Methods for treating COPD by administering an il-33 antagonist

Abstract

To provide methods for treating or preventing COPD and related conditions.SOLUTION: A disclosed method comprises a step of administering a therapeutic composition comprising an interleukin-33 (IL-33) such as an anti-IL-33 antibody or antigen binding fragment thereof to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 944,878, filed December 6, 2019, U.S. Provisional Patent Application No. 62 / 964,966, filed January 23, 2020, and U.S. Provisional Patent Application No. 63 / 082,502, filed September 24, 2020, the entire disclosures of each of which are hereby incorporated by reference in their entirety.

[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 interleukin-33 (IL-33) antagonists to treat or prevent COPD and / or reduce acute exacerbation of COPD (AECOPD) events in patients in need thereof. [Background technology]

[0003] Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with an abnormal pulmonary inflammatory and immune response to harmful particles and gases. Chronic inflammation causes structural changes, narrowing of small airways, and destruction of lung parenchyma, which leads to loss of alveolar attachment to small airways and reduced lung elastic recoil. Chronic inflammation leads to progressive airway obstruction that is only partially reversible or even irreversible. The inflammatory component of COPD is thought to involve many cell types, including structural cells, T lymphocytes, neutrophils, macrophages, and their biological products. Some patients, especially those with clinical overlap with asthma, may also have increased levels of eosinophils, T helper (Th)2, or group 2 innate lymphoid cells. While smoking is the primary cause of COPD, other factors such as air pollution, occupational exposures, and genetic susceptibility have been identified. The most common respiratory symptoms include chronic dyspnea, cough, and / or sputum production. The disease is further exacerbated by exacerbations, especially in severe COPD. These are frequently due to 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 at which 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 a range of disease severity.

[0004] Chronic obstructive pulmonary disease (COPD) is a highly prevalent, severe, and progressive disease that results in 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 disability and death. Globally, approximately 3 million people die from COPD each year. With the increasing prevalence of smoking in developing countries and the aging of populations in high-income countries, prevalence is expected to rise, with the number of deaths expected to reach 4.5 million by 2030.

[0005] Standard treatment for moderate COPD begins with a bronchodilator (e.g., a long-acting muscarinic antagonist (LAMA) or a long-acting beta-2 agonist (LABA)), and as the disease progresses, the bronchodilator is 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 These include modest efficacy and a risk of respiratory infection. 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 treatments that prevent the decline in forced expiratory volume in one second (FEV1) over time or alter the progressive disease course of COPD. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Adeloye et al. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J Glob Health. 2015 December;5(2):020415 [Non-patent document 2] Guarascio et al., The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon. Outcomes Res. 2013 Jun 17;5:235-45 [Non-patent document 3] Aaron et al., Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone-Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial. Ann Intern Med. 2007 Apr 17;146(8):545-55 [Non-patent document 4] Calverley et al., Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomized clinical trials. Lancet. 2009 Aug 29;374(9691):685-94 Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, a significant unmet medical need continues to exist in the ever-growing patient population with COPD. Therefore, there is a need in the art for new targeted therapies for the treatment and / or prevention of COPD and / or the reduction of acute exacerbation of COPD (AECOPD) events. [Means for solving the problem]

[0008] In one aspect, provided is a method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising administering to the subject 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. In one aspect, provided is 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 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 a subject. In certain exemplary embodiments, the one or more COPD-related parameters include annualized rate of moderate to severe acute exacerbation of COPD (AECOPD), annualized 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 rate (FEF) 25%-75%, exhaled oxygen saturation (EOS), and / or exhaled saline (EXA). The subject's blood glucose level is selected from the group consisting of: FeNO, frequency or dose of chronic obstructive pulmonary disease (COPD) relief medication, frequency or dose of systemic corticosteroids, frequency or dose of antibiotics, daily steps, frequency or dose of oral corticosteroids, resting oxygen saturation, and resting respiratory rate. In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved in the subject. In certain exemplary embodiments, the annualized rate of AECOPD is reduced in the subject.

[0010] In certain exemplary embodiments, the subject's score improves on one or more questionnaires or assessments selected from the group consisting of the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), Exacerbations in Chronic Obstructive Pulmonary Disease Tool (EXACT), Evaluation of Respiratory Symptoms in COPD (E-RS), Body Mass Index, Airway Obstruction, Dyspnea, and Exercise Capacity (BODE) index, and Euro Quality of Life-5 Item Questionnaire (EQ-5D).

[0011] In certain exemplary embodiments, the COPD is moderate to severe COPD that is not well controlled with background therapy. In certain exemplary embodiments, the background therapy includes treatment with at least two of the following: a long-acting beta-2 adrenergic agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS). In certain exemplary embodiments, the background therapy includes a LABA and a LAMA. In certain exemplary embodiments, the background therapy includes a LABA and an ICS. In certain exemplary embodiments, the background therapy includes a LAMA and an ICS. In certain exemplary embodiments, the background therapy includes treatment with a LABA, a LAMA, and an 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 itepekimab).

[0013] In certain exemplary embodiments, the subject has a blood eosinophil count 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 a blood eosinophil count of greater than or equal to about 250 cells per μL prior to treatment. In certain exemplary embodiments, the subject has a blood eosinophil count 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 a blood eosinophil count of greater than or equal to about 300 cells per μL prior to treatment. In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved. In certain exemplary embodiments, the post-bronchodilator FEV1 is improved. In certain exemplary embodiments, the pre-bronchodilator FVC 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 more than or equal to 10 packs per year.In certain exemplary embodiments, the former smoker has quit smoking for at least 6 months.In certain exemplary embodiments, the smoker intends to quit smoking permanently.

[0015] In certain exemplary embodiments, the annual rate of moderate to severe AECOPD events is In certain exemplary embodiments, the time to first moderate to severe AECOPD event is reduced. In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved. In certain exemplary embodiments, the post-bronchodilator FEV1 is improved. In certain exemplary embodiments, the pre-bronchodilator FVC is improved. In certain exemplary embodiments, blood eosinophil levels are 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 first severe AECOPD event is reduced. In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved. In certain exemplary embodiments, the post-bronchodilator FEV1 is improved. In certain exemplary embodiments, the rate of decline in pre-bronchodilator FEV1 is reduced. In certain exemplary embodiments, the rate of decline in post-bronchodilator FEV1 is reduced. In certain exemplary embodiments, the pre-bronchodilator FVC is improved. In certain exemplary embodiments, lung function is maintained or lung function decline is reduced. In certain exemplary embodiments, blood eosinophil levels are reduced. In certain exemplary embodiments, the subject has high eosinophil blood levels and / or is a former 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 every week (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 pre-bronchodilator FEV1 is improved within four weeks of the first administration of the antibody or antigen-binding fragment thereof, hi certain exemplary embodiments, the pre-bronchodilator FEV1 is maintained throughout treatment.

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

[0021] In another aspect, a method is provided for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising 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 that 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 is provided 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), the antibody comprising 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), the antibody comprising 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, wherein the antibody is administered to the subject in an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg, the antibody being administered subcutaneously every two weeks.

[0024] In another aspect, a method is provided 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), the antibody comprising 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), the antibody comprising 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, wherein the antibody is administered to the subject in an initial dose of about 300 mg, followed by 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, the one or more chronic obstructive pulmonary disease (COPD) related parameters are selected from the group consisting of annualized rate of moderate to severe acute exacerbation of COPD (AECOPD), forced expiratory volume in one second (FEV1), rate of decline in FEV1, peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, exhaled nitric oxide (FeNO), number or dose of COPD relief medication, number or dose of systemic corticosteroids, and number or dose of antibiotics.

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

[0028] In certain exemplary embodiments, at least two additional therapeutic agents are administered to the subject, hi certain exemplary embodiments, the at least two additional therapeutic agents are selected from the group consisting of a long-acting beta-2 adrenergic agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS).

[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, a method is provided for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising 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 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. In another aspect, 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 is provided for use in reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), wherein the antibody or antigen-binding fragment thereof is administered to the subject at an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg.

[0031] 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.

[0032] In another aspect, provided is a method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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 moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), wherein the antibody is administered to the subject at an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg, wherein the antibody is administered subcutaneously every two weeks.

[0033] In another aspect, provided is a method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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 former 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 moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD) who is a former smoker, wherein the antibody is administered to the subject at an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg, wherein the antibody is administered subcutaneously every two weeks.

[0034] In another aspect, a method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD) is provided, comprising administering to a subject a compound selected from the group consisting of IL-33, IL-13, IL-23, IL-34, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-33, IL-40, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL- 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 reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), wherein the antibody is administered to the subject at an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg, wherein the antibody is administered subcutaneously every four weeks.

[0035] In another aspect, provided is a method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), the method comprising administering to the subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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, wherein the subject is a former 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 moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD) who is a former smoker, wherein the antibody is administered to the subject at an initial dose of about 300 mg, followed by one or more subsequent doses of about 300 mg, wherein the antibody is administered subcutaneously every four weeks.

