Il-5r-alpha antibodies for treating eosinophilic granulomatosis with polyangiitis

Abstract

Provided herein are methods of treating Eosinophilic Granulomatosis with Polyangiitis (EGPA) comprising administering to the subject a therapeutically effective amount of an anti- interleukin-5 receptor alpha (IL-5Rα) antibody or an antigen-binding fragment thereof such as benralizumab.

Description

IL-5R- ALPHA ANTIBODIES FOR TREATING EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITISCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 584,453, filed on September 21, 2023; U.S. Provisional Application No. 63 / 597,634, filed on November 9, 2023; and U.S. Provisional Application No. 63 / 648,325, filed on May 16, 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 (Name: 2943_261PC03_Seqlisting_ST26.xml; Size: 15,327 bytes; and Date of Creation: September 16, 2024) filed with the application, is incorporated herein by reference in its entirety.FIELD OF DISCLOSURE

[0003] The present disclosure relates to methods of treating Eosinophilic Granulomatosis with Polyangiitis (EGPA) using an anti-interleukin- 5 receptor alpha (IL-5Ra) antibody or an antigen-binding fragment thereof, e.g., benralizumab.BACKGROUND

[0004] Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg- Strauss syndrome) is a rare inflammatory disorder of systemic necrotizing vasculitis of small-to- medium-sized blood vessels. The disease is characterized by potentially life-threatening systemic eosinophilic small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Patients with EGPA generally have a greater blood and tissue eosinophil burden than, for example, patients with severe asthma. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. Before the use of corticosteroids for EGPA, more than 50% of patients died within 3 months of diagnosis.While systemic corticosteroid therapy is the cornerstone therapy for the treatment of EGPA patients, the use of corticosteroids, particularly longer term, is associated with significant adverse effects, including weight gain, osteoporosis, hyperglycemia, depression, and increased risk of infection, which limit the treatment benefits. Furthermore, although remission can be achieved in a proportion of patients with corticosteroid therapy alone, the addition of more potent immunosuppressive therapies (e.g., azathioprine, methotrexate, or mycophenolate mofetil) to maintain remission is commonly required.

[0005] In general, although the use of these treatments can be effective for establishing remission, patients remain vulnerable to either the complications of long-term use of these therapies and / or the risk of relapse, particularly if the dose of corticosteroid or immunosuppressant is reduced or stopped. Specifically, a relapse rate of 30% to 40% is reported, which increases with time. Notably, recurrent relapse places the patient at risk of permanent tissue and / or organ damage secondary to the vasculitic process.

[0006] An IL-5 cytokine inhibitor, mepolizumab was recently approved for treatment of EGPA in several countries based on a single Phase III study. Although, mepolizumab increased the time that patients were in remission compared with placebo in this study, 47% of patients treated with mepolizumab did not meet the primary endpoint definition of remission in the study (Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376: 1921-32).

[0007] Therefore, there is an unmet medical need for treatments of EGPA that induce and maintain remission whilst reducing the burden of corticosteroid usage and other immunosuppressive therapies.BRIEF SUMMARY

[0008] Methods of treating Eosinophilic Granulomatosis with Polyangiitis (EGPA) 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 eosinophilic granulomatosis with polyangiitis (EGPA) in a patient in need thereof, comprises administering to the patient a therapeutically effective amount of an antibody or an antigen-binding fragmentthereof that immunospecifically binds to IL5Ra, 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.

[0009] In certain aspects of a method provided herein, the antibody or antigen-binding fragment is a humanized IgGl monoclonal antibody.

[0010] In certain aspects of a method provided herein, the antibody is benralizumab.

[0011] In certain aspects of a method provided herein, the patient has asthma.

[0012] In certain aspects of a method provided herein, the patient has eosinophilia.

[0013] In certain aspects of a method provided herein, the patient has at least 2 of the following: (a) a biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation; (b) neuropathy; (c) pulmonary infiltrates; (d) a sino-nasal abnormality; (e) cardiomyopathy; (f) glomerulonephritis; (g) alveolar hemorrhage; (h) palpable purpura; and (i) a positive test for ANCA immunofluorescence, myeloperoxidase (MPO) antibodies, and / or proteinase-3 (PR3) antibodies.

[0014] In certain aspects of a method provided herein, the patient does not have severe eosinophilic asthma.

[0015] In certain aspects of a method provided herein, the patient has had EGPA for at least six months.

[0016] In certain aspects of a method provided herein, the patient has ANCA positive EGPA.

[0017] In certain aspects of a method provided herein, the patient has ANCA negative EGPA.

[0018] In certain aspects of a method provided herein, the patient has a history of relapsing or refractory disease.

[0019] In certain aspects of a method provided herein, the patient has a history of relapsing EGPA.

[0020] In certain aspects of a method provided herein, the patient has a history of at least 3 EGPA relapses.

[0021] In certain aspects of a method provided herein, the patient has a history of refractoryEGPA.

[0022] In certain aspects of a method provided herein, the patient uses an oral corticosteroid (OCS) prior to the administration, optionally wherein the patient has been using an OCS for at least 4 weeks prior to the administration.

[0023] In certain aspects of a method provided herein, the OCS is a glucocorticoid.

[0024] In certain aspects of a method provided herein, the OCS is prednisolone or prednisone.

[0025] In certain aspects of a method provided herein, the OCS is methylprednisolone.

[0026] In certain aspects of a method provided herein, the patient uses at least 7.5 mg / day or about 7.5 mg / day to about 50 mg / day of the OCS prior to the administration.

[0027] In certain aspects of a method provided herein, the administration reduces the OCS usage to 7.5 mg / day or less.

[0028] In certain aspects of a method provided herein, the administration reduces the OCS usage to 4 mg / day or less.

[0029] In certain aspects of a method provided herein, the administration eliminates OCS usage.

[0030] In certain aspects of a method provided herein, the OCS daily dose is reduced from at least 7.5 mg / day prior to the administration to 4 mg / day or less after the administration.

[0031] In certain aspects of a method provided herein, the administration reduces the OCS daily dose 50% or more.

[0032] In certain aspects of a method provided herein, the administration reduces the OCS daily dose by 100%.

[0033] In certain aspects of a method provided herein, the reduction in OCS daily dose occurs within 52 weeks of the first administration of the antibody or an antigen-binding fragment thereof to the patient.

[0034] In certain aspects of a method provided herein, the reduction in OCS daily dose does not decrease the patient's lung function. In some aspects, the patient's lung function is measured by spirometry.

[0035] In certain aspects of a method provided herein, the reduction in OCS daily dose does not increase the severity of the patient's asthma. In some aspects, the severity of the patient's asthma is measured by the asthma control questionnaire-6 (ACQ-6).

[0036] In certain aspects of a method provided herein, the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS).

[0037] In certain aspects of a method provided herein, the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS) more than administration of mepolizumab reduces it.

[0038] In certain aspects of a method provided herein, the administration reduces the patient's BVAS to 0.

[0039] In certain aspects of a method provided herein, the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less. In some aspects, the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less within 24 weeks of the first administration. In further aspects, the reduction in BVAS to 0 and the OCS dose to 4 mg / day or less is maintained for at least about 52 weeks after the first administration.

[0040] In certain aspects of a method provided herein, the method comprises administering at least two doses of the antibody or an antigen-binding fragment thereof to the patient.

[0041] In certain aspects of a method provided herein, the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less after at least 3 doses, at least 6 doses, at least 9 doses, or at least 12 doses of the antibody or an antigen-binding fragment thereof to the patient.

[0042] In certain aspects of a method provided herein, the administration increases the time to EGPA relapse.

[0043] In certain aspects of a method provided herein, the administration increases the time to EGPA relapse more than administration of mepolizumab increases it.

[0044] In certain aspects of a method provided herein, the administration decreases the annual relapse rate.

[0045] In certain aspects of a method provided herein, the administration decreases the annual relapse rate more than administration of mepolizumab decreases it.

[0046] In certain aspects of a method provided herein, the administration decreases the likelihood of an EGPA relapse.

[0047] In certain aspects of a method provided herein, the administration decreases the likelihood of an EGPA relapse more than administration of mepolizumab decreases it.

[0048] In certain aspects of a method provided herein, the administration decreases the likelihood of an increase in the vasculitis damage index (VDI) of the patient.

[0049] In certain aspects of a method provided herein, the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient.

[0050] In certain aspects of a method provided herein, the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient more than administration of mepolizumab improves it.

[0051] In certain aspects of a method provided herein, the administration improves the sino- nasal outcome test-22 (SNOT-22) score of the patient.

[0052] In certain aspects of a method provided herein, the administration improves the sino- nasal outcome test-22 (SNOT-22) score of the patient more than administration of mepolizumab improves it.

[0053] In certain aspects of a method provided herein, the administration improves the Patient Global Impression of Severity (PGIS) score.

[0054] In certain aspects of a method provided herein, the administration improves the Patient Global Impression of Severity (PGIS) score more than administration of mepolizumab improves it.

[0055] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered at about 30 mg per dose.

[0056] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks.

[0057] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for 12 weeks.

[0058] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for 24 weeks.

[0059] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for 36 weeks.

[0060] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for 48 weeks.

[0061] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for at least four doses.

[0062] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for at least eight doses.

[0063] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for at least twelve doses.

[0064] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for three doses and then once every eight weeks.

[0065] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered parenterally.

[0066] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0067] In certain aspects of a method provided herein, the administration is into the upper arm, thigh, or abdomen.

[0068] 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.

[0069] 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

[0070] Figure 1A shows a flow diagram for a clinical trial demonstrating the efficacy of benralizumab compared to mepolizumab, an IL- 5 cytokine inhibitor, to treat eosinophilicgranulomatosis with polyangiitis (EGPA). Figure IB shows the patient disposition throughout the study. (See Examples 1 and 2.)

[0071] Figure 2 outlines the algorithm for reversibility testing. (See Example 1.)

[0072] Figure 3A shows patients achieving remission at weeks 36 and 48 following treatment with benralizumab versus mepolizumab. Figure 3B shows the proportion of patients with reduction from baseline in the average daily oral glucocorticoid (OGC) dose during weeks 48- 52 (full analysis set). Figure 3C shows the proportion of patients who achieved remission by time point. Vertical lines represent 95% confidence intervals, calculated using the Clopper- Pearson method.

