[0499] Intravenous immunoglobulin (IVIG) therapy.

[0500] Live attenuated vaccine.

[0501] Beta-adrenergic receptor blockers (excluding selective beta-1 adrenergic receptor blockers used at a stable dose one month prior to the first visit).

[0502] Other investigational drugs.

[0503] The following is a list of permitted concomitant medications during the trial: Maintenance therapy for COPD with ICS, LABA, and LAMA at stable dosages.

[0504] Systemic corticosteroids for acute exacerbations of up to 6 weeks.

[0505] Rescue medication consisting of a SABA or a short-acting antimuscarinic agent (e.g., atrovent).

[0506] Any medications or vaccines (including over-the-counter or prescription drugs, vitamins and / or herbal supplements) that participants were receiving at the time of registration or during the trial had to be recorded, along with dosage information including the reason for use, start and end dates of administration, and dosage and frequency.

[0507] Post-trial intervention Upon completion of the treatment period (52 weeks) or early termination, the study drug was no longer provided to the participants.

[0508] Discontinuation of research intervention Withdrawal of consent to a procedure (i.e., discontinuation of the procedure at the patient's request) was distinguished from withdrawal of (additional) consent to follow-up visits and withdrawal of consent to non-patient contact follow-up (e.g., checking medical records). The facility recorded any withdrawal of consent.

[0509] IMP was continued whenever possible. If IMP was stopped, a temporary shutdown was considered feasible, and permanent shutdown of IMP was a last resort. Any termination of IMP was fully recorded in the eCRF.

[0510] Permanent cancellation Permanent discontinuation of intervention meant discontinuing the intervention at any point during the trial period when the principal investigator decided not to re-expose the patient to IMP, or when there was a definitive decision that the patient would not be re-exposed to IMP for any reason.

[0511] Every effort was made to document the reasons for the trial's discontinuation, and this has been documented in the eCRF.

[0512] The patient must withdraw from the trial for the following reasons: At the patient's own request or at the request of a legally authorized representative (a legally authorized representative means an individual, judicial body, or other body authorized under applicable law to give consent on behalf of a patient who is willing to participate in the procedures involving the study).

[0513] If, in the opinion of the principal investigator, continuing the trial intervention is detrimental to the patient's health.

[0514] In response to specific requests from sponsors.

[0515] If a deviation from the protocol occurs at the discretion of the principal investigator or sponsor.

[0516] If the code requested by the principal investigator was violated, it resulted in the permanent discontinuation of the trial intervention.

[0517] If you become pregnant.

[0518] In cases of anaphylactic or systemic allergic reactions related to IMP that require treatment.

[0519] Diagnosis of experimental malignancies, excluding intraepithelial carcinoma of the cervix or squamous cell carcinoma or basal cell carcinoma of the skin.

[0520] Any opportunistic infection, such as TB or other infections, whose nature or course may suggest an immunocompromised state.

[0521] Serum ALT > 3 ULN and total bilirubin > 2 ULN.

[0522] If baseline ALT is ≤2 ULN, serum ALT is >5 ULN; or if baseline ALT is >2 ULN, ALT is >8 ULN.

[0523] If a patient failed to receive the drug four or more consecutive doses, the patient was permanently discontinued from the study intervention.

[0524] Abnormal clinical laboratory values ​​or ECG parameters should be immediately retested for confirmation before deciding to permanently discontinue IMP in the affected patient.

[0525] Temporary discontinuation of the trial intervention Temporary discontinuation of the trial intervention may be considered by the principal investigator due to adverse events (AEs). Treatment with IMP was restarted under close and appropriate clinical and / or laboratory monitoring when the principal investigator, acting in accordance with their best medical judgment, considered the AEs to be sufficiently resolved and the likelihood of recurrence after restarting IMP treatment to be low.

[0526] In addition, the following conditions were grounds for temporary discontinuation of the trial intervention: infections or parasitic conditions that did not respond to medical treatment, and any abnormal laboratory values ​​that met the criteria for temporary discontinuation of treatment.

[0527] For all temporary discontinuations of the trial intervention, the duration must be recorded in the eCRF by the principal investigator. Following a temporary interruption or medication error, IMP treatment should have been resumed with the next scheduled dose while maintaining the original dose.

[0528] Disease-Specific Efficacy Scale Severity of COPD exacerbations as defined by protocol A "moderate exacerbation" was recorded by the principal investigator and defined as AECOPD requiring either systemic corticosteroids (intramuscular, intravenous, or oral, etc.) and / or antibiotics. A "severe exacerbation" was recorded by the principal investigator and defined as AECOPD requiring hospitalization, or requiring >24-hour observation in an emergency / emergency medical facility, or resulting in death.

[0529] All other exacerbations were classified as "mild."

[0530] For both moderate and severe events to be counted as separate events, they must be separated by at least 14 days.

[0531] Clinical symptoms of COPD exacerbations In addition to the exacerbations defined in the COPD protocols listed above, clinical signs and symptoms of COPD exacerbations (including, but not limited to, increased dyspnea, increased wheezing, increased cough, increased sputum volume, and / or increased purulent sputum) were incorporated into the eCRF.

[0532] Management of COPD exacerbations COPD exacerbations were managed as deemed necessary by the investigator. Following successful management of acute COPD exacerbations (e.g., with oral corticosteroids and / or antibiotics), all efforts were made to restart the initial background COPD treatment regimen if, in the investigator's opinion, this was medically acceptable. After one severe or two moderate exacerbations of COPD, dose adjustments in background therapy were permitted as needed for symptom control and for the remainder of the study period.

[0533] COPD exacerbation events, as defined in the protocol, were collected as efficacy endpoints via the exacerbation eCRF. These events should not have been reported as AEs unless they met the severity criteria.

[0534] Spirometry Spirometry performed upon arrival at the clinical facility should have been conducted in accordance with the European Respiratory Society (ERS) / American Thoracic Society (ATS) guidelines and prior to administration of the investigational drug. (See Miller, et al. “ATS / ERS TASK FORCE: Standardization of Lung Function Testing” Eur Resir J. 2005 Aug;26(2):319-38).

[0535] Spirometry was performed on pre-administration bronchodilator parameters, including FEV1, FVC, and forced expiratory flow (FEF) 25%–75%, after the bronchodilator washout period according to the duration of action of the bronchodilator. For example, the final dose of salbutamol / albuterol or levosalbutamol / levalbuterol was withheld for at least 6 hours, the final dose of LABAs for at least 12 hours (long-acting LABAs such as vilanterol should be withheld for at least 24 hours), the final dose of ipratropium for at least 8 hours, and the final dose of LAMAs for at least 24 hours. This was validated before performing the measurements.

