Methods for treating chronic obstructive pulmonary disease in enriched patient populations using benralizumab

Abstract

Provided herein are methods for treating chronic obstructive pulmonary disease (COPD) in a patient, the method comprising administering to the patient an effective amount of benralizumab or an antigen-binding fragment thereof.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on March 26, 2020, is named IL5R-607-WO-PCT_SL.txt and is 16,008 bytes in size. [Background technology]

[0002] Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence and is predicted to become the third leading cause of death and disability worldwide by 2020. The cost to society of treating COPD is high, accounting for approximately 3.4% of the total health 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, response to oral and inhaled corticosteroids (ICS) is related to the intensity of airway eosinophilic inflammation, and a sputum eosinophil count 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 used to control sputum eosinophilia above 3% in COPD has resulted in a decrease in the frequency of severe COPD exacerbations requiring hospital admission when patients progress to oral corticosteroid therapy. Standard therapy for acute exacerbations of COPD (AECOPD) includes treatment of inflammation with systemic corticosteroids, which leads to a decrease in the length of hospitalization and accelerated recovery. Corticosteroids cause early apoptosis of eosinophils, generally resulting in a decrease in eosinophilia. However, long-term therapy with corticosteroids is associated with serious side effects such as suppression of the hypothalamic-pituitary-adrenal axis and osteoporosis, and corticosteroids do not prevent exacerbations in all patients with eosinophilic COPD.

[0005] COPD patients with elevated sputum eosinophil counts have a reduced forced vital capacity in 1 second (FEV1), which is associated with decreased sputum eosinophil counts and eosinophil cationic protein (ECP) levels. 1 ) and quality of life scores. Thus, therapy that specifically targets 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 cellular cytotoxicity.

[0007] Therefore, given the strong unmet need to treat COPD without corticosteroid-induced side effects and the fact that some patients with COPD have an eosinophilic component, we examined the effect of benralizumab for COPD in adult subjects. Summary of the Invention [Means for solving the problem]

[0008] Provided herein are methods of treating chronic obstructive pulmonary disease (COPD) in a human COPD patient.

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

[0010] In certain aspects, described herein is a method of reducing the annual exacerbation rate of COPD, comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to a human COPD patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced two or more prior exacerbations in the year prior to administration, and (c) is receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). In certain aspects, described herein is a method of reducing the annual exacerbation rate of severe or very severe COPD, comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to a human COPD patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced 2 or more prior exacerbations in the year prior to administration, and (c) is receiving a triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0011] In certain embodiments, the forced vital capacity in 1 second (FEV) in human chronic obstructive pulmonary disease (COPD) patients is 1Described herein is a method for increasing eosinophil count (EGFR) in patients with rheumatoid arthritis (HA) comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced two or more prior exacerbations in the year prior to administration, and (c) is receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

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

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

[0014] In some embodiments, patients receiving benralizumab are concurrently treated with a triple background therapy, the triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0015] In some embodiments, patients receiving benralizumab are not currently being treated with a triple background therapy, the triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (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 Pulmonary 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 of the first administration of benralizumab or an antigen-binding fragment thereof. In some embodiments, the exacerbation rate is reduced within six months of the first administration of benralizumab or an antigen-binding fragment thereof.

[0019] In some embodiments, the patient has a post-bronchodilator FEV of 80% or less (e.g., 70% or less, or 65% or less) of the predicted normal value prior to administration of benralizumab or an antigen-binding fragment thereof. 1 had.

[0020] In some embodiments, administration reduces the patient's FEV 1 In certain embodiments, increased FEV 1 is the pre-bronchodilator FEV 1In some embodiments, the pre-bronchodilator FEV 1 In some embodiments, the pre-bronchodilator FEV 1 In some embodiments, the FEV 1 The increase in FEV after bronchodilator therapy 1 In some embodiments, the post-bronchodilator FEV 1 In certain embodiments, the post-bronchodilator FEV 1 In some embodiments, the pre-bronchodilator FEV 1 and post-bronchodilator FEV 1 In some embodiments, the FEV 1 increases within one year of 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 pre-bronchodilator FVC. In some embodiments, the increase in FVC is post-bronchodilator FVC. In some embodiments, the pre-bronchodilator FVC and the post-bronchodilator FVC are increased. In some embodiments, the FVC is increased by at least 3%. In some embodiments, the FVC is increased within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0022] In some embodiments, administration improves a COPD questionnaire score that measures 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 (symptoms) score is reduced by at least 5. In certain aspects, the patient's SGRQ-C (symptoms) score is reduced by at least 7.

[0023] In some embodiments, the patient has an FEV of less than 0.70 prior to administration of benralizumab or an antigen-binding fragment thereof. 1 / had forced vital capacity (FVC).

[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 on 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 one 4-week dosing interval, then at least one 8-week dosing interval. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at three 4-week dosing intervals, 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 once every 8 weeks thereafter.

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

[0027] In certain aspects, described herein is a method of treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to the patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced 3 or more prior exacerbations in the year prior to administration, and (c) is receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0028] In certain aspects, described herein is a method of reducing exacerbation rate of chronic obstructive pulmonary disease (COPD) in a human COPD patient, comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to the patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced 3 or more prior exacerbations in the year prior to administration, and (c) is receiving a triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0029] In certain embodiments, the forced vital capacity in 1 second (FEV) in human chronic obstructive pulmonary disease (COPD) patients is 1 Described herein is a method for increasing eosinophil count (EGFR) in patients with rheumatoid arthritis (HA) comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to a patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced 3 or more prior exacerbations in the year prior to administration, and (c) is receiving a triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

[0030] In certain aspects, described herein is a method of increasing forced vital capacity (FVC) in a human chronic obstructive pulmonary disease (COPD) patient, comprising administering a dose of 100 mg of benralizumab or an antigen-binding fragment thereof to the patient, where prior to administration, the patient: (a) has a blood eosinophil count of 300 eosinophils / μL or greater, (b) has experienced 3 or more prior exacerbations in the year prior to administration, and (c) is receiving a triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 shows the study flow chart described in Examples 1 and 2. [Diagram 2] Figures 2A-B are graphs showing the annualized exacerbation rates (all = Figure 2A and severe = Figure 2B) for patients in the studies described in Examples 1 and 2. The data show that 100 mg of benralizumab is more effective than the 10 mg and 30 mg doses in reducing annualized exacerbation rates for COPD, and is particularly effective than the 10 mg and 30 mg doses in reducing severe COPD exacerbations. [Diagram 3] 3A-B are graphs showing the change from baseline in lung function (FEV1) for GALATHEA and TERRANOVA (FIG. 3A), and the change from baseline in SGRQ scores for GALATHEA and TERRANOVA (FIG. 3B). Overall, the data show that 100 mg benralizumab has a superior treatment effect in improving lung function (FEV1) and SGRQ scores at doses of 10 mg and 30 mg. [Figure 4] 4A-B are graphs showing median blood eosinophil counts over time with benralizumab treatment for patients with baseline blood eosinophil counts of 220 cells / μL or greater in GALATHEA (FIG. 4A) and TERRANOVA (FIG. 4B). [Diagram 5] Figures 5A-B are graphs showing the annualized COPD exacerbation rate ratios for patients receiving 100 mg benralizumab in TERRANOVA, analyzed by prior exacerbation (Figure 5A) and background therapy (Figure 5B) in patients with baseline blood eosinophil counts ≥ 220 cells / μL. TERRANOVA showed a 23% reduction in annualized exacerbation rate (AER) for patients with ≥ 3 exacerbations in the pretreatment year compared to a 2% reduction in AER for patients with ≤ 2 exacerbations in the pretreatment year. TERRANOVA also showed a 17% reduction in AER for patients receiving triple inhalation therapy compared to a 7% reduction in AER for the overall population. [Figure 6]Figures 6A-B are graphs showing annualized COPD exacerbation rate ratios for patients receiving 100 mg of benralizumab in GALATHEA, analyzed by prior exacerbation (Figure 6A) and background therapy (Figure 6B) in patients with baseline blood eosinophil counts ≥ 220 cells / μL. GALATHEA showed a 2% reduction in annualized exacerbation rate (AER) for patients with ≤ 2 exacerbations in the prior year, and a 39% reduction in AER for patients with ≥ 3 exacerbations in the prior year, compared with an 18% reduction in AER for patients receiving triple inhalation therapy compared with placebo. [Figure 7] Figures 7A-B show annualized COPD exacerbation rate ratios analyzed by baseline blood eosinophil levels for GALATHEA (Figure 7A) and for TERRANOVA (Figure 7B). As a stratification criterion only, there was no clear trend between increasing baseline blood eosinophil counts and treatment effect. [Figure 8] Figures 8A-8D show the annualized overall exacerbation rate (ERR) and severe exacerbation rate (severe ERR) for GALATHEA and TERRANOVA in patients with ≥300 eosinophils / μL and receiving triple background therapy (ICS / LABA / LAMA), analyzed by prior exacerbation in the year prior to dosing - ERR in patients with ≤2 exacerbations (Figure 8A); Severe ERR in patients with ≤2 exacerbations (Figure 8B); ERR in patients with ≥3 exacerbations (Figure 8C); and Severe ERR in patients with ≥3 exacerbations (Figure 8D). The data show that patients with ≥300 eosinophils / μL, receiving triple background therapy (ICS / LABA / LAMA), and having ≤2 exacerbations in the year prior to dosing experienced benefit from benralizumab therapy. Patients with ≥ 300 eosinophils / μL, receiving triple background therapy (ICS / LABA / LAMA), and with ≥ 3 exacerbations in the previous year experienced the greatest benralizumab treatment effect, especially at the 100 mg dose. [Figure 9]9A-D show annualized COPD exacerbation rate ratios analyzed by respiratory disease characteristics for GALATHEA (FIGS. 9A, 9C) and TERRANOVA (FIGS. 9B, 9D) at doses of 30 mg and 100 mg in patients with baseline eosinophil counts ≥ 220 cells / μL. The data show that [Figure 10] 10A-B show the effect of benralizumab versus placebo on annualized exacerbation rate (AER) in moderate / severe and severe patients. [Figure 11] FIG. 11 shows the study flow chart described in Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] This disclosure describes novel study populations identified based on the findings of GALATHEA and TERRANOVA, a clinical Phase 3 trial 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 those receiving triple background therapy as most likely to respond to benralizumab 100 mg treatment. In particular, the results of the subgroup analyses were as follows: -Compared to placebo, benralizumab 100 mg reduced the annual rate of severe COPD exacerbations by more than 30%. -Patients on triple (ICS / LABA / LAMA) background therapy (approximately 70% and 60% of patients in GALATHEA and TERRANOVA, respectively) showed consistent treatment effects on annualized COPD exacerbation rate with benralizumab 100mg in both studies. With benralizumab 100mg, GALATHEA demonstrated an 18% reduction in AER compared to placebo in patients on triple background therapy. With benralizumab 100mg, TERRANOVA demonstrated a 17% reduction in AER in patients on triple background therapy compared to a 7% reduction in AER in the overall population. - Patients with more frequent exacerbations (≥3 vs ≤2) in the year prior to benralizumab treatment had a greater treatment effect with benralizumab 100 mg on annual COPD exacerbation rate and annual severe COPD exacerbation rate. However, patients with ≤2 exacerbations in the year prior to treatment still experienced a benefit from benralizumab therapy. – No effect of treatment on annual COPD exacerbation rate was observed in patients with baseline blood eosinophil counts below 220 cells / μL.