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

[0037] [Figure 1]Figure 1 graphically depicts the clinical trial described in Example 1 herein, showing patient placement, randomization, and outcomes of the study, which was designed to evaluate the efficacy, safety, and tolerability of SAR440340 in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Stars indicate treatment time points, which consisted of two 1.5 mL injections of SAR440340 or placebo. The variable treatment duration was determined by the end of the 52-week treatment period or the end of treatment (EOT visit) of the last patient to achieve planned treatment, whichever occurred first. All patients were to receive at least 24 weeks of treatment. The end of treatment (EOT) visit was to occur two weeks after the last dose of investigational medicinal product (IMP). The end of study (EOS) visit was to occur 20 weeks after the last dose of IMP. [Figure 2A] Figures 2A-2C depict baseline disease characteristics related to exacerbation history. Figure 2A shows the number of moderate or severe acute exacerbations of COPD (AECOPD) in the past year of core data. [Figure 2B] Figures 2A-2C depict baseline disease characteristics related to exacerbation history, and Figure 2B shows the number of moderate AECOPD exacerbations in the past year of core data. [Figure 2C] Figures 2A-2C depict baseline disease characteristics related to exacerbation history. Figure 2C shows the number of severe AECOPD exacerbations in the past year core data. [Figure 3A] Figures 3A-E depict baseline disease characteristics related to smoking. Figure 3A shows smoking history in the placebo and SAR440340 groups. [Figure 3B] Figures 3A-3E depict baseline disease characteristics related to smoking. Figure 3B shows smoking status in the placebo and SAR440340 groups in the subpopulation with high blood eosinophil levels (EOS > 250 / mm3). [Figure 3C]Figures 3A-3E depict baseline disease characteristics related to smoking. Figure 3C shows total packs per year in the placebo and SAR440340 groups. [Figure 3D] Figures 3A-3E depict baseline disease characteristics related to smoking. Figure 3D shows smoking status in the placebo and SAR440340 groups in the subpopulation with low blood eosinophil levels (EOS<250 / mm). [Figure 3E] Figures 3A-3E depict baseline disease characteristics related to smoking. Figure 3E shows years since quitting among ever smokers in the placebo and SAR440340 groups. [Figure 4A] Figures 4A-4C depict baseline disease characteristics related to background medications, showing that most patients were receiving inhaled corticosteroid (ICS)-containing regimens. Figure 4A shows a summary of background medications in the placebo and SAR440340 groups. [Figure 4B] Figures 4A-4C depict baseline disease characteristics related to background medications, showing that most patients were receiving an inhaled corticosteroid (ICS)-containing regimen. Figure 4B shows the number of participants enrolled in an ICS-containing regimen in the placebo and SAR440340 groups. [Figure 4C] Figures 4A-4C depict baseline disease characteristics related to background medications, showing that most patients were receiving an inhaled corticosteroid (ICS)-containing regimen. Figure 4C shows inhaled corticosteroid dosing among participants enrolled in an ICS-containing regimen. [Figure 5A] Figures 5A-5C depict baseline disease characteristics related to blood eosinophil levels. Figure 5A shows blood eosinophil levels at screening. [Figure 5B] Figures 5A-5C depict baseline disease characteristics related to blood eosinophil levels. Figure 5B shows baseline blood eosinophil levels. [Figure 5C] 5A-5C depict baseline disease characteristics related to blood eosinophil levels. FIG. 5C shows the mean baseline eosinophil counts for participants in the placebo group, the SAR440340-treated group, and all participants. FIG. 5C also shows the percentage of participants with higher or lower baseline eosinophil levels at Visit 2 compared to the baseline mean blood eosinophil counts for placebo and SAR440340 and their respective eosinophil counts by screening at Visit 1. [Figure 6] Figure 6 shows the annualized rate of moderate-to-severe AECOPD exacerbations in the placebo and SAR440340 treatment groups. SAR440340 treatment reduced AECOPD exacerbations by approximately 18% in the combined group, which included participants with both high and low eosinophil levels. [Figure 7A] Figures 7A-7B depict the annualized rate of moderate-to-severe AECOPD exacerbations. Figure 7A shows the adjusted annualized rate of moderate-to-severe AECOPD exacerbations in participants with low blood eosinophil counts, EOS < 250. Figure 7B shows the adjusted annualized rate of moderate-to-severe AECOPD exacerbations in participants with high blood eosinophil counts, EOS ≥ 250. SAR440340 treatment reduced AECOPD exacerbations similarly regardless of baseline EOS count (low: 15% vs. high: 20%). [Figure 7B] Figures 7A-7B depict the annualized rate of moderate-to-severe AECOPD exacerbations. Figure 7A shows the adjusted annualized rate of moderate-to-severe AECOPD exacerbations in participants with low blood eosinophil counts, EOS < 250. Figure 7B shows the adjusted annualized rate of moderate-to-severe AECOPD exacerbations in participants with high blood eosinophil counts, EOS ≥ 250. SAR440340 treatment reduced AECOPD exacerbations similarly regardless of baseline EOS count (low: 15% vs. high: 20%). [Figure 8]Figure 8 depicts a statistical analysis of the time to first moderate to severe AECOPD exacerbation in the combined group of high and low eosinophil subjects treated with SAR440340 or placebo. A 17% relative reduction in the time to first moderate to severe AECOPD exacerbation event was observed. [Figure 9A] Figures 9A-9B depict statistical analyses of time to first moderate-to-severe AECOPD exacerbation. Figure 9A shows time to first moderate-to-severe AECOPD exacerbation in the low eosinophil subgroup, EOS < 250. Figure 9B shows time to first moderate-to-severe AECOPD exacerbation in the high eosinophil subgroup, EOS ≥ 250. [Figure 9B] Figures 9A-9B depict statistical analyses of time to first moderate-to-severe AECOPD exacerbation. Figure 9A shows time to first moderate-to-severe AECOPD exacerbation in the low eosinophil subgroup, EOS < 250. Figure 9B shows time to first moderate-to-severe AECOPD exacerbation in the high eosinophil subgroup, EOS ≥ 250. [Figure 10] Figure 10 depicts the least mean squares change in pre-BD FEV1 from baseline to weeks 16-24 in the placebo and SAR440340 treatment groups (high and low EOS). SAR440340 improved pre-bronchodilator (pre-BD) forced expiratory volume in one second (FEV1) by 60 mL. [Figure 11] Figure 11 is a graphical depiction of the mean change in BD pre-FEV1 from baseline to week 48. SAR440340 had a rapid and sustained effect on BD pre-FEV1. [Figure 12A] Figures 12A-12B depict the change in pre-BD-FEV1 from baseline to weeks 16-24 in high and low eosinophil level subgroups. Figure 12A shows the change in pre-BD-FEV1 from baseline to weeks 16-24 vs. placebo in the low eosinophil group, EOS<250. [Figure 12B]Figures 12A-12B depict the change in pre-BD-FEV1 from baseline to weeks 16-24 in the high and low eosinophil subgroups. Figure 12B shows the change in pre-BD-FEV1 from baseline to weeks 16-24 vs. placebo in the high eosinophil group, EOS ≥ 250. SAR440340 improved pre-BD-FEV1 by 110 mL in the high EOS subgroup. [Figure 13A] Figures 13A-13B graphically depict the mean change in pre-BD FEV1 from baseline to week 44 for the high eosinophil group (Figure 13B) and week 48 for the low eosinophil group (Figure 13A). SAR440340 treatment resulted in rapid and sustained improvements in lung function in the high EOS subgroup. [Figure 13B] Figures 13A-13B graphically depict the mean change in pre-BD FEV1 from baseline to week 44 for the high eosinophil group (Figure 13B) and week 48 for the low eosinophil group (Figure 13A). SAR440340 treatment resulted in rapid and sustained improvements in lung function in the high EOS subgroup. [Figure 14A] 14A-14B depict the change in post-BD FEV1 from baseline to week 24 in a combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Figure 14A shows post-BD FEV1 at week 24, mean vs. placebo. [Figure 14B] Figures 14A-14B depict the change in post-BD FEV1 from baseline to week 24 in a combined group of high and low eosinophil subjects treated with SAR440340 or placebo. Figure 14B shows the mean change in post-BD FEV1 from baseline to week 52 vs. placebo. The SAR440340 group had a modest effect on post-BD FEV1. [Figure 15A] Figures 15A-15B depict the change in post-BD FEV1 from baseline to week 24 in high and low eosinophil subgroups. Figure 15A shows post-BD FEV1 at week 24 in the low eosinophil group, EOS<250. [Figure 15B] Figures 15A-15B depict the change in post-BD FEV1 from baseline to week 24 in the high and low eosinophil subgroups. Figure 15B shows post-BD FEV1 at week 24 in the high eosinophil group, EOS ≥ 250. There was a 70 mL improvement in post-BD FEV1 in the high EOS subgroup. [Figure 16A] 16A-16B depict the mean change in FEV1 from baseline to week 24. Figure 16A shows the mean change in FEV1 from baseline to week 24 vs. placebo in the low eosinophil group, EOS<250. [Figure 16B] Figures 16A-16B depict the mean change in FEV1 from baseline to week 24. Figure 16B shows the mean change in FEV1 from baseline to week 24 vs. placebo in the high eosinophil group, EOS > 250. SAR440340 showed a trend toward an early and sustained improvement in FEV1 after BD administration in the high EOS group. [Figure 17A] Figures 17A-17B depict the cumulative and annualized rates of moderate-to-severe AECOPD exacerbations 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 former smokers (Figure 17A) as subgroups. SAR440340 treatment reduced the adjusted annualized rate of AECOPD by 42% in former smokers. [Figure 17B] Figures 17A-17B depict the cumulative and annualized rates of moderate-to-severe AECOPD exacerbations 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 former smokers (Figure 17A) as subgroups. SAR440340 treatment reduced the adjusted annualized rate of AECOPD by 42% in former smokers. [Figure 18A]Figures 18A-18B show the change from baseline in pre-BD FEV1 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 former smokers (Figure 18A) as subgroups. SAR440340 resulted in a 90 mL improvement in pre-BD FEV1. [Figure 18B] Figures 18A-18B show the change from baseline in pre-BD FEV1 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 former smokers (Figure 18A) as subgroups. SAR440340 resulted in a 90 mL improvement in pre-BD FEV1. [Figure 19A] Figures 19A-19B depict the change from baseline in post-BD FEV1 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 former smokers (Figure 19A) as subgroups. SAR440340 resulted in an improvement in post-BD FEV1 in former smokers. [Figure 19B] Figures 19A-19B depict the change from baseline in post-BD FEV1 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 former smokers (Figure 19A) as subgroups. SAR440340 resulted in an improvement in post-BD FEV1 in former smokers. [Figure 20] Figure 20 depicts the efficacy outcome relationship between smoking status and eosinophil levels. The greatest efficacy in preventing AECOPD was observed in ever smokers treated with SAR440340, regardless of eosinophil levels. [Figure 21]FIG. 21 shows the St. George's Respiratory Questionnaire (SGRQ) score change from baseline in a combined group of participants with both high and low eosinophil levels, demonstrating that there was no change in SGRQ with SAR440340 treatment. [Figure 22A] Figures 22A-B depict the change in SGRQ from baseline in the high and low eosinophil subgroups, showing that SAR440340 resulted in an improvement in SGRQ in the high eosinophil subgroup. Figure 22A shows the change in SGRQ from baseline to week 52 in the low eosinophil group, EOS<250. [Figure 22B] Figures 22A-22B depict the SGRQ change from baseline in the high and low eosinophil subgroups, showing that SAR440340 resulted in an improvement in SGRQ in the high eosinophil subgroup. Figure 22B shows the SGRQ change from baseline to week 36 in the high eosinophil group, EOS > 250. [Figure 23A] 23A to 23D are graphs showing changes in blood eosinophils from baseline to week 24. Fig. 23A shows the mean change in blood eosinophils from baseline to week 52. [Figure 23B] Figures 23A-23D show the change in blood eosinophils from baseline to week 24. Figure 23B shows the mean percent change in blood eosinophils from baseline to week 52. [Figure 23C] Figures 23A-23D show the change in blood eosinophils from baseline to week 24. Figure 23C shows the percent change from baseline at week 24. These data demonstrate that SAR440340 treatment resulted in a rapid and sustained reduction in blood eosinophils with a median change of approximately -42%. [Figure 23D] Figures 23A-23D show the change in blood eosinophils from baseline to week 24. Figure 23D shows the absolute change from baseline at week 24 (mean change of -107 / mm3). [Figure 24A]Figures 24A-B depict the mean and median percent change in IgE, showing that there was a slight decrease in IgE levels from baseline in the SAR440340 group. Figure 24A shows the mean change in IgE. [Figure 24B] Figures 24A-B depict the mean and median percent change in IgE, showing that there was a slight decrease in IgE levels from baseline in the SAR440340 group. Figure 24B shows the median percent change in IgE. [Figure 25A] Figures 25A-B depict the mean change from baseline in select biomarkers. These data show a significant effect of SAR440340 treatment on IL-33, but not sST2. Figure 25A shows the mean change in total IL-33. [Figure 25B] Figures 25A-25B depict the mean change from baseline in select biomarkers. These data show a significant effect of SAR440340 treatment on IL-33, but not sST2. Figure 25B shows the mean change in sST2. [Figure 26A] Figures 26A-26B depict the annualized rates of moderate to severe AECOPD events in the subgroups of current smokers versus former smokers in the intention-to-treat population. Figure 26A shows the unadjusted and adjusted annualized rates of moderate to severe AECOPD events in former smokers. Figure 26B shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events in current smokers. SAR440340 treatment reduced AECOPD events by 42% in former smokers. [Figure 26B]Figures 26A-26B depict the annualized rates of moderate to severe AECOPD events in the subgroups of current smokers versus former smokers in the intention-to-treat population. Figure 26A shows the unadjusted and adjusted annualized rates of moderate to severe AECOPD events in former smokers. Figure 26B shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events in current smokers. SAR440340 treatment reduced AECOPD events by 42% in former smokers. [Figure 27A] Figures 27A-27B depict the annualized rates of moderate to severe AECOPD events in the moderate COPD vs. severe COPD category in the intention-to-treat (ITT) population, showing that there were no significant differences based on COPD categorization with treatment. Figure 27A shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events, moderate COPD. Figure 27B shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events, severe COPD. [Figure 27B] Figures 27A-27B depict the annualized rates of moderate to severe AECOPD events in the moderate COPD vs. severe COPD category in the intention-to-treat (ITT) population, showing that there were no significant differences based on COPD categorization with treatment. Figure 27A shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events, moderate COPD. Figure 27B shows the adjusted and unadjusted annualized rates of moderate to severe AECOPD events, severe COPD. [Figure 28A] Figures 28A-28B show pre-BD FEV1 LS mean change from baseline, LS mean, demonstrating that SAR440340 improved pre-BD FEV1 by 60 mL. Figure 28A shows pre-BD FEV1, LS mean vs. PBO, weeks 16-24. [Figure 28B] Figures 28A-28B show pre-BD FEV1 LS mean change from baseline, LS mean, demonstrating that SAR440340 improved pre-BD FEV1 by 60 mL. Figure 28B shows pre-BD FEV1, LS mean vs. PBO, 24 weeks. [Figure 29A] Figures 29A-29B depict the change in pre-BD FEV1, LS mean, from baseline to weeks 16-24 for blood EOS <250 and ≥250 in the ITT population, showing that SAR440340 improved pre-BD FEV1 by 110 mL in the high EOS subgroup. Figure 29A shows pre-BD FEV1, LS mean vs. PBO, weeks 16-24 for blood EOS <250. [Figure 29B] Figures 29A-29B depict pre-BD FEV1, LS mean, change from baseline to weeks 16-24 for blood EOS <250 and ≥250 in the ITT population, showing that SAR440340 improved pre-BD FEV1 by 110 mL in the high EOS subgroup. Figure 29B shows pre-BD FEV1, LS mean vs. PBO, weeks 16-24 for blood EOS ≥250. [Figure 30A] Figures 30A-30B show pre-BD FEV1 LS mean change from baseline, LS mean, in current smokers vs. ever smokers in the ITT population, demonstrating that SAR440340 improved pre-BD FEV1 by 90 mL. Figure 30A shows pre-BD FEV1, LS mean vs. PBO, 16-24 weeks in ever smokers. [Figure 30B] Figures 30A-30B show pre-BD FEV1 LS mean change from baseline, LS mean, in current smokers vs. former smokers in the ITT population, demonstrating that SAR440340 improved pre-BD FEV1 by 90 mL. Figure 30B shows pre-BD FEV1, LS mean vs. PBO, weeks 16-24 in current smokers. [Figure 31A] Figures 31A-31B show BD pre-dose FEV1 LS mean change from baseline, LS mean, in moderate vs. severe COPD categories in the ITT population, demonstrating that SAR440340 improved pre-BD FEV1 in patients with lower pulmonary function. Figure 31A shows pre-BD FEV1, LS mean vs. PBO, 16-24 weeks, moderate COPD. [Figure 31B]Figures 31A-31B show BD pre-dose FEV1 LS mean change from baseline, LS mean, in moderate vs. severe COPD categories in the ITT population, demonstrating that SAR440340 improved pre-dose FEV1 in patients with lower pulmonary function. Figure 31B shows pre-dose FEV1, LS mean vs. PBO, 16-24 weeks, severe COPD. [Figure 32A] Figures 32A-32B show the change in post-BD FEV1, LS mean, from baseline to week 24 in the ITT population, demonstrating a moderate effect on post-BD FEV1 in the SAR440340 group. Figure 32A shows post-BD FEV1, LS mean vs. PBO, week 24. [Figure 32B] Figures 32A-B show LS mean change in FEV1 after BD administration from baseline to week 24 in the ITT population, demonstrating a moderate effect on FEV1 after BD administration in the SAR440340 group. Figure 32B shows LS mean change from baseline to week 52 vs. placebo. [Figure 33A] Figures 33A-33B show post-BD FEV1, LS mean, change from baseline to week 24 in patients with EOS < 250 and EOS ≥ 250 in the ITT population, demonstrating a 70 mL improvement in post-BD FEV1 in the high EOS subgroup. Figure 33A shows post-BD FEV1, LS mean vs. PBO, week 24 in patients with EOS < 250. [Figure 33B] Figures 33A-33B show post-BD FEV1, LS mean, change from baseline to week 24 for EOS < 250 and EOS ≥ 250 in the ITT population, demonstrating a 70 mL improvement in post-BD FEV1 in the high EOS subgroup. Figure 33B shows post-BD FEV1, LS mean vs. PBO, week 24 for EOS ≥ 250. [Figure 34A]Figures 34A-B depict the post-BD FEV1 LS mean change from baseline, LS mean, in current smokers vs. former smokers in the ITT population, showing that SAR440340 improved post-BD FEV1 in former smokers. Figure 34A shows post-BD FEV1, LS mean vs. PBO, 24 weeks in former smokers. [Figure 34B] Figures 34A-34B depict the post-BD FEV1 LS mean change from baseline, LS mean, in current smokers vs. former smokers in the ITT population, showing that SAR440340 improved post-BD FEV1 in former smokers. Figure 34B shows post-BD FEV1, LS mean vs. PBO, 24 weeks in current smokers. [Figure 35A] Figures 35A-35B depict post-BD FEV1 LS mean change from baseline, LS mean, in moderate vs. severe COPD categories in the ITT population, demonstrating that SAR440340 improved post-BD FEV1 in patients with lower pulmonary function. Figure 35A shows post-BD FEV1, LS mean vs. PBO, 24 weeks in moderate COPD. [Figure 35B] Figures 35A-35B depict post-BD FEV1 LS mean change from baseline, LS mean, in moderate vs. severe COPD categories in the ITT population, showing that SAR440340 improved post-BD FEV1 in patients with lower pulmonary function. Figure 35B shows post-BD FEV1, LS mean vs. PBO, 24 weeks in severe COPD. [Figure 36A] 36A and 36B are graphs depicting the mean changes from baseline in FeNO before and after BD administration, showing that FeNO decreased. [Figure 36B] 36A and 36B are graphs depicting the mean changes from baseline in FeNO before and after BD administration, showing that FeNO decreased. [Figure 37]Figure 37 is a graphical depiction of the patient population of the clinical trial described in Example 1. All randomized patients received treatment. There were few study withdrawals. There were 395 patients (95.9%) in the post-treatment follow-up period. [Figure 38A] Figures 38A-38D are graphical depictions of 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. [Figure 38B] Figures 38A-38D are graphical depictions of 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. [Figure 38c] Figures 38A-38D are graphical depictions of 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. [Figure 38D] Figures 38A-38D are graphical depictions of 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. [Figure 39A] Figures 39A-B are graphical depictions of the effect of SAR440340 on pre-BD FEVl. Data are presented for ever smokers (Figure 39A) and current smokers (Figure 39B), showing that among ever smokers, SAR440340 improved pre-BD FEVl by 90 mL. [Figure 39B]Figures 39A-B are graphical depictions of the effect of SAR440340 on pre-BD FEVl. Data are presented for ever smokers (Figure 39A) and current smokers (Figure 39B), showing that among ever smokers, SAR440340 improved pre-BD FEVl by 90 mL. [Figure 40A] Figures 40A-B depict the mean change in blood eosinophils in former versus current smokers, respectively. Similar effects were observed in both groups, with a greater effect seen in former smokers. [Figure 40B] Figures 40A-B depict the mean change in blood eosinophils in former versus current smokers, respectively. Similar effects were observed in both groups, with a greater effect seen in former smokers. [Figure 41A] 41A-41B are graphs depicting the mean change in neutrophil counts for former smokers versus current smokers, respectively. [Figure 41B] 41A-41B are graphs depicting the mean change in neutrophil counts for former smokers versus current smokers, respectively. [Figure 42A] Figures 42A-B depict the mean change in total IL-33 in former smokers versus current smokers, respectively. [Figure 42B] Figures 42A-B depict the mean change in total IL-33 in former smokers versus current smokers, respectively. [Figure 43A] 43A and 43B are graphs depicting the mean change in pre-bronchodilator (pre-BD) FeNO in former smokers versus current smokers, respectively. [Figure 43B] 43A and 43B are graphs depicting the mean change in pre-bronchodilator (pre-BD) FeNO in former smokers versus current smokers, respectively. [Figure 44A] 44A and 44B are graphs depicting the mean change in FeNO after bronchodilator administration (after BD administration) in former smokers versus current smokers, respectively. [Figure 44B]44A and 44B are graphs depicting the mean change in FeNO after bronchodilator administration (after BD administration) in former smokers versus current smokers, respectively. [Figure 45A] Figures 45A-B depict the percent change in the overall population and by smoker subgroup. Figure 45A depicts pre-BD FEV1. Figure 45B depicts post-BD FEV1. [Figure 45B] Figures 45A-B depict the percent change in the overall population and by smoker subgroup. Figure 45A depicts pre-BD FEV1. Figure 45B depicts post-BD FEV1. [Figure 46] FIG. 46 is a graphical depiction of the percent reduction in moderate-to-severe and severe AECOPD between the core and post-treatment periods, final data. [Figure 47] FIG. 47 is a graphical depiction of the percent reduction in moderate to severe AECOPD between the core and post-treatment periods and the effect relative to pre-BD administration, final data. [Figure 48A] 48A-B depict the change in post-BD FEV1 (FIG. 48A) and pre-BD FVC (FIG. 48B) during the core and post-treatment periods in the total ITT population. [Figure 48B] 48A-B depict the change in post-BD FEV1 (FIG. 48A) and pre-BD FVC (FIG. 48B) during the core and post-treatment periods in the total ITT population. [Figure 49A] 49A-49B depict BD pre-dose FEV1 during the core and post-treatment periods for former and current smokers, respectively. [Figure 49B] 49A-49B depict BD pre-dose FEV1 during the core and post-treatment periods for former and current smokers, respectively. [Figure 50A] 50A-50B depict post-BD FEV1 during the core and post-treatment periods for ever smokers and current smokers, respectively. [Figure 50B]50A-50B depict post-BD FEV1 during the core and post-treatment periods for ever smokers and current smokers, respectively. [Figure 51] Figure 51 is a graphical depiction of PK / PD during the core and post-treatment periods by smoking subgroup. [Figure 52] FIG. 52 is a graphical depiction of blood eosinophil levels during the core and post-treatment periods by smoking subgroup. [Figure 53] Figure 53 is a graphical depiction of AECOPD-related clinical outcomes in ever smokers during the core treatment period. [Figure 54] Figure 54 summarizes the results for selected primary and secondary efficacy endpoints: modified intention to treat (mITT); mITT with baseline eosinophil levels greater than or equal to 250 mm3; mITT with baseline eosinophil levels less than 250 mm3; ever smokers; and current smokers. [Figure 55] Figure 55 is a graphical depiction of time to first AECOPD in the mITT population. [Figure 56] Figure 56 is a graphical depiction of time to first AECOPD in ever smokers (left panel) and current smokers (right panel). [Figure 57] Figure 57 is a graphical depiction of the change from baseline in pre-BD FEV1 in the mITT population. Red shading, endpoint: mean 16-24 weeks. Gray shading, variable treatment duration 24-52 weeks. Due to variable treatment duration, not all patients were on treatment after 24 weeks, and this is reflected in the number of patients at each time point. [Figure 58] Figure 58 graphically depicts the change from baseline in pre-BD FEV1 among ever smokers in the mITT population. Red shading, endpoint: mean 16-24 weeks. Gray shading, variable treatment duration 24-52 weeks. Due to variable treatment duration, not all patients were on treatment after 24 weeks, and this is reflected in the number of patients at each time point. [Figure 59] Figure 59 graphically depicts lung function in current smokers as change from baseline in pre-BD FEV1 over time in the mITT population. Red shading, endpoint: mean 16-24 weeks. Gray shading, variable treatment duration 24-52 weeks. Due to variable treatment duration, not all patients were on treatment after 24 weeks, and this is reflected in the number of patients at each time point. [Figure 60] Figure 60 summarizes the FEV1 results after BD administration at week 24 (mITT, baseline eosinophils <250 or ≥250 / mm3, former / current smokers). [Figure 61] Figure 61 is a graphical depiction of lung function over time in the mITT population. [Figure 62A] Figures 62A-62B depict pulmonary function (post-BD FEV1) over time in (Figure 62A) former smokers and (Figure 62B) current smokers. Red shading, endpoint: mean 16-24 weeks. Gray shading, variable treatment duration 24-52 weeks. Due to variable treatment duration, not all patients were treated after 24 weeks, and this is reflected in the number of patients at each time point. [Figure 62B] Figures 62A-62B depict pulmonary function (post-BD FEV1) over time in (Figure 62A) former smokers and (Figure 62B) current smokers. Red shading, endpoint: mean 16-24 weeks. Gray shading, variable treatment duration 24-52 weeks. Due to variable treatment duration, not all patients were treated after 24 weeks, and this is reflected in the number of patients at each time point. [Figure 63] Figure 63 is a graphical depiction of the mean change from baseline in blood eosinophil count (109 / mL) in the safety population. [Figure 64] FIG. 64 is a graphical depiction of percent change in pre-BD FEV1 and post-BD FEV1 in the overall population and by smoker subgroup. [Figure 65] Figure 65 is a graphical depiction of the comparison of PK and FEV1 in the ITT population. [Figure 66] Figure 66 is a graphical depiction of the comparison of EOS and FEV1 in the ITT population. [Figure 67A] Figures 67A-67D depict genetic association results for the rare splice acceptor variant rs146597587 in IL-33. The rs146597587:C allele was associated with a 46% reduction in serum total IL-33 protein levels (Figure 67A) (N=437; P=7×10-39); (Figure 67B) a 0.26 standard deviation (SD) unit reduction in peripheral blood eosinophil count (N=549,261; meta-analysis P=6.3×10-84); (Figure 67C) a 39% reduction in asthma risk (68,019 cases and 335,065 controls; meta-analysis P=1.7×10-20); and (Figure 67D) a 21% reduction in COPD risk (22,352 cases and 335,065 controls; meta-analysis P=0.0049). CI means confidence interval, COPD means chronic obstructive pulmonary disease, GHS means Geisinger Health Service, OR means odds ratio, SD means standard deviation, SE means standard error, and UKB means UK Biobank study. [Figure 67B] Figures 67A-67D depict genetic association results for the rare splice acceptor variant rs146597587 in IL-33. The rs146597587:C allele was associated with a 46% reduction in serum total IL-33 protein levels (Figure 67A) (N=437; P=7×10-39); (Figure 67B) a 0.26 standard deviation (SD) unit reduction in peripheral blood eosinophil count (N=549,261; meta-analysis P=6.3×10-84); (Figure 67C) a 39% reduction in asthma risk (68,019 cases and 335,065 controls; meta-analysis P=1.7×10-20); and (Figure 67D) a 21% reduction in COPD risk (22,352 cases and 335,065 controls; meta-analysis P=0.0049). CI means confidence interval, COPD means chronic obstructive pulmonary disease, GHS means Geisinger Health Service, OR means odds ratio, SD means standard deviation, SE means standard error, and UKB means UK Biobank study. [Figure 67C]Figures 67A-67D depict genetic association results for the rare splice acceptor variant rs146597587 in IL-33. The rs146597587:C allele was associated with a 46% reduction in serum total IL-33 protein levels (Figure 67A) (N=437; P=7×10-39); (Figure 67B) a 0.26 standard deviation (SD) unit reduction in peripheral blood eosinophil count (N=549,261; meta-analysis P=6.3×10-84); (Figure 67C) a 39% reduction in asthma risk (68,019 cases and 335,065 controls; meta-analysis P=1.7×10-20); and (Figure 67D) a 21% reduction in COPD risk (22,352 cases and 335,065 controls; meta-analysis P=0.0049). CI means confidence interval, COPD means chronic obstructive pulmonary disease, GHS means Geisinger Health Service, OR means odds ratio, SD means standard deviation, SE means standard error, and UKB means UK Biobank study. [Figure 67D] Figures 67A-67D depict genetic association results for the rare splice acceptor variant rs146597587 in IL-33. The rs146597587:C allele was associated with a 46% reduction in serum total IL-33 protein levels (Figure 67A) (N=437; P=7×10-39); (Figure 67B) a 0.26 standard deviation (SD) unit reduction in peripheral blood eosinophil count (N=549,261; meta-analysis P=6.3×10-84); (Figure 67C) a 39% reduction in asthma risk (68,019 cases and 335,065 controls; meta-analysis P=1.7×10-20); and (Figure 67D) a 21% reduction in COPD risk (22,352 cases and 335,065 controls; meta-analysis P=0.0049). CI means confidence interval, COPD means chronic obstructive pulmonary disease, GHS means Geisinger Health Service, OR means odds ratio, SD means standard deviation, SE means standard error, and UKB means UK Biobank study. [Figure 68] Figure 68 shows the association between a common regulatory variant in IL-33 (rs992969; effect allele: G) and risk of asthma and COPD in the UK Biobank and GHS studies. [Figure 69-1]Figure 69 shows Mendelian randomization (MR) analysis between soluble IL-33 receptor (sIL-33R) levels and risk of asthma and COPD. [Figure 69-2] Continuation of Figure 69-1. [Figure 70-1] Figure 70 depicts the aggregate association between two common regulatory variants (rs992969; influence allele: G) in IL-33 (rs992969) and IL1RL1 (rs1420101; influence allele: T) and the risk of asthma and COPD in the UK Biobank and GHS studies. The aggregate effect was assessed using logistic regression analysis to examine the association between genetic risk score (GRS, defined as the total number of minor alleles spanning two variants for each individual; ranging from 0 to 4) and disease case-control status. GRS was also expressed as a quantitative trait (ranging from 0 to 4; trend test) and as a binary trait comparing individuals with GRS1 vs. GRS0, GRS2 vs. GRS0, and GRS3 or 4 vs. GRS0. CI denotes confidence interval, COPD denotes chronic obstructive pulmonary disease, GHS denotes Geisinger Health Services, OR denotes odds ratio, and UKB denotes UK Biobank study. [Figure 70-2] Continuation of Figure 70-1. [Figure 71] Figure 71 is a schematic depicting the study design representing ever smokers according to the AERIFY-1 and AERIFY-2 (ever-smoker cohort) Phase 3 study design. SC, subcutaneous; Q2W, every 2 weeks; Q4W, every 4 weeks; ICS, inhaled corticosteroids; LABA, long-acting beta-2 adrenergic agonist; LAMA, long-acting muscarinic antagonist. [Figure 72] Figure 72 is a schematic depicting the AERIFY-2 Phase 3 study design showing the current smoker cohort. SC, subcutaneous; Q2W, every 2 weeks; ICS, inhaled corticosteroids; LABA, long-acting beta-2 adrenergic agonist; LAMA, long-acting muscarinic antagonist. DETAILED DESCRIPTION OF THE INVENTION

[0038] Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited 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 by up to 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

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

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

[0043] Methods for reducing the incidence of COPD exacerbations Methods are provided for reducing the incidence of one or more COPD exacerbations in a subject in need thereof, comprising administering a pharmaceutical composition comprising an interleukin-33 (IL-33) antagonist. According to certain embodiments, the IL-33 antagonist is an antibody or 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 featured in the present invention are described herein.