[0536] When spirometry was evaluated both before and after bronchodilator administration, post-bronchodilator spirometry was performed in accordance with the mechanism of action of the palliative (i.e., 30 minutes for albuterol or another SABA).

[0537] Spirometry was performed at every visit, usually in the morning, with afternoon / evening spirometry permitted only in exceptional circumstances where morning spirometry could not be performed. Spirometry should have been performed at approximately the same time at each visit throughout the study. Existing smokers were instructed not to smoke at least one hour before spirometry. Spirometry was performed at every visit using the same spirometer and standard spirometric techniques, including calibration, and the same person performed the measurements whenever possible.

[0538] Where possible, three measurements meeting the ATS acceptance and reproducibility criteria were obtained at each visit.

[0539] Patient-Reported Outcome Questionnaire An electronic diary was issued to the patient during screening (visit 1). The patient was instructed and trained on the use of the device by a member of the clinical staff, and written instructions regarding the use of the electronic device were provided to the patient.

[0540] During screening and treatment, patients used an electronic diary daily to complete questions on the COPD exacerbation and symptom scales of the EXACT tool and to record the use of established controller inhalation therapy. The electronic diary was used for other patient-related questionnaires, such as the SGRQ from the protocol. During the post-IMP treatment period, patient responses were not recorded daily in the electronic diary. Patient-reported outcome questionnaires were completed upon facility visit before any other assessments or procedures.

[0541] St.George Respiratory Questionnaire (SGRQ) The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire designed to measure and quantify the health status of adult patients with chronic airflow limitation. (See Jones et al. “The St George's Respiratory Questionnaire” Respir Med. 1991 Sep;85 Suppl B:25-31;discussion 33-7). The global score ranges from 0 to 100. Scores for each item (dimension) are calculated across three domains: symptoms, activities and impacts (psychosocial), and the overall score. A lower score indicates a better quality of life (QoL).

[0542] Part 1 ("Symptoms") assesses relative symptoms, including the frequency and severity of cough, sputum production, wheezing, and shortness of breath, as well as the duration and frequency of shortness of breath or wheezing episodes. Part 2 has two components: "Activity" and "Impact." The "Activity" section addresses impairments to the patient's daily physical activity. The "Impact" section covers the various impacts that the chest disease may have on the patient's daily living and psychosocial functioning (e.g., activities and functions of daily living, work, physical functioning, emotional impact, discrimination, and the patient's perception during treatment). The recall period for the questionnaire is the past four weeks.

[0543] The psychometric test has demonstrated reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. The minimum change in a 4-unit score has been established as clinically relevant after examination of both the patient and the clinician. The SGRQ is used in a variety of disease groups, including asthma, COPD, and bronchiectasis.

[0544] Exacerbation tool for chronic lung disease (EXACT) The EXACT tool quantifies and measures COPD exacerbations and assesses the signs of these exacerbations. This tool is a diary consisting of a total of 14 items representing the following domains: shortness of breath (5 items), cough and sputum (2 items), chest symptoms (3 items), difficulty in coughing (1 item), fatigue or weakness (1 item), sleep disturbance (1 item), and anxiety or worry (1 item).

[0545] The tool's development and validation history is consistent with guidelines proposed by the FDA, EMA, and well-known measurement principles. The EXACT total score assesses COPD exacerbations. A higher score indicates more severe symptoms.

[0546] The Respiratory Symptom Assessment (E-RS) (E-RS:COPD) scale is part of the EXACT tool. It is a derivative used to measure the effectiveness of treatment on the severity of respiratory symptoms in stable COPD. The E-RS utilizes 11 respiratory symptom items included in the 14-item EXACT. The RS-Total Score represents the overall severity of respiratory symptoms. Three subscales can be used to assess the following: 1) Shortness of breath (RS-Shortness of breath), 2) Cough and sputum (RS-Cough and sputum), and 3) Chest-related symptoms (RS-Chest symptoms). A higher score indicates more severe symptoms.

[0547] Five levels of Euro Quality of Life - 5 Dimension Questionnaire (EQ-5D-5L) The EQ-5D-5L is a standardized health quality of life questionnaire developed by the EuroQol Group to provide a simple and common measure of health for clinical and economic assessment. The EQ-5D is designed to be self-completed by the patient. The EQ-5D consists of a descriptive system and an EQ visual analog scale (VAS). The descriptive system includes five items: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each item has five levels: no problem, mild problem, moderate problem, severe problem, and very serious problem. The EQ VAS records the patient's subjective sense of health on a vertical visual analog scale.

[0548] Other clinical outcome assessments Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index (BODE Index) The BODE index is a composite scale composed of performance outcome measures, patient-reported outcome measures, and biomarkers. The BODE index is a multidimensional scoring system for evaluating the respiratory and systemic manifestations of COPD (Celli et al. “The Body-mass Index, Airflow obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease” N Engl J Med. 2004 Mar 4;350(10):1005-12). It includes four domains: 1) degree of lung impairment (FEV1), 2) patient's perception of symptoms (mMRC), and two independent domains: 6-minute walk distance (6MWD) and body mass index (BMI). Each domain can be scored independently, and the global score ranges from 0 to 10, with higher scores indicating a higher risk of death.

[0549] Safety evaluation The same safety assessment was applied to both arms. Adverse events, including standard adverse events (SAEs) and particularly noteworthy adverse events (AESIs), were collected at each visit.

[0550] Physical examination A comprehensive physical examination included the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, digestive system, nervous system, lymphatic system, and musculoskeletal system. All deviations from normal, including those attributable to the patient's disease, were recorded.

[0551] The principal investigator paid special attention to clinical signs related to prior serious illness or signs of infection. New clinically significant findings or worsening of prior findings were reported as new adverse events.

[0552] Pharmacokinetics Blood samples were collected to determine functional dupilumab and anti-dupilumab antibodies in the serum. The date and time of collection were recorded in the patient's e-CRF.

[0553] Pharmacodynamics Pharmacodynamic variables / biomarkers Pharmacodynamic responses to selected biomarkers, including PARC, eotaxin-3, FeNO (after bronchodilator administration), total IgE, and fibrinogen, were assayed. Serum / plasma were collected for storage. Induced sputum for RNA expression was also collected (this was optional for patients at some institutions).

[0554] whole blood biomarkers Eosinophil and neutrophil counts were measured as part of the total white blood cell count (WBC) including the standard 5-part differential count using an automated hematology analyzer.

[0555] Plasma / serum biomarkers PARC was assayed using validated enzyme immunoassays. Fibrinogen was also assayed. Eotaxin-3 was measured in heparinized plasma using validated enzyme immunoassays. Total IgE was measured using a quantitative method approved for diagnostic testing (e.g., Phadia ImmunoCAP).

