Method of treatment

Abstract

The present invention relates to methods of treating chronic obstructive pulmonary disesse (COPD) in an enhanced patient population, particularly by administering an anti- IL5 antibody or fragment thereof.

Description

[0001] 70540W001

[0002] METHOD OF TREATMENT

[0003] FIELD OF THE INVENTION

[0004] The present disclosure relates to methods of treating chronic obstructive pulmonary disease (COPD), particularly by administering mepolizumab. The present invention further relates to mepolizumab for use in the treatment of chronic obstructive pulmonary disease (COPD). In an aspect, the present invention relates to mepolizumab for use in the treatment of COPD in an enhanced patient population. In another aspect, the present invention relates to mepolizumab for use in the treatment of COPD

[0005] BACKGROUND TO THE INVENTION

[0006] Chronic obstructive pulmonary disease (COPD) is a common disease characterized by progressive airflow obstruction, chronic inflammation in the lungs, and the occurrence of persistent symptoms and acute exacerbations. It is estimated that up to 40% of patients with COPD exhibit features of Type 2 inflammation, characterized by blood eosinophil counts (BEC) of >300 cells / uL, increased presence of inflammatoryFIG cytokines such as interleukin (IL)-5, IL-4, and IL-13, and additional type 2 innate lymphoid cells and type 2 helper cells. (GOLD 2024: global strategy for the diagnosis, management and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease, 2024; Oishi K et al. J Clin Med 2020;9(8); Zhang C et al. Front Pharmacol 2021 ; 12:754268). IL-5 is a central cytokine in the mediation of type 2 inflammation, with multidirectional effects on at least 10 diferent immune and structural cells within the type 2 inflammatory cascade, including eosinophils. In COPD specifically, IL-5 contributes to eosinophil growth, differentiation, activation, maturation, and survival, which can lead to increased eosinophils in the blood and pulmonary tissues. This IL-5-driven increase in eosinophil recruitment and activation can lead to epithelial cell damage, triggering repair pathway activation and epithelial-to- mesenchymal transition, which underpins airway remodeling. Such changes to the airways ultimately lead to more frequent and severe exacerbations and disease deterioration in patients with COPD.

[0007] Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment guidelines for COPD recommend maintenance use of triple inhaled therapy that includes a combination of inhaled glucocorticoids, long-acting p2-agonists, and long-acting muscarinic- receptor antagonists in patients with frequent exacerbations who do not have adequate outcomes with other treatments. However, approximately 30 to 40% of patients are reported to continue to have moderate or severe exacerbations despite receiving triple inhaled therapy (Vestbo et al. Lancet 2017;389:1919-1929; Mullerova et al. Am J Respir Crit Care Med 2017;195:A4986-A4986. Abstract). 70540W001

[0008] Further, because asthma and COPD are pulmonary disorders characterized with overlapping symptoms and pathogenesis, it can be difficult to identify treatments that are effective for COPD, especially in patients with COPD concurrently diagnosed with asthma or have a history of asthma. To date, no biologic therapy directed to interleukin-5 (IL- 5) or interleukin-5 receptor (IL-5R) has been approved for the treatment of COPD. The efficacy and safety of mepolizumab in patients with COPD who experience exacerbations despite maximal inhaled triple therapy was investigated in the METREX and METREO trials (NCT02105948 / NCT02105961); however, the reduction in rate of annual moderate or severe exacerbations seen for mepolizumab compared with placebo was not shown to be statistically significant for both trials, after adjusting for multiplicity in one of the trials. Additionally, benralizumab (directed to IL-5R) did not significantly reduce exacerbations compared with placebo as shown in the GALATHA and TERRANOVA trials (NCT02138916 / NCT02155660).

[0009] In light of the above, it is clear that there is a need for more effective treatments for COPD. In particular, there exists a need for an efficacious treatment for IL-5 mediated diseases such as COPD in an enhanced patient population. There also exists a need for an efficacious treatment for I L-5 mediated diseases such as COPD in wide spectrum of patients with COPD.

[0010] SUMMARY OF THE DISCLOSURE

[0011] The present disclosure provides an anti-IL-5 antibody or fragment thereof for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0012] In some instances, the COPD is associated with chronic bronchitis in the patient.

[0013] In some instances, the COPD is moderate COPD, moderate-to-severe COPD, or severe COPD. 70540W001

[0014] In some instances, the patient has a history of at least one or at least two moderate, or at least one severe, acute exacerbations of COPD (aeCOPD) in the 12 months prior to treatment.

[0015] In some instances, the patient is a current smoker or a former smoker and ptionally wherein the patient has a smoking history of at least 10 pack-years.

[0016] In some instances, the patient has a post bronchodilator forced expiratory volume in 1 second (FEVi) to forced vital capacity (FVC) ratio (post-BD-FEVi / FVC) of less than (<) 0.70.

[0017] In some instances, prior to treatment, the patient has a post bronchodilator forced expiratory volume in 1 second (post-BD FEVi) greater than 20% and <80% of predicted normal volume.

[0018] In some instances, the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA; ICS and LABA; or ICS, LABA, and LAMA.

[0019] In some instances, the method improves a patient’s score in one or more questionnaires selected from COPD Assessment Test (CAT), Evaluating Respiratory Symptioms in COPD (E-RS: COPD), St George’s Respiratory Questionnaire (SGRQ), St George’s Respiratory Questionnaire for COPD (SGRQ-C), Exacerbations of Chronic Pulmonary Disease Tool-Patient-Reported-Outcome (EXACT-PRO), Breathlessness, Cough and Sputum Scale (BCSS), 5-level EuroQol-5 Dimension (EQ-5D-5L), Work Productivity and Activity Impairment Questionnaire (WPAI-GH), Patient Global Impression of Severity (PGIS) or Patient Global Impression of Change (PGIC).

[0020] In some instances, the method improves the patient’s CAT score by >2 points from baseline; improves the patient’s SGRQ or SGRQ-C score by >4 points from baseline; or improves the patient’s E-RS: COPD score by >2 points from baseline.

[0021] In some instances, the annualised rate of moderate or severe COPD exacerbations is reduced in the patient and / or the time to first moderate or severe COPD exacerbation is increased.

[0022] In some instances, the anti-IL-5 antibody or fragment thereof comprises a heavy chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 4.

[0023] In some instances, the anti-IL-5 antibody or fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2. 70540W001

[0024] In some instances, the anti-IL-5 antibody is mepolizumab.

[0025] In some instances, the IL-5 antibody or fragment thereof is in a pharmaceutical composition.

[0026] The present disclosure further provides a method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0027] The present dislosure also provides a method of reducing the annualized rate of moderate or severe COPD exacerbations for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0028] The present disclosure also provides a method of reducing the annualized rate of COPD exacerbations requiring emergency department (ED) visits and / or hospitalization for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the I L-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence 70540W001 shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0029] The present disclosure further provides a method of reducing the time to first moderate or severe COPD exacerbation in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0030] In some instances, the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA; ICS and LABA; or ICS, LABA, and LAMA.

[0031] BRIEF DESCRIPTION OF DRAWINGS

[0032] FIG. 1. MATINEE summary of study population

[0033] FIG. 2. Annualized rate of moderate / severe exacerbations

[0034] FIG. 3. Time to first moderate / severe exacerbation

[0035] FIG. 4. Exacerbations requiring ED / hospital visit

[0036] FIG. 5. CAT Responder analysis

[0037] FIG. 6. E-RS: COPD Responder analysis

[0038] FIG. 7. SGRQ Responder analysis

[0039] FIG. 8A-B. Moderate / severe exacerbations by subgroup: Smoking status

[0040] FIG. 9. Moderate / severe exacerbations by subgroup: Symptoms of Chronic Bronchitis FIG. 10. Annualized rate of exacerbations in patients with severe prior exacerbations FIG. 11 Annualized rate of exacerbations requiring ED / hospital visit in patients with and without severe exacerbations 70540W001

[0041] FIG. 12. Mean decrease in SGRQ score when stratified by airflow obstruction subgroups (GOLD 2-4)

[0042] FIG. 13. Annualized rate of exacerbations requiring ED / hospital visit in patients with >1 prior severe exacerbation

[0043] DETAILED DESCRIPTION OF THE INVENTION

[0044] DEFINITIONS

[0045] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0046] The singular terms "a", "an", and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "plurality" refers to two or more. The term “at least one” refers to one or more.

[0047] Additionally, numerical limitations given with respect to concentrations or levels of a substance, such as solution component concentrations or ratios thereof, are intended to be approximate. Unless specified otherwise, where a numerical range is provided, it is inclusive, i.e., the endpoints are included.

[0048] "About" as used herein when referring to a measurable value such as an amount and the like, is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0049] The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g. a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136). Alternative antibody formats are also contemplated and include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer or an EGF domain. The antibody may be derived from rat, mouse, primate {e.g., cynomolgus, Old World monkey or Great Ape), human or 70540W001 other sources such as nucleic acids generated using molecular biology techniques which encode an antibody molecule.

[0050] The antibody may comprise a constant region, which may be of any isotype or subclass. The constant region may be of the IgG isotype, for example, IgGi, lgG2, IgGs, lgG4 or variants thereof. The antibody constant region may be IgGi . The antibodies of the invention can be, for example, I gGi antibodies.