[0033] These subpopulation findings were consistent across studies and supported by pooled analyses. Collectively, these characteristics identify patients most likely to benefit from benralizumab treatment.

[0034] It should be noted that an entity preceded by the term "a" or "an" refers to one or more of that entity, for example, "an 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] Provided herein is a method for treating chronic obstructive pulmonary disease (COPD). The method includes administering an effective amount of benralizumab or an antigen-binding fragment thereof.

[0036] Information regarding benralizumab (or a fragment thereof) for use 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. Benralizumab and antigen-binding fragments thereof for use in the methods provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a further aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises any one of the amino acid sequences of SEQ ID NOs: 1-4. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 4. In a specific embodiment, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NOs: 7-9, and the light chain variable region comprising the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NOs: 10-12. One of skill in the art would be able to readily identify Chothia-defined, Abm-defined, or other CDRs. In a specific embodiment, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy and variable light chain CDR sequences of the KM1259 antibody disclosed in U.S. Patent No. 6,018,032, which is incorporated herein by reference in its entirety.

[0037] An acute exacerbation of COPD (AECOPD) is a persistent worsening of a patient's condition from a stable state that is acute in onset and goes beyond normal day-to-day fluctuations, necessitating a change in usual medication in patients with underlying COPD.

[0038] In certain embodiments, patients with COPD presenting to a doctor's office or emergency department (ED) 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 US Patent Publication No. 2010 / 0291073), benralizumab or an antigen-binding fragment thereof may be administered only once or only infrequently while still providing benefit to the patient. In further embodiments, the patient is administered further follow-on doses. The follow-on doses may be administered at various time intervals depending on the patient's age, weight, ability to follow physician's orders, clinical evaluation, eosinophil counts (blood or sputum eosinophil or eosinophilic cationic protein (ECP) measurements), or other factors including the judgment of the attending physician. The intervals between doses may be every 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, or longer. In certain embodiments, the dose intervals can be every 4 weeks or every 8 weeks. In certain embodiments, the dose intervals 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., at days 0, 4, and 8), followed by 8-week dosing intervals (i.e., at 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, followed by once every 8 weeks.

[0039] In certain embodiments, a single dose or a first dose is administered to a COPD patient shortly after the patient has an acute exacerbation, e.g., a mild, moderate, or severe exacerbation. For example, a single dose or a first dose of benralizumab or an antigen-binding fragment thereof is administered during a clinic or hospital visit or, in the case of a very severe exacerbation, within 1, 2, 3, 4, 5, 6, 7 or more days, e.g., within 7 days, of the acute exacerbation, allowing the patient's condition to be stabilized prior to administration of benralizumab.

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

[0041] The amount of benralizumab or an antigen-binding fragment thereof administered to a patient may 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 dependent on eosinophil levels.

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

[0043] In certain aspects, the administration of benralizumab or an antigen-binding fragment thereof according to 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 simultaneously with additional therapy. Such therapy includes, without limitation, corticosteroid therapy (including inhaled corticosteroids (ICS)), long-acting beta agonists (LABA, including long-acting beta 2 agonists), long-acting muscarinic antagonists (LAMA, including tiotropium), or other standard therapy. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered by the methods provided herein in combination with or simultaneously with ICS and LABA, LABA and LAMA, or ICS, LABA, and LAMA. In certain embodiments, "triple background therapy" refers to ICS, LABA, and LAMA.

[0045] In certain cases, administration of benralizumab or an antigen-binding fragment thereof reduces COPD exacerbations, including, for example, as measured by exacerbation rate, annualized exacerbation rate, time to first exacerbation, and / or annualized 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., administration of benralizumab or an antigen-binding fragment thereof, reduces the number of exacerbations experienced by a patient compared to the number of exacerbations expected by the patient's medical history, compared to the average number of exacerbations expected in a comparable population of patients, or compared to a comparable population treated with a placebo over the same period of time. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients with an eosinophil count of at least 300 eosinophils / μL prior to administration. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients with an eosinophil count of at least 400 eosinophils / μL prior to administration. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients with 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 (2018 revision). In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients with very severe COPD as defined by GOLD. In certain embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients with severe or very severe COPD as defined by GOLD. In certain aspects, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations in COPD patients receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting beta-agonists (LABAs) (e.g., long-acting beta 2 agonists), and long-acting muscarinic antagonists (LAMAs) (including, e.g., tiotropium).

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

[0048] In certain aspects, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations (e.g., reduces the annualized exacerbation rate) in COPD patients who exhibit the following characteristics prior to administration: a) have a blood eosinophil count of 300 eosinophils / μL or greater, b) have experienced 2 or more prior exacerbations in the year prior to administration, and c) are receiving triple background therapy including inhaled corticosteroids (ICS), a long-acting beta-agonist (LABA) (e.g., a long-acting beta2 agonist), and a long-acting muscarinic antagonist (LAMA) (e.g., including tiotropium). In certain aspects, administration of benralizumab or an antigen-binding fragment thereof reduces the number of exacerbations (e.g., reduces the annualized exacerbation rate) in COPD patients who exhibit the following characteristics prior to administration: a) have a blood eosinophil count of 300 eosinophils / μL or greater, b) have experienced 3 or more prior exacerbations in the year prior to administration, and c) are receiving triple background therapy including inhaled corticosteroids (ICS), a long-acting beta-agonist (LABA) (e.g., a long-acting beta2 agonist), and a long-acting muscarinic antagonist (LAMA) (e.g., including tiotropium).

[0049] In certain aspects, administration of benralizumab or an antigen-binding fragment thereof treats chronic obstructive pulmonary disease (COPD) in patients who exhibit the following characteristics prior to administration: (a) a blood eosinophil count of 300 eosinophils / μL or greater; (b) three or more prior exacerbations in the year prior to administration; and (c) receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), and after administration of 100 mg of benralizumab once every 4 weeks for 12 weeks and once every 8 weeks thereafter, the patient is no longer receiving triple background therapy. In certain aspects, administration of benralizumab or an antigen-binding fragment thereof treats chronic obstructive pulmonary disease (COPD) in patients who exhibit the following characteristics prior to administration: (a) a blood eosinophil count of 300 eosinophils / μL or greater, (b) two or more prior exacerbations in the year prior to administration, and (c) receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), and after administration of 100 mg of benralizumab once every 4 weeks for 12 weeks and once every 8 weeks thereafter, the patient is no longer receiving triple background therapy.

[0050] In certain aspects, administration of benralizumab or an antigen-binding fragment thereof reduces exacerbations 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, exacerbations are reduced by about 17%, or about 18%. In some embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces severe exacerbations 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 exacerbations are reduced by about 32%, or about 43%. Exacerbations (moderate or severe) can be reduced, for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof. In one embodiment, exacerbations (moderate or severe) can be reduced within six months of the first administration of benralizumab or an antigen-binding fragment thereof.

[0051] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces exacerbation rate (e.g., reduces annualized 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.

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

[0053] The methods provided herein can also reduce exacerbation rates (e.g., reduce annual exacerbation rates) in COPD patients with severe or very severe COPD (as defined by GOLD), e.g., 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 annual exacerbation rates in patients with moderate to very severe COPD. In determining annual COPD exacerbation rates, a COPD exacerbation is defined as a symptomatic worsening of COPD requiring: Use of systemic corticosteroids for at least 3 days (a dose of a single depot injectable solution of corticosteroids 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 first COPD exacerbation after a first administration of benralizumab or an antigen-binding fragment thereof compared to after a first administration of a 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) compared to the likelihood of a COPD exacerbation following treatment with a placebo.

[0057] In some instances, administration of benralizumab or an antigen-binding fragment thereof reduces the annual rate of emergency room or hospitalization-associated COPD exacerbations compared to administration of a placebo.

[0058] In certain instances, administration of benralizumab or an antigen-binding fragment thereof can be used to improve, for example, forced vital capacity in 1 second (FEV 1 ) or forced vital capacity, improves lung function in COPD patients.

[0059] The methods provided herein include measuring forced vital capacity in 1 second (FEV) in COPD patients. 1 ) can be increased by 100%. The increase is based on the predicted FEV 1 Based on the FEV 1 Based on the individual patient's FEV 1 In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, can be measured based on a patient's baseline FEV 1 Compared with FEV 1 In some embodiments, the FEV 1 The increase in FEV before bronchodilator 1 In some embodiments, the FEV 1 The increase in FEV after bronchodilator therapy 1 In some embodiments, the FEV 1 The increase in FEV before bronchodilator 1 and post-bronchodilator FEV 1 FEV 1 (e.g., pre-bronchodilator and / or post-bronchodilator FEV 1 ) can be increased, for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0060] As used herein, "bronchodilator" refers to any drug that widens or expands the bronchi, bronchioles, or airways of the lungs, reduces the resistance of respiratory airways, and / or relaxes bronchial smooth muscle, thereby facilitating breathing.For example, bronchodilator includes short- and long-acting β2 agonists, such as albuterol / salbutamol and other drugs commonly used to treat asthma.

[0061] In some embodiments, the patient has a post-bronchodilator FEV ≤ 80% (e.g., ≤ 70% or ≤ 65%) of the predicted normal value prior to administration of benralizumab or an antigen-binding fragment thereof. 1 had.

[0062] In certain aspects, the methods provided herein include administering to a subject a subject in need of treatment with FEV 1 In certain embodiments, the methods provided herein can increase FEV by at least 5% or at least 10%. 1 In certain embodiments, the methods provided herein can increase pre-bronchodilator FEV by about 12%. 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV by at least 5% or at least 10%. 1 can be increased by approximately 12%.

[0063] In certain aspects, the methods provided herein include administering to a subject a subject in need of treatment with FEV 1 In certain embodiments, the methods provided herein can increase FEV by at least 5%. 1 In certain embodiments, the methods provided herein can increase the post-bronchodilator FEV by about 7%. 1 In certain embodiments, the methods provided herein can increase the post-bronchodilator FEV by at least 5%. 1 can be increased by approximately 7%.