[0556] Exhaled nitric oxide FeNO was analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden) or a similar analyzer at a flow rate of 50 mL / second, and reported in parts per billion (ppb). This evaluation was performed prior to spirometry and after at least one hour of fasting.

[0557] Pharmacogenomics Pharmacogenetic / pharmacogenomics testing was optional and voluntary. Written informed consent was obtained before sampling. For patients who consented to the optional pharmacogenetic / pharmacogenomics sample collection section of the Informed Consent Form (ICF), blood samples for exploratory genetic analysis of DNA or RNA were collected at the time of the trial visit as specified in the SoA, and these samples were stored for future analysis.

[0558] Use of medical resources Questionnaires regarding the use of medical resources (including palliative care, physician consultations, hospitalization, visits to emergency or emergency medical facilities, and sick leave, including loss of normal working days) were collected by the principal investigator from all participants throughout the study.

[0559] result The results of the BOREAS trial are shown in Figures 3 to 10. In summary, dupilumab was safe and effective in patients with uncontrolled COPD accompanied by type 2 inflammation. These patients had uncontrolled moderate to severe COPD and type 2 inflammation (screening Eos ≥ 0.3 Giga / L) despite standard treatment (LABA + LAMA + ICS unless ICS was contraindicated).

[0560] The BOREAS trial met all multiplicity-adjusted endpoints. Compared to baseline, dupilumab improved moderate to severe exacerbations, lung function (FEV1), HRQoL / health status as measured by SGRQ, and symptoms as measured by ERS:COPD RS total score in patients with COPD with type 2 inflammation. The following results were observed: • A statistically significant and clinically meaningful reduction in the annual rate of moderate to severe exacerbations (relative risk reduction of 30% (RRR), p=0.0005). • Rapid and sustained improvement in lung function. At week 12, LSM diff FEV1 was +83 ml (p<0.0001), which was consistent with week 52. • Consistently higher benefits for exacerbation and FEV1 (multiplicity adjusted) in the FeNO ≥ 20 ppb subgroup. • Rapid and sustained improvement in HRQoL (LSM diff SGRQ -3.363 at week 52 (p=0.0017) and SGRQ ≥ 4 (placebo (pbo) 43.1% vs. dupilumab (dupi) 51.5%, p=0.0089)), • Rapid and sustained improvement of all symptoms (shortness of breath, cough / sputum, chest). At week 52, LSM diff ERS-COPD tot-1.137 (p=0.0012), and Benefits were observed across multiple subgroups of demographic, clinical, and biomarker subgroups.

[0561] In addition, dupilumab therapy was well-tolerated, exhibiting a safety profile that was generally consistent with the known safety profile of dupilumab. The incidence of TEAEs was similar between dupilumab and placebo (pbo 76% vs. dupi 77%). SAEs (16% pbo vs. 14% dupi) and TEAEs leading to treatment discontinuation were similar between the treatment groups (pbo 3.4% vs. dupi 3.0%). • TEAEs differed by 1%, with a prevalence of ≥2%. In the placebo (pbo) group, more common adverse events included URTIs, LRTIs, pneumonia, COVID-19, hypertension, and gastroenteritis. In the dupilumab (dupi) group, more common adverse events included headache, back pain, UTIs, diarrhea, gastritis, and toothache. • TEAEs leading to death were balanced between treatment groups (pbo 1.7% vs dupi 1.5%), including deaths due to OJ (pbo 0.6% vs dupi 0.2%). • COPD-related SOCs (State of Emergency Conditions) of the respiratory, cardiovascular, and vascular systems, plus adj. MACE, were more frequent with placebo (placebo vs. Dupixent: 17% vs. 16%, 8.5% vs. 7.0%, 9.6% vs. 7.0%, 1.9% vs. 0.9%, respectively). • TEAE COVID-19 was higher in the placebo group (pbo 8.1% vs dupi 6.2%). • Malignant tumors were generally well-balanced across treatment groups (pbo 1.9% vs dupi 1.7%). • The incidence of AESIs or other selected AEs during treatment was balanced across treatment groups. A small number of opportunistic AESIs included one case of TB and one case of post-treatment aspergillosis in the dupi group, as well as two cases of herpes zoster in the pbo group and one case in the dupi group. • No adverse events associated with eosinophilia, no reports of keratitis, severe conjunctivitis / blepharitis or parasitic infections, and There were no significant differences in the test results.

[0562] patient A total of 939 participants were randomized (468 in dupilumab and 471 in placebo). A high percentage of participants completed the 52-week study period (95.1% in dupilumab vs. 93.4% in placebo, Figure 29). Participant demographic and disease characteristics were balanced between groups at baseline (Figures 13A-13E). The mean (SD) age of participants was 65.1 (8.1) years. Participants were predominantly male and non-Hispanic / Latino Caucasian. Overall, 30.0% of participants were current smokers, and 27.4% were taking high-dose ICS (≥1000 μg of beclomethasone dipropionate equivalent (Table 12)).

[0563] [Table 36]

[0564] Almost all participants (97.6%) were receiving triple therapy with ICS + LAMA + LABA. The mean number of moderate or severe exacerbations in the previous year, SGRQ score, and E-RS score were similar between groups. The mean (SD) baseline absolute serum eosinophil count was 401 (298) cells / μL, and the FENO level was 24.33 (22.40) ppb.

[0565] Primary endpoints Annual rate of COPD exacerbations The mean annual rate of moderate or severe exacerbations in the dupilumab group was 0.776 per year (rate ratio to placebo 0.705, 95% confidence interval [CI] 0.581–0.857, p=0.0005), compared to 1.101 per year in the placebo group, which corresponds to a 30% relative risk reduction at the primary endpoint (Table 13).

[0566] [Table 37]

[0567] [Table 38]

[0568] [Table 39]

[0569] The cumulative mean number of moderate or severe exacerbations during the 52-week treatment period was lower in participants receiving dupilumab compared to placebo. Dupilumab delayed the time to the first moderate or severe exacerbation (hazard ratio 0.803 [95% CI 0.658~0.980], nominal p=0.0309).

[0570] Table 14 presents a summary of moderate or severe exacerbations during the 52-week treatment period. This includes all moderate or severe exacerbation events that occurred during the 52-week treatment period, regardless of whether the participant was receiving treatment.

[0571] [Table 40]

[0572] Secondary endpoints and other endpoints Lung function Treatment with dupilumab resulted in a statistically significant improvement in lung function (pre-BD FEV1) within the first two weeks of initial administration and was sustained throughout the study. At week 12, the least squares mean (LSM) change in pre-BD FEV1 from baseline was 0.160 L with dupilumab compared to 0.077 L with placebo (LSM difference 0.083 L, 95% CI 0.042–0.125, p<0.0001), and this improvement persisted throughout week 52 (LSM difference 0.083 L, 95% CI 0.038–0.128, p<0.001). Several pulmonary function parameters, including post-BD FEV1, post-BD FEV1 / FVC ratio, pre-BD FVC, and pre-BD forced expiratory flow rate (FEF 25%-75%), were improved by dupilumab compared to placebo (Figures 31A-31B).