[0044] In one embodiment, a subject is identified as having "mild," "moderate," "severe," or "very severe" COPD if the subject receives a physician diagnosis of such COPD based on the Global Obstructive Pulmonary Disease (GOLD) Guidelines (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2017 Report) available at goldcopd.org / wp-content / uploads / 2016 / 12 / wms-GOLD-2017-Pocket-Guide.pdf). In these embodiments, COPD is classified based on the severity of airway limitation as measured using a post-bronchodilator FEV1. 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 expected FEV1. The expected value for FEV1 is based on the FEV1 value for a typical person of similar age, race, height, and sex 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% of predicted FEV1 but less than 80% of 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% of predicted FEV1 but less than 50% of predicted FEV1. A subject's COPD is classified as "very severe" by the GOLD classification system if the subject's FEV1 is less than 53% of predicted FEV1.

[0045] In another aspect, a method for reducing the incidence or recurrence of COPD or a COPD exacerbation in a subject in need thereof is provided, the method comprising administering a pharmaceutical composition comprising an IL-33 antagonist. A pharmaceutical composition comprising an IL-33 antagonist is provided for use in reducing the incidence or recurrence of COPD or a COPD exacerbation in a subject in need thereof. As used herein, the phrase "COPD exacerbation" refers to 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 deterioration in a subject's respiratory health that requires and / or is treatable by therapeutic intervention for COPD (e.g., steroid treatment, antibiotic treatment, inhaled corticosteroid treatment, hospitalization, etc.). In some embodiments, a moderate exacerbation is defined as an AECOPD event requiring 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 requiring hospitalization, an emergency care visit, or resulting in death. According to certain embodiments, the annualized rate of moderate to severe acute exacerbations of COPD (AECOPD) includes moderate exacerbations and severe exacerbations.

[0046] A "reduced incidence or recurrence" of COPD exacerbations means that a subject receiving a pharmaceutical composition of the invention experiences fewer COPD exacerbations after treatment than before treatment (i.e., at least one "Reduced incidence or recurrence" of COPD exacerbations means that, following administration of a pharmaceutical composition of the invention, the subject is less likely to experience a COPD exacerbation (e.g., fewer exacerbations) or not experiencing a COPD exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14, or more weeks) following initiation of treatment with a pharmaceutical composition of the invention. A "reduced incidence or recurrence" of COPD exacerbations alternatively means that, following administration of a pharmaceutical composition of the 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 not receiving a pharmaceutical composition of the invention.

[0047] A method for reducing the incidence of COPD exacerbations in a subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist and administering to the subject one or more maintenance doses of a second, or a second and a third, regulator, e.g., 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 one or more maintenance doses of a second, or a second and a third, regulator, e.g., a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS), to reduce the incidence of COPD exacerbations in a subject in need thereof. A pharmaceutical composition comprising an IL-33 antagonist in combination with one or more maintenance doses of a second or second and third regulator, e.g., a long-acting beta agonist (LABA), a long-acting muscarinic antagonist (LAMA), and / or an inhaled corticosteroid (ICS), is provided for use in reducing the incidence of COPD exacerbations in a subject in need thereof.

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

[0049] Suitable ICS 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®), and the like.

[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®), and the like.

[0051] Suitable LAMA and LABA combinations 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] Methods are provided for reducing the incidence of COPD exacerbations in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising one or more IL-33 antagonists and administering to the subject one or more alleviating agents to eliminate or reduce one or more COPD-related symptoms. Pharmaceutical compositions comprising an IL-33 antagonist are provided for use in combination with one or more alleviating agents that eliminate or reduce one or more COPD-related symptoms to reduce the incidence of COPD exacerbations in a subject in need thereof. Pharmaceutical compositions comprising an IL-33 antagonist and one or more alleviating agents that eliminate or reduce one or more COPD-related symptoms are provided for use in reducing the incidence of COPD exacerbations in a subject in need thereof. Suitable alleviating agents include, but are not limited to, fast-acting beta2-adrenergic receptor agonists, such as albuterol / salbutamol or levalbuterol / levosalbutamol (including ipratropium or ipratropium / short-acting beta-agonist (SABA) combinations).

[0053] Methods for improving COPD-related parameters Methods are provided for improving one or more COPD-related parameters in a subject in need thereof (also referred to herein as "COPD-modifying" or "disease-modifying"), comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist. Pharmaceutical compositions comprising an IL-33 antagonist are provided for use in improving one or more COPD-related parameters in a subject in need thereof. While (as noted above) a reduced incidence of COPD exacerbations 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) annualized rate of moderate-to-severe AECOPD; (2) annualized rate of severe AECOPD; (3) relative absolute change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) (e.g., at 52 weeks); (4) relative absolute change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) (e.g., at 24 weeks); (5) relative absolute change from baseline in post-bronchodilator forced expiratory volume in one second (FEV1) (e.g., at 52 weeks); (6) relative absolute change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) (e.g., at 52 weeks). (7) relative percent change from baseline in forced expiratory volume in one second (FEV1) after bronchodilator administration (e.g., at week 24); (8) relative rate of decline (e.g., slope) in 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 worsening COPD tool (EXACT) score (e.g., at week 24); (11) change from baseline in respiratory symptoms assessed by COPD (E-RS) score (e.g., at week 24). (12) change from baseline in St. George's Respiratory Questionnaire (SGRQ) score (e.g., at week 24); (13) change from baseline in EuroQuality of Life 5-item Questionnaire (EQ-5D) score (e.g., at week 24); (14) rate of moderate-to-severe AECOPD; (15) change from baseline in forced vital capacity (FVC) from weeks 16 to 24; (16) change from baseline in modified Medical Research Council (mMRC) score (e.g., at week 24); (17) change from baseline in Health-Related Quality of Life Questionnaire (HRQOL) score (18) change from baseline in Body Mass Index, Airway Obstruction, Dyspnea, and Exercise Capacity (BODE) score (e.g., at week 24); (19) change from baseline in Daily Steps (e.g., at week 24); (20) days of oral corticosteroids; (21) days of antibiotics; (22) change from baseline in resting oxygen saturation (e.g., at week 24); (23) change from baseline in resting respiratory rate (e.g., at week 24); (24) maintenance of lung function (e.g., compared with no treatment or treatment with a placebo);and (25) a reduction in pulmonary function decline (e.g., compared to no treatment or treatment with a placebo).

[0055] "Improvement in COPD-related parameters" was defined as an increase in FEV1 or time to first moderate or severe AECOPD and / or a reduction from baseline in AECOPD rates. As used herein, the term "baseline" with respect to a COPD-related parameter means the 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 "improved," the parameter is quantified at baseline and at time points after administration of a pharmaceutical composition described herein. For example, the COPD-related parameter can be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or more after initial treatment with the pharmaceutical composition. The difference between the value of a parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured) of the COPD-related parameter.

[0057] As used herein, the term "obtain" or "obtaining" means gaining possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, e.g., a COPD-related parameter. "Directly obtaining" means performing a method (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" 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 obtained directly). Directly obtaining a physical entity includes performing a method that involves a physical transformation of a material entity, e.g., a starting material. Exemplary transformations include creating a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities in a mixture, and performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Obtaining a value directly includes performing a method that involves a physical change of a sample or another substance, such as performing an analytical method that involves a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis").

[0058] Indirectly obtained information can be provided, for example, in the form of a report, provided in written or electronic form, e.g., an online database or application ("App"), etc. The report or information can be provided, for example, by a medical institution, e.g., a hospital or clinic; or a health care provider, e.g., a doctor or nurse.

[0059] Forced Exhausted 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 meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. The ATS / ERS Standardization of Spirometry can be used as a guideline. Spirometry is typically performed between 6-10 AM after at least 6 hours of albuterol withdrawal. Pulmonary function tests are typically performed in the sitting position, and the peak reading is recorded as FEV1 (in liters).

[0060] The present disclosure includes a method of treatment that results in an increase in FEV1 from baseline of at least 0.01 L at 24 weeks following initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist. Included are pharmaceutical compositions comprising an anti-IL-33 antagonist for use in increasing FEVl from baseline. For example, administration of an IL-33 antagonist increases FEVl 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 24 weeks.

[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 patient's FVC can be measured using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. The ATS / ERS standards for spirometry may be used as a guideline. Spirometry is typically performed between 6 and 10 AM after at least 6 hours of albuterol withdrawal. Pulmonary function tests are typically performed in a sitting position, with the highest measure of FVC recorded (in liters).

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

[0063] The present disclosure includes treatments that result in a reduction in AECOPD from baseline of at least 5% at 24 weeks following initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist. The disclosure includes a pharmaceutical composition comprising an anti-IL-33 antagonist for use in reducing AECOPD by at least 5% at 24 weeks following initiation of treatment with said pharmaceutical composition. For example, according to the present invention, administration of an IL-33 antagonist to a subject in need thereof results in 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 reduction in AECOPD from baseline at 24 weeks.

[0064] The present disclosure includes treatments that result in at least a 5% reduction in the likelihood of first AECOPD at a particular time point at 24 weeks following initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist, compared to baseline. The present disclosure includes pharmaceutical compositions comprising an anti-IL-33 antagonist for use in reducing the likelihood of first AECOPD at a particular time point at 24 weeks following initiation of treatment with said pharmaceutical composition, compared to baseline. For example, according to the present invention, administration of an IL-33 antagonist to a subject in need thereof reduces the likelihood of first AECOPD at a particular time point at about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50 ... A decrease of 5%, about 60%, about 65%, about 70%, or more.

[0065] Use of albuterol / levalbuterol. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a reduction in daily albuterol or levalbuterol use from baseline. The number of inhalations of albuterol / levalbuterol can be recorded daily by the patient using a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, albuterol / levalbuterol can generally be used non-regularly or prophylactically as needed for symptoms. The baseline number of inhalations of albuterol / levalbuterol per day can be calculated based on the average over the 7 days prior to administration of the first dose of a pharmaceutical composition comprising an IL-33 antagonist.

[0066] The present invention includes methods of treatment that result in a reduction in albuterol / levalbuterol use from baseline of at least 0.25 puffs per day at 12 weeks after initiation 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 reduction in albuterol / levalbuterol use from 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 baseline in daily steps, e.g., an increase in daily steps over a period of time compared to the 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 reduces the number of days the patient receives oral corticosteroids. According to certain embodiments, administration of an IL-33 antagonist to a patient results in a reduction in the number of days the patient receives antibiotics over a period of time compared to the number of days the patient received 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 baseline in resting oxygen saturation, e.g., an increase in resting oxygen saturation above 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 in resting respiratory rate from baseline, e.g., a decrease or 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 compared to the resting respiratory rate prior to administration of the IL-33 antagonist.

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

[0072] COPD Assessment Test (CAT) score. According to certain embodiments, administration of an IL-33 antagonist to a patient reduces the CAT score from baseline. An anti-IL-33 antagonist is provided for use in patients to reduce baseline CAT scores. The CAT is a questionnaire designed for patients with COPD to measure the impact of their disease on their quality of life (COPD Assessment Test, available at 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. CAR scores range from 0 to 40, with higher scores indicating greater impact on health status. The test covers cough, sputum production, chest tightness, dyspnea, activity limitations, confidence, sleep, and energy. Patients score questions from 1 to 5 according to their feelings about the disease (1 = I am very happy; 5 = I am very sad).

[0073] St. George's Respiratory Questionnaire (SGRQ). According to certain embodiments, administration of an IL-33 antagonist to a patient reduces the SGRQ score from baseline. An anti-IL-33 antagonist is provided for use in a patient to reduce the SGRQ score from baseline. The St. George's Respiratory Questionnaire (SGRQ) is a 50-item questionnaire designed to measure and quantify health-related well-being 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. 1992 June;145(6):1321-7). Overall scores range from 0 to 100. Phase scores are calculated for three domains: symptoms, activities and impact (psychosocial), and a total score. A lower score indicates a better quality of life (QoL). The first part ("Symptoms") assesses symptomatology, including cough frequency, sputum production, wheezing, shortness of breath, and the duration and frequency of bouts of shortness of breath or wheezing. The second part has two components: "Activities" and "Impact." The "Activities" part addresses activities that cause or are limited by shortness of breath. The "Impact" part addresses a range of factors, including impact on employment, having control over health, fear, stigmatization, need for medication, side effects of prescribed therapy, health expectations, and interference with daily life. The questionnaire's recall period spans the past four weeks. Psychometric testing has demonstrated its reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. A minimum score change of four units was established as clinically relevant following patient and clinician testing. The SGRQ has been used in a range of disease groups, including asthma, COPD, and bronchiectasis.

[0074] Exacerbation of Chronic Obstructive Pulmonary Disease Tool (EXACT). According to certain embodiments, administration of an IL-33 antagonist to a patient reduces the EXACT score from baseline. Anti-IL-33 antagonists are provided for use in patients to reduce the EXACT score from baseline. The EXACT total score measures acute, persistent worsening of symptoms of Acute Bacterial Exacerbation of Chronic Bronchitis-COPD (ABECB-COPD), i.e., signs and symptoms beyond day-to-day fluctuations. The instrument's total score is composed of 14 items representing the following domains: shortness of breath (5 items), cough and sputum (2 items), chest symptoms (3 items), difficulty expectorating (1 item), fatigue or weakness (1 item), sleep disturbance (1 item), and fear or anxiety (1 item). The EXACT is a diary to be completed nightly before bed. The instrument was developed with electronic administration in mind, and the interview was conducted using a paper-and-pen booklet and a The study was conducted using a personal digital assistant (PDA) and a mobile device to describe respondent understanding of either modality and user acceptance of the PDA.

[0075] Assessment of Respiratory Symptoms in COPD (E-RS). According to certain embodiments, administration of an IL-33 antagonist to a patient results in the patient reporting better health on the Assessment of Respiratory Symptoms in COPD (E-RS). An anti-IL-33 antagonist is provided for use in a patient such that the patient reports better health on 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. The E-RS is based on 11 respiratory symptom items from the 14-item EXACT, a diary used to measure COPD exacerbations. The E-RS provides a total score quantifying overall respiratory symptom severity and three subscale scores assessing shortness of breath, cough and sputum, and chest symptoms. This allows for two validated uses for a single diary: quantification of respiratory symptoms in stable COPD using E-RS total and subscale scores and assessment of acute exacerbations (changes in exacerbation symptoms with symptom-defined events frequency, severity, duration and medically treated events) using the EXACT total score.

[0076] EuroQual Questionnaire (EQ-5D-3L or EQ-5D-5L). According to certain embodiments, administration of an IL-33 antagonist to a patient causes the patient to report better health on the EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). An anti-IL-33 antagonist is provided for use in a patient such that the patient reports better health on the EuroQual 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 a simple and comprehensive measure of health for clinical and economic evaluations.

[0077] Modified Medical Research Council Questionnaire (mMRC). According to certain embodiments, administration of an IL-33 antagonist to a patient causes the patient to report better health on a modified Medical Research Council Questionnaire (mMRC). An anti-IL-33 antagonist is provided for use in a patient such that the patient reports better health on a modified Medical Research Council Questionnaire (mMRC). The modified Medical Research Council Questionnaire (mMRC) is a questionnaire that assesses shortness of breath (Fletcher et al., Standardized questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960;2:1662).

[0078] Health-Related Quality of Life (HRQOL) Questionnaires. According to certain embodiments, administration of an IL-33 antagonist to a patient causes the patient to report better health 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.) An anti-IL-33 antagonist is provided for use in a patient such that the patient reports better health on an HRQOL questionnaire.

[0079] Biomarkers. In certain embodiments, the subject experiences improved lung function as measured by biomarkers. In certain exemplary embodiments, the subject experiences an increase in biomarker levels after administration of an anti-IL-33 antagonist (e.g., an anti-IL-33 antagonist). In certain exemplary embodiments, the subject experiences a decrease in biomarker levels after administration of the anti-IL-33 antagonist (compared to the biomarker levels before administration of the anti-IL-33 antagonist). For example, the biomarkers may include blood eosinophils, blood neutrophils, exhaled nitric oxide (FeNO) (e.g., FeNO before bronchodilator administration), total IL-33, soluble IL-33 receptor (sST2), calcitonin, lung and activation-regulated chemokine (PARC), blood C-reactive protein, blood IL-6, eotaxin-3, total IgE, fibrinogen, calcitonin, procalcitonin, calcitonin gene-related peptide (CGRP), receptor agonist (RGD), and / or receptor agonist (RGD). The target gene may be selected from the group consisting of IL-33, IL-33 receptor agonist ... In certain embodiments, improvement in lung function is indicated by a decrease or increase at 4, 12, or 24 weeks (as appropriate) after treatment.

[0080] Methods for Treating COPD In some embodiments, methods are provided for treating COPD, including, for example, moderate to severe COPD, in a subject in need thereof, the methods comprising administering a pharmaceutical composition comprising an IL-33 antagonist. In certain embodiments, the methods are useful for treating moderate to severe COPD in a subject. In certain embodiments, the methods are useful for reducing one or more AECOPD events. Pharmaceutical compositions comprising an anti-IL-33 antagonist are provided for treating COPD, including, for example, moderate to severe COPD, in a subject in need thereof. Pharmaceutical compositions comprising an anti-IL-33 antagonist are provided for treating moderate to severe COPD in a subject in need thereof. Pharmaceutical compositions comprising an anti-IL-33 antagonist are also provided for reducing one or more AECOPD events in a patient.

[0081] In one aspect, a method for treating COPD is provided, comprising the steps of (a) selecting a patient exhibiting 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 exhibits a blood eosinophil level equal to or greater than 300 cells per microliter.

[0082] In one aspect, a method for treating COPD is provided, comprising the steps of (a) selecting a patient exhibiting 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 exhibits 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 the steps of: (a) selecting a patient exhibiting blood eosinophil levels 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 exhibits blood eosinophil levels of less than 300 cells per microliter. Shows blood eosinophil levels.

[0084] In another aspect, a method for treating COPD is provided, comprising the steps of (a) selecting a patient exhibiting 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 exhibits a blood eosinophil level of 150-299 cells per microliter.

[0085] In another embodiment, 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 embodiment of the composition for use, the patient has a blood eosinophil level of less than 150 cells per microliter.

[0086] In a related aspect, methods for treating COPD are provided, the methods comprising add-on therapy to background therapy. In a related aspect, an IL-33 antagonist is provided for use in treating COPD in a patient, wherein 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 been receiving background therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or longer) (also referred to as a "stable phase"). In certain embodiments, an IL-33 antagonist is provided for use in treating COPD in a patient, wherein the IL-33 antagonist is administered as add-on therapy to a COPD patient who has been receiving background therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or longer). In certain embodiments, the IL-33 antagonist is provided for use in treating COPD in a patient, wherein the IL-33 antagonist is administered as add-on therapy to a COPD patient who has been receiving background therapy for a period of time. In some embodiments, the background therapy includes an ICS and a LABA. In other embodiments, the background therapy includes an ICS and a LAMA. In other embodiments, the background therapy includes a LABA and a LAMA. In other embodiments, background therapy includes an ICS, a LAMA, and a LABA. In some embodiments, background therapy includes a PDE-4 inhibitor, such as roflumilast. In other embodiments, background therapy includes azithromycin.

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

[0088] In some embodiments, the present invention comprises a method for treating one or more COPD exacerbations in a patient chronically using an ICS, a LAMA, or a LABA, comprising: (a) selecting a patient with moderate to severe COPD who is chronically using an ICS, a LABA, a LAMA, or a combination thereof; and administering to the patient 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 COPD exacerbations in a patient with moderate to severe COPD who is chronically using an ICS, a LABA, a LAMA, or a combination thereof.

[0089] Interleukin-33 (IL-33) antagonist The methods featured in the invention include administering to a subject in need thereof a therapeutic composition comprising an IL-33 antagonist. As used herein, an "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 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 antigen-binding fragment thereof that can be used in the context of the methods featured in the present invention as described elsewhere herein. For example, in one embodiment, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and comprises the heavy and light chain (complementarity-determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 2 and 10, respectively. In another embodiment, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and comprises the 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 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 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 (sequence number 1)

[0093] SAR440340 (REGN3500) HCVR 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 the heavy chain of SAR440340 (REGN3500): aggtgcagct ggtggagtct gggggaaact tggaac agcc tggggggtcc cttagactct cctgtacagc ctctggattc acctttagca gatctgccat gaactgggtc cgccgggctc cagggaaggg gctggagtgg gtctcaggaa ttagtggtag tggtggtcga acatactacg cagactccgt gaagggcc tgcaaatgaa cagcctgagc gccgaggaca cggccgcata ttactgtgcg aaagattcgt atactaccag ttggtacgga ggtatggacg tctggggcca cgggaccacg gtcaccgtct cctcagcctc caccaagggc ccatcggtct tcccctggc gccctgctcc aggagcacct ccgagagcac agccgc cctg ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcag c gatcacaagc ccagcaacac caaggtggac aagagagttg agtccaaata tggtccccca tgcccaccct gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggc gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 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: VQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMD VWGHGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLGK (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 ccctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag (SEQ ID NO: 19)

[0111] SAR440340 (REGN3500) light chain amino acid sequence: 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 contains a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V LThe light chain constant region comprises one domain (C L 1) V H and V L The region can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of an anti-IL-33 antibody, or antigen-binding portion thereof, can be identical to human germline sequences or can be naturally or artificially modified. An amino acid consensus sequence can be defined based on side-by-side analysis of two or more CDRs.