[0064] In certain aspects, the methods provided herein include measuring pre-bronchodilator and post-bronchodilator FEV 1 In certain embodiments, the methods provided herein can increase pre-bronchodilator FEV by at least 5%. 1 at least 10% and post-bronchodilator FEV 1 In certain embodiments, the methods provided herein can increase pre-bronchodilator FEV by at least 5%. 1 12% and FEV after bronchodilator therapy 1 can be increased by approximately 7%.

[0065] As provided herein, administration of benralizumab or an antigen-binding fragment thereof can also be used to improve, for example, predicted FEV in COPD patients pre-bronchodilator and / or post-bronchodilator. 1 For example, the predicted FEV 1 The percentage can be increased by about 3.0, about 3.5, about 4.0, or about 4.5.

[0066] The methods provided herein are intended to assess FEV 1 in COPD patients with blood eosinophil counts of at least 300 eosinophils / μL, and / or in patients receiving corticosteroids (e.g., inhaled corticosteroids (ICS), long-acting beta-agonists (LABAs) (e.g., long-acting beta 2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium), and / or in patients who have experienced 2 or more or 3 or more prior exacerbations in the year prior to treatment. 1In 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 beta-agonists (LABAs) (e.g., long-acting beta2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium), and c) have experienced 2 or more prior exacerbations in the year prior to dosing. 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 beta-agonists (LABAs) (e.g., long-acting beta2-agonists), and long-acting muscarinic antagonists (e.g., tiotropium), and c) have experienced 3 or more prior exacerbations in the year prior to dosing. In certain embodiments, the methods provided herein include measuring FEV 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by at least 10% or at least 15%. 1 In certain embodiments, the methods provided herein can increase the post-bronchodilator FEV in such patients by at least 10% or at least 15%. 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by about 10%. 1 and post-bronchodilator FEV 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by at least 10%. 1 at least 15% and post-bronchodilator FEV 1 can be increased by at least 10%.

[0067] The methods provided herein provide for the assessment of FEV in COPD patients with blood eosinophil counts of at least 300 eosinophils / μL or in COPD patients with severe or very severe COPD as defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD). 1 In certain embodiments, the methods provided herein can increase FEV in such patients. 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by at least 15% or at least 20%. 1 In certain embodiments, the methods provided herein can increase the post-bronchodilator FEV in such patients by at least 15% or at least 20%. 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by about 15%. 1 and post-bronchodilator FEV 1 In certain embodiments, the methods provided herein can increase the pre-bronchodilator FEV in such patients by at least 15%. 1 at least 20% and post-bronchodilator FEV 1 can be increased by at least 15%.

[0068] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, results in an increase in FEV 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. 1 In certain aspects, administration of benralizumab or an antigen-binding fragment thereof increases FEV 1 Use of the methods provided herein improves FEV 1may be increased 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 COPD patients. The increase can be measured based on expected FVC based on a large patient population before administration, on FVC measured in a control population, or on the FVC of an individual patient. In certain aspects, the 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 pre-bronchodilator FVC. In some embodiments, the increase in FVC is post-bronchodilator FVC. In some embodiments, the increase in FVC is pre-bronchodilator FVC and post-bronchodilator FVC. FVC (e.g., pre-bronchodilator and / or post-bronchodilator FVC) can be increased, for example, within one 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 pre-bronchodilator FVC by at least 2%, at least 3%, at least 5%, or at least 10%. In certain embodiments, the methods provided herein can increase post-bronchodilator FVC by at least 2%, at least 3%, at least 5%, or at least 10%. In certain embodiments, the methods provided herein can increase pre-bronchodilator and post-bronchodilator FVC by at least 2%, at least 3%, at least 5%, or at least 10%. In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, increases 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, or within 56 weeks or more.

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

[0072] Also provided herein is a method for improving respiratory symptoms, as measured by baseline dyspnea index / transitional dyspnea index (TDI).For example, administration of benralizumab or an antigen-binding fragment thereof can improve (increase) the BDI score of a COPD patient by at least 1, at least 2, or at least 3 and / or produce a positive TDI score.The BDI / TDI score can improve, for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0073] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves BDI / TDI scores 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.

[0074] Also provided herein is a method for improving respiratory symptoms as measured by Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS). For example, administration of benralizumab or an antigen-binding fragment thereof can improve (reduce) the E-RS score of a COPD patient 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 be improved, for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0075] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves 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.

[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 Tool (CAT).

[0077] Provided herein is a method for improving COPD symptoms, 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 of the first administration of benralizumab or an antigen-binding fragment thereof.

[0078] In certain aspects, the 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, or within 56 weeks, or more. In certain aspects, 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] Also provided herein is a method for improving COPD symptoms, as determined using a COPD questionnaire, such as the COPD-specific St. George's Respiratory Questionnaire (SGRQ-C). For example, administration of benralizumab or an antigen-binding fragment thereof can improve the SGRQ-C (symptoms) score of a COPD patient 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 (symptoms) score can improve, for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0080] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves SGRQ-C (symptoms) 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.

[0081] Also provided herein is a method for improving COPD symptoms, for example as determined using the COPD Assessment Tool (CAT). For example, administration of benralizumab or an antigen-binding fragment thereof can improve (reduce) the CAT score of a COPD patient 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 be improved (reduced), for example, within one year of the first administration of benralizumab or an antigen-binding fragment thereof.

[0082] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves (reduces) 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 more.

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

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

[0085] In certain aspects, use of the methods provided herein, i.e., 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 aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces the annual rate of hospitalization due to COPD.

[0087] In certain aspects, use of the methods provided herein, i.e., 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 aspects, use of the methods provided herein, i.e., 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 an antigen-binding fragment thereof, reduces the annual rate of unscheduled medical encounters due to COPD.

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

[0091] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces the annual rate of severe COPD exacerbations, where a severe COPD exacerbation is defined as a symptomatic worsening of COPD requiring hospitalization for treatment or resulting in death from COPD.

[0092] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof to a COPD patient, reduces forced vital capacity in 1 second (FEV 1 ), increasing forced vital capacity (FVC), reducing COPD exacerbation rates, and / or improving COPD questionnaire scores (e.g., COPD Control Questionnaire).

[0093] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof to COPD patients, reduces the annual COPD exacerbation rate, improves SGRQ scores, and improves FEV 1 (e.g., in COPD patients with baseline blood eosinophil counts ≥ 300 cells / μL).

[0094] In certain embodiments, the COPD patient was prescribed or used corticosteroids (e.g., inhaled corticosteroids (ICS)), long-acting beta-agonists (LABAs, e.g., long-acting beta 2 agonists), and long-acting muscarinic antagonists (LAMAs) prior to administration of benralizumab or an antigen-binding fragment thereof. In certain embodiments, the COPD patient is treated with ICS, LABA, and LAMA simultaneously with benralizumab or an antigen-binding fragment thereof. In certain embodiments, the COPD patient is not treated with ICS, LABA, and LAMA simultaneously with benralizumab or an antigen-binding fragment thereof.

[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 an antigen-binding fragment thereof. In certain embodiments, the exacerbation history includes at least three exacerbations in the year prior to administration of benralizumab or an antigen-binding fragment thereof. In certain embodiments, the patient has a forced vital capacity (FEV) of less than 80% of predicted prior to administration. 1 In certain embodiments, the patient has an FEV of less than 0.70 prior to administration. 1 / FVC.

[0096] In certain embodiments, the COPD patient has a certain blood eosinophil count, e.g., before administration of benralizumab or an antigen-binding fragment thereof. The blood eosinophil count can be measured, e.g., using a complete blood count (CBC) with cell differential. In certain embodiments, the COPD patient has a blood eosinophil count of 300 eosinophils / μL or more before administration of benralizumab or an antigen-binding fragment thereof. In certain embodiments, the patient has a blood eosinophil count of 300-450 eosinophils / μL before administration of benralizumab or an antigen-binding fragment thereof. In certain embodiments, the patient has a blood eosinophil count of more than 400 eosinophils / μL before administration of benralizumab or an antigen-binding fragment thereof. In certain embodiments, the patient has a blood eosinophil count of more than 450 eosinophils / μL before administration of benralizumab or an antigen-binding fragment thereof.

[0097] In a particular embodiment, the COPD patient has moderate COPD as defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), i.e. GOLD II. In a particular embodiment, the COPD patient has severe COPD as defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), i.e. GOLD III. In a particular embodiment, the COPD patient has very severe COPD as defined by GOLD, i.e. GOLD IV. In a particular embodiment, the COPD patient has severe or very severe COPD as defined by GOLD, i.e. GOLD III or IV. EXAMPLES

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

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

[0100] Eligible patients will be stratified by country and blood eosinophil count (≥300 cells / μL and <300 cells / μL). In the cohorts with baseline eosinophil counts <220 cells / μL, 220-299 cells / μL, and ≥300 cells / μL, recruitment was centrally restricted to maintain a predefined cohort size and an approximately 2:1 ratio of patients with eosinophil counts ≥220 cells / μL and <220 cells / μL (primary analysis population). This design enriched the study population with patients likely to respond to benralizumab (blood eosinophil counts ≥220 cells / μL) and allowed evaluation of the benralizumab benefit:risk ratio in COPD patients across a range of blood eosinophil counts. Dose selection was based on the approved asthma dose of 30 mg, 100 mg to inform a safety margin, and 10 mg to evaluate the dose-effectiveness relationship.

[0101] At randomization, eligible patients were assigned in a 1:1:1 or 1:1:1:1 ratio to receive placebo or benralizumab (GALATHEA, 30 mg or 100 mg; TERRANOVA, 10 mg, 30 mg, or 100 mg), respectively. Complete eligibility criteria are provided in the study protocol (available at NEJM.org). Study medication was administered by subcutaneous injection every 4 weeks for the first three doses and every 8 weeks thereafter. Patients' maintenance and rescue medication use was recorded daily via electronic diary (eDiary) during the study. Eligibility for randomization included ≥70% compliance with 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 of 220 cells / μL or higher. The primary endpoint for both studies was the annualized rate of COPD exacerbations at week 56. Key secondary endpoints included pre-bronchodilator forced vital capacity in 1 second (FEV 1 Clinical outcomes and outcomes included change from baseline in schizophrenia, nausea, vomiting, and vomiting severity (SGH) and the St. George's Respiratory Questionnaire (SGRQ) score. Safety outcomes included type and frequency of adverse events (AEs).