[0573] Patient-related outcomes Dupilumab improved the total SGRQ score at week 52 compared to placebo (-9.732 vs. -6.369, LSM difference -3.363, 95% CI -5.459 to -1.266, p=0.0017). This improvement was rapid and sustained (Figure 30A). A higher proportion of participants in the dupilumab group compared to the placebo group was associated with an improvement in SGRQ score exceeding the minimum clinically significant difference of 4 units at week 52 (dupilumab 51.5% vs. placebo 43.1%, odds ratio (OR) 1.439, 95% CI 1.096 to 1.890, p=0.0089).

[0574] Dupilumab treatment compared to placebo was associated with a significantly greater reduction in the E-RS:COPD total score from baseline to week 52 (LSM change -2.694 vs. -1.558, LSM difference -1.137, 95% CI -1.823 to -0.450, p=0.0012) (Figure 30B). Participants reported a decrease in symptom severity as early as week 2, and these decreases persisted until week 52.

[0575] Subgroups with FeNO ≥ 20 ppb In a subgroup of patients with FeNO ≥ 20 ppb, dupilumab reduced the annual rate of moderate or severe exacerbations by only 37% compared to placebo (rate ratio 0.625 to placebo, 95% CI 0.450–0.869, p=0.0052) (Table 12). Dupilumab resulted in a 0.124 L improvement in pre-BD FEV1 at week 12 compared to placebo (LSM difference 0.127 L, 95% CI 0.042–0.212, p=0.0034) over 52 weeks (LSM difference, 95% CI 0.045–0.203, p=0.0022).

[0576] Biomarkers for type 2 inflammation Dupilumab substantially reduced FENO, serum IgE, lung and activated regulatory chemokine (PARC) and eotaxin levels, as well as other markers of type 2 inflammation, throughout the entire 52-week treatment period (Table 15).

[0577] [Table 41]

[0578] [Table 42]

[0579] Subgroups with serum eosinophil counts of <300 cells / μL or ≥300 cells / μL at baseline. Dupilumab demonstrated a greater improvement from baseline in pre-BD FEV1 at week 52 in a subgroup of patients with baseline serum eosinophil counts ≥300 cells / μL (Table 16). The median change from baseline in serum eosinophils was -30.00 cells / μL in both groups at week 52.

[0580] No clinically symptomatic eosinophilia was observed.

[0581] [Table 43]

[0582] [Table 44]

[0583] [Table 45]

[0584] safety Dupilumab was generally well-tolerated in terms of its safety profile, consistent with the known safety profiles for other approved indications. Overall, more participants receiving dupilumab completed the trial (dupilumab 95.1% vs. placebo 93.4%), and the proportion of participants experiencing TEAEs was similar between the groups (dupilumab 77.4% vs. placebo 76.0%). Adverse events (AEs) more commonly observed with dupilumab than with placebo included headache (8.1% vs. 6.8%), diarrhea (5.3% vs. 3.6%), and lower back pain (5.1% vs. 3.4%). TEAEs leading to treatment discontinuation (dupilumab 3% vs. placebo 3.4%), and TEAEs leading to SAEs and death were well-balanced between the groups. Adverse events in the organ-specific categories commonly reported in COPD, including major cardiovascular events, respiratory, cardiac, and vascular events, were more frequent in the placebo group (placebo vs. dupilumab: 17.0% vs. 16.0%, 8.5% vs. 7.0%, 9.6% vs. 7.0%, and 1.9% vs. 0.9%, respectively).

[0585] conclusion In two phase 3 trials, dupilumab significantly reduced moderate to severe exacerbations, improved lung function (FEV1), HRQoL / health status (SGRQ), and symptoms (E-RS: COPD RS-total score), shortened the annual total SCS treatment duration associated with exacerbations, and reduced the course of total SCS due to exacerbations and moderate to severe exacerbations in patients with COPD with type 2 inflammation. The efficacy of dupilumab was rapid, observed as early as week 2, and sustained well to week 52 across all multiplicity-adjusted endpoints. By week 12, dupilumab improved FEV1 (unadjusted for pbo) by only +160 ml in ITT and blFeNO by only +232 ml at approximately 20 ppb. Improvements in lung function were observed across multiple parameters, including FEV1, FVC, and FEV1 / FVC after BO administration. Symptom improvement was observed in all domains of E-RS:COPD (dyspnea, cough and sputum, chest symptoms). Consistent benefits were observed regardless of demographics, ICS dose (high / low), smoking status, GOLD severity of airflow limitation (baseline), and history of exacerbations. Increased improvement was observed with increasing levels of type 2 biomarkers. The safety profile was generally consistent with other dupilumab indications.

[0586] Dupilumab reduced type 2 biomarkers (serum EOS, FeNO, and IgE) over time.

[0587] Dupilumab reduced the use of systemic corticosteroids (courses and durations) and antibiotics (courses and durations).

[0588] Dupilumab was well-tolerated with a safety profile consistent with its known safety profile. No new safety concerns were observed. Fewer cardiac and respiratory events were observed in patients treated with dupilumab. Overall, the incidence of malignancies and mortality was balanced.

[0589] In BOREAS, the mean (SD) post-BD FEV1 was 1.39 L (0.47) with dupilumab and 1.41 L (0.47) with placebo. At week 12, the mean least squares (LS) change from baseline in FEV1 after BD administration was 0.156 L (95% CI 0.121~0.192) for dupilumab compared to 0.084 L (95% CI 0.048~0.120) for placebo (mean LS difference 0.072 L [95% CI 0.030~0.115], nominal P=0.001). At week 52, the mean LS change from baseline in FEV1 after BD administration was 0.138 L (95% CI 0.101~0.174) for dupilumab compared to 0.058 L (95% CI 0.021~0.096) for placebo (mean LS difference 0.079 L [95% CI [0.034~0.124], nominal P=0<001). At week 52, the proportion of patients whose post-BD FEV1 increased to ≥100 mL was 38.3% in the dupilumab group and 29.5% in the placebo group. The mean [SD] baseline post-BD FEV1 / FVC ratio was 0.49 (0.12) in the dupilumab group and 0.49 (0.11) in the placebo group. At week 12, the mean change in LS from baseline in FEV1 / FVC after BD administration was 0.037 (95% CI 0.030~0.044) for dupilumab compared to 0.023 (95% CI 0.015~0.030) for placebo (mean LS difference 0.014 [95% CI 0.005~0.023], nominal P=0.002). At week 52, the mean change in LS from baseline FEV1 / FVC after BD administration was 0.033 (95% CI 0.025~0.041) for dupilumab compared to 0.023 (95% CI) for placebo. The range was 0.016 to 0.031 (mean difference in LS 0.010 [95% TBC -0.000 to 0.019], nominal P = 0.055). The results indicate that dupilumab improved post-BD FEV1 and FEV1 / FVC ratio as early as week 2 in patients with COPD and T2 inflammation.

