Methods for treating chronic obstructive pulmonary disease in enhanced patient population using benralizumab

Abstract

To provide methods of treating chronic obstructive pulmonary disease (COPD).SOLUTION: A method of treating chronic obstructive pulmonary disease (COPD) in a human COPD patient is provided, the method comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient: (a) has a blood eosinophil count of at least 300 eosinophils / μL, (b) has experienced two or more prior exacerbations in the year prior to administration, and (c) is on triple background therapy comprising inhaled corticosteroid (ICS), long-acting β agonist (LABA), and long-acting muscarinic antagonist (LAMA).SELECTED DRAWING: None

Description

Technical Field

[0001] Sequence Listing This application is electronically submitted in ASCII format and includes a Sequence Listing that is incorporated herein by reference in its entirety. The name of the above ASCII copy created on March 26, 2020, is IL5R-607-WO-PCT_SL.txt, and its size is 16,008 bytes.

Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a serious cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is on the rise in prevalence and is predicted to be the third leading cause of death and disability worldwide by 2020. The cost to society for treating COPD is high, accounting for approximately 3.4% of the total healthcare budget of the European Union. In the United States, the direct and indirect costs of COPD are estimated to exceed $30 billion.

[0003] Approximately 30% of patients with COPD have elevated levels of airway eosinophils, as measured by sputum induction or bronchoalveolar lavage. In COPD, the response to oral and inhaled corticosteroids (ICS) is related to the intensity of airway eosinophilic inflammation, and an increase in sputum eosinophils of more than 3% has been demonstrated to be a good predictor of response to steroids in COPD.

[0004] The strategy of increasing therapy with corticosteroids to control sputum eosinophilia exceeding 3% in COPD has led to a reduction in the frequency of severe COPD exacerbations requiring hospitalization when patients progress to oral corticosteroid therapy. The standard therapy for acute exacerbations of COPD (AECOPD) includes treatment of inflammation with systemic corticosteroids, which leads to a shortening of the length of hospitalization and acceleration of recovery. Corticosteroids cause early apoptosis of eosinophils and generally result in a reduction in eosinophilia. However, long-term therapy with corticosteroids is associated with serious side effects such as hypothalamic-pituitary-adrenal axis suppression and osteoporosis, and corticosteroids do not prevent exacerbations in all eosinophilic COPD patients.

[0005] COPD patients with increased sputum eosinophil counts have been shown to have significant improvement in the forced expiratory volume in 1 second (FEV1) and quality of life scores associated with a decrease in sputum eosinophil counts and eosinophil cationic protein (ECP) levels. Therefore, therapies that specifically target eosinophils in COPD may have beneficial effects.

[0006] Benralizumab is a humanized afucosylated monoclonal antibody (mAb) that specifically binds to the alpha chain of the human interleukin-5 receptor alpha (IL-5Rα) expressed on eosinophils. Benralizumab induces apoptosis of these cells via antibody-dependent cell-mediated cytotoxicity.

[0007] Therefore, considering the strong unmet need to treat COPD without corticosteroid-induced side effects and the fact that some patients with COPD have an eosinophilic component, the effect of benralizumab on COPD in an adult population was examined. Summary of the Invention Means for Solving the Problems

[0008] Methods for treating chronic obstructive pulmonary disease (COPD) in human COPD patients are provided herein.

[0009] In certain embodiments, a method for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering to the COPD patient a 100 mg dose of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced two or more pre-exacerbations in the year prior to administration, and (c) is receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0010] In certain embodiments, a method for reducing the annual exacerbation rate of COPD, comprising administering to a human COPD patient a 100 mg dose of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced two or more pre-exacerbations in the year prior to administration, and (c) is receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein. In certain embodiments, a method for reducing the annual exacerbation rate of severe or very severe COPD, comprising administering to a human COPD patient a 100 mg dose of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced two or more pre-exacerbations in the year prior to administration, and (c) is receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0011] In certain embodiments, a method of increasing the forced expiratory volume in one second (FEV1) in a human patient with chronic obstructive pulmonary disease (COPD), the method comprising administering a 100 mg dose of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, and (c) been receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0012] In certain embodiments, a method of increasing the forced vital capacity (FVC) in a human patient with chronic obstructive pulmonary disease (COPD), the method comprising administering to the patient a 100 mg dose of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, and (c) been receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0013] In some embodiments, the patient has a history of two or three or more exacerbations in the year prior to administration of benralizumab or an antigen-binding fragment thereof.

[0014] In some embodiments, a patient receiving benralizumab is being co-treated with triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0015] In some embodiments, patients receiving benralizumab are not currently being treated with triple background therapy, which includes inhaled corticosteroids (ICS), long-acting β-agonists (LABA), and long-acting muscarinic antagonists (LAMA).

[0016] In some embodiments, the patient has a blood eosinophil count of at least 300 eosinophils / μL prior to administration. In some embodiments, the patient has a blood eosinophil count of 300 - 450 eosinophils / μL prior to administration. In certain aspects, the patient has a blood eosinophil count of greater than 400 eosinophils / μL prior to administration. In certain aspects, the patient has a blood eosinophil count of greater than 450 eosinophils / μL prior to administration. In some aspects, the patient has a blood eosinophil count of greater than 500 eosinophils / μL prior to administration.

[0017] In some embodiments, the patient has moderate, severe, or very severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). In some embodiments, the patient has severe COPD as defined by GOLD. In other embodiments, the patient has very severe COPD as defined by GOLD.

[0018] In some embodiments, administration reduces the exacerbation rate of COPD. In some embodiments, the exacerbation rate is reduced by at least 20% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%). In some embodiments, the exacerbation rate is reduced within one year from the first administration of benralizumab or its antigen-binding fragment. In some embodiments, the exacerbation rate is reduced within six months from the first administration of benralizumab or its antigen-binding fragment.

[0019] In some embodiments, the patient had a post-bronchodilator FEV1 that was 80% or less (e.g., 70% or less, or 65% or less) of the predicted normal value prior to administration of benralizumab or its antigen-binding fragment.

[0020] In some embodiments, administration increases the patient's FEV1. In certain aspects, the increased FEV1 is the pre - bronchodilator FEV1. In some embodiments, the pre - bronchodilator FEV1 increases by at least 10%. In some embodiments, the pre - bronchodilator FEV1 increases by about 12%. In some embodiments, the increase in FEV1 is the post - bronchodilator FEV1. In some embodiments, the post - bronchodilator FEV1 increases by at least 5%. In certain aspects, the post - bronchodilator FEV1 increases by about 7%. In some embodiments, both the pre - bronchodilator FEV1 and the post - bronchodilator FEV1 increase. In some embodiments, the FEV1 increases within 1 year from the first administration of benralizumab or an antigen - binding fragment thereof.

[0021] In some embodiments, administration increases the patient's FVC. In certain aspects, the increase in FVC is the pre - bronchodilator FVC. In some embodiments, the increase in FVC is the post - bronchodilator FVC. In some embodiments, both the pre - bronchodilator FVC and the post - bronchodilator FVC increase. In some embodiments, the FVC increases by at least 3%. In some embodiments, the FVC increases within 1 year from the first administration of benralizumab or an antigen - binding fragment thereof.

[0022] In some embodiments, administration improves the COPD questionnaire score that assesses COPD symptoms. In certain aspects, the COPD questionnaire is the COPD - specific St. George's Respiratory Questionnaire (SGRQ - C). In certain aspects, the patient's SGRQ - C (symptom) score decreases by at least 5. In certain aspects, the patient's SGRQ - C (symptom) score decreases by at least 7.

[0023] In some embodiments, the patient had an FEV1 / forced vital capacity (FVC) of less than 0.70 before administration of benralizumab or an antigen - binding fragment thereof.

[0024] In some embodiments, at least two doses of benralizumab or an antigen-binding fragment thereof are administered. In some embodiments, a first dose of benralizumab or an antigen-binding fragment thereof is administered on day 0, and a second dose is administered at week 4. In some embodiments, at least one dose of benralizumab or an antigen-binding fragment thereof is administered at an interval of 8 weeks after the previous dose. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at least once at a dosing interval of 4 weeks, and then at least once at a dosing interval of 8 weeks. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at three dosing intervals of 4 weeks, and then at an 8-week dosing interval.

[0025] In some embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks to once every 12 weeks. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 8 weeks. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks for 12 weeks and then once every 8 weeks.

[0026] In some embodiments, the administration is subcutaneous administration.

[0027] In certain aspects, a method of treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, the method comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced three or more exacerbations in the year prior to administration, and (c) is receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) is described herein.

[0028] In certain embodiments, a method of reducing the exacerbation rate of chronic obstructive pulmonary disease (COPD) in human COPD patients, the method comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced three or more prior exacerbations in the year prior to administration, and (c) been receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0029] In certain embodiments, a method of increasing the forced expiratory volume in one second (FEV1) in human chronic obstructive pulmonary disease (COPD) patients, the method comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced three or more prior exacerbations in the year prior to administration, and (c) been receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein.

[0030] In certain embodiments, a method of increasing the forced vital capacity (FVC) in human chronic obstructive pulmonary disease (COPD) patients, the method comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) experienced three or more prior exacerbations in the year prior to administration, and (c) been receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), is described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0031]

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DETAILED DESCRIPTION OF THE INVENTION

[0032] This disclosure describes a novel study population identified based on the findings of GALATHEA and TERRANOVA and the clinical phase 3 trials of benralizumab in patients with moderate to very severe COPD, as described in Examples 1 and 2. Subgroup analyses of GALATHEA and TERRANOVA consistently identified patients with a history of more frequent exacerbations and patients receiving triple background therapy as being most likely to respond to 100 mg of benralizumab treatment. In particular, the results of the subgroup analyses are as follows: - Compared to placebo, 100 mg of benralizumab reduced the annual exacerbation rate of severe COPD by more than 30%. - Patients receiving triple (ICS / LABA / LAMA) background therapy (approximately 70% and 60% of the patients in GALATHEA and TERRANOVA, respectively) showed a consistent treatment effect on the annual COPD exacerbation rate with 100 mg of benralizumab in both studies. With 100 mg of benralizumab, GALATHEA showed an 18% reduction in AER compared to placebo in patients receiving triple background therapy. With 100 mg of benralizumab, TERRANOVA showed a 17% reduction in AER in patients receiving triple background therapy, compared to a 7% reduction in AER in the overall population. - In the year before the administration of benralizumab, patients with more frequent exacerbations (more than 3 times vs. 2 times or less) had a greater treatment effect on the annual exacerbation rate of COPD and the annual exacerbation rate of severe COPD with 100 mg of benralizumab. However, patients with 2 or fewer exacerbations in the year before administration still experienced the effect of benralizumab therapy. - In patients with a baseline blood eosinophil count of less than 220 cells / μL, no treatment effect on the annual exacerbation rate of COPD was observed.

[0033] The findings in these subgroups were consistent throughout the study and were supported by a pooled analysis. In summary, these characteristics identify the patients most likely to benefit from benralizumab treatment.

[0034] It should be noted that entities preceded by the term "a" or "an" refer to one or more of those entities. For example, "anti-IL-5α antibody" is understood to mean one or more anti-IL-5α antibodies. In such cases, "a" (or "an"), "one or more", and "at least one" may be used interchangeably herein.

[0035] Methods for treating chronic obstructive pulmonary disease (COPD) are provided herein. The provided methods include administering an effective amount of benralizumab or an antigen-binding fragment thereof.

[0036] Information regarding the use of the anti-CD20 antibody rituximab (or fragments thereof) in the methods provided herein can be found, for example, in US Patent Application Publication No. 2010 / 0291073A1, the disclosure of which is incorporated herein by reference in its entirety. The rituximab and antigen-binding fragments thereof for use in the methods provided herein include a heavy and light chain or a heavy chain variable region and a light chain variable region. In a further aspect, the rituximab or antigen-binding fragment thereof for use in the methods provided herein includes any one of the amino acid sequences of SEQ ID NOs: 1-4. In a specific aspect, the rituximab or antigen-binding fragment thereof for use in the methods provided herein includes a light chain variable region having the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 3. In a specific aspect, the rituximab or antigen-binding fragment thereof for use in the methods provided herein includes a light chain having the amino acid sequence of SEQ ID NO: 2 and a heavy chain having the amino acid sequence of SEQ ID NO: 4. In a specific aspect, the rituximab or antigen-binding fragment thereof for use in the methods provided herein includes a heavy chain variable region and a light chain variable region, the heavy chain variable region including CDR1, CDR2, and CDR3 sequences defined by Kabat of SEQ ID NOs: 7-9, and the light chain variable region including CDR1, CDR2, and CDR3 sequences defined by Kabat of SEQ ID NOs: 10-12. One of ordinary skill in the art will be able to readily identify CDRs defined by Chothia, Abm, or others. In a specific aspect, the rituximab or antigen-binding fragment thereof for use in the methods provided herein includes the variable heavy and variable light chain CDR sequences of the KM1259 antibody disclosed in US Patent No. 6,018,032, which is incorporated herein by reference in its entirety.