[0103] A COPD exacerbation was defined as a symptomatic worsening of COPD, which resulted in oral corticosteroid use and / or antibiotic use for ≥3 days and / or COPD-related hospitalization or death (see Supplementary Appendix). Respiratory symptoms were recorded daily in the eDiary and assessed at the center visit. Patients completed the SGRQ during the center visit. Additional assessments utilized but not reported included the COPD Assessment Test, Baseline Dyspnea Index / Transitional Dyspnea Index, Exacerbations of Chronic Lung Disease Tool-Patient Reported Endpoint, and EuroQOL 5D 5L. Spirometry data were collected at the center visit along with safety data, but the readout of results was centralized (see Supplementary Appendix).

[0104] Study Procedure Data were collected from all patients during the following time periods: -Registered (-4th week) - Every 2 weeks during the run-in / screening period (weeks -3 to -1) - Randomization (week 0) and during the induction period (week 2) - Every 4 weeks during the reduction and maintenance phase (weeks 4-56) -Follow-up (week 60)

[0105] Spirometry Patients underwent pre-bronchodilator spirometry at enrollment, at visit 2 (week 3) during the run-in / screening period, and at weeks -3, 0, 4, 8, 16, 24, 32, 40, 48, and 56 during the treatment period. Patients underwent post-bronchodilator spirometry at visit 2 (week -3), and a subset of patients also underwent post-bronchodilator spirometry at enrollment, weeks -3, 0, 4, 8, 16, 24, 32, 40, 48, and 56. Spirometry was performed by study investigators or certified representatives in accordance with American Thoracic Society / European Respiratory Society guidelines.

[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. The instrument uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. Content includes items related to coughing, phlegm, chest tightness, shortness of breath when climbing hills / steps, activity limitations at home, confidence to leave the house, sleep, and energy. The CAT total 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. CAT testing was completed by patients at the following study center visits: Visit 4 (week 0), Visit 6 (week 4), Visit 7 (week 8), Visit 9 (week 16), Visit 11 (week 24), Visit 13 (week 32), Visit 15 (week 40), Visit 17 (week 48), and Visit 19 (week 56).

[0107] Assessment of COPD exacerbations A COPD exacerbation is defined as a change in a patient's usual COPD symptoms that lasts for more than two days, goes beyond the usual day-to-day variations, is acute in 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 injectable solution of corticosteroids that is considered equivalent to a 3-day course of systemic corticosteroids - Antibiotic use - Hospitalization for treatment of COPD (defined as a stay of 24 hours or more in a hospital, observation area, emergency department, or other equivalent healthcare facility, depending on the country and healthcare system)

[0108] A COPD exacerbation was considered moderate if it required treatment with systemic steroids and / or antibiotics and did not result in hospitalization or death. An exacerbation was considered severe if it resulted in hospitalization or death. Symptoms were judged by the patient every morning via the eDiary for the purpose of a symptom exacerbation alert. The purpose of this alert was to inform both the patient and the study center of symptoms of a potential exacerbation event that would warrant contact between the patient and the center for further evaluation. Every morning, patients completed three questions regarding the major symptoms of an exacerbation event (dyspnea, sputum volume, and sputum color). Patient-reported exacerbations of one or more of these symptoms were considered to be mild symptoms of an exacerbation event (sore throat, cold, fever without other cause, cough, and pantness Questions about the severity of symptoms relative to the patient's usual state had three response options (e.g., How breathless have you been in the past 24 hours? Less breathless than usual, usual level of breathlessness, more breathless than usual). Questions about 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 a sore throat).

[0109] An alert was generated by the eDiary system directed to the patient and the site if at least two major symptoms or one major and one minor symptom worsened for two consecutive days. As mentioned above, if an event was not associated with an eDiary symptom worsening alert (e.g., technical issues, patient self-reports symptom worsening / exacerbation event, exacerbation identified during a visit or phone contact, exacerbation assessed and treated at a non-study center, or acute / severe symptom worsening occurs not captured by the ePRO system), the investigator interviewed the patient and assessed the potential worsening and duration of the following symptoms: shortness of breath, mucus volume, mucus purulence, cough, wheezing, sore throat, cold symptoms such as runny or stuffy nose, fever, chest tightness, among other findings. The onset of an exacerbation was defined as the start date of systemic corticosteroid or antibiotic treatment or hospitalization, whichever occurred first, and the end date was defined as the last day of systemic corticosteroid or antibiotic treatment or discharge, whichever occurred later. COPD exacerbations occurring within 7 days of the last dose of systemic steroids (oral, intramuscular, intravenous) or antibiotics, or the last day of hospitalization, were counted as the same exacerbation event.

[0110] Assessment of blood eosinophils Patients were stratified by absolute blood eosinophil count assessed by a central laboratory (blood sample taken at Visit 1 [week -4]). Randomization was restricted at study level to baseline eosinophil cohorts (<220 cells / μL, 220–299 cells / μL, and ≥300 cells / μL) to maintain predefined cohort sample sizes and an approximately 2:1 ratio of patients above and below the 220 cells / μL boundary. Once any of the eosinophil cohorts were filled, patients assigned to that particular cohort based on Visit 1 eosinophil count failed screening.

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

[0112] Research Formulation Benralizumab for injection 20 mg / mL, 30 mg / mL, or 100 mg / mL solutions in accompanying prefilled syringes corresponding to 10 mg, 30 mg, and 100 mg were administered at the study center by subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks, with the final dose of benralizumab administered at week 48. Matching placebo solution for injection in accompanying prefilled syringes was administered at the study center by subcutaneous injection on the same schedule as benralizumab. Each study patient received two syringes, filled with 1 mL and 0.5 mL, respectively, to achieve blinding by a double-dummy design.

[0113] Clinical evaluation 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. The instrument uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. Content includes items related to coughing, phlegm, chest tightness, shortness of breath when climbing hills / steps, activity limitations at home, confidence to leave the house, sleep, and energy. The CAT total 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. CAT testing was completed by patients at the following study center visits: Visit 4 (week 0), Visit 6 (week 4), Visit 7 (week 8), Visit 9 (week 16), Visit 11 (week 24), Visit 13 (week 32), Visit 15 (week 40), Visit 17 (week 48), and Visit 19 (week 56).

[0114] St. George's Respiratory Questionnaire: The St. George's Respiratory Questionnaire (SGRQ) is a 50-item PRO instrument developed to measure the health status of patients with airway obstructive 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 condition. The SGRQ results in a total score as well as three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on the overall health status. This total score is expressed as a percentage of overall 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 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: Visit 4 (week 0), Visit 6 (week 4), Visit 7 (week 8), Visit 9 (week 16), Visit 11 (week 24), Visit 13 (week 32), Visit 15 (week 40), Visit 17 (week 48), and Visit 19 (week 56).

[0115] Baseline Dyspnea Index / Transition Dyspnea Index: The Baseline Dyspnea Index / Transition Dyspnea Index (BDI / TDI) are instruments developed to provide a multidimensional measure of dyspnea with respect to activities of daily living. The BDI provides a measure of dyspnea at each state, baseline, and the TDI assesses the change in dyspnea from the baseline state. The instruments consist of three components: impairment, task magnitude, and effort magnitude, rated on a 5-point scale for the BDI and a 7-point scale for the TDI. The BDI was completed by patients at the 4th study center visit (week 0). The TDI was completed by patients at the following study center visits: Visit 6 (week 4), Visit 7 (week 8), Visit 9 (week 16), Visit 11 (week 24), Visit 13 (week 32), Visit 15 (week 40), Visit 17 (week 48), and Visit 19 (week 56).

[0116] The Modified Medical Research Council Shortness of Breath Scale: The mMRC Shortness of Breath Scale uses a simple rating system to determine a patient's level of dyspnea consisting of five statements about perceived shortness of breath. It is an interviewer-administered ordinal scale in which patients rate their dyspnea on a five-point scale of increasing severity. The mMRC Shortness of Breath Scale was completed at the fourth study center visit (week 0).

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

[0118] EuroQOL 5D 5L: The EuroQOL 5D 5L assessed five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five response options reflecting increasing levels of difficulty (no problems, slight problems, moderate problems, severe problems, and extreme problems). Patients completed the EuroQOL 5D 5L weekly (± 2 days) at home.

[0119] Safety assessment Complete physical examination baseline data were collected at visit 1. Any new findings or worsening of existing findings were reported as adverse events. In addition to the physical examination, the following were recorded at each visit: smoking status, anthropometry, and vital signs. A 12-lead electrocardiogram (ECG) was also performed in the supine position after participants rested for at least 5 minutes. ECGs were performed at intervals.

[0120] A safety laboratory assessment was also performed for clinical chemistry, hematology, and urinalysis. Clinical chemistry characteristics included: 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] Hematology analyses included differential hematocrit, hemoglobin, mean corpuscular volume, platelet count, red blood cell count, and white blood cell count.

[0122] Urinalysis included: appearance, blood, color, glucose, ketones, white and red blood cell microscopy, pH, and specific gravity.

[0123] statistical analysis The primary analysis used the number of COPD exacerbations observed in patients during the 56-week double-blind treatment period as the response variable. Annual exacerbation rate = number of exacerbations * 365.25 / (last follow-up date – 4th visit date + 1).

[0124] Exacerbation rates in each benralizumab group were compared to the placebo group via a negative binomial model. The model included covariates for treatment group, eosinophil cohort (220-299 cells / μL or ≥300 cells / μL), country, background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA), and number of exacerbations in the year prior to the study. The logarithm of follow-up time was used as an offset variable in the model.

[0125] All secondary efficacy outcomes were analyzed in patients with baseline blood eosinophil counts ≥ 220 cells / μL. Pretreatment / pre-bronchodilator FEV at Week 56 1 Changes from baseline in baseline pre-treatment / pre-bronchodilator FEV in the full analysis set were 1 and at least one post-randomization pre-dose / pre-bronchodilator FEV 1 Comparisons were made between each of the three benralizumab dose groups and placebo by repeated measures analysis in patients with ≥ 100% CI, 0.01 to 0.05. The dependent variable was pre-bronchodilator FEV at any protocol-specified visit after baseline (up to the end-of-treatment visit). 1 Treatment group was fitted as an explanatory variable, along with eosinophil cohort (220–299 cells / μL or ≥300 cells / μL), country, background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA), visit, the interaction between visit and treatment, and pre-bronchodilator FEV 1 Baseline at was fitted as a covariate. Visit was fitted as a categorical variable and the variance-covariance matrix was estimated to be unstructured. The model was: FEV 1 Change in FEV1 = treatment group + eosinophil cohort (220-299 cells / μL or ≥300 cells / μL) + baseline FEV1 1 +Country+Background therapy (ICS / LABA, LABA / LAMA, or ICS / LABA / LAMA)+Visit+Treatment * It was a visit.