[0590] Baseline pre-BD FEV1 was 1.28 L (SD) for dupilumab and 1.32 L (SD) for placebo. At week 12, the mean least squares (LS) change from baseline in FEV1 before BD administration was 0.160 L (95% CI 0.126~0.195) for dupilumab compared to 0.077 L (95% CI 0.042~0.112) for placebo (mean difference 0.083 L [95% CI 0.042~0.125], P<0.001). At week 52, the mean change in LS from baseline in FEV1 before BD administration was 0.153 L (95% CI 0.116~0.189) for dupilumab compared to 0.070 L (95% CI 0.033~0.107) for placebo (mean difference 0.083 L [95% CI 0.038~0.128], P<0.001). At week 52, the percentage of patients who improved their pre-BD FEV1 to ≥100 mL was 41.1% in the dupilumab group and 34.3% in the placebo group. The mean (SD) pre-BD FVC was 2.71 L (0.74) in the dupilumab group and 2.83 L (0.90) in the placebo group. At week 12, the mean change in LS from baseline in FVC before BD administration was 0.098 L [95% CI 0.054~0.141] in the dupilumab group compared to 0.029 L [95% CI -0.015~0.072] in the placebo group (mean LS difference 0.069 [95% CI 0.016~0.121], nominal P=0.01). At week 52, the mean change in LS from baseline in FVC before BD administration was 0.079 L [95% CI 0.032~0.127] in the dupilumab group compared to -0.009 L [95% CI -0.057~0.039] in the placebo group (mean LS difference 0.088 L [95% CI 0.029~0.148], nominal P=0.004). These results indicate that dupilumab improved pre-BD lung function measures as early as week 2 in patients with COPD and T2 inflammation.

[0591] Individual total annual exacerbation-related systemic corticosteroid (SCS) intake was shorter in dupilumab (18.73 days) compared to placebo (20.99 days). At weeks 12 and 52, dupilumab improved pre-BD administration FEV1 compared to placebo, with mean LS differences of 82 mL (P=0.0001) and 62 mL (P=0.0182), respectively. Dupilumab improved SGRQ scores at week 52 compared to placebo (mean LS difference -3.37, nominal P=0.0068). The adjusted total annual SCS courses taken due to exacerbations were 0.639 (0.535–0.763) in dupilumab patients compared to 0.966 (0.817–1.142) in placebo.

[0592] Consideration Dupilumab significantly reduced moderate or severe exacerbations in symptomatic COPD patients at high exacerbation risk who had evidence of type 2 inflammation and were receiving optimized inhalation therapy. Dupilumab also significantly improved lung function, health-related quality of life, and respiratory symptom severity, with benefits observed as early as two weeks after initiation of treatment and sustained throughout the 52-week treatment period. These results highlight a significant unmet need in this patient population who have evidence of type 2 inflammation, remain symptomatic, and experience exacerbations while receiving standard triple inhalation therapy.

[0593] Studies investigating IL-5 or its receptor-targeted biological agents have shown limited effects on other aspects of type 2 inflammation, and so far, mixed results regarding exacerbation reduction have been obtained. Despite the peripheral blood eosinophil depletion observed with these drugs, there is no evidence of improvement in lung function, quality of life, or symptoms (Pavord 2017; Criner 2019).

[0594] The BOREAS trial used serum eosinophil counts of ≥300 cells / μL as a biomarker to identify COPD patients with type 2 inflammation that constitute a COPD subgroup at high risk of exacerbation. IL-4 and IL-13 are broadly involved in several important type 2 inflammatory pathological processes in COPD, including inflammatory infiltration, airway fibrosis and remodeling, epithelial barrier dysfunction, goblet cell hyperplasia, mucociliary dysfunction, and mucus hypersecretion (GOLD 2023, Bade 2014).

[0595] In the BOREAS trial, the clinical benefit of dupilumab, a fully human monoclonal antibody that blocks the co-receptor components of IL-4 and IL-13, is to confirm the role of IL-4 and / or IL-13 in the pathophysiology of this COPD subpopulation with type 2 inflammation.

[0596] Treatment with dupilumab resulted in a sustained reduction in FeNO, a biomarker reflecting IL-13 activity (Suresh 2007), and in patients with baseline FeNO ≥ 20 ppb, dupilumab was associated with a greater reduction in exacerbations and improvement in lung function. The magnitude of the larger response in participants with FeNO ≥ 20 ppb is consistent with the known important and central role of IL-4 / IL-13 in type 2 inflammation (Higham 2021, Kolsum 2017, Garudadri 2018, Barnes 2019). Through inhibition of the IL-4 / IL-13 pathway, dupilumab may play a unique role in reducing goblet cell hyperplasia, mucus hypersecretion, and airway remodeling. While not intended to be bound by scientific theory, this study suggests that airway obstruction may be reduced through changes in mucus, decreased airway inflammation, reduced edema, and / or decreased airway resistance, thus potentially improving FEV1, and the observed improvement in FVC may reflect improved air trapping. In addition, dupilumab may reduce upregulation of nitric oxide synthase, Th2 cell differentiation, and the recruitment of type 2 inflammation-associated effector cells such as eosinophils, mast cells, and basophils. All of these mechanisms of action may theoretically contribute to improvement of exacerbations, lung function, and bronchitis symptoms (Brightling 2010; Suresh 2007).

[0597] The strengths of the BOREAS trial include its large-scale, multinational nature, its strict exclusion of patients with current and historical asthma, and its consistent clinically relevant outcomes across multiple aspects of key COPD outcomes while maintaining a similar safety profile across treatment groups. The trial was conducted during the Covid-19 pandemic, which impacted the conduct of clinical research and patient exposure / behavior worldwide, resulting in limitations for the BOREAS trial, including recruitment challenges and reduced exacerbation rates. Despite these limitations, BOREAS demonstrated a low dropout rate, and dupilumab showed potent efficacy compared to placebo. Treatment was robust and consistent across multiple subgroups and regions. Despite extensive recruitment efforts to ensure a representative population, the number of self-identified Black / African American participants was low. Finally, while treatment randomization was not specifically stratified by smoking status, the final treatment group was balanced in this domain, suggesting this potential limitation is unlikely to impact outcomes.

