Method for treating COPD by administering an IL-33 antagonist

Abstract

Methods for treating or preventing COPD and related conditions in a patient are provided, comprising administering to a subject in need thereof a therapeutic composition comprising interleukin-33 (IL-33), such as an anti-IL-33 antibody or antigen-binding fragment thereof.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 944,878, filed Dec. 6, 2019; U.S. Provisional Patent Application No. 62 / 964,966, filed Jan. 23, 2020; and U.S. Provisional Patent Application No. 63 / 082,502, filed Sep. 24, 2020. The entire disclosure of each of these applications is hereby incorporated by reference in its entirety herein.

[0002] The present invention relates to the treatment and / or prevention of chronic obstructive pulmonary disease (COPD) and related conditions. More particularly, the present invention relates to the administration of an interleukin-33 (IL-33) antagonist for treating or preventing COPD and / or reducing acute exacerbation of COPD (AECOPD) events in patients in need thereof.

Background Art

[0003] Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with an abnormal inflammatory immune response of the lungs to harmful particles and gases. Chronic inflammation causes destruction of the lung parenchyma, which results in structural changes, narrowing of the small airways, and loss of alveolar attachment to the small airways, reducing the elastic recoil of the lungs. Chronic inflammation leads to a progressive airway obstruction that is only partially reversible or even irreversible. The inflammatory components of COPD are thought to involve many cell types, including structural cells, T lymphocytes, neutrophils, macrophages, and their biological products. In some patients, eosinophils, T helper (Th) 2 or group 2 innate lymphoid cells may increase, especially when there is a clinical overlap with asthma. The main cause of COPD is smoking, but other factors such as air pollution, occupational exposure, and genetic susceptibility have been identified. The most common respiratory symptoms include chronic dyspnea, cough, and / or sputum production. This disease, especially in severe COPD, deteriorates further due to exacerbations. These are, in most cases, caused by viral and bacterial infections of the lungs that trigger an inflammatory response, tissue destruction, and resulting hypoxia. Exacerbations in COPD patients are associated with rapid disease progression (the rate of lung function declines over time) and an increased risk of death. Medical comorbidities such as cardiovascular disease, diabetes, lung cancer, skeletal muscle dysfunction, osteoporosis, psychological disorders, and metabolic syndrome are common among COPD patients and occur across the spectrum of disease severity.

[0004] Chronic obstructive pulmonary disease is a highly prevalent, severe, and progressive disease that causes significant morbidity, mortality, and economic burden (Non-Patent Document 1; Non-Patent Document 2). In the United States alone, there are over 12 million diagnosed patients, and the incidence of COPD is expected to increase rapidly with the aging of the population. COPD is a progressive, partially reversible or irreversible inflammatory lung disease that is periodically interrupted by disease exacerbations that result in long-term physical disability and death. Worldwide, approximately 3 million people die each year due to COPD. With the increasing prevalence of smoking in developing countries and the aging of the population in high-income countries, the prevalence is rising, and the number of deaths is expected to reach 4.5 million by 2030.

[0005] Standard treatment for moderate COPD is initiated with bronchodilators (e.g., long-acting muscarinic antagonists (LAMA) or long-acting β2 agonists (LABA)), and as the disease progresses, the bronchodilators are combined with other medications such as inhaled corticosteroids (ICS) and phosphodiesterase type 4 (PDE-4) inhibitors (roflumilast) (Non-Patent Document 3; Non-Patent Document 4). Major limitations of existing medications for COPD include modest efficacy and the risk of respiratory infections. Oral or systemic corticosteroids have an unacceptable long-term safety profile in the COPD population and are reserved for the treatment of exacerbations. There are no approved therapeutics that prevent the decline in forced expiratory volume in one second (FEV1) over time or alter the progressive disease pathway of COPD.

Prior Art Documents

Non-Patent Documents

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Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0007] Therefore, significant unmet medical needs continue to exist in the growing population of patients with COPD. Accordingly, there is a need in the art for new targeted therapies for the treatment and / or prevention of COPD and / or for the reduction of acute exacerbation of COPD (AECOPD) events.

Means for Solving the Problems

[0008] In one aspect, there is provided a method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering to the subject an antibody or an antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy-chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light-chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16. In one aspect, an antibody or an antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy-chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light-chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16 is provided for use in treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof.

[0009] In certain exemplary embodiments, one or more COPD-related parameters are improved in the subject. In certain exemplary embodiments, one or more COPD-related parameters are selected from the group consisting of the annual rate of moderate to severe acute exacerbations of COPD (AECOPD), the annual rate of severe acute exacerbations of COPD (AECOPD), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, fractional exhaled nitric oxide (FeNO), the number or dosage of chronic obstructive pulmonary disease (COPD) reliever medications, the number or dosage of systemic corticosteroids, the number or dosage of antibiotics, daily steps, the number or dosage of oral corticosteroids, resting oxygen saturation, and resting respiratory rate. In certain exemplary embodiments, pre-bronchodilator FEV1 is improved in the subject. In certain exemplary embodiments, the annual rate of AECOPD is reduced in the subject.

[0010] In certain exemplary embodiments, the score is improved for a subject with respect to one or more questionnaires or assessments selected from the group consisting of the Chronic Obstructive Pulmonary Disease Assessment Test (CAT), the St. George's Respiratory Questionnaire (SGRQ), the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT), the Evaluated Respiratory Symptoms in COPD (E-RS), the Body Mass Index, airway obstruction, dyspnea, the Body-Mass Index, airway obstruction, dyspnea, exercise capacity (BODE) index, and the EuroQol-5 Dimensions questionnaire (EQ-5D).

[0011] In certain exemplary embodiments, the COPD is moderate to severe COPD that is not well managed with background therapy. In certain exemplary embodiments, the background therapy comprises a treatment having at least two of the following: a long-acting β2-adrenergic agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS). In certain exemplary embodiments, the background therapy comprises LABA and LAMA. In certain exemplary embodiments, the background therapy comprises LABA and ICS. In certain exemplary embodiments, the background therapy comprises LAMA and ICS. In certain exemplary embodiments, the background therapy comprises a treatment having LABA, LAMA, and ICS.

[0012] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 0 (also known as SAR440340, REGN3500, or itepkinumab).

[0013] In certain exemplary embodiments, the subject has an eosinophil count in the blood of greater than or equal to about 250 cells per μl or less than 250 cells per μL prior to treatment. In certain exemplary embodiments, the subject has an eosinophil count in the blood of greater than or equal to about 250 cells per μl prior to treatment. In certain exemplary embodiments, the subject has an eosinophil count in the blood of greater than or equal to about 300 cells per μl or less than 300 cells per μL prior to treatment. In certain exemplary embodiments, the subject has an eosinophil count in the blood of greater than or equal to about 300 cells per μl prior to treatment. In certain exemplary embodiments, the FEV1 prior to bronchodilator administration is improved. In certain exemplary embodiments, the FEV1 after bronchodilator administration is improved. In certain exemplary embodiments, the FVC prior to bronchodilator administration is improved.

[0014] In certain exemplary embodiments, the subject is a current smoker, a former smoker, or a non-smoker. In certain exemplary embodiments, the subject is a former smoker. In certain exemplary embodiments, the former smoker has a smoking history of greater than or equal to 10 packs per year. In certain exemplary embodiments, the former smoker has abstained from smoking for at least 6 months. In certain exemplary embodiments, the smoker intends to permanently abstain from smoking.

[0015] In certain exemplary embodiments, the annual rate of moderate to severe AECOPD events is reduced in the subject. In certain exemplary embodiments, the time to the first moderate to severe AECOPD event is reduced. In certain exemplary embodiments, the FEV1 prior to bronchodilator administration is improved. In certain exemplary embodiments, the FEV1 after bronchodilator administration is improved. In certain exemplary embodiments, the FVC prior to bronchodilator administration is improved. In certain exemplary embodiments, the level of blood eosinophils is reduced.

[0016] In certain exemplary embodiments, the annual rate of severe AECOPD events is reduced in the subject. In certain exemplary embodiments, the time to the first severe AECOPD event is reduced. In certain exemplary embodiments, the FEV1 before bronchodilator administration is improved. In certain exemplary embodiments, the FEV1 after bronchodilator administration is improved. In certain exemplary embodiments, the rate of decline of FEV1 before bronchodilator administration is decreased. In certain exemplary embodiments, the rate of decline of FEV1 after bronchodilator administration is decreased. In certain exemplary embodiments, the FVC before bronchodilator administration is improved. In certain exemplary embodiments, lung function is maintained or the decline in lung function is reduced. In certain exemplary embodiments, the level of blood eosinophils is reduced. In certain exemplary embodiments, the subject has a high blood eosinophil level and / or is a smoker.

[0017] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg to about 600 mg, about 100 mg to about 400 mg, or about 300 mg. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

[0018] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered weekly (q1w), every two weeks (q2w), every three weeks (q3w), every four weeks (q4w), every five weeks (q5w), every six weeks (q6w), every seven weeks (q7w), or every eight weeks (q8w). In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered every two weeks (q2w). In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0019] In certain exemplary embodiments, the FEV1 before bronchodilator administration is improved within four weeks from the first administration of the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the FEV1 before bronchodilator administration is maintained during the treatment.

[0020] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered as two injections. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, needle and syringe, or pen-type delivery device.

[0021] In another aspect, there is provided a method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering to the subject an initial amount of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, and one or more subsequent doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0022] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10.

[0023] In another aspect, a method for treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every two weeks. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the antibody being administered to the subject at an initial dose of about 300 mg and then at one or more subsequent doses of about 300 mg, the antibody being administered subcutaneously every two weeks.

[0024] In another aspect, a method for treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every four weeks. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the antibody being administered to the subject at an initial dose of about 300 mg and then at one or more subsequent doses of about 300 mg, the antibody being administered subcutaneously every four weeks.

[0025] In certain exemplary embodiments, one or more COPD-related parameters are improved in the subject.

[0026] In certain exemplary embodiments, one or more chronic obstructive pulmonary disease (COPD)-related parameters are selected from the group consisting of the annual rate of moderate to severe acute exacerbation of COPD (AECOPD), forced expiratory volume in one second (FEV1), the rate of decline of FEV1, peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, fractional exhaled nitric oxide (FeNO), the number or dosage of COPD-relieving medications, the number or dosage of systemic corticosteroids, and the number or dosage of antibiotics.

[0027] In certain exemplary embodiments, FEV1 before bronchodilator administration is improved. In certain exemplary embodiments, the annual rate of moderate to severe acute exacerbation of COPD (AECOPD) is reduced in the subject. In certain exemplary embodiments, the annual rate of severe acute exacerbation of AECOPD is reduced in the subject.

[0028] In certain exemplary embodiments, at least two additional therapeutic agents are administered to the subject. In certain exemplary embodiments, the at least two additional therapeutic agents are selected from the group consisting of long-acting β2-adrenergic agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs).

[0029] In certain exemplary embodiments, the at least two additional therapeutic agents include a LABA and an ICS. In certain exemplary embodiments, the at least two additional therapeutic agents include a LAMA and an ICS. In certain exemplary embodiments, all three additional therapeutic agents including a LABA, a LAMA, and an ICS are administered to the subject.

[0030] In another aspect, there is provided a method for reducing the annual rate of moderate to severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in a subject having moderate to severe chronic obstructive pulmonary disease (COPD), the method comprising administering to the subject an initial amount of about 300 mg of an antibody or an antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, and one or more subsequent doses of about 300 mg of the antibody or an antigen-binding fragment thereof. In another aspect, an antibody or an antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16 is provided for use in reducing the annual rate of moderate to severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in a subject having moderate to severe chronic obstructive pulmonary disease (COPD), wherein the antibody or an antigen-binding fragment thereof is administered to the subject at an initial amount of about 300 mg, followed by one or more subsequent doses of about 300 mg.

[0031] In certain exemplary embodiments, the antibody or an antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10.

[0032] In another aspect, a method for reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject having moderate to severe chronic obstructive pulmonary disease (COPD) is provided, the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every two weeks. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject having moderate to severe chronic obstructive pulmonary disease (COPD), the antibody being administered to the subject at an initial dose of about 300 mg and then at one or more subsequent doses of about 300 mg, and the antibody being administered subcutaneously every two weeks.

[0033] In another aspect, a method for reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject having moderate to severe chronic obstructive pulmonary disease (COPD) is provided, the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every two weeks, wherein the subject is a smoker. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject who is a smoker and has moderate to severe chronic obstructive pulmonary disease (COPD), the antibody being administered to the subject at an initial dose of about 300 mg and then at one or more subsequent doses of about 300 mg, and the antibody being administered subcutaneously every two weeks.

[0034] In another aspect, a method for reducing the annual rate of acute exacerbation (AECOPD) from moderate to severe in subjects with moderate to severe chronic obstructive pulmonary disease (COPD) is provided, the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every 4 weeks. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in reducing the annual rate of acute exacerbation (AECOPD) from moderate to severe in subjects with moderate to severe chronic obstructive pulmonary disease (COPD), the antibody being administered to the subject at an initial dose of about 300 mg and then at one or more subsequent doses of about 300 mg, and the antibody being administered subcutaneously every 4 weeks.

[0035] In another aspect, there is provided a method for reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject having moderate to severe chronic obstructive pulmonary disease (COPD), the method comprising administering to the subject an initial amount of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and one or more subsequent doses of about 300 mg of the antibody administered subcutaneously every 4 weeks, wherein the subject is a smoker. In another aspect, an antibody that specifically binds interleukin-33 (IL-33) and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20 is provided for use in reducing the annual rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from moderate to severe in a subject who is a smoker and has moderate to severe chronic obstructive pulmonary disease (COPD), the antibody being administered to the subject at an initial amount of about 300 mg and then at one or more subsequent doses of about 300 mg, and the antibody being administered subcutaneously every 4 weeks.

[0036] The foregoing and other features and advantages of the invention will be more fully understood from the following detailed description of the exemplary embodiments, taken in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0037]

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DETAILED DESCRIPTION OF THE INVENTION

[0038] Before describing the present invention, it is to be understood that the present invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terms used in this specification are for the purpose of describing only particular embodiments and are not intended to be limiting, since the scope of the present invention is defined only by the appended claims.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0040] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by up to 1% below or above. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0041] As used herein, the terms "treat," "treating," or the like mean to reduce a symptom, to remove the cause of a symptom temporarily or permanently, or to prevent or slow the appearance of a symptom of a named disorder or condition (e.g., prevent the worsening of one or more symptoms of COPD).

[0042] Any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, but typical methods and materials are described herein. All publications mentioned herein are incorporated herein by reference in their entirety.

[0043] Method for reducing the incidence of COPD exacerbations A method for reducing the incidence of one or more COPD exacerbations in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising an interleukin-33 (IL-33) antagonist. According to certain embodiments, the IL-33 antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-33. Exemplary anti-IL-33 antibodies that can be used in the context of the methods characterized in the present invention are described herein.

[0044] In one aspect, a subject is identified as having such COPD if the subject has received a diagnosis of having "mild", "moderate", "severe", or "very severe" COPD from a physician based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (2017 Report) (available from: goldcopd.org / wp-content / uploads / 2016 / 12 / wms-GOLD-2017-Pocket-Guide.pdf)). In these aspects, COPD is classified based on the severity of airway limitation as measured using FEV1 after administration of a bronchodilator. A subject's COPD is classified as "mild" using the GOLD classification system if the subject's FEV1 is greater than or equal to 80% of the predicted FEV1. The predicted value for FEV1 is based on the FEV1 value for an average person of similar age, race, height, and gender with healthy lungs. A subject's COPD is classified as "moderate" by the GOLD classification system if the subject's FEV1 is greater than or equal to 50% but less than 80% of the predicted FEV1. A subject's COPD is classified as "severe" by the GOLD classification system if the subject's FEV1 is greater than or equal to 30% but less than 50% of the predicted FEV1. A subject's COPD is classified as "very severe" by the GOLD classification system if the subject's FEV1 is less than 30% of the predicted FEV1.

[0045] In another aspect, there is provided a method for reducing the incidence or recurrence of COPD, or COPD exacerbation, in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising an IL-33 antagonist. The pharmaceutical composition comprising an IL-33 antagonist is provided for use in reducing the incidence or recurrence of COPD, or COPD exacerbation, in a subject in need thereof. As used herein, the expression "COPD exacerbation" means an increase in the severity and / or frequency and / or duration of one or more symptoms or signs of COPD. "COPD exacerbation" also includes any worsening of the respiratory health of a subject who requires and / or is treatable by therapeutic intervention for COPD (such as steroid treatment, antibiotic treatment, inhaled corticosteroid treatment, hospitalization, etc.). In some embodiments, a moderate exacerbation is defined as an AECOPD event that requires treatment with systemic corticosteroids (such as intramuscular, intravenous or oral) and / or antibiotics. In some embodiments, a severe exacerbation is defined as an AECOPD event that requires hospitalization, an emergency treatment visit, or results in death. According to certain embodiments, the annual rate of acute exacerbation of COPD from moderate to severe (AECOPD) includes moderate and severe exacerbations.

[0046] "Reduction in the incidence or recurrence of COPD exacerbation" means that a subject who has received the pharmaceutical composition of the present invention experiences fewer COPD exacerbations after treatment than before treatment (i.e., at least one has fewer exacerbations), or does not experience a COPD exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14, or more weeks) following the initiation of treatment with the pharmaceutical composition of the present invention. "Reduction in the incidence or recurrence of COPD exacerbation" alternatively means that following administration of the pharmaceutical composition of the present invention, the likelihood that a subject will experience a COPD exacerbation is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) compared to a subject who has not received the pharmaceutical composition of the present invention.

[0047] A method for reducing the incidence of COPD exacerbations in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist and administering to the subject a second single or maintenance dose(s) or second and third control agents, such as a long-acting beta agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS). The pharmaceutical composition comprising an IL-33 antagonist is provided for use in combination with a second single or maintenance dose(s) or second and third control agents, such as a long-acting beta agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS), for reducing the incidence of COPD exacerbations in a subject in need thereof. A combination of a pharmaceutical composition comprising an IL-33 antagonist and a second single or maintenance dose(s) or second and third control agents, such as a long-acting beta agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS), is provided for use for reducing the incidence of COPD exacerbations in a subject in need thereof.

[0048] Suitable LABAs include, but are not limited to, salmeterol (e.g., Serevent®), formoterol (e.g., Foradil®, Perforomist®), indacaterol (e.g., Arcapta®), albuterol (e.g., Brovana®), olodaterol (e.g., Stiverdi®), and the like.

[0049] 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®), etc.

[0050] Suitable LAMAs include, but are not limited to, tiotropium bromide (e.g., Spiriva®), aclidinium bromide (e.g., Eklira®, Tudorza®), glycopyrronium bromide (e.g., Seebri®), umeclidinium (e.g., Incruse®), etc.

[0051] Suitable combinations of LAMA and LABA include, but are not limited to, umeclidinium and vilanterol (e.g., Anoro), olodaterol and tiotropium (e.g., Stiolto), indacaterol and glycopyrrolate (e.g., Utibron), and glycopyrrolate and formoterol (e.g., Bevespi).

[0052] A method for reducing the incidence of COPD exacerbations in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising one or more IL-33 antagonists to remove or reduce one or more COPD-related symptoms and administering to the subject one or more palliative agents. The pharmaceutical composition comprising an IL-33 antagonist is provided for use in combination with one or more palliative agents to remove or reduce one or more COPD-related symptoms in order to reduce the incidence of COPD exacerbations in a subject in need thereof. A combination comprising a pharmaceutical composition comprising an IL-33 antagonist and one or more palliative agents to remove or reduce one or more COPD-related symptoms is provided for use in reducing the incidence of COPD exacerbations in a subject in need thereof. Suitable palliative agents include, but are not limited to, fast-acting beta2-adrenergic agonists such as albuterol / salbutamol or levalbuterol / levosalbutamol (including ipratropium or ipratropium / short-acting beta agonist (SABA) combinations).

[0053] Method for improving COPD-related parameters A method (also referred to herein as "COPD modification" or "disease modification") for improving one or more COPD-related parameters in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist. The pharmaceutical composition comprising an IL-33 antagonist is provided for use in improving one or more COPD-related parameters in a subject in need thereof. A decrease in the incidence of exacerbations of COPD (as described above) may correlate with an improvement in one or more COPD-related parameters; such a correlation is not necessarily observed in all cases.

[0054] Examples of "COPD-related parameters" are: (1) annual rate of moderate to severe AECOPD; (2) annual rate of severe AECOPD; (3) relative absolute change from baseline in forced expiratory volume in one second (FEV1) before bronchodilator administration (e.g., 52 weeks); (4) relative absolute change from baseline in forced expiratory volume in one second (FEV1) before bronchodilator administration (e.g., 24 weeks); (5) relative absolute change from baseline in forced expiratory volume in one second (FEV1) after bronchodilator administration (e.g., 52 weeks); (6) relative percent change from baseline in forced expiratory volume in one second (FEV1) before bronchodilator administration (e.g., weeks 24 and 52); (7) relative percent change from baseline in forced expiratory volume in one second (FEV1) after bronchodilator administration (e.g., week 24); (8) relative decline rate (e.g., slope) of forced expiratory volume in one second (FEV1) before and / or after bronchodilator administration; (9) time to first moderate or severe AECOPD; (10) change from baseline in deterioration of COPD Tool (EXACT) score (e.g., week 24); (11) change from baseline in respiratory symptoms evaluated by COPD (E-RS) score (e.g., week 24); (12) change from baseline in St. George's Respiratory Questionnaire (SGRQ) score (e.g., week 24); (13) change from baseline in EuroQol 5-Dimension Questionnaire (EQ-5D) score (e.g., week 24); (14) rate of moderate to severe AECOPD; (15) change from baseline in forced vital capacity (FVC) from 16 to 24 weeks; (16) change from baseline in modified Medical Research Council Questionnaire (mMRC) score (e.g., week 24); (17) change from baseline in Health-Related Quality of Life Questionnaire (HRQOL) score (e.g., week 24); (18) change from baseline in Body Mass Index, Airway Obstruction, Dyspnea, Exercise capacity (BODE) score (e.g., week 24); (19) change from baseline in daily steps (e.g., week 24); (20) days of oral corticosteroids; (21) days of antibiotics; (22) change from baseline in resting oxygen saturation (e.g., week 24); (23) change from baseline in resting respiratory rate (e.g., week 24); (24) maintenance of lung function (e.g., compared to no treatment or treatment with placebo).and (25) reducing the decline in lung function (e.g., compared to no treatment or treatment with a placebo), including but not limited to one or any combination thereof;

[0055] "Improvement of COPD-related parameters" means an increase in FEV1 or the time to the first moderate or severe AECOPD and / or a decrease from the baseline rate of AECOPD. 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 comprising an IL-33 antagonist.

[0056] To determine whether a COPD-related parameter is "improving", the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein. For example, the COPD-related parameter can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th day, or at the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th week, or more, after the first treatment with the pharmaceutical composition. The difference between the value of the parameter at a specific time point after the start of treatment and the value of the parameter at baseline is used to establish whether "improvement" (e.g., an increase or decrease, depending on the specific parameter being measured) of the COPD-related parameter has occurred.

