IL-5R-alpha antibodies for treatment of eosinophilic polyvasculitis

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 584,453, filed September 21, 2023; U.S. Provisional Application No. 63 / 597,634, filed November 9, 2023; and U.S. Provisional Application No. 63 / 648,325, filed May 16, 2024, the entire contents of each of which are incorporated herein by reference.

[0003] Reference to the sequence listing submitted electronically

[0004] The contents of the electronically submitted sequence list (name: 2943_261PC03_Seqlisting_ST26.xml; size: 15,327 bytes; creation date: September 16, 2024) are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure relates to a method of treating eosinophilic granulomatous polyangiitis (EGPA) using an anti-interleukin-5 receptor α (IL-5Rα) antibody or an antigen-binding fragment thereof (e.g., benalizumab). Background Technology

[0006] Eosinophilic granulomatous polyangiitis (EGPA, formerly known as Churg-Strauss syndrome) is a rare inflammatory condition of systemic necrotizing vasculitis affecting small and medium-sized vessels. The disease is characterized by potentially life-threatening systemic eosinophilic small vessel vasculitis associated with asthma, sinusitis, and pulmonary infiltration. Patients with EGPA typically have a greater blood and tissue eosinophil load than, for example, patients with severe asthma. Multiple organs may be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. Before corticosteroids were used for EGPA, more than 50% of patients died within 3 months of diagnosis. While systemic corticosteroid therapy is the foundational treatment for EGPA, the use of corticosteroids, especially long-term use, is associated with significant adverse effects, including weight gain, osteoporosis, hyperglycemia, depression, and an increased risk of infection, which limits the benefits of treatment. In addition, although remission can be achieved in some patients who receive only corticosteroid therapy, more potent immunosuppressive therapies (such as azathioprine, methotrexate, or mycophenolate mofetil) are usually added to maintain remission.

[0007] Generally, although these treatments can effectively achieve remission, patients remain susceptible to the risks of complications and / or relapse associated with long-term use, especially if the dosage of corticosteroids or immunosuppressants is reduced or discontinued. Specifically, relapse rates have been reported to be 30% to 40%, increasing over time. Notably, repeated relapses expose patients to the risk of secondary permanent tissue and / or organ damage due to vasculitis.

[0008] Based on a phase III study, the IL-5 cytokine inhibitor mepolizumab has recently been approved in several countries for the treatment of EGPA. Although mepolizumab increased the time to remission compared to placebo in this study, 47% of patients treated with mepolizumab did not meet the primary endpoint of remission defined 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. NEngl J Med. 2017; 376:1921-32).

[0009] Therefore, there is an unmet medical need for EGPA therapy to induce and maintain remission while reducing the burden of corticosteroid use and other immunosuppressive therapies. Summary of the Invention

[0010] This article provides a method for treating eosinophilic granulomatous polyangiitis (EGPA) using an anti-interleukin-5 receptor α (IL-5Rα) antibody or an antigen-binding fragment thereof (e.g., benalizumab). In some aspects, a method for treating eosinophilic granulomatous polyangiitis (EGPA) in a patient in need comprises: administering to the patient a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to IL5Rα, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 1.

[0011] In some aspects of the methods provided herein, the antibody or antigen-binding fragment is a humanized IgG1 monoclonal antibody.

[0012] In some respects of the methods provided herein, the antibody is benazepril.

[0013] In some aspects of the methods presented in this article, the patient suffers from asthma.

[0014] In some aspects of the methods presented in this article, the patient suffers from eosinophilia.

[0015] In some aspects of the methods provided herein, the patient has at least two of the following: (a) histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation on biopsy; (b) neuropathy; (c) pulmonary infiltration; (d) sinus abnormality; (e) cardiomyopathy; (f) glomerulonephritis; (g) alveolar hemorrhage; (h) palpable purpura; and (i) positive ANCA immunofluorescence, myeloperoxidase (MPO) antibody, and / or proteinase-3 (PR3) antibody tests.

[0016] In some aspects of the methods presented in this article, the patient did not have severe eosinophilic asthma.

[0017] In some aspects of the methods presented in this article, the patient has had EGPA for at least six months.

[0018] In some aspects of the methods presented in this article, the patient has ANCA-positive EGPA.

[0019] In some aspects of the methods presented in this article, the patient has ANCA-negative EGPA.

[0020] In some aspects of the methods presented in this article, the patient has a history of recurrent or refractory disease.

[0021] In some aspects of the methods presented in this article, the patient has a history of recurrent EGPA.

[0022] In some aspects of the methods presented in this article, the patient has a history of at least three EGPA relapses.

[0023] In some aspects of the methods presented in this article, the patient has a history of refractory EGPA.

[0024] In some aspects of the methods provided herein, the patient uses an oral corticosteroid (OCS) prior to administration, optionally wherein the patient has been using an OCS for at least 4 weeks prior to administration.