[0114] The term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, e.g., from intact antibody molecules, using any appropriate standard technique, e.g., proteolytic digestion or recombinant genetic engineering techniques employing the manipulation and expression of DNA-encoded antibody variable and, optionally, constant domains. Such DNA is known and / or readily available, e.g., from commercial sources, DNA libraries (including, e.g., phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated, e.g., by using chemical or molecular biology techniques, to arrange one or more variable and / or constant domains in the 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) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of antibodies (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the scope of the term "antigen-binding fragment."

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

[0117] In certain embodiments, an antigen-binding fragment of an antibody comprises at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found within the antigen-binding fragments of antibodies described herein include: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)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 LIn 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 one another or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule; typically, the hinge region is between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Additionally, the antigen-binding fragments of the antibodies described herein may be composed of one or more monomeric V H Or V L The domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above in non-covalent association (e.g., via disulfide bonds).

[0118] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally comprise at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antigen-binding fragments of 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 antibody isotype 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, human antibodies featured in the present invention may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[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 a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (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 human immunoglobulin gene sequences into 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, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) to thereby modify the V and V regions of the recombinant antibody. H and V L The amino acid sequence of the region is human germline V H and V L When derived from and related to sequences, they are sequences that cannot naturally occur within the human antibody germline repertoire in vivo.

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

[0123] The frequency of occurrence of the second form in various intact IgG isotypes is unclear. This is due to structural differences associated with, but not limited to, antibody hinge region isotypes. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level commonly observed with human IgG1 hinges. The present invention provides a method for the identification of a single amino acid substitution in the hinge region of a human IgG4 hinge, C. H 2, or C H Antibodies with one or more mutations in the three regions are included, which may be desirable, for example, to improve the yield of the desired antibody form in manufacturing.

[0124] An "isolated antibody" refers to 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 or removed from at least one component of an organism, or an antibody that has been separated or removed from the tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." Isolated antibodies also 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, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0125] The term "specifically binds" or the like means that an antibody or antigen-binding fragment thereof 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, antibodies that "specifically bind" IL-33 as characterized in the present invention include antibodies, or portions thereof, that bind to IL-33, 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 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 present methods may contain one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention includes methods involving the use of antibodies, and antigen-binding fragments thereof, derived from any of the amino acid sequences disclosed herein, in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) within one or more framework and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) CDR regions of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 for a tetrameric antibody or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) are mutated to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues within a domain are mutated back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, and certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0127] The present invention also includes methods involving the use of anti-IL33 antibodies that comprise variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the present invention includes the use of anti-IL-33 antibodies that have HCVR, LCVR, and / or CDR amino acid sequences with, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer 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 allows for the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0129] The term “K D " refers to the equilibrium dissociation constant of a particular 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 the paratope. A single antigen can have more than one epitope. Thus, different antibodies can bind to different regions of an antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include carbohydrate, phosphoryl, or sulfonyl moieties on an antigen.

[0131] Human antibody production Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to generate human antibodies that specifically bind human IL-33.

[0132] VELOCIMMUNE® technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or monoclonal antibodies. Using any other known method for generating a human antibody, a high-affinity chimeric antibody to IL-33 having a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the generation of transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the antibody heavy and light chain variable regions 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 fully human antibodies.

[0133] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphoid cells (e.g., B cells) are harvested from the mice that express the antibody. The lymphoid cells can be fused with a myeloma cell line to produce an immortal hybridoma cell line, which is screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions 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, DNA encoding antigen-specific chimeric antibodies or variable domains of the light and heavy chains 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 desired 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, such as a wild-type or modified IgG1 or IgG4. The constant region selected can vary depending on the particular use, with the characteristics of high-affinity antigen binding and target specificity residing in the variable region.

[0135] Generally, antibodies that can be used in this method have high affinity, as measured by binding to an antigen immobilized in a solid phase or in a solution phase, as described above. The mouse constant region is replaced with a desired human constant region to produce a fully human antibody characterized in this invention. The constant region selected may vary depending on the specific 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 antigen-binding fragment thereof that specifically binds IL-33 that can be used in the context of the methods featured in the 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 designated HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. 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, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Immunol. 1999, 14:139-147. See 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) derived from the heavy and light chain variable region amino acid sequence pair (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 pair of SEQ ID NOs: 2 and 10, and the heavy chain / light chain amino acid sequence pair of SEQ ID NOs: 18 and 20.

[0142] Pharmaceutical Composition The present invention includes methods comprising administering an IL-33 antagonist to a patient, wherein the IL-33 antagonist is contained within a pharmaceutical composition. The present invention also includes IL-33 antagonists for use, wherein the IL-33 antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions featured in the present invention are formulated with suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerance, etc. Many suitable formulations can be found in a 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, emulsions of 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 dose of an antibody administered to a patient may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. Doses are 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. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-33 antibodies can be determined empirically. For example, the patient's progress can be monitored by periodic evaluation, and the dosage adjusted as appropriate. 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 featured in the present invention, including, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated enzymes, and the like. The mechanism of action of the present invention is 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 may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other bioactive agents.

[0145] The pharmaceutical compositions featured in the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, pen delivery devices (e.g., pen autoinjectors) are easily adapted to deliver the pharmaceutical compositions featured in the present invention. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, disposable pen delivery devices are pre-filled with the pharmaceutical composition, which is held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0146] Numerous reusable pen and autoinjector delivery devices find use in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN™, to name just a few. STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices that find use in the subcutaneous delivery of the pharmaceutical compositions featured in this invention include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name just a few.Examples of large-volume delivery devices (e.g., large-volume injectors) include, but are not limited to, bolus injectors, such as BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, and the like.

[0147] For direct administration to the sinuses, the pharmaceutical compositions featured in the present invention may be administered using, for example, a microcatheter (e.g., an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. This includes administering an IL-33 antagonist in the form of a solubilized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-33 may be administered to treat COPD in a patient. Aerosolized antibodies can be produced, for example, as described in U.S. Patent No. 8,178,098, the entire contents of which are incorporated herein by reference.

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

[0149] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, intravenous drip infusions, and the like. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying an antibody or a salt thereof described above in a sterile aqueous or oily medium commonly used for injections. Aqueous media for injection include, for example, 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)), and the like. Oily media include, for example, sesame oil and soybean oil, which may be used in combination with solubilizers, such as benzyl benzoate and benzyl alcohol. Therefore, the injections that are produced are generally filled into suitable ampoules.

[0150] Advantageously, the aforementioned pharmaceutical compositions for oral or parenteral use are prepared in dosage forms with unit doses suitable for the dose of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0151] Dosage The amount of an IL-33 antagonist (e.g., an anti-IL-33 antibody or antigen-binding fragment thereof) administered to a subject according to the methods featured herein or for use according to the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of an IL-33 antagonist that results in one or more of the following: (a) a reduction in the incidence of COPD exacerbations; (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, the therapeutically effective amount is 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 120 mg, about 140 mg, about 160 mg, about 180 mg, about 190 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, 0mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about The dose may be 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 an anti-IL-33 antibody is administered.

[0153] The amount of IL-33 antagonist contained within a particular dose range 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 dose of about 0.0001 to about 10 mg per kg of patient body weight. For example, the IL-33 antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0154] In certain embodiments, the methods include an initial dose of about 200 to about 600 mg of an IL-33 antagonist, for example, about 300 mg of an IL-33 antagonist.

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

[0156] In certain embodiments, the ICS and LABA are administered for the duration of administration of the IL-33 antagonist. In certain embodiments, the ICS and LAMA are administered for the duration of administration of the IL-33 antagonist. In certain embodiments, the LAMA and LABA are administered for the duration of administration of the IL-33 antagonist. In certain embodiments, the ICS, LAMA, and LABA are administered for 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 the antibody or antigen-binding fragment thereof administered every other week.

[0158] In other embodiments, the initial dose comprises 300 mg of the anti-IL-33 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.

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

[0160] In other embodiments, the initial dose comprises 300 mg of the anti-IL-33 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 three weeks.

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

[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 administration of the pharmaceutical composition comprising an 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 administration of the pharmaceutical composition comprising an IL-33 antagonist. Administration "concurrently 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 less than 5 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising an IL-33 antagonist, or is administered to the subject as a combined single-dose formulation comprising the additional therapeutic agent and an IL-33 antagonist.

[0163] The additional therapeutic agent may be, for example, another IL-33 antagonist, an IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibodies described in U.S. Pat. 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, or an antifungal agent. The therapeutic agent may be an NSAID, a long-acting muscarinic antagonist (e.g., tiotropium, aclidinium, 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 a combination comprising a long-acting beta2 agonist and an inhaled corticosteroid (e.g., fluticasone plus salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide plus formoterol [e.g., SYMBICORT® (Astra Zeneca)]). In other embodiments, the IL-33 antagonist is administered in a combination comprising a long-acting beta2 agonist and an inhaled corticosteroid (e.g., fluticasone plus salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide plus formoterol [e.g., SYMBICORT® (Astra Zeneca)]). In yet other embodiments, pharmaceutical compositions comprising an IL-33 antagonist are administered in a combination comprising a long-acting muscarinic antagonist and an inhaled corticosteroid (e.g., fluticasone and salmeterol (e.g., Advair® (GlaxoSmithKline)); or budesonide and formoterol (e.g., SYMBICORT® (Astra Zeneca))). In yet other embodiments, pharmaceutical compositions comprising an IL-33 antagonist are administered in a combination comprising a long-acting muscarinic antagonist, a long-acting beta-2 agonist, and an inhaled corticosteroid (e.g., fluticasone and salmeterol (e.g., Advair® (GlaxoSmithKline)); or budesonide and formoterol (e.g., SYMBICORT® (Astra Zeneca))).

[0164] Dosing regimen According to certain embodiments, multiple doses of an IL-33 antagonist may be administered (or used) to a subject over a defined time course. Such methods comprise sequentially administering multiple doses of an IL-33 antagonist to a subject. As used herein, "sequentially administering" means that each dose of an IL-33 antagonist is administered to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Included are methods (or uses) comprising sequentially administering to a patient a single initial dose of an 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 provides a method for administering the drug about 4 times a week, twice a week, once a week (q1w), every other week (every 2 weeks or q2w), once every 3 weeks (every 3 weeks or q3w), once every 4 weeks (monthly or q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 7 weeks (q7w), once every 8 weeks (q8w), once every 9 weeks (q9w), once every 10 weeks (q10w), once every 11 weeks (q12w), once every 12 weeks (q13w), once every 13 weeks (q14w), once every 14 weeks (q15w), once every 15 weeks (q16w), once every 16 weeks (q17w), once every 17 weeks (q18w), once every 18 weeks (q19w), once every 19 weeks (q20w), once every 20 weeks (q21w), once every 21 weeks (q22w), once every 22 weeks (q23w), once every 23 weeks (q24w), once every 24 weeks (q25w), once every 25 weeks (q26w), once every 26 weeks (q27w), once every 27 weeks (q28w), once every 28 weeks (q29w), once every 29 weeks (q30w), once every 30 weeks (q31w), once every 31 weeks (q32w), once every 32 weeks (q33w), once every 33 weeks (q34w), once every 34 weeks (q35w), once every 34 weeks (q36w), once every 35 weeks (q37w), once every 35 weeks (q38w), once every 36 weeks (q39w), once every 37 weeks (q38w), once every 38 weeks (q39w), once every 39 weeks (q39w), once The present invention also includes a method (or use) comprising administering to a subject a pharmaceutical composition comprising an IL-33 antagonist at a dosing frequency of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg (q11w), once every 12 weeks (q12w), or less frequently as long as a therapeutic response is achieved. In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-33 antibody, weekly dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-33 antibody, biweekly dosing (once every two weeks dosing) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-33 antibody, once every three weeks dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, dosing once every four weeks (monthly dosing) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, dosing once every five weeks in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, dosing once every six weeks in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody, dosing once every eight weeks in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-33 antibody, a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg once every 12 weeks can be used. In one embodiment, the route of administration is subcutaneous.

[0166] The term "week" refers to (n x 7 days) ± 3 days, for example (n x 7 days) ± 1 day, or (n x 7 days ), where "n" indicates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 or more weeks.

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

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

[0169] In certain embodiments, the subsequent dose is 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 amount of 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, and 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, and 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 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 or more) weeks after the immediately preceding dose. By single dose, it is meant the dose of an IL-33 antagonist that is administered to a patient before the administration of the next dose in a sequence that does not interfere with that dose.

[0176] The method (or use) can include administering multiple second and / or third doses of an 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 including multiple subsequent or second doses, each subsequent or second dose may be administered at the same frequency as the other subsequent or second doses. For example, each subsequent or second dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments including multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency at which the second and / or third doses are administered to the patient may vary during the treatment regimen. The frequency of administration may also be adjusted during treatment by the physician according to the individual patient's needs after clinical testing.

[0178] The present invention includes methods for treating COPD or a related condition, comprising sequential administration of an IL-33 antagonist and an additional therapeutic agent to a patient. The present invention also includes an IL-33 antagonist for use in a patient to treat 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 to treat COPD or a related condition, wherein the patient is treated with sequential administration of an IL-33 antagonist and an additional therapeutic agent. In some embodiments, the method comprises administering one or more doses of an IL-33 antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the additional therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-33 antagonist may be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an additional therapeutic agent (e.g., an inhaled corticosteroid or beta2-agonist or muscarinic antagonist or any other therapeutic agent, as described elsewhere herein) to treat, alleviate, reduce, or ameliorate one or more symptoms of COPD. In some embodiments, the IL-33 antagonist is administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) that result in improvement in one or more COPD-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one symptom of COPD. An alternative embodiment involves co-administration of an 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 an IL-33 antagonist are administered, and an additional therapeutic agent is administered in a separate dosage at similar or different 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 every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or more weeks. In other embodiments, the IL-33 antagonist is administered every four weeks for 12, 16, 20, 24, 28, 32, 36, 38, 40, 42, 44, 46, 48 or more weeks. In particular embodiments, the IL-33 antagonist is administered for at least 24 weeks.

[0180] The present invention includes methods for treating a subject with moderate to severe COPD, 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, wherein the multiple maintenance doses are administered during the treatment period.

[0181] In another embodiment, a method for treating a subject with 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 multiple subsequent doses of the antibody or antigen-binding fragment thereof. In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) is provided for use in treating a subject with moderate to severe COPD, wherein the antibody or antigen-binding fragment thereof is administered to the subject in an initial dose of about 300 mg, followed by multiple subsequent doses. In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) is also provided for use in treating a subject with 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, followed by multiple subsequent doses. Each subsequent dose is about 300 mg of the antibody or antigen-binding fragment thereof, and multiple subsequent doses are administered during a treatment period, including an induction period, an oral corticosteroid (OCS) tapering period, and a maintenance period, wherein 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 methods (or uses) featured in the present invention comprise administering a therapeutic composition comprising an IL-33 antagonist to a subject in need thereof. The term "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of COPD (e.g., moderate to severe COPD) or that has been diagnosed with COPD. For example, a "subject in need thereof" may include a subject that, prior to treatment, exhibits (or has exhibited) one or more COPD-related parameters, such as, for example, a decline in FEV1 (e.g., less than 2.0 L), and / or has experienced one or more exacerbations of COPD events, e.g., an acute exacerbation of COPD (AECOPD) event.

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

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

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

[0186] In some embodiments, a "subject in need thereof" is a subject who is a former smoker. In some embodiments, the subject is a former smoker with a history of smoking cigarettes. In some embodiments, the subject is a former smoker with a history of smoking 10 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking fewer than 10 packs per year. In some embodiments, the subject is a former smoker with a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking about 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more. In some embodiments, the subject is a former 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 former smoker who has quit smoking for at least 6 months. In some embodiments, the subject is a former smoker who intends to quit smoking permanently.

[0187] In some embodiments, a "subject in need thereof" may be a subject classified as having "mild" COPD according to the GOLD classification system. In other embodiments, a "subject in need thereof" may be a subject classified as having "moderate" COPD according to the GOLD classification system. In another embodiment, a "subject in need thereof" may be a subject classified as having "severe" COPD according to the GOLD classification system. In yet another embodiment, a "subject in need thereof" may be a subject classified as having "very severe" COPD according to the GOLD classification system. In another embodiment, a "subject in need thereof" may be a subject classified as having COPD that falls between "moderate" and "severe" according to the GOLD classification system, e.g., a subject with "moderate-to-severe" COPD.

[0188] In some embodiments, a "subject in need thereof" may be a subject with 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% of, or less than, the predicted FEV1.

[0189] Normal IgE levels in healthy subjects are less than about 100 kU / L (e.g., as measured using the IMMUNOCAP® assay [Phadia, Inc. Portage, MI]). Thus, serum IgE levels 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, and the like are considered to be elevated or decreased. The present invention provides methods for treating IL-33 deficiency, including the steps of: selecting a subject exhibiting elevated serum IgE levels of greater than about 4500 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 methods comprising administering an IL-33 antagonist to treat a patient with elevated eotaxin-3 levels, e.g., 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 (Alwing et al., 1993, Eur. Respir. J. 6:1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is the Aerocrine By using a NIOX device by AB, Solna, Sweden. Assessment is performed before spirometry and after at least one hour of fasting. Included herein is a method comprising administering an IL-33 antagonist to a patient with elevated exhaled NO (FeNO) levels, e.g., 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 according to methods known in the art, e.g., according to the European Respiratory Society guidelines.

[0193] In some embodiments, the subject is classified 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 of 299 to 150 cells / μL (or cells / mm 3 ) (moderate 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 receive an IL-33 antagonist with a dose or dosing regimen that is optionally based on eosinophil levels.

[0194] Methods for assessing pharmacodynamic COPD-related parameters The present disclosure also includes methods for assessing one or more pharmacodynamic COPD-related parameters in a subject in need thereof resulting from administration of a pharmaceutical composition comprising an IL-33 antagonist. Although a reduction in the incidence of COPD exacerbations (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 may not be 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) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement of pharmacodynamic COPD-related parameters" refers to, for example, an improvement in one or more of the following: "Baseline" refers to a decrease from baseline in one or more biomarkers, such as TARC, eotaxin-3, or IgE, sputum eosinophils or neutrophils, FeNO, or blood eosinophil count. As used herein, the term "baseline" with respect to a pharmacodynamic COPD-related parameter refers to the value of the pharmacodynamic COPD-related parameter for a patient before or at the time of administration of a pharmaceutical composition described herein.

[0196] To assess 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 first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or fourteenth day, or at three, four, five, six, seventh, eighth, nineteenth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or more weeks after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there is a change, e.g., "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured), in the pharmacodynamic COPD-related parameter.

[0197] In certain embodiments, administration of an IL-33 antagonist to a subject with COPD results in 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, exhaled nitric oxide (FeNO), total IL-33, soluble IL-33 receptor (sST2), calcitonin, PARC, eotaxin-3, total IgE, blood C-reactive protein (CRP), blood IL-6, fibrinogen, etc.

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

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

[0202] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this invention, and are not intended to limit the scope of what the inventors regard as their invention. While efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0203] An exemplary IL-33 antagonist used in the following examples is a human anti-IL-33 antibody designated SAR440340, which is also referred to as REGN3500 or by its International Nonproprietary Name (INN) as itepekimab. [Example]

[0204] A randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept (PoC) study 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 highly prevalent disease worldwide, associated with a significant economic burden, for which available standard treatments have shown inadequate therapeutic effects on symptoms, lung function, exacerbations, and the long-term evolution of the disease. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that initiates and amplifies innate and adaptive inflammatory cascades in response to epithelial cell stress or injury resulting from exposure to airborne allergens, viruses, cigarette smoke, and air pollutants.

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

[0206] Secondary objectives of the study were to investigate the effect of SAR440340 compared to placebo on improving respiratory function as measured by pre-bronchodilator FEV1; to evaluate the effect of SAR440340 compared to placebo on post-bronchodilator FEV1; to evaluate the effect of SAR440340 compared to placebo on the duration from baseline to the first moderate to severe AECOPD event; and to evaluate the effect of SAR440340 compared to placebo on safety and tolerability.