[0057] As used herein, the term "acquire" or "acquiring" means obtaining ownership of a physical entity or value, e.g., a COPD-related parameter, by "directly acquiring" or "indirectly acquiring" the physical entity or value, e.g., a numerical value. "Directly acquiring" means performing a method (e.g., performing a synthesis or analytical method) to obtain a physical entity or value. "Indirectly acquiring" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory where the physical entity or value is directly acquired). Directly acquiring a physical entity includes performing a method that involves a physical change in the substance, e.g., a physical change in the 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 separate entities into a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Directly acquiring a value includes performing a method that involves a physical change in a sample or another substance, e.g., performing an analytical method that involves a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as "physical analysis").

[0058] Indirectly acquired information can be provided in the form of a report, e.g., in written or electronic form, e.g., in an online database or application ("App"). The report or information can be provided, e.g., by a medical institution, e.g., a hospital or clinic; or a healthcare provider, e.g., a physician or nurse.

[0059] Forced expiratory volume in one second (FEV1). According to certain embodiments, administration of an IL-33 antagonist to a patient 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, FEV1 can be measured in a patient using a spirometer that complies with the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. ATS / ERS Standardization of Spirometry can be used as a guideline. Spirometry is generally performed between 6 and 10 AM after at least 6 hours of albuterol withholding. Pulmonary function tests are generally measured in the seated position, and the best measurement is recorded for FEV1 (in liters).

[0060] The present disclosure includes a treatment method that results in an increase in FEV1 from baseline of at least 0.01 L at week 24 following the start of treatment using a pharmaceutical composition comprising an anti-IL-33 antagonist. The present disclosure includes a pharmaceutical composition comprising an anti-IL-33 antagonist for use in increasing FEV1 from baseline by at least 0.01 L at week 24 following the start of treatment using the pharmaceutical composition. For example, administration of an IL-33 antagonist increases FEV1 from baseline by about 0.01 L, 0.02 L, 0.03 L, 0.04 L, 0.05 L, 0.10 L, 0.12 L, 0.14 L, 0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L, 0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L, 0.48 L, 0.50 L or more at week 24.

[0061] Forced vital capacity (FVC). According to certain embodiments, administration of an IL-33 antagonist to a patient 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 a patient's FVC. The ATS / ERS standards for spirometry may be used as guidelines. Spirometry is typically performed between 6 - 10 AM after at least 6 hours of albuterol withholding. Pulmonary function tests are usually measured in the seated position, and the highest measurement for FVC (in liters) is recorded.

[0062] FEF25 - 75%. According to certain embodiments, administration of an IL-33 antagonist to a patient results in an increase in FEF25 - 75% (forced expiratory flow between 25% and 75%) from baseline. Methods for measuring FEF are known in the art. For example, an FEV1 can be measured in a patient using a spirometer that complies with the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. FEF25 - 75% is the speed (in liters per second) at which a person can empty the middle half of the air during a maximal exhalation (i.e., forced vital capacity or FVC). The parameter relates to the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled. The FEF25 - 75% of a subject provides information regarding small airway function, such as the degree of small airway disease and / or inflammation. A change in FEF25 - 75% is an early indicator of obstructive lung disease. In certain embodiments, an improvement and / or increase in the FEF25 - 75% parameter is an improvement of at least 10%, 25%, 50% or more when compared to baseline. In certain embodiments, the methods of the present invention result in normal FEF25 - 75% values (e.g., values in the range of 50 - 60% to 130% on average) in a subject.

[0063] The present disclosure includes a treatment method that results in at least a 5% reduction in AECOPD from the baseline at the 24th week following the start of treatment using a pharmaceutical composition comprising an anti-IL-33 antagonist. The present disclosure includes a pharmaceutical composition comprising an anti-IL-33 antagonist for use in reducing AECOPD by at least 5% from the baseline at the 24th week following the start of treatment using the pharmaceutical composition. For example, according to the present invention, by administering an IL-33 antagonist to a subject in need thereof, AECOPD is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or more at the 24th week from the baseline.

[0064] The present disclosure includes a treatment method that results in at least a 5% reduction in the likelihood of the first AECOPD at a specific time point at the 24th week following the start of treatment using a pharmaceutical composition comprising an anti-IL-33 antagonist as compared to the baseline. The present disclosure includes a pharmaceutical composition comprising an anti-IL-33 antagonist for use in reducing the likelihood of the first AECOPD at a specific time point by at least 5% at the 24th week following the start of treatment using the pharmaceutical composition. For example, according to the present invention, by administering an IL-33 antagonist to a subject in need thereof, the likelihood of the first AECOPD at a specific time point is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or more at the 24th week as compared to the baseline.

[0065] Use of albuterol / levalbuterol. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease from the baseline use of daily albuterol or levalbuterol. The number of inhalations of albuterol / levalbuterol can be recorded daily by the patient using a diary, a PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, albuterol / levalbuterol may generally be used as needed for symptoms, not regularly or prophylactically. The baseline number of inhalations of albuterol / levalbuterol per day can be calculated based on the average over 7 days prior to administration of the first dose of the pharmaceutical composition comprising the IL-33 antagonist.

[0066] The present invention includes a method of treatment that results in a decrease in the use of albuterol / levalbuterol from a baseline of at least 0.25 puffs per day 12 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist. For example, administration of an IL-33 antagonist to a subject in need thereof results in a decrease in the use of albuterol / levalbuterol from a baseline of about 0.25 puffs per day, 0.50 puffs per day, 0.75 puffs per day, 1.00 puffs per day, 1.25 puffs per day, 1.5 puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day or more at 12 weeks.

[0067] Daily steps. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a change from the baseline of daily steps, for example, an increase in daily steps over a period of time compared to daily steps over a period of time prior to administration of the IL-33 antagonist.

[0068] Corticosteroid / antibiotic use. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease in the number of days the patient is receiving oral corticosteroids. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease in the number of days the patient is receiving antibiotics over a period of time as compared to the number of days the patient was receiving antibiotics over a period of time prior to administration of the IL-33 antagonist.

[0069] Oxygen saturation. In some embodiments, administration of an IL-33 antagonist to a patient results in a change from a baseline of resting oxygen saturation, e.g., an increase in resting oxygen saturation as compared to that obtained prior to administration of the IL-33 antagonist.

[0070] Respiratory rate. In some embodiments, administration of an IL-33 antagonist to a patient results in a change from a baseline of resting respiratory rate, e.g., a decrease or an increase in respiratory rate. In certain exemplary embodiments, administration of an IL-33 antagonist to a patient results in a decrease in resting respiratory rate from baseline as compared to the resting respiratory rate prior to administration of the IL-33 antagonist.

[0071] Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Capacity (BODE) index. According to certain embodiments, administration of an IL-33 antagonist to a patient results in an improvement in the BODE index score from baseline. In some embodiments, administration of an IL-33 antagonist to a patient results in an improvement in the BODE index score by more than 1 point from baseline. The BODE index incorporates body mass index, airflow limitation (FEV1), dyspnea, and 6-minute walk distance and predicts mortality in patients with COPD. (Celli et al., The Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Performance (BODE) index in chronic obstructive pulmonary disease. New Eng. J. Med. 2004; 350: 1005-1012.)

[0072] The COPD Assessment Test (CAT) score. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease in the CAT score from baseline. The anti-IL-33 antagonist is provided for use in a patient for the decrease from the baseline CAT score. The CAT is a questionnaire devised for patients with COPD to measure the impact of the disease on their quality of life (COPD Assessment Test. Available from the website: catestonline.org / . The CAT is an 8-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, and a higher score indicates a greater impact on health status. The test relates to cough, sputum, chest constriction, dyspnea, activity limitation, confidence, sleep, and energy. Patients score the questions from 1 to 5 according to their own feelings about the disease (1 = I am very happy; 5 = I am very sad).

[0073] The St. George's Respiratory Questionnaire (SGRQ). According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease in the SGRQ score from baseline. The anti-IL-33 antagonist is provided for use in a patient to decrease the SGRQ score from baseline. The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire devised to measure and quantify health-related quality of life in adult patients with chronic airflow limitation (Jones et al., A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. June 1992;145(6):1321-1327). The overall score ranges from 0 to 100. The domain scores are calculated for three domains: symptoms, activity and impact (psychosocial) as well as the total score. A lower score indicates a better quality of life (QoL). The first part (“symptoms”) assesses overall symptoms including frequency of cough, sputum production, wheeze, breathlessness and duration and frequency of episodes of breathlessness or wheeze. The second part has two components: “activity” and “impact”. The “activity” part addresses activities that trigger breathlessness or are limited by breathlessness. The “impact” part addresses a range of factors including impact on employment, managing health, fear, blame, need for medication, side effects of prescribed therapies, prognosis of health and disruption of daily life. The recall period for the questionnaire is over the past four weeks. Psychometric testing has demonstrated its reproducibility, reliability and validity. Sensitivity has been demonstrated in clinical trials. A minimum change in score of 4 units has been established as clinically relevant after examination by patients and clinicians. The SGRQ has been used in the range of disease groups including asthma, COPD and bronchiectasis.

[0074] Worsening of chronic obstructive pulmonary disease tool (EXACT). According to certain embodiments, administration of an IL-33 antagonist to a patient results in a decrease in the EXACT score from baseline. The anti-IL-33 antagonist is provided for use in a patient to decrease the EXACT score from baseline. The EXACT total score measures symptoms of acute bacterial exacerbation of chronic bronchitis - COPD (ABECB-COPD), i.e., signs and symptoms of acute, persistent worsening above daily variation. The total score of the instrument consists of a total of 14 items representing the following areas: shortness of breath (5 items), cough and sputum (2 items), chest symptoms (3 items), difficulty expectorating sputum (1 item), fatigue or weakness (1 item), sleep disturbance (1 item), and fear or worry (1 item). EXACT is a diary to be filled out every night before going to bed. The instrument was developed with electronic diary management in mind, and interviews are conducted using a paper-pencil booklet and a personal digital assistant (PDA), describing the responder's understanding and PDA user acceptance in either format.

[0075] Evaluation of respiratory symptoms (E-RS) in COPD. According to certain embodiments, administration of an IL-33 antagonist to a patient results in the patient reporting better health in the evaluation of respiratory symptoms (E-RS) in COPD. The anti-IL-33 antagonist is provided for use in a patient to enable the patient to report better health in the E-RS. The E-RS scale is designed to serve as a primary, secondary, or exploratory endpoint in clinical trials evaluating the effect of treatment on respiratory symptoms in COPD. E-RS is a diary used to measure exacerbations in COPD and is based on 11 respiratory symptom items derived from the 14-item EXACT. E-RS yields a total score quantifying overall respiratory symptom severity, as well as three subscale scores evaluating shortness of breath, cough and sputum, and chest symptoms. This allows for two validated uses for a single diary: quantification of stable respiratory symptoms in COPD using the E-RS total and subscale scores and evaluation of acute exacerbations (change in exacerbation symptoms having frequency, severity, duration of symptom-defined events, and events receiving medical treatment) using the EXACT total score.

[0076] EuroQol questionnaire (EQ-5D-3L or EQ-5D-5L). According to certain embodiments, administration of an IL-33 antagonist to a patient results in the patient reporting better health on the EuroQol questionnaire (EQ-5D-3L or EQ-5D-5L). The anti-IL-33 antagonist is provided for use in a patient such that the patient reports better health on the EuroQol questionnaire (EQ-5D-3L or EQ-5D-5L). EQ-5D-5L and EQ-5D-3L are standardized health-related QoL questionnaires developed by the EuroQol Group to provide simple and comprehensive health criteria for clinical and economic evaluation.

[0077] Modified Medical Research Council questionnaire (mMRC). According to certain embodiments, administration of an IL-33 antagonist to a patient results in the patient reporting a better health state on the modified Medical Research Council questionnaire (mMRC). The anti-IL-33 antagonist is provided for use in a patient such that the patient reports a better health state on the modified Medical Research Council questionnaire (mMRC). The modified Medical Research Council questionnaire (mMRC) is a questionnaire that assesses breathlessness (Fletcher et al., Standardised 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).

[0078] Health-related quality of life (HRQOL) questionnaire. According to certain embodiments, administration of an IL-33 antagonist to a patient results in the patient reporting a better health state on a health-related quality of life (HRQOL) questionnaire. (Centers for Disease Control and Prevention. Measuring Healthy Days. Atlanta, Georgia: CDC, November 2000, Available at the website: cdc.gov / hrqol / pdfs / mhd.pdf.). The anti-IL-33 antagonist is provided for use in a patient such that the patient reports a better health state on the HRQOL questionnaire.

[0079] Biomarkers. In certain embodiments, the subject experiences an improvement in lung function as measured by the biomarker. In certain exemplary embodiments, the subject experiences an increase in biomarker level (compared to the biomarker level prior to administration of the anti-IL-33 antagonist) following administration of the anti-IL-33 antagonist. In certain exemplary embodiments, the subject experiences a decrease in biomarker level (compared to the biomarker level prior to administration of the anti-IL-33 antagonist) following administration of the anti-IL-33 antagonist. For example, the biomarker can be selected from the group consisting of blood eosinophils, blood neutrophils, exhaled nitric oxide (FeNO) (e.g., FeNO prior to bronchodilator administration), total IL-33, soluble IL-33 receptor (sST2), calcitonin, pulmonary and activation-regulated chemokine (PARC), blood C-reactive protein, blood IL-6, eotaxin-3, total IgE, fibrinogen, calcitonin, procalcitonin, calcitonin gene-related peptide (CGRP), resistin-like alpha (RETNA), chemokine (C-C motif) ligand 8 (Ccl8), serum amyloid A3 (Saa3), Gm1975 (BC117090), killer cell lectin-like receptor (Kirg1), stefin A1 (Csta), transmembrane 4-domain (Ms4a8a), chemokine (C-C motif) ligand 11 (Ccl11), serine (or cysteine) peptide (serpinA3f), and the like. 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 research on exploratory biomarkers of disease or drug effects. In certain embodiments, the samples are used for research to develop methods, assays, prognoses, and / or companion diagnostics related to IL-33, disease progression, pathways related to disease state, and / or the mechanism of action of a test intervention. In certain embodiments, the improvement in lung function is indicated by a decrease or increase at 4 weeks, 12 weeks, or 24 weeks post-treatment (as needed).

[0080] Method for treating COPD In some embodiments, provided is a method for treating COPD, including moderate to severe COPD, in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising an IL-33 antagonist. In certain embodiments, the method is useful for treating moderate to severe COPD in a subject. In certain embodiments, the method is useful for reducing one or more AECOPD events. A pharmaceutical composition comprising an anti-IL-33 antagonist is provided for treating COPD, including moderate to severe COPD, in a subject in need thereof. A pharmaceutical composition comprising an anti-IL-33 antagonist is provided for treating moderate to severe COPD in a subject in need thereof. A pharmaceutical composition comprising an anti-IL-33 antagonist is also provided for reducing one or more AECOPD events in a patient.

[0081] In one aspect, provided is a method for treating COPD, the method comprising: (a) selecting a patient having a blood eosinophil level equal to or greater than 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist. In one aspect of the composition for use, the patient has a blood eosinophil level equal to or greater than 300 cells per microliter.

[0082] In one aspect, provided is a method for treating COPD, the method comprising: (a) selecting a patient having a blood eosinophil level equal to or greater than 250 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist. In one aspect of the composition for use, the patient has a blood eosinophil level equal to or greater than 250 cells per microliter.

[0083] In one aspect, a method for treating COPD is provided, comprising: (a) selecting a patient having a blood eosinophil level of less than 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist. In one aspect of the composition for use, the patient has a blood eosinophil level of less than 300 cells per microliter.

[0084] In another aspect, a method for treating COPD is provided, comprising: (a) selecting a patient having a blood eosinophil level of 150-299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist. In one aspect of the composition for use, the patient has a blood eosinophil level of 150-299 cells per microliter.

[0085] In another aspect, a method for treating COPD is provided, 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-33 antagonist. In one aspect of the composition for use, the patient has a blood eosinophil level of less than 150 cells per microliter.

[0086] In related aspects, a method for treating COPD is provided, the method including add-on therapy to background therapy. In related aspects, an IL-33 antagonist is provided for use in treating COPD in a patient, where the IL-33 antagonist is used as add-on therapy to background therapy. In certain embodiments, the IL-33 antagonist is administered as add-on therapy to a COPD patient who has received 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 longer) (also referred to as the "stable phase"). In certain embodiments, an IL-33 antagonist is provided for use in treating COPD in a patient, where the IL-33 antagonist is administered as add-on therapy to a COPD patient who has received background therapy for a period of time. In some embodiments, the background therapy includes ICS and LABA. In other embodiments, the background therapy includes ICS and LAMA. In other embodiments, the background therapy includes LABA and LAMA. In other embodiments, the background therapy includes ICS, LAMA and LABA. In some embodiments, the background therapy includes a PDE-4 inhibitor such as roflumilast. In other embodiments, the background therapy includes azithromycin.

[0087] In some embodiments, the present invention includes the steps of: (a) selecting patients with moderate to severe COPD that is not adequately controlled with a background therapy including an ICS, LABA, LAMA, or a combination thereof; and administering to the patients a pharmaceutical composition comprising an IL-33 antagonist. The present invention includes a method for reducing dependence on ICS, LAMA, or LABA in the treatment of one or more exacerbations of COPD. The pharmaceutical composition comprising an IL-33 antagonist is provided for use in reducing the dependence of patients with COPD on ICS, LAMA, or LABA for the treatment of one or more exacerbations of COPD in patients with moderate to severe COPD that is not well managed with a background COPD therapy including an ICS, LABA, LAMA, or a combination thereof.

[0088] In some embodiments, the present invention is a method for the treatment of one or more exacerbations of COPD in patients chronically using an ICS, LAMA, or LABA, the method including the steps of: (a) selecting patients with moderate to severe COPD who are chronically using an ICS, LABA, LAMA, or a combination thereof; and administering to the patients a pharmaceutical composition comprising an IL-33 antagonist. The pharmaceutical composition comprising an IL-33 antagonist is provided for use in treating one or more exacerbations of COPD in patients chronically using an ICS, LABA, LAMA, or a combination thereof in patients with moderate to severe COPD.

[0089] Interleukin-33 (IL-33) antagonist The method characterized in the present invention includes the step of administering a therapeutic composition comprising an IL-33 antagonist to a subject in need thereof. As used herein, "IL-33 antagonist" is any agent that binds to or interacts with IL-33 and inhibits the normal biological signaling function of IL-33 when IL-33 is expressed in cells in vitro or in vivo.

[0090] Non-limiting examples of categories of IL-33 antagonists include small molecule IL-33 antagonists, anti-IL-33 aptamers, peptide-based IL-33 antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-33.

[0091] According to certain embodiments, the IL-33 antagonist comprises an anti-IL-33 antibody or an antigen-binding fragment thereof that can be used in the context of the methods characterized in the present invention as described elsewhere herein. For example, in one embodiment, the IL-33 antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-33 and comprises heavy and light chain (complementary determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 2 and 10, respectively. In another embodiment, the IL-33 antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-33 and comprises heavy and light chain CDR sequences of SEQ ID NOs: 4, 6 and 8 and SEQ ID NOs: 12, 14 and 16, respectively. In another embodiment, the IL-33 antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-33 and comprises the HCVR / LCVR pairs of SEQ ID NOs: 2 and 10, respectively.

[0092] DNA sequence encoding the SAR440340 (REGN3500) HCVR: aggtgcagct ggtggagtct gggggaaact tggaacagcc tggggggtcc cttagactct cctgtacagc ctctggattc acctttagca gatctgccat gaactgggtc cgccgggctc cagggaaggg gctggagtgg gtctcaggaa ttagtggtag tggtggtcga acatactacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaat acgctatatc tgcaaatgaa cagcctgagc gccgaggaca cggccgcata ttactgtgcg aaagattcgt atactaccag ttggtacgga ggtatggacg tctggggcca cgggaccacg gtcaccgtct cctca(SEQ ID NO: 1)

[0093] SAR440340 (REGN3500) HCV R amino acid sequence: VQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMDVWGHGTTVTVSS(SEQ ID NO: 2)

[0094] DNA sequence encoding SAR440340 (REGN3500) HCDR1: ggattcacctt tagcagatct gcc(SEQ ID NO: 3)

[0095] SAR440340 (REGN3500) HCDR1 amino acid sequence: GFTFSRSA(SEQ ID NO: 4)

[0096] DNA sequence encoding SAR440340 (REGN3500) HCDR2: attagtggtag tggtggtcga aca(SEQ ID NO: 5)

[0097] SAR440340 (REGN3500) HCDR2 Amino Acid Sequence: ISGSGGRT (SEQ ID NO: 6)

[0098] DNA Sequence Encoding SAR440340 (REGN3500) HCDR3: gcgaaagattc gtatactacc agttggtacg gaggtatgga cgtc (SEQ ID NO: 7)

[0099] SAR440340 (REGN3500) HCDR3 Amino Acid Sequence: AKDSYTTSWYGGMDV (SEQ ID NO: 8)

[0100] DNA Sequence Encoding SAR440340 (REGN3500) LCVR: acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac agagtcacca tcacttgtcg ggcgagtcag ggtattttca gctggttagc ctggtatcag cagaaaccag gaaaagcccc taagctcctg atctatgctg cttccagttt acaaagtggg gtcccatcaa gattcagcgg cagtggatct gggacagatt tcactctcac catcagcagc ctgcagcctg aggattttgc aatttactat tgtcaacagg ctaacagtgt cccgatcacc ttcggccaag ggacacgact ggagattaaa cga (SEQ ID NO: 9)

[0101] SAR440340 (REGN3500) LCVR Amino Acid Sequence: IQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEIKR (SEQ ID NO: 10)

[0102] DNA sequence encoding SAR440340 (REGN3500) LCDR1: cagggtatttt cagctgg (SEQ ID NO: 11)

[0103] SAR440340 (REGN3500) LCDR1 amino acid sequence: QGIFSW (SEQ ID NO: 12)

[0104] DNA sequence encoding SAR440340 (REGN3500) LCDR2: gctgcttcc (SEQ ID NO: 13)

[0105] SAR440340 (REGN3500) LCDR2 amino acid sequence: AAS (SEQ ID NO: 14)

[0106] DNA sequence encoding SAR440340 (REGN3500) LCDR3: caacaggctaa cagtgtcccg atcacc (SEQ ID NO: 15)

[0107] SAR440340 (REGN3500) LCDR3 amino acid sequence: QQANSVPIT (SEQ ID NO: 16)

[0108] DNA sequence encoding SAR440340 (REGN3500) heavy chain: aggtgcagct ggtggagtct gggggaaact tggaacagcc tggggggtcc cttagactct cctgtacagc ctctggattc acctttagca gatctgccat gaactgggtc cgccgggctc cagggaaggg gctggagtgg gtctcaggaa ttagtggtag tggtggtcga acatactacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaat acgctatatc tgcaaatgaa cagcctgagc gccgaggaca cggccgcata ttactgtgcg aaagattcgt atactaccag ttggtacgga ggtatggacg tctggggcca cgggaccacg gtcaccgtct cctcagcctc caccaagggc ccatcggtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca tgcccaccct gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgtggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc ctctacagca ggctcaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac tacacacaga agtccctctc cctgtctctg ggtaaatga(SEQ ID NO:17)

[0109] SAR440340 (REGN3500) heavy chain amino acid sequence: VQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMDVWGHGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:18)

[0110] DNA sequence encoding the light chain of SAR440340 (REGN3500): acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac agagtcacca tcacttgtcg ggcgagtcag ggtattttca gctggttagc ctggtatcag cagaaaccag gaaaagcccc taagctcctg atctatgctg cttccagttt acaaagtggg gtcccatcaa gattcagcgg cagtggatct gggacagatt tcactctcac catcagcagc ctgcagcctg aggattttgc aatttactat tgtcaacagg ctaacagtgt cccgatcacc ttcggccaag ggacacgact ggagattaaa cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag(SEQ ID NO: 19)

[0111] Amino acid sequence of the light chain of SAR440340 (REGN3500): IQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)

[0112] The term "human IL-33" (hIL-33) refers to a human cytokine that specifically binds to the interleukin-33 receptor (IL-33R).