[0073] Figure 4 show subgroup analysis of the proportion of patients who achieved remission at both weeks 36 and 48. Remission was defined as Birmingham Vasculitis Activity Score (BVAS) = 0 and OGC dose < 4 mg / day. The remission rates and the difference (benralizumab - mepolizumab) were estimated using marginal standardization method in a logistic regression model. The covariates in the model include treatment arm, baseline dose of prednisone, baseline BVAS, region, the subgroup and interaction between treatment arm and the subgroup (treatment arm* subgroup). The covariate region is not in the model when the subgroup is geographical region or race, to avoid confounding.

[0074] Figure 5A shows the average daily dose of OGC (prednisone / prednisolone) during weeks 48-52 in patients following treatment with benralizumab versus mepolizumab. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using a proportional odds model, with treatment arm, baseline dose of OGC, baseline BVAS, and region as covariates. Figure 5B shows the mean average daily OGC dose by time (week). OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration.

[0075] Figure 6 shows the percentage of patients achieving > 50% reduction in OGC dose and the percentage of patients achieving 100% reduction in OGC dose at weeks 48-52 following treatment with benralizumab versus mepolizumab. Secondary endpoints were not multiplicity protected; p-values are nominal. Rates and difference were estimated using a marginal standardization method in a logistic regression model, with treatment arm, baseline dose of OGC, baseline BVAS, and region, as covariates.

[0076] Figure 7A shows the percentage of patients achieving accrued remission, and Figure 7B shows the percentage of patients achieving remission by week 24 and maintaining remission until week 52, following treatment with benralizumab versus mepolizumab. P- values for secondary endpoints are nominal. Remission was defined as BVAS = 0 and OGC dose < 4 mg / day (patients achieving remission who had, at any subsequent visit, a BVAS = 1 that did not require an increase in OGC dose > 4 mg / day or any other significant clinical intervention / investigation, were considered to be in continued remission). OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration. OR and 95% CI were estimated with a proportional odds model. Covariates included treatment arm, baseline dose of OGC, baseline BVAS, and region.

[0077] Figure 8 shows the percentage of patients achieving clinical benefit or complete response following treatment with benralizumab versus mepolizumab. P-values for secondary endpoints are nominal. Remission was defined as BVAS = 0 and OGC dose < 4 mg / day. Response rates and difference were estimated using marginal standardization method in a logistic regression model. The covariates included treatment arm, baseline dose of OGC, baseline BVAS, and region. OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration.

[0078] Figure 9 is Kaplan-Meier plot of time to first relapse. The percentage of patients with relapses and time to first relapse for benralizumab versus mepolizumab treatment groups is shown. Relapse was defined as worsening or persistence of active disease characterized by: active vasculitis (BVAS > 0), or active symptoms and / or signs of asthma with a corresponding worsening in Asthma Control Questionnaire (6-item version, ACQ-6) score, or active nasal and / or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions; warranting: an increase of OGCs, or an increased dose or addition of an immunosuppressive therapy, or hospitalization related to worsening of EGPA. The hazard ratios HR (benralizumab vs mepolizumab) and associated 95% CI were estimated using a Cox regression model with Efron method to control for ties. The covariates in the model included treatment arm, baseline dose of OGC (prednisone / prednisolone), baseline BVAS, and region. P-value was calculated using unstratified log-rank test; p-values for secondary endpoints are nominal.

[0079] Figure 10 shows blood eosinophil count over time in patients following treatment with benralizumab versus mepolizumab.

[0080] Figure 11 shows Birmingham Vasculitis Activity Score (BVAS) and change from baseline over time in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.

[0081] Figure 12 shows the change from baseline in Vasculitis Damage Index (VDI) in patients following treatment with benralizumab versus mepolizumab. Analysis of covariance (ANCOVA) used an unstructured variance-covariance matrix. Covariates included treatment group, baseline OGC dose, baseline BVAS score, region, baseline VDI, visit (week 24 and week 52), and visit by treatment group.

[0082] Figure 13 shows the least-squares change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) over time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.

[0083] Figure 14A shows the least-squares change from baseline in Asthma Control Questionnaire (6-Item Version (ACQ-6) score over time (weeks) in patients following treatment with benralizumab versus mepolizumab. Figure 14B shows the least-squares change from baseline in Sino-Nasal Outcome Test-22 (SNOT-22) total score over time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.

[0084] Figure 15 shows the Medical Outcomes Study 36-item Short Form Health Survey version 2 (36v2) least-squares mean change from baseline by time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.

[0085] Figure 16 shows Patient Global Impression of Severity (PGI-S) category at baseline and week 52 in patients following treatment with benralizumab versus mepolizumab.

[0086] Figure 17 shows Patient Global Impression of Change (PGI-C) category at baseline and week 52 in patients following treatment with benralizumab versus mepolizumab.

[0087] Figure 18A shows the time (weeks) to first >50% reduction in OGC use in patients following treatment with benralizumab versus mepolizumab. Figure 18B shows the time(weeks) to first 100% reduction in OGC use in patients following treatment with benralizumab versus mepolizumab.

[0088] Figure 19 shows a heatmap of OGC dose (average daily dose of prednisolone / prednisone, mg / day) by time and relapse in patients following treatment with benralizumab versus mepolizumab.

[0089] Figure 20A shows the total accrued duration (weeks) of OGC = 0 mg / day in patients following treatment with benralizumab versus mepolizumab. Figure 20B shows percentage reduction from baseline in average daily dose of OGC during Weeks 48-52. The OR for higher percent reduction and 95% CI were estimated using a proportional odds model, including treatment arm, baseline dose of prednisone, baseline BVAS, and region as covariates.

[0090] Figure 21A shows the correlation of pre-bronchodilator (BD) FEV1 and accrued duration of OGC=0 mg / day in patients following treatment with benralizumab versus mepolizumab. Figure 21B shows the correlation of ACQ-6 and accrued duration of OGC=0 mg / day in patients following treatment with benralizumab versus mepolizumab.DETAILED DESCRIPTIONDefinitions

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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).

[0097] 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 antigenrecognition 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, IgGl, 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.

[0098] 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 any animal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced.

[0099] 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 antigen-binding fragments thereof refers to such antibodies and antigen-binding fragments thereof made in any number ofmanners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0100] 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., nonhuman primate) variable region. In some aspects, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0101] 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.

[0102] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

[0103] The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

[0104] 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).

[0105] 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 35A nor 35B is present, the loop ends at 32; if only 35A 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 ChothiaLI L24-L34 L24-L34 L24-L34L2 L5O-L56 LSO-I..56 L50-L56L3 I.89-L97 L89-L97 L89-L97Hl H31-H35B H26-H35B H26-H32..34(Kabat Numbering)Hl H31-H35 H26-H35 H26-H32(Chothia Numbering )

[0106] 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 generallyhas 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).

[0107] 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 (8), epsilon (s), 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.

[0108] 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.

[0109] 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 non-human 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 antigen-binding 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 ofthe 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.

[0110] 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.

[0111] 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.

[0112] The term "treating" or "treatment" as used herein refers to the administration of a composition to a subject for therapeutic purposes.

[0113] 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.

[0114] 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 noadditional components which are unacceptably toxic to a subject to which the formulation would be administered. The formulation can be sterile.

[0115] 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 antigenbinding 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.

[0116] 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.

[0117] The term "relapsing" EGPA refers to the recurrence or worsening of EGPA. In some embodiments, relapsing EGPA refers to recurrence or worsening of EGPA following a period of remission.

[0118] The term "refractory" EGPA refers to EGPA in subjects that have been treated for EGPA but have not achieved remission.

[0119] 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.

[0120] 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.Anti-interleukin-5 receptor-alpha (IL-5Ra) antibodies and antigen-binding fragments

[0121] 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

[0122] 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 (X) 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 antigen-binding fragment thereof.

[0123] 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 DNAtechnology. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells by recombinant DNA technology.

[0124] 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.

[0125] 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:l-4. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3. In a specific aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:2 and 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:l-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

[0126] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered only once. In further aspects, the patient is administered additional follow-on doses. Follow-on doses can be administered at various time intervals.

[0127] 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.

[0128] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered about every 1 week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, or longer intervals. In certain aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered every 4 weeks.

[0129] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) can be administered every 1-5 weeks, every 2-5 weeks, every 3-5 weeks, or every 4-5 weeks. In some aspects, the intervals can be every 1-9 weeks, every 2-9 weeks, every 3-9 weeks, every 4-9 weeks, every 5-9 weeks, every 6-9 weeks, every 7-9 weeks, or every 8- 9 weeks. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered every 4 weeks.

[0130] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered at a frequency sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.

[0131] In some aspects, 30 mg the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered every 4 weeks

[0132] In some aspects, at least two doses the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) are administered to the patient. In some aspects, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least 9 doses, at least 10 doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, at least 20 doses, at least 21 doses, at least 22 doses, at least 23 doses, at least24 doses, at least 25 doses, at least 26 doses, at least 27 doses, at least 28 doses, at least 29 doses, or at least 30 doses are administered to the patient.

[0133] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered over the course of about four weeks, over the course of about eight weeks, over the course of about 12 weeks, over the course of about 24 weeks, over the course of about 28 weeks, over the course of about 52 weeks, over the course of about 76 weeks, or over the course of about 104 weeks.

[0134] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered over the course of at least four weeks, over the course of at least eight weeks, over the course of at least 12 weeks, over the course of at least 24 weeks, over the course of at least 28 weeks, over the course of at least 52 weeks, over the course of at least 76 weeks, or over the course of at least 104 weeks.

[0135] 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 2 mg to about 100 mg, for example about 20 mg to about 100 mg, or about 30 mg to 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 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some aspects, the dose is about 20 mg. In some aspects, the dose is about 30 mg.

[0136] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered in an amount sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.

[0137] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered in an amount and at a frequency sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.

[0138] In some aspects, a dose is about 30 mg of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered once every four weeks (Q4W).

[0139] 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 parenteraladministration. 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.

[0140] 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.

[0141] 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.

[0142] 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 Eosinophilic Granulomatosis with Polyangiitis (EGPA) therapies. 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 EGPA therapies that are standard of care for treating EGPA. Such standard of care therapies include, without limitation, immunosuppressive therapies and biologies. In some aspects, the immunosuppressive therapy is azathioprine, methotrexate, or mycophenolate mofetil. 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 is methylprednisolone. In certain aspects, the corticosteroid dose is < 4 mg / day. In certain aspects, the corticosteroid dose is < 7.5 mg / day. In certain aspects, the corticosteroid dose is > 7.5 mg / day In certain aspects, the corticosteroid dose is > 7.5 mg / day but not > 50 mg / day.

