Anti-il5r-alpha treatment for acute exacerbations of asthma and COPD

Abstract

Provided herein are methods of treating acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) comprising administering to the patient an anti-interleukin- 5 receptor alpha (IL-5Rα) antibody or an antigen-binding fragment thereof such as benralizumab.

Description

ANTI-IL5R- ALPHA TREATMENT FOR ACUTE EXACERBATIONS OF ASTHMA AND COPDCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 691,927, filed on September 6, 2024 and U.S. Provisional Application No. 63 / 706,138, filed on October 11, 2024, each of which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted Sequence Listing XML (Name: 2943_313PC02_SequenceListing_ST26.xml; Size: 15,318 bytes; and Date of Creation: August 7, 2025) filed with the application is incorporated herein by reference in its entirety.FIELD OF DISCLOSURE

[0003] The present disclosure relates to methods of treating acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) using an anti-interleukin-5 receptor alpha (IL-5Ra) antibody or an antigen-binding fragment thereof, e.g., benralizumab.BACKGROUND

[0004] Asthma and chronic obstructive pulmonary disease (COPD) are the most common obstructive lung diseases observed during clinical practice. On average, an exacerbation of asthma or COPD occurs every 10 seconds, an asthma / COPD patient is hospitalized every 5 minutes, and an asthma / COPD patient dies every hour. There have been no new treatments for acute eosinophilic exacerbations of asthma and COPD for 50 years. Oral corticosteroid treatment may be used, but the burden is high and the treatment is associated with morbidity in asthma and mortality in COPD. Further, the treatment effect is short and treatment failure rates are high. Accordingly, there is a need for improved treatments for acute exacerbations of asthma and COPD.BRIEF SUMMARY

[0005] Methods of treating an acute exacerbation of asthma using an anti-interleukin-5 receptor alpha (IL-5Ra) antibody or an antigen-binding fragment thereof, e.g., benralizumab, are provided herein. In certain aspects, a method of treating an acute exacerbation of asthma in a patient in need thereof, comprises administering to the patient a single dose of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

[0006] Methods of treating an acute exacerbation of chronic obstructive pulmonary disease (COPD) using an anti-interleukin-5 receptor alpha (IL-5Ra) antibody or an antigen-binding fragment thereof, e.g., benralizumab, are provided herein. In certain aspects, a method of treating an acute exacerbation of COPD in a patient in need thereof, comprises administering to the patient a single dose of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

[0007] In certain aspects of a method provided herein, the acute exacerbation is an acute eosinophilic exacerbation.

[0008] In certain aspects of a method provided herein, the patient has an eosinophil count of >300 cells / uL at the time of the acute exacerbation.

[0009] In certain aspects of a method provided herein, the patient has an eosinophil count of >150 cells / uL at the time of the acute exacerbation.

[0010] In certain aspects of a method provided herein, the antibody or antigen-binding fragment is a humanized IgGl monoclonal antibody.

[0011] In certain aspects of a method provided herein, the antibody is benralizumab.

[0012] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered at dose of about 30 mg.

[0013] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered at a dose of about 100 mg.

[0014] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered parenterally.

[0015] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0016] In certain aspects of a method provided herein, the administration is into the upper arm, thigh, or abdomen.

[0017] In certain aspects of a method provided herein, the method further comprises administering a corticosteroid to the patient.

[0018] In certain aspects of a method provided herein, the corticosteroid is prednisolone.

[0019] In certain aspects of a method provided herein, the prednisolone is administered in a 30 mg dose.

[0020] In certain aspects of a method provided herein, the prednisolone is administered orally (PO).

[0021] In certain aspects of a method provided herein, the method does not further comprise administering a corticosteroid to the patient.

[0022] In certain aspects of a method provided herein, the patient has asthma and COPD.

[0023] In certain aspects of a method provided herein, the patient has experienced at least1 exacerbation in the last year.

[0024] In certain aspects of a method provided herein, the patient has experienced at least2 exacerbations in the last year.

[0025] In certain aspects of a method provided herein, the patient has experienced at least3 exacerbations in the last year.

[0026] In certain aspects of a method provided herein, the patient has experienced at least4 exacerbations in the last year.

[0027] In certain aspects of a method provided herein, the patient has an elevated baseline fractional exhaled nitric oxide (FeNo).

[0028] In certain aspects of a method provided herein, the patient has a baseline FeNo of greater than 30 parts per billion (ppb).

[0029] In certain aspects of a method provided herein, the patient has a baseline eosinophil count of >250 cells / uL.

[0030] In certain aspects of a method provided herein, the patient uses an inhaled corticosteroid (ICS).