[0113] 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 multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H for short) and a heavy chain constant region. The heavy chain constant region comprises three domains, C H 1, C H 2, and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L for short) and a light chain constant region. The light chain constant region comprises one domain (C L 1). The V H and V L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) and dispersed in more conserved regions called framework regions (FRs). Each V H and V LIt consists of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the anti-IL-33 antibody, or antigen-binding portion thereof, may be identical to the human germline sequences or may be modified naturally or artificially. The amino acid consensus sequence can be defined based on the side-by-side analysis of two or more CDRs.

[0114] The term "antibody" also includes antigen-binding fragments of a complete antibody molecule. As used herein, the terms "antigen-binding portion of an antibody", "antigen-binding fragment of an antibody", etc. include any naturally occurring, enzymatically obtained, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived, for example, from a complete antibody molecule using any suitable standard techniques, such as protein digestion or recombinant genetic engineering techniques using DNA encoding antibody variable, and optionally, constant domains manipulation and expression. 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, for example, by chemical or molecular biology techniques to arrange one or more variable and / or constant domains in an appropriate configuration, or to introduce codons, create cysteine residues, modify, add, or delete amino acids.

[0115] Non-limiting examples of antigen-binding fragments include, but are not limited to: (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) hypervariable regions of antibodies (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides, etc.), or minimal recognition units consisting of amino acid residues that mimic a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetravalent antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, etc., are also encompassed within the scope of the expression "antigen-binding fragment".

[0116] Antigen-binding fragments of antibodies generally include at least one variable domain. The variable domain can be of any size or amino acid composition and generally includes at least one CDR that is a framework unit adjacent to or having one or more framework sequences. V L domain related to the V H In an antigen-binding fragment having a V H and V L domain, the V H and V H domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V L or V L -V L dimers. Alternatively, an antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0117] In certain embodiments, an antigen-binding fragment of an antibody can comprise at least one variable domain covalently attached to at least one constant domain. Exemplary arrangements of variable and constant domains that can be found within the antigen-binding fragments of the antibodies described herein, without limitation, include (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) 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 Lis included. In any arrangement of variable and constant domains, including any of the exemplary arrangements listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. A hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a mobile or semi-mobile linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Generally, a hinge region can consist of between 2 and 60 amino acids, generally between 5 and 50, or generally between 10 and 40 amino acids. Further, the antigen-binding fragments of the antibodies described herein can non-covalently associate (e.g., by disulfide bonds) with each other and / or with one or more monomeric V H or V L domains to include homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above.

[0118] Similar to a complete antibody molecule, an antigen-binding fragment can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody generally includes at least two different variable domains, each of which is capable of specifically binding to a different antigen or to different epitopes on the same antigen. Any multispecific antibody format can be adapted for use in connection with the antigen-binding fragments of the antibodies described herein using routine techniques available in the art.

[0119] 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.

[0120] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies characterized in the present invention can include, for example, in the CDRs, particularly in CDR3, amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutations in vivo). 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, have been transplanted into a human framework sequence.

[0121] The term "recombinant human antibody" includes all human antibodies produced, expressed, created or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from recombinant, combinatorial human antibody libraries (described further below), antibodies isolated from animals that are transgenic for human immunoglobulin genes (e.g., mice) (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies produced, expressed, created or isolated by any other means involving 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, if an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions may be sequences that do not naturally occur within the human antibody germline repertoire in vivo when derived from and related to human germline V H and V L sequences.

[0122] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a suitable four-chain construct in which the dimers are linked by inter-chain heavy chain disulfide bonds and approximately 150 - 160 kDa. In the second form, dimers are not linked by inter-chain disulfide bonds, and molecules of approximately 75 - 80 kDa composed of covalently linked light and heavy chains (half-antibodies) are formed. These forms are extremely difficult to separate even after affinity purification.

[0123] The frequency of the appearance of the second form in various untreated IgG isotypes is due to, but not limited to, structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30: 105) to levels generally observed using the human IgG1 hinge. The present invention encompasses antibodies having one or more mutations in the hinge, C H 2, or C H 3 region, which may be desirable, for example, in manufacturing to improve the yield of the desired antibody form.

[0124] "Isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated from or removed from at least one component of an organism, or an antibody that has been separated from or removed from a tissue or cell that exists or is produced naturally, is an "isolated antibody". Isolated antibodies include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular materials and / or chemical substances.

[0125] The term "specifically binds" and the like means that an antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-33 as characterized in the present invention includes, respectively, an antibody that binds to IL-33, or a portion thereof, and K D is less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured in a surface plasmon resonance assay. However, an isolated antibody that specifically binds to human IL-33 may have cross-reactivity to other antigens, for example, IL-33 molecules obtained from other (non-human) species.

[0126] Anti-IL-33 antibodies useful for the methods can include one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein, for example, to germline sequences available from public antibody sequence databases. The invention includes methods involving the use of antibodies and their antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more frameworks and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a tetrameric antibody or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of an antibody) CDR regions contain one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) that are mutated to the corresponding residues of the germline sequence from which the antibody is derived, or to the corresponding residues of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). One of ordinary skill 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 and light chain variable region sequences disclosed herein. In certain embodiments, V H and / or V LAll framework and / or CDR residues within the domain mutate back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues mutate back to the residues found in the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residues mutate to the corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody is originally derived). Further, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues mutate to the corresponding residues of a particular germline sequence, and certain other residues different from the original germline sequence are maintained or mutate to the corresponding residues of a different germline sequence. After acquisition, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, (optionally) improved or enhanced antagonist or agonist biological properties, reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in such a general manner is encompassed within the present invention.

[0127] The invention also includes methods involving the use of anti-IL33 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the invention includes the use of anti-IL-33 antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0128] The term "surface plasmon resonance" refers to an optical phenomenon that enables the analysis of real-time interactions, for example, by detecting changes in protein concentration within a biosensor matrix using, e.g., a BIAcore (trademark) system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0129] The term "K D " refers to the equilibrium dissociation constant of a specific antibody-antigen interaction.

[0130] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. A single antigen can have more than one epitope. Thus, different antibodies can bind to different regions on an antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by amino acids that are spatially juxtaposed from different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acid residues in a polypeptide chain. In certain situations, an epitope can include a carbohydrate, phosphoryl group, or sulfonyl group moiety on an antigen.

[0131] Production of Human Antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to produce a human antibody that specifically binds human IL-33.

[0132] Using the VELOCIMMUNE® technology (see, e.g., U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, high-affinity chimeric antibodies to IL-33 having human variable regions and murine constant regions are first isolated. The VELOCIMMUNE® technology uses the generation of transgenic mice having a genome comprising human heavy and light chain variable regions operably linked to the endogenous murine constant region locus such that the mouse produces antibodies comprising human variable regions and murine constant regions in response to antigen stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0133] Generally, VELOCIMMUNE® mice are exposed to the antigen of interest and lymphocytes (e.g., B cells) are recovered from the mouse expressing the antibody. The lymphocytes can be fused with a myeloma cell line to produce an immortalized hybridoma cell line, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. The DNA encoding the variable regions of the heavy and light chains can be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells, e.g., CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the light and heavy chains of the antibody can be isolated directly from antigen-specific lymphocytes.

[0134] 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 characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody characterized in the present invention, for example, wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the particular use, and the characteristics of high-affinity antigen binding and target specificity reside in the variable region.

[0135] Generally, the antibodies that can be used in the present method have high affinity as measured by binding to an antigen immobilized in the solid phase or in solution phase, as described above. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody characterized in the present invention. The selected constant region may vary depending on the particular use, and the characteristics of high-affinity antigen binding and target specificity reside in the variable region.

[0136] In one embodiment, a human antibody or an antigen-binding fragment thereof that specifically binds to IL-33 and can be used in the context of the method characterized in the present invention comprises three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 2. The antibody or antigen-binding fragment can comprise three light-chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 10.

[0137] 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 the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence diversity, 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. See, e.g., 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.

[0138] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) obtained from the heavy and light chain variable region amino acid sequence pairs (HCVR / LCVR) of SEQ ID NOs: 2 and 10.

[0139] 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 NOs: 4 / 6 / 8 / 12 / 14 / 16.

[0140] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 2 and 10.

[0141] In one embodiment, the antibody is SAR440340, which comprises the HCVR / LCVR amino acid sequence pairs of SEQ ID NOs: 2 and 10 and the heavy chain / light chain amino acid sequence pairs of SEQ ID NOs: 18 and 20.

[0142] Pharmaceutical composition The present invention includes a method comprising the step of administering an IL-33 antagonist to a patient, wherein the IL-33 antagonist is contained within a pharmaceutical composition. The present invention also includes an IL-33 antagonist for use, wherein the IL-33 antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions characterized in the present invention are formulated with suitable carriers, additives, and other agents that provide for appropriate movement, delivery, tolerance, etc. Numerous suitable formulations can be found in the formulary known to all pharmacists: Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., “Compendium of excipients for parenteral formulations” PDA (1998) J. Pharm. Sci. Technol. 52:238-311.

[0143] The dosage of the antibody administered to a patient can vary depending on the patient's age and size, symptoms, condition, route of administration, etc. The dosage is generally calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. An effective dosage and schedule for administering a pharmaceutical composition containing an anti-IL-33 antibody can be determined based on experience. For example, the progression of the patient can be monitored by regular evaluations and appropriately adjusted dosages. 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).

[0144] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions characterized in the present invention, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelial or mucosal skin lining (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents.

[0145] The pharmaceutical composition characterized in the present invention can be delivered subcutaneously or intravenously by standard needles and syringes. Further, with respect to subcutaneous delivery, pen-type delivery devices (e.g., pen-type autoinjectors) can be readily applied in delivering the pharmaceutical composition characterized in the present invention. Such pen-type delivery devices can be reusable or disposable. Reusable pen-type delivery devices generally utilize replaceable cartridges containing the pharmaceutical composition. When all of the pharmaceutical composition within 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-type delivery device can then be reused. In disposable pen-type delivery devices, there are no replaceable cartridges. Rather, disposable pen-type delivery devices are pre-filled with the pharmaceutical composition held in a reservoir within the device. When the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0146] A number of reusable pen-type and self-injector delivery devices are useful in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, just 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™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen-type delivery devices useful in the subcutaneous delivery of pharmaceutical compositions characterized in the present invention include, but are not limited to, just a few, SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ self-injector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA™ pen (Abbott Labs, Abbott Park IL).Examples of large delivery devices (e.g., large syringes) include, but are not limited to, bolus syringes such as the BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, and the like.

[0147] In the case of direct administration into a cavity, the pharmaceutical composition characterized in the present invention may be administered, for example, using a microcatheter (e.g., an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer or an inhaler. The method includes administration of an IL-33 antagonist in the form of an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-33 may be administered to treat COPD in a patient. The aerosolized antibody can be produced, for example, as described in U.S. Patent No. 8,178,098, which is incorporated herein by reference in its entirety.

[0148] In certain circumstances, the pharmaceutical composition can be delivered by a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed near the target of the composition, and thus requires only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0149] Injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, intravenous drip infusion, etc. These injectable preparations can be manufactured by known methods. For example, an injectable preparation can be manufactured by dissolving, suspending or emulsifying, for example, an antibody or a salt thereof described above in a sterile aqueous medium or an oily medium commonly used for injection. As the aqueous medium for injection, for example, there are physiological saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with appropriate solubilizers, such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. As the oily medium, for example, sesame oil, soybean oil, etc. are used, and these may be used in combination with solubilizers, such as benzyl benzoate, benzyl alcohol, etc. Therefore, the injections produced are generally filled into appropriate ampoules.

[0150] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are manufactured in dosage forms with unit dosages suitable for conforming to the dosage of the active ingredient. Such dosage forms in unit dosages include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0151] Dosage The amount of an IL-33 antagonist (e.g., an anti-IL-33 antibody or an antigen-binding fragment thereof) to be administered to a subject or used in accordance with the invention according to the method characteristic of the invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of an IL-33 antagonist that results in (a) a decrease in the incidence of exacerbation of COPD; (b) an 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 an upper airway inflammatory condition. A "therapeutically effective amount" also includes an amount of an IL-33 antagonist that suppresses, prevents, reduces, or delays the progression of COPD in a subject.

[0152] In the case of an anti-IL-33 antibody, a therapeutically effective amount can be from about 0.05 mg to about 700 mg of the anti-IL-33 antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In certain embodiments, 300 mg of the anti-IL-33 antibody is administered.

[0153] The amount of the IL-33 antagonist contained within an individual dosage can be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-33 antagonist may be administered to a patient at a dosage of from about 0.0001 to about 10 mg per kg of patient body weight. For example, the IL-33 antagonist can be administered at a dosage of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0154] In certain embodiments, the method includes an initial amount of from about 200 to about 600 mg of the IL-33 antagonist, for example, about 300 mg of the IL-33 antagonist.

[0155] In certain embodiments, the method comprises one or more subsequent doses of the IL-33 antagonist of about 200 to about 400 mg. For example, it comprises about 300 mg of the IL-33 antagonist.

[0156] In certain embodiments, the ICS and LABA are administered during the duration of administration of the IL-33 antagonist. In certain embodiments, the ICS and LAMA are administered during the duration of administration of the IL-33 antagonist. In certain embodiments, the LAMA and LABA are administered during the duration of administration of the IL-33 antagonist. In certain embodiments, the ICS, LAMA and LABA are administered during the duration of administration of the IL-33 antagonist.

[0157] In certain embodiments, the initial dose comprises 300 mg of an anti-IL-33 antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every other week.

[0158] In other embodiments, the initial dose comprises 300 mg of an anti-IL-33 antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every four weeks.

[0159] In other embodiments, the initial dose comprises 300 mg of an anti-IL-33 antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered once a week.

[0160] In other embodiments, the initial dose comprises 300 mg of an anti-IL-33 antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every three weeks.

[0161] Combination therapy Certain embodiments of the method characterized in the present invention include administering to a subject one or more additional therapeutic agents in combination with an IL-33 antagonist. Certain embodiments of the present invention include an IL-33 antagonist for use in combination with an additional therapeutic agent. Certain embodiments of the present invention include a combination of an IL-33 antagonist with an additional therapeutic agent for use. As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with the pharmaceutical composition comprising the IL-33 antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of the IL-33 antagonist and the additional therapeutic agent. The present invention includes methods of treating COPD or a related condition or complication or reducing at least one exacerbation comprising administering an IL-33 antagonist in combination with an additional therapeutic agent for additive or synergistic activity. The present invention includes an IL-33 antagonist for use in treating COPD or a related condition or complication or reducing at least one exacerbation in combination with an additional therapeutic agent for additive or synergistic activity. The present invention includes a combination comprising an IL-33 antagonist and an additional therapeutic agent for additive or synergistic activity for use in treating COPD or a related condition or complication or reducing at least one exacerbation.

[0162] For example, when administered "before" a pharmaceutical composition comprising an IL-33 antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the administration of the pharmaceutical composition comprising the IL-33 antagonist. When administered "after" a pharmaceutical composition comprising an IL-33 antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the administration of the pharmaceutical composition comprising the IL-33 antagonist. "Concurrent" administration with a pharmaceutical composition comprising an IL-33 antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within a range of less than 5 minutes (before, after, or simultaneously therewith) of the administration of the pharmaceutical composition comprising the IL-33 antagonist, or is administered to the subject as a combined single dosage formulation comprising the additional therapeutic agent and the IL-33 antagonist.

[0163] Additional therapeutic agents can be, for example, an IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonist described in U.S. Patent No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibody described in U.S. Patent No. 7,582,298), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal agent, an NSAID, a long-acting muscarinic antagonist (e.g., tiotropium, acridinium, glycopyrronium bromide or umeclidinium), a long-acting beta2 agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), a methylxanthine, nedocromil sodium, cromolyn sodium, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-33 antagonist is administered in combination with a long-acting beta2 agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., SYMBICORT® (Astra Zeneca)]). In other embodiments, a pharmaceutical composition comprising an IL-33 antagonist is administered in combination with a long-acting muscarinic antagonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol (e.g., Advair® (GlaxoSmithKline)); or budesonide + formoterol (e.g., SYMBICORT® (Astra Zeneca))).In yet other embodiments, the pharmaceutical composition comprising an IL-33 antagonist is administered in combination with a long-acting muscarinic antagonist, a long-acting beta2 agonist, and an inhaled corticosteroid (e.g., fluticasone + salmeterol (e.g., Advair® (GlaxoSmithKline)); or budesonide + formoterol (e.g., SYMBICORT® (Astra Zeneca))).

[0164] Dosing regimen According to certain embodiments, multiple doses of the IL-33 antagonist may be administered (or used) to a subject over a defined period of time. Such methods include the step of sequentially administering multiple doses of the IL-33 antagonist to a subject. As used herein, "administered sequentially" means that each dose of the IL-33 antagonist is administered to the subject at different times, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Methods (or uses) are included that comprise the step of sequentially administering to a patient a single initial dose of the IL-33 antagonist, followed by one or more second doses of the IL-33 antagonist, optionally followed by one or more third doses of the IL-33 antagonist.

[0165] The present invention includes a method (or use) comprising the step of administering to a subject a pharmaceutical composition comprising an IL-33 antagonist at a dosing frequency of about 4 times per week, twice per week, once per week (q1w), 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 dosing frequency less than this as long as a therapeutic response is achieved. In certain embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-weekly dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-two-weeks (bi-weekly) dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-three-weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-four-weeks (monthly) dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-five-weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-six-weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-eight-weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments comprising the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a once-every-twelve-weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used.In one embodiment, the route of administration is subcutaneous.

[0166] The term "week" means a period of (n × 7 days) ± 3 days, for example (n × 7 days) ± 1 day, or (n × 7 days), where "n" indicates the number of weeks, for example, 1, 2, 3, 4, 5, 6, 8, 12 weeks or more.

[0167] The terms "first dose", "second dose", and "third dose" refer to the time sequence of administration of the IL-33 antagonist. Thus, the "first dose" is the dose administered at the start of the treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the first dose; and the "third dose" is the dose administered after the second dose. The first dose, second dose, and third dose can all contain the same amount of the IL-33 antagonist and can differ from each other with respect to the number of administrations. However, in certain embodiments, the amount of the IL-33 antagonist contained in the first dose, second dose, and / or third dose changes relative to each other during the treatment (for example, adjusted up or down as needed). In certain embodiments, two or more doses (for example, 2, 3, 4, or 5 doses or more) are administered at the start of the treatment regimen as the "first dose" or "loading dose", followed by subsequent doses administered in fewer numbers (for example, the "maintenance dose"). In one embodiment, the maintenance dose may be less than the loading dose or the first dose. For example, one or more loading doses of 600 mg of the IL-33 antagonist can then be followed by a maintenance dose of about 75 mg to about 300 mg.

[0168] In certain embodiments, the first dose is about 200 to about 600 mg of the IL-33 antagonist. In one embodiment, the first dose is 300 mg of the IL-33 antagonist.

[0169] In certain embodiments, subsequent doses are from about 200 to about 300 mg of the IL-33 antagonist. In one embodiment, the subsequent dose is 200 mg of the IL-33 antagonist. In another embodiment, the subsequent dose is 300 mg of the IL-33 antagonist.

[0170] In certain embodiments, the initial dose is twice the subsequent dose(s). In certain embodiments, the initial dose is the same amount as the subsequent dose(s).

[0171] In some embodiments, the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0172] In some embodiments, the subject has moderate to severe COPD, the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0173] In some embodiments, the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0174] In some embodiments, the subject has moderate to severe COPD, the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more subsequent doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0175] In an exemplary embodiment, each second and / or third dose is administered 1 to 14 (e.g., 1, 1 and 1 / 2, 2, 2 and 1 / 2, 3, 3 and 1 / 2, 4, 4 and 1 / 2, 5, 5 and 1 / 2, 6, 6 and 1 / 2, 7, 7 and 1 / 2, 8, 8 and 1 / 2, 9, 9 and 1 / 2, 10, 10 and 1 / 2, 11, 11 and 1 / 2, 12, 12 and 1 / 2, 13, 13 and 1 / 2, 14, 14 and 1 / 2 or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" means the dose of the IL-33 antagonist that is administered to the patient prior to the administration of the next dose in a series of multiple administrations in an order that does not interfere with that dose.

[0176] The method (or use) can include the step of administering a significant number of second and / or third doses of the IL-33 antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. For example, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0177] In embodiments that include a plurality of subsequent or second doses, each subsequent or second dose may be administered the same number of times as the other subsequent or second doses. For example, each subsequent or second dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments that include a plurality of third doses, each third dose may be administered the same number of times as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the number of times the second and / or third doses are administered to the patient may vary during the treatment regimen. The number of administrations can also be adjusted by a physician during treatment according to the needs of an individual patient after a clinical examination.

[0178] The present invention includes methods comprising sequential administration to a patient of an IL-33 antagonist and an additional therapeutic agent for treating COPD or a related condition. The present invention also includes an IL-33 antagonist for use in a patient for treating COPD or a related condition, wherein the IL-33 antagonist is used in sequential administration with an additional therapeutic agent. The present invention further includes an IL-33 antagonist for use in a patient for treating COPD or a related condition, wherein the patient is treated with sequential administration of the IL-33 antagonist and an additional therapeutic agent. In some embodiments, the method comprises administering one or more doses of the IL-33 antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of an additional therapeutic agent. For example, one or more doses of the IL-33 antagonist of about 75 mg to about 300 mg are administered, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of an additional therapeutic agent (e.g., an inhaled corticosteroid or a beta2-agonist or a muscarinic antagonist or any other therapeutic agent as described elsewhere herein) to treat, alleviate, reduce or remit one or more symptoms of COPD. In some embodiments, the IL-33 antagonist is administered in one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses that result in improvement of one or more COPD-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one symptom of COPD. Alternative embodiments relate to co-administration of the IL-33 antagonist and an additional therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the IL-33 antagonist are administered and the additional therapeutic agent is administered in separate dosages at a similar or different number of times relative to the IL-33 antagonist. In some embodiments, the additional therapeutic agent is administered before, after or simultaneously with the IL-33 antagonist.