[0126] Changes from baseline in SGRQ total score and three domain scores (symptoms, activity, and impact) at week 56 were measured using pre-treatment / pre-bronchodilator FEV 1 The data were analyzed separately via a model similar to that described above for the change from baseline in

[0127] Sensitivity analyses for the primary and key secondary endpoints based on different missing data mechanism assumptions, including those expected to be more conservative, such as missing not at random, were used to explore the robustness of any treatment effects to multiple imputation approaches.

[0128] For each of the 30 mg and 100 mg treatment groups (for patients with baseline blood eosinophil counts of 220 cells / μL or higher), the primary endpoint (exacerbation rate) and two key secondary endpoints (FEV 1 To account for variability in testing the 100-item scale (100-item scale and SGRQ), the following testing strategy was used to control the overall type I error rate at a level of 0.05.

[0129] Step 1: Two trials of annualized COPD exacerbation rates (one trial for each dose vs. placebo) were performed via the Hochberg procedure with a family-wise error rate (FWER) of 0.04. 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 doses were tested as a family via the Holm procedure with a FWER of 0.05.

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

[0132] Secondary endpoints Both studies reported improvements in SGRQ scores for patients; however, an overall improvement in SGRQ scores was reported in patients from all treatment groups as well as the placebo group (least squares mean change from baseline, GALATHEA, placebo [-3.86] vs 10 mg [0.00] vs 30 mg [-4.87] vs 100 mg [-5.99]; 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 are designed to: 1) treat patients with moderate to very severe COPD (FEV after bronchodilator therapy); 1 / Forced vital capacity < 0.70 and predicted normal post-bronchodilator FEV 1 Patients aged 40-85 years were included if they had: 1) cumulative or past smoking exposure of >10 pack-years (screening >20% and ≤65%); 2) cumulative or past smoking exposure of >10 pack-years; 3) symptomatic (modified Medical Research Council breathlessness score ≥1 at screening); and 4) a documented history of ≥2 moderate COPD exacerbations requiring treatment with oral corticosteroids and / or antibiotics or ≥1 COPD exacerbation requiring hospitalization in the year prior to enrollment despite treatment with double (ICS / LABA or LABA / LAMA) or triple (ICS / LABA / LAMA) therapy throughout the previous year. Patients were excluded if they had a primary diagnosis of asthma (previous 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 significant pulmonary disease other than COPD (e.g., active pulmonary infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-associated hypoventilation syndrome, lung cancer, alpha-1 antitrypsin deficiency, and primary ciliary dyskinesia) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts (e.g., allergic bronchopulmonary aspergillosis / mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome) and / or radiological findings suggestive of a respiratory disease other than COPD contributing to the patient's respiratory symptoms; - Major physical disorder and / or any disorder that, in the opinion of the investigator, has not stabilized, including but not limited to: cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or any disorder that may be stable: -Affects patient safety throughout the study; - Influence the results or interpretation of the study; or - Interfering with the patient's ability to complete the study period. - Treatment with systemic corticosteroids and / or antibiotics and / or hospitalization for a COPD exacerbation within the 2 weeks prior to enrollment (Visit 1) or within the enrollment and screening / run-in period (based on the last dose of steroids or last date of hospitalization, whatever occurred thereafter). - Acute upper or lower respiratory tract infection within the 2 weeks prior to enrollment (Visit 1) or during the enrollment and screening / run-in period. - Pneumonia within 8 weeks prior to enrollment (Visit 1) based on the last date of antibiotic treatment or date of hospitalization (whatever occurred thereafter or after or during the enrollment and screening / run-in period).

[0135] statistical analysis For sample size calculations, an estimated 348 patients with baseline blood eosinophil counts ≥220 cells / μL per treatment group (total patients overall: GALATHEA, 1,044; TERRANOVA, 1,392) were required for the primary endpoint to provide 90% power to detect a 30% reduction in annualized exacerbation rate between the benralizumab 30 mg or 100 mg groups and placebo assuming a two-sided 4% alpha-level test.

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

[0137] Secondary efficacy outcomes were analyzed in patients with baseline blood eosinophil counts ≥ 220 cells / μL. Analyses of secondary outcomes were not multiply protected. Pre-bronchodilator FEV at Week 56 1 Changes from baseline in CI were compared between each of the benralizumab dose groups and placebo using repeated measures analysis. Changes from baseline in SGRQ total score at week 56 were analyzed separately with a similar model. Safety parameters were analyzed by count summary by study period.

[0138] Prespecified subgroup analyses by patient demographics, respiratory disease characteristics, prior medication use, and prior exacerbations (<3 or ≥3) were conducted for each study's primary efficacy variable. The studies were not designed or powered to evaluate efficacy within these subgroups; therefore, these analyses are considered exploratory.

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

[0140] In GALATHEA and TERRANOVA, ≥83% and ≥79% of patients, respectively, completed treatment across all treatment arms. The main reasons for discontinuation were AEs and patient discretion (data not shown).

[0141] [Table 1]

[0142] [Table 2]

[0143] Primary endpoint: In GALATHEA, patients treated with benralizumab compared with placebo had a reduction in annualized COPD exacerbation rate at week 56. Estimates (95% confidence intervals [CI]) of annualized exacerbation rates were 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; treatment effects vs. placebo were 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 vs. 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 reduction in annualized COPD exacerbation rate at week 56 compared with placebo. Estimates (95% CI) of annualized exacerbation rates were 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; treatment effects vs. placebo were 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 annual severe exacerbation rate (treatment effect vs. placebo, benralizumab 10 mg, 30 mg, and 100 mg, 0.75 [nominal P = 0.1478], 0.88 [nominal P = 0.4835], and 0.68 [nominal P = 0.0516], respectively) (Table 2, Figure 2).

[0145] Ranked Secondary Endpoints: At week 56, the differences in secondary endpoints for benralizumab compared with placebo were not statistically significant. In GALATHEA, pre-bronchodilator FEV 1The change from baseline vs. placebo was 7 mL and 21 mL for benralizumab 30 mg and 100 mg, respectively. For SGRQ total score, the benralizumab treatment effect vs. placebo was -1.011 and -2.136 for benralizumab 30 mg and 100 mg, respectively (Table 2 and Figure 3). TERRANOVA showed that pre-bronchodilator FEV 1 Changes from baseline vs. placebo were 15 mL, -7 mL, and 20 mL for benralizumab 10 mg, 30 mg, and 100 mg, respectively. For SGRQ total score, the benralizumab treatment effects vs. placebo were -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, there was also a large improvement in SGRQ scores for 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, all doses of benralizumab resulted in complete depletion of blood eosinophils from week 4 to the end of the study, compared with no depletion with placebo (Figure 4). In the GALATHEA substudy, benralizumab caused near-complete depletion at week 24 (mean: 0.02% and 0.13% for 30 mg and 100 mg, respectively, vs. 5.38% for placebo), which was maintained through week 56.

[0148] Prespecified subgroup analyses: Point estimates of the COPD exacerbation rate ratios (RRs) favored benralizumab 100 mg over placebo in all demographic subgroups (point estimate of 1.00), except for current smokers in GALATHEA, in which similar results were obtained with benralizumab and placebo. The subgroup of patients with ≥3 prior exacerbations compared with <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 baseline eosinophil counts ≥220 cells / µL showed a greater reduction in exacerbation rate with benralizumab 100 mg (RR vs placebo [95% CI]: GALATHEA, 0.83 [0.69, 1.00]; TERRANOVA, 0.93 [0.78, 1.10]) compared with patients with baseline eosinophil counts <220 cells / µL (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 counts and treatment effect (Figure 7).

[0149] Benralizumab 100 mg increased the treatment effect in patients receiving triple therapy compared with other treatment regimens (reduction in COPD exacerbation rate vs. placebo: GALATHEA, 18%; TERRANOVA, 17%) (Figures 5 and 6). In both studies, patients with frequent prior exacerbations (≥3) or very severe GOLD airflow severity had a greater benefit from benralizumab treatment compared with patients with few prior exacerbations or moderate GOLD airflow severity. 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 in the benralizumab and placebo groups, and mortality was low (Table 3). The most common AEs were related to COPD or respiratory conditions. Fewer than 15% of patients had a positive anti-drug antibody (ADA) response (Table 3), which did not appear to affect clinical endpoints.

[0151] [Table 4]

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

[0153] Most benralizumab doses were associated with modest improvements from baseline in lung function. Benralizumab treatment also improved SGRQ scores similar to placebo. All patients received inhaled therapy during the study, which may have differentially improved endpoints compared with the placebo group. This, combined with the large placebo effect, may have contributed to the failure of benralizumab to reach statistical significance for improvements in lung function and other endpoints.

[0154] During these trials, AEs / severe AEs were balanced between treatment arms and mortality was low. These safety data are consistent with those reported in 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 pathology caused by various mechanisms, resulting in a variety of clinical disease symptoms (Singh et al., BRN Review, 4:34-52, 2018). Biologics such as benralizumab target distinct underlying pathological mechanisms (eosinophilic inflammation). By week 4 and by week 56, benralizumab resulted in complete blood and sputum eosinophil depletion. This finding, together with a similar effect on eosinophils observed in the mepolizumab trial, suggests that eosinophil depletion may not fully improve exacerbation endpoints in COPD patients, with minimal impact on COPD exacerbation rates. Furthermore, peripheral blood eosinophil counts may not accurately reflect airway eosinophilia. Clinical characteristics of COPD are an additional important factor. Both GALATHEA and TERRANOVA showed that patients who had more frequent COPD exacerbations in the year prior to enrollment, despite receiving triple inhalation therapy, experienced the greatest benralizumab treatment benefit. We believe this is an important finding because both variables are easily identified and, together with blood eosinophil count, may help to individualize the use of benralizumab for the treatment of patients with COPD.

[0156] Example 3: Further Phase 3 studies This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, Phase 3 study to evaluate the efficacy and safety of benralizumab 100 mg dose administered by subcutaneous (SC) injection every 4 weeks for the first three doses and then every 8 weeks (hereafter 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). Eligible patients must have a history of ≥ 2 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 ≥ 300 cells / μL at screening, supported by at least one prior result of ≥ 150 cells / μL within the previous year.

[0157] In the phase 3 clinical trials GALATHEA and TERRANOVA, 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, with no appreciable differences in safety outcomes between the three dose groups.