[0031] In certain aspects of a method provided herein, the patient uses a long-acting betaagonist (LABA).

[0032] In certain aspects of a method provided herein, the patient uses a long-acting muscarinic antagonist (LAMA).

[0033] In certain aspects of a method provided herein, the patient has a baseline forced expiratory volume in one second (FEVi) at steady state of less than 2.5 L.

[0034] In certain aspects of a method provided herein, the patient has a baseline FEVi of less than 75 % at steady state.

[0035] In certain aspects of a method provided herein, the patient has a baseline FEW forced vital capacity (FVC) at steady state of less than 0.7.

[0036] In certain aspects of a method provided herein, the patient has an exhaled nitric oxide at exacerbation of at least 30 ppb.

[0037] In certain aspects of a method provided herein, the patient has an exhaled nitric oxide at exacerbation of at least 35 ppb.

[0038] In certain aspects of a method provided herein, the patient has an exhaled nitric oxide at exacerbation of at least 40 ppb.

[0039] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 125.

[0040] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 130.

[0041] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 130.

[0042] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of 125-200.

[0043] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof increases an asthma quality of life questionnaire (AQLQ) score of the patient by at least 0.5 within 30 days.

[0044] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof increases an asthma control test (ACT) score of the patient by at least 1.5 within 30 days.

[0045] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof decreases an asthma control questionnaire 7 (ACQ7) score of the patient by at least 0.5 within 30 days.

[0046] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof decreases a COPD assessment test (CAT) score of the patient by at least 3.5 within 30 days.

[0047] In certain aspects of a method provided herein, the administration of the antibody or antigen-binding fragment thereof decreases the likelihood of one or more of death, hospitalization, and retreatment within 90 days after the administration.

[0048] In certain aspects, provided herein is an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra for use in any one of the methods provided herein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1.

[0049] In certain aspects, provided herein is the use of antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra in the preparation of a medicament for use in any one of the methods provided herein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0050] Figure 1 shows eosinophilic endotype of exacerbations.

[0051] Figure 2 summarizes the randomization treatment groups (BENRA+PRED; PRED; and BENRA) and the co-primary and secondary outcomes as described in the Example.

[0052] Figure 3 summarizes the total number of patients recruited, randomized, treated, and completed a 90-day and 30-day follow up as described in the Example.

[0053] Figure 4 is a table summarizing the baseline characteristics of all 158 randomized patients for the following characteristics: women, n (%), age, years; never smoker, n (%); former smoker, n (%); current smoker, n (%); pack year history; asthma, n (%); COPD, n (%); asthma + COPD, n (%); inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA), exacerbation frequency requiringsystemic glucocorticoids in previous year; forced expiratory volume in one second (FEVi) at steady state, L; FEVi % at steady state; FEVi / FVC at steady state; blood eosinophil count at exacerbationA, cells / uL; and exhaled nitric oxide at exacerbationA, ppb.

[0054] Figure 5 is table summarizing the treatment failure at 90 days [odds ratio vs. PRED (95% Confidence Interval)]; change in total visual analogue scale (VAS) of cough, wheeze, dyspnoea, sputum production, and sputum purulence symptoms from exacerbation to day 28 (mean change (95% CI) in mm and least square mean difference versus PRED).

[0055] Figures 6A-B show Kaplan-Meier plots of time to first treatment failure event within 90 days. Figure 6A shows the fraction of patients without an event in the pooled BENRA group compared to the PRED group for study weeks 0-12. Figure 6B shows the fraction of patients without an event in the PRED, BENRA, and BENRA+PRED treatment groups.

[0056] Figure 7A shows the change in Medical Research Council breathlessness / dyspnoea scale in the BENRA pooled group compared to the PRED group up to 90 days after dose administration. Figure 7B shows the change in Medical Research Council breathlessness / dyspnoea scale in in the PRED, BENRA, and BENRA+PRED treatment groups.

[0057] Figures 8A-D show the change (mean, 95% CI) in Asthma Quality of Life Questionnaire (AQLQ, Figure 8A), Asthma Control Test (ACT, Figure 8B), Asthma Control Questionnaire (ACQ-7, Figure 8C), and COPD Assessment Test (CAT, Figure 8D) for the pooled BENRA group compared to the PRED group.

[0058] Figure 9 is a table summarizing the results of sub-group analysis between the PRED, BENRA, and BENRA+PRED groups for co-primary and secondary outcomes, as described in the Example.