[0051] The antibodies of the invention can be used in any of the pharmaceutical compositions, dosage regimens, or method of treatments of the invention.

[0052] The term “interleukin-5” or “IL- 5” as used herein includes human IL-5 comprising the amino acid sequence shown in SEQ ID NO: 11.

[0053] The term “interleukin-5 receptor” or “IL-5R” as used herein includes human IL-5 Receptor Subunit Alpha Isoform 1 comprising the amino acid sequence shown in SEQ ID NO: 12.

[0054] The term “binds”, as used herein in relation to antigen binding proteins means that the antigen binding protein binds to a target antigen as well as a discrete domain, or discrete amino acid sequence, within a target antigen with no or insignificant binding to other (for example, unrelated) proteins. This term, however, does not exclude the fact that the antigen binding proteins may also be cross- reactive with closely related molecules (for example, those with a high degree of sequence identity or from another genera or species). The antigen binding proteins described herein may bind to human IL-5 with at least 2, 5, 10, 50, 100, or 1000-fold greater affinity than they bind to closely related molecules.

[0055] By “isolated”, it is intended that the molecule, such as an antibody, is removed from the environment in which it may be found in nature. For example, the molecule may be purified away from substances with which it would normally exist in nature.

[0056] The terms “VH” and “VL” are used herein to refer to the heavy chain variable region and light chain variable region, respectively, of an antibody.

[0057] “CDRs” are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, "CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least one CDR and wherein the at least one CDR is CDRH3. Framework regions follow each of these CDR regions. Acceptable heavy chain variable region and light chain variable region framework 1 , framework 2 and framework 3 regions are readily recognized by those of ordinary skill in the art. Acceptable heavy chain constant regions (including hinge regions) and light chain constant regions are readily recognized by those 70540W001 of ordinary skill in the art as well. Acceptable antibody isotypes are similarly readily recognized by those of ordinary skill in the art.

[0058] Throughout this specification, amino acid residues in variable domain sequences and full length antibody sequences are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the specification follow the Kabat numbering convention.

[0059] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out according to the Chothia numbering convention. The structure and protein folding of the antibody may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person.

[0060] Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. The minimum overlapping region using at least two of the Kabat, Chothia, AbM and contact methods can be determined to provide the “minimum binding unit”. The minimum binding unit may be a sub-portion of a CDR.

[0061] The term “chronic obstructive pulmonary disease” or “COPD” as used herein means a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and / or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and / or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.

[0062] A diagnosis of COPD in a subject may be made according to the guidance provided by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document (2024 update).

[0063] In pulmonary function testing, a post-bronchodilator FEVi / FVC ratio of <0.7 is commonly considered diagnostic for COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) system categorises airflow limitation into stages (see Table 1).

[0064] Table 1. GOLD grades and severity of airflow obstruction in COPD (based on postbronchodilator FEV1) 70540W001

[0065] Initial pharmacological treatment of COPD may be based on GOLD ABE category as shown in Table 2 (adapted from GOLD, 2023 update). Table 2. Initial pharmacological treatment based on GOLD ABE category. mMRC: modified Medical Research Council dyspnea questionnaire; CAT: COPD

[0066] Assessment Test

[0067] The term “pharmaceutical composition” as used herein means a composition suitable for administration to a patient.

[0068] The term “therapeutically effective amount” as used herein means an amount of an agent (such as an antibody or a pharmaceutical composition comprising an antibody), which provides a therapeutic benefit in the treatment or management of one or more symptoms of COPD. Examples of such treatment or management of one or more symptoms of COPD include:

[0069] 1) Reduction in annualised rate of moderate or severe COPD exacerbations

[0070] 2) Reduction in the time to first moderate or severe COPD exacerbation

[0071] 3) Reduction in the annualised rate of COPD exacerbations leading to emergency department (ED) visit or hospitalisation 70540W001

[0072] 4) Change from baseline in St Georges Respiratory Questionnaire (SGRQ) score

[0073] 5) Change from basline in daily symptom scores using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) questionnaire.

[0074] Therapeutically effective amounts and treatment regimens are generally determined empirically and may be dependent on factors, such as the age, weight, and health status of the patient and disease or disorder to be treated. Such factors are within the purview of the attending physician.

[0075] As used herein, the term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. As is recognised in the art, drugs employed as therapeutic agents in methods of treatment may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents. Simply reducing the impact of a disease (for example, by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reducing the likelihood that the disease will occur (for example by delaying the onset of the disease) or worsen in a subject, is sufficient.

[0076] As used herein, the term "patient" refers to a human. The terms “individual”, “subject” and “patient” are used herein interchangeably. The patient may be an adult (>18 years).

[0077] As used herein, the phrase “every four weeks” means that in a typical four week period consisting of about twenty-eight (28) days, a subject is administered one dose of the antibody of the invention.

[0078] As used herein, the term “annualised rate of exacerbations” or “annualised rate of clinically significant exacerbations” refers to the number of moderate-to-severe or severe COPD exacerbations that occur over a year (i.e., 52-week period). In some cases where the patient follow-up period is more or less than 52 weeks, the number of exacerbations is normalized to an annual rate.

[0079] If desired, the effective dose of an antibody of the disclosure (e.g., as a pharmaceutical composition) may be administered as a unit dosage form.

[0080] TREATMENT OF COPD

[0081] COPD may be characterised by persistent respiratory symptoms and airflow limitation, as reported through airway spirometry, preferably post-bronchodilator (post-BD) airway spirometry. As used herein, "post-bronchodilator (post-BD) airway spirometry" refers to airway spirometry performed following the administration of a bronchodilator typically 70540W001 administered via an inhaler or nebuliser. In some embodiments, the bronchodilator is selected from albuterol or salbutamol. Post-BD spirometry results may be expressed as forced expiratory volume in one second (FEVi), or forced vital capacity (FVC).

[0082] The disclosure provides for treatments of COPD. In some instances, the COPD is moderate-to-severe COPD. Moderate-to-severe COPD is generally characterised by the subject having a post-BD forced expiratory volume in one second (FEVi) less than or equal to (<) 80% of the predicted normal value (i.e. , the value predicted for healthy patients). In some instances, the patient has a post-BD FEV1 of < 80%, < 75%, < 70%, < 65%, < 60%,

[0083] < 55%, < 50%, < 45%, < 40% or < 35% of the predicted normal value. In some instances, the patient has a post-BD FEVi which is < 80% and greater than (>) 20% of the predicted normal value. In some instances, the patient has a post-BD FEVi which is < 80% and >20%,

[0084] < 75% and 20%, < 70% and > 20%, < 65% and > 20%, < 60% and > 20% of the predicted normal value, < 55% and > 20% of the predicted normal value, < 50% and > 30% of the predicted normal value, < 45% and > 20% of the predicted normal value, < 40% and >20% of the predicted normal value.

[0085] In some instances, the patient has a post-BD FEV1 which is > 20% of the predicted normal value. In some instances, the subject has a post-DB FEV1 which >21%, >22%, >23%, >24%, >25%, >26%, >27%, >28%, >29% or >30% of the predicted normal value.

[0086] In some instances, the COPD is characterised by the presence of a prebronchodilator (pre-BD) and post-bronchodilator (post-BD) FEVi / forced vital capacity (FVC) ratio of < 0.70, < 0.65, < 0.60 < 0.55, < 0.50, < 0.45, < 0.40, < 0.35 or < 0.30. In an embodiment, the COPD is characterised by the presence of a pre-BD and post-BD FEW FVC ratio of < 0.70.

[0087] A patient with COPD may experience one or more acute exacerbation of COPD (AECOPD, also referred to herein as a "COPD exacerbation"), which may be separated by a period with relatively few symptoms. As used herein, an "AECOPD" or" aeCOPD" is a change in the patient’s usual COPD symptoms that lasts 2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a change in regular medication or even hospitalisation.

[0088] An AECOPD may be classified as mild, moderate, or severe. The American Thoracic Society (ATS) and the European Respiratory Society (ERS) classify COPD exacerbations as mild, moderate, or severe based on the intensity of the medical intervention required to control the patient’s symptoms. (American Thoracic Society, European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients with COPD. Version 1.2. New York, NY: American Thoracic Society; 2004.) As used herein, a "severe AECOPD" is one which requires hospitalisation or evaluation of the 70540W001 patient in the emergency department. (For example, a patient being hospitalized for the COPD exacerbation or admitted for > 24 hours to the emergency department, or other equivalent healthcare facility depending on the country and healthcare system). Severe AECOPD may result in a COPD-related death. As used herein, a "moderate AECOPD" is one which requires treatment with systemic corticosteroids or antibiotics to control. Finally, as used herein, a "mild AECOPD" is an exacerbation which does not meet the criteria for "severe" or "moderate". A mild AECOPD can be controlled with an increase in dosage of regular medications.

[0089] For severe AECOPD, the start date of the AECOPD may be the earlier of the date of hospitalisation, or, for moderate AECOPD, the start date of systemic corticosteroid or antibiotic treatment, and the end date may be the latest of the end date of the systemic corticosteroid or antibiotic treatment, or the date of hospital discharge.