[0025] In some respects of the methods presented in this article, OCS is a glucocorticoid.

[0026] In some aspects of the methods presented in this paper, OCS is prednisolone or prednisolone.

[0027] In some aspects of the methods presented in this paper, OCS is methylprednisolone.

[0028] In some aspects of the methods provided herein, patients use at least 7.5 mg / day or about 7.5 mg / day to about 50 mg / day of OCS prior to administration.

[0029] In some aspects of the methods provided in this article, administration reduces OCS usage to 7.5 mg / day or less.

[0030] In some aspects of the methods provided in this article, administration reduces OCS usage to 4 mg / day or less.

[0031] In some aspects of the method presented in this paper, the application eliminates the use of OCS.

[0032] In some aspects of the methods provided herein, the daily dose of OCS is reduced from at least 7.5 mg / day prior to administration to 4 mg / day or less prior to administration.

[0033] In some aspects of the methods provided herein, administration reduces the daily dose of OCS by 50% or more.

[0034] In some aspects of the methods provided herein, administration reduces the daily dose of OCS by 100%.

[0035] In some aspects of the methods described herein, the reduction in the daily dose of OCS occurs within 52 weeks of the first administration of the antibody or its antigen-binding fragment to the patient.

[0036] In some aspects of the methods presented herein, reducing the daily dose of OCS does not decrease the patient's lung function. In other aspects, the patient's lung function is measured by spirometry.

[0037] In some respects of the methods presented in this paper, reducing the daily dose of OCS does not increase the severity of asthma in patients. In other respects, the severity of asthma in patients is measured using the Asthma Control Questionnaire-6 (ACQ-6).

[0038] In some aspects of the methods presented in this article, the Birmingham Vasculitis Activity Score (BVAS) is reduced in patients.

[0039] In some respects of the methods presented in this article, administration reduced patients’ Birmingham Vasculitis Activity Score (BVAS) to a greater extent than administration of mepolizumab.

[0040] In some aspects of the methods presented in this article, administration reduces the patient's BVAS to 0.

[0041] In some aspects of the methods provided herein, administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less. In some aspects, within 24 weeks of the first administration, administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg / day or less. In other aspects, after the first administration, the reduction of BVAS to 0 and the reduction of the OCS dose to 4 mg / day or less are maintained for at least approximately 52 weeks.

[0042] In some aspects of the method provided herein, the method includes administering at least two doses of an antibody or an antigen-binding fragment thereof to a patient.

[0043] In some aspects of the methods provided herein, after administering at least 3, 6, 9, or 12 doses of the antibody or its antigen-binding fragment to the patient, administration reduces the patient's BVAS to 0 and reduces the OCS dose to 4 mg / day or less.

[0044] In some aspects of the methods presented in this article, application prolongs the time to EGPA recurrence.

[0045] In some aspects of the methods presented in this paper, the degree to which administration prolongs the time to EGPA relapse is greater than the degree to which administration of mepolizumab prolongs the time.

[0046] In some aspects of the methods presented in this article, application reduces the annual recurrence rate.

[0047] In some aspects of the methods presented in this paper, the reduction in annual relapse rate is greater with the administration of mepolizumab than with the administration of mepolizumab.

[0048] In some aspects of the methods presented in this article, application reduces the likelihood of EGPA recurrence.

[0049] In some aspects of the methods presented in this paper, the degree to which administration reduces the likelihood of EGPA relapse is greater than the degree to which administration of mepolizumab reduces the likelihood.

[0050] In some aspects of the methods presented in this article, administration may reduce the likelihood of an increase in the vasculitis injury index (VDI) in patients.

[0051] In some aspects of the methods presented in this article, the Asthma Control Questionnaire-6 (ACQ-6) score is applied to improve patients' asthma control.

[0052] In some respects of the methods presented in this article, administration improved patients’ Asthma Control Questionnaire-6 (ACQ-6) scores to a greater extent than administration of mepolizumab.

[0053] In some aspects of the methods presented in this article, the Sinus Outcome Test-22 (SNOT-22) score is applied to improve patients' sinus outcomes.

[0054] In some respects of the methods presented in this article, administration of the drug improved patients’ sinus outcome test-22 (SNOT-22) scores to a greater extent than administration of mepolizumab.

[0055] In some aspects of the methods presented in this article, the Patient Overall Severity Impression (PGIS) score is applied.

[0056] In some aspects of the methods presented in this article, administration improved the Patient Overall Severity Impression (PGIS) score to a greater extent than administration of mepolizumab.

[0057] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered at a dose of approximately 30 mg.

[0058] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered once every four weeks.

[0059] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered every four weeks for a period of 12 weeks.

[0060] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered every four weeks for 24 weeks.