[0158] 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 COPD annualized exacerbation rates (combined moderate and severe) and severe annualized exacerbation rates, as well as all other exacerbation endpoints, in patients with baseline blood eosinophil counts of 220 cells / μL or greater. The 10 mg dose of benralizumab (TERRANOVA only) provided inconsistent results compared with the 100 mg dose across exacerbation endpoints. 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 baseline blood eosinophil counts of 220 cells / μL or greater (32% and 25% reductions, respectively, over placebo). In patients with more frequent prior exacerbations (≥3 exacerbations in the previous year) and baseline blood eosinophil counts ≥220 cells / μL, a much greater treatment effect of the 100 mg dose of benralizumab than the 10 mg dose was evident for COPD exacerbations (combined moderate and severe; 23% vs. 9% reduction over placebo, respectively) and severe exacerbations (34% vs. 17% reduction over placebo). In general, any improvement observed in benralizumab-treated patients was greater in the 100 mg group compared with the 30 mg group. In both studies, benralizumab 100 mg reduced the annual rate of severe exacerbations by >30% compared with placebo. However, in GALATHEA, patients receiving benralizumab 30 mg had a higher rate of severe exacerbations compared with placebo. These results suggest that a higher dose of benralizumab may be required to achieve a therapeutic response in COPD patients than in asthma patients, where 30 mg of benralizumab is sufficient to achieve a therapeutic effect in asthma. Given the more consistent efficacy findings, especially in the subpopulation with more frequent exacerbations and elevated eosinophils (≥220 cells / μL), a dose of 100 mg of benralizumab was selected in this study.

[0159] Potentially eligible patients will enter a 5-week run-in period. Patients who meet the eligibility criteria will be randomized in a 1:1 ratio to receive either benralizumab 100 mg or placebo Q8W. Treatment duration will vary and will continue until the last patient has had the opportunity to complete a minimum of 56 weeks, at which point all patients will have completed the study. The primary endpoint will be analyzed at week 56.

[0160] At randomization, patients will be stratified by country and number of exacerbations in the previous year (2 or ≥ 3). Randomization to the 2 exacerbations in the previous year stratum will be capped to ensure that at least 70% of patients in the study population have ≥ 3 exacerbations in the previous year.

[0161] Patients will be maintained on triple (ICS / LABA / LAMA) background therapy throughout enrollment, induction 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 matching placebo arm.

[0163] Treatment and duration: Upon enrollment, patients will enter a minimum 5-week run-in period that can be extended up to 13 weeks. Following the run-in period, patients who are confirmed eligible will be randomized in a 1:1 ratio to receive benralizumab 100 mg or placebo SCQ8W. Treatment duration will vary and will continue until the last patient has had the opportunity to complete a minimum of 56 weeks. Once the last patient's end-of-treatment (EOT) visit has been confirmed, a final visit for all patients will be scheduled. The study will close once all patients have completed the final visit.

[0164] statistical methods Efficacy analyses were performed using the full analysis set (FAS), which included all randomized patients receiving at least one IP dose, regardless of protocol compliance and continued participation in the study, according to the intention-to-treat principle.

[0165] The primary efficacy outcome measures are the annualized rates of moderate and severe COPD exacerbations over the first 56 weeks. Treatment-based estimates will be applied to the primary analysis of the primary outcome measure (along with the main analyses of key secondary outcome measures) and will include all data, regardless of whether patients remained in blinded IP.

[0166] The primary endpoint will be assessed first in the primary population (patients with 3 or more exacerbations in the previous year) and then in the overall population of patients with 2 or more exacerbations in the previous year. The exacerbation rate in the benralizumab 100 mg group will be compared to the exacerbation rate in the placebo group using a negative binomial model. The response variable in the model will be the number of COPD exacerbations over the first 56 weeks of the treatment period. The model includes covariates for treatment group, region, and number of exacerbations in the previous year. The logarithm of follow-up time in the first 56 weeks was used as an offset variable in the model. Hypothesis testing for the primary analysis will be performed at a two-sided 5% significance level.

[0167] Annualized rates of COPD exacerbations resulting in hospitalization or death (i.e. severe exacerbations) will be analyzed through the EOT using a negative binomial model similar to that outlined for the primary efficacy variable.

[0168] Unless otherwise noted, all secondary efficacy endpoints will be analyzed in patients with a history of 3 or more exacerbations in the prior year and will be repeated in patients with a history of 2 or more exacerbations in the prior year using data through week 56. If continuously measured endpoints (e.g., SGRQ and FEV1) are also collected beyond week 56, additional models similar to those fitted to data through week 56 will be used to evaluate these endpoints through the EOT.

[0169] The study will recruit patients on triple (ICS / LABA / LAMA) background therapy with baseline eosinophil counts ≥ 300 eosinophils / μL and ≥ 2 exacerbations in the previous year, with at least 70% of patients having ≥ 3 exacerbations in the previous year. The study will be powered for the primary population of patients with ≥ 3 exacerbations in the previous year. For the primary endpoint of annualized exacerbation rate during the first 56 weeks, a minimum of 304 patients / group (608 total) with ≥ 3 exacerbations in the previous year will be randomized to achieve at least 90% powering to detect a 30% decline in benralizumab 100 mg vs. placebo. This calculation assumes a two-sided alpha level of 5%, a 2-year annualized placebo rate, and a negative binomial variance parameter of 0.5.

[0170] A total of 868 patients are expected to be randomized in the study, which will also include a cohort of patients with two exacerbations in the previous year (approximately 260 patients) to characterize 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, clinical phase 3 trials of benralizumab in patients with moderate to very severe COPD. The two phase 3 trials had nearly identical study designs 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 in GALATHEA and TERRANOVA. In this new study, the primary population is patients with a baseline eosinophil count of ≥300 eosinophils / μL, receiving triple background therapy (ICS / LABA / LAMA), and having ≥3 exacerbations in the previous year. The overall population is patients with a baseline eosinophil count of ≥300 eosinophils / μL, receiving triple background therapy (ICS / LABA / LAMA), and having ≥2 exacerbations in the previous year.

[0173] In the primary analyses from GALATHEA and TERRANOVA, the 100 mg dose of benralizumab reduced the primary endpoint of annualized COPD exacerbation (composite of moderate and severe) rate by 17% and 7% compared with placebo in GALATHEA and TERRANOVA, respectively. However, clinically relevant reductions in severe exacerbations (defined as exacerbations resulting in hospitalization or death) were observed in both studies, with the greatest benefit observed in the benralizumab 100 mg group (43% and 32% in GALATHEA and TERRANOVA, respectively).

[0174] Pre-planned analyses assessed specific subpopulations with the following results: -Patients receiving triple (ICS / LABA / LAMA) background therapy (approximately 70% and 60% of patients in GALATHEA and TERRANOVA, respectively) showed consistent treatment effects on annualized COPD exacerbation rate with benralizumab 100 mg in both studies: 18% and 17% reductions compared to placebo, respectively. - Patients with more frequent exacerbations in the previous year (≥3 vs ≤2) had a greater treatment effect with benralizumab 100 mg on annualized COPD exacerbation rate and annualized severe COPD exacerbation rate. – No effect of treatment on annual COPD exacerbation rate was observed in patients with baseline blood eosinophil counts below 220 cells / μL.

[0175] These subpopulation findings were consistent across studies and supported by pooled analyses. Collectively, these characteristics identify patients most likely to benefit from benralizumab treatment.

[0176] This study uses an eosinophil cut point of ≥300 cells / μL. Previous GALATHEA and TERRANOVA studies did not find efficacy in patients with low eosinophil counts (<220 cells / μL). Treatment response was similar between patients with ≥220 cells / μL and ≥300 cells / μL. GOLD 2019 references a threshold of 300 cells / μL for response to ICS, with a cutoff of 300 cells / μL being more practical from a clinical perspective and consistent with the resolution of laboratory blood count data.

[0177] A history of frequent (≥3) exacerbations in the previous year was the strongest and most consistent predictor of treatment response in GALATHEA and TERRANOVA. Therefore, the study is powered for the primary population of patients with ≥3 exacerbations in the previous year. Study enrollment was expanded to include patients with ≥2 exacerbations in the previous year to allow further investigation in a broader population (patients with ≥2 exacerbations in the previous year) given that in the GALATHEA and TERRANOVA studies there was evidence of treatment benefit in this subset of patients receiving triple (ICS / LABA / LAMA) background therapy and baseline blood eosinophil counts ≥220 cells / μL. In a pooled post-hoc analysis in this population (≥220 blood eosinophils, ≥2 exacerbations in the previous year, receiving triple therapy), benralizumab 100 mg treatment resulted in a 20% reduction in annualized exacerbation rate compared to placebo, and a 55% reduction in annualized severe exacerbation rate compared to placebo.

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

[0179] Selection Criteria - Patients (male or female) must be between 40 and 85 years of age at the time of signing the ICF. - Current or former smoker with 10 or more pack-years of smoking history (1 pack-year = 20 cigarettes smoked per day for 1 year) (Note: use of electronic cigarettes [e-cigarettes] does not affect pack-years for eligibility). History of moderate to very severe COPD with a post-bronchodilator FEV1 / forced vital capacity (FVC) of less than 0.70 and a post-bronchodilator FEV1 of 65% or less of predicted normal on screening central spirometry assessment. - Documented history of 2 or more moderate and / or severe COPD exacerbations requiring treatment with systemic corticosteroids (at least 3 days or a single depot injection) and / or hospitalization within 52 weeks prior to enrollment: (a) Exacerbations treated with antibiotics alone are not considered to meet the criteria unless they were accompanied by treatment with systemic corticosteroids and / or hospitalization. (b) Hospitalization is defined as admission to a hospital, observation area, emergency department, or other equivalent health care facility for 24 hours or more, depending on the country and health care system. (c) The prior exacerbation must have occurred while the patient was receiving stable triple (ICS / LABA / LAMA) background therapy for COPD and was not the result of a treatment step-down, i.e., a change from triple to dual therapy. - Documented use of triple (ICS / LABA / LAMA) background therapy for COPD throughout the entire year (52 weeks) prior to enrollment. (a) The dose of ICS should be equivalent to at least 500 mcg of fluticasone propionate per day. (b) The total cumulative period during which patients were off triple (ICS / LABA / LAMA) background therapy must not exceed 2 months, although patients may have switched and / or stepped down for a short period of time during the previous year. (c) Patients must have been on stable therapy / medication for the last 3 months prior to randomization. (Changing or switching individual components between devices is permitted as long as the patient is maintained on an acceptable ICS / LABA / LAMA dose equivalent to ≥ 500 mcg fluticasone propionate daily.) - Blood eosinophil count ≥ 300 cells / μL at central laboratory testing screening, supported by at least one documented history of blood eosinophil count ≥ 150 cells / μL within 52 weeks of enrollment. In the absence of historical data, additional blood eosinophil counts may be obtained by repeating testing during the run-in period (at least 4-week intervals). - CAT total score ≥ 15 at Visit 1. An exacerbation is considered moderate if it requires treatment with systemic corticosteroids and does not result in hospitalization. An exacerbation is considered severe if it results in hospitalization.