[0598] By 2060, the World Health Organization estimates that there will be more than 5.4 million deaths annually attributable to COPD and related comorbidities (World Health Organization, 2023). Regardless of severity, COPD exacerbations lead to increased hospitalizations, higher mortality rates, and a reduced quality of life (Bollmeier 2020, Sato 2016, Seemungal 1998, Belanger 2018, Prudente 2021, David 2021, Ortega 2018).

[0599] BOREAS is the first trial of a biological agent to demonstrate a significant reduction in exacerbations and improvements in lung function, quality of life, and symptoms in COPD patients with type 2 inflammation.

[0600] References Kerkhof M,Voorham J,Dorinsky P,et al.Association between COPD exacerbations and lung function decline during maintenance therapy.Thorax.2020;75(9):744-753. The Global Initiative for Chronic Obstructive Lung Diseases(GOLD).Global Strategy for Diagnosis,Management and Prevention of COPD 2023 Report.goldcopd.org / wp-content / uploads / 2022 / 11 / GOLD-2023-ver-1.0-14Nov2022_WMV.pdf.Accessed April 03,2023. Celli BR,Fabbri LM,Aaron SD,et al.Differential Diagnosis of Suspected COPD Exacerbations in the Acute Care Setting:Best Practice.Am J Respir Crit Care Med.January 26,2023[Online ahead of print]atsjournals.org / doi / abs / 10.1164 / rccm.202209-1795CI. MacLeod M,Papi A,Contoli M,et al.Chronic obstructive pulmonary disease exacerbation fundamentals:Diagnosis,treatment,prevention and disease impact.Respirology 2021;26(6):532-551. Garudadri S,Woodruff PG.Targeting chronic obstructive pulmonary disease phenotypes,endotypes,and biomarkers.Ann Am Thorac Soc.2018;15(Suppl 4):S234-S238. Higham A,Beech A,Wolosianka S,Jackson N,Long G,Kolsum U,Southworth T,Pham TH,Sridhar S,McCrae C,Newbold P,Singh D.Type 2 inflammation in eosinophilic chronic obstructive pulmonary disease.Allergy.2021;76(6):1861-1864. Kolsum U,Damera G,Pham TH,et al.Pulmonary inflammation in patients with chronic obstructive pulmonary disease with higher blood eosinophil counts.J Allergy Clin Immunol.2017;140(4):1181-1184. Barnes PJ.Inflammatory endotypes in COPD.Allergy 2019;74(7):1249-1256. Bade G,Khan MA,Srivastava AK,et al.Serum cytokine profiling and enrichment analysis reveal the involvement of immunological and inflammatory pathways in stable patients with chronic obstructive pulmonary disease.Int J Chron Obstruct Pulmon Dis 2014;9:759-73. 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Bachert C,Han JK,Desrosiers M,et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps(LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52):results from two multicentre,randomised,double-blind,placebo-controlled,parallel-group phase 3 trials.The Lancet 2019;394(10209):1638-1650. Castro M et al.Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.N Engl J Med 2018;378:2486-2496. Pavord ID,Chanez P,Criner GJ,et al.Mepolizumab for eosinophilic chronic obstructive pulmonary disease.N Engl J Med.2017;377(17):1613-1629. Criner GJ,Celli BR,Brightling CE,et al.Benralizumab for the prevention of COPD exacerbations.N Engl J Med.2019;381(11):1023-1034. Suresh V,Mih JD,George SC.Measurement of IL-13-induced iNOS-derived gas phase nitric oxide in human bronchial epithelial cells.Am J Respir Cell Mol Biol.2007;37(1):97-104. Brightling CE,Saha S,Hollins F.Interleukin-13:prospects for new treatments.Clin Exp Allergy.2010;40(1):42-49. 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Prudente R,Ferrari R,Mesquita CB,et al.Peripheral blood eosinophils and nine years mortality in COPD patients.Int J Chron Obstruct Pulmon Dis 2021;16:979-985. David B,Bafadhel M,Koenderman L,De Soyza A.Eosinophilic inflammation in COPD:from an inflammatory marker to a treatable trait.Thorax 2021;76:188-195. Ortega H,Llanos JP,Lafeuille MH,et al.Burden of disease associated with a COPD eosinophilic phenotype.Int J Chron Obstruct Pulmon Dis 2018;13:2425-2433. Jones PW,Quirk FH,Baveystock CM,Littlejohns P.A self-complete measure of health status for chronic airflow limitation.The St.George’s Respiratory Questionnaire.Am Rev Respir Dis 1992;145(6):1321-7. Bafadhel M,Peterson S,De Blas MA,Calverley PM,Rennard SI,Richter K,Fageras M.Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease:a post-hoc analysis of three randomised trials.Lancet Respir Med.2018 Feb;6(2):117-126. 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[0601] Example 2. Dupixent significantly reduced COPD exacerbations in a second prospective Phase 3 trial, accelerating FDA application and confirming its potential to become the first approved biologic for this serious disease. In the interim analysis, the NOTUS trial met its primary endpoint with overwhelming efficacy, confirming the results from the groundbreaking BOREAS pivotal trial. Dupixent reduced exacerbations by only 34% compared to placebo in patients with moderate to severe COPD and evidence of type 2 inflammation (i.e., serum eosinophils ≥ 300 cells / μL). Dupixent also rapidly and significantly improved lung function (139 mL at FEV1) compared to placebo (57 mL at FEV1).

[0602] An interim analysis of the second clinical trial, the Phase 3 Chronic Obstructive Pulmonary Disease (COPD) trial (NOTUS), confirmed the positive published results from the groundbreaking Phase 3 BOREAS trial, which showed that Dupixent significantly reduced exacerbations (34%). This trial also confirmed that Dupixent treatment resulted in rapid and significant improvement in lung function by 12 weeks, sustained for up to 52 weeks. The NOTUS trial evaluated the investigational use of Dupixent compared to placebo in adults currently receiving maximum standard inhaled therapy (triple therapy) with evidence of uncontrolled COPD and type 2 inflammation ...

Claims

1. A method for treating a subject with chronic obstructive pulmonary disease (COPD), comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

2. A method for treating a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

3. A method for treating a subject with chronic obstructive pulmonary disease (COPD) accompanied by type 2 inflammation, comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

4. A method for treating a subject with moderate to severe chronic obstructive pulmonary disease (COPD) accompanied by type 2 inflammation, comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

5. A method for treating a subject with chronic obstructive pulmonary disease (COPD) that is not adequately controlled with background therapy, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

6. A method for treating a subject with chronic obstructive pulmonary disease (COPD) accompanied by unified airway disease (UAD), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

7. A method for treating a subject having chronic obstructive pulmonary disease (COPD), wherein the COPD is coexisting with at least one type 2 inflammatory disease, and the method comprises administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

8. The method according to any one of claims 1 to 7 or 45 to 50, wherein the subject has a baseline blood eosinophil count of ≥300 cells / μL, ≥350 cells / μL, ≥400 cells / μL, ≥450 cells / μL, or ≥500 cells / μL.