[0143] In some aspects, the subject has been using a corticosteroid (e.g., prednisone / prednisolone) for at least 4 weeks prior to administration of the IL-5Ra antibodyor antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.Formulations

[0144] In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) for use according to the methods provided herein, is present in a formulation, e.g., a pharmaceutical formulation. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is present in the formulation at a concentration of about 1 mg / mL to about 200 mg / mL. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is present in the formulation at a concentration of about 30 mg / mL.

[0145] In some aspects, the formulation comprising IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) for methods and uses of the present disclosure comprise various other components.

[0146] In some aspects, the formulation comprises histidine. In some aspects, the formulation comprises from about 1 mM to about 100 mM histidine, for example, from about 5 mM to about 80 mM histidine, from about 10 mM to about 60 mM histidine, from about 15 mM to about 50 mM histidine, from about 15 mM to about 30 mM histidine, or about 20 mM histidine. In some aspects, the formulation comprises about 20 mM histidine / histidine hydrochloride monohydrate.

[0147] In some aspects, the formulation comprises a surfactant, for example, a polysorbate such as polysorbate 20 (PS20). In some aspects, the formulation comprises about 0.001% to about 0.02%, about 0.002% to about 0.015%, about 0.002% to about 0.01%, about 0.004% to about 0.009%, about 0.005% to about 0.008%, about 0.007%, or about 0.006% PS20. In some aspects, the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.010%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, or about 0.020% (w / v) polysorbate 20. In some aspects, the formulation comprises about 0.006% (w / v) polysorbate 20.

[0148] In some aspects, the formulation comprises an uncharged excipient, for example, trehalose. In some aspects, the uncharged excipient (e.g., trehalose dihydrate) is present in theformulation in an amount of from about 1 mM to about 500 mM. In some aspects, the formulation comprises about 1 mMto about 250 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 100 mM to about 400 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 200 mM to about 300 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 100 mM, about 150 mM, about 200 mM, about 250 mM, about 300 mM, about 350 mM, or about 400 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 0.25 M trehalose dihydrate.

[0149] In some aspects, the formulation is sterile and preservative-free.

[0150] In some aspects, the formulation comprises 30 mg / mL anti-IL5R antibody, 20 mM histidine / histidine HC1, and 250 mM trehalose dihydrate, pH 6.0 with either no surfactant or 0.0004% polysorbate 80, 0.0012% PS80, 0.02% poloxamer 188, or 0.08% poloxamer 188.

[0151] In some aspects, the formulation comprises 30 mg / mL anti-IL5R antibody, 1.4 mg L- histidine, 2.3 mg L- histidine hydrochloride monohydrate, 0.06 mg polysorbate 20, and 95 mg a,a-trehalose dehydrate in water.Eosinophilic Granulomatosis with Polyangiitis (EGPA)

[0152] Provided herein are methods for treating EGPA. In aspects, the methods provided herein can significantly reduce EGPA disease severity.

[0153] EGPA remains only partly understood, but it is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs) usually directed against myeloperoxidase (MPO) or proteinase-3 (PR3) on enzyme-linked immunosorbent assay in approximately 40% of patients. Two different phenotypes of EGPA are described: ANCA positive and ANCA negative. Data show differences in clinical disease presentation based on ANCA status and indicate that ANCA-positive patients should be treated more aggressively (Sokolowska B, Szczeklik W, Wludarczyk A, Kuczia P, Jakiela B, Gasior J, et al. ANCA-positive and ANCA- negative phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA): Outcome and long-term follow-up of 50 patients from a single Polish centre. Clin Exp Rheumatol. 2014;32(Suppl 82):S41-7). In some aspects, a subject treated with IL-5Ra antibody or antigenbinding fragment thereof (e.g., benralizumab) according to the methods provided herein isANCA positive. In some aspects, a subject treated with IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein is ANCA negative. In some aspects, a subject treated with IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein is ANCA positive or ANCA negative.

[0154] In aspects, EGPA is defined based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x 109 / liter and / or > 10% of leukocytes).

[0155] Additional features of EGPA can include:

[0156] (a) A biopsy showing histopathological evidence of eosinophilic vasculitis, OR perivascular eosinophilic infiltration, OR eosinophil-rich granulomatous inflammation

[0157] (b) Neuropathy, mono or poly (motor deficit or nerve conduction abnormality)

[0158] (c) Pulmonary infiltrates, non-fixed

[0159] (d) Sino-nasal abnormality

[0160] (e) Cardiomyopathy (established by echocardiography or magnetic resonance imaging)

[0161] (f) Glomerulonephritis (hematuria, red cell casts, proteinuria)

[0162] (g) Alveolar hemorrhage (by bronchoalveolar lavage)

[0163] (h) Palpable purpura

[0164] (i) Positive test for ANCA immunofluorescence and / or positive test for MPO and / orPR3 antibodies.

[0165] In aspects, EGPA is defined based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x 109 / liter and / or > 10% of leukocytes) plus at least 2 of the additional features listed as (a) to (i) above.

[0166] In aspects, subjects with EGPA do not have severe eosinophilic asthma.

[0167] In aspects, subjects have a history of relapsing or refractory EGPA. In some aspects, history of relapsing EGPA is present when a subject has had an increase in oral corticosteroid (OCS) dose, initiation or increased dose of immunosuppressive therapy, and / or hospitalization. In some aspects, subjects have a history of at least 1, 2, or 3 EGPA relapses.

[0168] In aspects, a history of refractory EGPA is present when a subject has not attained remission following induction treatment with corticosteroid therapy administered for at least 1 month, 2 months, or 3 months. In some aspects, a history of refractory EGPA is present whena subject has not attained remission following induction treatment with corticosteroid therapy administered for at least 3 months. In some aspects, a history of relapsing EGPA is present when a subject has a recurrence of symptoms of EGPA while tapering OCS. In some aspects, a history of relapsing EGPA is present when a subject has a recurrence of symptoms of EGPA while tapering OCS occurring at any dose level > 7.5 mg / day prednisolone or equivalent.EGPA Treatment

[0169] In some aspects, a method of treating EGPA in a subject comprises administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab). The EGPA can be relapsing or refractory EGPA. The subject can be a subject that is receiving corticosteroid therapy prior to the administration of an antibody or antigen-binding fragment thereof.

[0170] In some aspects, provided herein is an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of EGPA. The EGPA can be relapsing or refractory EGPA. The subject can be a subject that is receiving corticosteroid therapy prior to the administration of an antibody or antigen-binding fragment thereof.

[0171] In some aspects, provided herein is an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for use in the preparation of a medicament for the treatment of EGPA. The EGPA can be relapsing or refractory EGPA. The subject can be a subject that is receiving corticosteroid therapy prior to the administration of an the antibody or antigen-binding fragment thereof.

[0172] In some aspects, provided herein is the use of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of EGPA.

[0173] In some aspects, provided herein is the use of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of relapsing or refractory EGPA.

[0174] In some aspects, provided herein is the use of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of relapsing or refractory EGPA in a subject on corticosteroid therapy.Efficacy of EGPA Treatment

[0175] Provided herein are methods for treating EGPA. In aspects, the methods provided herein can significantly reduce EGPA disease activity.

[0176] In certain aspects, EGPA disease activity of can be measured using one or more clinical outcome assessments. In certain aspects the clinical outcome assessments include, but are not limited to, Birmingham Vasculitis Activity Score (BVAS), EGPA relapse / remission, Vasculitis Damage Index (VDI), Patient-Reported Outcome (PRO) Assessments, and / or Spirometry.

[0177] In certain aspects, the clinical outcomes assessments can be used to measure EGPA disease activity at about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks following initiation of treatment the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0178] In aspects, use of the methods provided herein reduces the Birmingham Vasculitis Activity Score (BVAS). In certain aspects, the BVAS is reduced by 1 point, 2 points, 3 points, 4 points, or 5 points. 6 points, 7 points, 8 points, 9 point, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points, 24 points, 25 points, 26 points, 27 points, 28 points, 29 points, 30 points, 31 points, 32 points, 33 points, 34 points, 35 points, 36 points, 37 points, 38 points, 39 points, 40 points, 41 points, 42 points, 43 points 44 points, 45 points, 46 points, 47 points, 48 points, 49 points, 50 points, 51 points, 52 points, 53 points, 54 points, 55 points, 56 points, 57 points, 58points, 59 points, 60 points, 61 points, 62 points, or 63 points. In certain aspects, the BVAS is reduced to 0.

[0179] In aspects, EGPA remission includes, but is not limited to, a BVAS = 0 and OCS dose of prednisolone / prednisone < 4 mg / day. In certain aspects, EGPA remission includes, but is not limited to, BVAS = 0 plus OCS dose of prednisolone / prednisone < 7.5 mg / day. In aspects, use of the methods provided herein reduces the time to achieve remission. In aspects, use of the methods provided herein increases EGPA remission duration. In aspects, use of the methods provided herein increases accrued EGPA remission duration. In aspects, use of the methods provided herein increases EGPA remission frequency.

[0180] In some aspects, use of the methods provided herein reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less within about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0181] In certain aspects, remission is achieved after about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks following initiation of treatment the IL- 5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0182] In certain aspects, remission is achieved for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0183] In certain aspects, remission is maintained for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 52 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0184] In certain aspects, the reduction in BVAS to 0 and the OCS dose to 4 mg / day or less is maintained for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 52 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0185] In some aspects, use of the methods provided herein reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less within 24 weeks after the first administration of the IL- 5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein. In further aspects, the reduction in BVAS to 0 and the OCS dose to 4 mg / day or less is maintained for at least about 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0186] In aspects, use of the methods provided herein reduces the EGPA relapse rate. In aspects, use of the methods provided herein reduces the annual EGPA relapse rate. In aspects, use of the methods provided herein increases the time to EGPA relapse.

[0187] In some aspects, use of the methods provided herein reduces the EGPA annualized relapse rate to less than 40%. In some aspects, use of the methods provided herein reduces the EGPA annualized relapse rate to less than 30%.