[0061] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered every four weeks for 36 weeks.

[0062] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered every four weeks for 48 weeks.

[0063] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered once every four weeks for at least four doses.

[0064] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered once every four weeks for at least eight doses.

[0065] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered once every four weeks for at least twelve doses.

[0066] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered once every four weeks for three consecutive weeks, and then once every eight weeks.

[0067] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered parenterally.

[0068] In some aspects of the methods provided herein, the antibody or its antigen-binding fragment is administered subcutaneously.

[0069] In some aspects of the methods provided in this article, application is performed into the upper arm, thigh, or abdomen.

[0070] In some respects, this document provides an antibody or antigen-binding fragment thereof for use in any of the methods provided herein that specifically binds to IL5Rα, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 1.

[0071] In some respects, this article provides the use of an antibody or antigen-binding fragment thereof that specifically binds to IL5Rα in the preparation of a medicament for use in any of the methods provided herein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 1. Attached Figure Description

[0072] Figure 1A The flowchart of the clinical trial is shown, which demonstrated the efficacy of benalizumab (an IL-5 cytokine inhibitor) in treating eosinophilic granulomatous polyangiitis (EGPA) compared to mepolizumab. Figure 1B Patient management throughout the study is illustrated. (See Examples 1 and 2.)

[0073] Figure 2 The algorithm used for reversibility testing is outlined. (See Example 1.)

[0074] Figure 3A Patients who achieved remission at weeks 36 and 48 after treatment with benazepril and mepolizumab are shown. Figure 3B The proportion of patients whose mean daily oral glucocorticoid (OGC) dose decreased relative to baseline during weeks 48 to 52 is shown (full analysis set). Figure 3C The percentage of patients achieving remission at different time points is shown. The vertical lines represent the 95% confidence intervals calculated using the Clopper-Pearson method.

[0075] Figure 4Subgroup analyses showing the proportions of patients achieving remission at both weeks 36 and 48 are presented. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and an OGC dose ≤ 4 mg / day. Remission rates and differences (benazolizumab-mepolizumab) were assessed using marginal normalization in a logistic regression model. Covariates in the model included the treatment group, baseline prednisone dose, baseline BVAS, region, subgroup, and the interaction between the treatment group and subgroup (treatment group). Subgroups). When a subgroup is a geographic region or ethnicity, the covariate region is not included in the model to avoid confusion.

[0076] Figure 5A The mean daily dose of OGC (prednisone / prednisolone) during weeks 48 to 52 is shown in patients treated with benazepril zumab versus mepolizumab. The odds ratio (OR) and 95% confidence interval (CI) were estimated using a proportional advantage model with treatment group, baseline OGC dose, baseline BVAS, and region as covariates. Figure 5B The average daily OGC dose is shown over time (week). The OGC dose is calculated as a daily dose of prednisone or prednisolone, regardless of the reason for administration.

[0077] Figure 6 The percentages of patients achieving a ≥50% reduction in OGC dose and a 100% reduction in OGC dose at weeks 48–52 after treatment with benazepril tuzumab versus mepolilimumab are shown. Secondary endpoints were not subject to multiple protection; p-values ​​are nominal. Ratios and differences were estimated using marginal standardization in a logistic regression model with treatment group, baseline OGC dose, baseline BVAS, and region as covariates.

[0078] Figure 7A The percentage of patients achieving cumulative remission is shown, and Figure 7B This figure shows the percentage of patients who achieved remission by week 24 and maintained remission until week 52 after treatment with benazepril tuzumab and mepolilimumab. P-values ​​for secondary endpoints are nominal. Remission was defined as BVAS=0 and OGC dose ≤4 mg / day (at any subsequent visit, BVAS=1, without requiring an increase in OGC dose to >4 mg / day or any other significant clinical intervention / investigation; patients achieving remission were considered to be in sustained remission). OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration. The odds ratio (OR) and 95% CI were estimated using a proportional advantage model. Covariates included treatment group, baseline OGC dose, baseline BVAS, and region.

[0079] Figure 8The percentage of patients achieving clinical benefit or complete response after treatment with benazepril umab versus mepolilimumab is shown. P-values ​​for secondary endpoints are nominal. Response was defined as BVAS = 0 and OGC dose ≤ 4 mg / day. Marginal standardization in a logistic regression model was used to estimate response rates and differences. Covariates included treatment group, baseline OGC dose, baseline BVAS, and region. OGC dose was calculated as a daily dose of prednisone or prednisolone, regardless of the reason for administration.