[0090] In some instances, the patient to be treated may have a history of at least one moderate or severe AECOPD in the 12 months prior to treatment (i.e. prior to administration of the first dose). In some instances, the subject may have a history of at least one optionally at least two, moderate, or at least one severe AECOPD in the 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 months prior to treatment (i.e. prior to administration of the first dose). In some instances, the patient may have a history of at least two moderate AECOPD in the 12 months prior to treatment. In some instances, the subject may have a history or at least two moderate AECOPD within 52 weeks prior to treatment. In some instances, the subject may have a history or at least one severe AECOPD in the 12 months prior to treatment. In some instances, the subject may have a history or at least one severe AECOPD within 52 weeks prior to treatment. In some instances, the patient to be treated may have a history in the twelve months prior to treatment of at least one or at least two moderate exacerbations that were treated with systemic corticosteroids (intramuscular (IM), intravenous (IV), or oral) with or without antibiotics. In some instances, the patient to be treated may have a history in the twelve months prior to treatment of at least two moderate exacerbations that were treated with systemic corticosteroids (intramuscular (IM), intravenous (IV), or oral) with or without antibiotics. In some instances, the patient to be treated may have a history in the twelve months prior to treatment of at least one sesvere exacerbation requiring hospitalization.

[0091] In some instances, COPD may be classified by the COPD Assessment Test (CAT) score. The CAT is a questionnaire that is designed for patients with COPD to measure the effects of the disease on their quality of lives. The CAT is an 8 item patient-completed questionnaire assessing globally the impact of COPD (cough, sputum, dyspnea, chest tightness) on health status. The CAT ranges in scope from 0 to 40. Higher scores denote a more severe impact of COPD on a patient’s life. In some instances, the patient to be treated has a CAT score prior to therapy of at least 10. 70540W001

[0092] In some instances, the COPD may be classified using the St George's Respiratory Questionnaire (SGRQ). The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction. A global score ranges from 0 to 100. Scores by dimension are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. Lower score indicates better quality of life (QoL). The first part ("symptoms") evaluates symptomatology, including frequency of cough, sputum production, wheeze, breathlessness and the duration and frequency of attacks of breathlessness or wheeze. The second part has two components: "activity" and "impacts." The "activity" section addresses activities that cause breathlessness or are limited because of breathlessness. The "impacts" section covers a range of factors including influence on employment, being in control of health, panic, stigmatization, the need for medication, side effects of prescribed therapies, expectations for health and disturbances of daily life. The recall period of the questionnaire is over the past 4 weeks. Psychometric testing has demonstrated its repeatability, reliability and validation. Sensitivity has been demonstrated in clinical trials. A minimum change in 4 units was established as clinically relevant after patient and clinician testing (Jones COPD 2005 2(1):75-9 ).

[0093] In some instances, COPD is classified using Exacerbations of Chronic Pulmonary Disease Tool - Patient-reported Outcomes (EXACT) score. The EXACT is a 14-item patient reported outcome instrument developed to assess the frequency, severity and duration of COPD exacerbations (Jones et al 2011 ; Leidy et al 2011). The instrument was developed for daily, at home, administration using a handheld electronic device. Respondents are instructed to complete the diary each evening just prior to bedtime and to answer the questions while considering their experiences "today". The daily EXACT total score has a range of 0 to 100 with higher scores indicative of greater severity. Total score changes are used to identify the onset and recovery from an EXACT defined exacerbation event. In identifying event onset and recovery, the EXACT can provide information on event frequency and duration as well as event severity. In some instances, the subject to be treated has an EXACT score of at least 50, at least 60, at least 70, or at least 80 prior to treatment with an anti-l L5 antibody or fragment thereof as described herein.

[0094] In some instances, the COPD may be classified through E-RS: COPD, an 11-item patient reported outcome tool developed to evaluate the severity of respiratory symptoms of COPD (Leidy et al 2014a; Leidy et al 2014b). The E-RS:COPD is a subset of items from the EXACT. The E-RS: COPD was designed to be captured as part of the daily EXACT assessment. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity. In addition to the total score, symptom domain scores can be calculated for breathlessness (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11) and chest symptoms (3 items; score 70540W001 range: 0 to 12) by summing the responses of items within a respective domain. In some instances, the patient to be treated has an E-RS: COPD score of at least 20, at least 25, at least 30, or at least 35. In some instances, the patient to be treated has an E-RS: COPD score in the cough and sputum domain of at least 6, at least 7, at least 8, at least 9, at least 10, or 11. In some instances, the patient to be treated has an E-RS: COPD score in the chest symptom domain of at least 7, at least 8, at least 9, at least 10, at least 11 , or 12. In some instances, the patient to be treated has an E-RS: COPD score in the breathlessness domain of at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, or 17.

[0095] COPD may also be classified through the Breathlessness, Cough and Sputum Scale (BCSS) score relative to baseline. As used herein, "baseline", with regard to any COPD marker disclosed herein, such as BCSS score, means the numerical value of that parameter for a patient prior to or at the time of the first administration of the anti-IL-5 antibody. The BCSS is a 3-item daily diary (Leidy et al 2003) that assesses the severity of the 3 symptoms: breathlessness, sputum, and cough, each on a 5-point scale. Item scores can be reported as domains scores and are summed to yield a total score. In some instances, the patient has a total BCSS score of 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, or 14 or more prior to treatment with the anti-IL-5 antibody or fragment thereof. In some instances, the patient has a score of 2 or more, 3 or more, 4 or more, or 5 in the cough domain prior to treatment with the anti-IL-5 antibody or fragment thereof. In some embodiments, the patient has a score of 2 or more, 3 or more, 4 or more, or 5 in the sputum domain prior to treatment with the anti-IL-5 antibody or fragment thereof. In some instances, the BSCC score "prior to treatment" is an average of the daily scores recorded over the 4 weeks prior to treatment with anti-IL-5 antibody or fragment thereof as described herein.

[0096] In some instances, COPD is classified using the 5-level EuroQol-5 Dimension (EQ- 5D-5L). The EQ-5D-5L is a 5-level standardised instrument for use as a measure of health outcome. Applicable to a wide range of health conditions and treatment, it provides a simple descriptive profile and a single index value for health status. The EQ-5D-5L consists of 2 assessments, a descriptive system, and a visual analogue scale (VAS). The descriptive system comprises of the following 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 5 severity levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L index score can be calculated based upon participants' responses to the 5 dimensions and using an appropriate value set, which is known to physicans. The EQ-5D VAS records the respondent's self-rated health on a 20 cm, 0 to 100 vertical scale with endpoints labelled "the best health you can imagine" and "the worst health you can 70540W001 imagine", with higher scores corresponding to a better health state. This information is used as a quantitative measure of health as judged by the individual respondents.

[0097] In some instances, COPD is classified using the Work Productivity and Activity Impairment Questionnaire (WPAI-GH). The WPAI-GH (version 2.0) is a self-administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. The WPAI-GH outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity (Reilly et al 1993).

[0098] In some instances, COPD is classified using the Patient Global Impression of Severity (PGIS). The PGIS is a single item designed to capture the participant's perception of overall COPD symptom severity at the time of completion using a 6-point scale (0 - no symptoms to 5 - very severe).

[0099] In some instances, COPD is classified using the Patient Global Impression of Change (PGIC). The PGIC is a single item designed to capture the participant's perception in change in overall COPD symptoms since first dose of IP using a 7-point scale (1 - much better to 7 - much worse).

[0100] In some instances, COPD is associated with chronic bronchitis in the patient. A patient with chronic bronchitis may have suffered from the symptoms of bronchitis (cough, production of mucus / sputum, fatigue, shortness of breath, fever, chills, and / or chest discomfort) for a period of more than 8 weeks, more than 16 weeks, more than 32 weeks, or more than 52 weeks.

[0101] In some instances, the patient is a current smoker or former smoker of cigarettes. In some instances, the patient has a smoking history of 10 or more pack-years (i.e., >10 pack-years). Pack-years are calculated as (average number of cigarettes per day I 20) x number of years smoked. For example, 10 pack-years = 20 cigarettes smoked per day for 10 year or 10 cigarettes per day for 20 years. In some instances, the patient is a current smoker.

[0102] In other instances, the patient is a former smoker. A “former smoker” may be defined as someone who has stopped smoking for at least 6 months prior to therapy.

[0103] In some instances, the patient may have a history of inadequate response or intolerance to other medications for COPD, such as inhaled corticosteroids (ICS), long- acting beta agonists (LABA), and / or long-acting muscarinic antagonists (LAMA), or other medications for COPD may otherwise be medically inadvisable. As used herein, an "inadequate response" to a treatment means if administration of said treatment does not result in the short- and / or long-term amelioration of one of more symptoms of COPD as 70540W001 described herein. Alternatively, an inadequate response may result in a return of the condition to moderate-to-severe levels following cessation of said treatment. In some instances, COPD may have been previously treated with an ICS and a LABA (ICS / LABA), an ICS and a LAMA (ICS / LAMA), a LABA and a LAMA (LABA / LAMA), or an ICS, a LABA and a LAMA (ICS / LABA / LAMA), and has been shown to be unresponsive to said treatment. COPD may be classified as having an inadequate response to a treatment if the COPD remains moderate to severe despite the treatment, or if the subject experiences a moderate or severe AECOPD event following cessation or completion of the course of therapy. A patient with an "intolerance" to a treatment is one for whom the treatment provokes one or more side-effects which make continuation of the treatment inadvisable. For example, allergic reactions to treatment may be indicative of an intolerance.