[0037] An acute exacerbation of COPD (AECOPD) is an acute onset, persistent worsening of a patient's condition from a stable state that exceeds normal daily variations and requires a change in the usual medication regimen in a patient with underlying COPD.

[0038] In certain embodiments, patients presenting at a clinic or emergency department (ED) with COPD are administered benralizumab or an antigen-binding fragment thereof. Given benralizumab's ability to reduce or eliminate eosinophil counts for up to 12 weeks or more (see U.S. Patent Application Publication No. 2010 / 0291073), benralizumab or an antigen-binding fragment thereof may be administered only once or only rarely while still providing benefit to the patient. In further embodiments, the patient is administered a follow-on dose. The follow-on dose may be administered at various time intervals depending on the patient's age, weight, ability to follow physician instructions, clinical evaluation, eosinophil count (blood or sputum eosinophils or eosinophil cationic protein (ECP) measurements), or other factors including the judgment of the treating physician. The dosing interval can be every 4 weeks, every 5 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, or at longer intervals. In certain embodiments, the dosing interval can be every 4 weeks or every 8 weeks. In certain embodiments, the dosing interval can be every 4 weeks and every 8 weeks. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered at three 4-week dosing intervals (i.e., on days 0, 4, and 8), and then at 8-week dosing intervals (i.e., on weeks 16, 24, 32, etc.). In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks for 12 weeks. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks for 12 weeks and then once every 8 weeks.

[0039] In certain embodiments, a single or first dose is administered to a COPD patient immediately following an acute exacerbation, such as a mild, moderate, or severe exacerbation. For example, a single or first dose of benralizumab or an antigen-binding fragment thereof is administered within 1, 2, 3, 4, 5, 6, 7 days or more, e.g., within 7 days, of the acute exacerbation while the patient is present at a clinic or hospital visit, or in the case of a very severe exacerbation, and can stabilize the patient's symptoms prior to administration of benralizumab.

[0040] In some embodiments, at least two doses of benralizumab or an antigen-binding fragment thereof are administered to a patient. In some embodiments, at least three doses, at least four doses, at least five doses, at least six doses, or at least seven doses are administered to a patient. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered over a course of 4 weeks, over a course of 8 weeks, over a course of 12 weeks, over a course of 24 weeks, over a course of 48 weeks, or over a course of more than 1 year.

[0041] The amount of benralizumab or an antigen-binding fragment thereof administered to a patient can depend on various parameters such as the patient's age, weight, clinical evaluation, eosinophil count (blood or sputum eosinophils, eosinophil cationic protein (ECP) measurement, or eosinophil-derived neurotoxin (EDN) measurement), or other factors including the judgment of the attending physician. In certain embodiments, the dosage or dosing interval is not eosinophil-level dependent.

[0042] In certain embodiments, a patient is administered one or more doses of benralizumab or an antigen-binding fragment thereof, and the dose is about 100 mg.

[0043] In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof by the methods provided herein is via parenteral administration. For example, benralizumab or an antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection. In certain embodiments, benralizumab or an antigen-binding fragment thereof can be administered by subcutaneous injection.

[0044] In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered by the methods provided herein in combination with or concurrently with additional therapies. Such therapies include, without limitation, corticosteroid therapies (including inhaled corticosteroids (ICS)), long-acting β-agonists (LABA, including long-acting β2-agonists), long-acting muscarinic antagonists (LAMA, including tiotropium), or other standard therapies. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered by the methods provided herein in combination with or concurrently with ICS and LABA, LABA and LAMA, or ICS, LABA, and LAMA. In certain embodiments, "triple background therapy" means ICS, LABA, and LAMA.

[0045] In certain cases, administration of benralizumab or an antigen-binding fragment thereof reduces COPD exacerbations, including those measured by, for example, exacerbation rate, annual exacerbation rate, time to first exacerbation, and / or annual rate of COPD exacerbations associated with emergency room visits or hospitalizations.

[0046] The methods provided herein can reduce the exacerbation rate in COPD patients. In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or antigen-binding fragments thereof, reduces the number of exacerbations experienced by a patient as compared to the expected number of exacerbations based on the patient's medical history, as compared to the mean expected number of exacerbations in an equivalent population of patients, or as compared to an equivalent population treated with placebo over the same period. In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients having an eosinophil count of at least 300 eosinophils / μL prior to administration. In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients having an eosinophil count of at least 400 eosinophils / μL prior to administration. In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients having severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Revised 2018). In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients having very severe COPD as defined by GOLD. In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients having severe or very severe COPD as defined by GOLD. In certain embodiments, the administration of benralizumab or antigen-binding fragments thereof reduces the number of exacerbations in COPD patients receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting β-agonists (LABA) (e.g., long-acting β2-agonists), and long-acting muscarinic antagonists (LAMA) (e.g., including tiotropium)).

[0047] In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof decreases the number of exacerbations of COPD (e.g., decreases the annual exacerbation rate) in patients who have experienced two or more prior exacerbations in the year prior to administration. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof decreases the number of exacerbations of COPD (e.g., decreases the annual exacerbation rate) in patients who have experienced three or more prior exacerbations in the year prior to administration. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof decreases the number of severe exacerbations of COPD (e.g., decreases the annual severe exacerbation rate) in patients who have experienced three or more prior exacerbations in the year prior to administration.

[0048] In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof decreases the number of exacerbations of COPD (e.g., decreases the annual exacerbation rate) in COPD patients who exhibit the following characteristics prior to administration: a) have an eosinophil count in the blood of 300 eosinophils / μL or more, b) have experienced two or more prior exacerbations in the year prior to administration, and c) are receiving triple background therapy that includes an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA) (e.g., a long-acting β2-agonist), and a long-acting muscarinic antagonist (LAMA) (e.g., including tiotropium). In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof decreases the number of exacerbations of COPD (e.g., decreases the annual exacerbation rate) in COPD patients who exhibit the following characteristics prior to administration: a) have an eosinophil count in the blood of 300 eosinophils / μL or more, b) have experienced three or more prior exacerbations in the year prior to administration, and c) are receiving triple background therapy that includes an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA) (e.g., a long-acting β2-agonist), and a long-acting muscarinic antagonist (LAMA) (e.g., including tiotropium).

[0049] In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof treats chronic obstructive pulmonary disease (COPD) in patients who, prior to administration, exhibit the following characteristics: (a) have an eosinophil count in the blood of 300 eosinophils / μL or greater, (b) have experienced three or more pre-exacerbations in the year prior to administration, (c) have received triple background therapy including inhaled corticosteroid (ICS), long-acting β-agonist (LABA), and long-acting muscarinic antagonist (LAMA), and after administering 100 mg of benralizumab once every four weeks for 12 weeks and then once every eight weeks, the patient no longer receives triple background therapy. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof treats chronic obstructive pulmonary disease (COPD) in patients who, prior to administration, exhibit the following characteristics: (a) have an eosinophil count in the blood of 300 eosinophils / μL or greater, (b) have experienced two or more pre-exacerbations in the year prior to administration, (c) have received triple background therapy including inhaled corticosteroid (ICS), long-acting β-agonist (LABA), and long-acting muscarinic antagonist (LAMA), and after administering 100 mg of benralizumab once every four weeks for 12 weeks and then once every eight weeks, the patient no longer receives triple background therapy.

[0050] In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces exacerbation by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55%, or at least 60%. In some embodiments, exacerbation is reduced by about 17% or about 18%. In some embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces severe exacerbation by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55%, or at least 60%. In some embodiments, severe exacerbation is reduced by about 32% or about 43%. Exacerbation (moderate or severe) can be reduced, for example, within 1 year from the first administration of benralizumab or an antigen-binding fragment thereof. In one embodiment, exacerbation (moderate or severe) can be reduced within 6 months from the first administration of benralizumab or an antigen-binding fragment thereof.

[0051] In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces the exacerbation rate in COPD (e.g., moderate or severe) within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, or within 52 weeks (e.g., reduces the annual exacerbation rate).

[0052] The methods provided herein can also reduce the exacerbation rate of COPD (e.g., reduce the annual exacerbation rate) by, for example, at least 20%, at least 30%, at least 50%, or at least 60% in patients having an eosinophil count of 300 eosinophils / μL or more prior to administration.

[0053] The methods provided herein can also reduce the exacerbation rate (e.g., reduce the annual exacerbation rate) in COPD patients having severe or very severe COPD (as defined by GOLD), for example, by at least 40%, at least 50%, at least 60%, or at least 70%.

[0054] As used herein, the terms "annual exacerbation rates", "annualized exacerbation rate", "rate of exacerbation", or "rate of annual exacerbation" are used interchangeably. The methods provided herein can reduce the annual exacerbation rate in patients with moderate to very severe COPD. When determining the annual COPD exacerbation rate, a COPD exacerbation is defined as a symptomatic worsening of COPD that requires: Use of systemic corticosteroids for at least 3 days (the dose of a single depot injection of corticosteroid is considered equivalent to a 3-day course of systemic corticosteroids; and / or Use of antibiotics; and / or Hospitalization for treatment of COPD.

[0055] The methods provided herein can shorten the time to the first COPD exacerbation after the first administration of benralizumab or an antigen-binding fragment thereof as compared to after the first administration of placebo.

[0056] In some cases, administration of benralizumab or an antigen-binding fragment thereof reduces the likelihood of a COPD exacerbation (e.g., within 52 weeks of the first administration of benralizumab or an antigen-binding fragment thereof) as compared to the likelihood of a COPD exacerbation after treatment with placebo.

[0057] In some cases, administration of benralizumab or an antigen-binding fragment thereof reduces the annual rate of COPD exacerbations associated with emergency room visits or hospitalizations as compared to administration of placebo.

[0058] In certain cases, administration of benralizumab or an antigen-binding fragment thereof improves lung function in patients with COPD, as measured, for example, by forced expiratory volume in 1 second (FEV1) or forced vital capacity.

[0059] The methods provided herein can increase the forced expiratory volume in 1 second (FEV1) in patients with COPD. The increase can be measured based on the FEV1 predicted from a large patient population, based on the FEV1 measured in a control population, or based on the FEV1 of an individual patient prior to administration. In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, can increase FEV1 compared to the patient's baseline FEV1. In some embodiments, the increase in FEV1 is the FEV1 before bronchodilator. In some embodiments, the increase in FEV1 is the FEV1 after bronchodilator. In some embodiments, the increase in FEV1 is the FEV1 before bronchodilator and the FEV1 after bronchodilator. The FEV1 (e.g., the FEV1 before and / or after bronchodilator) can be increased, for example, within 1 year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0060] As used herein, "bronchodilator" refers to any agent that facilitates breathing by widening or dilating the bronchi, bronchioles, or airways of the lungs, reducing the resistance of the respiratory airways, and / or relaxing the bronchial smooth muscle. For example, bronchodilators include short- and long-acting β2 agonists such as albuterol / salbutamol and other agents commonly used to treat asthma.

[0061] In some embodiments, the patient had an FEV1 after bronchodilator that was 80% or less (e.g., 70% or less or 65% or less) of the predicted normal value before administration of benralizumab or an antigen-binding fragment thereof.

[0062] In certain embodiments, the methods provided herein can increase FEV1 by at least 5% or at least 10%. In certain embodiments, the methods provided herein can increase FEV1 by about 12%. In certain embodiments, the methods provided herein can increase FEV1 before bronchodilator by at least 5% or at least 10%. In certain embodiments, the methods provided herein can increase FEV1 before bronchodilator by about 12%.

[0063] In certain embodiments, the methods provided herein can increase FEV1 by at least 5%. In certain embodiments, the methods provided herein can increase FEV1 by about 7%. In certain embodiments, the methods provided herein can increase FEV1 after bronchodilator by at least 5%. In certain embodiments, the methods provided herein can increase FEV1 after bronchodilator by about 7%.

[0064] In certain embodiments, the methods provided herein can increase FEV1 before and after bronchodilator by at least 5%. In certain embodiments, the methods provided herein can increase FEV1 before bronchodilator by at least 10% and FEV1 after bronchodilator by at least 5%. In certain embodiments, the methods provided herein can increase FEV1 before bronchodilator by about 12% and FEV1 after bronchodilator by about 7%.

[0065] As provided herein, administration of benralizumab or an antigen-binding fragment thereof can also increase the predicted FEV1 percentage in COPD patients, for example, before and / or after bronchodilator. By way of example, the predicted FEV1 percentage can be increased by about 3.0, about 3.5, about 4.0, or about 4.5.