[0059] Figure 10 summarizes the results of the following between the BENRA pooled group and the PRED group: primary analysis, adjudicated diagnose, baseline forced expiratory volume in one second (FEVI) strata, smoking history, gender, age, eosinophils, and fractional exhaled nitric oxide (FeNO).DETAILED DESCRIPTIONDefinitions

[0060] 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 to which this disclosure belongs. In case of conflict, the present application including the definitions will control. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications, patents and other references mentioned herein are incorporated by reference in their entireties for all purposes as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0061] Although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods and examples are illustrative only and are not intended to be limiting. Other features and advantages of the disclosure will be apparent from the detailed description and from the claims.

[0062] It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "an anti-IL-5Ra antibody" is understood to represent one or more anti-IL-5Ra antibodies. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0063] The term "about" is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower). It is understood that wherever aspects are described herein with the language "about" a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range (without "about") are also provided.

[0064] Where a value is explicitly recited, it is to be understood that values that are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each sub-combination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed,combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0065] The term "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0066] The term "antibody" as used herein refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as IL-5Ra through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0067] The term "antibody fragment" or "antigen-binding fragment" are used interchangeably and refer to a portion of an intact antibody. An "antigen-binding fragment, " "antigen-binding domain," or "antigen-binding region," refer to a portion of an intact antibody that binds to a target such as IL-5Ra. An antigen-binding fragment can contain the antigenic determining regions of an intact antibody (e.g., the complementarity determining regions (CDR)). Examples of antigen-binding fragments of antibodies include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies. An antigen-binding fragment of an antibody can be derived from anyanimal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced.

[0068] A "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, "monoclonal" antibodies or antigenbinding fragments thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0069] The term "variable region" as used herein refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In some aspects, the variable region is a human variable region. In some aspects, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In some aspects, the variable region is a primate (e.g., non-human primate) variable region. In some aspects, the variable region comprises rodent or murine CDRs and primate (e.g., non- human primate) framework regions (FRs).

[0070] The term "complementarity determining region" or "CDR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (hypervariable loops) and / or contain the antigen-contacting residues. Antibodies can comprise six CDRs, e.g., three in the VH and three in the VL.

[0071] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

[0072] The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

[0073] The term "Kabat numbering" and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof. In some aspects, CDRs can be determined according to the Kabat numbering system see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).

[0074] Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35 A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.Loop Kabat AbM Chothia1.1 L24-L34 1,24-134 L24-L341.2 L50-L56 I..50-I. ,56 L50-L561.3 L89-L97 L89-L97 L89-L97Hl H31-H35B H26-H35B H26-H32..34(Kabat N umbering)Hl H.31-H35 H26-H35 H26-H32(Chothia Numbering)

[0075] As used herein, the term "constant region" or "constant domain" are interchangeable and have its meaning common in the art. The constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain. In some aspects, an antibody or antigen-binding fragment comprises a constant region or portion thereof that is sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).

[0076] As used herein, the term "heavy chain" when used in reference to an antibody can refer to any distinct type, e.g., alpha (a), delta (5), epsilon (a), gamma (y), and mu (p), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGl, IgG2, IgG3, and IgG4. Heavy chain amino acid sequences are well known in the art. In some aspects, the heavy chain is a human heavy chain.

[0077] As used herein, the term "light chain" when used in reference to an antibody can refer to any distinct type, e.g., kappa (K) or lambda (X) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In some aspects, the light chain is a human light chain.

[0078] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a nonhuman species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability ("CDR grafted") (Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988)). In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody or fragment from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody or antigenbinding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody or antigen-binding fragment thereof specificity, affinity, and / or capability. In general, the humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895- 904 (1996). In some aspects, a "humanized antibody" is a resurfaced antibody.

[0079] As used herein, the terms "immunospecifically binds," "immunospecifically recognizes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies or antigen-binding fragments thereof. These terms indicate that the antibody or antigen-binding fragment thereof binds to an epitope via its antigen-binding domain and that the binding entails some complementarity between the antigen binding domain and the epitope.

[0080] A polypeptide, antibody, polynucleotide, vector, cell, or composition which is "isolated" is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cell or compositions include those that have been purified to a degree that they are no longer in a form in which they are found in nature. In some aspects, an antibody, polynucleotide,vector, cell, or composition that is isolated is substantially pure. As used herein, "substantially pure" refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0081] The term "treating" or "treatment" as used herein refers to the administration of a composition to a subject for therapeutic purposes.

[0082] As used herein, the terms "patient" and "subject" are used interchangeably and refer to members of the animal kingdom including but not limited to human beings. In some aspects, the patient is human.

[0083] The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. The formulation can be sterile.

[0084] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that may be used to enable delivery of a drug, e.g., an antibody or antigen-binding fragment thereof (e.g., subcutaneous administration). Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa.