[0179] In certain embodiments, the IL-33 antagonist is administered bi-weekly for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or more. In other embodiments, the IL-33 antagonist is administered once every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks or more. In a particular embodiment, the IL-33 antagonist is administered for at least 24 weeks.

[0180] The present invention includes a method for treating a subject having moderate to severe COPD, the method comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-33. In certain embodiments, the method includes administering to the subject multiple maintenance doses of one or more antibodies or antigen-binding fragments thereof, the multiple maintenance doses being administered during the course of treatment.

[0181] In another aspect, a method for treating a subject having moderate to severe COPD comprises administering to the subject an initial dose of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33), and administering to the subject a plurality of subsequent doses of the antibody or antigen-binding fragment thereof. In another aspect, an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) is provided for use in treating a subject having moderate to severe COPD, wherein the antibody or antigen-binding fragment thereof is administered to the subject at an initial dose of about 300 mg and then administered to the subject at a plurality of subsequent doses. In another aspect, an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) is also provided for use in treating a subject having moderate to severe COPD, wherein the subject is treated with an initial dose of about 300 mg of the antibody or antigen-binding fragment thereof and then at a plurality of subsequent doses. Each subsequent dose is about 300 mg of the antibody or antigen-binding fragment thereof, and the plurality of subsequent doses are administered during the course of treatment, including an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences, and the heavy and light chain CDR sequences comprise SEQ ID NOs: 4, 6, 8, 12, 14, and 16.

[0182] Treatment population The method (or use) characterized in the present invention comprises the step of administering a therapeutic composition comprising an IL-33 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), or a human or non-human animal diagnosed with COPD. For example, a "subject in need thereof" may be a subject that, prior to treatment, has exhibited (or has shown) one or more COPD-related parameters, such as, for example, a decrease in FEV1 (e.g., less than 2.0 L), and / or has experienced one or more exacerbations of COPD events, such as, for example, an acute exacerbation of COPD (AECOPD) event.

[0183] As used herein, "exacerbation of COPD" refers to an acute exacerbation of one or more respiratory symptoms over a period of time, which may be further characterized by an exacerbation rate, the first exacerbation, or the time to one or more exacerbations. Exacerbations of COPD can include, but are not limited to, an increase in dyspnea, an increase in wheezing, an increase in cough, an increase in the amount of sputum, and / or an increase in purulent sputum. Acute exacerbations of COPD (AECOPD) may require treatment with systemic corticosteroids (oral, intravenous, or intramuscular), antibiotics, and / or hospitalization. In various embodiments, those methods can be used to treat mild, moderate, moderate to severe, and severe AECOPD events in patients in need thereof.

[0184] In some embodiments, the "subject in need thereof" is a subject between 40 and 75 years of age. In some embodiments, the subject is at least 40 years old. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject is between 40 and 85 years of age. In some embodiments, the subject is younger than 40 years old.

[0185] In some embodiments, the "subject in need thereof" is a subject who is a habitual smoker. In some embodiments, the subject is a habitual smoker who smokes cigarettes. In some embodiments, the subject is a habitual smoker with a smoking history of smoking 10 or more cases of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of smoking less than 10 cases of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of smoking 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 cases or more of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more.

[0186] In some embodiments, the "subject in need thereof" is a subject who has smoking experience. In some embodiments, the subject is a smoker with a history of smoking cigarettes. In some embodiments, the subject is a smoker with a smoking history of smoking 10 or more cases of cigarettes per year. In some embodiments, the subject is a smoker with a smoking history of smoking less than 10 cases per year. In some embodiments, the subject is a smoker with a smoking history of smoking 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 cases or more of cigarettes per year. In some embodiments, the subject is a smoker with a smoking history of smoking approximately 10, 15, 20, 25, 30, 35, 40, 45, 50 cases or more of cigarettes per year. In some embodiments, the subject is a smoker with a smoking history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more. In some embodiments, the subject is a smoker who has quit smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, the subject is a smoker who has quit smoking for at least 6 months. In some embodiments, the subject is a smoker who intends to permanently quit smoking.

[0187] In some embodiments, the "subject in need thereof" may be a subject classified as having "mild" COPD based on the GOLD classification system. In other embodiments, the "subject in need thereof" may be a subject classified as having "moderate" COPD based on the GOLD classification system. In another embodiment, the "subject in need thereof" may be a subject classified as having "severe" COPD based on the GOLD classification system. In yet another embodiment, the "subject in need thereof" may be a subject classified as having "very severe" COPD based on the GOLD classification system. In another embodiment, the "subject in need thereof" may be a subject classified as having COPD falling between "moderate" and "severe" based on the GOLD classification system, for example, a subject having "moderate to severe" COPD.

[0188] In some embodiments, the "subject in need thereof" may be a subject having a test FEV1 value that is less than 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 20%, 15%, or 10%, or less than the predicted FEV1.

[0189] Normal IgE levels in healthy subjects are less than about 100 kU / L (as measured, for example, using the IMMUNOCAP® assay [Phadia, Inc. Portage, MI]). Accordingly, there is provided a method comprising the steps of selecting a subject showing an increase in serum IgE level that is greater than about 100 kU / L, greater than 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-33 antagonist.

[0190] Eotaxin-3 belongs to a group of chemokines released by airway epithelial cells that are upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al., 1999, J. Allergy Clin. Immunol. 104:786-790). The present invention includes a method comprising administering an IL-33 antagonist to treat a patient having an elevated eotaxin-3 level, for example, greater than about 100 pg / ml, greater than about 150 pg / ml, greater than about 200 pg / ml, greater than about 300 pg / ml, or greater than about 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0191] Exhaled nitric oxide (FeNO) is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines including IL-4 and IL-13 (Alving et al., 1993, Eur. Respir. J. 6:1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). A exemplary assay for measuring FeNO is by using the NIOX device by Aerocrine AB, Solna, Sweden. Assessments are made before spirometry and after at least 1 hour of fasting. Included herein is a method comprising administering an IL-33 antagonist to a patient having an elevated level of exhaled NO (FeNO), for example, greater than about 30 ppb, greater than about 31 ppb, greater than about 32 ppb, greater than about 33 ppb, greater than about 34 ppb, or greater than about 35 ppb.

[0192] Eosinophils and neutrophils in induced sputum are well-established direct markers of airway inflammation (Djukanovic et al., 2002, Eur. Respire. J. 37:1S-2S). Sputum is induced by inhalation of hypertonic saline and processed for cell counts by methods known in the art, for example, according to the guidelines of the European Respiratory Society.

[0193] In some embodiments, the subject is stratified into the following groups: blood eosinophil count ≥ 300 cells / μL (or cells / mm 3 ) or ≥ 250 cells / μL (or cells / mm 3 )(high blood eosinophils); blood eosinophil count between 299 and 150 cells / μL (or cells / mm 3 )(medium blood eosinophils); blood eosinophil count < 150 cells / μL (or cells / mm 3 )(low blood eosinophils); or blood eosinophil count < 300 cells / μL (or cells / mm 3 ) and an IL-33 antagonist is administered at a dose or dosing regimen that may be based on eosinophil level, if appropriate.

[0194] Method for evaluating pharmacodynamic COPD-related parameters The present disclosure also includes a method for evaluating one or more pharmacodynamic COPD-related parameters in a subject in need thereof, caused by administration of a pharmaceutical composition comprising an IL-33 antagonist. A decrease in the incidence of exacerbation of COPD (as described above) or an improvement in one or more COPD-related parameters (as described above) may correlate with an improvement in one or more pharmacodynamic COPD-related parameters; such a correlation is not necessarily observed in all cases.

[0195] Examples of "pharmacodynamic COPD-related parameters" include, for example, the following: (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) eosinophil and neutrophil levels in induced sputum; (d) fractional exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement of pharmacodynamic COPD-related parameters" means, for example, a decrease from baseline of one or more biomarkers, such as TARC, eotaxin-3 or IgE, a decrease in eosinophils or neutrophils in sputum, FeNO, or blood eosinophil count. As used herein, the term "baseline" with respect to a pharmacodynamic COPD-related parameter 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.

[0196] 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 can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th day, or at the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th week, or more, after the first treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there is a change in the pharmacodynamic COPD-related parameter, such as "improvement" (e.g., an increase or decrease, depending in some cases on the particular parameter being measured).

[0197] In certain embodiments, administration of an IL-33 antagonist to a subject having COPD causes a change such as a decrease or increase in the expression of a particular biomarker.

[0198] IL-33-related biomarkers include, but are not limited to, calcitonin, procalcitonin, calcitonin gene-related peptide (CGRP), resistin-like alpha (RETNA), chemokine (C-C motif) ligand 8 (Ccl8), serum amyloid A3 (Saa3), Gm1975 (BC117090), killer cell lectin-like receptor (Kirg1), stefin A1 (Csta), transmembrane 4-domain (Ms4a8a), chemokine (C-C motif) ligand 11 (Ccl11), and serine (or cysteine) peptide (serpinA3f).

[0199] COPD-related biomarkers include, but are not limited to, fractional exhaled nitric oxide (FeNO), total IL-33, soluble IL-33 receptor (sST2), calcitonin, PARC, eotaxin-3, total IgE, C-reactive protein (CRP) in blood, IL-6 in blood, fibrinogen, etc.

[0200] In certain embodiments, administration of an IL-33 antagonist to a subject having COPD can cause a decrease in one or more of the total serum IgE level or the eotaxin-3 level. In other embodiments, administration of an IL-33 antagonist to a subject having COPD can cause a decrease in one or more IL-33-related biomarkers. The decrease in one or more biomarkers can be detected at week 1, week 2, week 3, week 4, week 5, or later after administration of the IL-33 antagonist. The expression of biomarkers can be assayed by methods known in the art. For example, the protein level can be measured by ELISA (enzyme-linked immunosorbent assay). The RNA level can be measured, for example, by reverse transcription coupled to polymerase chain reaction (RT-PCR).

[0201] As discussed above, biomarker expression can be assayed by detecting proteins or RNAs in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with the response to treatment with an IL-33 antagonist. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., the RNA levels of biomarkers, and in other embodiments, the RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

Example

[0202] The following examples are provided to give those skilled in the art a complete disclosure and description of how to make and use the methods and compositions characterized in this invention, and are not intended by the inventors to limit the scope of what they consider their invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0203] The exemplary IL-33 antagonist used in the following examples is a human anti-IL-33 antibody named SAR440340, which is also known as REGN3500 or itepkimab by the International Nonproprietary Name (INN).

Example

[0204] A randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept (PoC) trial to evaluate the efficacy, safety, and tolerability of SAR440340 in patients with moderate to severe chronic obstructive pulmonary disease (COPD) A. Study Objectives, Endpoints, and Overview Chronic obstructive pulmonary disease (COPD) is a very prevalent disease worldwide, with a significant economic burden, and the available standard treatments for it have insufficient therapeutic effects on the symptoms, lung function, exacerbations, and long-term evolution of this disease. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that initiates and amplifies the innate adaptive inflammatory cascade in response to epithelial cell stress or damage caused by exposure to allergens, viruses, tobacco smoke, and air pollutants in the atmosphere.

[0205] The primary objective of this trial was to examine the effect of SAR440340 (anti-IL-33 mAb) on the annual rate of moderate to severe acute exacerbations of COPD (AECOPD) compared to placebo.

[0206] The second objectives of this trial were to examine the effect of SAR440340 on the improvement of respiratory function as evaluated by FEV1 before bronchodilator administration compared to placebo; to evaluate the effect of SAR440340 on FEV1 after bronchodilator administration compared to placebo; to evaluate the effect of SAR440340 on the duration from baseline to the first moderate to severe AECOPD event compared to placebo; and to evaluate the effect of SAR440340 on safety and tolerability compared to placebo.

[0207] The exploratory objectives of this trial were in all patients treated with SAR440340 / placebo and in patients with high blood eosinophil levels (≥250 / mm 3 ) and low blood eosinophil levels (<250 / mm 3In the subpopulation with , evaluate the effect of SAR440340 on the symptoms reported by patients and the quality of life described using the electronic diary and the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT), the St. George's Respiratory Questionnaire (SGRQ), and the Euroqol-5 Dimensions (EQ-5D) questionnaire, compared to placebo; evaluate the pharmacokinetic (PK) profile of SAR440340 in serum; evaluate the effect of SAR440340 anti-drug antibodies (ADA); in the subpopulation with high blood eosinophil levels (≥250 / mm 3 ) and low blood eosinophil levels (<250 / mm 3 ) and in subpopulations according to the use / non-use of inhaled corticosteroids (ICS) with bronchodilators as background therapy, fibrinogen levels, and smoking status, evaluate the effect of SAR440340 on FEV1, AECOPD, and other selected endpoints, compared to placebo; evaluate the effect of pharmacogenomics on SAR440340; evaluate the effect of SAR440340 on other respiratory assessments (expanded AECOPD endpoints), compared to placebo; in the subpopulation with high blood eosinophil levels (≥250 / mm 3 ) and low blood eosinophil levels (<250 / mm 3 ) and in subpopulations according to the use / non-use of ICS with bronchodilators as background therapy, fibrinogen levels, and smoking status, evaluate the clinical symptoms of COPD in all patients treated with SAR440340 / placebo compared to patients treated with placebo; evaluate the pharmacodynamic effect of SAR440340; evaluate the effect of SAR440340 on parameters of sleep, activity, and home spirometry, compared to placebo; and compare the usefulness of home spirometry to clinic spirometry.

[0208] The primary endpoint of this trial was the annual rate of moderate to severe (AECOPD) over the treatment period. Moderate exacerbations were recorded by the treating physicians and defined as AECOPDs requiring systemic corticosteroids (such as intramuscular, intravenous or oral) and / or antibiotics. Severe exacerbations were recorded by the treating physicians and defined as AECOPDs requiring hospitalization, an emergency department visit or resulting in death.

[0209] The secondary endpoint was the mean change from baseline in FEV1 (before bronchodilator administration) up to 16 - 24 weeks. Model - based means across 16, 20 and 24 weeks were compared between treatment groups.

[0210] Another secondary endpoint was the change from baseline in FEV1 (after bronchodilator administration) up to 24 weeks. After bronchodilator administration means 30 minutes after salbutamol / albuterol 400 mcg (4 puffs of 100 mcg each) or ipratropium bromide 80 mcg (4 puffs of 20 mcg each).

[0211] Yet another secondary endpoint was the time to the first moderate or severe AECOPD.

[0212] Still other secondary endpoints were treatment - emergent adverse events (TEAE) and serious adverse events (SAE).

[0213] The tertiary endpoints included the change from baseline in the EXACT, SGRQ, or EQ - 5D score at week 24.

[0214] Other tertiary endpoints included serum functional SAR440340 concentration; anti - drug antibodies (ADA) to SAR440340; change from baseline in FEV1 (before and after bronchodilator administration) up to 24 weeks; and the rate of moderate to severe AECOPD.

[0215] Other additional tertiary endpoints included DNA or RNA samples for pharmacogenomics substudies to identify genomic associations with clinical or biomarker response, as well as other clinical outcomes and future evaluation of possible AEs; change from baseline in FVC up to 16 - 24 weeks (% predicted and absolute value in mL); time to first moderate and severe exacerbation or time to discontinuation of the investigational drug due to lack of efficacy based on the judgment of the investigator (after week 4) (extended AECOPD endpoint); and first clinically important deterioration (CID) defined by a decrease in trough FEV1 of > 100 mL from baseline and / or a 4 - unit worsening of SGRQ, and / or time from moderate to severe AECOPD up to 24 weeks (and over a variable treatment period of 52 weeks).

[0216] Other tertiary endpoints related to pharmacodynamics included blood eosinophil and neutrophil counts; levels of biomarkers of interleukin (IL) - 33 and / or type 2 inflammatory pathways, including total IL - 33, sST2 levels, calcitonin levels, PARC levels, eotaxin - 3 levels, total IgE levels, and fibrinogen levels; induced sputum for RNA expression (in a subset of sites, optionally by the patient); optionally including messenger ribonucleic acid sequencing or whole transcriptome analysis; and optionally DNA / RNA samples were collected for pharmacogenomic effects.

[0217] Other tertiary endpoints related to actigraphy (sleep and activity) and home spirometry included sleep and activity parameters, including sleep (total sleep time, awakenings after sleep onset, number of movements during the night), activity (number of movements during the day, percentage of time spent in sedentary activity, percentage of time spent in moderate to vigorous physical activity), and changes in mean spirometry (FEV1) measurements from baseline (2 weeks before randomization) to mean measurements over 10 - 12 weeks (2 weeks before visit 8) and 22 - 24 weeks (2 weeks before visit 14). FEV1 measurements were obtained from both home and clinic spirometry.

[0218] B. Test Design This study was a multinational, randomized, double-blind, placebo-controlled, parallel-group (two-group), proof-of-concept (PoC) trial designed to evaluate the efficacy, safety, and tolerability of SAR440340 in patients with moderate to severe COPD receiving established long-acting β2-adrenergic agonist (LABA), long-acting muscarinic antagonist (LAMA), and / or ICS background therapy (dual or triple combination therapy). Patients were to be treated with SAR440340 or placebo for a minimum of 24 weeks and a maximum of 52 weeks * and up to 20 weeks of safety follow-up. Approximately 343 patients were randomized into two treatment groups of 171 or 172 patients per group. * The trial used a flexible treatment duration of 24 to 52 weeks to maximize data on the primary endpoint (annual rate of exacerbations) in a time-efficient manner. Patients enrolled in the trial remained on treatment for up to 52 weeks or until the last randomized patient completed a minimum treatment period of 24 weeks.

[0219] As shown in Figure 1, the clinical trial consisted of three phases. First, a screening period (10 days to 4 weeks) to determine whether patients met the enrollment criteria of having received a 3-month standard treatment background therapy prior to visit 2 / randomization, including dual combination therapy (LABA + LAMA or ICS + LABA or ICS + LAMA) or triple combination therapy (ICS + LABA + LAMA), and having been taking it stably for at least 1 month prior to screening visit 1. Second, a randomized treatment period in which patients meeting the inclusion and exclusion criteria were randomized to receive SAR440340 (300 mg) as a 2SC injection every 2 weeks (q2w) for 24 to 52 weeks or a matching dose of placebo as a 2SC injection q2w for 24 to 52 weeks. Third, a post-treatment period including 20 weeks of observation-based follow-up.

[0220] The schedule of activities (SoA) for patients who have completed the planned treatment is shown in Table 1.

[0221]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0222] C. Patient Selection The schema of the selected patients is shown in Figure 37. Approximately 340 patients were randomized in this trial (170 patients per arm), and approximately 50% of these patients had a blood eosinophil count ≥ 250 / mm 3 and approximately 50% of the patients had a blood eosinophil count < 250 / mm 3 .

[0223] A summary of the important inclusion and exclusion criteria is presented in Table 2 below.

[0224]

Table 2

[0225] Participants aged 40 to 75 years were eligible to participate in the trial. Participants were eligible to be included in the trial only if all of the following criteria were met: (1) Participants with a diagnosis of COPD for at least 1 year (as found in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of chronic obstructive pulmonary disease).International Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2017 Report) (cited March 8, 2018); available from the website goldcopd.org / wp-content / uploads / 2016 / 12 / wms-GOLD-2017-Pocket-Guide.pdf; (2) participants with moderate to severe COPD at visits 1 and 2 (FEV1 / forced vital capacity [FVC] < 70% after bronchodilator administration and FEV1% predicted < 80% but ≥ 30% after bronchodilator administration); (3) participants with a COPD Assessment Test (CAT) score ≥ 10 at screening visit 1 and visit 2 / randomization; (4) participants with a reported history of signs and symptoms of chronic bronchitis (chronic wet cough for 3 months out of 1 year up to screening in patients in whom other causes of chronic cough (e.g., gastroesophageal reflux, chronic rhinosinusitis, bronchiectasis) have been excluded); (5) participants with a documented history (medical record proof) of ≥ 2 moderate exacerbations or ≥ 1 severe exacerbation within 1 year prior to screening, where a moderate exacerbation is defined as an AECOPD requiring treatment with systemic corticosteroids (oral, intravenous, or intramuscular) and / or antibiotics (however, use of antibiotics alone is not suitable as a "moderate exacerbation" if documentation of the need for antibiotic use for treatment of exacerbation symptoms in COPD is not available), and a severe exacerbation is defined as an AECOPD requiring hospitalization; (6) participants who have received standard background therapy for 3 months prior to visit 2 / randomization, including dual therapy (LABA + LAMA or ICS + LABA or ICS + LAMA) or triple therapy (ICS + LABA + LAMA), and have been taking it stably for at least 1 month prior to screening; (7) current smokers or ex-smokers with a smoking history of ≥ 10 pack-years; (8) body mass index (BMI) ≥ 18.0 kg / m² (including 18.0); (9) both males and females; and (10) able to submit a signed informed consent. 2 (including 18.0); (9) both males and females; and (10) able to submit a signed informed consent.