[0104] In some instances, the subject to be treated may have received or is receiving a course of ICS, LAMA and / or LABA therapy (e.g. ICS / LAMA, ICS / LABA, LAMA / LABA or ICS / LAMA / LABA therapy, collectively referred to as "COPD inhaled maintenance therapies") prior to treatment with the anti-IL-5 antibody or fragment thereof as described herein. In some instances, the course of therapy may have begun at least s months prior to the administration of the first dose of the anti-l L-5 antibody or fragment thereof as described herein, and may be at least 3 months long. In some instances, the course of therapy began at least 3 months prior to the administration of the first dose of the anti-IL-5 antibody or fragment thereof as described herein, and may be ongoing at the start of and may be continued during the treatment window with said anti-IL-5 antibody or fragment thereof. In some instances, the patient is receiving ICS / LAMA / LABA (referred herein as “inhaled triple therapy” or “ICS-based triple therapy”) prior to treatment (e.g., before administration of the first dose of the anti-IL-5 antibody or fragment thereof) and / or during treatment. In some instances, the patient is receiving an ICS dose of >500 mcg / day at least 3 months prior to treatment. In some instances, the patient is receiving fluticasone propionate at a dose of >500 mcg / day at least 3 months prior to treatment. In an embodiment, the patient is receiving >500 mcg / day fluticasone propionate and LABA and LAMA, for at least 3 months prior to treatment. In another embodiment, the patient (i) has received ICS / LABA / LAMA for 12 months prior to treatment, and (ii) for at least 3 months prior to treatment is receiving >500 mcg / day fluticasone priopionate and LABA and LAMA (ICS / LABA / LAMA). In a further embodiment, the patient is receiving ICS plus LABA (ICS / LABA) or ICS plus LAMA (ICS / LAMA) for 12 months prior to treatment. In further embodiment, the patient is receiving ICS plus LABA (ICS / LABA) and SABA / SAMA; or ICS plus LAMA (ICS / LAMA) and SABA / SAMA, for 12 months prior to treatment but not within 3 months immediately prior to treatment.As used herein, "inhaled corticosteroids (ICS)" refers to any corticosteroid treatment administered for the treatment of COPD through use of a nebuliser, inhaler, or 70540W001 vaporiser. The ICS may be selected from fluticasone propionate, budesonide, and / or beclometasone dipropionate.

[0105] As used herein, "long-acting beta-2 adrenergic receptor agonists (LABA)" refers to any beta-adrenoceptor agonist with a duration of action of approximately 12 hours or more. This is in contrast to short-acting beta agonists (SABA) such as salbutamol, which have a duration of action of approximately 4-6 hours. Exemplary LABAs include arformoterol, bambuterol, clenbuterol, formoterol, salmeterol, protokylol. A LABA may be administered through any suitable route, for example through use of a nebuliser, inhaler, or vaporiser.

[0106] As used herein, long-acting muscarinic antagonists (LAMA) are anticholinergic agents that block the activity of the muscarinic acetylcholine receptor. This is in contrast to short-acting muscarinic antagonists (SAMA), which have a duration of action of approximately 4-6 hours. Exemplary LAMA include tiotropium bromide, glycopyrronium bromide, and aclidinium bromide. A LAMA may be administered through any suitable route, for example through use of a nebuliser, inhaler, or vaporiser.

[0107] In some instances, the COPD to be treated is moderate-to-severe COPD with type 2 inflammation characterised by an eosinophilic phenotype. In some instances, the moderate-to-severe COPD is characterised by one or more of the following:

[0108] • A peripheral blood eosinophil count of > 300 cells / pL

[0109] • A historical blood eosinophil count of > 150 cells / pL in the 12 months prior to treatment

[0110] • The patient is a current smoker

[0111] • The patient is a former smoker

[0112] • A history of <2, 3, or >4 moderate exacerbations that were treated with systemic steroids in the 12 months prior to treatment

[0113] • A history of 0 or >1 severe exacerbation requiring hospitalization the 12 months prior to treatment

[0114] • A history of two or more moderate COPD exacerbations that were treated with systemic corticosteroids, or at least one severe exacerbation of COPD requiring hospitalization, in the 12 months prior to treatment

[0115] • A pre-bronchodilator (pre-BD) post-bronchodilator (post-BD) forced expiratory volume in 1 second (FEVi) to forced vital capacity (FVC) ratio (pre- and post-BD FEVi / FVC) ratio of <0.70, and / or a post-BD FEVi > 20% and < 80% predicted normal value

[0116] • Mild airflow limitation according to GOLD guidelines

[0117] • Moderate airflow limitation according to GOLD guidelines

[0118] • Severe airflow limitation according to GOLD guidelines 70540W001

[0119] Very severe airflow limitation according to GOLD guidelines.

[0120] In some instances, the COPD to be treated is characterised by:

[0121] • A current smoker at time of treatment

[0122] • A peripheral blood eosinophil count of > 300 cells / pL

[0123] • A historical blood eosinophil count of > 150 cells / pL in the 12 months prior to treatment

[0124] • A history of two or more moderate COPD exacerbations that were treated with systemic corticosteroids, or at least one severe acute exacerbation of COPD requiring hospitalization, in the 12 months prior to treatment,

[0125] • A pre-bronchodilator (pre-BD) post-bronchodilator (post-BD) forced expiratory volume in 1 second (FEVi) to forced vital capacity (FVC) ratio (pre- and post-BD FEVi / FVC) ratio of <0.70, and / or a post-BD FEVi > 20% and < 80% predicted normal value.

[0126] In an embodiment, the patient has a blood eosinophil count of greater than or equal to about 300 cells / pL prior to treatment. In another embodiment, the patient has a historical blood eosinophil count of greater than or equal to 150 cells / pL in the 12 monts prior to treatment (e.g., measured between 12 months and 1 month prior to treatment and not within 14 days of a COPD exacerbation).

[0127] In some instances, the methods disclosed herein improve one or more indicators of COPD. Indicators of COPD include, for example, annualized rate of moderate or severe COPD exacerbations, time to first moderate or severe COPD exacerbation, time to first severe COPD exacerbation, annualized rate of exacerbations requiring emergency department (ED) visits and / or hospitalization, FEVi, FVC, E-RS COPD total score, SGRQ score, CAT score, among others.

[0128] In some instances, an improvement in CAT score means a subject has experienced a decrease in CAT score of more than or equal to (>) 2 points compared to baseline.

[0129] In some instances, an improvement in SGRQ score means a subject has experienced a decrease in SGRQ total score of more than or equal to (>) 4 points compared to baseline. In some instances, the subject has been diagnosed with COPD classified as GOLD 2-4. In some instances, the subject has been diagnosed with COPD classified as GOLD 2. In some instances, the subject has been diagnosed with COPD classified as GOLD 3. In some instances, the subject has been diagnosed with COPD classified as GOLD 4. 70540W001

[0130] In some instances, an improvement in E-RS COPD score means a subject has experienced a decrease in CAT score of greater than or equal to (>) 2 points compared to baseline.

[0131] Treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result in an increase in forced expiratory volume in 1 second (FEVi) as defined herein. In some instances, the increase in FEVi is observed at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36 or 52 relative to baseline. In some instances, the increase in FEVi may be observed at week 4, 12, 24, 36 or 52 relative to baseline. In some instances, the increase in FEVi may be by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% of the FEVi observed prior to treatment. In some instances, the increase in FEVi may be to > 70 %, > 75% or >80% of the predicted normal value.

[0132] In some instances, treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result in an increase in FEVi / FVC ratio relative to baseline. In some instances, the increase in FEV1 / FVC ratio may be of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% of the pre-BD or post-BD FEVi / FVC ratio relative to baseline. In some instances, the increase in FEVi / FVC ratio may be an increase of at least 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6 or 0.7. In some instances, the increase in FEVi / FVC ratio may be to > 0.70. In some instances, the increase in FEVi / FVC ratio may be to > 0.75, > 0.80, > 0.85, > 0.90, > 0.95 or > 0.99.

[0133] In other instances, treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result a decrease in the frequency, duration, or severity of AECOPD, optionally the frequency, duration or severity of moderate or severe AECOPD, relative to baseline. In some instances, the decrease in the frequency, duration, or severity of AECOPD may be observed at week 2, 4, 8, 12, 16, 29, 24, 28, 32, 36, 40, 44, 48 or 52 relative to baseline. In some instances, the decrease in the frequency, duration, or severity of AECOPD may be observed at week 52 relative to baseline.