[0188] In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) do not experience a relapse for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, or for at least 120 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0189] In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) have a BVAS = 0 and prednisolone / prednisone dose < 4 mg / day) after administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0190] In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) have > 50% reduction in their daily prednisolone / prednisone dose within 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein. In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) have > 50% reduction in their daily prednisolone / prednisone dose within 4 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0191] In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) are EGPA relapse free for at least 48 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein. In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab):

[0192] (1) have a BVAS = 0 and prednisolone / prednisone dose < 4 mg / day) after administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein,

[0193] (2) have > 50% reduction in their daily prednisolone / prednisone dose within 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein, and

[0194] (3) are EGPA relapse free for at least 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0195] In some aspects, subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab):

[0196] (1) have a BVAS = 0 and prednisolone / prednisone dose < 4 mg / day) after administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein,

[0197] (2) have > 50% reduction in their daily prednisolone / prednisone dose within 4 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein, and

[0198] (3) are EGPA relapse free for at least 48 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0199] In certain aspects, the PRO assessments include, but are not limited to, Corticosteroid Medication Usage, Asthma Control Questionnaire (6-Item Version, ACQ-6), Sino-nasal Symptom Questionnaire (SSQ), Sino-Nasal Outcome Test-22 (SNOT-22), Short Form-36 Version 2 (Acute Recall, SF-36v), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Work Productivity and Activity Impairment Questionnaire (WPAI).

[0200] In aspects, use of the methods provided herein decreases the likelihood of an increase in the Vasculitis Damage Index (VDI).

[0201] In aspects, use of the methods provided herein reduces the daily oral corticosteroid (OCS) dose. In certain aspects, the daily OCS dose is reduced by about 100%, about 95%,about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%. In certain aspects, the daily OCS dose is reduced to < 7.5 mg / day. In certain aspects, the daily OCS dose is reduced to < 4.0 mg / day. In certain aspects, the daily OCS dose is reduced by 50% or more. In certain aspects, use of OCS is eliminated. In aspects, the daily OCS dose is reduced at least 12 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, or at least 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0202] In aspects, use of the methods provided herein reduces the daily oral glucocorticoid (OGC) dose. In certain aspects, the daily OGC dose is reduced by about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%. In certain aspects, the daily OGC dose is reduced to < 7.5 mg / day. In certain aspects, the daily OGC dose is reduced to < 4.0 mg / day. In certain aspects, the daily OGC dose is reduced by 50% or more. In certain aspects, use of OGC is eliminated. In aspects, the daily OGC dose is reduced at least 12 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, or at least 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.

[0203] In aspects, use of the methods provided herein reduces the ACQ-6 score. In certain aspects, the score is reduced to 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5. In certain aspects the score is reduced by 0.5. In certain aspects the score is reduced to < 1.5. In aspects, use of the methods provided herein reduces the SSQ score to 3, 2, 1, or 0.

[0204] In aspects, use of the methods provided herein reduces the SNOT-22 score. In certain aspects, the SNOT-22 score is reduced by at least 8.90 points. In certain aspects, the SNOT- 22 score is reduced by by about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%.

[0205] In aspects, use of the methods provided herein increases the SF-36v2. In aspects, the use of the methods provided herein increases the psychometrically-based physical health component summary score (PCS) and mental health component summary score (MCS).

[0206] In aspects, use of the methods provided herein reduces the Patient Global Impression of Severity (PGIS). In certain aspects, the PGIS is reduced to 4, 3, 2, 1, or 0.

[0207] In aspects, use of the methods provided herein reduces Patient Global Impression of Change (PGIC). In certain aspects, the PGIC is reduced to 6, 5, 4, 3, 2, or 1.

[0208] In aspects, use of the methods provided herein reduces the Work Productivity and Activity Impairment (WPAI) percentage.

[0209] In aspects, use of the methods provided herein, improves one or more of the following spirometry measures: forced expiration volume in 1 second, percent reversibility, and postbronchodilator forced expiration volume in 1 second.EXAMPLESEXAMPLE 1 : Efficacy of benralizumab in human patients with EGPA

[0210] A clinical trial, MANDARA, is conducted to demonstrate the efficacy of benralizumab compared to mepolizumab to treat eosinophilic granulomatosis with polyangiitis (EGPA) in human patients.(a) SUBJECTS

[0211] Subjects in this study are > 18 years of age and meet the following inclusion criteria for type of patient and disease characteristics.

[0212] Subjects have an EGPA diagnosis for at least 6 months before screening visit (Visit 1) date based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x l 09 / liter and / or > 10% of leukocytes) plus documentation of at least 2 of the following additional features of EGPA:

[0213] (a) A biopsy showing histopathological evidence of eosinophilic vasculitis, OR perivascular eosinophilic infiltration, OR eosinophil-rich granulomatous inflammation

[0214] (b) Neuropathy, mono or poly (motor deficit or nerve conduction abnormality)

[0215] (c) Pulmonary infiltrates, non-fixed

[0216] (d) Sino-nasal abnormality

[0217] (e) Cardiomyopathy (established by echocardiography or magnetic resonance imaging)

[0218] (f) Glomerulonephritis (hematuria, red cell casts, proteinuria)

[0219] (g) Alveolar hemorrhage (by bronchoalveolar lavage)

[0220] (h) Palpable purpura

[0221] (i) Positive test for ANCA immunofluorescence and / or positive test for MPO and / orPR3 antibodies

[0222] Subjects are also required to have a history of relapsing OR refractory disease defined as:

[0223] Relapsing disease: Subjects must have a history of at least one confirmed EGPA relapse (i.e., requiring increase in oral corticosteroid (OCS) dose, initiation / increased dose of immunosuppressive therapy or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of > 7.5 milligram per day (mg / day).

[0224] For study sites in Japan, patients must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of IV prednisolone or equivalent, initiation / increased dose of immunosuppressive therapy, initiation / increased dose of IV immunoglobulin or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of > 7.5 mg / day.Refractory disease:

[0225] Defined as either: Subjects who have not attained remission within the 6 months prior to Visit 1 (BVAS [scale 0-63] = 0 and OCS dose < 7.5 mg / day prednisolone or equivalent) following induction treatment with a standard regimen, administered for at least 3 months. OR: Subjects who, within 6 months prior to screening (Visit 1), had recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) while tapering OCS, occurring at any dose level > 7.5 mg / day prednisolone or equivalent.

[0226] Notably, (a) subjects who have received cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed intravenous (IV) CYC prior to baseline (Visit 2), if their total WBC is> 4 X 109 / L prior to randomization; (b) subjects who have received an azathioprine, methotrexate, or my cophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to baseline (Visit 2); and (c) subjects who have received an induction regimen comprising corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment and the corticosteroids dose is > 15 mg / day prednisolone for the 4 weeks prior to baseline (Visit 2).

[0227] The prescribed dose of oral prednisolone or prednisone must be stable (i.e., no adjustment of the dose) and must be > 7.5 mg / day but not > 50 mg / day) for at least 4 weeks prior to baseline (Visit 2). Stable doses of OCS other than prednisolone or prednisone may be acceptable.

[0228] If receiving immunosuppressive therapy (excluding CYC), the dosage must be stable for the 4 weeks prior to baseline (Visit 2). The dose of immunosuppressive therapy must not exceed the maximal doses used in clinical practice.

[0229] Subjects are required to have electrocardiogram (ECG) evaluation at screening (Visit 1) within the following range: QT interval corrected by Fredericia’s (QTcF) < 450 msec or QTcF < 480 msec for patients with bundle branch block. The QT interval corrected (QTc) was based on averaged QTc values of triplicate ECGs obtained over a brief recording period.

[0230] Subjects will be excluded from the study if any of the following criteria apply: :

[0231] (1) Diagnosed with granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) or microscopic polyangiitis.

[0232] (2) Organ-threatening EGPA: as per the European League against Rheumatism criteria(Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR / ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75:1583-94.), i.e, organ failure due to active vasculitis, creatinine > 5.8 mg / dL (> 513 pmol / L) within 3 months prior to screening (Visit 1) and through randomization (Visit 2).

[0233] (3) Imminently life-threatening EGPA disease: defined as any of the following within3 months prior to screening (Visit 1) and through randomization (Visit 2).

[0234] - Intensive care required

[0235] - Severe alveolar hemorrhage or hemoptysis requiring transfusion or ventilation or hemoglobin < 8 g / dL (< 80 g / L) or drop in hemoglobin > 2 g / dL (> 20 g / L) over a 48-hour period due to alveolar hemorrhage

[0236] - Rapidly progressive glomerulonephritis with creatinine > 2.5 mg / dL (> 221 pmol / L) or rise in creatinine > 2 mg / dL (> 177 pmol / L) over a 48-hour period

[0237] - Severe gastrointestinal involvement, for example, gangrene, bleeding requiring surgery

[0238] - Severe central nervous system involvement

[0239] - Severe cardiac involvement, for example, life-threatening arrhythmia, cardiac failure: ejection fraction < 20%, NYHA Class III / IV (American Heart Association. Classes of Heart Failure. Available from URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart-Failure_UCM_306328_Article.jsp. Accessedl4 August 2012), acute myocardial infarction.

[0240] (4) Malignancy: current malignancy, or history of malignancy, except, subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the subject is in remission and curative therapy was completed at least 12 months prior to screening (Visit 1); and subjects who have had other malignancies are eligible provided that the subject is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.

[0241] (5) Liver disease: unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).

[0242] (6) Cardiovascular: subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:

[0243] - Known ejection fraction < 30%, OR

[0244] - Severe heart failure that meets NYHA Class IV (American Heart Association. Classes of Heart Failure. Available from URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart- Failure_UCM_306328_Article.jsp. Accessedl 4 August 2012.), OR

[0245] - Hospitalized in the 12 months prior to screening (Visit 1) for severe heart failure meeting NYHA Class III (American Heart Association. Classes of Heart Failure. Available from URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart-Failure_UCM_306328_Article.jsp. Accessedl4 August 2012), OR

[0246] - Angina diagnosed within 3 months prior to screening (Visit 1) and through randomization (Visit 2).

[0247] (7) Infectious disease: chronic or ongoing active infectious disease requiring systemic treatment.

[0248] (8) Parasitic infection: a helminth parasitic infection diagnosed within 6 months prior to screening (Visit 1) and through randomization (Visit 2) that has not been treated with or had failed to respond to standard of care therapy.

[0249] (9) Hepatitis status: chronic stable hepatitis B and C (including positive testing forHBsAg or hepatitis C antibody), or other stable chronic liver disease are acceptable if the subject otherwise meets the eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.

[0250] (10) Immunodeficiency: a history of known immunodeficiency disorder including a positive HIV test.

[0251] (11) History of known allergy, intolerance, or anaphylaxis to any biologic therapy or vaccine.

[0252] (12) Known history of allergy or reaction to any component of any study treatment.

[0253] (13) Other concurrent medical conditions: subjects who have known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurologic, renal, gastrointestinal, hepatic, hematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment. And subjects who had any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening / run-in period, which may put the subject at risk, because of his / her participation in the study, or may influence the results of the study, or the patients’ ability to complete entire duration of the study.