[0180] Exclusion criteria 1. Clinically significant pulmonary disease other than COPD (e.g. active pulmonary infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, obesity-associated hypoventilation syndrome, lung cancer, alpha-1 antitrypsin deficiency, or primary ciliary dyskinesia). 2. Current diagnosis of asthma according to Global Initiative for Asthma (GINA) or other accepted guidelines, history of asthma, or asthma-COPD overlap. 3. Radiologic evidence suggestive of a respiratory disease other than COPD causing the patient's respiratory symptoms. Radiologic evidence of a solitary pulmonary nodule or evidence suggestive of acute infection without demonstration of stability with appropriate follow-up and standard treatment. 4. Another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis / mycosis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome).

[0181] Investigational treatment is defined as an investigational medicinal product (including marketed product comparators and placebo) or medical device intended to be administered to patients according to the study protocol. Investigational treatment in this study refers to benralizumab or placebo.

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

[0183] COPD medications taken at the time of the previous exacerbation, including any recent changes in these medications relevant to the timing of the exacerbation, will be captured in the eCRF.

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

[0185] Background (maintenance) medications All patients must have been treated with triple (ICS / LABA / LAMA) background therapy for COPD in the year prior to enrollment and throughout the study period. Patients must have been on stable ICS / LABA / LAMA therapy / administration for the last 3 months prior to randomization and be using a tolerated ICS dose equivalent to 500 mcg or more fluticasone propionate per day.

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

[0187] Minor changes to a patient's background inhaled medication regimen, such as changing individual components (e.g., from fluticasone to budesonide at equivalent doses) or switching between devices (e.g., from budesonide / formoterol to fluticasone / salmeterol), are permitted as long as the patient remains on ICS / LABA / LAMA at an acceptable ICS dose. In case of such minor changes, patients must be stable on the new treatment regimen for at least 4 weeks prior to randomization.

[0188] Rescue medication Rescue medications such as short-acting beta2-agonists (SABAs, e.g. salbutamol, albuterol, terbutaline, levalbuterol), short-acting muscarinic antagonists (SAMAs), SABA / SAMA combinations, or alternatives to topical standard of care may be used during exacerbation events of COPD symptoms.

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

[0190] [Table 5]

[0191] [Table 6]

[0192] Example 4: Study Assessments and Procedures Assessment of COPD exacerbations: For purposes of the protocol, a COPD exacerbation is defined as a worsening of a patient's usual COPD symptoms that goes beyond the usual day-to-day fluctuations, is acute in onset, lasts more than two days (or one day if the exacerbation is so rapid and severe that the treating physician determines that intensification of treatment cannot be delayed), may warrant a change in usual medication, and leads to any of the following:

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

[0194] The exacerbation / development of symptoms must include at least one major COPD symptom from the following list and at least one other major or minor symptom: -Main COPD symptoms: difficulty breathing, amount of sputum, and color of sputum -Minor COPD symptoms: cough, wheezing, sore throat, cold symptoms (runny or stuffy nose), and fever without other causes

[0195] An exacerbation is considered moderate if it requires treatment with systemic corticosteroids and / or antibiotics and does not result in hospitalization or death. An exacerbation is considered severe if it results in hospitalization or death.

[0196] Spirometry Patients must be instructed not to use ICS / LABA / LAMA medications within 12 hours (24 hours for once-daily dosing) of a scheduled on-site visit spirometry, as this will affect pre / post bronchodilator FEV1 values; they may then be taken on-site. For the same reason, patients should not use rescue (SABA and / or SAMA) medications within 6 hours of a scheduled on-site visit spirometry.

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

[0198] Post-bronchodilator spirometry Maximal bronchodilation will be induced using four inhalations of albuterol (measured dose of 90 μg) or salbutamol (measured dose of 100 μg) with or without a spacer device within 30 ± 15 min of the final pre-bronchodilator spirometry measurement. Post-bronchodilator spirometry will be performed 20-30 min later. If the patient cannot tolerate four inhalations of a beta-agonist, a reduction in the number of inhalations may be considered at the investigator's clinical judgment.

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

[0200] St George's Respiratory Questionnaire (SGRQ) The SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstructive diseases (Jones et al 1991). 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 condition. The SGRQ results in a total score as well as three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on the overall health status. This total score is expressed as a percentage of global impairment, with 100 indicating the worst possible health status and 0 indicating the best possible health status. Similarly, the domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details about the scoring algorithm are provided by the developers in the user manual (Jones 2009).

[0201] Patients will complete the SGRQ in the eDiary on-site for Visit 1 screening and Visit 3 (randomization) prior to any other study procedures. During the run-in period and up to Week 56 of the treatment period, the SGRQ will be available every 28±7 days and will preferably be completed at home prior to the study visit or on-site during a scheduled visit. After Week 56, the SGRQ will be available every 56±7 days and will preferably be completed at home prior to the study visit or on-site during a 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). The instrument uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. Content includes items related to coughing, phlegm, chest tightness, shortness of breath when climbing hills / steps, activity limitations at home, confidence to leave the house, sleep, and energy. The CAT total 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.

[0203] Patients will complete the CAT on-site for Visit 1 (screening) and Visit 3 (randomization) prior to any other study procedures. During the run-in period and up to Week 56 of the treatment period, the CAT will be available every 28±7 days and will preferably be completed in-home prior to the study visit or on-site during a scheduled visit. After Week 56, the CAT will be available every 56±7 days and will preferably be completed in-home prior to the study visit or on-site during a scheduled visit.

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

[0205] Patients are asked to indicate their current health status by selecting the most appropriate level for each of the five dimensions. The questionnaire also includes a visual analog scale (VAS) where patients are asked to grade their current health on a scale of 0 to 100, with 0 being the worst possible health status. Patients complete the EQ-5D-5L in the eDiary on-site for Visit 1 (screening) and Visit 3 (randomization) prior to any other study procedures. During the run-in period and up to Week 56 of the treatment period, the EQ-5D-5L is available every 28 ± 7 days and is preferably completed at home prior to the study visit or on-site during a scheduled visit. After Week 56, the EQ-5D-5L is available every 56 ± 7 days and is preferably completed at home prior to the study visit or on-site during a scheduled visit.

[0206] Statistical Considerations The primary efficacy outcome measure is the annualized rate of moderate and severe COPD exacerbations over the first 56 weeks. The primary outcome measure will be evaluated first in the primary population (patients with 3 or more exacerbations in the previous year) and then in the overall population of patients with 2 or more exacerbations in the previous year. Treatment-directed estimates will be applied in the primary analysis of the primary outcome measure and will include all data, regardless of whether patients remain in blinded IP or not.

[0207] The null hypothesis is that the exacerbation rate for benralizumab 100 mg is equal to the exacerbation rate for placebo. The alternative hypothesis is that the exacerbation rate for benralizumab 100 mg is not equal to the exacerbation rate for placebo, i.e.: H 0 :Ratio (benralizumab 100 mg vs. placebo) = 1 H 1 :Ratio (benralizumab 100 mg vs. placebo) ≠ 1

[0208] The primary analysis, the annualized rate of moderate and severe COPD exacerbations over 56 weeks in patients with 3 or more exacerbations in the previous year, will be tested at a two-sided 5% significance level. If the p-value is less than 0.05 in favor of benralizumab, then the H 0 Refuses and H 1Accept.

[0209] Determining sample size The study will recruit patients on triple (ICS / LABA / LAMA) background therapy with baseline eosinophil counts ≥ 300 eosinophils / μL and ≥ 2 exacerbations in the previous year, with at least 70% of patients having ≥ 3 exacerbations in the previous year. The study will be powered for the primary population of patients with ≥ 3 exacerbations in the previous year. For the primary endpoint of annualized exacerbation rate during the first 56 weeks, a minimum of 304 patients / group (608 total) with ≥ 3 exacerbations in the previous year will be randomized to achieve at least 90% powering to detect a 30% decline in benralizumab 100 mg vs. placebo. This calculation assumes a two-sided alpha level of 5%, a 2-year annualized placebo rate, and a negative binomial variance parameter of 0.5.

[0210] A total of 868 patients are expected to be randomized in the study, which will include a cohort of patients with two exacerbations in the previous year to characterize efficacy in patients with two or more exacerbations in the previous year.

[0211] For the key secondary endpoint of annualized severe exacerbation rate over the entire treatment period with EOT, at least 80% potentiation is expected to detect a 40% reduction with benralizumab 100 mg compared to placebo in patients with 3 or more exacerbations in the previous year, and at least 90% potentiation is expected in patients with 2 or more exacerbations in the previous year. This calculation assumes placebo rates of 0.30 and 0.27 for the primary and overall populations, respectively, a negative binomial variance parameter of 2.7, and a mean follow-up period of 2 years. Following multiple testing procedures, a two-sided 5% significance level is assumed for the >3 and >2 prior exacerbations groups.

[0212] Efficacy endpoints All efficacy endpoints (shown in Table 5) will be analyzed in patients with a history of 3 or more exacerbations in the previous year (main population) and repeated in patients with a history of 2 or more exacerbations in the previous year (total population). If continuously measured endpoints (e.g., SGRQ and FEV1) are also collected beyond week 56, additional models similar to those fitted to data through week 56 will be used to evaluate these endpoints over the longer follow-up period through EOT.

[0213] [Table 7]

[0214] Main analysis method The primary efficacy variable was the annualized rate of moderate and severe COPD exacerbations during the first 56 weeks, and the primary analysis was to compare the annualized rate of COPD exacerbations with benralizumab 100 mg versus placebo in patients with a history of three or more exacerbations 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 in the model was the number of COPD exacerbations over the first 56 weeks of the treatment period. The model included covariates for treatment group, region, and number of exacerbations in the previous year. The logarithm of the follow-up time for the first 56 weeks was used as an offset variable in the model.

[0216] The estimated treatment effects (i.e., rate ratios for benralizumab vs. placebo), corresponding 95% confidence intervals (CIs), and two-sided p-values ​​for the rate ratios are presented. In addition, progression rates within each treatment group and corresponding 95% CIs are presented.

[0217] Analytical methods for secondary efficacy variables The primary analysis will be repeated in patients with a history of 2 or more exacerbations in the previous year. All secondary efficacy endpoints will be analyzed in patients with a history of 3 or more exacerbations in the previous year and repeated in patients with a history of 2 or more exacerbations in the previous year. If continuously measured endpoints (e.g., SGRQ and FEV1) are also collected beyond week 56, additional models similar to those fitted to data through week 56 will be used to evaluate these endpoints over the longer follow-up period through EOT.

[0218] Annualized rates of COPD exacerbations resulting in hospitalization or death (i.e., severe exacerbations) will be analyzed through EOT using a negative binomial model similar to that outlined above. Annualized rates of COPD exacerbations associated with emergency room visits or hospitalizations will be analyzed similarly through EOT.