[0080] Figure 9 This is a Kaplan-Meier curve of time to first relapse. It shows the percentage of patients who relapsed and the time to first relapse in the benalizumab vs. mepolizumab treatment groups. Relapse was defined as a worsening or persistence of active disease characterized by: active vasculitis (BVAS > 0), or active symptoms and / or signs of asthma with a corresponding worsening of the Asthma Control Questionnaire (6-item version, ACQ-6) score, or active nasal and / or sinus disease with a corresponding worsening of at least one of the sinus symptom problems; guaranteed by: an increase in OGC, or an increased dose or addition of immunosuppressive therapy, or hospitalization associated with a worsening of EGPA. The hazard ratio (HR) (benalizumab vs. mepolizumab) and associated 95% CI were estimated using a Cox regression model and the Efron method to control for the tie point. Covariates in the model included the treatment group, baseline dose of OGC (prednisone / prednisolone), baseline BVAS, and region. P-values ​​were calculated using an unstratified log-rank test; p-values ​​for secondary endpoints were nominal.

[0081] Figure 10 The blood eosinophil count over time is shown in patients treated with benazepril and mepolizumab.

[0082] Figure 11 The Birmingham Vasculitis Activity Score (BVAS) and its change over time relative to baseline are shown in patients treated with benazepril and mepolizumab. Vertical bars indicate 95% confidence intervals.

[0083] Figure 12 The changes in the vasculitis injury index (VDI) relative to baseline are shown in patients treated with benazepril and mepolizumab. Analysis of covariance (ANCOVA) was performed using an unstructured variance-covariance matrix. Covariates included treatment group, baseline OGC dose, baseline BVAS score, region, baseline VDI, visits (weeks 24 and 52), and visits through the treatment group.

[0084] Figure 13This shows the least-squares change in forced expiratory volume in the first second before bronchodilator administration (FEV1) relative to baseline over time (weeks) in patients treated with benazepril and mepolizumab. Vertical bars indicate 95% confidence intervals.

[0085] Figure 14A The least-squares change of Asthma Control Questionnaire (ACQ-6) scores relative to baseline over time (weeks) is shown in patients treated with benazeprizumab and mepolizumab. Figure 14B The least-squares change from baseline in the total Sinus Outcome Test-22 (SNOT-22) score over time (weeks) is shown in patients treated with benazepril zumab and mepolizumab. Vertical bars indicate 95% confidence intervals.

[0086] Figure 15 This chart shows the least-squares mean change over time (weeks) relative to baseline in patients treated with benazepril and mepolizumab from the 36 Brief Health Survey version 2 (36v2) medical outcome studies. Vertical bars indicate 95% confidence intervals.

[0087] Figure 16 The Patient Overall Severity Impression (PGI-S) categories at baseline and week 52 are shown in patients treated with benazepril zumab and mepolizumab.

[0088] Figure 17 The patient overall change impression (PGI-C) categories at baseline and week 52 are shown in patients treated with benazeprizumab and mepolizumab.

[0089] Figure 18A The time (weeks) for OGC use to first decrease by ≥50% was shown in patients treated with benazepril and mepolilizumab. Figure 18B The time (weeks) for OGC use to first decrease by 100% was shown in patients treated with benazepril and mepolilizumab.

[0090] Figure 19 A heatmap showing OGC dose (mean daily dose of prednisolone / prednisolone, mg / day) by time and relapse in patients treated with benalizumab versus mepolizumab is presented.

[0091] Figure 20A The total cumulative duration (weeks) of OGC=0 mg / day in patients treated with benazeprizumab and mepolizumab is shown. Figure 20BThe percentage reduction in mean daily dose of OGC relative to baseline is shown during weeks 48 to 52. A proportional advantage model was used to estimate the OR and 95% CI for the higher percentage reduction, including treatment group, baseline prednisone dose, baseline BVAS, and region as covariates.

[0092] Figure 21A The correlation between pre-bronchodilator (BD) FEV1 and cumulative duration of OGC=0 mg / day was shown in patients treated with benazepril and mepolizumab. Figure 21B The correlation between ACQ-6 and the cumulative duration of OGC=0 mg / day was shown in patients treated with benazepril and mepolizumab. Detailed Implementation

[0093] definition

[0094] Unless otherwise defined, 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 pertains. In case of any discrepancy, this application (including the definitions) shall prevail. Unless the context otherwise requires, singular terms shall include plural forms and plural terms shall include singular forms. All publications, patents and other references mentioned herein are incorporated herein by reference for all purposes as if each individual publication or patent application were specifically and individually identified as incorporated by reference.

[0095] While similar or equivalent methods and materials may be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of this disclosure will become apparent from the detailed description and claims.

[0096] It should be noted that the terms “an” or “a type” refer to one or more of the same entity; for example, “anti-IL-5Rα antibody” should be understood to mean one or more anti-IL-5Rα antibodies. Therefore, the terms “an” (or “a type”), “one or more” and “at least one” are used interchangeably herein.