[0207] The exploratory objectives of this study were to evaluate the efficacy and safety of eosinophils 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 3To assess the effect of SAR440340 compared to placebo on patient-reported symptoms and quality of life as described by electronic diary and using the Exacerbation of Chronic Obstructive Pulmonary Disease Tool (EXACT), St. George's Respiratory Questionnaire (SGRQ), and Euroqol-5 Item (EQ 5D) questionnaires in a subpopulation with pulmonary edema; to evaluate the pharmacokinetic (PK) profile of SAR440340 in serum; to evaluate the effect of SAR440340 anti-drug antibodies (ADAs); and to evaluate high blood eosinophil levels (≥ 250 / mm 3 ) and low blood eosinophil levels (<250 / mm 3 To evaluate the effect of SAR440340 compared to placebo on FEV1, AECOPD, and other selected endpoints in subpopulations with bronchodilator therapy and in subpopulations according to ICS use / non-use, fibrinogen levels, and smoking status To evaluate the effect of pharmacogenomics on SAR440340; To evaluate the effect of SAR440340 on other respiratory assessments (extended AECOPD endpoints) compared to placebo; To evaluate the effect of SAR440340 on high blood eosinophil levels (≥ 250 / mm 3 ) and low blood eosinophil levels (<250 / mm 3 To assess the clinical symptoms of COPD in SAR440340 vs. placebo-treated patients in all SAR440340 / placebo-treated patients, in the subpopulation with COPD (associated with COPD-related COPD), and in subpopulations according to ICS use / non-use with bronchodilators as background therapy, fibrinogen levels, and smoking status; to assess the pharmacodynamic effects of SAR440340; to assess the effects of SAR440340 compared with placebo on sleep, activity, and home spirometry parameters; and to compare the utility of home spirometry versus clinic-based spirometry.

[0208] The primary endpoint of this study was the annualized rate of moderate-to-severe AECOPD over the treatment period. Moderate exacerbations were documented by the investigator and defined as AECOPD requiring systemic corticosteroids (such as intramuscular, intravenous, or oral) and / or antibiotics. Severe exacerbations were documented by the investigator and defined as AECOPD requiring hospitalization, emergency department visit, or death.

[0209] Secondary endpoints were mean changes from baseline in FEV1 (pre-bronchodilator) from weeks 16 to 24. Model-based means across weeks 16, 20, and 24 were compared between treatment groups.

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

[0211] A further secondary endpoint was time to first moderate or severe AECOPD.

[0212] Further secondary endpoints were treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

[0213] Tertiary endpoints included change from baseline in EXACT, SGRQ, or EQ-5D scores at 24 weeks.

[0214] Other tertiary endpoints included serum functional SAR440340 concentrations; anti-drug antibodies (ADA) to SAR440340; change from baseline in FEV1 (pre-bronchodilator and post-bronchodilator) to 24 weeks; and rate of moderate-to-severe AECOPD.

[0215] Further tertiary endpoints included DNA or RNA samples for a pharmacogenomic substudy to identify genomic associations with clinical or biomarker response and prospective assessment of other clinical outcome measures and possible AEs; change from baseline in FVC (% predicted and absolute value in mL) from 16 to 24 weeks; time to first moderate and severe worsening or time to study drug discontinuation due to lack of efficacy (after week 4) based on investigator judgment (an extended AECOPD endpoint); and time to first clinically significant worsening (CID) and / or moderate to severe AECOPD by week 24 (and over the 52-week variable treatment period), defined by a decrease from baseline in trough FEV1 of >100 mL and / or a 4-unit worsening in the SGRQ.

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

[0217] Other tertiary endpoints related to actigraphy (sleep and activity) and home spirometry included sleep and activity parameters including sleep (total sleep time, wakefulness after sleep onset, number of overnight activities), activity (number of daytime activities, percent of time spent sedentary, percent of time spent in moderate to vigorous physical activity) and change in spirometry (FEV1) from the mean measurement over baseline (2 weeks before randomization) to the mean measurement over weeks 10-12 (2 weeks before Visit 8) and 22-24 (2 weeks before Visit 14). FEV1 measurements were obtained from both home and clinic-performed spirometry.

[0218] B. Study Design This was a multinational, randomized, double-blind, placebo-controlled, parallel-group (two-arm), proof-of-concept (PoC) study designed to evaluate the efficacy, safety, and tolerability of SAR440340 in patients with moderate to severe COPD receiving established long-acting beta-2 adrenergic agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and / or ICS background therapy (dual or triple therapy). Patients were treated for a minimum of 24 weeks and a maximum of 52 weeks. * Patients were to receive treatment with SAR440340 or placebo until 20 weeks of age, as well as for a 20-week safety follow-up period. Approximately 343 patients were randomized into two treatment arms with 171 or 172 patients per arm. * The trial used a variable treatment duration ranging from 24 to 52 weeks to maximize data on the primary endpoint (annualized rate of deterioration) 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 the minimum 24-week treatment period.

[0219] As shown in Figure 1, the clinical trial consisted of three phases. First, a screening period (10 days to 4 weeks) was conducted to determine whether patients met the enrollment criteria of receiving standard-of-care background therapy, including dual combination therapy (LABA + LAMA or ICS + LABA or ICS + LAMA) or triple combination therapy (ICS + LABA + LAMA), for 3 months prior to Visit 2 / randomization and stable dosing for at least 1 month prior to Screening Visit 1. Second, a randomized treatment period was conducted in which patients meeting the inclusion and exclusion criteria were randomized to receive either SAR440340 (300 mg) administered as 2 SC injections every 2 weeks (q2w) for 24 to 52 weeks or a matching dose of placebo for SAR440340 administered as 2 SC injections q2w for 24 to 52 weeks. Third, a post-treatment period included a 20-week observational follow-up.

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

[0221] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0222] C. Patient Selection A schematic of the selected patients is shown in Figure 37. Approximately 340 patients were randomized in the study (170 patients per arm), of which approximately 50% had blood eosinophil counts > 250 / mm 3 Approximately 50% of patients had a blood eosinophil count <250 / mm 3 showed.

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

[0224] [Table 2]

[0225] Participants between the ages of 40 and 75 were eligible to participate in the study. Participants were eligible for inclusion in the study only if they met all of the following criteria: (1) participants with a diagnosis of COPD for at least 1 year (based on the Global Guidelines for Chronic Obstructive Pulmonary Disease (GOLD) definition found in the Global Guidelines for Chronic Obstructive Pulmonary Disease).(2) participants with moderate to severe COPD at Visits 1 and 2 (post-bronchodilator FEV1 / forced vital capacity [FVC] <70% and post-bronchodilator FEV1 / forced vital capacity [FVC] <70%). (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 productive cough for 3 months of the year prior to screening in patients in whom other causes of chronic cough (e.g., gastroesophageal reflux, chronic rhinosinusitis, bronchiectasis) have been ruled out); (5) ≥ 2 moderate exacerbations within the year prior to screening or participants with a documented history (medical record evidence) of ≥ 1 severe exacerbation, where a moderate exacerbation was defined as AECOPD requiring treatment with systemic corticosteroids (oral, intravenous, or intramuscular) and / or antibiotics (however, the use of antibiotics alone does not qualify as a "moderate exacerbation" unless documented evidence is available that antibiotic use is necessary to treat worsening COPD symptoms), and a severe exacerbation was defined as AECOPD requiring hospitalization; (6) participants receiving standard of care 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 who had been taking it stably for at least 1 month prior to screening; (7) current or former smokers with a smoking history of ≥ 10 pack-years; (8) body mass index (BMI) ≥ 18.0 kg / m. 2 (including 18.0); (9) either male or female; and (10) able to provide 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 investigator's judgment, could affect the conduct of the study; (2) severe comorbidities or complications that contraindicate the use of ICS (e.g., active pulmonary tuberculosis) or LABA (e.g., diagnosis of significant cardiovascular disease, insulin-dependent diabetes mellitus, hyperthyroidism, thyrotoxicosis, pheochromocytoma, history of hypokalemia); (3) use of injectable glucocorticosteroids or oral systemic glucocorticoids within 1 month prior to Visit 1 / screening. (4) use of corticosteroids or more than four courses of IV glucocorticosteroids within the 6 months prior to Visit 1; (5) systemic corticosteroids (except when used to treat an exacerbation; note: one short course (up to 6 days) of systemic corticosteroids is permitted at 24 weeks if medically necessary for reasons unrelated to AECOPD, e.g., severe poison ivy exposure); PDE-4 inhibitors such as roflumilast; methylxanthines (theophylline, aminophylline); leukotriene receptor antagonists or leukotriene synthesis inhibitors; lipoxygenase inhibitors; anti-IL5 mAbs (e.g., benralizumab; mepolizumab); anti-IgE therapy (e.g., omalizumab); anti-IL4R mAbs (e.g., dupilumab); systemic immunosuppressants (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-releasing medications other than salbutamol / albuterol, levosalbutamol / levalbuterol, or ipratropium (the use of which is not recommended during the study and should be used only in special circumstances (e.g., if you are not participating in the study)). (2) Participants receiving prohibited concomitant medications or therapies, including other investigational drugs. The following concomitant medications were permitted during the study: antihistamines, ophthalmic, intranasal, and topical corticosteroids. (3) Participants with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurological, hematological, ophthalmological, respiratory, gastrointestinal, cerebrovascular, or other significant medical disease or disorder that, in the investigator's judgment, may interfere with the study or require treatment that may interfere with the study. Specific examples include, but are not limited to, poorly controlled insulin-dependent diabetes mellitus; (6) participants with bronchial thermoplasty treatment (up to 3 years prior to Visit 1); (7) tuberculosis (TB)-related exclusions: history of active or incompletely treated TB. Confirmed QuantiFERON-positive patients (not active disease) will be excluded from the study unless they meet the following conditions: a history of previously documented complete chemoprophylaxis for latent TB infection (with a treatment regimen according to local guidelines) or treatment of active TB infection, if consultation with a specialist to rule out or treat active TB infection has been obtained; patients with suspected extrapulmonary TB infection, or patients at high risk for contractile TB, such as close contact with an individual with active or latent TB; (8) a current diagnosis of asthma according to the Global Initiative for Asthma Management and Prevention (GINA) guidelines (Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (GINA 2018). 2018. [cited March 8, 2018]).Available at the website: ginasthma.org / 2018-gina-report-global-strategy-for-asthma-management-and-prevention); (9) significant lung disease other than COPD (e.g., pulmonary fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, eosinophilic granulomatosis with polyangiitis, significant sleep apnea due to bilevel positive airway pressure, etc.) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts; (10) diagnosed alpha-1 antitrypsin deficiency; (11) advanced disease with the need for chronic (>15 hours / day) oxygen support (12) participants with a moderate or severe AECOPD event within 4 weeks prior to screening; (13) participants who have experienced an upper or lower respiratory tract infection within 4 weeks prior to screening / Visit 1 or during the screening period; (14) previous or planned lung resection or lung volume reduction surgery; (15) participants with a history of systemic hypersensitivity reaction to mAb drugs; (16) anti-IgE therapy (e.g., omalizumab (XOLAIR®)) within 130 days prior to Visit 1 or any other biologic therapy for asthma (anti-IL5) within 2 months or 5 half-lives prior to Visit 1, whichever is longer. (17) current history of substance and / or alcohol abuse; (18) inability to comply with study procedures (e.g., due to language difficulties, psychiatric disorders) or to read, understand, and complete questionnaires or use an electronic planner without assistance; (19) exposure to another investigational drug (small molecule as well as mAb, including dupilumab) within a period prior to Visit 1 that is <5 PK half-lives of the antibody. If the half-life is unknown, the minimum interval since exposure to the previous investigational antibody is 6 months.The minimum interval since exposure to any other (non-antibody) investigational drug is 30 days prior to Visit 1; (20) patients participating in the acute phase of a pulmonary rehabilitation program, i.e., patients who started rehabilitation <4 weeks prior to screening (Note: patients in the maintenance phase of a rehabilitation program may be included); (21) clinically relevant (based on the investigator's judgment) abnormal laboratory values ​​suggesting an unknown disease and requiring further evaluation; (22) participants who have previously received treatment in any clinical trial of SAR440340; (23) participants who are the investigator, or any sub-investigator, research assistant, pharmacist, clinical trial coordinator, other staff, or their associates directly involved in the conduct of the trial; (24) ) Prisoners and legally institutionalized participants; (25) known allergies to doxycycline or related compounds or known allergies to SAR440340 excipients; (26) lactating, breastfeeding, or pregnant women; (27) women of childbearing potential (premenopausal women who are biologically capable of becoming pregnant) who are not protected by one of the acceptable forms of effective contraception or who have not confirmed a negative serum beta-human chorionic gonadotropin (β-hCG) test at Visit 1 and a negative urine pregnancy test prior to Visit 2 / randomization (postmenopausal women, defined as the absence of menstruation for at least 12 consecutive months, are not required to use additional contraception); male participants with a female partner of childbearing potential must adhere to the following usual preferred lifestyles for both of them: (28) Abstinence from penile-vaginal intercourse (long-term sustained abstinence) and remaining abstinent, or if engaging in penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant, use of a male condom, and the partner must use a contraceptive method with a failure rate of <1% per year; men with pregnant or breastfeeding partners must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each penile penetration session to be eligible to participate; (29) Have been diagnosed with, suspected of having, or are at high risk for an active parasitic infection (helminths), or have not had an active infection ruled out by clinical and (if necessary) laboratory evaluation before randomization; (30) Have human immunodeficiency virus (HIV) infection or HIV History of positive serology; (30) known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite resolution of the infection; or, in the investigator's judgment, unusually frequent, recurrent, or prolonged infections; (31) vaccination with live attenuated vaccine within 12 weeks prior to Visit 1 or planned vaccination with live attenuated vaccine during the study;(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 titers of autoantibodies at screening who are suspected, at the discretion of the investigator or sponsor, to be at high risk for developing an autoimmune disease; (33) Patients with acute myocardial infarction within the past year or unstable angina within the past 6 months, cardiovascular diseases / conditions including unstable ischemic heart disease, arrhythmias including paroxysmal (e.g., intermittent) atrial fibrillation, will be excluded. Persistent atrial fibrillation, as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta-blockers, calcium channel blockers, pacemaker placement, digoxin, or ablation therapy), and a stable, adequate level of anticoagulation for at least 6 months, may be considered for inclusion; cardiomyopathy, as defined by stage III-IV (New York Heart Association) heart failure, or other associated cardiovascular disorders that, in the investigator's judgment, may place the patient at risk or negatively affect study outcomes; and uncontrolled hypertension (i.e., systolic blood pressure [BP] >180 mm Hg or diastolic BP >110 mm Hg, regardless of the use of antihypertensive therapy). (34) hepatitis B and / or C serology indicating active or chronic infection; (35) any previous history of malignancy or progressive malignancy, including lymphoproliferative disorders, within the 5 years prior to Visit 2 (excluding successfully treated in situ cancer of the cervix, nonmetastatic 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), <10 g / dL for men and <9 g / dL for women, hemoglobin <1.5 K / mm; 3 neutrophils (<1K / mm in Africans) 3 ), <100K / mm 3clinically significant laboratory tests at Screening / Visit 1, including platelets of ≥ 100 μmol / L, or creatinine of ≥ 150 μmol / L; (37) patients receiving macrolide (e.g., azithromycin) therapy who have not received stable therapy for > 1 year; (38) patients receiving PDE-4 inhibitors (roflumilast) or leukotriene blockers (montelukast, singulair, etc.); and (40) enrollment / randomization has been stopped at the trial level despite patient screening.

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

[0228] Baseline demographics of study participants are presented in Table 3. Demographics were balanced between the treatment and placebo groups, with women making up over 40% of the population.

[0229] [Table 3]

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

[0231] In the group receiving IMP, sterile SAR440340 was provided in one 20 mL vial containing 287 mg of lyophilized formulation. One vial of lyophilized formulation (287 mg) or placebo was reconstituted with 2.5 mL of sterile water for injection, yielding 2.9 mL of 100 mg / mL SAR440340 or placebo. A volume of 1.5 mL was drawn from the vial per injection. Patients received two subcutaneous injections per dose. The subcutaneous injection sites were located on the upper thigh, in each of the four quadrants of the abdomen, or between the upper arms to prevent the same site from being injected twice between consecutive visits. The study drug (IMP) or placebo was administered every 14 ± 3 days (q2w) for 24 to 52 weeks.

[0232] [Table 4]

[0233] Non-clinical drug At Screening Visit 1, all patients were receiving standard of care 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 on stable therapy for at least 1 month prior to Screening / Visit 1.

[0234] Background therapy was prescribed via dry powder inhaler (DPI), metered dose inhaler (MDI), or pocket nebulizer. Route of administration of background therapy was oral inhalation. Dose regimen of background therapy was as prescribed.

[0235] Throughout the study, patients were to continue their established background therapy for COPD. Patients were to continue receiving their established background medications for COPD throughout the study period. After successful management of an acute COPD exacerbation (e.g., with oral corticosteroids and / or antibiotics), patients were to resume their initial background COPD treatment regimen if, in the investigator's opinion, medically acceptable. After one severe or two moderate exacerbations of COPD, dose adjustment of background therapy was to be permitted for symptom control and, if necessary, for the remainder of the study period.

[0236] Patients could use albuterol / salbutamol or levalbuterol / levosalbutamol (with ipratropium or ipratropium / short-acting beta-agonist [SABA] combinations) as relievers as needed during the study. Nebulized solutions could be used as an alternative delivery method.

[0237] Relief medication prescriptions included dry powder inhalers (DPIs), metered-dose inhalers (MDIs), or pocket nebulizers. The route of administration for relief medications was oral inhalation. The dose regimen for background therapy was as prescribed.

[0238] Efficacy evaluation The severity of COPD exacerbations was protocol-defined. A "moderate exacerbation" was recorded by the investigator and defined as an AECOPD that required systemic corticosteroids (such as intramuscular, intravenous, or oral) and / or antibiotics. A "severe exacerbation" was recorded by the investigator and defined as an AECOPD that required hospitalization, an emergency care visit, or resulted in death. In addition to these protocol-defined exacerbations of COPD, 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 deemed necessary by the investigator. After successful management of an acute COPD exacerbation (e.g., with oral corticosteroids and / or antibiotics), every effort was made to resume the original background COPD treatment regimen if medically acceptable in the investigator's opinion. After one severe or two moderate COPD exacerbations, dose adjustments of background therapy were permitted for symptom control and for the remainder of the study period, as needed.

[0240] Spirometry during clinical visits is based on the European Respiratory Society (ERS) / American Thoracic Society (ATS) It should be performed according to guidance (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. 2005 Aug;26(2):319-38) and prior to administration of investigational drug. For parameters measured before bronchodilator administration, including FEV1, PEF, FVC, and forced expiratory flow (FEF) 25%–75%, spirometry was performed after the bronchodilator withdrawal period according to its duration of action, e.g., withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for at least 6 hours, withholding the last dose of a long-acting antihistamine (LABA) for at least 12 hours (the ultra-long-acting LABA-like vilanterol 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 a long-acting antihistamine (LAMA) for at least 24 hours. This was confirmed before measurements were performed. If both pre- and post-bronchodilator spirometry were assessed, post-bronchodilator spirometry was performed consistent with the mechanism of action of the reliever (i.e., 30 minutes for albuterol or other SABAs). At all visits, spirometry was preferably performed in the morning, with afternoon / evening permitted in exceptional circumstances where morning spirometry could not be performed; spirometry was performed at approximately the same time at each visit throughout the study. Current smokers were reminded not to smoke for at least 1 hour before spirometry. Spirometry was performed at all visits using the same spirometer and standard spirometry technique, including calibration, and whenever possible, the same person performed the measurements. Whenever possible, three measurements meeting ATS acceptability and reproducibility criteria were obtained at every visit.

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

[0242] Optional actigraphy (sleep and activity) assessments and home spirometry were also included. Patients were provided with an actigraphy wristband and asked to wear it constantly (including overnight) throughout the three monitoring periods. Actigraphy data were used to measure sleep parameters and daytime activity. Actigraphs were worn during the screening period and two monitoring periods during the treatment phase. Data from the device was 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 home spirometry with electronic data storage to measure FEV1. Patients were instructed to perform the expiratory flow maneuver as described in the study manual at least twice daily between 06:00 and 12:00 and 18:00 and 24:00 during the screening period and at 2-week intervals during the treatment and follow-up periods.

[0243] A subset of study sites was selected to perform induced sputum assessment, and patients at these selected sites had the option to participate in this assessment. Sputum induction is a relatively non-invasive method of obtaining sputum for cellular or fluid-phase inflammatory indices, culture, or cytology. Sputum induction is performed using an aerosol of normal saline or hypertonic saline produced by an ultrasonic nebulizer. This aerosol is a potential bronchoconstrictor irritant and is rendered safe in a dose-response manner by pretreatment with salbutamol and inhalation.