9. The method according to any one of claims 1 to 7 or 45 to 50, wherein the subject has a baseline blood eosinophil count of less than 300 cells / μL.

10. The method according to any one of claims 1 to 9, wherein the subject has a baseline exhaled nitric oxide (FeNO) concentration level of ≥20 ppb, ≥25 ppb, ≥30 ppb, ≥35 ppb, or ≥40 ppb.

11. The method according to any one of claims 1 to 9, wherein the subject has a baseline exhaled nitric oxide concentration (FeNO) level of less than 20 ppb.

12. The method according to any one of claims 1 to 11, wherein the subject has a baseline immunoglobulin E level (IgE) of ≥ 100 kU / L.

13. The method according to any one of claims 1 to 11, wherein the subject has a baseline immunoglobulin E level (IgE) of less than 100 kU / L.

14. The method according to any one of claims 1 to 13, wherein the COPD is oxygen-dependent COPD.

15. The method according to any one of claims 1 to 14, wherein the subject has chronic bronchitis.

16. The method according to any one of claims 1 to 15, wherein the subject has emphysema.

17. The method according to any one of claims 1 to 16, wherein the subject is a current smoker.

18. The method according to any one of claims 1 to 16, wherein the subject is a former smoker.

19. The method according to any one of claims 1 to 18, further comprising background therapy in addition to the antibody or its antigen-binding fragment.

20. The method according to claim 19, wherein the background therapy comprises an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), a leukotriene receptor antagonist (LTRA), a long-acting muscarinic antagonist (LAMA), methylxanthine, a phosphodiesterase inhibitor which is optionally roflumithrust or theophylline, or a mixture thereof.

21. The method according to claim 20, wherein the background therapy comprises LABA, LAMA, and ICS, and optionally, the COPD is not controlled at baseline despite the background therapy alone.

22. The method according to claim 20 or 21, wherein the background therapy includes a high dose of ICS.

23. The method according to claim 20 or 21, wherein the background therapy includes a non-high dose of ICS.

24. The method according to claim 20, wherein the background therapy comprises LABA and LAMA, and optionally, the COPD is not controlled at baseline despite the background therapy alone.

25. The method according to any one of claims 19 to 24, wherein inhaled corticosteroids (ICS) are contraindicated in the subject.

26. The method according to any one of claims 19 to 25, wherein the background therapy includes loflumithrust.

27. The method according to any one of claims 19 to 26, wherein the background therapy comprises theophylline.

28. The method according to any one of claims 1 to 27, wherein one or more COPD-related parameters are improved in the subject.

29. The one or more COPD-related parameters mentioned above are: (1) Annual rate of acute moderate or severe exacerbations of COPD (AECOPD), (2) Annual rate of severe AECOPD, (3) Time to the first moderate or severe AECOPD, (4) Forced expiratory volume in one second (FEV1) (before or after administration of bronchodilators), (5) forced vital capacity (FVC), (6) Forced expiratory flow rate (FEF) 25% to 75%, (7) Exhaled nitric oxide concentration (FeNO), (8) Exacerbation tool for chronic obstructive pulmonary disease (EXACT), (9) St. George Respiratory Questionnaire (SGRQ), (10) Evaluation of respiratory symptoms in COPD (E-RS: COPD), (11) Body Mass Index, airflow obstruction, dyspnea, exercise capacity (BODE) index, (12) Euro Quality of Life-5 Dimension Questionnaire (EQ-5D), (13) Modified British Medical Research Council Questionnaire (mMRC), (14) Health-related quality of life questionnaire (HRQoL), (15) Course of steroids (e.g., systemic corticosteroids) over a period of days, (16) Course of antibiotics over a period of days, (17) Resting respiratory rate, (18) FEV １ / FVC ratio, (19) Mucus plug, or Any combination of them The method according to claim 28, selected from the group consisting of the following.

30. The method according to any one of claims 1 to 29, wherein the treatment reduces the level of one or more biomarkers in the subject, selected from the group consisting of blood eosinophil (Eos) count, exhaled nitric oxide (FeNO) concentration level, serum immunoglobulin E level (IgE), eotaxin (e.g., eotaxin-3) level, and lung and activation control chemokine (PARC) levels.

31. The method according to any one of claims 1 to 30, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences each containing SEQ ID NOs: 3, 4, and 5, and three light chain CDR sequences each containing SEQ ID NOs: 6, 7, and 8.

32. The method according to any one of claims 1 to 31, wherein the antibody or its antigen-binding fragment is administered to the subject as an initial dose, followed by one or more secondary doses.

33. The method according to claim 32, wherein the initial dose is approximately 300 mg, and each of the one or more secondary doses is approximately 300 mg.

34. The method according to claim 33, wherein the secondary dose is administered every other week (q2w).

35. The method according to any one of claims 1 to 34, wherein the subject is at least 40 years old.

36. The method according to any one of claims 1 to 35, wherein, prior to the initiation of treatment, the subject has a baseline Medical Research Council (MRC) dyspnea scale grade score of ≥ 2 or a baseline modified Medical Research Council (mMRC) dyspnea scale grade score of ≥ 2.

37. The subject is a person with a history of high exacerbation risk, according to any one of claims 1 to 36.

38. The method according to any one of claims 1 to 37, wherein the subject has two or more severe exacerbations per year leading to hospitalization.

39. The method according to any one of claims 1 to 38, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO:

2.

40. The method according to claim 39, wherein the antibody is dupilumab.

41. The method according to any one of claims 1 to 40, wherein the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

42. The method according to claim 41, wherein the antibody or its antigen-binding fragment is administered using a pre-filled device.

43. The method according to any one of claims 1 to 42, wherein the antibody or its antigen-binding fragment is administered subcutaneously.

44. The method according to any one of claims 1 to 43, comprising the step of determining the baseline level of a biomarker selected from the group consisting of PARC, eotaxin-3, FeNO (after administration of a bronchodilator), total IgE, fibrinogen, and any mixture thereof, in the subject.