[0254] (14) Prohibited medications: subjects receiving any of the following prohibited medications:

[0255] - OCS dose of > 50 mg / day prednisolone / prednisone in the 4-week period prior to baseline (Visit 2)

[0256] - Intravenous (IV), intramuscular (IM), or subcutaneous (SC) corticosteroids in the 4- week period prior to baseline (Visit 2)

[0257] - Omalizumab within 130 days prior to screening (Visit 1)

[0258] - Oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to baseline (Visit 2)

[0259] - Rituximab within 6 months prior to screening (Visit 1); in addition, the subject must have shown recovery of peripheral B-cell count to within the normal range

[0260] - IV or SC immunoglobulin within 30 days prior to screening (Visit 1)

[0261] - Interferon-a within 6 months prior to screening (Visit 1)

[0262] - Anti-tumor necrosis factor therapy within 12 weeks prior to screening (Visit 1)

[0263] - Anti-CD52 (alemtuzumab) within 6 months prior to screening (Visit 1)

[0264] - Any prior or current treatment with mepolizumab, reslizumab, dupilumab, or benralizumab either as a marketed or investigational biologic.

[0265] - Receipt of any other marketed or investigational biologic products, either marketed or investigational, within 4 months or 5 half-lives prior to screening, whichever is longer.

[0266] Other exclusions include:

[0267] (15) Other laboratory parameter exclusions at screening (Visit 1) and on repeat testing(if applicable) prior to Visit 2:

[0268] - Creatinine > 2.5 mg / dL (221 pmol / L)

[0269] - White blood cell (WBC) < 4 x 1 o9 / L

[0270] - Platelet count < 120000 / mm3

[0271] - Hemoglobin < 8 g / dL (< 80 g / L)

[0272] (16) Subjects who had a history (or suspected history) or alcohol misuse or substance abuse within 2 years prior to screening (Visit 1).

[0273] (17) Alcohol / substance abuse: a history (or suspected history) or alcohol misuse or substance abuse within 2 years prior to screening (Visit 1).

[0274] (18) Other investigational non-biologic product: receipt of any investigational nonbiologic product within 30 days or 5 half-lives prior to screening (Visit 1), whichever is longer.

[0275] (19) Adherence: subjects who have known evidence of lack of adherence to prescribed medications and / or ability to follow physician's recommendations.

[0276] (20) Alanine transaminase (ALT) or aspartate transaminase (AST) level > 3 times the upper limit of normal (ULN) confirmed during screening period, confirmed by repeated testing (if applicable) during screening period. Subjects who have transient increase of AST / ALT level that resolves by the time of randomization is acceptable if the patient did not have an active liver disease and meets other eligibility criteria.

[0277] (21) Subjects who have any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening / run-in period, which may put the patient at risk, because of his / her participation in the study, or may influence the results of the study, or the patients’ ability to complete entire duration of the study. Subjects who have any other medical illness that precludes study involvement.

[0278] (22) Subjects who receive blood products within 30 days prior to screening (Visit 1).

[0279] (23) Subjects who receive live attenuated vaccines 30 days prior to screening (Visit 1).(b) DESIGN OF THE STUDY

[0280] This study is a Phase III randomized, double blind, active-controlled, parallel group, multicenter study comparing the efficacy and safety of benralizumab 30 mg versus mepolizumab 300 mg administered by SC injection Q4W in patients with relapsing or refractory EGPA on corticosteroid therapy with or without stable immunosuppressive therapy. The dosing regimen (30 mg Q4W) was selected to ensure blood eosinophil depletions in EGPA, including in patients with higher eosinophil burden.

[0281] This study comprises 2 distinct periods: (i) a 52- week double-blind (DB) treatment period, during which patients will be randomized to receive either benralizumab or mepolizumab, and (ii) an open-label extension (OLE), during which all patients will receive benralizumab alone.

[0282] Study treatment in this study refers to benralizumab, mepolizumab, placebo to benralizumab, and placebo to mepolizumab. Placebo to mepolizumab and placebo tobenralizumab are used only to ensure blinding for the study treatments. The study treatments are shown in Table 3 below.Table 3: Study TreatmentsaMepolizumab is sourced locally in Japan.bMepolizumab / placebo to mepolizumab in Japan will be administrated with a 2-3 mL polypropylene syringe and 21-27 gauge needle.

[0283] Potentially eligible subjects will enter a screening period of up to 4 weeks (minimum of one week) and are be required to be on a stable dose of OCS > 7.5 mg / day prednisolone / prednisone (but not > 50 mg / day), for at least 4 weeks prior to baseline (Visit 2). If dose adjustment is necessary during the screening period, or the subject has not maintained a stable dose, the subject will be screen failed. Subjects on immunosuppressive therapy will be required to be on a stable dose for at least 4 weeks prior to baseline (Visit 2) and to remain on the same dose until the end of the DB period (if the patient does not enter the OLE) or until completion of the first 6 months of the OLE period (if the patient continues into the OLE). Dose reductions for safety reasons will be permitted. All eligible subjects will be randomized 1 : 1 at baseline (Visit 2), to receive study treatments Q4W for a 52- week DB treatment period. The number of patients with ANCA-positive status or an eosinophil count < 150 cells / pL (< 0.15 x 109 / L) will be restricted to approximately 10% and 40%, respectively, of the total number of randomized patients.

[0284] Between baseline (Visit 2) and Week 4, patients will be required to maintain a stable oral prednisolone / prednisone dose of > 7.5 mg / day (but not > 50 mg / day). If necessary, upward adjustments are permitted for clinical management of the patient. From Week 4 onward, if the patient’s BVAS = 0 their oral prednisolone / prednisone dose will be tapered downwards according to standard-of-care practice, using a recommended tapering schedule that enabled a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisone / prednisolone dose of 4 mg / day or less.

[0285] The final dose of the DB treatment period will be given at Week 48, and the DB treatment period will be completed at Week 52. All patients who complete the 52-week DB treatment period will be eligible to continue into the OLE period. The OLE period allows each patient at least one year of treatment with open-label benralizumab 30 mg administered SC every fourth week (earlier enrolled patients were therefore be in the OLE for longer than one year).

[0286] The study flow diagram is shown in Figure 1.(c) DEMONSTRATION OF EFFICACYClinical Outcome AssessmentsThe following assessments will be completed, according the schedule of assessments, as shown in Table 4: Birmingham Vasculitis Activity Score (BVAS), EGPA relapse / remission, and Vasculitis Damage Index (VDI).Table 4. Schedule of Assessments - Double Blind Treatment PeriodVisit 17 is the last double-blind visit and the first OLE visit. All assessments at Visit 17 to be performed BEFORE administration of open-label benralizumab.2Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits.3If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.4In case of early discontinuation from drug to be administered, procedures of this visit to be performed 4 weeks (± 7 days) after last dose of drug to be administered (replaces regular scheduled visit assessments).5The subject reports OCS medication usage each evening using the provided ePRO device (Visit 1-17).6The OCS dose will be recorded in the eCRF at each study visit and check compliance against subject reported use between study visits.7In the event of an EGPA relapse, blood and urine to be collected. In addition, for subjects participating in the mechanistic sub-study, a sputum and relevant biopsy sample (if possible) should be collected.8Visit 2 will be confirmed on the handheld device prior to baseline ePRO questionnaires completion by the subject. Sites will ensure subjects complete all baseline ePRO assessments. For subsequent visits, confirm is performed either on the web portal Study Works or on the device.9ePRO assessments include: Corticosteroid medication usage, Asthma Control Questionnaire (6-item version), Sino-nasal questionnaire, Sino- nasal Outcome Test-22, Short Form 36-Item Health Survey (version 2, acute recall), Patient Global Impression of Change, Patient Global Impression of Severity, and Work Productivity and Activity Impairment Questionnaire (General Health version 2.0).10From baseline (Visit 2) until the second visit of the OLE (Week 56 [Visit 18]), eosinophil, basophil, and monocyte counts will be redacted from all central laboratory reports in order to maintain the blind.11eGFR will be calculated according to the CKD-EPI formula at each visit where serum chemistry is collected.12Subject must be in fasting state. If subject has not fasted, he / she may return to collect this sample as soon as possible. The period of fasting may be adjusted for subjects with relevant metabolic conditions (e.g., diabetes mellitus).13Additional troponin assessments can be performed using a central test as clinically indicated during other visits.Haematuria to be checked by dipstick test provided centrally.15Only for Women of child-bearing potential (WOCBP).16FSH test done only for female subjects to confirm postmenopausal status in women < 50 years who have been amenorrhoeic for > 12 months.17Only in sites with the required equipment will collect nasal secretion samples.18On dosing visits, PK will be collected pre-dose.19ADA / nAb analysis will only be done on samples from patients who received benralizumab. Neutralizing antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.20Optional genetic sample: Sample collection is recommended at baseline (Visit 2) but may be drawn at any time after the subject is randomized.21Each participating subject will be interviewed twice. The first interview will take place at least 7 and up to 21 days after Visit 2. The second will take place at least 7 and up to 21 days after Visit 16.ADA, Anti-drug antibodies; AE(s), adverse event(s); ANCA, anti-neutrophil cytoplasmic antibodies; BD, bronchodilator; BVAS, Birmingham Vasculitis Activity Score; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CRP, C-reactive protein; CSP, clinical study protocol; disc., discontinuation; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; EGPA, eosinophilic granulomatosis with polyangiitis; ePRO, electronic patient reported outcome; ESR, erythrocyte sedimentation rate; FEIA, fluorenzyme immunoassay; FEV1, forced expiratory volume in 1 second; FSH, follicle stimulating hormone; HIV, human immunodeficiency virus; IgE, Immunoglobulin E; IWRS, Interactive Web Response System; min, minimum; MPO, myeloperoxidase; nAb, neutralizing antibodies; OCS, oral corticosteroid; OLE, open-label extension; PK, pharmacokinetics; PR3, proteinase-3; RNA, ribonucleic acid; SAE(s), serious adverse event(s); Unsch, unscheduled; V, Visit (number); VDI, Vasculitis Damage Index; WBC, white blood cells; Wks, weeks

[0287] Birmingham Vasculitis Activity Score (BVAS). The BVAS is a validated, clinician- completed tool used for the comprehensive multisystem clinical assessment of disease activity in systemic vasculitis (Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotising vasculitis. Q J Med. 1994;87:671-8; Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. Baillieres Clin Rheumatol. 1997;l l(2):423-46; Mukhtyar C, Lee L, Brown D, Carruthers D, Dasgupta B, Dubey S, et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 2009b;68: 1827-32). The BVAS form is divided into 9 organ-based systems, with each section including symptoms / signs that are typical of that particular organ involvement in systemic vasculitis. The form is designed to record features that are attributable to current vasculitis, after exclusion of other causes such as infection, hypertension, etc. The scoring sheet records the presence or absence of each item. Each item is weighted, and a maximum total score applied to each system. The total score on all 9 organ systems gives an indication of the disease activity of each subject at the time of scoring and reflects the need for therapy.