[0134] In some instances, treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result in a decrease in the frequency of AECOPD. In some instances, the decrease in frequency of AECOPD may be a decrease in the annualized rate of moderate or severe COPD exacerbation. In some instances, the decrease in frequency of AECOPD may be a decrease in the annualized rate of severe COPD exacerbation. In other instances, the decrease in frequency of AECOPD may be a decrease in the annualized rate of COPD exacerbations requiring emergency department visit and / or hospitalization. In some instances, the decrease in the frequency of AECOPD may be a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decrease in the frequency of AECOPD relative to baseline. In some instances, the decrease in frequency of AECOPD may be a 70540W001 decrease over 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In some instances, the decrease in frequency of AECOPD may be a decrease over 12 months. In some instances, the decrease in frequency of AECOPD may be a decrease to an average of one AECOPD in every 8 weeks, one AECOPD in every 16 weeks, one AECOPD in every 32 weeks, one AECOPD in every 52 weeks, or less than one AECOPD in every 52 weeks.

[0135] In other instances, treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result in a decrease in the average duration of AECOPD. In some instances, the decrease in average duration of AECOPD may be a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decrease in the average duration of AECOPD relative to baseline. In some instances, the decrease in average duration of AECOPD may be a decrease to an average duration of 24hrs or less.

[0136] In some instances, treatment with the anti-IL-5 antibody or fragment thereof, as described herein, may result in a decrease in the severity of AECOPD. A decrease in severity may result in a decrease in the frequency or duration of moderate and / or severe AECOPD relative to baseline, and this may be accompanied by an increase in the frequency or duration of mild AECOPD. A decrease in severity may result in a decrease in the frequency or duration of severe AECOPD relative to baseline, and this may be accompanied by an increase in the frequency or duration of moderate or mild AECOPD.

[0137] In some instances, the treatment results in a decrease in EXACT-PRO score relative to baseline. In some embodiments, the decrease may be of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95 or more points on the EXACT-PRO scale, relative to baseline. In some instances, the decrease may be from a baseline score of 50 or more to a post-treatment score of less than 50. In some instances, the decrease may be from a baseline score of 60 or more, of 70 or more, or of 80 or more, to a post-treatment score of less than 50. In some instances, the decrease may be from a baseline score of 50 or more, 60 or more, of 70 or more, or of 80 or more, to a post- treatment score of less than 40. In some instances, the decrease may be from a baseline score of 40 or more, 60 or more, of 70 or more, or of 80 or more, to a post-treatment score of less than 30.

[0138] In some instances, the treatment results in a decrease in E-RS™ :COPD score relative to baseline. In some instances, the decrease may be of 5, 10, 15, 20, 25, 30, 35 or more points on the E-RS™ :COPD scale, relative to baseline. In some instances, the decrease may be from a baseline score of 9 or more to a post-treatment score of less than 9 in the breathlessness domain. In some instances, the decrease may be from a baseline score of 6 or more to a post-treatment score of less than 6 in the cough and sputum domain. In some instances, the decrease may be from a baseline score of 7 or more to a posttreatment score of less than 7 in the chest symptom domain. 70540W001

[0139] In some instances, the treatment may result in an improvement in Cough visual analogue scale (Cough VAS) relative to baseline. Cough VAS, or cough severity VAS, comprises a 100 mm linear scale marked with a horizontal line by the subject, with 0 mm representing "no cough" and 100 mm representing "worst cough", measuring subjective assessment by the subject of the prior 24 hrs for severity of cough symptoms (Smith et al 2006). In some instances, the improvement may be a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more than 95% decrease in Cough VAS relative to baseline.

[0140] In some instances, the treatment results in an improvement in St George's Respiratory Questionnaire (SGRQ) score relative to baseline. The SGRQ is a 50-item ePRO instrument developed to measure the health status of participants with airway obstruction diseases (Jones et al 1991). The questionnaire is divided into 2 parts: Part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; Part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ yields a total score and 3 domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Based on empirical data and interviews with patients, a change of 4 units is associated with a minimum clinically important difference. Specific details on the scoring algorithms are provided by the developer in a user manual (Jones and Forde 2009). In some instances, the improvement may be a decrease of SGRQ score by 4 or more units relative to baseline. In some embodiments, the improvement may be a decrease of SGRQ score by 8, 12, 16, 20 or more units relative to baseline. In some instances, the improvement may be a decrease of SGRQ score by 5, 10, 20, 30, 40, 50, 60, 70, 80 or more units relative to baseline.

[0141] In some instances, the treatment results in an improvement in Breathlessness, Cough and Sputum Scale (BCSS) score relative to baseline. In some instances, the improvement may be a decrease in the total score relative to baseline. In some instances, the improvement may be a 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 point improvement in total score. In some instances, the improvement may comprise a decrease in the sputum and / or cough domain score relative to baseline. In some embodiments, the improvement may be a 2, 3, 4 or 5 point decrease in sputum, and / or cough domain score. In some instances, the improvement in BCSS score may comprise a reduction in sputum and / or cough domain score from >2 to < 2. In some instances, the improvement in BCSS score may comprise a reduction in sputum and / or cough domain score from >2 to <2. 70540W001

[0142] ADMINISTRATION REGIMENS

[0143] The present disclosure relates to dosage regimens of an anti-IL-5 antibody or fragment thereof, which finds particular effectiveness in the treatment of COPD. A dosage regimen is composed of one or more doses of a controlled size administered throughout a treatment window. Where there is more than one dose, the doses are separated by a dosing interval. The anti-IL-5 antibody or fragment thereof is administered in a therapeutically effective amount. As used herein, an “effective amount” or “therapeutically effective amount” of an agent, e.g., a pharmaceutical composition comprising an anti-IL-5 antibody, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect.

[0144] In an embodiment, the dose is 100 mg. In some instances, the anti-IL-5 antibody or fragment thereof may be administered by subcutaneous injection. The subcutaneous injection may be administered by a prefilled syringe or an autoinjector.

[0145] In an embodiment, the patient is an adult.

[0146] In an embodiment, the patient is receiving inhaled maintenance therapy, optionally ICS, LABA, and / or LAMA. In an embodiment, the patient is receiving triple inhaled maintenance therapy, optionally ICS / LABA / LAMA. In another embodiment, the patient is receiving triple inhaled maintenance thepray at least 6 months prior to treatment.

[0147] Administration of the anti-IL-5 antibody or fragment thereof is delivered by multiple doses separated by a dosing interval. In an embodiment, the dosing interval is 4 weeks (28 days). In a specific embodiment, the anti-IL-5 antibody or fragment thereof is administered to a patient at a dose of 100 mg every 4 weeks (Q4W).

[0148] When the dosing interval is expressed as a number of weeks, a margin of error is permissible such that a week may be expressed as 7 days ± 1 day. Therefore, in some instances, the dosing interval is 4 weeks ± 4 days. In some instances, the dosing interval may be 4 weeks ± 3 days. In some embodiments, the dosing interval may be 4 weeks ± 2 days. In some embodiments, the dosing interval may be 4 weeks ± 1 day. In some instances, the dosing interval may be exactly 4 weeks.

[0149] ANTI-IL-5 ANTIBODIES

[0150] Anti IL-5 antibodies and fragments thereof useful in the disclosed methods may comprise a heavy chain variable region comprising a CDRH1 having the sequence as set forth in SEQ ID NO: 5, a CDRH2 having the sequence of SEQ ID NO: 6, a CDRH3 having the sequence of SEQ ID NO: 7; and (b) a light chain variable region a CDRL1 having the 70540W001 sequence of SEQ ID NO: 8, a CDRL2 having the sequence of SEQ ID NO: 9, and a CDRL3 having the sequence of SEQ ID NO: 10.

[0151] In an embodiment, the anti-IL-5 antibody or fragment thereof for use in the disclosed methods comprises a heavy chain variable region (VH) sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) sequence as set forth in SEQ ID NO: 4.

[0152] In another embodiment, the anti-IL-5 antibody or fragment thereof for use in the disclosed methods comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

[0153] In a preferred embodiment, the anti-IL-5 antibody is mepolizumab.

[0154] PHARMACEUTICAL COMPOSITION

[0155] In one embodiment, the the anti-IL-5 antibody or fragment thereof may be formulated within a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the anti-IL-5 antibody or fragment thereof and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises an anti-IL-5 antibody or fragment thereof, wherein the anti-IL-5 antibody comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10, and a pharmaceutically acceptable excipient.

[0156] In one embodiment, the pharmaceutical composition comprises an aqueous liquid formulation comprising (a) 100 mg / mL of an anti-IL-5 antibody comprising a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10; (b) 15.5 mM sodium phosphate dibasic heptahydrate and 4.5 mM citric acid at pH about 6.2 to about 6.6; (c) 12% sucrose; (d) 0.02% polysorbate 80; and (e) 0.05 mM EDTA.

[0157] In one embodiment, the pharmaceutical composition comprises an aqueous liquid formulation comprising (a) 100 mg / mL of mepolizumab; (b) 15.5 mM sodium phosphate dibasic heptahydrate and 4.5 mM citric acid at pH about 6.2 to about 6.6; (c) 12% sucrose; (d) 0.02% polysorbate 80; and (e) 0.05 mM EDTA. 70540W001

[0158] In one embodiment, the pharmaceutical composition comprises an aqueous liquid formulation comprising (a) 100 mg / mL of mepolizumab; (b) 4.16 mg / mL sodium phosphate dibasic heptahydrate; (c) 0.95 mg / mL citric acid monohydrate; (d) 0.2 mg / mL polysorbate 80; and 0.019 mg / mL EDTA disodium dihydrate.