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

[0220] Time to first COPD exacerbation will be analyzed as another supportive efficacy variable for the primary objective to investigate how treatment with benralizumab delays the time to first exacerbation compared to placebo. Cox proportional hazards models will be fitted to the data including covariates of treatment, region, and number of exacerbations in the previous year.

[0221] Changes from baseline in the SGRQ total score and three domain scores (symptoms, activity, and impact) at week 56 will be compared between benralizumab and placebo using repeated measures analysis in a FAS. The dependent variable is the change from baseline in SGRQ score at post-baseline protocol-specified visits (up to the week 56 visit). Treatment group is fitted as an explanatory variable, and region, visit, the interaction between visit and treatment, and 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 + area + visit + treatment * It is a visit.

[0222] The proportion of patients in the benralizumab group who achieve a 4-point or greater reduction (improvement) in SGRQ total score at week 56 will be compared with the proportion in the placebo group using the Cochran-Mantel-Haenszel test controlling for domains.

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

[0224] The change from baseline in CAT total score at week 56 and the E-RS: COPD score and domain scores at week 56 will be analyzed separately using models similar to those for the change from baseline in SGRQ score. ***

[0225] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the following claims.

[0226] Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0227] Although the foregoing invention has been described in some detail by way of drawings and examples for purposes of clarity of understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims. Furthermore, the present invention includes the following aspects. 1. 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, wherein prior to administration, the patient: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 2 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 2. A method for reducing the annual exacerbation rate of chronic obstructive pulmonary disease (COPD), comprising administering a 100 mg dose of benralizumab or an antigen-binding fragment thereof to a human COPD patient, wherein prior to administration, the patient: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 2 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 3. Forced vital capacity in 1 second (FEV) in human patients with chronic obstructive pulmonary disease (COPD) 1 ), 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) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 2 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 4. A method of increasing forced vital capacity (FVC) in a human chronic obstructive pulmonary disease (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) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 2 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 5. The method according to any one of items 1 to 4, wherein the COPD questionnaire score for assessing COPD symptoms in the human COPD patient is improved. 6. The method according to any one of items 1 to 5, wherein the patient has severe or very severe COPD as defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD). 7. The method of claim 6, wherein the patient has very severe COPD as defined by GOLD. 8. The method according to any one of items 1 to 7, wherein the administration reduces the exacerbation rate of COPD. 9. The method according to any one of items 2 to 8, wherein the exacerbation rate is reduced by at least 20%. 10. The method according to any one of items 2 to 8, wherein the exacerbation rate is reduced by at least 30%. 11. The method according to any one of items 2 to 8, wherein the exacerbation rate is reduced by at least 40%. 12. The method according to any one of items 2 to 8, wherein the exacerbation rate is reduced by at least 50%. 13. The method according to any one of items 2 to 8, wherein the exacerbation rate is reduced by at least 60%. 14. The administration reduces the FEV 1 Item 14. The method according to any one of items 1 to 13, wherein the method increases 15. The method according to any one of paragraphs 1 to 13, wherein the administration increases the FVC of the patient. 16. The method according to paragraph 6, wherein the COPD questionnaire is the COPD-specific St. George's Respiratory Questionnaire (SGRQ-C). 17. The method of claim 16, wherein the patient's SGRQ-C (symptoms) score is reduced by at least 5. 18. The method according to any one of paragraphs 1 to 17, wherein the patient's SGRQ-C (symptoms) score is reduced by at least 9. 19. The method according to any one of paragraphs 1 to 17, wherein the patient has experienced three or more prior exacerbations in the year prior to the administration. 20. The method of any one of clauses 1 to 19, wherein the patient receiving benralizumab is concurrently treated with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). 21. The method of any one of clauses 1 to 19, wherein the patient receiving benralizumab is not being treated concomitantly with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). 22. The patient has an FEV of 80% or less predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. 1 22. The method according to any one of items 1 to 21, wherein the compound has the formula: 23. The patient has an FEV of 70% or less predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. 1 22. The method according to any one of items 1 to 21, wherein the compound has the formula: 24. The patient has an FEV of 65% or less predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. 1 22. The method according to any one of items 1 to 21, wherein the compound has the formula: 25. The patient has an FEV of less than 0.70 prior to the administration of benralizumab or an antigen-binding fragment thereof. 1 / The method according to any one of items 1 to 21, in which the subject had forced vital capacity (FVC). 26. The method of any one of paragraphs 1 to 25, wherein at least two doses of benralizumab or an antigen-binding fragment thereof are administered. 27. The method of claim 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks to once every 12 weeks. 28. The method of any one of paragraphs 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every four weeks. 29. The method of any one of paragraphs 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every 8 weeks. 30. The method of any one of paragraphs 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 items 1 to 30, wherein the administration is subcutaneous. 32. 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, wherein prior to administration, the patient: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 33. A method of reducing 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) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 34. Forced vital capacity in 1 second (FEV1) in human patients with chronic obstructive pulmonary disease (COPD) 1 ), 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) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 35. A method of increasing 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: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) receiving triple background therapy including inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). 36. The method of any one of clauses 32 to 25, wherein the patient receiving benralizumab is concurrently treated with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). 37. The method of any one of clauses 32 to 35, wherein the patient receiving benralizumab is not being treated concomitantly with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). 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, wherein prior to the first administration, the patient: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 2 or more prior exacerbations in the year prior to treatment; (c) a patient receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), wherein after administering 100 mg of benralizumab once every 4 weeks for 12 weeks and then once every 8 weeks, the patient is no longer receiving triple background therapy. 39. 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, wherein prior to the first administration, the patient: (a) Have a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) a patient receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), wherein after administering 100 mg of benralizumab once every 4 weeks for 12 weeks and then once every 8 weeks, the patient is no longer receiving triple background therapy.

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

[0229] SEQ ID NO:2 >US20100291073_2 Sequence from US Patent Publication No. 20100291073 Organism: Homo sapiens [ka]

[0230] SEQ ID NO:3 >US20100291073_3 Sequence from US Patent Publication No. 20100291073 Organism: Homo sapiens [ka]

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

[0232] SEQ ID NO:5 >US20100291073_5 Sequence from US Patent Publication No. 20100291073 5 Organism: Homo sapiens [ka]

[0233] SEQ ID NO:6 >US20100291073_6 Sequence 6 from US Patent Publication No. 20100291073 Organism: Mus musculus [ka]

[0234] SEQ ID NO:7-VH CDR1 SYVIH

[0235] SEQ ID NO:8-VH CDR2 YINPYNDGTKYNERFKG

[0236] SEQ ID NO:9-VH CDR3 EGIRYYGLLGDY

[0237] SEQ ID NO:10-VL CDR1 GTSEDIINYLN

[0238] SEQ ID NO:11-VL CDR2 HTSRLQS

[0239] SEQ ID NO:12-VL CDR3 QQGYTLPYT

Claims

1. 1. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, the composition 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) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced two or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

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

3. Forced vital capacity in 1 second (FEV1) in human patients with chronic obstructive pulmonary disease (COPD) １ 2. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for increasing IL-18 expression in a patient, the pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof, the pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof, (a) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced two or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

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

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

6. The pharmaceutical composition 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 Pulmonary Disease (GOLD).

7. The pharmaceutical composition of claim 6, wherein the patient has very severe COPD as defined by GOLD.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein said administration reduces the exacerbation rate of COPD.

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

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

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

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

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

14. The administration increases the FEV of the patient １ The pharmaceutical composition according to any one of claims 1 to 13, which increases

15. The pharmaceutical composition of any one of claims 1 to 13, wherein said administration increases FVC in said patient.

16. 7. The pharmaceutical composition of claim 6, wherein the COPD questionnaire is the COPD-specific St. George's Respiratory Questionnaire (SGRQ-C).

17. 17. The pharmaceutical composition of claim 16, wherein the patient's SGRQ-C (symptoms) score is reduced by at least 5.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the patient's SGRQ-C (symptoms) score is reduced by at least 9.

19. The pharmaceutical composition of any one of claims 1 to 17, wherein the patient has experienced 3 or more prior exacerbations in the year prior to said administration.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the patient receiving benralizumab is concurrently treated with a triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

21. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the patient receiving benralizumab is not being concomitantly treated with a triple background therapy, the triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

22. The patient has an FEV of 80% or less than predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. １ The pharmaceutical composition according to any one of claims 1 to 21, having the formula:

23. The patient has an FEV of 70% or less than predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. １ The pharmaceutical composition according to any one of claims 1 to 21, having the formula:

24. The patient has an FEV of 65% or less predicted prior to the administration of benralizumab or an antigen-binding fragment thereof. １ The pharmaceutical composition according to any one of claims 1 to 21, having the formula:

25. The patient has an FEV of less than 0.70 prior to the administration of benralizumab or an antigen-binding fragment thereof. １ The pharmaceutical composition according to any one of claims 1 to 21, having a forced vital capacity (FVC) of 0.01 to 0.

15.

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

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

28. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein benralizumab or an antigen-binding fragment thereof is administered once every four weeks.

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

30. 27. The pharmaceutical composition of 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 pharmaceutical composition according to any one of claims 1 to 30, wherein said administration is subcutaneous.

32. 1. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, the composition 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) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

33. 1. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for reducing exacerbation rate of chronic obstructive pulmonary disease (COPD) in a human COPD patient, the composition 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) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

34. Forced vital capacity in 1 second (FEV1) in human patients with chronic obstructive pulmonary disease (COPD) １ 2. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for increasing IL-18 expression in a patient, the pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof, the pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof, (a) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

35. 1. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for increasing forced vital capacity (FVC) in a human patient with chronic obstructive pulmonary disease (COPD), comprising administering to said patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to administration, said patient: (a) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced 3 or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition receiving triple background therapy including inhaled corticosteroids (ICS), long-acting β-agonists (LABAs), and long-acting muscarinic antagonists (LAMAs).

36. 26. The pharmaceutical composition of any one of claims 32 to 25, wherein the patient receiving benralizumab is concurrently treated with a triple background therapy comprising an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA).

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

38. 1. A pharmaceutical composition comprising benralizumab or an antigen-binding fragment thereof for treating chronic obstructive pulmonary disease (COPD) in a human COPD patient, the composition comprising administering to the patient a dose of 100 mg of benralizumab or an antigen-binding fragment thereof, wherein prior to a first administration, the patient: (a) having a blood eosinophil count of 300 eosinophils / μL or more; (b) had experienced two or more prior exacerbations in the year prior to treatment; (c) A pharmaceutical composition for use in a method for treating a patient receiving triple background therapy including an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), wherein after administering 100 mg of benralizumab once every 4 weeks for 12 weeks and once every 8 weeks thereafter, the patient is no longer receiving triple background therapy.

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

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