[0097] The term “about” is used herein to mean approximately, roughly, about, or in a range of… When the term “about” is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated value. Generally, the term “about” is used herein to modify values ​​that are above or below the stated value by varying by 10%. It should be understood that wherever the language “about” is used to describe a numerical value or range in this document, other similar aspects involving specific numerical values ​​or ranges (without “about”) are also provided.

[0098] Where values ​​are explicitly listed, it should be understood that values ​​of approximately the same quantity or amount as those listed are also within the scope of this disclosure. Where combinations are disclosed, each sub-combination of the elements of that combination is also specifically disclosed and within the scope of this disclosure. Conversely, where different elements or groups of elements are disclosed individually, their combinations are also disclosed. Where any element of this disclosure is disclosed as having multiple alternatives, examples of this disclosure in which each alternative is excluded individually or in arbitrary combination with other alternatives are also disclosed; more than one element of this disclosure may have such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0099] The term “and / or” as used herein should be understood to specifically disclose each of the two specified features or components, regardless of the presence of the other. Thus, the term “and / or” as used herein in phrases such as “A and / or B” is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: 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).

[0100] As used herein, the term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target (such as IL-5Rα) through at least one antigen recognition site within the variable region of an immunoglobulin molecule. As used herein, the term "antibody" encompasses complete polyclonal antibodies, complete monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, antibody-containing fusion proteins, and any other modified immunoglobulin molecules, provided that the antibody exhibits the desired biological activity. Antibodies can be any of the following five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains (referred to as α, δ, ε, γ, and μ, respectively). Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional conformations. Antibodies can be naked or conjugated to other molecules (such as toxins, radioisotopes, etc.).

[0101] The terms “antibody fragment” and “antigen-binding fragment” are used interchangeably and refer to a portion of a complete antibody. “Antigen-binding fragment,” “antigen-binding domain,” or “antigen-binding region” refers to a portion of a complete antibody that binds to a target, such as IL-5Rα. An antigen-binding fragment may contain the antigen-determining region (e.g., complementarity-determining region (CDR)) of the complete antibody. 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. Antigen-binding fragments of antibodies may be derived from any animal species, such as rodents (e.g., mice, rats, or hamsters) and humans, or may be artificially generated.

[0102] "Monoclonal" antibodies or their antigen-binding fragments refer to a homogeneous group of antibodies or antigen-binding fragments that participate in the highly specific recognition and binding of a single antigenic determinant or epitope. This contrasts with polyclonal antibodies, which typically consist of different antibodies targeting different antigenic determinants. The term "monoclonal" antibody or its antigen-binding fragment encompasses both complete monoclonal antibodies and full-length monoclonal antibodies, as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single-chain (scFv) mutants, fusion proteins including antibody portions, and any other modified immunoglobulin molecules including antigen recognition sites. Furthermore, "monoclonal" antibodies or their antigen-binding fragments refer to such antibodies and their antigen-binding fragments prepared in many ways, including but not limited to hybridoma, phage selection, recombinant expression, and transgenic animals.

[0103] As used herein, the term "variable region" refers to a portion of an antibody, typically a portion of the light or heavy chain, usually approximately 110 to 120 or 110 to 125 amino acids from the amino terminus of the mature heavy chain, and approximately 90 to 115 amino acids from the mature light chain. These amino acids vary widely in sequence between antibodies and are responsible for the binding and specificity of a particular antibody to its specific antigen. Sequence variability is concentrated in those regions called complementarity-determining regions (CDRs), while more highly conserved regions within the variable domain are called frame regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of both the light and heavy chains are primarily responsible for antibody-antigen interactions and specificity. In some respects, the variable region is a human variable region. In some respects, the variable region comprises a rodent or mouse CDR and a human frame region (FR). In some respects, the variable region is a primate (e.g., non-human primate) variable region. In some respects, the variable region comprises a rodent or mouse CDR and a primate (e.g., non-human primate) frame region (FR).

[0104] As used herein, the term "complementarity-determining region" or "CDR" refers to each region of an antibody's variable domain that is sequence-hypervariant and / or forms a structurally defined loop (hypervariant loop) and / or contains antigen-contacting residues. An antibody may contain six CDRs, for example, three in VH and three in VL.

[0105] The terms “VL” and “VL domain” are used interchangeably and refer to the variable region of the light chain of an antibody.

[0106] The terms "VH" and "VH domain" are used interchangeably and refer to the variable region of the heavy chain of an antibody.

[0107] The term "Kabat numbering" and similar terms are recognized in the art and refer to a system for numbering amino acid residues in the variable regions of the heavy and light chains of antibodies or their antigen-binding fragments. In some respects, CDRs can be determined according to the Kabat numbering system (see, for example, Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDR within the antibody heavy chain molecule is typically located at amino acid positions 31 to 35, which may optionally include one or two additional amino acids following 35 (referred to as 35A and 35B in the Kabat numbering scheme) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within antibody light chain molecules are typically located at amino acid positions 24 to 34 (CDR1), 50 to 56 (CDR2), and 89 to 97 (CDR3).