[0159] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing the dose for an entire day or sub-dose, or an appropriate fraction thereof, of an active ingredient. Unit doses that contain a sub-dose of the recommended dose for a day may therefore be administered more than once in order to make up the total dose for a day. For example, if a dose on a particular day is 100 mg, this may be contained in one unit or in multiple units (e.g. 2 units each comprising 50 mg of active ingredient). In one embodiment, the pharmaceutical composition is in unit dosage form.

[0160] PRE-FILLED SYRINGES

[0161] The disclosure also provides a pre-filled syringe comprising about 100 mg of an anti- IL-5 antibody or fragment thereof of the disclosure. In one embodiment, there is provided a pre-filled syringe comprising a pharmaceutical composition as disclosed herein.

[0162] In one embodiment, the pre-filled syringe comprises about 100 mg of an anti-IL-5 antibody or fragment thereof of the present disclosure. In one embodiment, the pre-filled syringe comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises the anti-IL-5 antibody or fragment thereof of the present disclosure and a pharmaceutically acceptable excipient.

[0163] In one embodiment, the pre-filled syringe is provided in a safety syringe device (SSD) or an autoinjector. Such devices are well known to a person skilled in the art.

[0164] CLAUSES

[0165] In summary, the disclosure includes:

[0166] 1. An anti-IL-5 antibody or fragment thereof for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the 12 months prior to administration, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable 70540W001 region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0167] 2. The anti-IL-5 antibody or fragment thereof for use according to claim 1 , wherein the patient is receiving ICS / LABA / LAMA

[0168] 3. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0169] 2, wherein the COPD is associated with chronic bronchitis in the patient.

[0170] 4. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0171] 3, wherein the COPD is moderate COPD, moderate-to-severe COPD, or severe COPD.

[0172] 5. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0173] 4, wherein the patient has a history in the 12 months prior to administration of at least one or at least two moderate, or at least one severeexacerbations of COPD .

[0174] 6. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0175] 5, wherein the patient has a history in the 12 months prior to administration of at least one or at least two moderate exacerbations that were treated with systemic corticosteroids.

[0176] 7. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0177] 6, wherein the patient has a history in the 12 months prior to administration of at least one severe exacerbation requiring hospitalization.

[0178] 8. The anti-IL-5 antibody or fragment thereof for use according to any one of claimsl-

[0179] 7, wherein the patient is a current smoker or a former smoker and optionally wherein the patient has a smoking history of at least 10 pack-years.

[0180] 9. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0181] 8, wherein the patient is a current smoker with a smoking history of at least 10 pack- years.

[0182] 10. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0183] 9, wherein the patient is a former smoker with a smoking history of at least 10 pack- years.

[0184] 11. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0185] 10, wherein, prior to treatment, the patient has a post bronchodilator forced expiratory volume in 1 second (FEVi) to forced vital capacity (FVC) ratio (post-BD- FEWFVC) of less than (<) 0.70. 70540W001

[0186] 12. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0187] 11 , wherein, prior to treatment, the patient has a post bronchodilator forced expiratory volume in 1 second (post-BD FEVi) <80% of predicted normal volume.

[0188] 13. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0189] 12, wherein the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA (LABA / LAMA); ICS and LABA (ICS / LABA); ICS and LAMA (ICS / LAMA); or ICS, LABA, and LAMA (ICS / LABA / LAMA).

[0190] 14. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0191] 13, wherein the patient received ICS / LABA / LAMA for 12 months prior to treatment.

[0192] 15. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0193] 14, wherein the patient is receiving an ICS dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

[0194] 16. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0195] 15, wherein the patient is receiving fluticasone propionate at a dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

[0196] 17. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0197] 16, wherein the method improves a patient’s score in one or more questionnaires selected from COPD Assessment Test (CAT), Evaluating Respiratory Symptioms in COPD (E-RS: COPD), St George’s Respiratory Questionnaire (SGRQ), St George’s Respiratory Questionnaire for COPD (SGRQ-C), Exacerbations of Chronic Pulmonary Disease Tool-Patient-Reported-Outcomes (EXACT), Breathlessness, Cough and Sputum Scale (BCSS), 5-level EuroQol-5 Dimension (EQ-5D-5L), Work Productivity and Activity Impairment Questionnaire (WPAI-GH), Patient Global Impression of Severity (PGIS) or Patient Global Impression of Change (PGIC).

[0198] 18. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0199] 17, wherein the method improves the patient’s CAT score by >2 points from baseline; improves the patient’s SGRQ or SGRQ-C score by >4 points from baseline; or improves the patient’s E-RS: COPD score by >2 points from baseline.

[0200] 19. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0201] 18, wherein the annualised rate of moderate or severe COPD exacerbations is reduced in the patient and / or the time to first moderate or severe COPD exacerbation is increased. 70540W001

[0202] 20. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0203] 19, wherein the anti-IL-5 antibody or fragment thereof comprises a heavy chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 4.

[0204] 21 . The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0205] 20, wherein the antibody or fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

[0206] 22. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-

[0207] 21 , wherein the antibody is mepolizumab.

[0208] 23. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1 to 22, wherein the IL-5 antibody or fragment thereof is in a pharmaceutical composition.

[0209] 24. A method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL- 5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0210] 25. A method of reducing the annualized rate of moderate or severe COPD exacerbations for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light 70540W001 chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0211] 26. A method of reducing the annualized rate of COPD exacerbations requiring emergency department (ED) visits and / or hospitalization for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0212] 27. A method of reducing the time to first moderate or severe COPD exacerbation in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL- 5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

[0213] 28. The method according to any one of claims 24-27, wherein the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA (LABA / LAMA); ICS and LABA (ICS / LABA); ICS and LAMA (ICS / LAMA); or ICS, LABA, and LAMA (ICS / LABA / LAMA). 70540W001

[0214] 29. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-28, wherein the patient received ICS / LABA / LAMA for 12 months prior to treatment.

[0215] 30. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-29, wherein the patient is receiving an ICS dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

[0216] 31. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-30, wherein the patient is receiving fluticasone propionate at a dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

[0217] EXAMPLES

[0218] The following examples illustrate various, non-limiting aspects of the invention. The examples are not intended to limit the scope of the invention in any way.

[0219] EXAMPLE 1 : Phase III COPD Trial

[0220] MATINEE (NCT04133909) was a Phase III, randomized, multicenter, placebo- controlled, double-blind, parallel group trial assessing mepolizumab 100 mg, administered subcutaneously every four weeks for at least 52 weeks and up to 104 weeks, in addition to inhaled corticosteroid-based triple-inhaled therapy, in patients with COPD with type 2 inflammation characterized by an eosinophilic phenotype (blood eosinophil count >300 cells / pL at screening and >150 cells / pL within the 12 months prior to screening.) The primary outcome was the annualized rate of moderate or severe exacerbations. Time to first moderate or severe exacerbation, COPD Assessment Test (CAT) score, St George’s Respiratory Questionnaire (SGRQ) total score, Proportion of Evaluating Respiratory Symptoms in COPD (E-RS: COPD) and annualized rate of exacerbations requiring emergency department (ED) visit and / or hospitalization were also measured (tested hierarchically to control for multiplicity) as secondary outcomes.

[0221] Trial

[0222] Patients were required to be at least 40 years of age at Screening Visit 1 with a documented diagnosis of COPD for at least one year based on the American Thoracic Society / European Respiratory Society definition and had a ratio of forced expiratory 70540W001 volume in 1 second (FEVi) to forced vital capacity (FVC) of <0.70 pre- and postsalbutamol and a FEVi >20% and <80% of the predicated value post-salbutamol. In the 12 months before screening patients were required to have at least two moderate (defined as clinically significant exacerbations that require treatment with oral / systemic corticosteroids with or without antibiotics) or at least one severe exacerbation (defined as clinically significant exacerbations that require inpatient hospitalisation [i.e. >24 h] or result in death) despite inhaled triple therapy and 12 months ICS-based maintenance therapy with at least three months history of ICS-based inhaler triple therapy (>500 mg / day fluticasone propionate or equivalent, plus LABA plus LAMA). Current or former smokers (>10 pack-years) were included. Participants with a history or concurrent diagnosis of asthma were excluded regardless of disease activity. The modified intention-to-treat (mITT) population consisted of all patients who received >1 dose. At screening Visit 0, patients are required to have a BEC >300 cells / pL and a BEC >150 cells / pL in the prior 12 months. Those without historical BEC >150 cells / pL were required to meet the threshold at Screening Visit 1 to be eligible. Patients who met these inclusion criteria entered a two- week run-in period.