[0085] The term "therapeutically effective amount" refers to an amount of a drug, e.g., one or more antibodies or antigen-binding fragments thereof effective to treat a disease or disorder in a subject.

[0086] It is to be understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of and / or "consisting essentially of' are also provided.

[0087] It is to be understood that headers are provided solely for ease of reading, and are not intended to be limiting. Aspects disclosed under one or more headers can be applicable to or combinable with aspects disclosed under one or more other headers.Treatment of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD)

[0088] Provided herein are methods for treating acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) using an antibody or antigen-binding fragmentthereof that binds to interleukin-5 receptor-alpha (IL-5Ra) (e.g., benralizumab).An acute exacerbation is an acute worsening of symptoms that requires an intervention. Eosinophlic endotypes of exacerbations are shown in Figure 1.

[0089] In aspects, the methods provided herein can significantly reduce the likelihood of one or more of death, hospitalization, and retreatment within 90 days after the administration.

[0090] In some aspects, the acute exacerbation is an acute eosinophilic exacerbation. In some aspects, the patient with the acute exacerbation has an eosinophil count of >150 cells / uL at the time of the exacerbation. In some aspects, the patient with the acute exacerbation has an eosinophil count of >300 cells / uL at the time of the exacerbation.

[0091] In some aspects, the patient has asthma. In some aspects, the patient has COPD. In some aspects, the patient has asthma and COPD.Anti-interleukin-5 receptor-alpha (IL-5Ra) antibodies and antigen-binding fragments

[0092] The methods provided comprise administering an effective amount of an antiinterleukin-5 receptor-alpha (IL-5Ra) antibody or antigen-binding fragment thereof such as benralizumab or an antigen-binding fragment thereof. The amino acid sequences of human and mouse IL-5Ra are provided below as SEQ ID NOs: 5 and 6, respectively.Table 1 : IL-5Ra Sequences

[0093] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is a humanized antibody. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is one of the following classes: IgA, IgD, IgE, IgG, or IgM. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is an IgG. In some aspects, the IL- 5Ra antibody or antigen-binding fragment thereof is one of the following subclasses IgGl, IgG2, IgG3, IgG4. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is an IgGl. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof has a kappa (K) or lambda ( ) type light chain. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof has a K type (K-class) light chain. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is benralizumab or an antigenbinding fragment thereof.

[0094] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof can be naturally-occurring or recombinantly produced. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is afucosylated. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced by recombinant DNA technology. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells by recombinant DNA technology.

[0095] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is benralizumab (MEDI-563). Benralizumab is a humanized monoclonal antibody (mAb) that binds to the alpha chain of IL-5R, which is expressed on eosinophils and basophils. It induces apoptosis of these cells via antibody-dependent cell cytotoxicity.

[0096] Information regarding benralizumab (or fragments thereof) for use in the methods provided herein can be found in U.S. 6,018,032, the disclosure of which is incorporated herein by reference in its entirety. Benralizumab and antigen-binding fragments thereof for use in the methods provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a further aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein includes any one of the amino acid sequences of SEQ ID NOs: 1-4. In a specific aspect, benralizumab oran antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:2 and heavy chain comprising the amino acid sequence of SEQ ID NO:4. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:7-9, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10-12. SEQ ID NOs: 1-12 are shown in Table 2 below. Those of ordinary skill in the art would easily be able to identify Chothia-defined, AbM-defined or other CDRs. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the KM1259 antibody as disclosed in U.S. 6,018,032, which is herein incorporated by reference in its entirety.Table 2: Antibody Sequence SummaryAdministration

[0097] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered only once. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered as a single injection at the time of an acute exacerbation.

[0098] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered into the upper arm, thigh, and / or abdomen.

[0099] In certain aspects, the subject is administered one or more doses of an IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab), wherein the dose is about 100 mg. In certain aspects, the patient is administered one or more doses of the IL- 5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab), wherein the dose is about 30 mg.

[0100] In certain aspects, administration of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein is through parenteral administration. For example, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered by intravenous infusion or by subcutaneous injection. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered by subcutaneous injection.

[0101] In aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered via a syringe. In aspects, the IL-5Ra antibody or antigenbinding fragment thereof (e.g., benralizumab) is administered via an accessorized prefilled syringe (APFS). In certain aspects, the syringe is glass.

[0102] In aspects, the syringe (e.g., prefilled syringe) contains about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 15 ml, or about 20 ml of a formulation provided herein. In some aspects, the syringe (e.g., prefilled syringe) contains about 1 ml a formulation provided herein.