[0066] The methods provided herein can increase FEV1 in COPD patients having a blood eosinophil count of at least 300 eosinophils / μL, and / or in patients receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting β-agonists (LABA) (e.g., long-acting β2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium)), and / or in patients who have experienced two or more or three or more pre-exacerbations in the year prior to administration. In certain embodiments, the methods provided herein can increase FEV1 in COPD patients who: a) have a blood eosinophil count of at least 300 eosinophils / μL, b) are receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting β-agonists (LABA) (e.g., long-acting β2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium)), and c) have experienced two or more pre-exacerbations in the year prior to administration. In certain embodiments, the methods provided herein can increase FEV1 in COPD patients who: a) have a blood eosinophil count of at least 300 eosinophils / μL, b) are receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting β-agonists (LABA) (e.g., long-acting β2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium)), and c) have experienced three or more pre-exacerbations in the year prior to administration. In certain embodiments, the methods provided herein can increase FEV1 by at least 10% or at least 15% in such patients. In certain embodiments, the methods provided herein can increase pre-bronchodilator FEV1 by at least 10% or at least 15% in such patients. In certain embodiments, the methods provided herein can increase post-bronchodilator FEV1 by about 10% in such patients. In certain embodiments, the methods provided herein can increase pre-bronchodilator FEV1 and post-bronchodilator FEV1 by at least 10% in such patients.In certain embodiments, the methods provided herein can increase the FEV1 before bronchodilator in such patients by at least 15% and the FEV1 after bronchodilator in such patients by at least 10%.

[0067] The methods provided herein can increase the FEV1 in COPD patients having an eosinophil count in blood of at least 300 eosinophils / μL or in COPD patients having severe or very severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). In certain embodiments, the methods provided herein can increase the FEV1 in such patients by at least 15% or at least 20%. In certain embodiments, the methods provided herein can increase the FEV1 before bronchodilator in such patients by at least 15% or at least 20%. In certain embodiments, the methods provided herein can increase the FEV1 after bronchodilator in such patients by about 15%. In certain embodiments, the methods provided herein can increase the FEV1 before bronchodilator and the FEV1 after bronchodilator in such patients by at least 15%. In certain embodiments, the methods provided herein can increase the FEV1 before bronchodilator in such patients by at least 20% and the FEV1 after bronchodilator in such patients by at least 15%.

[0068] In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, increases FEV1 within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, or within 56 weeks, or within more weeks. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof improves FEV1 within 52 weeks of the first administration of benralizumab or an antigen-binding fragment thereof. Use of the methods provided herein can increase FEV1 by at least 0.05 L, at least 0.1 L, at least 0.13 L, at least 0.15 L, at least 0.20 L, at least 0.21 L, at least 0.22 L, at least 0.23 L, at least 0.24 L, or at least 0.25 L, at least 0.30 L, at least 0.35 L, at least 0.40 L, at least 0.45 L, or at least 0.50 L over a 56-week period.

[0069] The methods provided herein can increase forced vital capacity (FVC) in patients with COPD. The increase can be measured relative to the expected FVC based on a large patient population before administration, the FVC measured in a control population, or the FVC of an individual patient. In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, can increase FVC compared to the patient's baseline FVC. In some embodiments, the increase in FVC is the FVC before bronchodilator. In some embodiments, the increase in FVC is the FVC after bronchodilator. In some embodiments, the increase in FVC is the FVC before bronchodilator and the FVC after bronchodilator. FVC (e.g., FVC before bronchodilator and / or FVC after bronchodilator) can be increased, for example, within 1 year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0070] In certain embodiments, the methods provided herein can increase FVC by at least 3%. In certain embodiments, the methods provided herein can increase FVC before bronchodilator by at least 2%, at least 3%, at least 5%, or at least 10%. In certain embodiments, the methods provided herein can increase FVC after bronchodilator by at least 2%, at least 3%, at least 5%, or at least 10%. In certain embodiments, the methods provided herein can increase FVC before and after bronchodilator by at least 2%, at least 3%, at least 5%, or at least 10%. In certain embodiments, the use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragment thereof, can increase FVC within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, within 56 weeks, or within more weeks.

[0071] In certain cases, administration of benralizumab or antigen-binding fragment thereof improves respiratory symptoms in COPD patients, as measured, for example, by the Baseline Dyspnea Index / Transition Dyspnea Index (BDI / TDI) and / or Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS).

[0072] Also provided herein is a method for improving respiratory symptoms, as measured by the Baseline Dyspnea Index / Transition Dyspnea Index (TDI). For example, administration of benralizumab or antigen-binding fragment thereof can improve (increase) the BDI score of COPD patients by at least 1, at least 2, or at least 3 and / or can result in a positive TDI score. The BDI / TDI score can improve, for example, within 1 year from the first administration of benralizumab or antigen-binding fragment thereof.

[0073] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, improves the BDI / TDI score within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, or within 56 weeks, or more weeks.

[0074] Methods for improving respiratory symptoms are also provided herein, as measured by the Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS). For example, the administration of benralizumab or an antigen-binding fragment thereof can improve (decrease) the E-RS score of COPD patients by at least 3, at least 4, at least 6, at least 7, at least 8, at least 9, or at least 10. The E-RS score can improve, for example, within 1 year from the first administration of benralizumab or an antigen-binding fragment thereof.

[0075] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, improves the E-RS score within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, or within 56 weeks, or more weeks.

[0076] In certain cases, administration of benralizumab or an antigen-binding fragment thereof improves health status and / or health-related quality of life in COPD patients, as measured, for example, by the St. George's Respiratory Questionnaire (SGRQ), the COPD-specific St. George's Respiratory Questionnaire (SGRQ-C), and / or the COPD Assessment Test (CAT).

[0077] For example, methods for improving COPD symptoms are provided herein, as determined using a COPD questionnaire such as the St. George's Respiratory Questionnaire (SGRQ). For example, administration of benralizumab or an antigen-binding fragment thereof can improve a patient's SGRQ score by at least 2, at least 3, at least 4, at least 6, at least 7, at least 8, at least 9, or at least 10. The SGRQ score can improve, for example, within one year from the first administration of benralizumab or an antigen-binding fragment thereof.

[0078] In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves the SGRQ score within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, within 56 weeks, or within more weeks. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof improves the SGRQ score within 52 weeks of the first administration of benralizumab or an antigen-binding fragment thereof.

[0079] For example, methods for improving COPD symptoms are also provided herein, as determined using a COPD questionnaire such as the St. George's Respiratory Questionnaire - COPD specific (SGRQ - C). For example, administration of benralizumab or an antigen - binding fragment thereof can improve the SGRQ - C (symptom) score in COPD patients by at least 2, at least 3, at least 4, at least 6, at least 7, at least 8, at least 9, or at least 10. The SGRQ - C (symptom) score can improve, for example, within 1 year from the first administration of benralizumab or an antigen - binding fragment thereof.

[0080] In certain embodiments, use of the methods provided herein, i.e., administration of benralizumab or an antigen - binding fragment thereof, can improve the SGRQ - C (symptom) score within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, within 56 weeks, or within more weeks.

[0081] For example, methods for improving COPD symptoms are also provided herein, as determined using a COPD Assessment Tool (CAT). For example, administration of benralizumab or an antigen - binding fragment thereof can improve (decrease) the CAT score in COPD patients by at least 2, at least 3, at least 4, at least 6, at least 7, at least 8, at least 9, or at least 10. The CAT score can improve (decrease), for example, within 1 year from the first administration of benralizumab or an antigen - binding fragment thereof.

[0082] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, improves (decreases) the CAT score within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, within 52 weeks, or within 56 weeks, or within more weeks.

[0083] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces nocturnal awakenings.

[0084] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces the use of rescue medications.

[0085] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces the severity, frequency, and / or duration of events as defined by EXACT-PRO.

[0086] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces the annual rate of hospitalizations due to COPD.

[0087] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces the annual rate of hospitalizations and emergency department visits due to COPD.

[0088] In certain embodiments, the use of the methods provided herein, i.e., the administration of benralizumab or an antigen-binding fragment thereof, reduces the annual rate of unscheduled outpatient visits due to COPD.

[0089] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragments thereof, reduces the annual rate of unscheduled medical encounters due to COPD.

[0090] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragments thereof, reduces COPD-specific resource utilization. For example, administration of benralizumab or antigen-binding fragments thereof can reduce unscheduled physician visits, unscheduled phone calls to physicians, and / or use of other COPD medications.

[0091] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragments thereof, reduces the annual exacerbation rate of severe COPD, where a severe COPD exacerbation is defined as a symptomatic worsening of COPD that requires hospitalization for treatment, or death due to COPD.

[0092] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragments thereof to a COPD patient, increases the forced expiratory volume in 1 second (FEV1), increases the forced vital capacity (FVC), reduces the COPD exacerbation rate, and / or improves the COPD questionnaire score (e.g., COPD Control Questionnaire).

[0093] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or antigen-binding fragments thereof to a COPD patient, reduces the annual COPD exacerbation rate, improves the SGRQ score, and increases the FEV1 (e.g., in COPD patients with a baseline blood eosinophil count of 300 cells / μL or more).

[0094] In certain embodiments, COPD patients were prescribed or were using corticosteroids (e.g., inhaled corticosteroids (ICS)), long-acting β-agonists (LABA, e.g., long-acting β2 agonists), and long-acting muscarinic antagonists (LAMA) prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, COPD patients are being treated with ICS, LABA, and LAMA concurrently with benralizumab or its antigen-binding fragment. In certain embodiments, COPD patients are not being treated concurrently with ICS, LABA, and LAMA, and benralizumab or its antigen-binding fragment.

[0095] In certain embodiments of the methods provided herein, the patient has a history of COPD exacerbations. In certain embodiments, the exacerbation history includes at least two exacerbations in the year prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, the exacerbation history includes at least three exacerbations in the year prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, the patient has a forced expiratory volume in 1 second (FEV1) of less than 80% of predicted value prior to administration. In certain embodiments, the patient has an FEV1 / FVC of less than 0.70 prior to administration.

[0096] In certain embodiments, COPD patients have a specific blood eosinophil count, for example, prior to administration of benralizumab or its antigen-binding fragment. Blood eosinophil count can be measured, for example, using a complete blood count (CBC) together with a cell differential. In certain embodiments, COPD patients have a blood eosinophil count of 300 eosinophils / μL or more prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, the patient has a blood eosinophil count of 300 - 450 eosinophils / μL prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, the patient has a blood eosinophil count exceeding 400 eosinophils / μL prior to administration of benralizumab or its antigen-binding fragment. In certain embodiments, the patient has a blood eosinophil count exceeding 450 eosinophils / μL prior to administration of benralizumab or its antigen-binding fragment.

[0097] In certain embodiments, the COPD patients have moderate COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), i.e., GOLD II. In certain embodiments, the COPD patients have severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), i.e., GOLD III. In certain embodiments, the COPD patients have very severe COPD as defined by GOLD, i.e., GOLD IV. In certain embodiments, the COPD patients have severe or very severe COPD as defined by GOLD, i.e., GOLD III or IV.

Example

[0098] Example 1: Patients and Methods GALATHEA and TERRANOVA were Phase III complementary trials designed to evaluate the efficacy (based on reduction in moderate to severe annual exacerbation rate) and safety (threshold predicted to select patients likely to respond to benralizumab based on previous results) of benralizumab in patients with moderate to very severe COPD, at risk of exacerbation, and with blood eosinophil counts of 220 cells / μL or more. The following examples report the main results of GALATHEA and TERRANOVA.

[0099] Study Design GALATHEA (NCT02138916) and TERRANOVA (NCT02155660) were Phase III randomized double-blind placebo-controlled parallel-group trials. Each trial consisted of a registration visit, a 3-week screening period, a 56-week randomized treatment period, and a follow-up visit (Figure 1).

[0100] Stratify eligible patients by country and blood eosinophil count (≥300 cells / μL and <300 cells / μL). In cohorts with baseline eosinophil counts of <220 cells / μL, 220 - 299 cells / μL, and ≥300 cells / μL, recruitment was centrally restricted (primary analysis population) to maintain a predefined cohort size and a ratio of patients with eosinophil counts ≥220 cells / μL to those <220 cells / μL of approximately 2:1. This design allowed for enrichment of the study population with patients likely to respond to benralizumab (blood eosinophil count ≥220 cells / μL) and enabled evaluation of the benefits of benralizumab: risk ratios in COPD patients across various blood eosinophil counts. The dose selection was based on the approved asthma dose of 30 mg, 100 mg to inform the safety margin, and 10 mg to evaluate the dose - efficacy relationship.