[0244] At screening (Visit 1), patients were issued an electronic diary. Patients were instructed on the use of this device, and written instructions for using the electronic device were provided to patients. Recorded information was downloaded from this device on other indicated days. Every day during screening and treatment, patients used the electronic diary to answer the COPD symptom scale questions in the EXACT tool, record daily use of COPD-relieving medications, and record use of systemic corticosteroids and / or antibiotics taken for COPD exacerbations. The electronic diary was used to record patient-recorded outcome questionnaires. These questionnaires are described below.

[0245] COPD Assessment Test (CAT™) The CAT™ is a new questionnaire designed for patients with COPD to measure the impact of the disease on quality of life. 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.

[0246] CAR™ scores range from 0 to 40, with higher scores indicating greater impact on health status. Examinations cover cough, sputum production, chest tightness, dyspnea, activity limitations, confidence, sleep, and energy. Patients score 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 well-being in adult patients with chronic airflow limitation. Overall scores range from 0 to 100. Dimensional scores are calculated for three domains: symptoms, activities, and impact (psychosocial) as well as a total score. Lower scores indicate better quality of life (QoL).

[0248] The first part ("Symptoms") assesses symptomatology, including cough frequency, sputum production, wheezing, shortness of breath, and the duration and frequency of bouts of shortness of breath or wheezing. The second part has two components: "Activities" and "Impact." The "Activities" part addresses activities that cause or are limited by shortness of breath. The "Impact" part addresses a range of factors, including impact on employment, being in control of health, fear, stigmatization, need for medication, side effects of prescribed therapy, health prospects, and interference with daily life. The recall period for the questionnaire covers the past four weeks.

[0249] The psychometric test has demonstrated its reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. A minimum score change of 4 units has been established as clinically relevant after patient and clinician testing. The SGRQ has been used in a range of disease groups, including asthma, COPD, and bronchiectasis.

[0250] Exacerbation of Chronic Obstructive Pulmonary Disease Tool (EXACT) The EXACT total score measures acute bacterial exacerbation of chronic bronchitis-COPD (ABECB-COPD) symptoms, i.e., acute, persistent worsening of signs and symptoms beyond day-to-day fluctuations. The total score of the instrument is calculated based on the following domains: shortness of breath (5 items); Cough and sputum (2 items); Chest symptoms (3 items), Difficulty coughing up sputum (1 item); fatigue or weakness (1 item); sleep disturbance (1 item), and Fear or worry (1 item) It consists of a total of 14 items that represent the following:

[0251] The EXACT is a diary to be completed every night before going to bed. The instrument was developed with electronic diary administration in mind, and cognitive interviews were conducted using a paper-and-pen booklet and a personal digital assistant (PDA) to describe respondent comprehension of either modality and user acceptance of the PDA.

[0252] Euro Quality of Life-5 Item Questionnaire (EQ-5D) The EQ-5D-5L is a standardized health-related quality of life questionnaire developed by the EuroQol group to provide a simple and common measure of health for clinical and economic assessment. The EQ-5D is designed for self-administration by patients.

[0253] Safety evaluation The same safety assessments were applied to the treatment and placebo groups. Adverse events, including SAEs and adverse events of special interest (AESIs), were collected at all visits.

[0254] A complete physical examination included the skin, nasal passages, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, 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), 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 visits.

[0256] Standard 12-lead electrocardiogram (ECG) recordings were performed on-site. At the randomization visit, an ECG was obtained prior to administration of the investigational drug. PR interval, QT / QTc interval, QRS complex, and heart rate were measured for each ECG, averaging a minimum of three complexes in the appropriate lead (lead II).

[0257] smokers Smoking status was determined for each subject. Smoking habits involved only tobacco (e.g., cigarettes, cigars, pipes). Chewing tobacco or pipe tobacco use was not reported. Subjects who smoked an average of less than one cigarette per day were given a score of "never smoked" and were considered nonsmokers. If a subject smoked an average of less than one cigarette per day during the past seven days, they were given a score of "current smoker." Subjects were given a score of "ex-smoker" if they had previously smoked but had quit at least eight days before the study. Duration of abstinence in the study ranged from approximately 1.2 months to 56.1 years, with a mean of 11.80 years and a median of 9.92 years.

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

[0259] [Table 5]

[0260] Figure 2 presents data related to baseline exacerbation history for the SAR440340-treated and placebo groups. In Figure 2A, data are presented for the number of moderate to severe AECOPD episodes over the past year for both groups. Data for the number of moderate (Figure 2B) and severe (Figure 2C) AECOPD episodes are also presented separately. The data show that both the SAR440340-treated and placebo groups were balanced in terms of exacerbation history.

[0261] Figure 3 shows the relationship between baseline smoking history for the SAR440340-treated and placebo groups. Data relating to the SAR440340-treated and placebo-treated groups are presented in Figure 3A. Data showing the number and percentage of participants who were current and former smokers 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 are presented showing total packs of cigarettes smoked per year (Figure 3C) and years since quitting smoking (Figure 3E) for the SAR440340-treated and placebo groups. The data show that both the SAR440340-treated and placebo groups were balanced in terms of smoking history.

[0262] Figure 4 presents data related to baseline background medications for the SAR440340 treatment and placebo groups. The following combinations of background medications were used: LABA + LAMA, ICS + LAMA, ICS + LABA, and ICS + LABA + LAMA. Data relating to the number of participants in each of the groups receiving ICS-containing background regimens are presented in Figure 4A. Additionally, 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, medium, or high) of participants receiving an ICS-containing background regimen in the SAR440340-treated and placebo groups are also presented in Figure 4C. These data indicate that the majority of patients were receiving an ICS-containing regimen.

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

[0264] Study participant baseline biomarker values ​​for participants receiving SAR440340 or placebo are shown in Table 6 below. The data demonstrate that the SAR440340 and placebo groups were balanced in terms of blood biomarkers at baseline. Study participant baseline biomarker values ​​for former and current smokers are shown in Table 7 below. These results demonstrate that former smokers had a higher mean EOS, more patients with an EOS greater than 250 and fewer patients with an EOS less than 150, a higher mean FeNO (only n=33 had FeNO measured), and lower mean serum IgE levels compared to the current smoker group.

[0265] [Table 6]

[0266] * Baseline pre-BD FeNO for placebo, SAR440340, and all, respectively, N=20, 12, 33. ** Baseline post-BD FeNO for placebo, SAR440340, and all, respectively, N=20, 12, and 33. Circulating biomarker abbreviations: sST2, soluble IL-33 receptor; PARC, lung and activation-regulated chemokine; FeNO, 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 SAR440340 treatment with placebo. The primary efficacy endpoint was the annualized rate of moderate-to-severe AECOPD over the treatment period.

[0269] For the primary efficacy endpoint, AECOPD, treatment differences were assessed using a negative binomial regression model. The model included the total number of events occurring during the treatment period (up to week 52) as the response variable, and treatment group, baseline eosinophil level, and region (combined country) as covariates. The log-transformed observation time was the offset variable. Parameters were estimated using maximum likelihood with the Newton-Raphson algorithm. Comparisons of annual event rates between treatment and placebo groups were performed within this model, and rate ratios and their 95% confidence intervals were estimated. In case of early discontinuation of study drug, a secondary analysis included events up to 14 days after the last dose.

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

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

[0272] Secondary Efficacy Endpoints Time to first moderate to severe AECOPD One secondary efficacy endpoint used in the study was the time to first moderate to severe AECOPD. Time to first moderate or severe AECOPD was analyzed using a Cox regression model with treatment, baseline eosinophil level, and region (combined country) as covariates. The Kaplan-Meier (KM) method was used to assess the probability of first AECOPD at specific time points for each group.

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

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

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

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

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

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

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

[0280] Figure 39 presents graphs of the mean change in pre-BD FEV1 from baseline through weeks 16-24 for both former smokers (Figure 39A) and current smokers (Figure 39B). These results show that among former smokers, SAR440340 treatment improved pre-BD FEV1 by 90 mL. In contrast, there was no improvement in pre-BD FEV1 among current smokers.

[0281] Post-bronchodilator (BD) FEV1 Another secondary efficacy endpoint used in the study was post-BD FEV1. Statistical analysis of the change from baseline to week 24 in post-bronchodilator FEV1 was performed in the same manner as for pre-bronchodilator FEV1. Similar analytical methods were applied to analyze the change from baseline through week 24 in FEV1 (both pre- and post-bronchodilator).

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

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

[0284] Figure 16 shows the graph of the mean change in FEV1 from baseline to weeks 16-24 after BD administration for both the high and low eosinophil groups. showed that SAR440340 treatment showed a trend towards early and sustained improvement in FEV1 after BD administration in the high eosinophil level subgroup.

[0285] Efficacy in smokers: current and former smokers subgroups Tables 8 and 9 show the baseline characteristics of the ever-smoker and current-smoker subgroups. Baseline characteristics were balanced except for FeNO levels, which presented as lower in current smokers. Furthermore, the ever-smoker subgroup had 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 former smokers (Figure 17A) as subgroups. In the former smoker subgroup, SAR440340 reduced annualized moderate-to-severe COPD exacerbations by 42% and improved pre-BD FEV1 by 90 mL. In contrast, there was a 12% increase and no improvement in FEV1 in the current smoker group. Figure 26A shows the unadjusted annualized rate of moderate-to-severe AECOPD compared with the adjusted annualized rate of moderate-to-severe AECOPD for the former smoker subgroup. Figure 26B shows the unadjusted annualized rate of moderate-to-severe AECOPD compared with the adjusted annualized rate of moderate-to-severe AECOPD for the current smoker subgroup. Adjusted and unadjusted annualized rates of moderate to severe AECOPD were presented as described above. The data show that SAR440340 treatment reduced AECOPD by approximately 42% in ever smokers.

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

[0290] Figure 19 shows the change in post-BD FEV1 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 former smokers (Figure 19A) as subgroups. Figure 34 presents this same data in a modified intention-to-treat analysis. The modified intention-to-treat analysis was performed as described above. These data show that SAR440340 treatment improved post-BD FEV1 by approximately 60 mL in former smokers. Ever smokers showed the greatest improvement in percent change in FEV1 both pre- and post-BD. It had good qualities (Figure 64).

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

[0292] The annualized rate of moderate to severe AECOPD events (primary endpoint) was 1.61 in the placebo group and 1.30 in the itepekimab group (relative risk [RR] 0.81; 95% CI [confidence interval] 0.61 to 1.07), and the LS mean change from baseline in pre-bronchodilator FEV1 from weeks 16 to 24 (a key secondary endpoint) was comparable to placebo in the mITT population. The reduction in COPD was 0.00 L with sebo and 0.06 L with itepekimab (LS mean difference, 0.06; 95% CI, 0.01-0.10). The entire benefit in both AECOPD and FEV1 was explained by a more pronounced treatment effect in the ever-smoker subgroup, with no treatment benefit observed in the complementary current-smoker subgroup. The overall AECOPD treatment effect was driven by a pronounced 42.5% reduction in AECOPD vs. placebo in the ever-smoker subgroup (RR, 1.09; 95% CI, 0.74-1.61; HR, 1.15; 95% CI, 0.75-1.77), compared with no effect observed in current smokers (RR, 1.09; 95% CI, 0.74-1.61; HR, 1.15; 95% CI, 0.75-1.77). Similarly, the FEV1 treatment effect was most pronounced in the subgroup of ever smokers (LS mean difference 0.09; 95% CI 0.02-0.15), but not in current smokers.

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

[0294] Figures 38A-38D graphically depict the effect of SAR440340 on blood eosinophil levels. The data show 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. Figure 38D) Presented as percent change.

[0295] Efficacy in moderate vs. severe COPD categories Figure 27A shows data representing the adjusted and unadjusted annualized rates of moderate to severe AECOPD in participants with moderate COPD in both the SAR440340-treated and placebo subgroups. Figure 27B shows data for the adjusted and unadjusted annualized rates of moderate to severe AECOPD in participants with severe COPD in both the SAR440340-treated and placebo subgroups. These results indicate that there were no significant differences in the efficacy of treatment based on COPD classification.

[0296] Figure 31A shows data representing BD pre-dose FEV1 for participants with moderate COPD treated with SAR440340 or placebo. Figure 31B shows data representing BD pre-dose FEV1 for participants with severe COPD treated with SAR440340 or placebo. These results demonstrate that SAR440340 improved BD pre-dose FEV1 in patients with relatively poor lung function.

[0297] Figure 35A shows data representing post-BD FEV1 for participants with moderate COPD treated with SAR440340 or placebo. Figure 35B shows data representing post-BD FEV1 for participants with severe COPD treated with SAR440340 or placebo. These results suggest that SAR440340 significantly improved FEV1 after BD administration. , indicating that FEV1 improved after BD administration in patients with relatively low pulmonary function.

[0298] St. George's Respiratory Questionnaire (SGRQ) Figure 21 shows the SGRQ change from baseline in the combined group of high and low eosinophil subjects treated with SAR440340 or placebo. These results show 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] Biomarkers Figure 23 shows data relating to blood eosinophil levels 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 demonstrate that SAR440340 treatment resulted in a rapid and sustained reduction in blood eosinophils, with a median change of approximately -42%.

[0301] Figure 24 shows data relating to 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 indicate that there was a slight reduction in IgE levels from baseline in the SAR440340-treated group.

[0302] Figure 25 shows data relating to total IL-33 and sST2 levels 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 indicate that there was a significant effect of SAR440340 treatment on IL-33, but no effect on sST2.

[0303] Figures 40A-B depict the mean change in blood eosinophils for ever smokers versus current smokers, respectively. Similar effects were observed in both groups, with a greater effect seen in ever smokers. Figures 41A-B depict the mean change in blood neutrophils for ever smokers versus current smokers, respectively. Figures 42A-B depict the mean change in total IL-33 for ever smokers versus current smokers, respectively. Figures 43A-B depict the mean change in pre-bronchodilator (pre-BD) FeNO for ever smokers versus current smokers, respectively. Figures 44A-B depict the mean change in pre-bronchodilator (post-BD) FeNO for ever smokers versus current smokers, respectively. Ever smokers had the greatest improvement in percent change in FEV1 (see Figures 45A-B).

[0304] FIG. 36 depicts the mean change from baseline in FeNO before and after BD administration, demonstrating that FeNO was reduced.

[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 participants' blood eosinophil levels. SAR440340 reduced moderate to severe exacerbations in COPD patients by 18% (ns, p=0.1647) in the overall population (low and high eosinophils). It improved pre-BD FEV1, with a clear trend towards greater efficacy with higher EOS (110 mL) compared with lower EOS (20 mL), and had a rapid onset of action (4 weeks). The efficacy levels observed in ever smokers were 42% (p=0.0066) and 90 mL (p=0.0072) improvements in both exacerbation reduction and FEV1 improvement, respectively. Collectively, these data suggest that SAR440340 is superior to standard of care (SOC) (dual or triple therapy). These results demonstrate that SAR440340 can independently exert bronchodilatory effects, have a rapid onset of action (primarily in patients with high EOS), and prevent exacerbations in the overall population. These beneficial effects were more pronounced in former smokers, suggesting that the absence of continuous epithelial stress from cigarette smoke allows for a more rapid repair / disease-modifying effect of SAR440340.

[0308] SAR440340 reduced the annualized rate of AECOPD numerically (19% reduction) and improved pre-bronchodilator FEV1 (0.06 L improvement), but did not achieve statistical significance. However, all of the potential benefit in AECOPD reduction and FEV1 improvement could be explained by the more pronounced benefit in the subgroup of ever smokers (45% reduction in AECOPD rate and 0.09 L improvement in FEV1), which represented approximately 55% of the patient population. In contrast, the remaining 45% of patients who were current smokers derive no benefit in terms of either AECOPD rate or FEV1.

[0309] Although subgroup analyses can often be misleading, there are substantial rationale for confidence in these findings. Most importantly, the overall analysis showed strong trends in clinical endpoints, both in terms of AECOPD and FEV1 criteria across all time points, all of which can be explained by more pronounced benefit in large, well-described subgroups, with the remaining patients not benefiting, but without the "negative subset" problem. Furthermore, the consistency of the apparent benefit attributable to ever smokers across all endpoints is highly supportive.

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

[0311] SAR440340 demonstrated an adequate safety profile in patients with moderate to severe COPD. No patients developed anti-drug antibodies (ADAs) after treatment. Overall TEAEs and SAEs were balanced between SAR440340 and placebo in terms of event and severity. The most frequent adverse events (AESIs) of particular note were infections and injection site reactions. Infections were slightly more common in the SAR440340-treated group. There were no serious AESIs.

[0312] [Table 11]

[0313] Table 12 below summarizes the efficacy analysis of SAR440340 across COPD overall and among ever smokers. Table 13 below summarizes the efficacy analysis of SAR440340 across COPD overall and among current smokers. Data are presented for relative rate reduction of exacerbations, pre-BD and post-BD FEV1, and St. George's Respiratory Questionnaire (SGRQ).

[0314] [Table 12]

[0315] [Table 13]

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

[0317] Pharmacokinetic (PK) / Pharmacodynamic (PD) Analysis Preliminary PK / PD analysis revealed that the treatment response observed using FEV1 appeared to be uncoupled from PK changes.

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

[0319] A comparison of PK and FEV1 in the ITT population was performed (Figure 65). PK declined 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 (active treatment minus placebo (SOC)) as mean change in FEV1 from baseline appeared to increase slightly more during follow-up, as the standard of care (SOC) effect diminished over time with placebo. Overall, FEV1 did not follow a direct effect relationship with PK. The offset of effect appeared to be significantly delayed.

[0320] A comparison of EOS and FEV1 was performed in the ITT population (Figure 66). EOS change from baseline showed a trend towards reversion 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 affecting PK. COPD was examined as a covariate only for 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 versus time was modeled using a target-mediated pharmacokinetic (TMDD) approach. All studies were included in the analysis. PopPK predicted PK for each individual was used to drive total IL-33 kinetics. Based on the analysis, a KD of 701 nM (95% CI, 6.2-7.9) was estimated, which yields a threshold structure-activity relationship (SAR) concentration of 9.5 mg / L (95% CI, 8.3-10.5) that satisfies 90% IL-33 binding (this was based on a baseline IL-33 assumption of 1 / 2 lower limit of quantitation (LLOQ)). Based on the calculated threshold, 300 mg Q2W, 300 mg Q4W, and 300 mg It is possible that Q8W can meet the threshold target to achieve 90% target binding.

[0323] conclusion Overall, the population PK modeling results indicate body weight as an important covariate affecting PK. The PD biomarker profile (IL-33) lagged behind the PK profile. FEV1 change and AECOPD were not directly associated with PK during follow-up. had a significant long-term delayed effect.

[0324] Primary and secondary efficacy endpoints Modified intention to treat (mITT) population, 250 mm 3 population with baseline eosinophil levels greater than or equal to 250 mm 3 Results for the population with baseline eosinophil levels below 0.01, former 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 ever smokers (left panel) and current smokers (right panel) is shown in Figure 56. Change from baseline in pre-BD FEV1 in the mITT population is shown in Figure 57. Change from baseline in pre-BD FEV1 in ever smokers in the mITT population is shown in Figure 58. Lung function over time in current smokers as change from baseline in pre-BD FEV1 in current smokers in the mITT population is shown in Figure 59.

[0325] FEV1 results after BD administration at week 24 (mITT, baseline eosinophils <250 or ≥250 mm 3 , former / current smokers) are shown in Figure 60. Lung function over time in the mITT population is shown in Figure 61. Lung function over time in former and current smokers is shown in Figures 62A-62B. Blood eosinophil counts (10 9 The mean changes from baseline in serotonin levels (mg / mL) are shown in Figure 63.

[0326] In this novel trial with variable treatment duration, including patients with both high and low baseline eosinophils, SAR440340 was associated with a lower annualized rate of moderate to severe AECOPD and a longer time to first moderate or severe AECOPD compared with placebo, as well as a small improvement in pre-BD FEV1 from baseline through weeks 16 to 24 in the mITT population. In patients with high baseline blood eosinophil counts, SAR440340 treatment was associated with a small improvement in pre-BD FEV1 from baseline through weeks 16 to 24. In ever-smokers in the mITT population, SAR440340 compared with placebo was associated with a small improvement in the rate of moderate or severe AECOPD and the time to first moderate or severe AECOPD, as well as a small improvement in pre-BD FEV1 from baseline through weeks 16 to 24. These effects were not observed in the current-smoker mITT population.

[0327] SAR440340 was generally well tolerated with an acceptable safety profile. The incidence of TEAEs and SAEs was balanced across the SAR440340 and placebo treatment groups. [Example]

[0328] Genetic association with serum IL-33 protein levels Two independent human genetic studies (including approximately 100,000 subjects in the Geisinger study, including approximately 11,000 individuals with COPD, and approximately 450,000 subjects in the UK Biobank, including approximately 11,000 individuals with COPD) evaluated rare IL33LOF (splice) variants associated with reduced risk of asthma, as well as two common GOF variants in IL33 and its receptor IL1RL1 that have previously been associated with increased asthma risk. After confirming the predicted association with asthma, a similar but weaker association was observed with COPD. The rare LOF variant was associated with a 21% reduction in the odds of COPD (meta-analysis p=0.005) and two common GOF variants were associated with increased odds of COPD individually (meta-analysis p<0.05 for each variant) and overall (trend p=0.0001) (Figure 70), indicating a gene dosage effect, with increasing genetic score of GOF variants increasing COPD risk. These associations supported the evaluation of a role for IL-33 blockade in COPD.