[0103] In certain aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered according to the methods provided herein in combination or in conjunction with additional COPD and / or asthma therapies. Such standard of care therapies include, without limitation, immunosuppressive therapies. In some aspects, the immunosuppressive therapy is a corticosteroid. In some aspects, the corticosteroid is a glucocorticoid. In some aspects, the corticosteroid is delivered orally. In certain aspects, the corticosteroid is prednisolone / prednisone. In certain aspects, the corticosteroid (e.g., prednisolone) dose is about 30 mg. In certain aspects, the corticosteroid (e.g., prednisolone) dose is about 30 mg administered orally.

[0104] In some aspects, the subject has been using a corticosteroid (e.g., prednisone / prednisolone) prior to administration of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.EXAMPLEEfficacy of benralizumab in human patients with acute eosinophilic exacerbations of asthma and chronic COPD

[0105] A multicenter, double-blind, double-dummy, active-comparator, placebo controlled randomized clinical trial, ABRA (Acute exacerbations treated with BenRAlizumab), was conducted to compare the efficacy of (i) a single dose of benralizumab alone or in combination with systemic glucocorticoids and (ii) systemic glucocorticoids in the treatment of acute eosinophilic exacerbations of COPD or asthma as shown in Figures 2- 10

[0106] Patients in this study were > 18 years of age and meet the following inclusion criteria:(a) diagnosis of asthma, or COPD or both(b) historic evidence in the previous 12 months of:- a history of at least 1 exacerbation- eosinophilic inflammation (i.e., elevated fractional exhaled nitric oxide (FeNO) or blood eosinophils > 250 cells / uL).

[0107] Patients with COPD were current or former smokers with a pack year history (PYH) of >10, and current or historic spirometric evidence of a postbronchodilator FEVi to forced vital capacity (FVC) ratio of <0.7. Patients with asthma were never or former smokers with a PYH <10 and current or historic evidence of variable airflow limitation (defined as any one of the following: FEVi bronchodilator reversibility >200mL; and / or FEVi% change >12%; and / or methacholine challenge (Pc20) <8mg / mL; and / or peak flow diurnal variation; and / or variable FEVi / FVC ratio). Never smokers were defined as those with less than 100 cigarette inhalations in a lifetime; while former smokers had ceased smoking at least 6 months prior to randomization.

[0108] Eosinophilic inflammation is a recognized endotype of asthma and COPD (see "Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 2011;184:662-71"), predicting increased risk of exacerbations (see "Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med 2018;6: 117-26" and "Zeiger RS, Schatz M, Li Q, et al. High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. The Journal of Allergy and Clinical Immunology: In Practice 2014;2:741-50. e4"). Moreover, eosinophilic inflammation at exacerbation, is a feature in up to 30% of COPD exacerbations (see Bafadhel et al., 2011) and almost 50% of asthma exacerbations (see "Hasegawa K, Stoll SJ, Ahn J, Bittner JC, Camargo Jr CA. Prevalence of eosinophilia in hospitalized patients with asthma exacerbation. Respiratory medicine 2015;109: 1230-2").

[0109] All exacerbations were assessed and confirmed by a study respiratory physician prior to randomization. The peripheral blood eosinophil count at the time of an exacerbation had to be > 300 cells / uL to fulfil eligibility for randomization.

[0110] Exclusion criteria for randomization included: any systemic glucocorticoids in the prior 28 days, long term immunosuppression including systemic glucocorticoids, regular treatment with any monoclonal antibody therapy, and allergy to prednisolone or benralizumab.[OHl] Patients were seen at 7, 14, 28, and 90 days after randomization. At each visit, Patients underwent post bronchodilator spirometry and exhaled nitric oxide (FeNO) testing, and they also completed patient reported outcome questionnaires. Patients with asthma completed the asthma control questionnaire-7 (ACQ-7), asthma control test (ACT), and asthma quality of life questionnaire (AQLQ). Patients with COPD completed the COPD assessment test (CAT). All patients completed the Medical Research Council Dyspnoea scale (MRC), the EuroQoL 5D-3L, and a visual analogue scale (VAS) for the symptoms of cough, wheeze, dyspnoea, sputum production, and sputum purulence. VAS was measured on a 100mm line, where 0 is the best symptoms and 100 is the worst symptoms. For VAS, the minimal clinical important difference was 9. All patients had safety laboratory tests for measurement of full blood count, blood electrolytes, blood glucose, liver function tests, plasma B natriuretic peptide, and plasma C-reactive protein. Women of childbearing potential had urinary pregnancy testing.