[0101] In randomization, eligible patients were assigned at a ratio of 1:1:1 or 1:1:1:1 each and received placebo or benralizumab (30 mg or 100 mg in GALATHEA; 10 mg, 30 mg, or 100 mg in TERRANOVA). The full eligibility criteria are provided in the study protocol (available at NEJM.org). The study drug was administered by subcutaneous injection every 4 weeks for the first 3 doses and then every 8 weeks thereafter. The use of maintenance and rescue medications by patients was recorded daily during the study via an electronic diary (eDiary). Eligibility for randomization included ≥70% compliance with the prescribed inhaled maintenance therapy during the run - in period (based on eDiary).

[0102] The primary population for all analyses included patients with baseline blood eosinophil counts ≥220 cells / μL. The primary endpoint for both trials was the annual rate of exacerbation of COPD at week 56. Important secondary endpoints included the change from baseline in the forced expiratory volume in 1 second (FEV1) before bronchodilator and the St. George's Respiratory Questionnaire (SGRQ) score. Safety assessment items included the types and frequencies of adverse events (AEs).

[0103] Exacerbation of COPD is defined as a symptomatic worsening of COPD, which is the use of oral corticosteroids for 3 days or more and / or the use of antibiotics and / or hospitalization or death related to COPD (see Supplementary Appendix). Respiratory symptoms were recorded daily in the eDiary and evaluated at the center visit. Patients completed the SGRQ during the center visit. Additional evaluations that were used but not reported included the COPD Assessment Test, the Baseline Dyspnea Index / Transition Dyspnea Index, the Exacerbation-Patient Reported Assessment Item of the Chronic Lung Disease Tool, and the EuroQOL 5D 5L. Spirometry data were collected at the center visit together with safety data, but the results were read in a unified manner (see Supplementary Appendix).

[0104] Study Procedures Data were collected from all patients during the following periods: - Enrollment (-4 weeks) - Every 2 weeks during the introduction / screening period (-3 weeks to -1 week) - Randomization (week 0) and during the induction period (week 2) - Every 4 weeks during the decline and maintenance periods (weeks 4 to 56) - Follow-up (week 60)

[0105] Spirometry Patients underwent pre-bronchodilator spirometry at enrollment, at the second visit during the introduction / screening period (week 3), and at weeks -3, 0, 4, 8, 16, 24, 32, 40, 48, and 56 during the treatment period. Patients underwent post-bronchodilator spirometry at the second visit (week -3), and a subset of patients also underwent post-bronchodilator spirometry at enrollment, at weeks -3, 0, 4, 8, 16, 24, 32, 40, 48, and 56. Spirometry was performed by the study investigator or an accredited representative according to the guidelines of the American Thoracic Society / European Respiratory Society.

[0106] COPD Assessment Test The COPD Assessment Test (CAT) is an 8-item patient-reported outcome (PRO) developed to measure the impact of COPD on health status. This tool uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. The content includes items related to cough, phlegm, chest discomfort, breathlessness when climbing hills / stairs, activity limitation at home, confidence to go out, sleep, and energy. The total CAT score is the sum of item responses. Scores range from 0 to 40, with higher scores indicating a greater impact of COPD on health status. The CAT test was completed by patients at the following study center visits: 4th visit (week 0), 6th visit (week 4), 7th visit (week 8), 9th visit (week 16), 11th visit (week 24), 13th visit (week 32), 15th visit (week 40), 17th visit (week 48), and 19th visit (week 56).

[0107] Assessment of COPD Exacerbation COPD exacerbation is defined as a change in the patient's usual COPD symptoms that lasts for more than 2 days, exceeds normal daily variations, has an acute onset, requires a change in usual medication, and results in any of the following: - Use of systemic corticosteroids for at least 3 days - A dose of a single depot injection of corticosteroid considered equivalent to a 3-day course of systemic corticosteroids - Use of antibiotics - Hospitalization for treatment of COPD (defined as an admission of more than 24 hours to a hospital, observation area, emergency department, or other equivalent healthcare facility, depending on country and healthcare system)

[0108] If treatment with systemic steroids and / or antibiotics was required and the patient did not require hospitalization or die, the COPD exacerbation was considered moderate. If hospitalization or death occurred, the exacerbation was considered severe. Symptoms were judged by the patient each morning via the eDiary for the purpose of the symptom exacerbation alert. The purpose of this alert was to notify both the patient and the research center of symptoms of potential exacerbation events that would warrant contact between the patient and the center for further evaluation. Each morning, the patient completed three questions regarding the major symptoms of the exacerbation event (dyspnea, amount of sputum, and color of sputum). Worsening of one or more of these symptoms reported by the patient served as the trigger for the assessment of mild symptoms of the exacerbation event (pharyngitis, cold, fever without other cause, cough, and wheezing). Questions regarding the severity of symptoms relative to the patient's normal state had three options (e.g., How short of breath have you been in the past 24 hours? Less short of breath than usual, normal level of shortness of breath, more short of breath than usual). Questions regarding the presence or absence of symptoms had dichotomous responses (e.g., Have you had a sore throat in the past 24 hours? No, Yes, I have had a sore throat)

[0109] If at least two major symptoms, or one major symptom and one minor symptom deteriorated continuously for two days, alerts were generated by the eDiary system for the patient and the site. As described above, if the event was not associated with an eDiary symptom deterioration alert (e.g., technical problems, the patient self-reported a symptom deterioration / worsening event, the worsening was identified during a visit or phone contact, the worsening was evaluated and treated at a non-research center, or an acute / severe symptom deterioration that could not be captured by the ePRO system occurred), the principal investigator interviewed the patient to evaluate the potential worsening and duration of the following symptoms: among other findings, shortness of breath, amount of mucus, purulence of mucus, cough, wheezing, throat pain, cold symptoms such as runny nose or nasal congestion, fever, chest pressure. The start of the worsening was defined as the earlier of the start dates of systemic corticosteroid or antibiotic treatment or hospitalization, and the end date was defined as the last day of the later of the end dates of systemic corticosteroid or antibiotic treatment or discharge. A COPD exacerbation occurring within 7 days of the last dose of systemic steroid (oral, intramuscular, intravenous) or antibiotic, or the last day of hospitalization, was counted as the same exacerbation event.

[0110] Evaluation of blood eosinophils Patients were stratified by the absolute blood eosinophil count evaluated by the central laboratory (blood samples taken at the first visit [-4 weeks]). Randomization at the study level for the baseline eosinophil cohorts (<220 cells / μL, 220 - 299 cells / μL, ≥300 cells / μL) was restricted, and the sample sizes of the pre-defined cohorts and the approximately 2:1 ratio of patients above and below the 220 cells / μL cut-off were maintained. If any of the eosinophil cohorts were filled, patients assigned to that specific cohort based on their eosinophil count at the first visit failed screening.

[0111] Safety An independent data monitoring committee evaluated the cumulative safety and other clinical trial data. Major cardiac adverse events and malignancies were evaluated by an independent adjudication committee.

[0112] Study prescription Injection benralizumab solutions of 20 mg / mL, 30 mg / mL, or 100 mg / mL in the accompanying prefilled syringes corresponding to 10 mg, 30 mg, and 100 mg were administered by subcutaneous injection at the research center every 4 weeks for the first 3 administrations and then every 8 weeks, with the last dose of benralizumab administered at week 48. An injection-compatible placebo solution in the accompanying prefilled syringe was administered by subcutaneous injection at the research center on the same schedule as benralizumab. Each study patient received two syringes with fill volumes of 1 mL and 0.5 mL, respectively, to achieve blinding in a double-dummy manner.

[0113] Clinical Evaluation COPD Assessment Test: The COPD Assessment Test (CAT) is an 8-item patient-reported outcome (PRO) measure developed to assess the impact of COPD on health status. This instrument uses a 6-point semantic differential response scale defined by contrasting adjectives to capture the impact of COPD. The content includes items related to cough, phlegm, chest discomfort, breathlessness when climbing hills / stairs, activity limitation at home, confidence to go out, sleep, and energy. The total CAT score is the sum of the item responses. Scores range from 0 to 40, with higher scores indicating a greater impact of COPD on health status. The CAT test was completed by patients at the following research center visits: 4th visit (week 0), 6th visit (week 4), 7th visit (week 8), 9th visit (week 16), 11th visit (week 24), 13th visit (week 32), 15th visit (week 40), 17th visit (week 48), and 19th visit (week 56).

[0114] St. George's Respiratory Questionnaire: The St. George's Respiratory Questionnaire (SGRQ) is a 50-item PRO measure developed to assess the health status of patients with airway obstruction diseases. The questionnaire is divided into two parts: Part 1 consists of 8 items related to the severity of respiratory symptoms in the previous 4 weeks; Part 2 consists of 42 items related to daily activities and the psychosocial impact of the individual's respiratory system status. The SGRQ yields a total score as well as three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of overall functional impairment, with 100 indicating the worst possible health state and 0 indicating the best possible health state. Similarly, the domain scores range from 0 to 100, with higher scores indicating greater functional impairment. Specific details of the scoring algorithm were provided by the developers in the user manual. 2 The SGRQ was completed by patients at the following study center visits: the 4th visit (Week 0), the 6th visit (Week 4), the 7th visit (Week 8), the 9th visit (Week 16), the 11th visit (Week 24), the 13th visit (Week 32), the 15th visit (Week 40), the 17th visit (Week 48), and the 19th visit (Week 56).

[0115] Baseline Dyspnea Index / Transition Dyspnea Index: The Baseline Dyspnea Index / Transition Dyspnea Index (BDI / TDI) is a means developed to provide a multidimensional measurement of dyspnea regarding activities of daily living. The BDI provides a measure of dyspnea at baseline for each state, and the TDI evaluates the change in dyspnea from the baseline state. This means consists of three components: dysfunction, job size, and effort size, and is evaluated on a 5-point scale for BDI and a 7-point scale for TDI. The BDI was completed by patients at the 4th research center visit (week 0). The TDI was completed by patients at the following research center visits: the 6th visit (week 4), the 7th visit (week 8), the 9th visit (week 16), the 11th visit (week 24), the 13th visit (week 32), the 15th visit (week 40), the 17th visit (week 48), and the 19th visit (week 56).

[0116] The Modified Medical Research Council Breathlessness Scale: The mMRC Breathlessness Scale uses a simple scoring system to determine the level of dyspnea in patients consisting of 5 descriptions of perceived breathlessness. It is an ordinal scale performed by an interviewer where patients rate their dyspnea on a 5-point scale with increasing severity. The mMRC Breathlessness Scale was completed at the 4th research center visit (week 0).

[0117] Exacerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome: EXACT-PRO / E-RS COPD is a 14-item PRO means developed to determine the frequency, severity, and duration of COPD exacerbations. This means was developed for daily home administration via a handheld electronic device. Respondents are instructed to complete a diary every night just before bedtime, considering the respondent's experience as "today" and answering the questions. The score ranges from 0 to 100, with higher scores indicating greater severity. Patients completed EXACT-PRO / E-RS COPD at home every evening.

[0118] EuroQOL 5D 5L: In EuroQOL 5D 5L, five aspects were evaluated: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each aspect had five response options (no problems, slight problems, moderate problems, severe problems, and extreme problems) that reflected increasing levels of difficulty. Patients completed EuroQOL 5D 5L at home weekly (±2 days).

[0119] Safety Assessment Baseline data of a complete physical examination were collected at the first visit. Any new findings or worsened existing findings were reported as adverse events. In addition to the physical examination, the following were recorded at each visit: smoking status, anthropometry, vital signs. After participants rested for at least 5 minutes, a 12-lead electrocardiogram (ECG) was also performed in the supine position. The ECG was performed between visits.

[0120] Laboratory safety assessments were also performed for clinical chemistry, hematology, and urine tests. Clinical chemistry characteristics included the following: alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, chloride, carbon dioxide, creatinine, gamma-glutamyl transpeptidase, glucose, phosphorus, sodium, total bilirubin, total cholesterol, and uric acid.

[0121] Hematological analysis included hematocrit, hemoglobin, mean corpuscular volume, platelet count, red blood cell count, and differential white blood cell count.

[0122] Urine tests included the following: appearance, blood, color, glucose, ketones, microscopic examination of white blood cells and red blood cells, pH, and specific gravity.

[0123] Statistical Analysis In the primary analysis, the number of COPD exacerbations observed in patients during the 56-week double-blind treatment period was used as the response variable. Annual exacerbation rate = Number of exacerbations * 365.25 / (Last follow-up observation date - Fourth visit date + 1).

[0124] The exacerbation rate of each in the benralizumab administration group was compared with that of the placebo group via a negative binomial model. The model included the treatment group, eosinophil cohort (220 - 299 cells / μL or 300 cells / μL and above), country, background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA), and the covariate of the number of exacerbations in the previous year of the study. The logarithm of the follow-up time was used as an offset variable in that model.