[0226] Patients who met all of the above inclusion criteria were screened for the following exclusion criteria: (1) Clinically significant abnormal electrocardiogram (ECG) at visit 1 that, in the judgment of the study physician, may affect the conduct of the trial; (2) Severe complications or comorbidities (e.g., significant cardiovascular disease, insulin-dependent diabetes, hyperthyroidism, thyrotoxicosis, pheochromocytoma, history of hypokalemia) for which the use of ICS (e.g., active pulmonary tuberculosis) or LABA is contraindicated; (3) Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 1 month prior to visit 1 / screening or more than 4 courses of IV glucocorticosteroids within 6 months prior to visit 1; (4) Systemic steroid medications (except when used to treat exacerbations, note: a short-term course (up to 6 days) of systemic corticosteroids is acceptable at 24 weeks if medically necessary for reasons unrelated to AECOPD, e.g., in cases of severe poison ivy exposure); PDE-4 inhibitors such as roflumilast; methylxanthines (theophylline, aminophylline); leukotriene receptor antagonists or leukotriene synthesis inhibitors; lipoxygenase inhibitors; anti-IL5 mAb (e.g., benralizumab; mepolizumab); anti-IgE therapy (e.g., omalizumab); anti-IL4R mAb (e.g., dupilumab); systemic immunosuppressive agents (e.g., methotrexate, any anti-TNF mAb, B and / or T cell-targeted immunosuppressive therapy); bronchial thermoplasty; intravenous immunoglobulin (IVIG) therapy; live attenuated vaccines; beta-adrenergic receptor blockers (except selective beta-1 adrenergic receptor blockers used at a stable dose 1 month prior to visit 1); COPD-relieving medications other than salbutamol / albuterol, levalbuterol / levosalbutamol, or ipratropium (their use is not recommended during the trial, and in cases of use under special circumstances (e.g., prescribed by a physician not participating in the trial), their use is recorded in the patient's chart and reported to the eCRF); participants receiving medications or therapies prohibited as concomitant medications including other investigational drugs. The following concomitant medications: antihistamines, ocular, intranasal, and topical corticosteroids were approved during the trial;(5) Participants with a history of clinically significant kidney, liver, cardiovascular, metabolic, neurological, hematological, ophthalmic, respiratory, gastrointestinal, cerebrovascular, or other significant medical diseases or disorders that may require treatment that could interfere with or potentially interfere with the trial, as determined by the treating physician. Specific examples include, but are not limited to, uncontrolled insulin-dependent diabetes; (6) Participants who have had bronchial thermoplasty treatment (up to 3 years prior to Visit 1); (7) Exclusions related to tuberculosis (TB): A history of active TB or incompletely treated TB, confirmed QuantiFERON-positive patients (not with active disease) will be excluded from the trial unless they meet the following criteria: A history of complete chemoprevention or treatment of latent TB infection (with a treatment regimen according to local guidelines), a history of treatment of active TB infection, patients with suspected extrapulmonary TB infection if an agreement has been obtained with an expert to rule out or treat active TB infection, or patients at high risk of contracting TB, such as close contact with an individual with active or latent TB; (8) Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines for asthma management (Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (GINA 2018). 2018. [Cited March 8, 2018]. Available from the website: ginasthma.org / 2018-gina-report-global-strategy-for-asthma-management-and-prevention); (9) Significant lung diseases other than COPD (e.g., pulmonary fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, eosinophilic granulomatosis with polyangiitis, significant sleep apnea with bilevel positive airway pressure, etc.) or another diagnosed lung or systemic disease associated with elevated peripheral eosinophil counts; (10) Diagnosis of α-1 antitrypsin deficiency; (11) Progressive COPD requiring chronic (>15 hours / day) oxygen support; (12) Participants who have had a moderate or severe AECOPD event within 4 weeks prior to screening;(13) Participants who had experienced an upper or lower respiratory tract infection within 4 weeks prior to Screening / Visit 1 or during the Screening period; (14) Past or planned pneumonectomy or lung volume reduction surgery; (15) Participants with a history of systemic allergic reaction to mAb drugs; (16) Anti-IgE therapy within 130 days prior to Visit 1 (e.g., omalizumab (XOLAIR®)) or any other biological therapy for asthma (anti-IL5 mAb, e.g., FASENRA® or mepolizumab (NUCALA®)) within 2 months or the longer of 5 half-lives prior to Visit 1 or any other inflammatory or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) and systemic immunosuppressive drugs (e.g., methotrexate) for treating other diseases; (17) Current history of substance and / or alcohol abuse; (18) Unable to follow the test procedures (e.g., due to language problems, mental disorders) or unable to read, understand, fill out the questionnaire or use an electronic diary without any assistance; (19) Exposure to another investigational drug (including small molecules and mAbs including dupilumab) within the period prior to Visit 1 with an antibody <5PK half-life. If the half-life is unknown, the minimum interval after exposure to the previous investigational antibody is 6 months. The minimum interval after exposure to any other (non-antibody) investigational drug is 30 days prior to Visit 1; (20) Participating in the acute phase of a pulmonary rehabilitation program, i.e., patients who started rehabilitation <4 weeks before Screening (Note: Patients in the maintenance phase of the rehabilitation program can be included); (21) Clinically relevant (based on the judgment of the treating physician) abnormal clinical test values suggesting an unknown disease and requiring further evaluation; (22) Participants who had received previous treatment in any clinical trial of SAR440340; (23) Participants who are the treating physician, or any sub-investigator, research assistant, pharmacist, trial coordinator, other staff or their relatives directly involved in the conduct of the trial; (24) Prisoners and participants legally confined in a facility;(25) Known allergy to doxycycline or related compounds, or known allergy to the excipients of SAR440340; (26) Women who are lactating, breastfeeding, or pregnant; (27) Women who are not protected by an acceptable form of effective contraception or who have not confirmed a negative serum β-human chorionic gonadotropin (β-hCG) test at Visit 1 and a negative urine pregnancy test prior to Visit 2 / randomization and who may be pregnant (pre-menopausal women who can biologically become pregnant) (post-menopausal women (defined as having no menstruation for at least 12 consecutive months) are not required to use additional contraception); male participants with female partners who may be pregnant shall abstain from penile-vaginal intercourse, as one of the following two normal preferred lifestyles (abstain for a long period of time), remain abstinent or, if having penile-vaginal intercourse with a woman who may be pregnant and is not currently pregnant, use a male condom plus the partner use a contraceptive method with a failure rate of <1% per year; men with partners who are pregnant or breastfeeding shall not participate unless they agree to remain abstinent from penile-vaginal intercourse or to use a male condom during each instance of penile penetration; (28) Diagnosed with an ongoing parasitic infection (helminth), suspected of having a parasitic infection or at high risk thereof, and if a progressive infection has not been excluded by clinical and (if necessary) laboratory evaluation prior to randomization; (29) History of human immunodeficiency virus (HIV) infection or positive HIV 1 / 2 serology; (30) History of immunosuppression including a history of invasive opportunistic infections (e.g., TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite cure of the infection is known or suspected; or, at the discretion of the investigator, unusually frequent, recurrent, or chronic infections; (31) Live attenuated vaccine administration within 12 weeks prior to Visit 1 or planned during the trial.(32) Patients with autoimmune diseases or patients using systemic immunosuppressive therapy for autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) or patients with high-titer autoantibodies at the time of screening who are suspected of having a high risk of developing autoimmune diseases at the discretion of the treating physician or the sponsor of the trial; (33) Patients with cardiovascular diseases / conditions including unstable ischemic heart diseases, including acute myocardial infarction within the past year or unstable angina within the past 6 months, and arrhythmias including paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Persistent atrial fibrillation defined by continuous atrial fibrillation for at least 6 months and controlled by a rate control strategy (i.e., selective β-blockers, calcium channel blockers, pacemaker placement, digoxin or ablation therapy), and stable appropriate levels of anticoagulation for at least 6 months may be considered included. Cardiomyopathy in cases defined by stage III-IV (New York Heart Association) heart failure, or other related cardiovascular disorders that may put the patient at risk or have a negative impact on the trial outcome at the discretion of the treating physician, and patients with uncontrolled hypertension (i.e., systolic blood pressure [BP] > 180 mmHg or diastolic BP > 110 mmHg regardless of the use of antihypertensive therapy); (34) Serological tests for hepatitis B and / or C indicating progressive or chronic infection; (35) Any prior history of malignancy including lymphoproliferative diseases or progressive malignancies within 5 years prior to Visit 2 (except for cancers successfully treated in situ of the cervix, non-metastatic squamous cell or basal cell carcinoma of the skin); (36) Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the upper limit of normal (ULN), hemoglobin < 10 g / dL in men and < 9 g / dL in women, < 1.5 K / mm; 3 of neutrophils (in African Americans < 1 K / mm 3 ), < 100 K / mm 3Platelets of [specific condition] or clinically significant clinical tests at the time of screening / initial visit including creatinine ≥ 150 μmol / L; (37) Patients receiving macrolide (e.g., azithromycin) therapy, if not on stable therapy for > 1 year; (38) Patients receiving PDE-4 inhibitor (roflumilast) or leukotriene blocker (montelukast, Singulair, etc.); and (40) Registration / randomization has been stopped at the study level despite screening of the patient.

[0227] Only patients who met all inclusion criteria and none of the exclusion criteria were included in the study.

[0228] The baseline demographics of the study participants are presented in Table 3. Demographics were balanced between the treatment and placebo groups, with women comprising more than 40% of the population.

[0229]

Table 3

[0230] D. Study Treatment Investigational Medicinal Product As shown in Table 4 below, the investigational medicinal product (IMP) included SAR440340 for subcutaneous injection and placebo during the study.

[0231] In the group receiving IMP, sterile SAR440340 was provided in one 20 mL vial containing 287 mg of the lyophilized formulation. One vial of the lyophilized formulation (287 mg) or placebo was reconstituted with 2.5 mL of sterile water for injection to obtain 2.9 mL of 100 mg / mL SAR440340 or placebo. A volume of 1.5 mL per injection was withdrawn from the vial. Patients received two subcutaneous injections per administration. The subcutaneous injection sites were rotated among the upper thigh, the four quadrants of the abdomen, or the upper arm so that the same site was not injected twice during consecutive visits. The investigational medicinal product (IMP) or placebo was administered every 14 ± 3 days (q2w) for 24 - 52 weeks.

[0232]

Table 4

[0233] Non - investigational drug At the time of Screening Visit 1, all patients had received a standard treatment background therapy for 3 months prior to Visit 2 / randomization, including dual therapy (LABA + LAMA or ICS + LABA or ICS + LAMA) or triple therapy (ICS + LABA + LAMA), and had been taking it stably for at least 1 month prior to Screening / Visit 1.

[0234] The prescription of background therapy was a dry powder inhaler (DPI), a metered - dose inhaler (MDI) or a pocket nebulizer. The administration route of background therapy was oral inhalation. The dose regimen of background therapy was as prescribed.

[0235] Throughout the trial, patients were to continue their established background therapy for COPD. Patients continued to receive their established background medications for COPD throughout the trial period. After successful management of an acute exacerbation of COPD (e.g., using oral corticosteroids and / or antibiotics), every effort should be made to resume the initial background COPD treatment regimen if, in the opinion of the investigator, it is medically acceptable. After one severe or two moderate exacerbations of COPD, dose adjustments of background therapy were permitted for symptom control and for the remainder of the trial period as necessary.

[0236] Patients could use albuterol / salbutamol or levalbuterol / levosalbutamol (including ipratropium or ipratropium / short - acting beta - agonist [SABA] combinations) as rescue medications as needed during the trial. Nebulizer solutions could be used as an alternative delivery method.

[0237] The prescription of relievers included a dry powder inhaler (DPI), a metered-dose inhaler (MDI) or a pocket nebulizer. The route of administration of relievers was oral inhalation. The dosage regimen of background therapy was as prescribed.

[0238] Efficacy evaluation The severity of COPD exacerbations was defined by protocol. "Moderate exacerbations" were recorded by the study physicians and defined as AECOPD requiring systemic corticosteroids (such as intramuscular, intravenous or oral) and / or antibiotics. "Severe exacerbations" were recorded by the study physicians and defined as AECOPD requiring hospitalization, an emergency department visit or resulting in death. In addition to these protocol-defined exacerbations of COPD, the clinical signs and symptoms of COPD exacerbations were captured in the eCRF (including but not limited to increased dyspnea, increased wheezing, increased cough, increased sputum volume and / or increased purulent sputum).

[0239] COPD exacerbations were treated as considered necessary by the study physicians. After successful management of an acute exacerbation of COPD (e.g., using oral corticosteroids and / or antibiotics), every effort was made to resume the initial background COPD treatment regimen if medically acceptable in the opinion of the study physicians. After one severe or two moderate exacerbations of COPD, dose adjustments of background therapy were permitted for symptom control and for the remainder of the study period if necessary.

[0240] Spirometry at the time of clinical presentation should be performed according to the European Respiratory Society (ERS) / American Thoracic Society (ATS) guidelines (Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al., Standardization of spirometry. Series “ATS / ERS TASK FORCE: Standardization of Lung Function Testing” Edited by Brusasco V, Crapo R, and Viegi G. Eur Respir J. August 2005;26(2):319-38) and prior to the administration of the investigational drug. For parameters measured before bronchodilator administration, including FEV1, peak expiratory flow (PEF), FVC, and forced expiratory flow (FEF) 25%-75%, spirometry was performed after the washout period of the bronchodilator according to its action period, e.g., withholding the last dose of salbutamol / albuterol or levalbuterol / levalbeterol for at least 6 hours, withholding the last dose of LABA for at least 12 hours (vilanterol, a long-acting LABA-like drug, should be withheld for at least 24 hours), withholding the last dose of ipratropium for at least 8 hours, and withholding the last dose of LAMA for at least 24 hours. This was confirmed before performing the measurement. When both pre- and post-bronchodilator spirometry were evaluated, post-bronchodilator spirometry was performed in accordance with the mechanism of action of the reliever drug (i.e., 30 minutes for albuterol or other SABA). At all visits, spirometry was preferably performed in the morning, and afternoon / night was permitted in exceptional situations where morning spirometry could not be performed; spirometry was performed at approximately the same time at each visit throughout the study. Current smokers were cautioned not to smoke for at least 1 hour before spirometry. Spirometry was performed at all visits using a standard spirometry technique including the same spirometer and calibration, and whenever possible, by the same person. If possible, three measurements meeting ATS acceptability and reproducibility criteria were obtained at all visits.

[0241] Exhaled nitric oxide (FeNO) was analyzed using a NIOX device (Aerocrine AB, Solna, Sweden) or a similar analyzer using a flow rate of 50 mL / second and reported in parts per billion (ppb). This assessment was performed prior to spirometry and following at least 1 hour of fasting.

[0242] Any assessment of actigraphy (sleep and activity) and home spirometry were also included. Patients were supplied with an actigraphic wristband and asked to wear it continuously (including at night) over three monitoring periods including the night. Actigraphy data were used to measure sleep parameters and daytime activity. The actigraphs ran out during two monitoring periods, during the screening period as well as during the treatment phase. Data from the device were uploaded to a computer at each clinical visit following the monitoring period. Patients received documented in-clinic training for the use of portable home spirometry during screening. During the study, patients were asked to use a home spirometer with electronic data storage to measure FEV1. Patients were instructed to perform the exhalation flow technique as described in the test manual at least twice a day between 06:00 and 12:00 and between 18:00 and 24:00 during the screening period and at two-week intervals during the treatment and follow-up periods.

[0243] A subset of the test facilities was selected to perform the assessment of induced sputum and patients at these selected facilities had the option to participate in this assessment. Sputum induction is a relatively non-invasive method of obtaining sputum for cell or liquid phase inflammatory indices, culture or cytology. Sputum induction is performed using an aerosol of saline or hypertonic saline generated by an ultrasonic nebulizer. Since this aerosol is a potential bronchoconstrictive stimulant, pretreatment and inhalation with salbutamol renders it safe in a dose-responsive manner.

[0244] At the time of screening (first visit), the patient was provided with an electronic diary. The patient was instructed on the use of this device, and written instructions regarding the use of the electronic device were provided to the patient. The information recorded was downloaded from this device on other instructed days. Daily, during screening and treatment, the patient used the electronic diary to answer the COPD symptom scale questions of the EXACT tool, record the daily use of COPD reliever medications, and record the use of systemic corticosteroids and / or antibiotics taken for COPD exacerbations. The electronic diary was used for the outcome questionnaires that the patient filled out. These questionnaires are described below.

[0245] COPD Assessment Test (CAT (trademark)) CAT (trademark) is a new questionnaire designed for patients with COPD to measure the impact of the disease on quality of life. CAT (trademark) is an 8-item self-administered questionnaire developed for use in routine clinical practice to measure the health status of patients with COPD.

[0246] The CAT (trademark) score ranges from 0 to 40, with higher scores indicating a greater impact on health status. The test relates to cough, sputum, chest tightness, breathlessness, activity limitation, confidence, sleep and energy. The patient scores the questions from 1 to 5 according to their own feelings about the disease (1 = I am very happy; 5 = I am very sad).

[0247] St. George's Respiratory Questionnaire (SGRQ) The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire designed to measure and quantify health-related quality of life in adult patients with chronic airflow limitation. The overall score ranges from 0 to 100. The domain scores are calculated for three areas: symptoms, activity and impact (psychosocial) as well as the total score. Lower scores indicate a better quality of life (QoL).

[0248] The first part ("symptoms") assesses overall symptoms including cough frequency, sputum production, wheezing, shortness of breath, and the duration and frequency of episodes of shortness of breath or wheezing. The second part has two components: "activity" and "impact". The "activity" part addresses activities that cause or are limited by shortness of breath. The "impact" part deals with a range of factors including impact on employment, managing health, fear, blame, need for medication, side effects of prescribed therapies, health prediction, and interference with daily life. The recall period for the questionnaire is over the past four weeks.

[0249] Psychometric tests have demonstrated its reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. A minimum change in score of 4 units has been established as clinically relevant after examination by patients and clinicians. The SGRQ has been used in the range of diseases including asthma, COPD, and bronchiectasis.

[0250] Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) The EXACT total score measures the symptoms of acute bacterial exacerbation of chronic bronchitis - COPD (ABECB - COPD), i.e., signs and symptoms of acute, persistent exacerbation above daily variation. The total score of the instrument is in the following areas: Shortness of breath (5 items), Cough and sputum (2 items), Chest symptoms (3 items), Difficulty expectorating sputum (1 item), Fatigue or weakness (1 item), Sleep disturbance (1 item), and Anxiety or worry (1 item) It is composed of a total of 14 items representing these.

[0251] EXACT is a diary to be filled in every night before going to bed. The instrument was developed with electronic diary management in mind, and the cognitive interview is conducted using a paper - pen booklet and a personal digital assistant (PDA), and describes the understanding of respondents and user acceptance of the PDA in either mode.

[0252] EuroQol Five-Dimension Questionnaire (EQ-5D) The EQ-5D-5L is a standardized health-related QoL questionnaire developed by the EuroQol Group to provide a simple and generic measure of health for clinical and economic appraisal. The EQ-5D is designed for self-completion by patients.

[0253] Safety assessment The same safety assessment was applied to the treatment and placebo groups. Adverse events, including SAEs, and particularly notable adverse events (AESIs) were collected at all visits.

[0254] Complete physical examinations included the skin, nasal cavity, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic, and musculoskeletal systems. All deviations from normal, including those attributable to the patient's disease, were recorded.

[0255] Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate, were measured at screening, baseline, and all subsequent site visits. Height (cm) was measured only at screening (Visit 1). Weight (kg) was measured at screening (Visit 1) and at the EOT / EOS visit.

[0256] Recordings of a standard 12-lead electrocardiogram (ECG) were performed on site. An ECG was performed at the randomization visit, prior to the administration of the investigational medicinal product. The PR interval, QT / QTc interval, QRS complex, and heart rate were measured for each ECG by averaging the minimum of 3 complexes in the appropriate lead (Lead II).

[0257] Smokers The smoking status was determined for the subjects. The smoking habit was only related to tobacco (e.g., cigarettes, cigars, pipes). The use of chewing tobacco or pipe tobacco was not reported in the study. The score of "non-smoker" was given to subjects who smoked less than 1 cigarette per day on average, and the subjects were considered non-smokers. If the subjects smoked less than 1 cigarette per day on average during these 7 days, the score of "current smoker" was given. The subjects who had smoked before but stopped at least 8 days before the test were given the score of "ever smoker". The duration of smoking cessation in the study ranged from approximately 1.2 months to 56.1 years, with an average of 11.80 years and a median of 9.92 years.

[0258] Baseline disease characteristics COPD-specific baseline disease characteristics are presented in Table 5 below. The SAR440340 treatment and placebo groups were balanced in terms of COPD disease-specific characteristics.

[0259]

Table 5

[0260] Figure 2 presents data related to the baseline exacerbation history for the SAR440340 treatment and placebo groups. In Figure 2A, data on the number of moderate to severe AECOPDs in this 1 year for both groups are presented. Data on the number of moderate (Figure 2B) and severe (Figure 2C) AECOPDs are also presented separately. This data indicates that both the SAR440340 treatment and the placebo group were balanced in terms of exacerbation history.

[0261] Figure 3 presents data related to the baseline smoking history for the SAR440340 treatment and placebo groups. In Figure 3A, data showing the number and percentage of participants who are current smokers and those with a smoking history in both groups are presented. Data for subgroups based on eosinophil levels (high, ≥250 / μl (Figure 3B) vs. low, <250 / μl (Figure 3D)) are also presented. Additional data showing the total packs of cigarettes smoked per year (Figure 3C) and the number of years since quitting smoking (Figure 3E) for the SAR440340 treatment and placebo groups are presented. This data indicates that both the SAR440340 treatment and the placebo group were balanced in terms of smoking history.

[0262] Figure 4 presents data related to the baseline background medications for the SAR440340 treatment and placebo groups. Data related to the number of participants in each of the groups taking the following combinations of background medications: LABA+LAMA, ICS+LAMA, ICS+LABA, and ICS+LABA+LAMA are presented in Figure 4A. Further, data showing the number of participants in each of the groups using an ICS-containing background regimen are presented in Figure 4B. Data showing the ICS dose (low, moderate, or high) of the participants receiving an ICS-containing background regimen in the SAR440340 treatment and placebo groups are also presented in Figure 4C. These data indicate that the majority of patients were on an ICS-containing regimen.

[0263] Figure 5 presents data showing the baseline blood eosinophils for the SAR440340 treatment and placebo groups. The data are presented for subgroups based on eosinophil levels (high, ≥250 / μl vs. low, <250 / μl). Data at screening (Figure 5A) and at baseline (Figure 5B) are presented. This data indicates that at screening, both eosinophil groups were represented approximately equally for the SAR440340 treatment and placebo groups. However, at baseline, there were more participants with low eosinophil levels in both the SAR440340 treatment and placebo groups.

[0264] The baseline biomarker values of the study participants who received either SAR440340 or placebo are shown in Table 6 below. This data indicates that the SAR440340 and placebo treatment groups were balanced at baseline with respect to blood biomarkers. The baseline biomarker values of the study participants with smoking experience and current smokers are shown in Table 7 below. These results indicate that participants with smoking experience had a higher mean eosinophil count (EOS) with more patients having EOS greater than 250 and fewer patients having EOS less than 150, a higher mean fractional exhaled nitric oxide (FeNO) (FeNO was measured in only n = 33), and a lower mean serum immunoglobulin E (IgE) level compared to the current smoker group.

[0265]

Table 6

[0266] * Placebo, SAR440340, and for all, FeNO before baseline BD administration, N = 20, 12, 33. ** Placebo, SAR440340, and for all, FeNO after baseline BD administration, N = 20, 12, 33. Blood biomarker abbreviations: sST2, soluble IL-33 receptor; PARC, pulmonary and activation-regulated chemokine; FeNO, fractional exhaled nitric oxide; pre-BD, before bronchodilator administration; and post-BD, after bronchodilator administration.

[0267]

Table 7

[0268] Efficacy Primary efficacy endpoint The primary analysis compared the SAR440340 treatment group to the placebo group. The primary efficacy endpoint was the annual rate of moderate to severe AECOPD over the treatment period.

[0269] For the primary efficacy endpoint, AECOPD, a negative binomial regression model was used to evaluate treatment differences. The model included the total number of events occurring during the treatment period (up to 52 weeks) as the response variable, and treatment group, baseline eosinophil stratum, and region (pooled countries) as covariates. The log-transformed observation time was the offset variable. Parameters were estimated using the maximum likelihood method with the Newton-Raphson algorithm. The comparison of annual event rates between the treatment group and the placebo group was done within this model, and the rate ratio and its 95% confidence interval were estimated. In the case of early discontinuation of the investigational drug, the secondary analysis included events up to 14 days after the last dose.

[0270] Figure 6 shows AECOPD for the combined groups of high and low eosinophil subjects treated with SAR440340 or placebo. These results indicate that treatment with SAR440340 resulted in an approximate 18% reduction in AECOPD in the combined high and low eosinophil groups.

[0271] As shown in Figure 7, subgroup analyses were performed separately by baseline eosinophil level (high and ≥250 / μl (Figure 7B) vs low and <250 / μl (Figure 7A)). These results indicate that treatment with SAR440340 resulted in a similar reduction in AECOPD regardless of baseline eosinophil count. An approximate 15% reduction in the low eosinophil group vs an approximate 20% reduction in the high eosinophil group.

[0272] Secondary efficacy endpoints Time from first moderate to severe AECOPD One of the secondary efficacy endpoints used in the study was the time from first moderate to severe AECOPD. The time to first moderate or severe AECOPD was analyzed using a Cox regression model with treatment, baseline eosinophil stratum, and region (pooled countries) as covariates. The Kaplan-Meier (K-M) method was used to estimate the probability of first AECOPD at specific time points for each group.