[0108] Chothia refers to the location of the structural loop (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When using the Kabat numbering convention, the end of the Chothia CDR-H1 loop varies between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion 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 region represents a compromise between the Kabat CDR and the Chothia structural loop and is used by Oxford Molecular Diagnostics' AbM antibody modeling software.

[0109]

[0110] As used herein, the terms “constant region” or “constant domain” are interchangeable and have their common meaning in the art. A constant region is an antibody portion, such as the carboxyl-terminal portion of the light chain and / or heavy chain, that does not directly participate in antibody-antigen binding but can exhibit various effector functions, such as interaction with Fc receptors. The constant regions of immunoglobulin molecules typically have a more conserved amino acid sequence than the variable domains of immunoglobulins. In some respects, antibody or antigen-binding fragments contain a constant region or a portion thereof sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).

[0111] As used herein, the term "heavy chain," when used to refer to antibodies, can refer to any different type of amino acid sequence based on a constant structural domain, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (µ), which produce IgA, IgD, IgE, IgG, and IgM antibodies, including subclasses of IgG, such as IgG1, IgG2, IgG3, and IgG4. The amino acid sequence of a heavy chain is well known in the art. In some respects, the heavy chain is the human heavy chain.

[0112] As used herein, the term "light chain" when referring to antibodies can refer to any different type, such as kappa (κ) or lambda (λ) based on the amino acid sequence of a constant structural domain. The amino acid sequence of a light chain is well known in the art. In some respects, the light chain is the human light chain.

[0113] The term “humanized” antibody or its antigen-binding fragment refers to a form of non-human (e.g., mouse) antibody or antigen-binding fragment that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof containing a minimal non-human (e.g., mouse) sequence. Typically, humanized antibodies or their antigen-binding fragments are human immunoglobulins in which residues from the complementarity-determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) with the desired specificity, affinity, and capability (“CDR transplantation”) (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, Fv framework region (FR) residues of human immunoglobulins are replaced by corresponding residues from antibodies or fragments of non-human species with the desired specificity, affinity, and capability. Humanized antibodies or their antigen-binding fragments can be further modified by substituting additional residues within the Fv framework region and / or substituted non-human residues to improve and optimize the specificity, affinity, and / or ability of the antibody or its antigen-binding fragment. Generally, humanized antibodies or their antigen-binding fragments will contain substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions corresponding to non-human immunoglobulins, and all or substantially all of the FR regions being those common sequences of human immunoglobulins. Humanized antibodies or their antigen-binding fragments may also contain at least a portion of the immunoglobulin constant region or domain (Fc), typically at least a portion of the constant region or domain of human immunoglobulins. Examples of methods for generating humanized antibodies are described in U.S. Patent 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 respects, “humanized antibodies” are surface-remodeling antibodies.

[0114] As used herein, the terms “immune-specific binding,” “immune-specific recognition,” “specific binding,” and “specific recognition” are similar terms in the context of an antibody or its antigen-binding fragment. These terms indicate that an antibody or its antigen-binding fragment binds to an epitope via its antigen-binding domain, and that this binding requires some complementarity between the antigen-binding domain and the epitope.

[0115] "Isolated" peptides, antibodies, polynucleotides, carriers, cells, or compositions are peptides, antibodies, polynucleotides, carriers, cells, or compositions in a form not found in nature. Isolated peptides, antibodies, polynucleotides, carriers, cells, or compositions include those that have been purified to the point that they no longer exist in a form found in nature. In some respects, isolated antibodies, polynucleotides, carriers, cells, or compositions are substantially pure. As used herein, "substantially pure" means material that 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.

[0116] As used herein, the term "treatment" refers to the administration of a composition to a subject for therapeutic purposes.

[0117] As used herein, the terms “patient” and “subject” are used interchangeably and refer to members of the animal kingdom, including but not limited to humans. In some respects, a patient is a human.

[0118] The term "pharmaceutical formulation" refers to a formulation in which the bioactivity of the active ingredient is effective and which does not contain any additional components that would have unacceptable toxicity to the subject to whom the formulation will be administered. The formulation may be sterile.

[0119] As used herein, the term "application," etc., refers to a method (e.g., subcutaneous administration) that can be used to deliver a drug (e.g., an antibody or its antigen-binding fragment). Application techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa.

[0120] The term "therapeutic effective amount" refers to the amount of a drug (e.g., one or more antibodies or their antigen-binding fragments) that is effective in treating a subject's disease or condition.

[0121] The term "relapsed" EGPA refers to a relapse or worsening of EGPA. In some implementations, relapsed EGPA refers to a relapse or worsening of EGPA after a period of remission.