[0329] Total IL-33 concentrations were measured in serum from 437 individuals (53% female) from the Geisinger Health System (GHS) who had previously been genotyped. To increase the power to detect association with rs146597587, samples were enriched for heterozygous carriers (115 in total) relative to the population frequency. IL-33 levels were measured on the Meso Scale. IL-33 levels were measured using an electrochemiluminescence immunoassay from Discovery (MD, USA). The method involved acid treatment of samples to release IL-33 complexed with endogenous binding partners, allowing detection of total IL-33 levels in serum. The assay utilized a biotinylated anti-human IL-33 monoclonal antibody as the capture reagent and recombinant human IL-33 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 serum. Differences in IL-33 levels between homozygous and heterozygous carriers were examined using linear regression, including age, sex, and asthma case-control status as covariates.

[0330] Genetic associations with eosinophil count, asthma, and COPD Genetic analysis of common gain-of-function (GOF) 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 genetically ascertained European ancestry from two previously described studies, the UK Biobank (UKB) and the GHS study.

[0331] UKB research Eosinophil counts (N = 448,848) were normalized using a rank-based inverse normal transformation and examined for association with imputed variants released by UKB using BOLT-LMM v0.4. Age, age 2, sex, age by sex, age 2 by sex, and major components providing information on ancestry were included as covariates. Asthma cases (N = 5) COPD cases (N=11,514) were individuals with (i) a self-reported physician diagnosis (data fields 6152 and 20002) or an ICD10 code for asthma (J45 or J46 in data field 41270 or GP clinical table); and (ii) no COPD (see below), emphysema, or chronic bronchitis (based on data fields 20002, 22128–22130). COPD cases (N=11,514) were individuals with (i) a self-reported physician diagnosis (data fields 6152 and 20002) or an ICD10 code 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 with (i) no asthma, COPD, or other respiratory or allergic conditions based on ICD10 codes and data fields 6152, 20002, 22126–22130; and (ii) FEV1 / FVC >= 0.7 and percent predicted FEV1 >= 0.8, if spirometry data were available. Association analyses were performed using SAIGE v0.6 [Zhou 2018] with the same covariates listed above.

[0332] GHS research Associations between eosinophil counts (N = 100,413) and complementary variants (reference panel: Haplotype Reference Consortium) were examined using BOLT-LMM as described for the UKB study. For individuals with longitudinal data, we analyzed the median of available findings. Association analyses were performed separately for samples genotyped using two different Illumina arrays (OMNI and GSA), and results were combined using inverse variance meta-analysis. Asthma cases (N = 14,829) were defined as individuals with an ICD10 code for asthma but without COPD, and vice versa for COPD cases (N = 10,838). Both analyses Controls (N = 63,665) were individuals who (i) did not have asthma, COPD, or other respiratory or allergic conditions based on ICD10 codes; (ii) were not taking medication for respiratory disease; and (iii) did not have available spirometry data because spirometry tests (regardless of results) have been found to be predictive of respiratory disease. Association analyses were performed using SAIGE.

[0333] Meta-analysis of UKB and GHS studies Association results were combined with inverse variance meta-analysis using 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. Corresponding intercepts from LD score regression were 1.21, 1.15, and 1.02.

[0334] Mendelian randomization analysis The causal effect of interleukin-1 receptor-like 1 (IL-33R, ST2) protein levels on disease risk was assessed 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 splice region), which reduced plasma IL-33R levels 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 Genetics Research To investigate the relationship between IL-33 and COPD, we investigated a rare splice acceptor allele (rs146597587:C, 0.4% frequency in Europeans) that produces a truncated IL-33 isoform that does not bind to the IL-33 receptor, resulting in a 40% reduction in total IL-33 mRNA and a roughly 50% reduction in asthma risk (Smith PLoS Genet. 2017;13(3):e1006659). Heterozygous individuals had a 46% reduction in serum IL-33 protein levels compared with noncarriers (Figure 67A), confirming the reported reduction in peripheral blood eosinophil counts (-0.26 standard deviation [SD] units, -30 cells / µL in the UK Biobank study) (Figure 67B) and protection from asthma (39% risk reduction) (Figure 67C). A meta-analysis including 22,352 COPD cases and 335,065 controls found a 21% reduction in disease risk (odds ratio [OR] = 0.794, 95% CI = 0.676-0.933, P = 0.0049) (Figure 67D).

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

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

[0338] Genetic analysis demonstrated an association between LOF in IL33 and reduced COPD risk, and between GOF (IL33 and IL-33 receptor IL1RL1) variants in the IL-33 pathway and increased risk. In randomized trials with placebo and itepekimab, AECOPD was associated with RRs of 1.61 and 1.30 (relative risk [RR] 0.81; 95% CI 0.01-0.05). The mean (LSM) change in prebronchodilator forced expiratory volume in one second (FEV1) from 16 to 24 weeks was 0.00 L and 0.06 L (LSM difference 0.06 L; 95% CI 0.01 to 0.10). Both AECOPD reduction and FEV1 improvement in the overall population were explained by a more pronounced benefit with itepekimab in ever smokers, with a marginally significant reduction in AECOPD (0.58; 0.39 to 0.85) and improvement in FEV1 (0.09 L; 0.02 to 0.15). Current smokers showed no significant benefit in either worsening (1.09; 0.74 to 1.61) or FEV1.

[0339] Taken together, 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 Study (AERIFY-1) to Evaluate the Efficacy, Safety, and Tolerability of SAR440340 / REGN3500 / Itepekimab (Anti-IL-33 mAb) in Ever-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 study to evaluate the efficacy, safety, and tolerability of two dosing regimens of itepekimab in ever-smoking patients with moderate-to-severe COPD receiving established dual-drug combinations (ICS + LABA or LAMA + LABA) or triple-drug controller therapy (LAMA + LABA + ICS). Study treatments were itepekimab 300 mg every 2 weeks (Q2W), itepekimab 300 mg every 4 weeks (Q4W), or matching placebo administered subcutaneously (SC) for a 52-week treatment period. The study design is depicted graphically in Figure 71.

[0341] The primary efficacy endpoint is the annualized rate of moderate or severe acute exacerbations of COPD (AECOPD) over the 52-week placebo-controlled treatment period. A moderate exacerbation is documented by the investigator and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (such as intramuscular (IM), intravenous (IV), or oral) and / or antibiotics. A severe exacerbation is documented by the investigator and defined as an AECOPD requiring hospitalization, observation in an emergency department / acute care facility for more than 24 hours, or death. For both a moderate and a severe event to be counted as two separate events, the two events must be separated by at least 14 days between any course of systemic corticosteroids / antibiotics or 14 days between discharge and new hospitalization in the case of hospitalization (severe events only).

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

[0343] Randomization was based on country (some countries may be combined into one), screening blood eosinophil count (<300 cells / mm 3 or ≥ 300 cells / mm 3 ), and at baseline The participants will be stratified by controller therapy (double or triple combination). To ensure enrollment according to the intended allocation of controller therapy and eosinophil counts, the number of participants enrolled in each stratification group will be controlled and monitored as follows: Dual controller therapy (ICS+LABA or LAMA+LABA): Approximately 35% of participants Eosinophils ≥ 300 cells / mm 3 Approximately 35% of participants

[0344] The trial period is outlined below: Screening period (3-5 weeks) Randomized investigational new drug (IMP) treatment period (52 weeks) Follow-up period after IMP treatment (20 weeks)

[0345] Participants were receiving SoC controller therapy for COPD for at least 3 months prior to screening (Visit 1A), with a stable dose of controller therapy for ≥1 month prior to screening (Visit 1A) and during the screening period, and remained on their established controller medication for COPD throughout the study period, with the exception of systemic corticosteroids and antibiotics used for AECOPD.

[0346] Participants who meet the inclusion criteria will be randomized (1:1:1) to one of the following IMP treatment arms, administered for 52 weeks: Itepekimab 300 mg administered Q2W as a single subcutaneous (SC) injection Itepekimab 300 mg administered Q4W as a single SC injection with alternating SC injections of matching doses of placebo at 2-week intervals between active IMPs Placebo, administered Q2W as a single SC injection of a matching dose of itepekimab

[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 itepekimab 300 mg Q2W, itepekimab 300 mg Q4W, or a matching placebo dose for itepekimab.

[0348] Intervention group and period It has three arms: Arm A: Itepekimab 300 mg SC Q2W Arm B: Itepekimab 300 mg SC Q4W Arm C: Matched dose placebo SC Q2W

[0349] Participants will be treated for 52 weeks.

[0350] Participant types and disease characteristics: Participants had a physician-diagnosed COPD (based on the GOLD definition) for at least one year.

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

[0352] Participants had moderate to severe COPD and an FEV1 / FVC ratio of ≤0.7 after BD administration. 0 and post-BD FEV1 % predicted ≥ 30% and < 80% at screening (Visit 1A) and baseline / randomization (Visit 2).

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

[0354] Participants will have a participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months of the year prior to screening in participants where other causes of chronic cough (e.g., inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis) are excluded).

[0355] Participants had a documented history of high exacerbation risk, defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to screening (Visit 1A), with at least one exacerbation treated with systemic corticosteroids. At least one exacerbation occurred while the participant was currently receiving their controller therapy. A moderate exacerbation was documented by the investigator and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (IM, V, or oral) and / or antibiotics (however, use of antibiotics alone does not qualify as a moderate exacerbation unless documented evidence is available that antibiotic use was necessary to treat worsening COPD symptoms); a severe exacerbation was documented by the investigator and defined as an AECOPD requiring hospitalization or observation in an emergency department / urgent care facility for >24 hours.

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

[0357] Study intervention: investigational drug Sterile itepekimab or matching dose placebo will be provided in prefilled syringes for SC administration. Each prefilled syringe contains a deliverable volume of 2 mL at an itepekimab concentration of 150 mg / mL or 0 mg / mL. Formulation: 2 mL solution for injection (150 mg / mL) Administration route: Subcutaneous (SC) Dosing regimen: All participants will receive Q2W dosing to maintain blinding. Q4W participants will receive alternating doses of IMP and placebo.

[0358] Non-clinical drug Participants will continue to receive their established controller therapy. Prescription: Dry powder inhaler (DPI), metered dose inhaler (MDI), or nebulizer Route of administration: Oral inhalation for LAMA, LABA, ICS, ICS+LABA, LAMA+LABA, or LAMA+LABA+ICS Dosage regimen: As prescribed

[0359] Relief medications (albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, ipratropium / albuterol) Participants were to receive albuterol / salbutamol, levalbuterol / levosalbutamol, ipratropium, or ipratropium / albutamol as reliever medications as needed during the study. Terol may be administered. Prescription: DPI, MDI, nebulizer Route of administration: oral inhalation, spray Dosage regimen: As needed, as prescribed

[0360] Statistical considerations Primary endpoint The primary analysis of the annualized rate of moderate or severe AECOPD during the 52-week placebo-controlled treatment period will be conducted according to the intention-to-treat principle. The primary estimate is a policy-based estimate. All moderate or severe AECOPD events during the 52-week treatment period will be included, with the observation period extending from randomization to Visit 28 (Week 52). Participants who permanently discontinue IMP will be asked and prompted to return to the clinic for all remaining study visits, and all off-treatment moderate or severe AECOPD events during the planned 52-week treatment period will be 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 date of last contact will be included in the analysis; in this case, the observation period will extend from randomization to the date of last contact. Imputation will not be performed for unobserved events that may occur after study discontinuation and up to Week 52. The annualized rate of moderate or severe AECOPD will be analyzed using a negative binomial regression model. The model included treatment group (placebo, itepekimab 300 mg SC Q2W, itepekimab 300 mg SC Q4W), region (consolidated country), screening eosinophil layer (<300 cells / mm 3 , ≧300 cells / mm 3 ), controller therapy (dual, triple) stratum, baseline disease severity (as % predicted post-bronchodilator FEV1 used as a continuous variable), and total number of severe AECOPD events (0 or ≥ 1) within the year prior to the study, along with total number of moderate or severe AECOPD events occurring during the treatment period (up to 52 weeks) as the response variable.

[0361] The log-transformed observation period will be the offset variable. Treatment comparisons with placebo will be performed using a step-down method to first compare itepekimab 300 mg SC Q2W vs. placebo. Comparisons of itepekimab 300 mg SC Q4W vs. placebo will be performed only if the comparison is statistically significant.

[0362] The estimates compare the rate of moderate or severe AECOPD for participants randomly assigned to itepekima regimen versus placebo, regardless of what treatment the participants actually received or whether the treatment regimen was implemented at all. The estimates evaluate the benefit of a treatment policy or strategy compared to placebo. Estimated annual event rates for each treatment group and their two-sided 95% confidence intervals (CIs) are derived from a negative binomial model. The event rate ratio (RR) for each itepekima regimen versus placebo, along with the corresponding two-sided 95% CI and p-value, are also provided.

[0363] An on-treatment analysis evaluating itepekimab efficacy excluding data measured when participants do not adhere to the protocol treatment regimen will also be conducted and used to estimate the benefit of adhering to itepekimab treatment. This analysis will include only AECOPD events observed during the on-treatment period (from the first dose of IMP to the last dose of IMP + 14 days). Off-treatment events in participants who permanently discontinue treatment will be excluded from the analysis. A negative binomial model will be used, using the same set of covariates specified in the primary analysis. The model will include moderate or severe AECOPD occurring during the on-treatment period as the response variable, and the log-transformed duration of the treatment period will be the offset variable. This approach will define estimates for assessing itepekimab efficacy during on-treatment.

[0364] Secondary endpoints: Change from baseline in pre-BD FEV1 at week 52 The primary analysis of change from baseline in pre-BD FEV1 at week 52 will assess the efficacy of itepekimab on lung function. Change from baseline in pre-BD FEV1 at week 52 will be analyzed using a mixed-effects model with repeated measures (MMRM) approach. The model includes change from baseline in pre-BD FEV1 through week 52 as the response variable and covariates: treatment, age (continuous variable in years), sex, baseline height (continuous variable), region (combined country), screening eosinophil stratum, controller therapy stratum (dual or triple therapy), visit, treatment-by-visit interaction, and baseline pre-BD FEV1 (continuous variable) and baseline pre-BD FEV1-by-visit interaction. Participants who discontinue IMP before week 52 will be asked and prompted to return to the clinic for all remaining study visits, and additional off-treatment pre-BD FEV1 values ​​measured through week 52 will be included in the analysis. For participants who drop out of the study before week 52, pre-BD FEV1 values ​​will be missing after study discontinuation or last contact. Imputation of missing values ​​is not performed in this analysis. This estimate compares the change from baseline in pre-BD FEV1 for participants randomized to the itepekima regimen versus those randomized to the placebo arm, regardless of the treatment the participant actually receives. This estimate assesses the benefit of a treatment policy or strategy compared to placebo.

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

[0366] To assess the treatment effect when participants adhere to prescribed study treatment, on-treatment pre-BD FEV1 measurements will be analyzed using a similar MMRM model as for the primary pre-BD FEV1 analysis, including the same set of covariates and estimation algorithms. The model will include on-treatment change from baseline in pre-BD FEV1 values ​​through week 52 as the response variable. A pre-BD FEV1 value will be considered on-treatment if it is measured on or before the last dose date + 14 days.

[0367] AECOPD Time to first moderate or severe AECOPD will be determined over a 52-week placebo-controlled treatment period. Annualized rate of severe AECOPD will be determined over a 52-week placebo-controlled treatment period. Time to first severe AECOPD will be determined over a 52-week placebo-controlled treatment period. Annualized rate of corticosteroid-treated AECOPD will be determined over a 52-week placebo-controlled treatment period.

[0368] respiratory symptoms Change from baseline in E-RS:COPD (Evaluation of Respiratory Symptoms in COPD) total score will be determined at week 52.

[0369] FEV1 gradient The rate of change in post-BD FEV1(L) from baseline (post-BD FEV1 slope) will be determined after 4 to 12 weeks.

[0370] HRQoL assessed by the SGRQ Change from baseline in the St. George's Respiratory Questionnaire (SGRQ) total score at 52 weeks The proportion of participants with at least a 4-point reduction from baseline in the SGRQ total score will be determined at Week 52.

[0371] Safety and Tolerability The incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and adverse events (AEs) leading to permanent treatment discontinuation will be determined. The incidence of potentially clinically significant laboratory, vital sign, and ECG abnormalities will be determined during the treatment-emergent period.

[0372] Pharmacokinetic (PK) profile Serum functional itepekimab concentrations will be determined from baseline to the end of the study.

[0373] immunogenicity The incidence of treatment-emergent anti-itepekimab antibody responses will be determined throughout the study.

[0374] Tertiary / Exploratory Endpoints: Medical use The number of days per year of healthcare resource utilization will be determined over a 52-week placebo-controlled treatment period.

[0375] Predictors of mortality The annual number of AECOPD-related ER and hospitalization days will be determined. The proportion of participants with a Body Mass Index, Airway Obstruction, Dyspnea, and Exercise Capacity (BODE) index score >1 point reduction (= improvement) will be determined at week 52.

[0376] Pulmonary function The proportion of participants with a pre-BD FEV1 improvement ≥ 100 mL will be determined at Week 52. The proportion of participants with a pre-BD FEV1 improvement ≥ 100 mL will be determined at Week 24.

[0377] Reduced oral corticosteroid and antibiotic use The number of days oral corticosteroids and antibiotics received over a 52-week period will be determined.

[0378] Respiratory vital signs Change from baseline in resting oxygen saturation will be determined at 52 weeks.

[0379] Biomarkers Changes from baseline in blood eosinophil and neutrophil levels will be determined at weeks 4, 8, 12, 24, 36, and 52. Changes from baseline will be 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 Study (AERIFY-2) to Evaluate the Efficacy, Safety, and Tolerability of SAR440340 / REGN3500 / Itepekimab (Anti-IL-33 mAb) in Ever-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 study to evaluate the efficacy, safety, and tolerability of itepekimab in two cohorts. One cohort consists of participants with moderate to severe COPD who are former 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 will receive an established triple combination (LAMA+LABA+ICS) or dual controller therapy (LAMA+LABA or ICS+LABA). The goal of the study in the former smoker cohort is to evaluate the efficacy of the two itepekimab dosing regimens and assess their safety and tolerability. The study treatment for former smokers will be itepekimab 300 mg administered subcutaneously every 2 weeks (Q2W), itepekimab 300 mg administered subcutaneously every 4 weeks (Q4W), or a matching placebo (3 treatment arms) for a 52-week randomized treatment period. Additionally, the study will evaluate the efficacy, safety, and tolerability of the itepekimab 300 mg Q2W dosing regimen compared with a matching placebo in a cohort of current smokers. The study treatment for current smokers will be itepekimab 300 mg Q2W administered subcutaneously for a 52-week randomized treatment period or a matching placebo (2 treatment arms).

[0382] The primary efficacy endpoint is the annualized rate of moderate or severe acute exacerbations of COPD (AECOPD) over a 52-week placebo-controlled treatment period in ever-smokers. A moderate exacerbation is documented by the investigator and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (such as intramuscular (IM), intravenous (IV), or oral) and / or antibiotics. A severe exacerbation is documented by the investigator and defined as an AECOPD requiring hospitalization, observation in an emergency department / acute care facility for more than 24 hours, or death. For both a moderate and a severe event to be counted as two separate events, the two events must be separated by at least 14 days between any course of systemic corticosteroids / antibiotics or 14 days between discharge and new hospitalization in the case of hospitalization (severe events only).

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

[0384] Separate randomizations will be performed for the primary cohort, the ever-smokers cohort, and the secondary cohort, the current smokers cohort.