[0288] EGPA relapse / remission. EGPA remission at any visit will be defined as a BVAS score of 0 with OCS dose of prednisolone / prednisolone < 4 mg / day. In the event a subject has achieved remission and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg / day or 7.5 mg / day (in accordance with the relevant remission definition), or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission. EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by:

[0289] - Active vasculitis (BVAS > 0); OR

[0290] - Active asthma symptoms and / or signs with a corresponding worsening in AsthmaControl Questionnaire (6-item version) (ACQ-6) score (compared to the most recent previous score); OR

[0291] - Active nasal and / or sinus disease, with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment);

[0292] warranting any of the following:

[0293] - an increased dose of OCS therapy to > 4 mg / day prednisolone total daily dose; OR

[0294] - an increased dose or addition of immunosuppressive therapy; OR

[0295] - hospitalization related to EGPA worsening.

[0296] In the event of a suspected EGPA relapse, the subject will attend an unscheduled visit, and a BVAS evaluation will be conducted at the time of the relapse, or as soon as possible afterwards.

[0297] The time of onset of a relapse will be defined as:

[0298] - the time of increase in dose of OCS therapy, and / or

[0299] - increase in dose or addition of immunosuppressive therapy, and / or

[0300] - hospitalization in association with the worsening in BVAS, asthma, or sino-nasal symptoms.

[0301] In the event a subject has achieved remission (i.e., BVAS = 0 and prednisolone / prednisone dose < 4 mg / day) and at a subsequent visit has a BVAS = 1, which does not require an increase in corticosteroid dose above 4 mg / day, or any other significant clinical intervention or investigation, this will not be considered a relapse.

[0302] A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS > 6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia / arthritis, fever > 38°C or weight loss > 2 kg]); OR an asthma relapse requiring hospitalization; OR sino-nasal relapse requiring hospitalization.

[0303] The minimally effective dose of OCS (prednisolone / prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0 to 3.5 mg prednisolone / prednisone, the minimally effective dose will be defined as 4.0 mg / day. Upwards dose adjustments within the 0 to 4.0 mg range are permitted without being considered a relapse.

[0304] The management of subjects who relapse will be according to standard of care and may involve increasing the dose of corticosteroids or adjustment in immunosuppressive therapy.

[0305] If the subject's first relapse is managed with the use of an increase in corticosteroid dose, tapering will be recommended as soon as the relapse has been appropriately controlled, as per standard of care practice. Once a minimally effective dose of OCS is achieved, any down-tapering below this dose level will be based on the clinical condition of the subject.

[0306] If a relapse is managed by increasing the dose of or initiating immunosuppressive therapy, the subject may be withdrawn from receiving further study treatment and where possible, continued to be followed up.

[0307] If a subject experiences an organ threatening or a life-threatening relapse, he / she may be withdrawn from receiving further study treatment and where possible, continue to be followed up.

[0308] Vasculitis Damage Index (VDI). VDI (Exley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers DM, Moots R. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI). Br J Rheumatol. 1998;37:57- 63) will be used to document those features of vasculitis, which are due to persistent damage, where there is no current disease activity. Damage is defined as the presence of non-healing scars and does not give any indication of current disease activity. The VDI is divided into 11 organ systems and records items of damage, due to vasculitis, treatment or unrelated, that have occurred since the onset of vasculitis. Completion of the form provides a numerical score. VDI sores are compared between subjects receiving benralizumab and mepolizumab treatment.

[0309] Patient-Reported Outcome (PRO) Assessments. The patient-reported outcome (PRO) assessments, including Corticosteroid Medication Usage, Asthma Control Questionnaire (6- Item Version), Sino-Nasal Symptom Questionnaire, Sino-Nasal Outcome Test-22, Short Form-36 Version 2 (Acute Recall), Patient Global Impression of Severity, Patient Global Impression of Change, Work Productivity and Activity Impairment Questionnaire, were completed as shown in Table 4.

[0310] Corticosteroid Medication Usage. The subject will be asked to report the daily dosage of OCS taken over the past 24 hours throughout the 52-week DB period. The daily OCS usage assessment will be completed by the subject each evening prior to going to sleep. The number of subjects on an OCS dose < 4.0 mg / day is compared between subjects receiving benralizumab and mepolizumab treatment to demonstrate that benralizumab reduces OCS dose. The proportion of subjects with > 50% reduction in OCS average daily dose from baseline based on the average daily prednisolone / prednisone dose during Weeks 48 through 52 is assessed.

[0311] Asthma Control Questionnaire (6-Item Version, ACQ-6). The ACQ-6 is an assessment of 5 asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and short-acting beta-agonist use. The ACQ-6 was developed for self-administration by adults and adolescents by omitting the forced expiratory volume in 1 second (FEV1) % predicted question (Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-7). Subjects are asked to record their experience with 5 symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and use of Short acting 02 agonist (SABA) over the previous week using a 7-point scale (0 = no impairment; 6 = maximum impairment). The ACQ-6 score is calculated by taking the mean of the 6 equally weighted items. The ACQ-6 score range is 0 (well controlled) to 6 (extremely poorly controlled). Individual score change of at least 0.5 is meaningful and is used to support the responder definition Mean ACQ scores < 0.75 indicate well-controlled asthma, scores between 0.75 and 1.5 indicate partly controlled asthma, and a score > 1.5 indicates poorly controlled asthma. See Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5): 553-8; Juniper EF, Bousquet J, Abetz L, Bateman ED, GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100(4):616-21. ACQ-6 scores are compared between subjects receiving benralizumab and mepolizumab treatment.

[0312] Sino-Nasal Symptom Questionnaire (SSQ). The SSQ captures the severity of 5 sinus and nasal symptoms. Specifically, the SSQ asks subjects to report the severity of their symptoms over the previous week: “Considering your sinus and nasal symptoms over the last week, rate each symptom against the following categories: very severe, severe, moderate, mild, none.” Symptoms include runny nose, post-nasal discharge (sensation of liquid in your throat), facial pain / pressure, loss or reduction in sense of taste / smell, and blockage / congestion of nose. Higher scores indicate greater severity (0 = none to 4 = very severe). SSQ scores are compared between subjects receiving benralizumab and mepolizumab treatment.

[0313] Sino-Nasal Outcome Test-22 (SNOT-22). The SNOT-22 is a condition-specific health status / health- related quality of life (HRQoL) assessment that captures subject- reportedphysical problems, functional limitations, and emotional consequences of sino-nasal conditions. Subject-reported symptom severity and symptom impact over the past 2 weeks are captured via a 6-point scale (0 = no problem to 5 = problem as bad as it can be). The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes). A Minimal Clinical Importance Difference of 8.90 has been established for individual score change. See, Piccirillo JF, Merritt Jr. MG, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126:41-7; Hopkins C, Gillett S, Slack R, Lund V, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009;34:447-54. SNOT- 22 scores are compared between subjects receiving benralizumab and mepolizumab treatment.

[0314] Short Form- 36 Version 2 (Acute Recall, SF-36v2). The SF-36v2 is a 36-item, selfreport survey of functional health and well-being, with a one-week recall period (Lincoln, RI. QualityMetric, I. User's manual for the SF-36v2 Health Survey (3 ed.). 2011). The 8-domain profile consists of the following subscales: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. Psychometrically-based physical health component summary score (PCS) and mental health component summary score (MCS) are computed from subscale scores.

[0315] Patient Global Impression of Severity (PGIS). The PGIS is a single item designed to capture the subject's perception of overall symptom severity. PGIS results are compared between subjects receiving benralizumab and mepolizumab treatment.

[0316] Patient Global Impression of Change (PGIC). The PGIC is a single item designed to capture the subject's overall evaluation of response to treatment. PGIC results are are compared between subjects receiving benralizumab and mepolizumab treatment.

[0317] Work Productivity and Activity Impairment Questionnaire (WPAI). The WP A I general health 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. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity (Reilly Associates. Scoring ofWPAI. Available from URL: http: / / www.reillyassociates.netAVPAI_Scoring.html. Accessed on May 16, 2012). WPAI results are compared between subjects receiving benralizumab and mepolizumab treatment.

[0318] Spirometry. Lung function (forced expiratory volume in 1 second (FEV1) and forced vital capacity) will be measured by spirometry. Spirometry will be performed according to American Thoracic Society / European Respiratory Society guidelines (Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38) according to the Schedule of Assessments shown in Table 4. Spirometry testing will be initiated in the morning between 0600 and 1100 at the baseline visit (Visit 2). All post-randomization spirometry assessments will be performed within ± 2 hours of the time of day that the baseline (Visit 2) spirometry is performed, if possible. The Global Lung Function Initiative equations, which are preprogrammed into the spirometer, will be used to determine the predicted normal value (PNV).

[0319] Forced expiration volume in 1 second, expressed as percent of the PNV, will be calculated as follows:

[0320] FEV1 % of PNV = (FEV1 measured / FEVl PNV) X 100

[0321] Percent reversibility will be calculated as follows:

[0322] Percent reversibility = (post- bronchodilator FEV - pre- bronchodilator (BD) FEV1) x 100% / pre- bronchodilator FEV1. The reversibility test and post-bronchodilator (BD) FEV1 efficacy assessment will be performed only at baseline (Visit 2). Endpoint maximal bronchodilation will be induced using albuterol (90 pg metered dose), salbutamol (100 pg metered dose), or levalbuterol (45 pg metered dose) 4 inhalations within 30 ± 15 minutes of the final pre-BD spirometry measurement. Post-BD spirometry is preferably performed 15 to 30 minutes after the short acting [32 agonist (SABA) dosing. It is preferable to use a spacer device for this procedure, and a nebulizer should not be used. The algorithm for reversibility testing is outlined in Figure 2.

[0323] Spirometry results are compared between subjects receiving benralizumab and mepolizumab treatment.

[0324] Clinical Benefit. Any clinical benefit is a composite endpoint that is defined as any of the following 3 component endpoints (Steinfeld I, Bradford ES, Brown I, Mallett S, YanceySW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143(6):2170-7.):

[0325] (1) Remission (defined as BVAS = 0 and prednisolone / prednisone dose < 4 mg / day) at any time during the double-blind treatment period.