[0122] The term "refractory" EGPA refers to EGPA in subjects who have received treatment for EGPA but have not yet achieved remission.

[0123] It should be understood that wherever the language “contains” is used to describe aspects in this document, other similar aspects described by “consisting of” and / or “substantially consisting of” are also provided.

[0124] It should be understood that the headings are provided for ease of reading only and are not intended to be restrictive. Aspects disclosed under one or more headings may apply to aspects disclosed under one or more other headings, or in combination with aspects disclosed under one or more other headings.

[0125] Anti-interleukin-5 receptor-α (IL-5Rα) antibody and antigen-binding fragment

[0126] The provided method involves administering an effective amount of an anti-interleukin-5 receptor-α (IL-5Rα) antibody or its antigen-binding fragment, such as benazepril zumab or its antigen-binding fragment. The amino acid sequences of human and mouse IL-5Rα are provided below as SEQ ID NO: 5 and 6, respectively.

[0127] Table 1: IL-5Rα sequence

[0128]

[0129] In some respects, the IL-5Rα antibody or its antigen-binding fragment is a humanized antibody. In some respects, the IL-5Rα antibody or its antigen-binding fragment is one of the following classes: IgA, IgD, IgE, IgG, or IgM. In some respects, the IL-5Rα antibody or its antigen-binding fragment is IgG. In some respects, the IL-5Rα antibody or its antigen-binding fragment is one of the following subclasses: IgG1, IgG2, IgG3, and IgG4. In some respects, the IL-5Rα antibody or its antigen-binding fragment is IgG1. In some respects, the IL-5Rα antibody or its antigen-binding fragment has a kappa (κ) or lambda (λ) type light chain. In some respects, the IL-5Rα antibody or its antigen-binding fragment has a κ-type (κ class) light chain. In some respects, the IL-5Rα antibody or its antigen-binding fragment is benazepril zumab or its antigen-binding fragment.

[0130] In some respects, IL-5Rα antibodies or their antigen-binding fragments can be naturally occurring or recombinantly generated. In some respects, IL-5Rα antibodies or their antigen-binding fragments are non-fucosylated. In some respects, IL-5Rα antibodies or their antigen-binding fragments are generated in Chinese hamster ovary cells. In some respects, IL-5Rα antibodies or their antigen-binding fragments are generated using recombinant DNA technology. In some respects, IL-5Rα antibodies or their antigen-binding fragments are generated in Chinese hamster ovary cells using recombinant DNA technology.

[0131] In some respects, the IL-5Rα antibody or its antigen-binding fragment is benalizumab (MEDI-563). Benalizumab is a humanized monoclonal antibody (mAb) that binds to the α chain of IL-5R expressed on eosinophils and basophils. It induces apoptosis in these cells via antibody-dependent cytotoxicity.

[0132] Information regarding benazepril umab (or fragments thereof) used in the methods provided herein can be found in US 6,018,032, the disclosure of which is incorporated herein by reference in its entirety. Benalizumab and its antigen-binding fragments used 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 another aspect, benazepril umab or its antigen-binding fragments used in the methods provided herein comprise any of the amino acid sequences of SEQ ID NO: 1 to 4. In a particular aspect, benazepril umab or its antigen-binding fragments used in the methods provided herein comprise a light chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3. In a particular aspect, benazepril umab or its antigen-binding fragments used in the methods provided herein comprise a light chain containing the amino acid sequence of SEQ ID NO: 2 and a heavy chain containing the amino acid sequence of SEQ ID NO: 4. In a particular aspect, the benalizumab or its antigen-binding fragment used 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 to 9, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10 to 12. SEQ ID NOs: 1 to 12 are shown in Table 2 below. Those skilled in the art will be able to readily identify the Chothia-defined CDR, the AbM-defined CDR, or other CDRs. In a particular aspect, the benalizumab or its antigen-binding fragment used in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the KM1259 antibody, as disclosed in its entirety in US 6,018,032, which is incorporated herein by reference.

[0133] Table 2: Overview of Antibody Sequences

[0134]

[0135] application

[0136] In some cases, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) may be administered only once. In other cases, additional follow-up doses are administered to the patient. These follow-up doses may be administered at various time intervals.

[0137] In some cases, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) can be administered to the upper arm, thigh, and / or abdomen.

[0138] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) may be administered at intervals of approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 11 weeks, approximately 12 weeks, or longer. In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) may be administered every 4 weeks.

[0139] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) may be administered every 1 to 5 weeks, every 2 to 5 weeks, every 3 to 5 weeks, or every 4 to 5 weeks. In some respects, the interval may be every 1 to 9 weeks, every 2 to 9 weeks, every 3 to 9 weeks, every 4 to 9 weeks, every 5 to 9 weeks, every 6 to 9 weeks, every 7 to 9 weeks, or every 8 to 9 weeks. In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) may be administered every 4 weeks.