[0273] Figure 8 shows the statistical analysis of the time from first moderate to severe AECOPD in the combined group of high and low eosinophil subjects treated with SAR440340 or placebo. These results indicate that treatment with SAR440340 reduced the likelihood of first AECOPD by approximately 17% at a specific time point.

[0274] As shown in Figure 9, subgroup analyses were performed separately by baseline eosinophil levels (high and ≥250 / μl (Figure 9B) vs. low and <250 / μl (Figure 9A)). These results indicate that treatment with SAR440340 reduced the likelihood of first AECOPD by approximately 24% at a specific time point in the low eosinophil level subgroup and by approximately 11% at a specific time point in the high eosinophil level subgroup.

[0275] FEV1 before bronchodilator (BD) administration Another secondary efficacy endpoint used in the study was FEV1 before BD administration. The mean change from baseline to weeks 16 to 24 in FEV1 before bronchodilator administration was analyzed using the mixed effects model for repeated measures (MMRM) approach. Model-based means at weeks 16, 20, and 24 were compared between treatment groups. The dependent variable was the change from baseline in FEV1 before bronchodilator administration at each time point. The model included as covariates the baseline FEV1 value, treatment group, visit, and treatment-by-visit interaction, baseline eosinophil stratum, and region (consolidated countries). The within-patient correlation was modeled using an unstructured correlation matrix. Parameters were estimated using the restricted maximum likelihood method with the Newton-Raphson algorithm. Additional covariates such as background medications, age, height, gender, race, and smoking status were considered for inclusion in the analysis model based on the blinded data evaluation and the final analysis model described in the statistical analysis plan (SAP). The comparison between the treatment and placebo groups was performed within this model, and the least squares mean difference and its 95% confidence interval were evaluated. In the case of early discontinuation of the investigational drug, the primary analysis included data up to 14 days after the last dose.

[0276] Figure 10 shows the change in pre - bronchodilator FEV1 from baseline in a composite group of high and low eosinophil subjects treated with SAR440340 or placebo. Results are presented as mean change from baseline up to 16 - 24 weeks. Figure 28 presents similar data for mean change from baseline up to 24 weeks.

[0277] Figure 11 shows a graph of the mean change in pre - bronchodilator FEV1 from baseline up to 16 - 24 weeks. These results indicate that SAR440340 treatment had a rapid and sustained effect on pre - bronchodilator FEV1.

[0278] As shown in Figure 12, subgroup analyses were performed separately by baseline eosinophil level (high EOS ≥ 250 / μl (Figure 12B) vs low EOS < 250 / μl (Figure 12A)). Figure 29 presents this same data in a modified intent - to - treat analysis. The modified intent - to - treat analysis was performed as described above. These results indicate that SAR440340 improved pre - bronchodilator FEV1 by 110 mL in the high eosinophil level subgroup and by 20 mL in the low eosinophil level subgroup.

[0279] Figure 13 presents a graph of the mean change in pre - bronchodilator FEV1 from baseline up to 16 - 24 weeks for both the high eosinophil level group (Figure 13B) and the low eosinophil level group (Figure 13A). These results indicate that SAR440340 treatment resulted in a rapid and sustained improvement in lung function in the high eosinophil level subgroup.

[0280] Figure 39 presents a graph of the mean change in pre - bronchodilator FEV1 from baseline up to 16 - 24 weeks for both the ex - smoker group (Figure 39A) and the current smoker group (Figure 39B). These results indicate that among ex - smokers, SAR440340 treatment improved pre - bronchodilator FEV1 by 90 mL. In contrast, there was no improvement in pre - bronchodilator FEV1 among current smokers.

[0281] FEV1 after administration of bronchodilator (BD) Another secondary efficacy endpoint used in the study was FEV1 after BD administration. Statistical analysis of the change from baseline in FEV1 after BD administration up to 24 weeks was analyzed in the same way as FEV1 before BD administration. A similar analysis method was applied to analyze the change from baseline up to the time point beyond 24 weeks for FEV1 (both before and after BD administration).

[0282] Figure 14 shows the change in FEV1 before BD administration from baseline in a combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Figure 32 presents this same data in a modified intent-to-treat analysis. The modified intent-to-treat analysis was performed as described above. These results indicate that there was a moderate effect on FEV1 after BD administration in the SAR440340 group.

[0283] As shown in Figure 15, subgroup analysis was performed separately by baseline eosinophil level (high EOS ≥ 250 / μl (Figure 15B) vs. low EOS < 250 / μl (Figure 15A)). Figure 33 presents this same data in a modified intent-to-treat analysis. The modified intent-to-treat analysis was performed as described above. These results show an improvement of 70 mL in FEV1 after BD administration in the high eosinophil level subgroup.

[0284] Figure 16 presents a graph of the average change in FEV1 after BD administration from baseline up to 16 - 24 weeks for both the high eosinophil level group and the low eosinophil level group. These results indicate that treatment with SAR440340 showed a tendency towards an early and sustained improvement in FEV1 after BD administration in the high eosinophil level subgroup.

[0285] Efficacy in smokers: Current smokers and ex-smoker subgroups Tables 8 and 9 show the baseline characteristics of the ex-smoker and current smoker subgroups. The baseline characteristics were balanced except for the FeNO levels presented as lower in current smokers. Additionally, in the ex-smoker subgroup, there were slightly more patients with baseline eosinophils ≥250, slightly fewer patients receiving LABA+LAMA, and slightly more patients receiving ICS-containing regimens.

[0286]

Table 8

[0287]

Table 9

[0288] Figure 17 shows the annualized and cumulative moderate to severe AECOPD in the combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Data are presented for both current smokers (Figure 17B) and ex-smokers (Figure 17A) as subgroups. In the ex-smoker subgroup, SAR440340 reduced the annualized moderate to severe COPD exacerbations by 42% and improved the pre-BD FEV1 by 90 mL. In contrast, there was a 12% increase in the current smoker group and no improvement in FEV1. Figure 26A shows the unadjusted annualized moderate to severe AECOPD compared to the adjusted annualized moderate to severe AECOPD for the ex-smoker subgroup. Figure 26B shows the unadjusted annualized moderate to severe AECOPD compared to the adjusted annualized moderate to severe AECOPD for the current smoker subgroup. The adjusted and unadjusted values for the annualized moderate to severe AECOPD are presented as described above. This data indicates that SAR440340 treatment reduced AECOPD by approximately 42% in ex-smokers.

[0289] Figure 18 shows the change in FEV1 before BD administration from baseline in a combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Data are presented for both current smokers (Figure 18B) and ex-smokers (Figure 18A) as subgroups. Figure 30 presents this same data in a modified intent-to-treat analysis. The modified intent-to-treat analysis was conducted as described above. These data indicate that treatment with SAR440340 improved FEV1 before BD administration by approximately 90 mL in ex-smokers and by approximately 20 mL in current smokers.

[0290] Figure 19 shows the change in FEV1 after BD administration from baseline in a combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Data are presented for both current smokers (Figure 19B) and ex-smokers (Figure 19A) as subgroups. Figure 34 presents this same data in a modified intent-to-treat analysis. The modified intent-to-treat analysis was conducted as described above. These data indicate that treatment with SAR440340 improved FEV1 after BD administration by approximately 60 mL in ex-smokers. Ex-smokers had the greatest improvement in percent change in FEV1 both before and after BD administration (Figure 64).

[0291] Figure 20 presents data relating to the efficacy outcome relationship with both smoking status and eosinophil subgroup. These data indicate that the highest efficacy for preventing AECOPD was observed in ex-smokers treated with SAR440340 regardless of eosinophil subgroup.

[0292] The annual rate (primary endpoint) of moderate-to-severe AECOPD events was 1.61 in the placebo group and 1.30 in the itepkinumab group (relative risk [RR] 0.81; 95% confidence interval [CI] 0.61 - 1.07), and the least-squares (LS) mean change from baseline to weeks 16 to 24 of pre-bronchodilator FEV1 (important secondary endpoint) was 0.00 L with placebo and 0.06 L with itepkinumab in the mITT population (LS mean difference 0.06; 95% CI 0.01 - 0.10). All of the benefits in both AECOPD and FEV1 could be explained by a more pronounced treatment effect in the subgroup of ever-smokers, and there was no treatment benefit in the subgroup of current smokers. The overall AECOPD treatment effect was driven by a marked 42.5% reduction in AECOPD in the subgroup of ever-smokers compared to the effect not observed in current smokers (RR 1.09; 95% CI 0.74 - 1.61; HR 1.15; 95% CI 0.75 - 1.77) (RR 0.58; 95% CI 0.39 - 0.85; HR for time to first AECOPD event 0.57; 95% CI 0.37 - 0.88). Similarly, the FEV1 treatment effect was highly pronounced in the subgroup of ever-smokers (LS mean difference 0.09; 95% CI 0.02 - 0.15), and there was no treatment effect in current smokers.

[0293] The treatment effect for AECOPD was not associated with eosinophil levels, but the treatment effect for FEV1 was higher in the subgroup of patients with eosinophils ≥ 250 cells / mm 3 (LS mean difference 0.12; 95% CI 0.02 - 0.21).

[0294] Figures 38A - 38D graphically depict the effect of SAR440340 on blood eosinophil levels. Data are presented for the median (Figure 38A) and mean (Figure 38B) percent change in eosinophils in ever-smokers and the median (Figure 38C) and mean (Figure 38D) percent change in eosinophils in current smokers.

[0295] Efficacy in the moderate COPD to severe COPD category Figure 27A shows data representing adjusted and unadjusted annual rates of moderate to severe AECOPD in participants with moderate COPD in both the SAR440340-treated subgroup and the placebo subgroup. Figure 27B shows data regarding adjusted and unadjusted annual rates of moderate to severe AECOPD in participants with severe COPD in both the SAR440340-treated subgroup and the placebo subgroup. These results indicate that there was no significant difference in the efficacy of treatment based on COPD classification.

[0296] Figure 31A shows data representing FEV1 before BD administration in participants with moderate COPD treated with SAR440340 or placebo. Figure 31B shows data representing FEV1 before BD administration in participants with severe COPD treated with SAR440340 or placebo. These results indicate that SAR440340 improved FEV1 before BD administration in patients with relatively low lung function.

[0297] Figure 35A shows data representing FEV1 after BD administration in participants with moderate COPD treated with SAR440340 or placebo. Figure 35B shows data representing FEV1 after BD administration in participants with severe COPD treated with SAR440340 or placebo. These results indicate that SAR440340 improved FEV1 after BD administration in patients with relatively low lung function.

[0298] St. George's Respiratory Questionnaire (SGRQ) Figure 21 shows the change in SGRQ from baseline in a composite group of high and low eosinophil subjects treated with SAR440340 or placebo. These results indicate that there was no change in SGRQ in the SAR440340 treatment group.

[0299] As shown in Figure 22, subgroup analyses were performed separately by baseline eosinophil levels (high EOS ≥ 250 / μl (Figure 22B) vs. low EOS < 250 / μl (Figure 22A)). These results show that SAR440340 improved SGRQ in the high EOS subgroup.

[0300] Biomarker Figure 23 shows data related to the levels of blood eosinophils in subjects treated with SAR440340 or placebo. Figure 23A shows the mean change in blood eosinophils, and Figure 23B shows the median percent change in blood eosinophils. Figure 23C shows the percent change from baseline at week 24. These data show that treatment with SAR440340 resulted in a rapid and sustained reduction in blood eosinophils, with a median change of approximately -42%.

[0301] Figure 24 shows data related to the levels of the biomarker IgE in subjects treated with SAR440340 or placebo. Figure 24A shows the mean percent change from baseline in IgE levels. Figure 24B shows the median percent change from baseline in IgE levels. These data show that there was a slight reduction in IgE levels from baseline in the SAR440340 treatment group.

[0302] Figure 25 shows data related to the levels of total IL-33 and sST2 in subjects treated with SAR440340 or placebo. Figure 25A shows the mean change in total IL-33. Figure 25B shows the mean change in sST2. These data show that there was a significant effect of SAR440340 treatment on IL-33 and no effect on sST2.

[0303] Figures 40A to 40B depict the average changes in blood eosinophils in smokers with smoking experience versus current smokers. Similar effects were observed in both groups, but a greater effect was seen in smokers with smoking experience. Figures 41A to 41B depict the average change amounts of blood neutrophils in smokers with smoking experience versus current smokers. Figures 42A to 42B depict the average change amounts of total IL-33 in smokers with smoking experience versus current smokers. Figures 43A to 43B depict the average change amounts of FeNO before administration of a bronchodilator (before BD administration) in smokers with smoking experience versus current smokers. Figures 44A to 44B depict the average change amounts of FeNO after administration of a bronchodilator (after BD administration) in smokers with smoking experience versus current smokers. Smokers with smoking experience had the greatest improvement in the percent change of FEV1 (see Figures 45A to 45B).

[0304] Figure 36 depicts the average change amounts from the baseline of FeNO before and after BD administration, indicating a reduction in FeNO.

[0305] The statistical methods used to analyze the primary and secondary endpoints are shown in Table 10 below.

[0306]

Table 10

[0307] Summary of Results As summarized in Table 11 below, SAR440340 reduced moderate to severe exacerbations in COPD patients by 18% (ns, p = 0.1647), regardless of participant blood eosinophil levels. SAR440340 improved pre - BD FEV1 by 60 mL in the overall population (low and high eosinophils), with a clear tendency for higher efficacy in high EOS (110 mL) compared to low EOS (20 mL), and onset of action was rapid (4 weeks). The efficacy levels observed in smokers were improved by 42% (p = 0.0066) and 90 mL (p = 0.0072) for exacerbation reduction and FEV1 improvement, respectively. Overall, these data indicate that SAR440340 can have an independent bronchodilatory effect, rapid onset of action (mainly in high EOS patients), and a preventive effect against exacerbations in the overall population, on top of standard of care (SOC) (dual or triple therapy). These beneficial effects were more pronounced in smokers, indicating that the absence of continuous epithelial stress from tobacco smoke allows for a more rapid repair / disease - modifying effect of SAR440340.

[0308] SAR440340 numerically decreased the annual rate of AECOPD (19% reduction) and also improved FEV1 before bronchodilator administration (0.06 L improvement), but did not meet statistical significance. However, all of the potential benefits in AECOPD reduction and FEV1 improvement could be explained by a more pronounced benefit in the smoker subgroup (45% reduction in AECOPD rate and 0.09 L improvement in FEV1), which comprised approximately 55% of the patient population. In contrast, the remaining 45% of patients who were current smokers did not derive any benefit, either in terms of AECOPD rate or FEV1.

[0309] Subgroup analyses are often misleading, but there is considerable theoretical basis for trusting these findings. Most importantly, the overall analysis showed a strong trend in clinical endpoints in terms of both AECOPD and FEV1 criteria over all time points, all of which could be explained by clearer benefits in larger well-defined subgroups, and the remaining patients had no benefits but did not have the "negative subset" problem. Furthermore, the consistency of clear benefits attributable to smokers across all endpoints is very supportive.

[0310] In summary, this is the first study to demonstrate potential benefits of biological therapies in terms of exacerbation rate and lung function when added to standard therapy in smokers with COPD.

[0311] SAR440340 demonstrated an adequate safety profile in patients with moderate to severe COPD. There were no anti-drug antibody (ADA) patients identified after treatment. Overall TEAE and SAE were balanced between SAR440340 and placebo in terms of events and severity. The most notable and frequent adverse events of special interest (AESI) were infections and injection site reactions. There were slightly more infections in the SAR440340 treatment group. There were no serious AESI.

[0312]

Table 11

[0313] The following Table 12 is a summary of the efficacy analysis of SAR440340 in overall COPD and among smokers. The following Table 13 is a summary of the efficacy analysis of SAR440340 in overall COPD and among current smokers. Data are presented on relative rate reduction of exacerbations, FEV1 before and after BD, and the St. George's Respiratory Questionnaire (SGRQ).

[0314]

Table 12

[0315]

Table 13

[0316] Results from treatment and post-treatment periods Moderate to severe AECOPD during the core and post-treatment periods are shown in Figure 46. Moderate to severe AECOPD and pre-BD administration FEV1 during the core and post-treatment periods are shown in Figure 47. The improvement in pre-BD administration FEV1 persisted during the core and post-treatment periods. Post-BD administration FEV1 and changes in pre-BD administration forced vital capacity (FVC) during the core and post-treatment periods are shown for the intention-to-treat (ITT) population in Figures 48A–48B. Sustained improvement was observed in post-BD administration FEV1 and pre-BD administration FVC in patients treated with SAR440340, while a decline was observed in the placebo arm. Pre-BD administration FEV1 during the core and post-treatment periods is shown for smokers and current smokers in Figures 49A–49B. Post-BD administration FEV1 during the core and post-treatment periods is shown for smokers and current smokers in Figures 50A–50B. Similar to the overall population, the effect was sustained throughout the post-treatment period, although there was a marked decline in the placebo group.

[0317] Pharmacokinetics (PK) / pharmacodynamics (PD) analysis Preliminary PK / PD analysis revealed that the treatment response observed using FEV1 appears to be decoupled from PK changes.

[0318] PK / PD during the core and post-treatment periods by the smoking subgroup is shown in Figure 51. Without intending to be bound by scientific theory, the slightly lower IL-33 levels observed in current smokers were not likely to explain differential efficacy. Blood eosinophil levels during the core and post-treatment periods by the smoking subgroup are shown in Figure 52. Blood eosinophil levels were reduced in both former and current smokers, with the latter having an overall blunted response. AECOPD-related clinical outcomes in former smokers during the core treatment period are shown in Figure 53. Reduced healthcare resource utilization (HCRU), respiratory assistance therapy (e.g., oxygen), and missed work / activity days were observed.

[0319] The comparison of PK and FEV1 in the ITT population was performed (Figure 65). PK decreased as expected for two-compartment PK. The mean change in FEV1 from baseline remained flat from end of treatment (EOT) to end of study (EOS). The treatment effect as the mean change in FEV1 from baseline (active treatment - placebo (SOC)) appeared to increase slightly further during the follow-up period as the placebo SOC effect decreased over time. Overall, FEV1 did not follow a direct effect relationship with PK. The effect offset was thought to be extremely delayed.

[0320] The comparison of EOS and FEV1 in the ITT population was performed (Figure 66). The change in EOS from baseline showed a tendency to return to baseline during follow-up.

[0321] PK data from all studies were modeled using a two-compartment PK model that reasonably described the data. Bioavailability was estimated to be 53%. Body weight was identified as the main covariate acting on PK. COPD was only examined as a covariate with respect to CL and V2. An effect on V2 (19% lower in COPD) was identified. No other disease-specific factors were identified as covariates.

[0322] Total IL-33 vs. time was modeled using a target-mediated drug disposition (TMDD) approach. All studies were included in the analysis. Total IL-33 kinetics were driven using PopPK predicted PK for each individual. Based on the analysis, KD = 701 nM (95% CI, 6.2 - 7.9) was evaluated, resulting in a threshold structure-activity relationship (SAR) concentration of 9.5 mg / L (95% CI, 8.3 - 10.5) to achieve 90% IL-33 binding. (This was based on the baseline IL-33 assumption of 1 / 2 lower limit of quantification (LLOQ)). Based on the calculated threshold, 300 mg Q2W, 300 mg Q4W, and 300 mg Q8W may be able to meet the threshold target to achieve 90% target binding.

[0323] Conclusion Overall, the population PK modeling results indicated body weight as an important covariate affecting PK. The PD biomarker profile (IL-33) was delayed relative to the PK profile. Changes in FEV1 and AECOPD were not directly related to PK during follow-up; there were significantly long-term delayed effects.

[0324] Primary and secondary efficacy endpoints Modified intent-to-treat (mITT) population, 250 mm 3 Population with baseline eosinophil levels greater than or equal to 250 mm 3 Results for populations with baseline eosinophil levels less than 250 mm, smokers and current smokers are shown in Figure 54. Time to first AECOPD in the mITT population is shown in Figure 55. Time to first AECOPD in smokers (left panel) and current smokers (right panel) are shown in Figure 56. Change from baseline FEV1 before BD administration in the mITT population is shown in Figure 57. Change from baseline FEV1 before BD administration in smokers in the mITT population is shown in Figure 58. Pulmonary function over time in current smokers as change from baseline FEV1 before BD administration in current smokers in the mITT population is shown in Figure 59.

[0325] FEV1 results after 24 weeks of BD administration (mITT, baseline eosinophils < 250 or ≥ 250 mm 3 , smokers / current smokers) are shown in Figure 60. The time-course pulmonary function in the mITT population is shown in Figure 61. The time-course pulmonary function in smokers and current smokers is shown in Figures 62A - 62B. The mean change from baseline in blood eosinophil count (10 9 / mL) in the safety population is shown in Figure 63.

[0326] In this novel trial using a variable treatment period, including patients with both high and low baseline eosinophils, SAR440340 was associated with a lower annual rate of moderate to severe AECOPD, a longer time to the first moderate or severe AECOPD, and a slight improvement in pre - BD administration FEV1 from baseline up to 16 - 24 weeks in the mITT population compared to placebo. In patients with high baseline blood eosinophil count, SAR440340 treatment was associated with a slight improvement in pre - BD administration FEV1 from baseline up to 16 - 24 weeks. In smokers in the mITT, SAR440340 compared to placebo was associated with a slight improvement in the rate of moderate or severe AECOPD and time to the first moderate or severe AECOPD and a slight improvement in pre - BD administration FEV1 from baseline up to 16 - 24 weeks. These effects were not observed in the population of current smokers in the mITT.

[0327] SAR440340 generally showed an acceptable safety profile and good tolerability. The incidence of TEAE and SAE was balanced across the SAR440340 and placebo treatment groups.

Example

[0328] Genetic association with serum IL - 33 protein levels Two independent human genetics studies (including approximately 100,000 subjects in the Geisinger study including approximately 11,000 with COPD and approximately 450,000 subjects in the UK Biobank including approximately 11,000 with COPD) evaluated rare IL33 LOF (splice) variants associated with reduced risk of asthma, as well as two common GOF variants of IL33 and its receptor IL1RL1 previously associated with increased asthma risk. After confirming the predicted associations with asthma, similar but weaker associations were observed with COPD. The rare LOF variant was individually associated with a 21% reduction in the odds of COPD (meta-analysis p = 0.005) and the two common GOF variants were associated with increased odds of COPD (meta-analysis p < 0.05 for each variant), and overall (trend p = 0.0001) (Figure 70), showing a gene dosage effect, with increasing gene scores for the GOF variants associated with increasing COPD risk. These associations supported the evaluation of the role of IL-33 blockade in COPD.

[0329] Total IL-33 concentrations were measured in sera from 437 individuals (53% female) from the Geisinger Health System (GHS) where the previous genotype had been identified. To enhance the power to detect an association with rs146597587, the sample was enriched for heterozygous carriers (total of 115) compared to the population frequency. IL-33 levels were measured using an electrochemiluminescence immunoassay manufactured by Meso Scale Discovery (MD, USA). The method involved acid treatment of the sample to cleave IL-33 complexed with endogenous binding partners to enable detection of total IL-33 levels in serum. In the assay, a biotinylated anti-human IL-33 monoclonal antibody was used as the capture reagent and recombinant human IL-33 was used as the standard. Captured IL-33 was detected using a ruthenium-labeled anti-human IL-33 monoclonal antibody. The assay was specific for the reduced form of IL-33 and had a sensitivity of 6.25 pg / mL in appropriate human sera. The difference in IL-33 levels between homozygous and heterozygous carriers was examined using linear regression with age, sex, and asthma case-control status included as covariates.