[0125] All secondary efficacy evaluation items were analyzed for patients with a baseline blood eosinophil count of 220 cells / μL and above. The change from the baseline of FEV1 before administration / pre - bronchodilator at week 56 was compared between each of the three benralizumab dose groups and placebo in the full analysis set by performing a repeated measures analysis in patients with baseline FEV1 before administration / pre - bronchodilator and at least one pre - administration / pre - bronchodilator FEV1 after randomization. The dependent variable was the change from the baseline of FEV1 before bronchodilator at the visits specified by the protocol after baseline (until the end - of - treatment visit). The treatment group was adjusted as an explanatory variable, and the eosinophil cohort (220 - 299 cells / μL or 300 cells / μL and above), country, background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA), visit, the interaction between visit and treatment, and the baseline in FEV1 before bronchodilator were adjusted as covariates. The visit was adjusted as a categorical variable, and the variance - covariance matrix was assumed to be unstructured. The model was: Change in FEV1 = Treatment group + Eosinophil cohort (220 - 299 cells / μL or 300 cells / μL and above) + Baseline FEV1 + Country + Background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA) + Visit + Treatment * was the visit.

[0126] Changes from baseline in the 56-week SGRQ total score and the three domain scores (symptoms, activity, and impact) were analyzed separately via a model similar to the above model for changes from baseline in pre-dose / before bronchodilator FEV1.

[0127] Using sensitivity analyses of the primary and key secondary endpoints based on assumptions of different missing data mechanisms, including those expected to be more conservative such as non-random missingness, the robustness of any treatment effect including multiple imputation approaches was investigated.

[0128] For each of the 30 mg and 100 mg treatment groups (for patients with a baseline blood eosinophil count of 220 cells / μL or more), to account for the multiplicity of testing the primary endpoint (exacerbation rate) and two key secondary endpoints (FEV1 and SGRQ), the following testing strategy was used to control the overall Type I error rate at the 0.05 level.

[0129] Step 1: Two tests of the annual exacerbation rate in COPD (one test for each dose versus placebo) were performed at a family-wise error rate (FWER) of 0.04 via the Hochberg procedure. If both p-values were < 0.04, Step 2 was performed; if the smaller p-value was < 0.02, Step 2a was performed. Otherwise, the null hypothesis was not rejected.

[0130] Step 2: The two key secondary endpoints for both treatments were tested as one family at an FWER of 0.05 via the Holm procedure.

[0131] Step 2a: The two secondary endpoints for the smaller P-value dose were tested at an FWER of 0.01 via the Holm procedure.

[0132] Secondary endpoint In both studies, an improvement in the SGRQ score for patients was reported; however, the overall improvement in the SGRQ score was reported in patients from the placebo group as well as all treatment groups (the least squares method means the change from baseline and was GALATHEA, placebo [-3.86] vs 10 mg [0.00] vs 30 mg [-4.87] vs 100 mg [-5.99], and TERRANOVA, placebo [-6.50] vs 10 mg [-7.51] vs 30 mg [-7.89] vs 100 mg [-7.10] (Figure 3)).

[0133] Patient GALATHEA and TERRANOVA included patients aged 40 to 85 years who had 1) moderate to very severe COPD (screening for FEV1 / forced vital capacity <0.70 after bronchodilator and FEV1 after bronchodilator >20% and ≤65% of predicted normal value); 2) cumulative or past smoking exposure of 10 pack-years or more; 3) symptoms (modified Medical Research Council dyspnea score ≥1 at screening); and 4) a medical history of two or more moderate COPD exacerbations requiring treatment with oral corticosteroids and / or antibiotics, or one or more COPD exacerbations requiring hospitalization, in the year prior to enrollment, despite treatment with double therapy (ICS / LABA or LABA / LAMA) or triple therapy (ICS / LABA / LAMA) in the year prior. Patients were excluded if they had received a primary diagnosis of asthma (a history of asthma [e.g., childhood or adolescence] was permitted).

[0134] Exclusion criteria Patients should not participate in this study if they meet any of the following exclusion criteria: - Clinically important lung diseases other than COPD (e.g., active pulmonary infections, clinically severe bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-related hypoventilation syndrome, lung cancer, alpha1-antitrypsin deficiency, and primary ciliary dyskinesia) or other diagnosed pulmonary or systemic diseases associated with an elevated peripheral eosinophil count (e.g., allergic bronchopulmonary aspergillosis / fungus, Churg-Strauss syndrome, eosinophilic syndrome) and / or radiographic findings suggesting a respiratory disease other than COPD contributing to the patient's respiratory symptoms; - Major physical impairments, including but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or unstable according to the investigator's opinion, and / or any potential impairments: - Affect the safety of the patient throughout the study; - Affect the results or interpretation of the study; or - Prevent the patient's ability to complete the study period. - Treatment using systemic corticosteroids, and / or antibiotics, and / or hospitalization due to a COPD exacerbation during the 2 weeks prior to registration (first visit) or during the registration and screening / introduction period (regardless of what occurred thereafter, based on the last dose of steroid or the last day of hospitalization). - Acute upper or lower respiratory tract infections during the 2 weeks prior to registration (first visit) or during the registration and screening / introduction period. - Pneumonia within 8 weeks prior to registration (first visit), based on the last day of antibiotic treatment or hospitalization (regardless of what occurred thereafter or during / after the registration and screening / introduction period).

[0135] Statistical Analysis In the calculation of the sample size, an estimated 348 patients (total patients overall: GALATHEA, 1,044; TERRANOVA, 1,392) with a baseline blood eosinophil count of 220 cells / μL or more per treatment group were required for the primary assessment to provide 90% power to detect a 30% reduction between the annual exacerbation rates in the benralizumab 30 mg or 100 mg groups and placebo assuming a two-sided 4% alpha level test.

[0136] For patients in the main analysis population with a baseline blood eosinophil count of 220 cells / μL or more, the exacerbation rates of benralizumab and placebo were compared using a negative binomial model. The model response variable was the number of exacerbations over the 56-week treatment period. The model included treatment group, eosinophil count cohort (220 - 299 cells / μL or 300 cells / μL or more), region, background therapy (ICS / LABA, LABA / LAMA, ICS / LABA / LAMA), and the covariate of the number of exacerbations in the previous year. Multiple protection of the overall type I error rate was accounted for by the Hochberg procedure. In TERRANOVA, the benralizumab 10 mg treatment group was not multiply protected.

[0137] Secondary efficacy evaluation items were analyzed for patients with a baseline blood eosinophil count of 220 cells / μL or more. The analysis of secondary evaluation items was not multiply protected. The change from baseline in FEV1 before bronchodilator at week 56 was compared between each of the benralizumab dose groups and placebo using repeated measures analysis. The change from baseline in the total SGRQ score at week 56 was analyzed separately using a similar model. Safety parameters were analyzed by count summaries for each study period.

[0138] Pre-specified subgroup analyses by patient population statistics, characteristics of respiratory diseases, previous drug use, and previous exacerbations (less than 3 or 3 or more) were performed for the primary efficacy variables of each trial. This study was not designed or powered to evaluate efficacy within these subgroups. Therefore, these analyses are considered exploratory.

[0139] Example 2: Results Study Population Overall, the patient characteristics and demographics of GALATHEA and TERRANOVA were similar to those of the primary analysis population with a baseline blood eosinophil count of 220 cells / μL or more (Table 1). Most patients were white males with a mean age of 65 years. The current (non-primary diagnosis) and past incidence of asthma was low (less than 7% and less than 10% respectively in all study groups) (Table 1). Most patients (93.0%) were classified into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D at baseline. The proportion of patients who changed background maintenance therapy during or after the treatment period was low (less than 5% and less than 1% respectively). All results reported were for the primary analysis population (GALATHEA, n = 1,120; TERRANOVA, n = 1,545).

[0140] In GALATHEA and TERRANOVA, in all treatment groups, more than 83% and more than 79% of patients respectively completed the treatment. The main reasons for treatment discontinuation were AE and patient decision (data not shown).

[0141]

Table 1

[0142]

Table 2

[0143] Main evaluation items: In GALATHEA, patients treated with benralizumab had a lower annual COPD exacerbation rate at week 56 compared with placebo. The estimated annual exacerbation rate (95% confidence interval [CI]) was 1.19 (1.04, 1.36), 1.03 (0.90, 1.19), and 1.24 (1.08, 1.42) for benralizumab 30 mg, 100 mg, and placebo, respectively; the treatment effect versus placebo was 0.96 (P = 0.6490) and 0.83 (P = 0.0525) for benralizumab 30 mg and 100 mg, respectively (Table 2, Figure 2). Benralizumab 100 mg also reduced the annual rate of severe exacerbations (treatment effect versus placebo, 0.57 [nominal P = 0.0175]) (Table 2, Figure 2).

[0144] In TERRANOVA, patients treated with benralizumab 10 mg or 100 mg had a lower annual COPD exacerbation rate at week 56 compared with placebo. The estimated annual exacerbation rate (95% CI) was 0.99 (0.87, 1.13), 1.21 (1.08, 1.37), 1.09 (0.96, 1.23), and 1.17 (1.04, 1.32) for benralizumab 10 mg, 30 mg, 100 mg, and placebo, respectively; the treatment effect versus placebo was 0.85 (P = 0.0638), 1.04 (P = 0.6575), and 0.93 (P = 0.3988) for benralizumab 10 mg, 30 mg, and 100 mg, respectively (Table 2). Numerical differences in favor of benralizumab were also observed for the reduction in the annual rate of severe exacerbations (treatment effect versus placebo, 0.75 [nominal P = 0.1478], 0.88 [nominal P = 0.4835], and 0.68 [nominal P = 0.0516] for benralizumab 10 mg, 30 mg, and 100 mg, respectively) (Table 2, Figure 2).

[0145] Key secondary endpoints: At week 56, the differences in secondary endpoints between benralizumab and placebo were not statistically significant. In GALATHEA, the change from baseline in FEV1 before bronchodilator to placebo was 7 mL and 21 mL for benralizumab 30 mg and 100 mg, respectively. For the SGRQ total score, the treatment effect of benralizumab versus placebo was -1.011 and -2.136 for benralizumab 30 mg and 100 mg, respectively (Table 2 and Figure 3). In TERRANOVA, the change from baseline in FEV1 before bronchodilator to placebo was 15 mL, -7 mL, and 20 mL for benralizumab 10 mg, 30 mg, and 100 mg, respectively. For the SGRQ total score, the treatment effect of benralizumab versus placebo was -1.011, -1.388, and -0.602 for benralizumab 10 mg, 30 mg, and 100 mg, respectively (Table 2 and Figure 3). At week 56, a significant improvement was also seen in the SGRQ scores of patients randomized to placebo in GALATHEA and TERRANOVA (mean change from baseline -3.856 and -6.863, respectively).

[0146]

Table 3

[0147] In both trials, complete depletion of blood eosinophils from week 4 until the end of the study was achieved with all doses of benralizumab, with no depletion with placebo (Figure 4). In a sub-study of GALATHEA, benralizumab caused near-complete depletion at week 24 (mean: 0.02% and 0.13% for 30 mg and 100 mg, respectively, versus 5.38% for placebo) and was maintained until week 56.

[0148] Pre-specified subgroup analyses: Point estimates of the annual rate ratio (RR) of exacerbations in COPD favored benralizumab 100 mg over placebo in all population statistical subgroups except current smokers in GALATHEA where similar results were obtained with benralizumab and placebo (point estimate of 1.00). Subgroups of patients with ≥3 prior exacerbations compared to <3 prior exacerbations showed a greater treatment effect with benralizumab 100 mg (reduction vs placebo: GALATHEA, 39% and 2% respectively; TERRANOVA, 23% and 2% respectively) (Figures 5 and 6). Patients with a baseline eosinophil count ≥220 cells / μL showed a substantial reduction in exacerbation rate with benralizumab 100 mg compared to patients with <220 cells / μL (RR vs placebo [95%CI]: GALATHEA, 0.83 [0.69, 1.00]; TERRANOVA, 0.93 [0.78, 1.10]) vs (RR vs placebo [95%CI]: GALATHEA, 1.02 [0.82, 1.27]; TERRANOVA, 1.02 [0.80, 1.30]). There was no trend between increasing eosinophil count and treatment effect (Figure 7).

[0149] Benralizumab 100 mg enhanced treatment effect in patients receiving triple therapy compared to other treatment regimens (reduction in COPD exacerbation rate vs placebo: GALATHEA, 18%; TERRANOVA, 17%) (Figures 5 and 6). In both trials, patients with frequent (≥3) or very severe GOLD airflow severity of prior exacerbations had a higher treatment effect with benralizumab compared to patients with few or moderate GOLD airflow severity of prior exacerbations. The treatment effect of benralizumab differed slightly by region (data not shown).