[0112] Patients were randomized as shown in Figure 2 to the treatment groups shown in Table 3. Specifically, patients were randomized to receive 30mg of prednisolone tablets to be taken orally for 5 days plus one dose of a placebo subcutaneous injection (PRED group); or one dose of lOOmg of benralizumab subcutaneous injection plus 5 days of placebo tablets to be taken orally for 5 days (BENRA group); or 30mg of prednisolone tablets to be taken orally for 5 days plus one dose of lOOmg of benralizumab subcutaneous injection (BENRA + PRED group). Treatment (i.e., benralizumab or placebo) was administered subcutaneously (SC) as a single injection at the time of an acute exacerbation.Table 3: Treatment Groups

[0113] The co-primary endpoints assessed were (i) VAS symptoms at day 28 following treatment (i.e., BENRA+PRED, PRED, or BENRA) and (ii) treatment failure rates (i.e., death, hospitalization, retreatment) at day 90 following treatment. Treatment failure was defined as a composite of death, hospitalization, and any need for re-treatment (nonresponse or new exacerbation) requiring systemic glucocorticoids and / or antibiotics. Treatment failure was self-reported by patients or by an independent healthcare practitioner not involved in the study (for example, a patient's primary care physician). The secondary outcomes assessed following treatment were: time to treatment failure; day 30 treatment failure rates, lung function, day 30 Asthma Control Questionnaire (ACQ-7), Asthma Control Test (ACT), Medical Research Council breathlessness / dyspnoea scale (MRC), Asthma Quality of Life Questionnaire (AQLQ), COPD Assessment Test (CAT), and standardized measures of health-related quality of life (EuroQoL).

[0114] As shown in Figure 3, 53 patients were randomized to PRED, 53 patients were randomized to BENRA, and 52 patients were randomized to BENRA+PRED.

[0115] The baseline characteristics of all 158 patients randomized are provided in Figure 4. Most patients reported their ethnicity as white (n=150, 94.9%). There were 88 (56%) patients with asthma, 51 (32%) patients with COPD (n=51, 32%), and 19 patients (12%) that had both asthma and COPD. There were 63 (40%) never smokers, 80 (51%) former smokers, and 15 (9%) current smokers. The mean (range) age was 57 (18-84) years. In patients with available steady state lung function (n=143), the mean (SD) FEVi (L) and FEVi percent predicted was 2. IL (0.9) and 71.8% (23.8) respectively. Almost all patients were already taking inhaled glucocorticoids prior to randomization (n=156, 99%); with 14.7%, 12.8% and 72.4% taking low-dose, medium-dose, and high-dose inhaled glucocorticoids, respectively. There were 21 (13%) patients recruited de-novo directly from the Emergency Department.

[0116] There were no withdrawals following randomization, and there were no patients lost to follow-up at day 90. There were 39 (73.6%), 25 (47.2%), and 22 (42.3%) treatment failures in the PRED, BENRA, and BENRA+PRED treatment groups respectively (see Figure 9 and Table 5). The results for the co-primary outcomes for the PRED and the pooled BENRA and BENRA+PRED treatment groups are shown in Figure 5 and Table 4. (The primary endpoint data for PRED, BENRA, and BENRA+PRED treatment groups is shown in Table 5). No significant differences were found between BENRA andBENRA+PRED for the co-primary outcomes or any of the secondary outcomes, so these groups were pooled (i.e., pooled BENRA) for certain analyses. There was a significant difference in proportions of treatment failures between the PRED and pooled BENRA treatment group favouring the pooled BENRA treatment group (OR 0.264, 95%CI 0.125 - 0.556, p<0.001; see Figure 5 and Table 4). The 28-day total VAS symptoms were significantly better in the pooled BENRA treatment groups compared to the PRED group (LS mean difference 49mm, 95% CI 14 to 84, p=0.006; see Figure 5 and Table 4).

[0117] The number of treatment failures within 30 days in the PRED, BENRA, and BENRA+PRED treatment groups were 24 (45.3%), 13 (24.5%), and 10 (19.2%), respectively. There was a significant reduction in treatment failure rates in the pooled BENRA treatment group compared to the PRED treatment group at 30 days (OR 0.299, 95%CI 0.141 - 0.630, p=0.001). As shown in Figure 6A, the time to first treatment failure event within 90 days was significantly longer in the pooled BENRA treatment group compared to the PRED treatment group (HR 0.393, 95%CI 0.252 to 0.612, log-rank p<0.001). The time to first treatment failure within 90 days between the individual BENRA and BENRA+PRED treatment groups is shown in Figure 6B (HR 0.761, 95%CI 0.426 to 1.360, log-rank p=0.681).