[0223] The primary endpoint was the annualized rate of moderate or severe exacerbations, moderate defined as clinically significant exacerbations that require treatment with oral / systemic corticosteroids and or antibiotic treatment, and severe as clinically significant exacerbations that require >24 hours in-patient hospitalization or resulted in death, respectively. Secondary endpoints assessed were the time to first moderate or severe exacerbation, annualized rate of exacerbations requiring emergency department (ED) visit and / or hospitalization, the proportion of COPD Assessment Test (CAT) score responders at Week 52 (defined as a >2-unit reduction in CAT score from baseline, scores range from 0 to 40 units and higher scores indicate greater effect of disease), the proportion of St. George’s Respiratory Questionnaire (SGRQ) total score responders at Week 52 measured using the SGRQ questionnaire for COPD (defined as a >4-point reduction in SGRQ total score from baseline, scores range from 0 to 100 points and higher scores indicate worse health status) and the proportion of Evaluating Respiratory Symptoms in COPD (E-RS: COPD) responders at Weeks 48-52 (defined as >2-point reduction in total score from baseline, scores range from 0 to 40 units with higher scores indicating more severe disease). Change from baseline in prebronchodilator FEVi was also assessed.

[0224] The safety endpoints included adverse events and serious adverse events. Immunogenicity was also assessed. For patients continuing the study beyond 52 weeks, 70540W001 vital signs and clinical safety were taken at less frequent intervals in the second year than in the first.

[0225] Statistical Analysis

[0226] With an assumed exacerbation rate of 1.7 exacerbations per year in the placebo arm, it was estimated that 800 patients (400 patients / arm( would provide the trial with 90% power to detect a 23% reduction in the annualized rate of moderate / severe exacerbations with 100 mg mepolizumab at a two-sided 5% level of significance. An additional 44 patients were included to account for the loss of patient years’ data from those who withdrew early from the trial, accounting for 5.5% of patient-years data being missing. Blinded re-evaluations of the sample size were carried out prior to randomization of the 800thparticipant to assess whether 800 participants would continue to provide sufficient power for the study based on the blinded overall exacerbation rate estimated from the available data..

[0227] The primary population for analysis of efficacy data was the mITT population. The primary endpoint included all moderate / severe exacerbations reported from the start of treatment up to the exit visit, regardless of study treatment discontinuation not associated with disruptions / restrictions imposed by the COVID pandemic. Rate of moderate / severe exacerbations was assessed using a negative binomial model including both on- andoff- treatment exacerbations with covariates of smoking status (current versus former smoker), number of exacerbations in the previous year (<2, 3, >4 as ordinal), baseline disease severity (as % predicted post-bronchodilator FEVi) and geographic region, natural log of time was included as an offset variable. For time to first moderate / severe exacerbation a Cox’s proportional hazards model was used with the same covariates as for the primary endpoint. For the proportion of CAT score responders and SGRQ total score responders patients with missing values at Week 52 were included as non-responders and sensitivity analyses to the assumption regarding missing data were performed using multiple imputation methods based on mixed pattern models. Analysis was performed using logistic regression model adjusting for baseline CAT score, smoking status, and geographic region. Primary and multiple secondary endpoints were controlled for multiplicity using a fixed hierarchical testing procedure.

[0228] Results

[0229] Patient population

[0230] In MATINEE, patients were recruited from October 2019 through August 2024. In total, 806 patients were randomized to either mepolizumab (N=402) or placebo (N=404). Of 70540W001 these, 804 were included in the mITT population. Patient demographics and characteristics were balanced between treatment arms. Concomitant medications were not increased in patients treated with mepolizumab compared with those treated with placebo. Representativeness of the trial population is described in Table 1 below. Patient demographics and clinical characteristics at baseline are described in Table 2 below. Table 1. 70540W001

[0231] Table 2. 70540W001

[0232] Data are reported as mean ± SD unless stated otherwise. *”Europe” includes Belgium, Denmark, France, Germany, Greece, Ireland, Italy, the Netherlands, Spain, Sweden, and the United Kingdom; “Eastern Europe” includes Hungary and Poland; “Asia” includes China, the Republic of Korea, and Taiwan; “South America” includes Argentina, Brazil and Mexico; “North America” includes Canada and the US; “Rest of the world” includes Australia, India, Israel, and New Zealand.

[0233] BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEVi , forced expiratory volume in 1 second; mMRC, modified Medical Research Council dyspnea scale; SC, subcutaneous; SD, standard deviation; SGRQ, St. George’s Respiratory Questionnaire.

[0234] Exacerbations

[0235] The primary and secondary efficacy endpoints are described in Table 3.

[0236] Table 3.

[0237] 70540W001

[0238] Data are reported as mean ± SD unless stated otherwise. Data are reported following the order of the statistical testing hierarchy of endpoints. Cis have not been adjusted for multiplicity and should not be used for inference. For CAT, SGRQ, and E-RS: COPD, the number of responders and non-responders do not equal the total number of participants as response status for the 9 and 8 patients in the mepolizumab and placebo groups, respectively, with an intercurrent event of either treatment interruption or treatment discontinuation related to the COVID-19 pandemic, was based on multiple imputation of data following the event (2000 imputations). Patients with missing baseline data were not included in the analysis.

[0239] *CAT responders: >2-point decrease from baseline.+The result was not significantly lower for mepolizumab compared with placebo, therefore no further statistical testing was performed according to the hierarchical testing procedure. *SGRQ responders: >4-point decrease from baseline.§E-RS: COPD responders: >2-point decrease from baseline.

[0240] CAT, COPD Assessment Test; Cl, confidence interval; COPD, chronic obstructive pulmonary disease; COVID- 19, Coronavirus disease 2019; ED, emergency department; E-RS: COPD, Evaluating Respiratory Symptoms of COPD; SC, subcutaneous; SD, standard deviation; SGRQ, St. George's Respiratory Questionnaire.

[0241] Primary End Point

[0242] The annualized rate of moderate or severe exacerbations at Week 52 was significantly higher in the mepolizumab group as shown in Table 4. The annualized rate of severe exacerbations at Week 52 was significantly higher in the mepolizumab group as shown in Table 5. Table 6 provides a summary of number of years follow-up for moderate / severe exacerbations.

[0243] Table 4.

[0244] Table 5. 70540W001

[0245] Table 6.

[0246] Secondary End Points

[0247] The time to first moderate or severe exacerbation in the mepolizumab versus placebo group was a median time of 202 versus 226 days, respectively (hazard ratio, 0.78; 95% Cl, 0.64;, 0.94 P=0.010). The annual rate of exacerbations leading to ED visit or hospitalization was significantly lower in the mepolizumab versus placebo group at 0.13 and 0.20, respectively (rate ratio, 0.65; 95% Cl, 0.44, 0.97; P=0.036) (Fig. 4).

[0248] Patient-reported outcomes

[0249] The proportion of CAT score responders at Week 52 in the mepolizumab versus placebo group was 41% vs 46% (hazard ratio, 0.81 ; 95% Cl, 0.60 to 1.09; P=0.161). The proportion E-RS: COPD responders in the mepolizumab group versus the placebo group was 31%% vs 34%% (hazard ratio; 1.17; 95% Cl, 0.87 to 1.57; P=0.291). The proportion of SGRQ responders at Week 52 responders was significantly greater for the mepolizumab group versus placebo (50% vs 46%; hazard ratio; 1.17; 95% Cl, 0.87 to 1.57; P=0.291).

[0250] Table 7.

[0251] SGRQ total score (Week 52)

[0252] LS mean change from baseline (95% Cl) -8.0 (-9.7, -6.3-) -5.7 (-7.4, -4.0-) 70540W001

[0253] Subgroup Analyses

[0254] The proportion of current smoker responders at Week 52 was significantly higher in the mepolizumab versus placebo group (0.68, 95% Cl), even compared to former smoker responders at Week 52 (0.83, 95% Cl). (Fig. 8).

[0255] The proportion of responders without symptoms of chronic bronchitis was significantly higher in the mepolizumab versus placebo group (0.73, 95% Cl), even compared to responders with symptoms of chronic bronchitis (0.80, 95% Cl). The annualized rate of moderate / severe exacerbations was 31% lower with mepolizumab versus placebo in patients with chronic bronchitis only. Numerical reductions were also seen in patients with emphysema only and chronic bronchitis + emphysema. (Fig. 9)

[0256] The annualized rates of exacerbations requiring ED visit and / or hospitalization were numerically lower with mepolizumab versus placebo in patients with CB only, emphysema only, and neither. (Fig. 10).

[0257] In an integrated analysis of data from the METREX, METREO, and MATINEE trials, the annualized rate of moderate / severe exacerbations was significantly reduced with mepolizumab versus placebo by 24% in patients with prior severe exacerbations and 22% in those without. (Fig. 11).

[0258] In an integrated analysis of data from the METREX, METREO, and MATINEE trials, the mean decrease from baseline to Week 52 in SGRQ total score was significantly greater with mepolizumab versus placebo in all patients. When stratified with airflow obstruction subgroups, there was significant improvement for patients with GOLD 2. (Fig. 12).