[0385] In the cohort of former smokers (primary population), participants were randomized to receive itepekimab 300 mg The study population was randomized to receive 100 mg of itepekimab 300 mg Q2W, itepekimab 300 mg Q4W, or matching placebo. The randomized controlled trial consisted of country-specific (some countries may be combined into one) interactive voice response system (IVRS) / interactive web response system (IWRS), screening blood eosinophil count (<300 / mm 3 or ≥ 300 / mm 3 ), and baseline controller therapy (doublet or triplet). The number of participants enrolled in each stratification group will be controlled and monitored as follows: Dual controller therapy (LAMA+LABA or ICS+LABA): Approximately 35% of participants Eosinophils ≥ 300 cells / mm 3 , approximately 35% of participants

[0386] In the current smoker cohort (secondary population), participant randomization (to itepekimab 300 mg Q2W or matching placebo) was performed similarly by country (some countries may be combined into one) (IVRS / IWRS), screening blood eosinophil count (<300 cells / mm 3 or ≥ 300 cells / mm 3 ), and baseline controller therapy (doublet or triplet). The number of participants enrolled in each stratification group will be controlled and monitored as follows: Dual controller therapy (LAMA+LABA or ICS+LABA): Participation Approximately 35% of people Eosinophils ≥ 300 cells / mm3 , approximately 35% of participants

[0387] The trial period is outlined below: Screening period (3-5 weeks) Randomized investigational new drug (IMP) treatment period (52 weeks) Follow-up period after IMP treatment (20 weeks)

[0388] Participants will be receiving SoC controller therapy for COPD for at least 3 months prior to screening (Visit 1A), with a stable dose of controller therapy for ≥1 month prior to screening (Visit 1A) and during the screening period. Participants will remain on their established controller medication for COPD throughout the study period, with the exception of systemic corticosteroids and antibiotics used for AECOPD.

[0389] Ever-smoker participants who meet the eligibility criteria will be randomized (1:1:1) to one of the following IMP treatment arms, administered for 52 weeks: Itepekimab 300 mg administered Q2W as a single subcutaneous (SC) injection Itepekimab 300 mg administered Q4W as a single SC injection with alternating SC injections of matching doses of placebo at 2-week intervals between active IMPs Placebo, administered Q2W as a single SC injection of a matching dose of itepekimab

[0390] Current smoker participants who meet the eligibility criteria will be randomized (1:1) to one of the following IMP treatment arms, administered for 52 weeks: Itepekimab 300 mg administered Q2W as a single subcutaneous (SC) injection Matched dose placebo to itepekimab, administered Q2W as a single SC injection

[0391] Number of participants: An estimated total of 1,170 participants who are former smokers (n=930) or current smokers (n=240) will be enrolled and randomized separately into different cohorts in this Phase 3 study. Approximately 930 former smokers will be randomized 1:1:1 to three treatment arms. Approximately 310 participants will be randomized per arm to receive itepekimab 300 mg Q2W, itepekimab 300 mg Q4W, or a matching placebo. Approximately 240 current smokers will be randomized, with 120 participants in each arm to receive itepekimab 300 mg Q2W or a matching placebo.

[0392] Intervention arm and duration For former smokers, there are three treatment arms: Arm A: Itepekimab 300 mg SC Q2W Arm B: Itepekimab 300 mg SC Q4W Arm C: Matched dose placebo SC Q2W Participants will be treated for 52 weeks.

[0393] For current smokers, there are two treatment arms: Arm A: Itepekimab 300 mg SC Q2W Arm B: Matched dose placebo SC Q2W Participants will be treated for 52 weeks.

[0394] Participant types and disease characteristics: Participants had a physician-diagnosed COPD (based on the GOLD definition) for at least one year. Participants had a smoking history of ≥10 pack-years.

[0395] For ever smokers: Participants report not currently smoking, intending to quit smoking permanently, and having quit smoking ≥ 6 months prior to screening (Visit 1A). Urinary cotinine levels will be tested at screening (Visit 1A) and at each subsequent visit during the study.

[0396] For current smokers: Participants reported that they currently smoke tobacco at the time of screening (Visit 1A) (participants smoked at least one cigarette per day, on average, over the past 7 days) and were not currently participating in or planning to start a smoking cessation intervention at the time of screening (Visit 1A) or during the screening period.

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

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

[0399] Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year preceding screening in participants who excluded other causes of chronic cough (e.g., inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis).

[0400] Participants had a documented history of high exacerbation risk, defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to screening (Visit 1A), with at least one exacerbation treated with systemic corticosteroids. At least one exacerbation occurred while the participant was currently receiving their controller therapy. A moderate exacerbation was documented by the investigator and defined as an acute worsening of respiratory symptoms requiring systemic corticosteroids (IM, IV, or oral) and / or antibiotics (however, use of antibiotics alone does not qualify as a moderate exacerbation unless documented evidence is available that antibiotic use was necessary to treat worsening COPD symptoms); a severe exacerbation was documented by the investigator and defined as an AECOPD requiring hospitalization or observation in an emergency department / urgent care facility for >24 hours.

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

[0402] Study intervention investigational drug Sterile itepekimab or matching dose placebo will be provided in prefilled syringes for SC administration. Each prefilled syringe contains a deliverable volume of 2 mL at an itepekimab concentration of 150 mg / mL (active) or 0 mg / mL (placebo). Formulation: 2 mL solution for injection (150 mg / mL) Administration route: SC Dosing regimen: All participants will receive Q2W dosing to maintain blinding. Ever-smoking participants receiving a Q4W dosing regimen will receive alternating doses of active IMP and placebo Q2W.

[0403] Non-clinical drug Participants will continue to receive their established controller therapy. Prescription: Dry powder inhaler (DPI), metered dose inhaler (MDI), or nebulizer Route of administration: Oral inhalation for LAMA, LABA, ICS, LAMA+LABA, ICS+LABA, or LAMA+LABA+ICS Dosage regimen: As prescribed

[0404] Relief 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, as prescribed

[0405] Statistical considerations Primary endpoint The primary analysis of the annualized rate of moderate or severe AECOPD during the 52-week placebo-controlled treatment period in ever-smokers will be conducted according to the intention-to-treat principle. The primary estimate is a policy-based estimate. All moderate or severe AECOPD events during the 52-week treatment period will be included, with the observation period extending from randomization to Visit 28 (Week 52). Participants who permanently discontinue IMP will be asked and prompted to return to the clinic for all remaining study visits, and all off-treatment moderate or severe AECOPD events during the planned 52-week treatment period will be 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 date of last contact will be included in the analysis; in this case, the observation period will extend from randomization to the date of last contact. Imputation will not be performed for unobserved events that may occur after study discontinuation and up to Week 52. The annualized rate of moderate or severe AECOPD will be analyzed using a negative binomial regression model. The model included treatment group (placebo, itepekimab 300 mg SC Q2W, itepekimab 300 mg SC Q4W), region (combined country), and screening eosinophil layer (<300 cells / mm ) as covariates. 3 , ≧300 cells / mm 3 The response variables included the total number of moderate or severe AECOPD events occurring during the treatment period (up to week 52), along with the controller therapy (dual or triple combination) stratum, baseline disease severity (as % predicted post-bronchodilator (BD) FEV1 used as a continuous variable), and the total number of severe AECOPD events (0 or ≥ 1) within the year prior to the study. The log-transformed observation period served as an offset variable. Treatment comparisons with placebo were performed first using a step-down method to compare itepekimab 300 mg SC Q2W vs. placebo; comparisons of itepekimab 300 mg SC Q4W vs. placebo were performed only if the comparison was statistically significant.

[0406] The estimates compare the rate of moderate or severe AECOPD for participants randomly assigned to itepeximab regimen versus placebo, regardless of what treatment the participant actually received or whether the treatment regimen was ever implemented. The estimates assess the benefit of a treatment policy or strategy compared with placebo. The estimated annual event rates for each treatment group and their two-sided 95% confidence intervals (CIs) are derived from a negative binomial model. The event rate ratio (RR) for each itepekima regimen versus placebo, as well as the corresponding two-sided 95% CI and p-value, are also provided.

[0407] An on-treatment analysis evaluating itepekimab efficacy excluding data measured when participants do not adhere to the protocol treatment regimen will also be conducted and used to estimate the benefit of adhering to itepekimab treatment. This analysis will include only AECOPD events observed during the on-treatment period (from the first dose of IMP to the last dose of IMP + 14 days). Off-treatment events in participants who permanently discontinue treatment will be excluded from the analysis. A negative binomial model will be used, using the same set of covariates specified in the primary analysis. This model will include moderate or severe AECOPD occurring during the on-treatment period as the response variable, with the log-transformed duration of the treatment period as the offset variable. This approach will define estimates for assessing itepekimab efficacy during on-treatment.

[0408] Secondary endpoints: Change from baseline in pre-BD FEV1 at week 52 The primary analysis of change from baseline in pre-BD FEV1 at week 52 will assess the efficacy of itepekimab on lung function in ever-smokers. Change from baseline in pre-BD FEV1 at week 52 will be analyzed using a mixed-effects model with repeated measures (MMRM) approach. The model includes change from baseline in pre-BD FEV1 through week 52 as the response variable and covariates: treatment, age (continuous variable in years), sex, baseline height (continuous variable), region (combined country), screening eosinophil stratum, controller therapy stratum (dual or triple therapy), visit, treatment-by-visit interaction, and baseline pre-BD FEV1 (continuous variable) and baseline pre-BD FEV1-by-visit interaction. Participants who discontinue IMP before week 52 will be asked and prompted to return to the clinic for all remaining study visits, and additional off-treatment pre-BD FEV1 values ​​measured through week 52 will be included in the analysis. For participants who withdraw from the study before week 52, pre-BD FEV1 values ​​will be missing after study discontinuation or last contact. Missing values ​​will not be imputed in this analysis. This estimate compares the change from baseline in pre-BD FEV1 for participants randomized to the itepekima regimen versus those randomized to the placebo arm, regardless of the treatment the participant actually receives. This estimate assesses the benefit of a treatment policy or strategy compared to placebo.

[0409] An unstructured correlation matrix is ​​used to model within-participant error. Parameters are estimated using restricted maximum likelihood with the Newton-Raphson algorithm. Statistical inference for on-treatment comparisons of change from baseline in pre-BD FEV1 at week 52 is derived from mixed-effects models. The least squares (LS) mean change difference from baseline, corresponding 95% CI, and p-value are provided for comparison of each itepeximab regimen versus placebo.

[0410] To assess the treatment effect when participants adhere to prescribed study treatment, on-treatment pre-BD FEV1 measurements will be analyzed using a similar MMRM model as for the primary pre-BD FEV1 analysis, including the same set of covariates and estimation algorithms. The model will include on-treatment change from baseline in pre-BD FEV1 values ​​through week 52 as the response variable. A pre-BD FEV1 value will be considered on-treatment if it is measured on or before the last dose date + 14 days.

[0411] Pulmonary function - former smokers Change from baseline in pre-BD FEV1 will be determined at week 52. Change from baseline in EV1 will be determined at week 52. Change from baseline in pre-BD FEV1 will be determined at week 24.

[0412] AECOPD-Former smokers Time to first moderate or severe AECOPD will be determined over a 52-week placebo-controlled treatment period.

[0413] Severe AECOPD - Former smokers Annualized rates of severe AECOPD will be determined over a 52-week placebo-controlled treatment period. Time to first severe AECOPD will be determined over a 52-week placebo-controlled treatment period.

[0414] Corticosteroid-treated AECOPD - former smokers The annualized rate of corticosteroid-treated AECOPD will be determined over a 52-week placebo-controlled treatment period.

[0415] Respiratory symptoms - former smokers Change from baseline in E-RS:COPD total score will be determined at week 52.

[0416] FEV1 slope - ever smokers The rate of change in post-BD FEV1(L) from baseline (post-BD FEV1 slope) will be determined after 4 to 12 weeks.

[0417] HRQoL assessed by SGRQ - Ever smokers Change from baseline in SGRQ total score will be determined at week 52. The proportion of participants with at least a 4-point reduction from baseline in SGRQ total score will be determined at week 52.

[0418] Safety and Tolerability - Ever Smokers The incidence of TEAEs, AESIs, SAEs, and AEs leading to permanent treatment discontinuation will be determined. The incidence of potentially clinically significant laboratory, vital sign, and ECG abnormalities will be determined during the treatment-emergent period.

[0419] PK profile - former smokers Serum functional itepekimab concentrations will be determined from baseline to the end of the study.

[0420] Immunogenicity - Former smokers The incidence of treatment-emergent anti-itepekimab antibody responses will be determined throughout the study.

[0421] AECOPD-Current Smoker The annualized rate of moderate or severe acute exacerbations of COPD (AECOPD) will be determined over a 52-week placebo-controlled treatment period.

[0422] Pulmonary Function - Current Smokers Change from baseline in pre-BD FEV1 will be determined at 52 weeks.

[0423] Safety and Tolerability - Current Smokers The incidence of TEAEs, AESIs, SAEs, and AEs leading to permanent treatment discontinuation will be determined. The incidence of potentially clinically significant laboratory, vital sign, and treatment-emergent ECG abnormalities will be determined.

[0424] PK Profile - Current Smoker Serum functional itepekimab concentrations will be determined from baseline to the end of the study.

[0425] Immunogenicity - Current Smokers The incidence of treatment-emergent anti-itepekimab antibody responses will be determined throughout the study.

[0426] Tertiary / Exploratory Endpoints: Medical Use - Former Smokers The number of days per year of healthcare resource utilization will be determined over a 52-week placebo-controlled treatment period.

[0427] Predictors of mortality - ever smokers The annual number of AECOPD-related ER and hospitalization days will be determined. The proportion of participants with a BODE index score >1 point reduction (=improvement) will be determined at 52 weeks.

[0428] Pulmonary function - former smokers The proportion of participants with a pre-BD FEV1 improvement ≥ 100 mL will be determined at week 52.

[0429] Reduction of oral corticosteroid and antibiotic use - former smokers The number of days oral corticosteroids and antibiotics received will be determined over a 52-week period.

[0430] Respiratory vital signs - former smokers Change from baseline in resting oxygen saturation will be determined at 52 weeks.

[0431] Biomarkers - Ever Smokers Changes from baseline in blood eosinophil and neutrophil levels will be determined at weeks 4, 8, 12, 24, 36, and 52. Changes from baseline will be 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 - former and current smokers Pharmacogenomic analysis, DNA sampling, and RNA sampling may be performed.

Claims

1. 1. A method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising: The method comprises the step of administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to 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.

2. 10. The method of claim 1, wherein one or more COPD-related parameters are improved in the subject.

3. 3. The method of claim 2, wherein the one or more COPD-related parameters are selected from the group consisting of annualized rate of moderate to severe acute exacerbation of COPD (AECOPD), annualized rate of severe acute exacerbation of COPD (AECOPD), forced expiratory flow in one second (FEV1), peak expiratory flow rate (PEF), forced vital capacity (FVC), forced expiratory flow rate (FEF) 25%-75%, exhaled nitric oxide (FeNO), number or dose of chronic obstructive pulmonary disease (COPD)-relieving medication, number or dose of systemic corticosteroid, number or dose of antibiotic, daily steps, number or dose of oral corticosteroid, resting oxygen saturation, and resting respiratory rate.

4. 4. The method of claim 3, wherein pre-bronchodilator FEV1 is improved in the subject.

5. 4. The method of claim 3, wherein the annualized rate of AECOPD is improved in the subject.

6. 10. The method of claim 1, wherein the subject has an improved score on one or more questionnaires or assessments selected from the group consisting of the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), Exacerbations in Chronic Obstructive Pulmonary Disease Tool (EXACT), Evaluation of Respiratory Symptoms in COPD (E-RS), Body Mass Index, Airway Obstruction, Dyspnea, Exercise Capacity (BODE) index, and Euro Quality of Life-5 Item Questionnaire (EQ-5D).

7. 10. The method of claim 1, wherein the COPD is moderate to severe COPD that is not well controlled with background therapy.

8. 8. The method of claim 7, wherein the background therapy comprises treatment with at least two of the following: a long-acting beta-2 adrenergic agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS).

9. 9. The method of claim 8, wherein the background therapy includes LABA and LAMA.

10. 9. The method of claim 8, wherein the background therapy includes LABA and ICS.

11. 9. The method of claim 8, wherein the background therapy comprises LAMA and ICS.

12. 9. The method of claim 8, wherein the background therapy includes treatment with LABA, LAMA, and ICS.

13. The method of claim 1, wherein 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.

14. The method of claim 13 , wherein 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:

20.

15. 10. The method of claim 1, wherein the subject has a blood eosinophil count of greater than or equal to about 250 cells per μL or less than 250 cells per μL prior to treatment.

16. 16. The method of claim 15, wherein the subject has a blood eosinophil count of greater than or equal to about 250 cells per μl prior to treatment.

17. 10. The method of claim 1, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μL or less than 300 cells per μL prior to treatment.

18. 16. The method of claim 15, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl prior to treatment.

19. 19. The method of claim 16 or 18, wherein pre-bronchodilator FEV1 and / or post-bronchodilator FEV1 are improved.

20. 19. The method of claim 16 or 18, wherein post-bronchodilator FVC is improved.

21. 20. The method of claim 1, 16 or 18, wherein the subject is a current smoker, former smoker or non-smoker.

22. 22. The method of claim 21, wherein the subject is an ex-smoker, optionally an ex-smoker with a smoking history of greater than or equal to 10 pack-years, has quit smoking for at least 6 months, and / or intends to quit smoking permanently.

23. 23. The method of claim 22, wherein the annual rate of moderate to severe AECOPD events is reduced in the subject.

24. 23. The method of claim 22, wherein the time to first moderate to severe AECOPD event is reduced.

25. 23. The method of claim 22, wherein pre-bronchodilator FEV1 and / or post-bronchodilator FEV1 are improved.

26. 23. The method of claim 22, wherein post-bronchodilator FVC is improved.

27. 23. The method of claim 22, wherein the rate of decline in FEV1 is reduced.

28. 23. The method of claim 22, wherein lung function is maintained or lung function decline is reduced.

29. 10. The method of claim 1, wherein blood eosinophil levels are reduced.

30. 10. The method of claim 1, wherein 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.

31. 31. The method of claim 30, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

32. 32. The method of claim 1 or 31, wherein the antibody or antigen-binding fragment thereof is administered every week (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).

33. 31. The method of claim 30, wherein the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

34. 31. The method of claim 30, wherein the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

35. 35. The method of claim 33 or 34, wherein the pre-bronchodilator FEV1 is improved within 4 weeks of the first administration of the antibody or antigen-binding fragment thereof and / or the FEV1 is maintained during treatment.

36. 35. The method of claim 33 or 34, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

37. 37. The method of claim 36, wherein the antibody or antigen-binding fragment thereof is administered as two injections.

38. 38. The method of claim 36 or 37, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, a needle and syringe, or a pen delivery device.

39. 1. A method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising: an initial dose 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 administering to the subject one or more subsequent doses of about 300 mg of the antibody or antigen-binding fragment thereof.

40. 37. The method of claim 36, wherein 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.

41. 1. A method for treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising: 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 The method comprises administering to a subject.

42. 1. A method for treating moderate to severe chronic obstructive pulmonary disease (COPD) in a subject in need thereof, comprising: 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 The method comprises administering to a subject.

43. 43. The method of claim 39, 41 or 42, wherein one or more COPD-related parameters are improved in the subject.

44. 44. The method of claim 43, wherein the one or more chronic obstructive pulmonary disease (COPD) related parameters are selected from the group consisting of annualized rate of moderate to severe acute exacerbation of COPD (AECOPD), forced expiratory volume in one second (FEV1), rate of decline in FEV1, peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, exhaled nitric oxide (FeNO), number or dose of COPD-relieving medication, number or dose of systemic corticosteroid, and number or dose of antibiotic.

45. 45. The method of claim 44, wherein the pre-bronchodilator FEV1 is improved.

46. 45. The method of claim 44, wherein the annual rate of moderate to severe acute exacerbations of COPD (AECOPD) is reduced in the subject.

47. 47. The method of any one of claims 1 to 46, wherein at least two additional therapeutic agents are administered to the subject.

48. 48. The method of claim 47, wherein the at least two additional therapeutic agents are selected from the group consisting of a long-acting beta-2 adrenergic agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS).

49. 49. The method of claim 48, wherein the at least two additional therapeutic agents comprise a LABA and an ICS.

50. 49. The method of claim 48, wherein the at least two additional therapeutic agents comprise a LAMA and an ICS.

51. 48. The method of claim 47, wherein all three additional therapeutic agents comprising a LABA, a LAMA, and an ICS are administered to the subject.

52. 1. A method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering an initial dose of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33), and the antibody or antigen-binding fragment 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 administering to the subject one or more subsequent doses of about 300 mg of the antibody or antigen-binding fragment thereof.

53. 53. The method of claim 52, wherein 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.

54. 1. A method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering to a subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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; One or more subsequent doses of about 300 mg of the antibody administered subcutaneously every two weeks The method comprises administering to a subject.

55. 1. A method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering to a subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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; One or more subsequent doses of about 300 mg of the antibody administered subcutaneously every two weeks to a subject who is a former smoker.

56. 1. A method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering to a subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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; One or more subsequent doses of about 300 mg of the antibody administered subcutaneously every four weeks The method comprises administering to a subject.

57. 1. A method for reducing the annual rate of moderate to severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a subject with moderate to severe chronic obstructive pulmonary disease (COPD), comprising administering to a subject an initial dose of about 300 mg of an antibody that specifically binds interleukin-33 (IL-33), the antibody comprising 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; One or more subsequent doses of about 300 mg of the antibody administered subcutaneously every four weeks to a subject who is a former smoker.

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