[0118] At day 28, there was a significant improvement in MRC dyspnoea scale between the pooled BENRA treatment group compared to the PRED treatment group (see Figure 7A). As shown in Figure 7A, the change in MRC showed a greater reduction in the BENRA pooled compared to the PRED group (difference 0.39, 95%CI 0.08-0.69, p=0.013). The treatment effect for the PRED, BENRA, and BENRA+PRED treatment groups at the study visits are shown in Figure 7B. Figures 8A-D show the change (mean, 95% CI) in AQLQ [Figure 8A, 0.5 (0.0- 1.0], ACT [Figure 8B, 1.6 (-0.4-3.6)], ACQ7[Figure 8C, 0.5 (0.1- 0.9)], and CAT [Figure 8D, 3.6 (-2.9-10.1)] for the pooled BENRA group compared to the PRED group. The asthma specific symptom questionnaires showed a significant and clinically meaningful improvement in the pooled BENRA treatment group compared to the PRED treatment group for ACQ? (mean difference 0.5, 95%CI 0.1-0.9, p=0.029; Figure 8C) and AQLQtotai (mean difference 0.53, 95%CI 0.04-1.02, p=0.035) at day 28. The results for ACT (mean difference 1.6, 95%CI -0.4-3.6, p=0.122) are shown in Figure 8B. The CAT showed a clinically meaningful but non statistically significant improvementfavouring the pooled BENRA treatment group compared to the PRED treatment group at day 90 (mean difference 3.6, 95%CI -2.9-10.1, p=0.274; Figure 8D).

[0119] The difference in the EuroQoL between the pooled BENRA treatment group compared to the PRED treatment group at day 90 did not reach statistical significance (data not shown). Further, the mean change in FEVi, FVC, or PEF between the PRED and the pooled BENRA treatment groups at day 28 also did not reach statistical significance (data not shown).

[0120] Figure 9 shows the results of sub-group analysis, and as described above, there were no differences between BENRA and BENRA+PRED for co-primary outcome and any of the secondary outcomes.

[0121] Figure 10 summarizes the results of the following between BENRA pooled and PRED: primary analysis, adjudicated diagnose, baseline forced expiratory volume in one second (FEVI) strata, smoking history, gender, age, eosinophils, and FeNO.Table 4: Primary endpoint data for the PRED and the pooled BENRA and BENRA+PRED treatment groupsTable 5: Primary endpoint data in the PRED, BENRA, and BENRA+PRED treatment groups.

[0122] The total number of reported adverse events was 324, occurring in 128 patients. These occurred 129, 95, and 100 times in 91%, 77%, and 75% of patients in the PRED, BENRA and BENRA+PRED treatment groups, respectively. Hyperglycemia and sinusitis / sinus infection only occurred in the treatment groups with prednisolone (Table 6).Table 6: Summary of treatment-emergent adverse events in safety population* Counted uniquely by reported term within patient

[0123] Overall, this study shows the first new treatment for exacerbations of asthma and COPD. Specifically, benralizumab as a single injection at the time of an acute eosinophilic exacerbation was superior to standard of care with prednisolone. The Number Needed to Treat (NNT) of 4 to reduce treatment failure was shown. In patients with an eosinophilic exacerbation of asthma or COPD, a single subcutaneous injection of benralizumab, with or without a short course of systemic glucocorticoids (i.e., oral prednisolone) was a successful acute treatment compared to standard care with a short course of systemic glucocorticoids. Benralizumab reduced treatment failures, prolonged time to first event, and improved respiratory symptoms and disease specific health quality following an exacerbation. Further, this study showed that in patients with eosinophilic exacerbations, the treatment failure rates were 74% in patients treated with systemic glucocorticoids. This was an unexpectedly high rate and is indicative of the high-risk population with eosinophilic inflammation and the lack of complete efficacy of systemic glucocorticoids. For the first time, this study showed an exacerbation treatment that significantly reduced treatment failures (absolute risk reduction of 28%).* * *

[0124] The invention is not to be limited in scope by the aspects described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0125] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0126] Some aspects are within the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating an acute exacerbation of asthma in a patient in need thereof, the method comprising administering to the patient a single dose of an antibody or an antigenbinding fragment thereof that immunospecifically binds to IL5Ra and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

2. A method of treating an acute exacerbation of chronic obstructive pulmonary disease (COPD) in a patient in need thereof, the method comprising administering to the patient a single dose of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra and comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

3. The method of claim 1 or 2, wherein the acute exacerbation is an acute eosinophilic exacerbation.

4. The method of claim 1 or 2, wherein the patient has an eosinophil count of >300 cells / uL at the time of the acute exacerbation.