45. (1) Subjects with chronic obstructive pulmonary disease (COPD), (2) Subjects with moderate to severe COPD, (3) Subjects with COPD accompanied by type 2 inflammation, (4) Subjects with moderate to severe COPD accompanied by type 2 inflammation, (5) Subjects with COPD that is not adequately managed with background therapy, (6) Subjects with COPD accompanied by Unified Airway Disease (UAD), and (7) Subjects having COPD, wherein the COPD coexists with at least one type 2 inflammatory disease. A method for improving one or more symptoms in a subject selected from the group consisting of the above, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

46. (1) Subjects with chronic obstructive pulmonary disease (COPD), (2) Subjects with moderate to severe COPD, (3) Subjects with COPD accompanied by type 2 inflammation, (4) Subjects with moderate to severe COPD accompanied by type 2 inflammation, (5) Subjects with COPD that is not adequately managed with background therapy, (6) Subjects with COPD accompanied by Unified Airway Disease (UAD), and (7) Subjects having COPD, wherein the COPD coexists with at least one type 2 inflammatory disease. A method for reducing or preventing moderate to severe exacerbations in subjects selected from the group comprising administering to the subjects an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

47. (1) Subjects with chronic obstructive pulmonary disease (COPD), (2) Subjects with moderate to severe COPD, (3) Subjects with COPD accompanied by type 2 inflammation, (4) Subjects with moderate to severe COPD accompanied by type 2 inflammation, (5) Subjects with COPD that is not adequately managed with background therapy, (6) Subjects with COPD accompanied by Unified Airway Disease (UAD), and (7) Subjects having COPD, wherein the COPD coexists with at least one type 2 inflammatory disease. A method for delaying the progression of lung function decline in a subject selected from the group consisting of the above, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

48. (1) Subjects with chronic obstructive pulmonary disease (COPD), (2) Subjects with moderate to severe COPD, (3) Subjects with COPD accompanied by type 2 inflammation, (4) Subjects with moderate to severe COPD accompanied by type 2 inflammation, (5) Subjects with COPD that is not adequately managed with background therapy, (6) Subjects with COPD accompanied by Unified Airway Disease (UAD), and (7) Subjects having COPD, wherein the COPD coexists with at least one type 2 inflammatory disease. A method for improving the health-related quality of life of a subject selected from the group consisting of the above, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

49. (1) Subjects with chronic obstructive pulmonary disease (COPD), (2) Subjects with moderate to severe COPD, (3) Subjects with COPD accompanied by type 2 inflammation, (4) Subjects with moderate to severe COPD accompanied by type 2 inflammation, (5) Subjects with COPD that is not adequately managed with background therapy, (6) Subjects with COPD accompanied by Unified Airway Disease (UAD), and (7) Subjects having COPD, wherein the COPD coexists with at least one type 2 inflammatory disease. A method for delaying the time to the first moderate or severe exacerbation in a subject selected from the group comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

50. A method for treating a subject with uncontrolled chronic obstructive pulmonary disease (COPD), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R).

51. The method according to claim 50, wherein the subject is an adult.

52. The method according to claim 50, wherein the subject receives triple therapy in addition to the antibody or its antigen-binding fragment.

53. The method according to claim 52, wherein the triple therapy comprises treatment with an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

54. The method according to claim 50, wherein ICS is contraindicated, and the subject receives dual therapy in addition to the antibody or its antigen-binding fragment.

55. The method according to claim 54, wherein the two-drug combination therapy comprises LABA and LAMA.

56. The method according to any one of claims 50 to 55, wherein the antibody or its antigen-binding fragment is an add-on therapy.

57. The method according to any one of claims 50 to 55, wherein the antibody or its antigen-binding fragment is maintenance therapy.

58. The method according to any one of claims 50 to 55, wherein the antibody or its antigen-binding fragment is an add-on maintenance therapy.

59. The method according to claim 50, wherein the subject has a history of COPD exacerbation.

60. The method according to claim 50, wherein the subject has a biomarker for type 2 inflammation at an elevated level compared to a control.

61. The method according to claim 60, wherein the biomarker is the number of eosinophils in the blood.

62. The method according to any one of claims 50 to 61, wherein the subject has a baseline blood eosinophil count of ≥300 cells / μL, ≥350 cells / μL, ≥400 cells / μL, ≥450 cells / μL, or ≥500 cells / μL.

63. The method according to any one of claims 50 to 61, wherein the subject has a baseline blood eosinophil count of less than 300 cells / μL.

64. The method according to any one of claims 50 to 63, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO:

2.

65. The method according to claim 64, wherein the antibody is dupilumab.

66. A combination therapy for use in the treatment of uncontrolled chronic obstructive pulmonary disease (COPD) with type 2 inflammation, i) An antibody or its antigen-binding fragment that specifically binds to the interleukin-4 receptor (IL-4R), ii) COPD background therapy and Combination therapy including

67. The combination therapy according to claim 66, relating to the aforementioned uncontrolled COPD and a history of exacerbations.

68. The combination therapy according to claim 66 or 67, wherein the treatment reduces the subject's dependence on systemic steroids in the COPD background therapy.

69. The subject is an adult, and the combination therapy is as described in any one of claims 66 to 68.

70. The combination therapy according to any one of claims 66 to 69, wherein the subject is a human.

71. The combination therapy according to any one of claims 66 to 70, wherein the COPD background therapy is a triple combination therapy.

72. The combination therapy according to claim 71, wherein the three-drug combination therapy includes treatment with an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

73. The combination therapy according to claim 72, wherein ICS is contraindicated, and the subject receives dual therapy.

74. The combination therapy according to claim 73, wherein the two-drug combination therapy comprises LABA and LAMA.

75. The subject is a person with a history of COPD exacerbation, and the combination therapy described in any one of claims 66 to 74.

76. The combination therapy according to any one of claims 66 to 75, wherein the subject has a biomarker for type 2 inflammation at an elevated level compared to the control.

77. The combination therapy according to claim 76, wherein the biomarker is the number of eosinophils in the blood.

78. The combination therapy according to claim 77, wherein the subject has a baseline blood eosinophil count of ≥300 cells / μL, ≥350 cells / μL, ≥400 cells / μL, ≥450 cells / μL, or ≥500 cells / μL.

79. The combination therapy according to claim 78, wherein the subject has a baseline blood eosinophil count of less than 300 cells / μL.

80. The combination therapy according to any one of claims 66 to 79, wherein the antibody or its antigen-binding fragment comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO:

2.

81. The combination therapy according to claim 80, wherein the antibody is dupilumab.

82. The combination therapy according to any one of claims 66 to 81, wherein the subject has a baseline exhaled nitric oxide concentration (FeNO) level of ≥20 ppb, ≥25 ppb, ≥30 ppb, ≥35 ppb, or ≥40 ppb.

83. The combination therapy according to any one of claims 66 to 82, wherein the antibody or its antigen-binding fragment is administered to the subject as an initial dose, followed by one or more secondary doses.

84. The combination therapy according to claim 83, wherein the initial dose is approximately 300 mg, and each of the one or more secondary doses is approximately 300 mg.

85. The combination therapy according to claim 84, wherein the secondary dose is administered every other week (q2w).

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