[0326] (2) > 50% reduction in average daily prednisolone / prednisone dose during Weeks 48 through 52.

[0327] (3) EGPA relapse free during the double-blind treatment period.

[0328] Complete response is a composite endpoint, and subjects meet complete response if all of the three components above are met.EXAMPLE 2: Results(a) ENROLLMENT AND BASELINE CHARACTERISTICS

[0329] The baseline characteristics of all 140 patients randomized to benralizumab (n=70) or mepolizumab (n=70) are provided in Table 5 below. Demographics, baseline disease characteristics, and concomitant medication use were generally balanced between treatment groups (Table 5; 60.0% were female, mean [standard deviation; SD] age was 52.3 [14.1] years).Table 5: Demographics and Baseline Clinical CharacteristicsStandard Deviation (SD); Body Mass Index (BMI); oral glucocorticoid (OGC) dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administrationaPatients with ANCA-positive status at screening were capped at 10%.bPatients with blood eosinophil count <150 cells / pL were capped at ~40% at recruitment.cA biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation.dMono- or polyneuropathy (motor deficit or nerve conduction abnormality)eEstablished by echocardiography or magnetic resonance imaging(b) EFFICACY

[0330] The primary endpoints, specifically, oral glucocorticoid (OGC) dose < 4 mg / day, and European Alliance of Associations for Rheumatology (EULAR)-defined remission at weeks 36 and 48 were compared in patients receiving benralizumab and mepolizumab (Figures 3A- 3C and 4; Remission: BVAS= 0 and OGC dose < 4 mg / day and EULAR-defined remission: BVAS = 0 and OGC dose < 7.5 mg / day). The primary endpoint of adjusted rate of remission at both weeks 36 and 48 was 59.2% for the benralizumab group and 56.5% for the mepolizumab group (difference in rates: 2.71%; 95% CI: -12.54, 17.96; p = 0.7278; Figures 3A-3C and 4) The adjusted rate of EULAR-defined remission at both weeks 36 and 48 was 79.0% for the benralizumab group and 73.6% for the mepolizumab group (difference in rates: 5.44%; 95% CI: -7.46, 18.34; Figure 3A). Pre-specified subgroup analyses showed that remission rates were similar between the benralizumab and mepolizumab groups regardless of patient clinical and disease characteristics, including ANCA-positivity status (Figure 4).

[0331] The external validity of the study was assessed using an approach which compares the observed benralizumab rate in this study with the historical placebo remission rate of 2 of 68 patients (2.9%) observed within the MIRRA study (Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921-32.). Comparisons with rates of remission in historic placebo and historic mepolizumab groups from the MIRRA trial are shown in Table 6 below.Table 6: Proportion of patients who achieved remission at both weeks 36 and 48, treatment comparison between benralizumab vs historical placebo (from MIRRA trial), and mepolizumab versus historical mepolizumab (from MIRRA trial)The historical placebo remission rate and historical mepolizumab remission rate are gathered from subjects observed within the phase 3 trial, MIRRA.

[0332] Benralizumab and mepolizumab groups had a similar average daily dose of OGC (OR 1.42; 95% CI: 0.77, 2.62; p = 0.2618) at weeks 48-52 (Figure 5A and 5B). The mean (SD) change from baseline in daily OGC dose was -8.12 (4.536) mg in the benralizumab group and -7.52 (7.070) mg in the mepolizumab group, at weeks 49-52 (Figure 5A). During weeks 48-52, 86.1% versus 73.9% patients, respectively, achieved >50% reduction in OGC use (difference in rates: 12.26; 95% CI: -0.57, 25.10). A higher proportion of benralizumab-treated patients fully tapered off OGCs versus mepolizumab (41.4% vs 25.8%, respectively; difference in rates: 15.69; 95% CI: 0.67, 30.71; Figures 3B and 6, and Table 7). The daily dose of OGC is shown in Table 7 below.Table 7. Daily dose of OGC during weeks 48-52

[0333] The secondary endpoint of total accrued duration of remission was similar in the benralizumab and mepolizumab groups (odds ratio [OR] 1.36; 95% CI: 0.75, 2.48; Table 8). Similar proportions of patients achieved remission within the first 24 weeks of treatment and remained in remission through week 52 (42.1% vs 36.5%; difference in remission rates: 5.54;95% CI: -9.30, 20.37; Figures 7A and 7B). Accrued remission duration is shown in Table 8 below.Table 8. Accrued remission duration during the double-blind phase

[0334] Similar rates of clinical benefit and clinical response were seen in the two treatment groups (Figure 8 and Table 9). Table 9 shows the proportion of patients who achieved any clinical benefit and complete response. Clinical benefit was defined as any of the following and complete response was defined as all of the following: remission at any time, >50% and >100% reduction in average daily OGC (prednisone / prednisolone) dose during weeks 48-52, EGPA relapse free during the double-blind treatment period.Table 9. Proportion of patients who achieved any clinical benefit and complete response

[0335] Further, in both groups, 30.0% of patients experienced a relapse, and the time to first relapse was similar between the groups (hazard ratio [HR] 0.98; 95% CI: 0.53, 1.82; Figure 9). In total, there were 34 versus 30 relapses in the benralizumab and mepolizumab groups, respectively, and these occurred in similar relapse categories (any vasculitis: 30.0% vs 25.7%; any asthma: 17.1% vs 12.9%; and any sino-nasal: 10.0% vs 11.4%, respectively). The annualized relapse rate was 0.50 (95% CI: 0.30, 0.83) versus 0.49 (95% CI: 0.28, 0.86) in the benralizumab and mepolizumab groups, respectively (rate ratio: 1.03; 95% CI: 0.56, 1.90). There were no major relapses in the benralizumab group, and three patients (4.3%) in the mepolizumab group experienced four major relapses. The proportion of patients with relapses, and time to first relapse was similar between the benralizumab and mepolizumab groups (40.43 vs 38.57 weeks, respectively; Figure 9).

[0336] Marked reductions in blood eosinophil counts were observed early following treatment initiation and were maintained throughout the double-blind period in both treatment groups. At Week 1, the LS mean change from baseline in blood eosinophil count was 0.15 (95% CI: 0.12, 0.18) versus 0.39 (95% CI: 0.32, 0.47) in benralizumab and mepolizumab recipients,respectively (adjusted geometric mean ratio: 0.38; 95% CI: 0.29, 0.49; Figure 10). At Week 52, the mean (SD) blood eosinophil count was 32.4 (40.8) and 71.8 (54.4) cells / pL in benralizumab and mepolizumab recipients, respectively.

[0337] Data for other secondary outcomes (BVAS; VDI; lung function [FEV1]; scores on the ACQ-6, Sino-Nasal Outcomes Test-22 , Sino-nasal Symptoms Questionnaire (SSQ), Medical Outcomes Study Short Form-36 Item Health Survey version 2, Patient Global Impression of Severity, Patient Global Impression of Change, and Work Productivity and Activity Impairment General Health Questionnaire (WPAI); and immunogenicity) are provided in Figures 11-17, and Tables 10-12 below.Table 10. SSQ scores and change from baseline by time pointTable 11. WPAI absenteeism and presenteeism scores at baseline and week 52 and change from baselineTable 12. Anti-drug antibody response to benralizumabADA, anti-drug antibody; nAb, neutralizing antibodiesaA positive post-baseline result and either treatment-induced ADA positive or treatment-boosted ADA positive.bTreatment-induced ADA positive is defined as ADA negative at baseline and at least one post-baseline ADA positive assessment.cTreatment-boosted ADA positive is defined as ADA positive at baseline and the baseline titre is boosted by greater than the variability of the assay (i.e., > 4-fold) at >1 post-baseline assessment.dNon-treatment-emergent ADA positive is defined as ADA positive but not fulfilling the conditions above for treatment-emergent ADA positive.ePersistently positive ADA is defined as ADA negative at baseline and having >2 post-baseline ADApositive assessments (with >16 weeks between first and last positive) or positive at the last available post baseline assessment.fTransiently positive ADA is defined as ADA negative at baseline and >1 post-baseline ADA positive assessment but not fulfilling the conditions of persistently positive.8The median of maximum post-baseline titre is calculated based on the maximum post-baseline titre of each ADA-positive patient.hnAb prevalence is defined as nAb positive at any visit including baseline and / or post-baseline.1nAb incidence is defined as nAb negative at baseline (or ADA negative at baseline) and nAb positive at any post-baseline visit.

[0338] Reduction in OGC use in patients with EGPA was further assessed in benralizumab and mepolizumab groups (see Tables 13-15 and Figures 18A-21B). During the study, mean cumulative oral glucocorticoid use was similar between groups (-2,000 mg); however, more benralizumab- than mepolizumab-treated patients completely tapered off OGCs (i.e., achieved 100% reduction in use of OGCs), and they were able to do so more quickly (see e.g., Table 14 and Figures 18B-20B). Table 15 shows complete remission (i.e., BVAS = 0 + OCS = 0 mg / day+ relapse free) at Week 36 and 48. Specifically, a higher proportion benralizumab- compared to mepolizumab-treated patients achieved complete remission.