[0150] Safety: In GALATHEA and TERRANOVA, the type and frequency of AEs were similar between the benralizumab and placebo groups and the mortality rate was low (Table 3). The most common AEs were related to COPD or respiratory status. Less than 15% of patients had a positive anti-drug antibody (ADA) response (Table 3), which did not appear to affect clinical assessment items.

[0151]

Table 4

[0152] Investigation: Although not statistically significant compared with placebo, benralizumab showed evidence of reducing the exacerbation rate as an additional maintenance therapy for moderate to very severe COPD patients receiving ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA inhaled therapy with a history of COPD exacerbation and blood eosinophil count of 220 cells / μL or more. Subgroup analysis in both studies consistently identified patients receiving triple background therapy (e.g., ICS / LABA / LAMA) as most likely to respond to 100 mg of benralizumab, with a blood eosinophil count of 300 eosinophils / μL or more and a history of more frequent exacerbations (e.g., 3 or more exacerbations in the year before dosing). Furthermore, compared with placebo, 100 mg of benralizumab reduced the annual exacerbation rate of severe COPD by more than 30%.

[0153] Most benralizumab doses were associated with a slight improvement from baseline in lung function. Benralizumab treatment also improved the SGRQ score, similar to placebo. All patients received investigational inhaled therapies that had the potential to differentially improve the assessment items in the placebo group. This, combined with a large placebo effect, may have contributed to benralizumab's inability to reach statistical significance for improvements in lung function and other assessment items.

[0154] During these trials, AE / serious AE were balanced between treatment groups and the mortality rate was low. These safety data are consistent with those reported in the Phase III trials of benralizumab for severe uncontrolled eosinophilic asthma (Bleecker et al., Lancet, 388:2115-2127, 2016; Fitzgerald et al., Lancet, 388:2128-2142, 2016).

[0155] COPD is a complex pathological condition caused by various mechanisms and causes symptoms of various clinical diseases (Singh et al., BRN Review, 4:34-52, 2018). Biological agents such as benralizumab target an individual potential pathological mechanism (eosinophilic inflammation). By week 4 and up to week 56, benralizumab resulted in complete depletion of blood and sputum eosinophils. This finding, along with the similar effect on eosinophils observed in the mepolizumab trial, suggests that it minimizes the impact on the rate of COPD exacerbation and that eosinophil depletion may not completely improve the exacerbation assessment items in COPD patients. Furthermore, the eosinophil count in peripheral blood may not accurately reflect airway eosinophilia. The clinical characteristics of COPD are additional important factors. Both GALATHEA and TERRANOVA showed that patients who had more frequent COPD exacerbations in the year before enrollment experienced the greatest treatment effect of benralizumab despite receiving triple inhaled therapy. This is an important finding as both variables can be easily identified and may help to individualize the use of benralizumab for the treatment of COPD patients along with the blood eosinophil count.

[0156] Example 3: Further Phase 3 Trial This is a randomized double-blind placebo-controlled parallel-group multi-center Phase 3 trial to evaluate the efficacy and safety of a 100 mg dose of benralizumab administered by subcutaneous (SC) injection at 4-week intervals for the first 3 doses and then at 8-week intervals (hereinafter referred to as Q8W) in patients with moderate to very severe COPD with a history of frequent COPD exacerbations and elevated peripheral blood eosinophils (300 cells / μL or more). Eligible patients must have a history of 2 or more moderate and / or severe COPD exacerbations in the previous year despite receiving triple (ICS / LABA / LAMA) background therapy. Eligible patients must also have an elevated blood eosinophil count of 300 cells / μL or more at screening, which is supported by at least 1 past result of 150 cells / μL or more within the previous year.

[0157] In the GALATHEA and TERRANOVA, which are phase 3 clinical trials, long-term treatment with benralizumab 10, 30, or 100 mg Q8W for up to 48 weeks was well tolerated in patients with moderate to very severe COPD. There were no appreciable differences in safety results among the three dose groups.

[0158] The results from both studies provided consistent and clear evidence that the 100 mg dose of benralizumab had a greater treatment effect than the 30 mg dose in reducing the annual exacerbation rate (moderate and severe combined) of COPD, the annual exacerbation rate of severe cases, and all other exacerbation assessment items in patients with a baseline blood eosinophil count of 220 cells / μL or more. The 10 mg dose of benralizumab (in TERRANOVA only) provided inconsistent results compared with the 100 mg dose across all exacerbation assessment items. However, for severe exacerbations, a greater treatment effect was observed with the 100 mg dose of benralizumab compared with the 10 mg dose in patients with a baseline blood eosinophil count of 220 cells / μL or more (32% and 25% lower than placebo, respectively). In patients with more frequent prior exacerbations (more than 3 exacerbations in the previous year) and a baseline blood eosinophil count of 220 cells / μL or more, the treatment effect of the 100 mg dose of benralizumab was much greater than that of the 10 mg dose, as demonstrated by COPD exacerbations (moderate and severe combined; 23% vs 9% lower than placebo, respectively) and severe exacerbations (34% vs 17% lower than placebo). Generally, any improvement observed in patients receiving benralizumab treatment was greater in the 100 mg group compared with the 30 mg group. In both studies, 100 mg of benralizumab reduced the annual severe exacerbation rate by more than 30% compared with placebo. However, in GALATHEA, patients receiving 30 mg of benralizumab had a higher severe exacerbation rate compared with placebo. These results suggest that a higher dose of benralizumab may be required to achieve a treatment response in COPD patients compared with asthma patients, where 30 mg of benralizumab is sufficient to achieve a treatment effect. In particular, in this study, the 100 mg dose of benralizumab was selected, considering the more consistent efficacy findings in the subgroup with more frequent exacerbations and elevated eosinophils (220 cells / μL or more).

[0159] Potentially eligible patients enter a 5-week lead-in period. Patients who meet the eligibility criteria are randomized in a 1:1 ratio to receive either benralizumab 100 mg or placebo Q8W. The treatment period varies and continues until the last patient has had the opportunity to complete at least 56 weeks, at which point all patients complete the study. The primary endpoint is analyzed at week 56.

[0160] For randomization, patients are stratified by country and number of exacerbations in the previous year (two or more times). To ensure that more than 70% of patients in the study population have had three or more exacerbations in the previous year, a ceiling is set for randomization to the stratum of two exacerbations in the previous year.

[0161] Patients are maintained on triple (ICS / LABA / LAMA) background therapy throughout the registration, lead-in, and treatment periods.

[0162] Number of patients: A total of 868 patients are expected to be randomized in the study in a 1:1 ratio to receive either benralizumab 100 mg SC or the corresponding placebo treatment group.

[0163] Treatment and treatment period: Upon registration, patients enter a lead-in period of at least 5 weeks, which can be extended up to 13 weeks. Following the lead-in period, patients who are confirmed to be eligible are randomized in a 1:1 ratio to receive either benralizumab 100 mg or placebo SC Q8W. The treatment period varies and continues until the last patient has had the opportunity to complete at least 56 weeks. When the end-of-treatment (EOT) visit of the last patient is confirmed, the final visit for all patients is scheduled. When all patients have completed the final visit, the study ends.

[0164] Statistical methods The efficacy analysis is conducted using the full analysis set (FAS), which includes all randomized patients who receive at least one IP administration, regardless of protocol compliance and continued participation in the study, in accordance with the principle of intention to treat.

[0165] The primary efficacy evaluation item is the annual exacerbation rate of moderate and severe COPD over the first 56 weeks. The estimated treatment effect is applied to the primary analysis of the primary evaluation item (along with the main analysis of important secondary evaluation items), and all data are included regardless of whether the patient remains blinded to the IP.

[0166] The primary evaluation item is first evaluated in the primary population (patients with three or more exacerbations in the previous year), and then in the overall population of patients with two or more exacerbations in the previous year. The exacerbation rate in the benralizumab 100 mg group is compared with that in the placebo group using a negative binomial model. The response variable of the model is the number of COPD exacerbations over the first 56 weeks of the treatment period. The model includes covariates of treatment group, region, and the number of exacerbations in the previous year. The logarithm of the follow-up time of the first 56 weeks was used as an offset variable in the model. The hypothesis test of the primary analysis is performed at a two-sided significance level of 5%.

[0167] The annual exacerbation rate of COPD leading to hospitalization or death (i.e., severe exacerbation) is analyzed through EOT using the same negative binomial model as outlined for the primary efficacy variable.

[0168] Unless otherwise noted, all secondary efficacy evaluation items are analyzed in patients with a history of three or more exacerbations in the previous year and repeated in patients with a history of two or more exacerbations in the previous year using data up to week 56. Continuously measured evaluation items (e.g., SGRQ and FEV1) are also evaluated through EOT using an additional model similar to the model fitted to the data up to week 56 if collected beyond week 56.

[0169] In this study, patients receiving triple (ICS / LABA / LAMA) background therapy with a baseline eosinophil count of 300 eosinophils / μL or more and with at least two exacerbations in the previous year, and in whom at least 70% of the patients had three or more exacerbations in the previous year, will be recruited. This study will be powered for the primary population of patients with three or more exacerbations in the previous year. For the primary endpoint of annual exacerbation rate during the first 56 weeks, at least 304 patients / group (608 patients in total) with three or more exacerbations in the previous year will be randomized to benralizumab 100 mg versus placebo to achieve at least 90% power to detect a 30% reduction. This calculation assumes a two-sided 5% alpha level, two annual placebo rates, and a negative binomial dispersion parameter of 0.5.

[0170] A total of 868 patients are expected to be randomized in this study, which will also include a cohort of patients with two exacerbations in the previous year (approximately 260 patients) to characterize the efficacy in patients with two or more exacerbations in the previous year.

[0171] The general study design is summarized in Figure 11.

[0172] The study population was identified based on the findings of GALATHEA and TERRANOVA and the Phase 3 clinical trials of benralizumab in patients with moderate to very severe COPD. The two Phase 3 trials had a nearly identical study design and included patients with a history of exacerbations, despite double or triple background therapy with ICS / LABA, LAMA / LABA, or ICS / LAMA / LABA across the range of baseline blood eosinophils. The primary population was patients with a baseline eosinophil count of 220 cells / μL or more in GALATHEA and TERRANOVA. In this new study, the primary population is patients with a baseline eosinophil count of 300 eosinophils / μL or more, receiving triple background therapy (ICS / LABA / LAMA), and having 3 or more exacerbations in the previous year. The overall population is patients with a baseline eosinophil count of 300 eosinophils / μL or more, receiving triple background therapy (ICS / LABA / LAMA), and having 2 or more exacerbations in the previous year.

[0173] In the primary analysis from GALATHEA and TERRANOVA, the 100 mg dose of benralizumab reduced the annual rate of COPD exacerbations (moderate and severe combined) by 17% and 7% respectively compared to placebo in the primary endpoints of GALATHEA and TERRANOVA. However, a clinically relevant reduction in severe exacerbations (defined as exacerbations leading to hospitalization or death) was observed in both studies, with the greatest effect seen in the 100 mg benralizumab group (43% and 32% in GALATHEA and TERRANOVA respectively).

[0174] Pre-planned analyses were conducted to evaluate specific subpopulations and the following results were obtained: - Patients receiving triple (ICS / LABA / LAMA) background therapy (approximately 70% and 60% of patients in GALATHEA and TERRANOVA respectively) showed a consistent treatment effect on the annual COPD exacerbation rate with 100 mg benralizumab in both studies: a reduction of 18% and 17% respectively compared to placebo. - The year before last, patients with more frequent exacerbations (more than 3 times vs. 2 times or less) had a greater treatment effect on the annual exacerbation rate of COPD and the annual exacerbation rate of severe COPD with benralizumab 100mg. - In patients with a baseline blood eosinophil count of less than 220 cells / μL, no treatment effect on the annual exacerbation rate of COPD was observed.

[0175] The findings of these subgroups were consistent throughout the study and were supported by a pooled analysis. In summary, these characteristics identify the patients who are most likely to benefit from benralizumab treatment.

[0176] In this study, an eosinophil cut-off point of 300 cells / μL or more was used. In the previous GALATHEA and TERRANOVA studies, no efficacy was seen in patients with low eosinophil counts (less than 220 cells / μL). The treatment response was similar between patients with 220 cells / μL or more and 300 cells / μL or more. GOLD2019 refers to a threshold of 300 cells / μL regarding the response to ICS, and a cut-off of 300 cells / μL is more practical from a clinical perspective and is consistent with the resolution of blood cell count data in clinical tests.

[0177] A history of frequent (≥3 times) exacerbations in the previous year was the most powerful and consistent predictor of treatment response in GALATHEA and TERRANOVA. Therefore, this study was strengthened for the main population of patients with ≥3 exacerbations in the previous year. The study enrollment was expanded to include patients with 2 exacerbations in the previous year, and given that there was evidence of treatment effect in this subset of patients who were on triple (ICS / LABA / LAMA) background therapy and had a baseline blood eosinophil count of ≥220 cells / μL in the GALATHEA and TERRANOVA studies, a broader population (patients with ≥2 exacerbations in the previous year) could be further investigated. In a pooled post - hoc analysis in this population (blood eosinophils ≥220 cells / μL, ≥2 exacerbations in the previous year, on triple therapy), treatment with benralizumab 100mg resulted in a 20% reduction in the annual exacerbation rate and a 55% reduction in the annual rate of severe exacerbations compared to placebo.