[0259] In an integrated analysis of data from the METREX, METRO, and MATINEE trials, patients with > 1 prior severe exacerbation were more likely to experience an exacerbation requiring ED visit and / or hospitalization than those without. Mepolizumab increased the time to first such exacerbation in both subgroups, with a statistically significant effect in those with > 1 prior severe exacerbation. (Fig. 13)

[0260] Safety 70540W001

[0261] The safety profile of mepolizumab was comparable to placebo, with a similar incidence of adverse events and serious adverse events between the mepolizumab and placebo groups. Table 8 describes the safety data for MATINEE. Table 9 describes the on- treatment malignancies (safety population).

[0262] Table 8. 70540W001

[0263] Table 9. 70540W001

[0264] A summary of the COPD medications started before randomization and continued during the study period, and COPD medications started during the study period are described in Table 10.

[0265] Table 10. 70540W001 70540W001 70540W001

[0266] 70540W001

[0267] SEQUENCE LISTINGS

[0268] SEQ ID NO: 1 - Mepolizumab Full length heavy chain

[0269] QVTLRESGPALVKPTQTLTLTCTVSGFSLTSYSVHWVRQPPGKGLEWLGVIWASGGTDY

[0270] NSALMSRLSISKDTSRNQWLTMTNMDPVDTATYYCARDPPSSLLRLDYWGRGTPVTVS

[0271] SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

[0272] SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL

[0273] GGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

[0274] QYN*STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP

[0275] SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0276] SEQ ID NO: 2 - Mepolizumab Full length light chain

[0277] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTR

[0278] ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGGTKLEIKRTVAAPS

[0279] VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY

[0280] SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0281] SEQ ID NO: 3 - Mepolizumab VH sequence

[0282] QVTLRESGPALVKPTQTLTLTCTVSGFSLTSYSVHWVRQPPGKGLEWLGVIWASGGTDY

[0283] NSALMSRLSISKDTSRNQVVLTMTNMDPVDTATYYCARDPPSSLLRLDYWGRGTPVTVS S

[0284] SEQ ID NO: 4 - Mepolizumab VL sequence

[0285] DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTR

[0286] ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVHSFPFTFGGGTKLEIK

[0287] SEQ ID NO: 5 - CDRH1

[0288] SYSVH

[0289] SEQ ID NO: 6 - CDRH2

[0290] VIWASGGTDYNSALMS

[0291] SEQ ID NO: 7 - CDRH3

[0292] DPPSSLLRLDY

[0293] SEQ ID NO: 8 - CDRL1

[0294] KSSQSLLNSGNQKNYLA 70540W001

[0295] SEQ ID NO: 9 - CDRL2

[0296] GASTRES

[0297] SEQ ID NO: 10 - CDRL3

[0298] QNVHSFPFT

[0299] SEQ ID NO: 11 - Human IL-5 (mature protein)

[0300] IPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCTEEIFQGIGTLESQTVQGG

[0301] TVERLFKNLSLIKKYIDGQKKKCGEERRRVNQFLDYLQEFLGVMNTEWIIES

[0302] SEQ ID NO: 12 - Human IL-5 Receptor Subunit Alpha Isoform 1 (mature protein)

[0303] DLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETRI

[0304] TESKCVTILHKGFSASVRTILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTEDN

[0305] YSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTEECQEYSKDTLGRNIACWFPR TFI LSKGRDWLAVLVNGSSKHSAI RPFDQLFALHAI DQI N PPLN VTAEI EGTRLSIQWEKPV SAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAGLWS

[0306] EWSQPIYVGNDEHKPLREWFVIVIMATICFILLILSLICKICHLWIKLFPPIPAPKSNIKDLFVT

[0307] TNYEKAGSSETEI EVICYI EKPGVETLEDSVF

Claims

70540W001CLAIMS1. An anti-IL-5 antibody or fragment thereof for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the 12 months prior to administration, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 Fiamino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

2. The anti-IL-5 antibody or fragment thereof for use according to claim 1 , wherein the patient is receiving ICS / LABA / LAMA3. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-2, wherein the COPD is associated with chronic bronchitis in the patient.

4. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-3, wherein the COPD is moderate COPD, moderate-to-severe COPD, or severe COPD.

5. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-4, wherein the patient has a history in the 12 months prior to administration of at least one or at least two moderate, or at least one severeexacerbations of COPD .

6. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-5, wherein the patient has a history in the 12 months prior to administration of at least one or at least two moderate exacerbations that were treated with systemic corticosteroids.

7. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-6, wherein the patient has a history in the 12 months prior to administration of at least one severe exacerbation requiring hospitalization.70540W0018. The anti-IL-5 antibody or fragment thereof for use according to any one of claimsl-7, wherein the patient is a current smoker or a former smoker and optionally wherein the patient has a smoking history of at least 10 pack-years.

9. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-8, wherein the patient is a current smoker with a smoking history of at least 10 pack-years.

10. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-9, wherein the patient is a former smoker with a smoking history of at least 10 pack-years.11 . The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-10, wherein, prior to treatment, the patient has a post bronchodilator forced expiratory volume in 1 second (FEVi) to forced vital capacity (FVC) ratio (post-BD- FEWFVC) of less than (<) 0.70.

12. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-11 , wherein, prior to treatment, the patient has a post bronchodilator forced expiratory volume in 1 second (post-BD FEVi) <80% of predicted normal volume.

13. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-12, wherein the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA (LABA / LAMA); ICS and LABA (ICS / LABA); ICS and LAMA (ICS / LAMA); or ICS, LABA, and LAMA (ICS / LABA / LAMA).

14. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-13, wherein the patient received ICS / LABA / LAMA for 12 months prior to treatment.

15. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-14, wherein the patient is receiving an ICS dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

16. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-15, wherein the patient is receiving fluticasone propionate at a dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.70540WQ0117. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-16, wherein the method improves a patient’s score in one or more questionnaires selected from COPD Assessment Test (CAT), Evaluating Respiratory Symptioms in COPD (E-RS: COPD), St George’s Respiratory Questionnaire (SGRQ), St George’s Respiratory Questionnaire for COPD (SGRQ-C), Exacerbations of Chronic Pulmonary Disease Tool- Patient-Reported-Outcomes (EXACT), Breathlessness, Cough and Sputum Scale (BCSS), 5-level EuroQol-5 Dimension (EQ-5D-5L), Work Productivity and Activity Impairment Questionnaire (WPAI-GH), Patient Global Impression of Severity (PGIS) or Patient Global Impression of Change (PGIC).

18. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-17, wherein the method improves the patient’s CAT score by >2 points from baseline; improves the patient’s SGRQ or SGRQ-C score by >4 points from baseline; or improves the patient’s E-RS: COPD score by >2 points from baseline.

19. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-18, wherein the annualised rate of moderate or severe COPD exacerbations is reduced in the patient and / or the time to first moderate or severe COPD exacerbation is increased.

20. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-19, wherein the anti-IL-5 antibody or fragment thereof comprises a heavy chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 3 and a light chain variable region sequence having the amino acid sequence shown in SEQ ID NO: 4.

21. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-20, wherein the antibody or fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 1 and a light chain having the amino acid sequence shown in SEQ ID NO: 2.

22. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1-21 , wherein the antibody is mepolizumab.

23. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 1 to 22, wherein the IL-5 antibody or fragment thereof is in a pharmaceutical composition.70540W00124. A method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the I L-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

25. A method of reducing the annualized rate of moderate or severe COPD exacerbations for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

26. A method of reducing the annualized rate of COPD exacerbations requiring emergency department (ED) visits and / or hospitalization for a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid70540WQ01 sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

27. A method of reducing the time to first moderate or severe COPD exacerbation in a patient, wherein the patient (i) has a blood eosinophil count of at least 300 cells / pL, (ii) had a blood eosinophil count of at least 150 cells / pL in the past year, and (iii) does not have a past history or concurrent diagnosis of asthma; wherein the method comprises administering subcutaneously a therapeutically effective amount of an IL-5 antibody or fragment thereof in a dose of about 100 mg at an interval of every 4 weeks (Q4W); and wherein the IL-5 antibody or variant thereof comprises a heavy chain variable region having the CDRH1 amino acid sequence shown in SEQ ID NO: 5, the CDRH2 amino acid sequence shown in SEQ ID NO: 6, and the CDRH3 amino acid sequence shown in SEQ ID NO: 7; and a light chain variable region having the CDRL1 amino acid sequence shown in SEQ ID NO: 8, the CDRL2 amino acid sequence shown in SEQ ID NO: 9, and the CDRL3 amino acid sequence shown in SEQ ID NO: 10.

28. The method according to any one of claims 24-27, wherein the patient is receiving inhaled maintenance therapy comprising a long acting beta 2 agonist (LABA), a long activating muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS), and wherein the inhaled maintenance therapy optionally comprises LABA and LAMA (LABA / LAMA); ICS and LABA (ICS / LABA); ICS and LAMA (ICS / LAMA); or ICS, LABA, and LAMA (ICS / LABA / LAMA).

29. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-28, wherein the patient received ICS / LABA / LAMA for 12 months prior to treatment.

30. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-29, wherein the patient is receiving an ICS dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

31. The anti-IL-5 antibody or fragment thereof for use according to any one of claims 24-30, wherein the patient is receiving fluticasone propionate at a dose of >500 mcg / day at least 3 months before administration of the first dose of the anti-IL-5 antibody or fragment thereof.

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