[0330] Genetic associations with eosinophil count, asthma, and COPD Genetic analysis of common gain-of-function (GOF) variants and rare loss-of-function (LOF) variants in the IL-33 pathway, previously associated with asthma risk, was characterized for COPD risk. Association analyses were performed in individuals of European ancestry genetically ascertained from two previously described studies, the UK Biobank (UKB) and the GHS study.

[0331] UKB study The number of eosinophils (N = 448,848) was normalized using rank-based inverse normal transformation and examined for association with imputed variants released by UKB using BOLT-LMM v0.4. Information on age, age2, sex, age by sex, age2 by sex and 10 principal components giving information on ancestry were included as covariates. Asthma cases (N = 53,190) were individuals who had (i) self-reported physician diagnosis (data fields 6152 and 20002) or ICD10 codes for asthma (J45 or J46 or GP clinical tables in data field 41270); and (ii) no COPD (see below), emphysema or chronic bronchitis (based on data fields 20002, 22128–22130). COPD cases (N = 11,514) were individuals who had (i) self-reported physician diagnosis (data fields 6152 and 20002) or ICD10 codes for COPD (J41, J42, J43 or J44); and (ii) no asthma (see above). A general set of controls (N = 271,400) was used for both asthma and COPD; these were individuals who had (i) no asthma, no COPD and no other respiratory or allergic conditions based on ICD10 codes and data fields 6152, 20002, 22126–22130; and (ii) had FEV1 / FVC >= 0.7 and percent predicted FEV1 >= 0.8 if spirometry data were available. Association analyses were carried out using SAIGE v0.6 [Zhou 2018] with the same covariates as listed above.

[0332] GHS study The association between eosinophil count (N = 100,413) and complement variants (reference panel: Haplotype Reference Consortium) was examined using BOLT-LMM as described for the UKB study. In individuals with longitudinal data, we analyzed the median of the available findings. Association analyses were performed separately for samples genotyped using two different Illumina arrays (OMNI and GSA), and the results were combined using inverse-variance meta-analysis. Asthma cases (N = 14,829) were defined as individuals with an ICD10 code for asthma but no COPD, and the reverse was true for COPD cases (N = 10,838). Controls (N = 63,665) for both analyses were (i) based on ICD10 codes, had no asthma, no COPD, and no other respiratory or allergic conditions; (ii) were not taking medication for respiratory diseases; and (iii) had no available spirometry data because spirometry (regardless of the results) was found to be a predictor of respiratory disease. Association analyses were performed using SAIGE.

[0333] Meta-analysis of UKB and GHS studies Association results were combined using inverse-variance meta-analysis with METAL. Genomic inflation factors (i.e., lambda) for common variants (frequency > 1%) were 1.57 for eosinophil count, 1.18 for asthma, and 1.07 for COPD. The corresponding intercepts from LD score regression were 1.21, 1.15, and 1.02.

[0334] Mendelian randomization analysis The causal effects of protein levels of interleukin 1 receptor-like 1 (IL-33R, ST2) on disease risk were evaluated using the inverse-variance weighting method described by Burgess et al. (Stat Med. 2016;35(11):1880-1906). The measured variables were rs10179654 (2:102305323:T:G, minor allele frequency [MAF] = 48%, located 6 Kb upstream of IL1RL1) and rs13029918 (2:102340831:A:G, MAF = 3%, located in the splicing region), which reduced the plasma levels of IL-33R by 0.85 (for the G allele; P = 10-391) and 1.28 (for the G allele; P = 10-213) SD units, respectively (Sun (2018) Nature. 558(7708):73-79).

[0335] Human genetic studies To investigate the association between IL-33 and COPD, a rare splice acceptor allele (rs146597587:C, frequency 0.4% in Europeans) that gives rise to a truncated IL-33 isoform that does not bind to the IL-33 receptor and reduces total IL33 mRNA by 40% and reduces asthma risk by approximately 50% (Smith PLoS Genet. 2017;13(3):e1006659) was examined. Heterozygous individuals had a 46% reduction in serum IL-33 protein levels compared to non-carriers (Figure 67A), and a reported reduction in peripheral blood eosinophil counts (-0.26 standard deviation [SD] units in the UK Biobank study, -30 cells / μL) (Figure 67B) and protection from asthma (39% risk reduction) (Figure 67C) were confirmed. In a meta-analysis including 22,352 COPD cases and 335,065 controls, a 21% reduction in disease risk was found (odds ratio [OR] = 0.794, 95% CI = 0.676-0.933, P = 0.0049) (Figure 67D).

[0336] Next, the total IL-33 mRNA in bronchial epithelial cells was examined at 4% (Ketelaar J Allergy Clin Immunol. 2020; S0091-6749(20)30680~1), the eosinophil count at 0.09 SD units (9 cells / μL), and the common intron variant in IL-33 that reduces the asthma risk by 13% (rs992969: G, 75% frequency) (Figure 68). This allele was associated with a 3% reduction in the COPD risk (OR = 0.973, 95% CI = 0.950~0.997, P = 0.026).

[0337] Finally, two common variants (Sun, supra) that increase the plasma levels of soluble IL-33R (ST2, a decoy receptor for IL-33) by 0.85 SD units (rs10179654: T) and 1.28 SD units (rs13029918: A), respectively, were examined. Based on a Mendelian randomization analysis using these two variants as measured variables, an increase of 1 SD unit in the soluble IL-33R level was found to be associated with a 3% reduction in the COPD risk (OR = 0.969, 95% CI = 0.948~0.991, P = 0.0061) (Figure 69).

[0338] Genetic analysis has demonstrated an association between loss-of-function (LOF) in IL33 and reduced COPD risk, and gain-of-function (GOF) variants in the IL-33 pathway (IL33 and the IL-33 receptor IL1RL1) and increased risk. In randomized trials using placebo and itepkinumab, AECOPD was 1.61 and 1.30 (relative risk [RR] 0.81; 95% CI 0.61–1.07), and the change in least-squares mean (LSM) forced expiratory volume in 1 s (FEV1) before bronchodilator administration up to 16–24 weeks was 0.00 L and 0.06 L (LSM difference 0.06 L; 95% CI 0.01–0.10). Both reduction in AECOPD and improvement in FEV1 in the overall population were explained by a more pronounced benefit with itepkinumab in ever-smokers, a slightly significant reduction in AECOPD (0.58; 0.39–0.85) and improvement in FEV1 (0.09 L; 0.02–0.15). Current smokers showed no significant benefit either in exacerbations (1.09; 0.74–1.61) or in FEV1.

[0339] In summary, these genetic findings are consistent with IL-33 blockade and protection from COPD.

Example

[0340] A randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial (AERIFY-1) to evaluate the efficacy, safety, and tolerability of SAR440340 / REGN3500 / itepekinumab (anti-IL-33 mAb) in smokers with moderate to severe chronic obstructive pulmonary disease (COPD) Overall design This is a multinational, randomized, double-blind, placebo-controlled, parallel-group (3-arm), 52-week, phase 3 trial to evaluate the efficacy, safety, and tolerability of two dosing regimens of itepkinumab in patients with moderate to severe COPD who are smokers and are receiving established dual (ICS+LABA or LAMA+LABA) or triple controller therapy (LAMA+LABA+ICS). The study treatment is itepkinumab 300 mg every 2 weeks (Q2W), itepkinumab 300 mg every 4 weeks (Q4W), or matching doses of placebo, administered subcutaneously (SC) during a 52-week treatment period. The study design is depicted graphically in Figure 71.

[0341] The primary efficacy endpoint is the annual rate of moderate or severe acute exacerbations of COPD (AECOPD) over a 52-week placebo-controlled treatment period. Moderate exacerbations are recorded by the study physician and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (such as intramuscular (IM), intravenous (IV), or oral) and / or antibiotics. Severe exacerbations are recorded by the study physician and defined as an AECOPD requiring hospitalization, observation for more than 24 hours in an emergency department / urgent care facility, or resulting in death. For both moderate and severe events to be counted as two separate events, the two events must be separated by at least 14 days during any course of systemic steroid / antibiotic use or, in the case of hospitalization (severe events only), 14 days between discharge and readmission.

[0342] For the efficacy endpoint analysis, the primary population is the intention-to-treat (ITT) population. In addition to the analysis in the current trial, statistical analysis for a subpopulation of participants with triple controller therapy will be further performed using the integrated data of this example and the data obtained in Example 4.

[0343] Randomization is by country (some countries may be combined into one), screening blood eosinophil count (< 300 cells / mm 3 or ≥ 300 cells / mm 3) and stratified by controller therapy (dual or triple therapy) at baseline. To ensure registration according to the intended distribution of controller therapy and eosinophil counts, the number of participants registered in each stratified group is controlled and monitored as follows: · Dual controller therapy (ICS+LABA or LAMA+LABA): up to approximately 35% of participants · Eosinophils ≥ 300 cells / mm 3 Approximately 35% of participants

[0344] The trial period is outlined as follows: · Screening period (3 - 5 weeks) · Randomized investigational medicinal product (IMP) treatment period (52 weeks) · Follow - up period after IMP treatment (20 weeks)

[0345] Participants have received SoC controller therapy for COPD for at least 3 months prior to screening (Visit 1A) using a stable dose of controller therapy for ≥ 1 month prior to screening and throughout the trial period, remaining on their established controller medication for COPD, except for systemic steroid medications and antibiotics used for AECOPD.

[0346] Participants meeting the inclusion criteria are randomized (1:1:1) to one of the following IMP treatment groups administered for 52 weeks: · Itolizumab 300 mg, administered Q2W as a single subcutaneous (SC) injection · Itolizumab 300 mg, administered Q4W as a single SC injection with placebo of a matching dose injected alternately at 2 - week intervals between active IMPs · Placebo, administered Q2W as a single SC injection of placebo of a matching dose to itolizumab

[0347] Number of participants: Approximately 930 participants will be randomized 1:1:1 to three treatment arms. Approximately 310 participants will be randomized per arm to receive either itepkinumab 300 mg Q2W, itepkinumab 300 mg Q4W, or a matching dose placebo of itepkinumab.

[0348] Intervention Groups and Period There are the following three arms: · Arm A: Itepkinumab 300 mg SC Q2W · Arm B: Itepkinumab 300 mg SC Q4W · Arm C: Matching dose placebo SC SC Q2W

[0349] Participants will receive treatment for 52 weeks.

[0350] Types of Participants and Disease Characteristics: Participants have been diagnosed by a COPD physician for at least one year (based on the GOLD definition).

[0351] Participants have a smoking history of ≥ 10 pack - years, are not currently smoking, intend to quit smoking permanently, and quit smoking ≥ 6 months before screening (Visit 1A). Urine cotinine levels will be tested at screening (Visit 1A) and at each subsequent visit during the study.

[0352] Participants have moderate to severe COPD, with an FEV1 / FVC ratio ≤ 0.70 after bronchodilator administration and an FEV1 % predicted after bronchodilator administration at screening (Visit 1A) and at baseline / randomization (Visit 2) of ≥ 30% and < 80%.

[0353] Participants have a COPD Assessment Test (CAT) score ≥ 10 at screening (Visit 1A) and at baseline / randomization (Visit 2).

[0354] Participants have a participant-reported medical history of signs and symptoms of chronic bronchitis (chronic wet cough for at least 3 months out of 1 year prior to screening in participants with other causes of chronic cough (e.g., inappropriate treatment of gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis) excluded).

[0355] Participants have a documented medical history of high exacerbation risk defined as having ≥2 moderate or ≥1 severe exacerbation within 1 year prior to screening (Visit 1A), with at least one exacerbation being treated with systemic corticosteroids. At least one exacerbation has occurred while the participant is on their current controller therapy: moderate exacerbations are recorded by the study physician and defined as an acute exacerbation of respiratory symptoms requiring systemic corticosteroids (IM, V, or oral) and / or antibiotics (however, use of antibiotics alone is not eligible as a moderate exacerbation unless documentation is available that the use of antibiotics was necessary for the treatment of exacerbating symptoms of COPD); severe exacerbations are recorded by the study physician and defined as AECOPD requiring hospitalization or >24-hour observation in the emergency department / urgent care facility.

[0356] Participants use SoC controller therapy at a stable dose, including dual therapy (i.e., ICS+LABA or LAMA+LABA) or triple therapy (LAMA+LABA+ICS) for ≥3 months prior to screening, and for at least 1 month prior to and during the screening period.

[0357] Study Intervention: Investigational Medicinal Product Aseptic itepkinumab or matching dose of placebo is provided in prefilled syringes for SC administration. Each prefilled syringe contains a deliverable volume of 2 mL at an itepkinumab concentration of 150 mg / mL or 0 mg / mL. · Prescription: 2 mL solution for injection (150 mg / mL) · Route of administration: Subcutaneous (SC) · Administration regimen: All participants receive Q2W dosing to maintain blinding. Participants on Q4W receive alternating doses of IMP and placebo.

[0358] Non-investigational drug Participants continue to receive their established controller therapy. · Prescription: Dry powder inhaler (DPI), metered-dose inhaler (MDI), or nebulizer · Route of administration: LAMA, LABA, ICS, ICS + LABA, LAMA + LABA, or LAMA + LABA + ICS are administered by oral inhalation · Administration regimen: As prescribed

[0359] Reliever medications (albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, ipratropium / albuterol) Participants may be administered albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, or ipratropium / albuterol as reliever medications as needed during the study. · Prescription: DPI, MDI, nebulizer · Route of administration: Oral inhalation, spray · Administration regimen: As needed, as prescribed

[0360] Statistical considerations Primary endpoint The primary analysis of the annual rate of moderate or severe AECOPD during the 52-week placebo-controlled treatment period is conducted according to the ITT principle. The primary estimate is the treatment policy estimate. All moderate or severe AECOPD events during the 52-week treatment period are included, and the observation period is from randomization to visit 28 (week 52) of the clinic visit. Participants who permanently discontinue the IMP are required, encouraged, and planned to return to the clinic for all remaining study visits, and all off-treatment moderate or severe AECOPD during the planned 52-week treatment period are included in the primary analysis. Similarly, if a participant drops out of the study prior to the end of the 52-week treatment period, all observed moderate or severe AECOPD events up to the last contact date are included in the analysis, and in this case, the observation period is from randomization to the last contact date. Complementation is not carried out for unobserved events that may occur after the study is stopped and up to 52 weeks. The annual rate of moderate or severe AECOPD is analyzed using a negative binomial regression model. The model includes, as covariates, treatment group (placebo, itepkinumab 300 mg SC Q2W, itepkinumab 300 mg SC Q4W), region (integrated countries), screening eosinophil layer (< cells 300 / mm 3 , ≥ cells 300 / mm 3 ), controller therapy (combination of 2 agents, combination of 3 agents) layer, baseline disease severity (as % predicted FEV1 after bronchodilator administration used as a continuous variable), and the total number of severe AECOPD events within 1 year prior to the study (0 or ≥ 1), and as the response variable, the total number of moderate or severe AECOPD events that occur during the treatment period (up to 52 weeks).

[0361] The log-transformed observation period becomes an offset variable. The treatment comparison with placebo is carried out using the step-down method to first compare itepkinumab 300 mg SC Q2W with placebo. The comparison of itepkinumab 300 mg SC Q4W with placebo is carried out only if the comparison is statistically significant.

[0362] This estimated value compares the rates of moderate or severe AECOPD for participants randomly assigned to the itepkinumab regimen versus placebo, regardless of what treatment the participants actually receive or whether the treatment regimen was even implemented. This estimated value assesses the benefit of the treatment approach or strategy compared to placebo. The annual event rate estimated for each treatment group and its two-sided 95% confidence interval (CI) is derived from a negative binomial model. The event rate ratio (RR) for each itepkinumab regimen versus placebo, as well as the corresponding two-sided 95% CI and p-value, are also provided.

[0363] An on-treatment analysis is also performed to evaluate the efficacy of itepkinumab by excluding data measured when participants do not fully execute the treatment regimen according to the protocol and is used to estimate the benefit when itepkinumab treatment is fully executed. In this analysis, only AECOPD events observed during the on-treatment period (from the first dose of IMP to 14 days after the last dose of IMP) are included. Off-treatment events for participants who permanently discontinue treatment are excluded from the analysis. A negative binomial model using the same set of covariates specified in the primary analysis is used. This model includes moderate or severe AECOPD occurring during the on-treatment period as the response variable, and the log-transformed period of the treatment duration is the offset variable. This approach defines an estimated value for assessing the efficacy of itepkinumab during on-treatment.

[0364] Secondary endpoints: Change from baseline in FEV1 before BD administration at week 52 The primary analysis of the change from baseline in pre - BD FEV1 at week 52 is to evaluate the efficacy of itepkinumab on lung function. The change from baseline in pre - BD FEV1 at week 52 is analyzed using a mixed - effects model for repeated measures (MMRM) approach. The model includes, as the response variable, the change from baseline in pre - BD FEV1 values through week 52, and as covariates, treatment, age (continuous variable (number of years)), gender, baseline height (continuous variable), region (consolidated countries), screening eosinophil stratum, controller therapy stratum (dual or triple therapy), visit, the interaction of treatment by visit, and the interaction of baseline pre - BD FEV1 value (continuous variable) and baseline pre - BD FEV1 by visit. Participants who discontinue the IMP before 52 weeks are asked, encouraged to return to the clinic for all remaining study visits, and the additional off - treatment pre - BD FEV1 values measured up to week 52 are included in the analysis. For participants who drop out of the study before 52 weeks, the pre - BD FEV1 values will be lost at the time of study discontinuation or last contact. No imputation is performed for missing values in this analysis. This estimate compares the change from baseline in pre - BD FEV1 for participants randomly assigned to the itepkinumab regimen versus those randomly assigned to the placebo arm, independent of the treatment the participants actually receive. This estimate assesses the benefit of the treatment regimen or strategy compared to placebo.

[0365] Intra - subject error is modeled using an unstructured correlation matrix. Parameters are estimated using restricted maximum likelihood with the Newton - Raphson algorithm. Statistical inference on the treatment comparison for the change from baseline in pre - BD FEV1 at week 52 is derived from the mixed - effects model. The difference in least - squares (LS) mean change from baseline, corresponding 95% CI, and p - value are provided for the comparison of each itepkinumab regimen to placebo.

[0366] To evaluate the treatment effect when participants perform the instructed investigational treatment to the fullest extent, the on-treatment BD pre-dose FEV1 measurements are analyzed using a similar MMRM model for the primary BD pre-dose FEV1 analysis, including the same set of covariates and the imputation algorithm. The model includes, as the response variable, the on-treatment change from baseline of the BD pre-dose FEV1 values through week 52. The BD pre-dose FEV1 value is considered on-treatment if it is measured on or before the last dosing day + 14 days.

[0367] AECOPD The time to the first moderate or severe AECOPD is determined over the 52-week placebo-controlled treatment period. The annual rate of severe AECOPD is determined over the 52-week placebo-controlled treatment period. The time to the first severe AECOPD is determined over the 52-week placebo-controlled treatment period. The annual rate of AECOPD treated with corticosteroids is determined over the 52-week placebo-controlled treatment period.

[0368] Respiratory symptoms The change from baseline of the E-RS:COPD (Evaluated Respiratory Symptoms in COPD) total score is determined at week 52.

[0369] FEV1 gradient The rate of change of the post-BD FEV1 (L) from baseline (post-BD FEV1 gradient) is determined 4 to 12 weeks later.

[0370] HRQoL evaluated by SGRQ The change from baseline of the St. George's Respiratory Questionnaire (SGRQ) total score is determined at week 52. The proportion of participants with at least a 4-point decrease from baseline of the SGRQ total score is determined at week 52.

[0371] Safety and tolerability The incidences of treatment-emergent adverse events (TEAEs), particularly adverse events of special interest (AESIs), serious adverse events (SAEs), and adverse events (AEs) resulting in permanent treatment discontinuation are determined. The incidences of potentially clinically important clinical laboratory tests, vital signs, and ECG abnormalities are determined during the period of treatment exposure.

[0372] Pharmacokinetic (PK) profile Functional itepkinumab concentrations in serum are determined from baseline through the end of the study.

[0373] Immunogenicity The incidence of anti-itepkinumab antibody responses that occur during treatment is determined throughout the study.

[0374] Tertiary / exploratory endpoints: Healthcare utilization The annual number of days of healthcare resource utilization is determined over a 52-week placebo-controlled treatment period.

[0375] Predictors of mortality The annual number of ER visits and hospitalizations related to AECOPD is determined. The percentage of participants with a Body Mass Index, airway obstruction, dyspnea, and exercise capacity (BODE) index score decrease of > 1 point (= improvement) is determined at week 52.

[0376] Lung function The percentage of participants with an FEV1 improvement ≥ 100 mL prior to BD administration is determined at week 52. The percentage of participants with an FEV1 improvement ≥ 100 mL prior to BD administration is determined at week 24.

[0377] Reduction in oral corticosteroid and antibiotic use The number of days of oral corticosteroid and antibiotic receipt is determined over 52 weeks.

[0378] Respiratory vital signs The change from baseline in resting oxygen saturation is determined at week 52.

[0379] Biomarker Changes from baseline in blood eosinophil levels and neutrophil levels are determined at weeks 4, 8, 12, 24, 36, and 52. Changes from baseline are determined for total blood IL-33 and blood C-reactive protein (CRP) at weeks 4, 12, 24, and 52.

[0380] Gene expression and genetic factors Pharmacogenomic analysis, DNA sampling, and RNA sampling may be performed.

Example

[0381] A randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial (AERIFY-2) to evaluate the efficacy, safety, and tolerability of SAR440340 / REGN3500 / teplizumab (anti-IL-33 mAb) in smokers with moderate to severe chronic obstructive pulmonary disease (COPD) Overall design This is a multinational, randomized, double-blind, placebo-controlled, parallel-group, 52-week, Phase 3 trial to evaluate the efficacy, safety, and tolerability of itepkinumab in two cohorts. One cohort consists of participants with moderate to severe COPD who are ex-smokers (primary population) (Figure 71), and one cohort consists of participants with moderate to severe COPD who are current smokers (secondary population) (Figure 72). All participants from both cohorts receive established triple therapy (LAMA+LABA+ICS) or dual therapy controller therapy (LAMA+LABA or ICS+LABA). The goal of the trial in the ex-smoker cohort is to evaluate the efficacy of two dosing regimens of itepkinumab and to evaluate its safety and tolerability. The test treatment for ex-smokers is itepkinumab 300 mg every 2 weeks (Q2W), itepkinumab 300 mg every 4 weeks (Q4W), or a matching dose of placebo (3 treatment groups) administered subcutaneously during a 52-week randomized treatment period. Additionally, the trial also evaluates the efficacy, safety, and tolerability of the itepkinumab 300 mg Q2W dosing regimen compared to a matching dose of placebo in the current smoker cohort. The test treatment for current smokers is itepkinumab 300 mg Q2W administered subcutaneously during a 52-week randomized treatment period, or a matching dose of placebo (2 treatment groups).