[0178] Chest CT imaging is included in the study to provide the necessary information related to exclusion criterion 3 and to assess the potential impact of structural lung disease on efficacy.

[0179] Selection Criteria - Patients (male or female) must be 40 - 85 years old at the time of signing the ICF. - Smokers or ex - smokers with a smoking history of ≥10 pack - years (1 pack - year = smoking 20 cigarettes per day for 1 year) (Note: Use of e - cigarettes does not affect the eligible pack - year count). - A history of moderate to very severe COPD with post - bronchodilator FEV1 / FVC <0.70 and post - bronchodilator FEV1 ≤65% of predicted normal values on central spirometry screening. - A documented history of treatment with systemic corticosteroids (≥3 days or single injection of depot preparation) and / or ≥2 moderate and / or severe COPD exacerbations requiring hospitalization within 52 weeks prior to enrollment. (a) Worsening treated only with antibiotics is not considered to meet the criteria unless it is accompanied by treatment with systemic corticosteroids and / or hospitalization. (b) Hospitalization is defined as an admission of more than 24 hours to a hospital, observation area, emergency department, or other equivalent medical facility, depending on the country and healthcare system. (c) Exacerbations must be confirmed to have occurred while the patient was on a stable triple (ICS / LABA / LAMA) background therapy for COPD and not be due to a step - down in treatment, i.e., a change from triple therapy to dual therapy. - Recorded use of triple (ICS / LABA / LAMA) background therapy for COPD throughout the entire year (52 weeks) prior to enrollment. (a) The dose of ICS must be equivalent to at least 500 mcg of fluticasone propionate per day. (b) The total cumulative period during which the patient was not on triple (ICS / LABA / LAMA) background therapy should not exceed 2 months, although the patient may have switched treatment and / or stepped down in the short term during the previous year. (c) The patient must have received stable treatment / administration during the last 3 months prior to randomization. (Individual component changes or switches between devices are permitted as long as the patient is maintaining ICS / LABA / LAMA with an acceptable ICS dose equivalent to at least 500 mcg of fluticasone propionate per day.) - Supported by a history of blood eosinophil count of 300 cells / μL or more at central laboratory screening and at least one recorded blood eosinophil count of 150 cells / μL or more within 52 weeks of enrollment. If there is no past data, additional blood eosinophil counts can be obtained by repeating the test during the introduction period (at least 4 - week intervals). - The total CAT score at the first visit is 15 or more. - If treatment with systemic corticosteroids is required and hospitalization does not occur, the exacerbation is considered moderate. If hospitalization occurs, the exacerbation is considered severe.

[0180] Exclusion Criteria 1. Clinically significant pulmonary diseases other than COPD (e.g., active pulmonary infections, clinically severe bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-related hypoventilation syndrome, lung cancer, alpha1-antitrypsin deficiency, or primary ciliary dyskinesia). 2. Current diagnosis of asthma, history of asthma, or asthma-COPD overlap according to the Global Initiative for Asthma (GINA) or other approved guidelines for asthma. 3. Radiological findings suggesting a respiratory disease other than COPD as the cause of the patient's respiratory symptoms. Radiological findings of an isolated pulmonary nodule without evidence of stability or findings suggesting an acute infection with appropriate follow-up and standard treatment. 4. Another diagnosed pulmonary or systemic disease associated with an elevated peripheral eosinophil count (e.g., allergic bronchopulmonary aspergillosis / fungus, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome).

[0181] Investigational treatment is defined as a clinical trial medicinal product (including commercially available product comparators and placebo) or medical device intended for administration to patients according to the study protocol. Investigational treatment in this study refers to benralizumab or placebo.

[0182] Concomitant Therapy - All background COPD medications (e.g., ICS / LABA / LAMA, chronic antibiotics, etc.) and treatments administered for COPD exacerbations in the 12 months prior to enrollment. - All other medications taken for any reason in the 3 months prior to enrollment - Concomitant treatments performed during the study and the reasons for treatment (at each study visit)

[0183] COPD medications taken at the time of past exacerbations, including any recent changes to these medications related to the timing of exacerbations, are to be captured in the eCRF.

[0184] The prescription, dosage, and regimen of the patient's usual triple (ICS / LABA / LAMA) background therapy, as well as any other additional permitted COPD medications that may have been taken prior to enrollment, must be continued throughout enrollment, initiation, and the treatment period.

[0185] Background (maintenance) medications All patients must be treated with triple (ICS / LABA / LAMA) background therapy for COPD during the year prior to enrollment and throughout the study period. Patients must have been on stable ICS / LABA / LAMA therapy / administration during the last 3 months prior to randomization and must use an acceptable ICS dosage equivalent to at least 500 mcg of fluticasone propionate per day.

[0186] The purpose of this study is to establish the therapeutic effect of benralizumab as an addition to triple therapy. Therefore, background medications should be maintained at the same dosage and schedule from enrollment until the end of the study.

[0187] Minor changes to the prescription of the patient's background inhaled medications, such as changes in individual components (e.g., from fluticasone to budesonide at equivalent dosages) or switching between devices (e.g., budesonide / formoterol to fluticasone / salmeterol), are permitted as long as the patient continues ICS / LABA / LAMA at an acceptable ICS dosage. In the case of such minor changes, the patient must have been stable on the new treatment regimen for at least 4 weeks prior to randomization.

[0188] Rescue medications Short-acting β2-agonists (SABA, e.g., salbutamol, albuterol, terbutaline, lev albuterol), short-acting muscarinic antagonists (SAMA), combinations of SABA / SAMA, or alternative rescue medications by local standard treatment can be used during exacerbation events of COPD symptoms.

[0189] A list of permitted, restricted, and prohibited pharmaceuticals is shown in Table 4.

[0190]

Table 5

[0191]

Table 6

[0192] Example 4: Research Evaluation and Procedures Evaluation of COPD Exacerbation: For the purposes of the protocol, an exacerbation of COPD is defined as a worsening of the patient's normal COPD symptoms, which exceeds normal daily variation, has an acute onset, and lasts for more than 2 days (or 1 day if the exacerbation is very rapid and severe and the treating physician determines that the intensification of treatment cannot be delayed), and may warrant a change in normal medication, leading to any of the following:

[0193] Use of systemic corticosteroids for at least 3 days; the dose of a single depot injection of corticosteroid is considered equivalent to a 3-day course of systemic corticosteroids - Use of antibiotics; - Hospitalization for treatment of COPD (defined as hospitalization for more than 24 hours in a hospital, observation area, emergency department, or other equivalent medical facility, depending on the country and healthcare system) - Resulting in death

[0194] A worsening / onset of symptoms must include at least one major COPD symptom from the following list and at least one other major or minor symptom: - Major COPD symptoms: Dyspnea, amount of sputum, and color of sputum - Minor COPD symptoms: Cough, wheeze, pharyngitis, cold symptoms (runny nose or nasal congestion), and fever without other cause

[0195] If treatment with systemic corticosteroids and / or antibiotics is required and the patient does not require hospitalization or die, the exacerbation is considered moderate. If hospitalization or death occurs, the exacerbation is considered severe.

[0196] Spirometry Patients must be instructed not to use ICS / LABA / LAMA medications within 12 hours (24 hours for once-daily dosing) of scheduled on-site visit spirometry to avoid affecting FEV1 values before and after bronchodilators; thereafter, they can be taken on-site. For the same reason, patients must not use rescue (SABA and / or SAMA) medications within 6 hours of scheduled on-site visit spirometry.

[0197] For each on-site spirometry session, multiple forced expiratory efforts (at least 3 but no more than 8) are performed. Spirometry grading follows the ATS / ERS criteria for acceptability and reproducibility as detailed in the spirometry manual. The highest FEV1 and FVC are based on the best effort that meets the acceptance criteria. The highest recorded FEV1 and FVC do not have to be from the same effort and can be derived from separate efforts. Record the absolute measurements (for FEV1 and FVC) and the percentage of predicted normal values (Quanjer et al 2012).

[0198] Post-bronchodilator spirometry Maximum bronchodilation is induced using 4 inhalations of albuterol (90 μg measured dose) or salbutamol (100 μg measured dose) within 30 minutes ± 15 minutes of the final pre-bronchodilator spirometry measurement, regardless of the presence or absence of a spacer device. Post-bronchodilator spirometry is performed 20 - 30 minutes later. If the patient cannot tolerate 4 inhalations of the β-agonist, the treating physician may consider reducing the number of inhalations based on clinical judgment.

[0199] Patient-reported assessment items - Daily: EXACT-PRO / E-RS: COPD (for the first 56 weeks only), questionnaires on use of background medications, use of rescue medications, and symptom severity - Every 4 weeks for the first 56 weeks, then every 8 weeks: SGRQ, CAT, and EQ-5D-5L - 1 week after each visit scheduled for IP administration: Start of the Outcomes Questionnaire (OEQ) - Question 2 (for the first 56 weeks only)

[0200] St. George's Respiratory Questionnaire (SGRQ) The SGRQ is a 50-item PRO measure developed to assess the health status of patients with airway obstruction diseases (Jones et al 1991). The questionnaire is split into two parts: Part 1 consists of 8 items related to the severity of respiratory symptoms in the previous 4 weeks; Part 2 consists of 42 items related to daily activities and the psychosocial impact of the individual's respiratory system status. The SGRQ yields a total score as well as three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of overall functional impairment, with 100 indicating the worst possible health state and 0 indicating the best possible health state. Similarly, the domain scores range from 0 to 100, with higher scores indicating greater functional impairment. Specific details on the scoring algorithm are provided by the developers in the user manual (Jones 2009).

[0201] Patients complete the SGRQ of the eDiary on-site for Visit 1 screening and Visit 3 (randomization) prior to other study procedures. During the lead-in period and up to Week 56 of the treatment period, the SGRQ is available every 28 ± 7 days and is preferably completed at home before the study visit or on-site during the scheduled visit. After Week 56, the SGRQ is available every 56 ± 7 days and is preferably completed at home before the study visit or on-site during the scheduled visit.

[0202] COPD Assessment Test (CAT) The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones et al 2009). This instrument uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. The content includes items related to cough, phlegm, chest discomfort, breathlessness when climbing hills / stairs, restriction of activities at home, confidence to go out of the house, sleep, and energy. The total CAT score is the sum of the item responses. The score ranges from 0 to 40, with higher scores indicating a greater impact of COPD on health status.

[0203] Patients complete the CAT in person at Visit 1 (screening) and Visit 3 (randomization) before other study procedures. During the lead-in period and up to Week 56 of the treatment period, the CAT is available every 28 ± 7 days and it is desirable to complete it at home before a study visit or in person during a scheduled visit. After Week 56, the CAT is available every 56 ± 7 days and it is preferred to complete it at home before a study visit or in person during a scheduled visit.

[0204] European Quality of Life-5 Dimensions (EQ-5D-5L) The EQ-5D-5L questionnaire assesses five domains: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each domain has five response options (no problems, slight problems, moderate problems, severe problems, and extreme problems) that reflect increasing levels of difficulty.

[0205] The patient is required to indicate their current health status by selecting the most appropriate level on each of five dimensions. The questionnaire also includes a Visual Analogue Scale (VAS) if the patient is required to rate their current health on a scale of 0 to 100 (where 0 represents the worst possible health state). The patient completes the eDiary EQ-5D-5L on-site at Visit 1 (Screening) and Visit 3 (Randomization) before any other study procedures. During the lead-in period and up to a maximum of 56 weeks during the treatment period, the EQ-5D-5L is available every 28 ± 7 days and it is preferred that it be completed at home before a study visit or on-site during a scheduled visit. After 56 weeks, the EQ-5D-5L is available every 56 ± 7 days and it is preferred that it be completed at home before a study visit or on-site during a scheduled visit.

[0206] Statistical Considerations The primary efficacy endpoint is the annual rate of moderate and severe COPD exacerbations over the first 56 weeks. The primary endpoint is first evaluated in the primary population (patients with three or more exacerbations in the previous year) and then in the overall population of patients with two or more exacerbations in the previous year. Estimates of treatment effect are applied to the primary analysis of the primary endpoint and include all data, regardless of whether the patient remained blinded to the IP.