[0339] Figure 19 shows a heatmap of OGC dose by time and relapse during the study. Figure 20A shows the total accrued duration (weeks) of OGC = 0 mg / day for both groups, and Figure 20B shows the percentage reduction from baseline in average daily dose of OGC during Weeks 48-52. Benralizumab-treated patients tapered OGCs faster than mepolizumab-treated patients and maintained the reduction in dose through to Week 52. A higher proportion of benralizumab-treated patients fully tapered off OGCs. There was also no deterioration in lung function (i.e., pre-BD FEV1, Figure 21 A) and no loss of asthma control score (ACQ-6, Figure 21B), despite OGC tapering. This data indicates that benralizumab enables oral glucocorticoid sparing in patients with EGPA, confirming that anti-IL-5 / Ra treatment is beneficial.Table 13. Cumulative OGC use during the studyTable 14. Time to OGC reduction during the 52-week treatment periodTime to first reduction was defined from the date of randomization to the first 4-weekly period when the reduction threshold was met during the double-blind period. For patients who did not reach the threshold, thetime to first reduction was right censored at the date of their last visit and at the date of last contact for patients lost-to-follow-up. a Calculated using the Kaplan-Meier technique; b The hazard ratio (HR, benralizumab vs mepolizumab) and 95% Cis were estimated using a Cox regression model with Efron method to control for ties. The covariates in the model included treatment arm, baseline dose of prednisone, baseline BVAS, and region. A hazard ratio >1 favored benralizumab. The p-value was from the unstratified log-rank test; c Calculated using a 2-sided, unstratified log-rank test; p-values were nominal.Table 15. Complete remission at week 36 and 48a The remission rates and the difference (Benralizumab - Mepolizumab) are estimated using marginal standardization method in a logistic regression model.The covariates in the model included treatment arm, baseline dose of prednisone, baseline BVAS and region (North America, Western Europe, and Japan). Baseline was defined as the last measurement on or prior to the date of randomization. b Nominal p-value(c) SAFETY

[0340] Benralizumab was well tolerated. During the double-blind phase, adverse events (AEs) were reported in 90.0% of benralizumab patients and 95.7% of mepolizumab patients (Table 16). The most commonly reported AEs were coronavirus disease 2019 (COVID-19; 21.4% vs 27.1%), headache (17.1% vs 15.7%), and arthralgia (17.1% vs 11.4%) in the benralizumab versus mepolizumab groups, respectively (Table 16). SAEs were reported in 5.7% ofbenralizumab and 12.9% of mepolizumab recipients (Table 16). The most common SAEs were infections and infestations (2.9% in benralizumab group vs 5.7% in the mepolizumab group). No benralizumab- and two mepolizumab-treated patients experienced AEs leading to discontinuation of treatment. Two mepolizumab-treated patients experienced serious events of prostate cancer; however, the events were not considered related to mepolizumab. There were no deaths during the double-blind period. The safety profile of the benralizumab group and the mepolizumab group is shown in Table 16 below.Table 16: Safety profile(d) DISCUSSION

[0341] This study provides evidence for the efficacy and utility of benralizumab in this population, confirming that anti-IL-5 treatment is beneficial for patients with EGPA. ThisPhase 3, randomized study comparing the efficacy of benralizumab and mepolizumab in patients with refractory / relapsing EGPA receiving standard of care, met the primary objective with regard to remission rates over 52 weeks in patients with relapsing / refractory EGPA receiving standard of care. There were few S AEs, and no new safety signals with benralizumab therapy.

[0342] More patients treated with benralizumab were able to eliminate OCS, and they were able to do so more quickly than patients treated with mepolizumab. A shorter time to first 100% reduction in OCS was observed in patients treated with benralizumab compared to patients treated with mepolizumab. Additionally, over the course of the 52- week double-blind period, more patients treated with benralizumab were OCS free for at least 24 weeks compared to patients treated with mepolizumab. Patients treated with benralizumab were more likely to eliminate and remain OCS free during the double-blind period than patients treated with mepolizumab. Additionally, similar proportions of patients achieved 100% OCS reduction regardless of ANCA status and immunosuppressive medication.

[0343] Consistent efficacy of benralizumab was observed across all secondary endpoints. Results demonstrated comparable control of disease activity with durability of response, and a similar duration of accrued and sustained remission with benralizumab and mepolizumab. There were similar annualized rates of relapse and time to first relapse between treatment groups. The majority of benralizumab-and mepolizumab-treated patients demonstrated clinical benefit, which is also reflected in the low number of discontinuations during the trial. More benralizumab-treated patients were able to achieve a reduction in average daily OGC dose of >50% and completely taper off their OGC use compared with mepolizumab.* * *

[0344] 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.

[0345] 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.

[0346] Some aspects are within the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating eosinophilic granulomatosis with polyangiitis (EGPA) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra, 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: 1.2 The method of claim 1 , wherein the antibody or antigen-binding fragment is a humanized IgGl monoclonal antibody.3 The method of claim 1 or 2, wherein the antibody is benralizumab.4 The method of any one of claims 1 to 3, wherein the patient has asthma.5 The method of any one of claims 1 to 4, wherein the patient has eosinophilia.6 The method of any one of claims 1 to 5, wherein the patient has at least 2 of the following:(a) a biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;(b) neuropathy;(c) pulmonary infiltrates;(d) a sino-nasal abnormality;(e) cardiomyopathy;(f) glomerulonephritis;(g) alveolar hemorrhage;(h) palpable purpura; and(i) a positive test for ANCA immunofluorescence, myeloperoxidase (MPO) antibodies, and / or proteinase-3 (PR3) antibodies.7 The method of any one of claims 1 to 6, wherein the patient does not have severe eosinophilic asthma.

8. The method of any one of claims 1 to 7, wherein the patient has had EGPA for at least six months.

9. The method of any one of claims 1 to 8, wherein the patient has ANCA positive EGPA.

10. The method of any one of claims 1 to 8, wherein the patient has ANCA negative EGPA.

11. The method of any one of claims 1 to 10, wherein the patient has a history of relapsing or refractory disease.

12. The method of any one of claims 1 to 11, wherein the patient has a history of relapsing EGPA.

13. The method of claim 12, wherein the patient has a history of at least 3 EGPA relapses.

14. The method of any one of claims 1 to 13, wherein the patient has a history of refractory EGPA.

15. The method of any one of claims 1 to 14, wherein the patient uses an oral corticosteroid (OCS) prior to the administration, optionally wherein the patient has been using an OCS for at least 4 weeks prior to the administration.

16. The method of claim 15, wherein the OCS is a glucocorticoid.

17. The method of claim 15, wherein the OCS is prednisolone or prednisone.

18. The method of claim 15, wherein the OCS is methylprednisolone.

19. The method of any one of claims 15 to 18, wherein the patient uses at least 7.5 mg / day or about 7 5 mg / day to about 50 mg / day of the OCS prior to the administration.20 The method of any one of claims 15 to 19, wherein the administration reduces the OCS usage to 7 5 mg / day or less.21 The method of any one of claims 15 to 20, wherein the administration reduces the OCS usage to 4 mg / day or less.22 The method of any one of claims 15 to 21, wherein the administration eliminates OCS usage.

23. The method of any one of claims 15 to 22, wherein the OCS daily dose is reduced from at least 7.5 mg / day prior to the administration to 4 mg / day or less after the administration.

24. The method of any one of claims 15 to 23, wherein the administration reduces OCS daily dose by 50% or more.

25. The method of claim 24, wherein the administration reduces OCS daily dose by 100%.

26. The method of claim 24 or 25, wherein the reduction in OCS daily dose occurs within 52 weeks of the first administration of the antibody or an antigen-binding fragment thereof to the patient.

27. The method of any one of claims 24 to 26, wherein the reduction in OCS daily dose does not decrease the patient's lung function.

28. The method of claim 27, wherein the patient's lung function is measured by spirometry.

29. The method of any one of claims 24 to 28, wherein the reduction in OCS daily dose does not increase the severity of the patient's asthma.

30. The method of claim 29, wherein the severity of the patient's asthma is measured by the asthma control questionnaire-6 (ACQ-6).

31. The method of any one of claims 1 to 30, wherein the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS).

32. The method of any one of claims 1 to 31, wherein the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS) more than administration of mepolizumab reduces it.

33. The method of claim 32, wherein the administration reduces the patient's BVAS to 0.

34. The method of any one of claims 15 to 33, wherein the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less.

35. The method of claim 34, wherein the reduction in BVAS to 0 and the OCS dose to 4 mg / day or less occurs within 24 weeks of the first administration of the antibody or an antigen-binding fragment thereof to the patient.

36. The method of claim 34 or 35, wherein the reduction in BVAS to 0 and the OCS dose to 4 mg / day or less is maintained for at least about 52 weeks after the first administration of the antibody or an antigen-binding fragment thereof to the patient.

37. The method of any one of claims 1 to 36, comprising administering at least two doses of the antibody or an antigen-binding fragment thereof to the patient.

38. The method of any one of claims 1 to 37, wherein the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less after at least 3 doses, at least 6 doses, at least 9 doses, or at least 12 doses of the antibody or an antigen-binding fragment thereof to the patient.

39. The method of any one of claims 1 to 38, wherein the administration increases the time to EGPA relapse.

40. The method of any one of claims 1 to 39, wherein the administration increases the time to EGPA relapse more than administration of mepolizumab increases it.

41. The method of any one of claims 1 to 40, wherein the administration decreases the annual relapse rate.

42. The method of any one of claims 1 to 41, wherein the administration decreases the annual relapse rate more than administration of mepolizumab decreases it.

43. The method of any one of claims 1 to 42, wherein the administration decreases the likelihood of an EGPA relapse.

44. The method of any one of claims 1 to 43, wherein the administration decreases the likelihood of an EGPA relapse more than administration of mepolizumab decreases it.

45. The method of any one of claims 1 to 44, wherein the administration decreases the likelihood of an increase in the vasculitis damage index (VDI) of the patient.

46. The method of any one of claims 1 to 45, wherein the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient.

47. The method of any one of claims 1 to 46, wherein the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient more than administration of mepolizumab improves it.

48. The method of any one of claims 1 to 47, wherein the administration improves the sino-nasal outcome test- 22 (SNOT-22) score of the patient.

49. The method of any one of claims 1 to 48, wherein the administration improves the sino-nasal outcome test-22 (SNOT-22) score of the patient more than administration of mepolizumab improves it50 The method of any one of claims 1 to 49, wherein the administration improves the Patient Global Impression of Severity (PGIS) score.51 The method of any one of claims 1 to 50, wherein the administration improves the Patient Global Impression of Severity (PGIS) score more than administration of mepolizumab improves it.52 The method of any one of claims 1 to 51, wherein the antibody or antigen-binding fragment thereof is administered at about 30 mg per dose.53 The method of any one of claims 1 to 52, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks.54 The method of any one of claims 1 to 53, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for 12 weeks.55 The method of any one of claims 1 to 54, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for 24 weeks.56 The method of any one of claims 1 to 55, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for 36 weeks.

57. The method of any one of claims 1 to 56, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for 48 weeks.

58. The method of any one of claims 1 to 57, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for at least four doses.

59. The method of any one of claims 1 to 58, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for at least eight doses.

60. The method of any one of claims 1 to 59, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for at least twelve doses.

61. The method of any one of claims 1 to 60, wherein the antibody or antigen-binding fragment thereof is administered once every four weeks for three doses and then once every eight weeks.

62. The method of any one of claims 1 to 61, wherein the antibody or antigen-binding fragment thereof is administered parenterally.

63. The method of any one of claims 1 to 62, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

64. The method of any one of claims 1 to 63, wherein the administration is into the upper arm, thigh, or abdomen.

65. An antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra for use in the method of any one of claims 1-64, 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.

66. 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 -64, 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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