[0382] The primary efficacy endpoint is the annual rate of moderate or severe acute exacerbations of COPD (AECOPD) over a 52-week placebo-controlled treatment period in ex-smokers. Moderate exacerbations are recorded by the study physician and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (such as intramuscular (IM), intravenous (IV), or oral) and / or antibiotics. Severe exacerbations are recorded by the study physician and defined as an AECOPD requiring hospitalization, observation for more than 24 hours in an emergency department / urgent care facility, or resulting in death. For both moderate and severe events to be counted as two separate events, the two events are separated by at least 14 days during any course of systemic steroid / antibiotic use or 14 days between discharge and readmission in the case of hospitalization (severe events only).

[0383] In the efficacy endpoint analysis, the primary population is the intention-to-treat (ITT) population of the smoker cohort.

[0384] Separate randomizations are performed for the primary population, the smoker cohort, and the secondary population, the current smoker cohort.

[0385] In the smoker cohort (primary population), participant randomization (to benralizumab 300 mg Q2W, benralizumab 300 mg Q4W, or matching-dose placebo) is stratified by country (some countries may be combined into one) using an automated voice response system (IVRS) / web automated response system (IWRS), screening blood eosinophil count (<300 / mm 3 or ≥300 / mm 3 ), and baseline controller therapy (dual or triple therapy). The number of participants enrolled in each stratified group is controlled and monitored as follows: · Dual controller therapy (LAMA+LABA or ICS+LABA): up to approximately 35% of participants · Eosinophils ≥300 cells / mm 3 , up to approximately 35% of participants

[0386] In the current smoker cohort (secondary population), participant randomization (to benralizumab 300 mg Q2W or matching-dose placebo) is stratified by country (some countries may be combined into one) in the same way (IVRS / IWRS), screening blood eosinophil count (<300 cells / mm 3 or ≥300 cells / mm 3 ), and baseline controller therapy (dual or triple therapy). The number of participants enrolled in each stratified group is controlled and monitored as follows: · Dual controller therapy (LAMA+LABA or ICS+LABA): up to approximately 35% of participants · Eosinophils ≥300 cells / mm 3 , up to approximately 35% of participants

[0387] The test period is outlined below: · Screening period (3 - 5 weeks) · Randomized investigational medicinal product (IMP) treatment period (52 weeks) · Follow - up period after IMP treatment (20 weeks)

[0388] Participants have received SoC controller therapy for COPD for at least 3 months prior to screening (Visit 1A) using a stable dose of controller therapy for ≥ 1 month prior to and during the screening period. Participants remain on their established controller medication for COPD throughout the test period, except for systemic steroid medications and antibiotics used for AECOPD.

[0389] Smoking - experienced participants meeting the eligibility criteria are randomized (1:1:1) to one of the following IMP treatment groups administered for 52 weeks: · Itolizumab 300 mg, administered Q2W as a single subcutaneous (SC) injection · Itolizumab 300 mg, administered Q4W as a single SC injection with placebo of a matching dose injected alternately at 2 - week intervals between active IMPs · Placebo, administered Q2W as a single SC injection of placebo of a matching dose to itolizumab

[0390] Current smoker participants meeting the eligibility criteria are randomized (1:1) to one of the following IMP treatment groups administered for 52 weeks: · Itolizumab 300 mg, administered Q2W as a single SC injection · Placebo of a matching dose to itolizumab, administered Q2W as a single SC injection

[0391] Number of participants: Approximately 1,170 participants who are either smokers with smoking experience (n = 930) or current smokers (n = 240) are enrolled and randomly assigned to different cohorts in this Phase 3 trial. Approximately 930 participants with smoking experience are randomly assigned in a 1:1:1 ratio to three treatment arms. Approximately 310 participants are randomly assigned per arm to receive either itepkinumab 300 mg Q2W, itepkinumab 300 mg Q4W, or a matching dose placebo of itepkinumab. Approximately 240 current smoker participants are randomly assigned, with 120 participants per arm receiving either itepkinumab 300 mg Q2W or a matching dose placebo of itepkinumab.

[0392] Intervention Arms and Duration Among smokers with smoking experience, there are the following three treatment arms: · Arm A: Itepkinumab 300 mg SC Q2W · Arm B: Itepkinumab 300 mg SC Q4W · Arm C: Matching dose placebo SC SC Q2W Participants receive treatment for 52 weeks.

[0393] Among current smokers, there are the following two treatment arms: · Arm A: Itepkinumab 300 mg SC Q2W · Arm B: Matching dose placebo SC SC Q2W Participants receive treatment for 52 weeks.

[0394] Participant Types and Disease Characteristics: Participants have received a diagnosis by a COPD physician for at least one year (based on the GOLD definition). Participants have a smoking history of ≥ 10 pack - years.

[0395] Among smokers with smoking experience: Participants are not currently smoking, intend to quit smoking permanently, and reported quitting smoking ≥ 6 months prior to screening (Visit 1A). Urine cotinine levels are tested at screening (Visit 1A) and at each subsequent visit during the trial.

[0396] Current smokers: Participants are currently smoking tobacco at the time of screening (Visit 1A) (participants smoked at least 1 cigarette per day on average over the past 7 days), and reported not currently participating in a smoking cessation intervention or having no plan to start one at the time of screening (Visit 1A) or during the screening period.

[0397] Participants have moderate to severe COPD, with an FEV1 / FVC ratio ≤ 0.70 after administration of BD, and a predicted FEV1 % ≥ 30% and < 80% after administration of BD at the time of screening (Visit 1A) and at baseline / randomization (Visit 2).

[0398] Participants have a COPD Assessment Test (CAT) score ≥ 10 at the time of screening (Visit 1A) and at baseline / randomization (Visit 2).

[0399] Self-reported medical history of symptoms and signs of chronic bronchitis (chronic wet cough for at least 3 months out of 1 year prior to screening in participants in whom other causes of chronic cough (e.g., inappropriate treatment of gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis) have been excluded).

[0400] Participants have a documented high-risk of exacerbation history, defined as having ≥2 moderate exacerbations or ≥1 severe exacerbation within 1 year prior to screening (Visit 1A), with at least one exacerbation being treated with systemic corticosteroids. At least one exacerbation has occurred while the participant is on their current controller therapy: Moderate exacerbations are recorded by the investigator and defined as an acute exacerbation of respiratory symptoms requiring systemic corticosteroids (IM, IV, or oral) and / or antibiotics (however, use of antibiotics alone is not eligible as a moderate exacerbation unless documentation is available that the use of antibiotics was necessary for the treatment of exacerbating symptoms of COPD); Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or >24-hour observation in the emergency department / urgent care facility.

[0401] Participants receive SoC controller therapy at a stable dose of controller therapy, including dual therapy (i.e., LAMA+LABA or ICS+LABA) or triple therapy (LAMA+LABA+ICS) for ≥3 months prior to screening (Visit 1A), and for at least 1 month prior to and during the screening period.

[0402] Study Intervention Investigational Medicinal Product Aseptic itepkinumab or matching dose placebo is provided in prefilled syringes for SC administration. Each prefilled syringe contains a deliverable volume of 2 mL at an itepkinumab concentration of 150 mg / mL (active) or 0 mg / mL (placebo). · Prescription: 2 mL solution for injection (150 mg / mL) · Route of administration: SC · Dosing regimen: All participants receive Q2W dosing to maintain blinding. Smoking-experienced participant receiving Q4W dosing regimen receives alternating doses of active IMP and placebo Q2W.

[0403] Non-investigational Medicinal Product Participants continue to receive their established controller therapy. · Prescription: dry powder inhaler (DPI), metered-dose inhaler (MDI), or nebulizer · Route of administration: LAMA, LABA, ICS, LAMA+LABA, ICS+LABA, or LAMA+LABA+ICS are by oral inhalation · Dosage regimen: as prescribed

[0404] Reliever medications (albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, ipratropium / albuterol) Participants may receive albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, or ipratropium / albuterol as reliever medications as needed during the study. · Prescription: DPI, MDI, nebulizer · Route of administration: oral inhalation, spray · Dosage regimen: as needed, by prescription

[0405] Statistical considerations Primary endpoint The primary analysis of the annual rate of moderate or severe AECOPD during the 52-week placebo-controlled treatment period in smokers is conducted according to the ITT principle. The primary estimate is the treatment policy estimate. All moderate or severe AECOPD events during the 52-week treatment period are included, and the observation period is from randomization to visit 28 (week 52) of the clinic visit. Participants who permanently discontinue the IMP are required, encouraged, and planned to return to the clinic for all remaining study visits, and all off-treatment moderate or severe AECOPD during the planned 52-week treatment period are included in the primary analysis. Similarly, if a participant withdraws from the study prior to the end of the 52-week treatment period, all observed moderate or severe AECOPD events up to the last contact date are included in the analysis, and in this case, the observation period is from randomization to the last contact date. No imputation is performed for unobserved events that may occur after the study is stopped and up to 52 weeks. The annual rate of moderate or severe AECOPD is analyzed using a negative binomial regression model. The model includes, as covariates, treatment group (placebo, itepkinumab 300 mg SC Q2W, itepkinumab 300 mg SC Q4W), region (integrated countries), screening eosinophil layer (< 300 cells / mm 3 , ≥ 300 cells / mm 3 ), controller therapy (dual therapy, triple therapy) layer, baseline disease severity (as % predicted FEV1 after bronchodilator (BD) administration used as a continuous variable), and the total number of severe AECOPD events within 1 year prior to the study (0 or ≥ 1), and, as the response variable, the total number of moderate or severe AECOPD events that occur during the treatment period (up to 52 weeks). The log-transformed observation period serves as an offset variable. The treatment comparison with placebo is first performed using a step-down method to compare itepkinumab 300 mg SC Q2W with placebo; the comparison of itepkinumab 300 mg SC Q4W with placebo is performed only if the comparison is statistically significant.

[0406] This estimated value compares the rates of moderate or severe AECOPD in participants randomly assigned to the itepkinumab regimen versus placebo, regardless of what treatment the participants actually receive or whether the treatment regimen was actually carried out. This estimated value assesses the benefits of the treatment approach or strategy compared to placebo. The annual event rate estimated for each treatment group and its two-sided 95% confidence interval (CI) is derived from a negative binomial model. The event rate ratio (RR) for each itepkinumab regimen versus placebo, as well as the corresponding two-sided 95% CI and p-value, are also provided.

[0407] An on-treatment analysis is also performed to evaluate the efficacy of itepkinumab by excluding data measured when participants do not fully execute the treatment regimen according to the protocol, and it is used to estimate the benefits when itepkinumab treatment is fully carried out. In this analysis, only AECOPD events observed during the on-treatment period (from the first dose of IMP to 14 days after the last dose of IMP) are included. Off-treatment events of participants who permanently discontinue treatment are excluded from the analysis. A negative binomial model using the same set of covariates specified in the primary analysis is used. This model includes moderate or severe AECOPD occurring during the on-treatment period as the response variable, and the log-transformed period of the treatment duration serves as an offset variable. This approach defines an estimated value for evaluating the efficacy of itepkinumab during on-treatment.

[0408] Secondary endpoints: Change from baseline in FEV1 before BD administration at week 52 The primary analysis of the change from baseline in pre-dose FEV1 at Week 52 is to evaluate the efficacy of itepkinumab on lung function in smokers. The change from baseline in pre-dose FEV1 at Week 52 is analyzed using a mixed-effects model for repeated measures (MMRM) approach. The model includes, as the response variable, the change from baseline in pre-dose FEV1 values through Week 52, and as covariates, treatment, age (continuous variable (years)), sex, baseline height (continuous variable), region (consolidated countries), screening eosinophil layer, controller therapy layer (dual or triple therapy), visit, treatment-by-visit interaction, and baseline pre-dose FEV1 value (continuous variable) and baseline pre-dose FEV1-by-visit interaction. Participants who discontinue IMP before Week 52 are asked, encouraged to return to the clinic for all remaining study visits, and the additional off-treatment pre-dose FEV1 values measured up to Week 52 are included in the analysis. For participants who withdraw from the study before Week 52, the pre-dose FEV1 values will be lost at study discontinuation or last contact. No imputation is performed for missing values in this analysis. This estimate compares the change from baseline in pre-dose FEV1 for participants randomly assigned to the itepkinumab regimen versus those randomly assigned to the placebo arm, independent of the treatment the participants actually receive. This estimate assesses the benefit of the treatment regimen or strategy compared to placebo.

[0409] Intra-subject error is modeled using an unstructured correlation matrix. Parameters are estimated using restricted maximum likelihood with the Newton-Raphson algorithm. Statistical inference on-treatment comparisons for the change from baseline in pre-dose FEV1 at Week 52 are derived from the mixed-effects model. The difference in least squares (LS) mean change from baseline, corresponding 95% CI, and p-value are provided for the comparison of each itepkinumab regimen to placebo.

[0410] To evaluate the treatment effect when participants perform the indicated investigational treatment to the fullest extent, the on-treatment BD pre-dose FEV1 measurements are analyzed using a similar MMRM model for the primary BD pre-dose FEV1 analysis that includes the same set of covariates and estimation algorithm. The model includes, as the response variable, the on-treatment change from baseline of the BD pre-dose FEV1 values through week 52. The BD pre-dose FEV1 value is considered on-treatment if it is measured on or before the last dose date + 14 days.

[0411] Lung function - Smokers The change from baseline of BD pre-dose FEV1 is determined at week 52. The change from baseline of post-dose FEV1 is determined at week 52. The change from baseline of BD pre-dose FEV1 is determined at week 24.

[0412] AECOPD - Smokers The time to the first moderate or severe AECOPD is determined over the 52-week placebo-controlled treatment period.

[0413] Severe AECOPD - Smokers The annual rate of severe AECOPD is determined over the 52-week placebo-controlled treatment period. The time to the first severe AECOPD is determined over the 52-week placebo-controlled treatment period.

[0414] Corticosteroid-treated AECOPD - Smokers The annual rate of AECOPD treated with corticosteroids is determined over the 52-week placebo-controlled treatment period.

[0415] Respiratory symptoms - Smokers The change from baseline of the E-RS: COPD total score is determined at week 52.

[0416] FEV1 slope - Smokers The rate of change of post-dose FEV1 (L) from baseline (post-dose FEV1 slope) is determined 4 to 12 weeks later.

[0417] HRQoL - Smokers Evaluated by SGRQ The change from the baseline of the SGRQ total score is determined at week 52. The proportion of participants with at least a 4 - point decrease from the baseline of the SGRQ total score is determined at week 52.

[0418] Safety and Tolerability - Smokers The incidence rates of TEAE, AESI, SAE, and AE resulting in permanent treatment discontinuation are determined. The incidence rates of potentially clinically important clinical laboratory tests, vital signs, and ECG abnormalities during the period of manifestation under treatment are determined.

[0419] PK Profile - Smokers The functional itepekimab concentration in serum is determined from baseline to the end of the trial.

[0420] Immunogenicity - Smokers The incidence rate of anti - itepekimab antibody response during manifestation under treatment is determined throughout the trial.

[0421] AECOPD - Current Smokers The annual rate of moderate or severe acute exacerbations of COPD (AECOPD) is determined over a 52 - week placebo - controlled treatment period.

[0422] Lung Function - Current Smokers The change from the baseline of FEV1 before BD administration is determined at week 52.

[0423] Safety and Tolerability - Current Smokers The incidence rates of TEAE, AESI, SAE, and AE resulting in permanent treatment discontinuation are determined. The incidence rates of potentially clinically important clinical laboratory tests, vital signs, and ECG abnormalities during the period of manifestation under treatment are determined.

[0424] PK Profile - Current Smokers The functional itepkinumab concentration in serum is determined from baseline to the end of the trial.

[0425] Immunogenicity - Current smokers The incidence of anti-itepkinumab antibody responses developed under treatment is determined throughout the trial.

[0426] Tertiary / exploratory endpoints: Medical utilization - Smokers with smoking experience The annual number of days of medical resource utilization is determined over a 52-week placebo-controlled treatment period.

[0427] Predictors of mortality - Smokers with smoking experience The annual number of ER visits and hospital days related to AECOPD is determined. The proportion of participants with a decrease in BODE index score > 1 point (= improvement) is determined at week 52.

[0428] Lung function - Smokers with smoking experience The proportion of participants with an improvement in FEV1 ≥ 100 mL before BD administration is determined at week 52.

[0429] Reduction in oral corticosteroid and antibiotic use - Smokers with smoking experience The number of days on which oral corticosteroids and antibiotics were received is determined over 52 weeks.

[0430] Respiratory vital signs - Smokers with smoking experience The change in resting oxygen saturation from baseline is determined at week 52.

[0431] Biomarkers - Smokers with smoking experience The changes in blood eosinophil levels and neutrophil levels from baseline are determined at weeks 4, 8, 12, 24, 36, and 52. The changes from baseline are determined for total blood IL-33 levels and for blood CRP levels at weeks 4, 12, 24, and 52.

[0432] Gene expression and genetic factors - Smokers with smoking experience and current smokers Pharmacogenomic analysis, DNA sampling, and RNA sampling may be performed.

Claims

1. A pharmaceutical composition for the treatment of chronic obstructive pulmonary disease (COPD) in a subject who is a smoker, comprising an antibody that specifically binds to interleukin-33 (IL-33) or an antigen-binding fragment thereof, wherein the subject who is a smoker has abstained from smoking for at least 1 month the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6 and 8 and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14 and 16, the treatment comprising: (a) selecting a subject who has COPD and is a smoker; (b) administering the antibody or antigen-binding fragment thereof to the subject; (c) improving one or more COPD-related parameters in the subject and said pharmaceutical composition.

2. (a) the treatment improves the annual rate of moderate to severe acute exacerbation of COPD (AECOPD), the annual rate of severe acute exacerbation of COPD (AECOPD), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25% to 75%, fractional exhaled nitric oxide (FeNO), the number or dose of COPD-relieving medications, the number or dose of systemic corticosteroids, the number or dose of antibiotics, daily steps, the number or dose of oral corticosteroids, resting oxygen saturation, and / or resting respiratory rate; or (b) the treatment improves one or more questionnaires or assessments selected from the group consisting of the COPD Assessment Test (CAT), the St. George's Respiratory Questionnaire (SGRQ), the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT), the Evaluated Respiratory Symptoms in COPD (E-RS), body mass index, airway obstruction, dyspnea, the Body-Mass Index, Obstruction, Dyspnea, Exercise (BODE) index, and the EuroQol-5 Dimensions questionnaire (EQ-5D), The pharmaceutical composition according to claim 1.

3. The COPD is the pharmaceutical composition according to claim 1 or 2, which is moderate to severe COPD with poor management by background therapy.

4. The background therapy includes a treatment having at least two of the following: long-acting β2 adrenergic agonist (LABA), long-acting muscarinic antagonist (LAMA), and inhaled corticosteroid (ICS), and is the pharmaceutical composition according to claim 3.

5. The antibody or its antigen-binding fragment includes a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 10, and is the pharmaceutical composition according to any one of claims 1 to 4.

6. The antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 18 and a light chain containing the amino acid sequence of SEQ ID NO: 20, and is the pharmaceutical composition according to claim 5.

7. The subject has a blood eosinophil count of less than 250 cells per μL prior to treatment, and is the pharmaceutical composition according to any one of claims 1 to 6.

8. The subject has a blood eosinophil count of more than or equal to 250 cells per μl prior to treatment, and is the pharmaceutical composition according to any one of claims 1 to 6.

9. The subject has a blood eosinophil count of less than 300 cells per μL prior to treatment, and is the pharmaceutical composition according to any one of claims 1 to 6.

10. The subject has a blood eosinophil count of more than or equal to 300 cells per μl prior to treatment, and is the pharmaceutical composition according to any one of claims 1 to 6.

11. The treatment is (a) improving FEV1 before bronchodilator administration; (b) improving FEV1 after bronchodilator administration; (c) improve FVC after bronchodilator administration in the subject; (d) reduce the annual rate of AECOPD or moderate to severe AECOPD events; (e) reduce the time to the first moderate to severe AECOPD event: (f) decrease the decline rate of FEV1; (g) maintain lung function or reduce the decline of lung function; (h) reduce the level of blood eosinophils; (i) improve FEV1 before bronchodilator administration within 4 weeks from the first administration of the antibody or its antigen-binding fragment; and / or (j) FEV1 is maintained during treatment, The pharmaceutical composition according to any one of claims 1 to 10.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the smoker has a smoking history of more than or equal to 10 packs per year and / or has quit smoking for at least 6 months.

13. The antibody or its antigen-binding fragment is formulated for administration at a dose of about 0.1 mg to about 600 mg, about 100 mg to about 400 mg, or about 300 mg, the pharmaceutical composition according to any one of claims 1 to 12.

14. The antibody or its antigen-binding fragment is administered every 2 weeks (q2w) or every 4 weeks (q4w), the pharmaceutical composition according to claim 13.

15. The antibody or its antigen-binding fragment is (a) administered subcutaneously, (b) administered as two injections, or (c) administered subcutaneously using an autoinjector, needle and syringe, or pen-type delivery device, The pharmaceutical composition according to claim 14.

16. A pharmaceutical composition for the treatment of chronic obstructive pulmonary disease (COPD) in subjects who are smokers, comprising an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33), wherein the subject who is a smoker has abstained from smoking for at least 1 month, and the treatment comprises (a) selecting a subject who has COPD and is a smoker; (b) administering to the subject an initial dose of about 300 mg of the antibody or an antigen-binding fragment thereof; and one or more subsequent doses of about 300 mg of the antibody or an antigen-binding fragment thereof every 2 weeks (q2w) or every 4 weeks (q4w) ; and (c) improving one or more COPD-related parameters in the subject, and the antibody or an antigen-binding fragment thereof comprises three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, said pharmaceutical composition.

17. One or more chronic obstructive pulmonary disease (COPD)-related parameters are selected from the group consisting of the annual rate of moderate to severe acute exacerbation (AECOPD) of COPD, forced expiratory volume in one second (FEV1), the rate of decline of FEV1, peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory velocity (FEF) 25% - 75%, fractional exhaled nitric oxide (FeNO), the number or dose of COPD reliever medications, the number or dose of systemic corticosteroids, and the number or dose of antibiotics, the pharmaceutical composition according to claim 16.

18. A pharmaceutical composition for use in a method for reducing the annual rate of moderate to severe acute exacerbation (AECOPD) of chronic obstructive pulmonary disease (COPD) in a subject who has moderate to severe chronic obstructive pulmonary disease (COPD) and is a smoker, comprising an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33), wherein the subject who is a smoker has abstained from smoking for at least 1 month, and the method comprises (a) selecting a subject having COPD and being a smoker; (b) administering to the subject an initial amount of about 300 mg of an antibody or an antigen-binding fragment thereof; and one or more subsequent doses of about 300 mg of the antibody or an antigen-binding fragment thereof every 2 weeks (q2w) or every 4 weeks (q4w); (c) improving one or more COPD-related parameters in the subject, wherein the antibody or an antigen-binding fragment thereof specifically binds to interleukin-33 (IL-33) and comprises three heavy-chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 4, 6, and 8 and three light-chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16. The pharmaceutical composition.

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