5. The method of claim 1 or 2, wherein the patient has an eosinophil count of >150 cells / uL at the time of the acute exacerbation.

6. The method of any one of claims 1-5, wherein the antibody or antigen-binding fragment is a humanized IgGl monoclonal antibody.

7. The method of any one of claims 1-6, wherein the antibody is benralizumab.

8. The method of any one of claims 1-7, wherein the antibody or antigen-binding fragment thereof is administered at dose of about 30 mg.

9. The method of any one of claims 1-7, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 100 mg.

10. The method of any one of claims 1-9, wherein the antibody or antigen-binding fragment thereof is administered parenterally.

11. The method of any one of claims 1-10, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

12. The method of any one of claims 1-11, wherein the administration is into the upper arm, thigh, or abdomen.

13. The method of any one of claims 1-12, further comprising administering a corticosteroid to the patient.

14. The method of claim 13, wherein the corticosteroid is prednisolone.

15. The method of claim 14, wherein the prednisolone is administered in a 30 mg dose.

16. The method of claim 14 or 15, wherein the prednisolone is administered orally (PO).

17. The method of any one of claims 1-12, wherein the method does not further comprise administering a corticosteroid to the patient.

18. The method of any one of claims 1-17, wherein the patient has asthma and COPD.

19. The method of any one of claims 1-18, wherein the patient has experienced at least 1 exacerbation in the last year.

20. The method of claim 19, wherein the patient has experienced at least 2 exacerbations in the last year.

21. The method of claim 19, wherein the patient has experienced at least 3 exacerbations in the last year.

22. The method of claim 18, wherein the patient has experienced at least 4 exacerbations in the last year.

23. The method of any one of claims 1-22, wherein the patient has an elevated baseline fractional exhaled nitric oxide (FeNo).

24. The method of any one of claims 1-23, wherein the patient has a baseline FeNo of greater than 30 parts per billion (ppb).

25. The method of any one of claims 1-24, wherein the patient has a baseline eosinophil count of >250 cells / uL.

26. The method of any one of claims 1-25, wherein the patient uses an inhaled corticosteroid (ICS).

27. The method of any one of claims 1-26, wherein the patient uses a long-acting beta-agonist (LABA).

28. The method of any one of claims 1-27, wherein the patient uses a long-acting muscarinic antagonist (LAMA).

29. The method of any one of claims 1-28, wherein the patient has a baseline forced expiratory volume in one second (FEVi) at steady state of less than 2.5 L.

30. The method of any one of claims 1-29, wherein the patient has a baseline FEVi of less than 75 % at steady state.

31. The method of any one of claims 1-30, wherein the patient has a baseline FEVi / forced vital capacity (FVC) at steady state of less than 0.7.

32. The method of any one of claims 1-31, wherein the patient has an exhaled nitric oxide at exacerbation of at least 30 ppb.

33. The method of claim 32, wherein the patient has an exhaled nitric oxide at exacerbation of at least 35 ppb.

34. The method of claim 32, wherein the patient has an exhaled nitric oxide at exacerbation of at least 40 ppb.

35. The method of any one of claims 1-34, wherein the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 125.

36. The method of claim 35, wherein the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 130.

37. The method of claim 35, wherein the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of at least 130.

38. The method of claim 35, wherein the administration of the antibody or antigen-binding fragment thereof results in a change in total VAS symptom score from the time of the exacerbation to 28 days later of 125-200.

39. The method of any one of claims 1 and 3-38, wherein the administration of the antibody or antigen-binding fragment thereof increases an asthma quality of life questionnaire (AQLQ) score of the patient by at least 0.5 within 30 days.

40. The method of any one of claims 1 and 3-39, wherein the administration of the antibody or antigen-binding fragment thereof increases an asthma control test (ACT) score of the patient by at least 1.5 within 30 days.

41. The method of any one of claims 1 and 3-40, wherein the administration of the antibody or antigen-binding fragment thereof decreases an asthma control questionnaire 7 (ACQ7) score of the patient by at least 0.5 within 30 days.

42. The method of any one of claims 2-41, wherein the administration of the antibody or antigen-binding fragment thereof decreases a COPD assessment test (CAT) score of the patient by at least 3.5 within 30 days.

43. The method of any one of claims 1-42, wherein the administration of the antibody or antigen-binding fragment thereof decreases the likelihood of one or more of death, hospitalization, and retreatment within 90 days after the administration.

44. An antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra for use in the method of any one of claims 1-43, wherein the antibody or antigenbinding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

45. Use of antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra in the preparation of a medicament for use in the method of any one of claims 1-43, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.

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