[0207] The null hypothesis is that the exacerbation rate of benralizumab 100mg is equal to the exacerbation rate of placebo. The alternative hypothesis is that the exacerbation rate of benralizumab 100mg is not equal to the exacerbation rate of placebo, i.e.: H0: Rate ratio (benralizumab 100mg vs placebo) = 1 H1: Rate ratio (benralizumab 100mg vs placebo) ≠ 1

[0208] The hypothesis test for the annual rate of moderate and severe COPD exacerbations over 56 weeks in patients with three or more exacerbations in the previous year, which is the primary analysis, is conducted at a two-sided 5% significance level. If the p-value is less than 0.05 and the treatment effect is favorable for benralizumab, H0 is rejected and H1 is accepted.

[0209] Determination of Sample Size In this study, patients receiving triple (ICS / LABA / LAMA) background therapy with a baseline eosinophil count of 300 eosinophils / μL or more and at least 70% of the patients having at least 3 exacerbations in the previous year, with at least 2 exacerbations in the previous year, will be recruited. This study is strengthened for the primary population of patients with at least 3 exacerbations in the previous year. For the primary assessment of the annual exacerbation rate during the first 56 weeks, at least 304 patients / group (608 in total) with at least 3 exacerbations in the previous year will be randomized to benralizumab 100 mg vs placebo to achieve at least 90% power to detect a 30% reduction. This calculation assumes a two-sided 5% alpha level, a placebo rate of 2 times per year, and a negative binomial dispersion parameter of 0.5.

[0210] A total of 868 patients are expected to be randomized in this study, which will also include a cohort of patients with 2 exacerbations in the previous year to characterize the efficacy in patients with at least 2 exacerbations in the previous year.

[0211] For the important secondary assessment of the annual rate of severe exacerbations over the entire treatment period by EOT, at least 80% power is expected to detect a 40% reduction in benralizumab 100 mg compared to placebo in patients with at least 3 exacerbations in the previous year, and at least 90% power is expected in patients with at least 2 exacerbations in the previous year. This calculation assumes placebo rates of 0.30 and 0.27 in the primary and overall populations respectively, a negative binomial dispersion parameter of 2.7, and an average follow-up period of 2 years. A two-sided 5% significance level is assumed for both the >3 and >2 pre-exacerbation groups according to the multiple testing procedure.

[0212] Efficacy Assessment Items All efficacy evaluation items (shown in Table 5) were analyzed in patients with a history of exacerbation three or more times in the previous year (the primary population) and repeated in patients with a history of exacerbation two or more times in the previous year (the overall population). For continuously measured evaluation items (e.g., SGRQ and FEV1), if collected beyond week 56, additional models similar to those fitted to the data up to week 56 were used to evaluate these evaluation items over a longer follow-up period through to EOT.

[0213]

Table 7

[0214] Primary analysis method The primary efficacy variable was the annual exacerbation rate of moderate and severe COPD in the first 56 weeks, and the primary analysis was to compare the annual exacerbation rate of COPD with 100 mg of benralizumab to placebo in patients with a history of exacerbation three or more times in the previous year.

[0215] The exacerbation rate in the benralizumab treatment group was compared to the exacerbation rate in the placebo group using a negative binomial model. The response variable of the model was the number of COPD exacerbations over the first 56 weeks of the treatment period. The model included covariates of treatment group, region, and the number of exacerbations in the previous year. The logarithm of the first 56 weeks of follow-up time was used as an offset variable in the model.

[0216] The estimated treatment effect (i.e., the rate ratio of benralizumab to placebo), the corresponding 95% confidence interval (CI), and the two-sided p-value of the rate ratio are presented. In addition, the exacerbation rate and the corresponding 95% CI within each treatment group are presented.

[0217] Analysis method for secondary efficacy variables The primary analysis is repeated in patients with a history of two or more exacerbations in the previous year. All secondary efficacy endpoints are analyzed in patients with a history of three or more exacerbations in the previous year and repeated in patients with a history of two or more exacerbations in the previous year. Continuously measured endpoints (e.g., SGRQ and FEV1) are also evaluated over a longer follow-up period through EOT using an additional model similar to the model fitted to the data up to week 56 if collected beyond week 56.

[0218] The annual exacerbation rate of COPD leading to hospitalization or death (i.e., severe exacerbations) is analyzed through EOT using a negative binomial model similar to that outlined above. The annual exacerbation rate of COPD related to emergency department visits or hospitalizations is similarly analyzed through EOT.

[0219] The proportion of patients with one or more COPD exacerbations is treated as a variable supporting the primary objective. The proportion in the benralizumab group is compared to the proportion in the placebo group using a logistic regression model with region and number of exacerbations in the previous year as covariates.

[0220] The time to the first COPD exacerbation is analyzed as another supporting efficacy variable for the primary objective to investigate how much treatment with benralizumab delays the time to the first exacerbation compared to placebo. A Cox proportional hazards model is fitted to data including covariates of treatment, region, and number of exacerbations in the previous year.

[0221] Changes from baseline in the 56-week SGRQ total score and the three domain scores (symptoms, activity, and impact) are compared between benralizumab and placebo using repeated measures analysis in the FAS. The dependent variable is the change from baseline in the SGRQ score at the visits specified by the protocol after baseline (up to the 56-week visit). The treatment group is fitted as an explanatory variable, and region, visit, the interaction between visit and treatment, and the baseline SGRQ score are fitted as covariates. Visit is fitted as a categorical variable, and the variance-covariance matrix is estimated in the following order: unstructured, Toeplitz, first-order autoregressive, compound symmetry, and variance components. If the procedure does not converge, the following covariance matrix is used. The model is: Change in SGRQ score = treatment group + baseline SGRQ score + region + visit + treatment * which is visit.

[0222] The proportion of patients with a reduction (improvement) of 4 points or more in the 56-week SGRQ total score in the benralizumab group is compared with the proportion in the placebo group using the Cochran-Mantel-Haenszel test controlling for region.

[0223] Changes from baseline in pre-dose / before bronchodilator FEV1 at week 56 are analyzed in patients with at least one post-randomization pre-dose / before bronchodilator FEV1 using a repeated measures analysis similar to the model for changes from baseline in pre-dose / before bronchodilator FEV1 and SGRQ score at baseline.

[0224] Changes from baseline in the 56-week CAT total score and the E-RS: COPD score and domain scores at week 56 are analyzed separately using a model similar to the model for changes from baseline in the SGRQ score. ***

[0225] One of ordinary skill in the art will appreciate or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims.

[0226] Various publications are cited in this specification, and the disclosures thereof are incorporated herein by reference in their entirety.

[0227] The foregoing invention has been described in some detail through the drawings and examples for clarity of understanding, but it will be apparent that certain changes and modifications can be made within the scope of the appended claims.

[0228] Sequence Listing SEQ ID NO: 1 >US20100291073_1 Sequence 1 from US Patent Application Publication No. 20100291073 Organism: Homo sapiens

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[0231] SEQ ID NO: 4 >US20100291073_4 Sequence 4 from US Patent Application Publication No. 20100291073 Organism: Homo sapiens

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[0232] Accession Number: 5 >US20100291073_5 Sequence 5 from US Patent Application Publication No. 20100291073 Organism: Homo sapiens

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[0233] Accession Number: 6 >US20100291073_6 Sequence 6 from US Patent Application Publication No. 20100291073 Organism: Mus musculus

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Claims

1. A method for treating chronic obstructive pulmonary disease (COPD) in human COPD patients, comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, (c) received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

2. A method for reducing the annual exacerbation rate of chronic obstructive pulmonary disease (COPD), comprising administering to a human COPD patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, (c) received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

3. A method of increasing the one-second volume of forced vital capacity (FEV １ ) in a human patient with chronic obstructive pulmonary disease (COPD), comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein, prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, (c) received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

4. A method for increasing the forced vital capacity (FVC) in a human patient with chronic obstructive pulmonary disease (COPD), comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced two or more pre-exacerbations in the year prior to administration, (c) received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

5. The method according to any one of claims 1 to 4, wherein the COPD questionnaire score for determining COPD symptoms in the human COPD patient is improved.

6. The method according to any one of claims 1 to 5, wherein the patient has severe or very severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).

7. The method according to claim 6, wherein the patient has very severe COPD as defined by GOLD.

8. The method according to any one of claims 1 to 7, wherein the administration reduces the exacerbation rate of COPD.

9. The method according to any one of claims 2 to 8, wherein the exacerbation rate is reduced by at least 20%.

10. The method according to any one of claims 2 to 8, wherein the exacerbation rate is reduced by at least 30%.

11. The method according to any one of claims 2 to 8, wherein the exacerbation rate is reduced by at least 40%.

12. The method according to any one of claims 2 to 8, wherein the exacerbation rate is reduced by at least 50%.

13. The method according to any one of claims 2 to 8, wherein the exacerbation rate is reduced by at least 60%.

14. wherein said administration increases the FEV of said patient １ The method according to any one of claims 1 to 13

15. The method according to any one of claims 1 to 13, wherein the administration increases the FVC of the patient.

16. The method according to claim 6, wherein the COPD questionnaire is the COPD-Specific St. George's Respiratory Questionnaire (SGRQ-C).

17. The method according to claim 16, wherein the SGRQ-C (symptom) score of the patient is reduced by at least 5.

18. The method according to any one of claims 1 to 17, wherein the SGRQ-C (symptom) score of the patient is reduced by at least 9.

19. The method according to any one of claims 1 to 17, wherein the patient has experienced three or more pre-exacerbations in the year prior to the administration.

20. The patient receiving benralizumab is being treated simultaneously with triple background therapy, which includes an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), according to any one of claims 1 to 19.

21. The patient receiving benralizumab is not being concurrently treated with triple background therapy, which includes inhaled corticosteroids (ICS), long-acting β-agonists (LABA), and long-acting muscarinic antagonists (LAMA), according to any one of claims 1 to 19.

22. wherein the patient had an FEV of 80% or less of the predicted value prior to said administration of benralizumab or an antigen-binding fragment thereof １ The method according to any one of claims 1 to 21.

23. wherein the patient had an FEV of 70% or less of the predicted value before the administration of benralizumab or an antigen-binding fragment thereof １ The method according to any one of claims 1 to 21

24. wherein the patient had an FEV of 65% or less of the predicted value prior to said administration of benralizumab or an antigen-binding fragment thereof １ The method according to any one of claims 1 to 21.

25. wherein the patient had an FEV １ / forced vital capacity (FVC) of less than 0.70 prior to said administration of benralizumab or an antigen-binding fragment thereof, the method according to any one of claims 1 to 21.

26. The method according to any one of claims 1 to 25, wherein at least two doses of benralizumab or an antigen-binding fragment thereof are administered.

27. The method according to claim 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks to once every 12 weeks.

28. The method according to any one of claims 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks.

29. The method according to any one of claims 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 8 weeks.

30. The method according to any one of claims 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks for 12 weeks and then once every 8 weeks.

31. The method according to any one of claims 1 to 30, wherein the administration is subcutaneous.

32. A method for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or more, (b) has experienced 3 or more pre-exacerbations in the year prior to administration, (c) is receiving triple background therapy including inhaled corticosteroids (ICS), long-acting β-agonists (LABA), and long-acting muscarinic antagonists (LAMA).

33. A method for reducing the exacerbation rate of chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or more, (b) has experienced 3 or more pre-exacerbations in the year prior to administration, A method of receiving a triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

34. A method for increasing the one-second volume of forced vital capacity (FEV １ ) in a human patient with chronic obstructive pulmonary disease (COPD), comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein, prior to administration, the patient has: (a) Having an eosinophil count in the blood of 300 eosinophils / μL or more, (b) Experiencing three or more pre-exacerbations in the year prior to administration, (c) A method of receiving a triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

35. A method for increasing the forced vital capacity (FVC) in a human patient with chronic obstructive pulmonary disease (COPD), comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, and prior to administration, the patient has: (a) Having an eosinophil count in the blood of 300 eosinophils / μL or more, (b) Experiencing three or more pre-exacerbations in the year prior to administration, (c) A method of receiving a triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

36. The patient receiving benralizumab is being simultaneously treated with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), the method according to any one of claims 32 to 25.

37. The patient receiving benralizumab is not being simultaneously treated with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), the method according to any one of claims 32 to 35.

38. A method of treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, and prior to the first administration, the patient has: (a) Having an eosinophil count in the blood of 300 eosinophils / μL or more, (b) Experiencing two or more pre-exacerbations in the year prior to administration, A method in which a patient who has received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) is administered 100 mg of benralizumab once every 4 weeks for 12 weeks and then once every 8 weeks, and thereafter the patient no longer receives triple background therapy.

39. A method for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to the first administration, the patient has: (a) a blood eosinophil count of 300 eosinophils / μL or more, (b) experienced 3 or more exacerbations in the year prior to administration, (c) received triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), and after administering 100 mg of benralizumab once every 4 weeks for 12 weeks and then once every 8 weeks, the patient no longer receives triple background therapy.

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