[0140] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered at a frequency sufficient to ensure blood eosinophil depletion in EGPA (including in patients with a high eosinophil load).

[0141] In some cases, 30 mg of IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril) is administered every 4 weeks.

[0142] In some respects, the patient is given at least two doses of an IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril). In some respects, the patient is given at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, or at least thirty doses.

[0143] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered over a period of approximately four weeks, approximately eight weeks, approximately 12 weeks, approximately 24 weeks, approximately 28 weeks, approximately 52 weeks, approximately 76 weeks, or approximately 104 weeks.

[0144] In some respects, IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is administered over a period of at least four weeks, at least eight weeks, at least 12 weeks, at least 24 weeks, at least 28 weeks, at least 52 weeks, at least 76 weeks, or at least 104 weeks.

[0145] In some respects, a subject is administered one or more doses of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab), wherein the dose is about 2 mg to about 100 mg, such as about 20 mg to about 100 mg, or about 30 mg to about 100 mg. In some respects, a patient is administered one or more doses of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab), wherein the dose is about 20 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 respects, the dose is about 20 mg. In some respects, the dose is about 30 mg.

[0146] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered in amounts sufficient to ensure blood eosinophil depletion in EGPA, including in patients with a high eosinophil load.

[0147] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered in amounts and at frequencies sufficient to ensure blood eosinophil depletion in EGPA, including in patients with a high eosinophil load.

[0148] In some cases, an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is administered at a dose of approximately 30 mg every four weeks (Q4W).

[0149] In some respects, the administration of IL-5Rα antibodies or antigen-binding fragments thereof (e.g., benalizumab) according to the methods provided herein is by parenteral administration. For example, IL-5Rα antibodies or antigen-binding fragments thereof (e.g., benalizumab) may be administered by intravenous infusion or subcutaneous injection. In some respects, IL-5Rα antibodies or antigen-binding fragments thereof (e.g., benalizumab) are administered by subcutaneous injection.

[0150] In some respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered via a syringe. In other respects, IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab) are administered via an aided pre-filled syringe (APFS). In some respects, the syringe is made of glass.

[0151] In various respects, the syringe (e.g., a pre-filled 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 the formulation provided herein. In some respects, the syringe (e.g., a pre-filled syringe) contains about 1 ml of the formulation provided herein.

[0152] In some respects, an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is administered in combination with or in combination with additional eosinophilic granulomatous polyangiitis (EGPA) therapy, according to the methods provided herein. In some respects, an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is administered in combination with or in combination with additional EGPA therapy, according to the methods provided herein, which is a standard of care for the treatment of EGPA. Such standard of care therapies include, but are not limited to, immunosuppressive therapies and biologics. In some respects, the immunosuppressive therapy is azathioprine, methotrexate, or mycophenolate mofetil. In some respects, the immunosuppressive therapy is a corticosteroid. In some respects, the corticosteroid is a glucocorticoid. In some respects, the corticosteroid is delivered orally. In some respects, the corticosteroid is prednisolone / prednisolone. In some respects, the corticosteroid is methylprednisolone. In some respects, the corticosteroid dose is ≤4 mg / day. In some respects, the corticosteroid dose is ≤7.5 mg / day. In some cases, the dosage of corticosteroids is ≥7.5 mg / day. In other cases, the dosage of corticosteroids is ≥7.5 mg / day but not >50 mg / day.

[0153] In some respects, the subject had been on corticosteroids (e.g., prednisone / prednisolone) for at least 4 weeks prior to administration of the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0154] preparation

[0155] In some aspects, the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) used according to the methods provided herein is present in the formulation (e.g., a pharmaceutical formulation). In some aspects, the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is present in the formulation at a concentration of about 1 mg / mL to about 200 mg / mL. In some aspects, the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) is present in the formulation at a concentration of about 30 mg / mL.

[0156] In some respects, formulations containing an IL-5Rα antibody or an antigen-binding fragment thereof (e.g., benalizumab) for use in the methods and uses of this disclosure contain a variety of other components.

[0157] In some aspects, the formulation contains histidine. In some aspects, the formulation contains about 1 mM to about 100 mM of histidine, such as about 5 mM to about 80 mM, about 10 mM to about 60 mM, about 15 mM to about 50 mM, about 15 mM to about 30 mM, or about 20 mM of histidine. In some aspects, the formulation contains about 20 mM of histidine / histidine hydrochloride monohydrate.

[0158] In some aspects, the formulation contains a surfactant, such as polysorbate, such as polysorbate 20 (PS20). In some aspects, the formulation contains 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% of 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) of polysorbate 20. In some aspects, the formulation comprises about 0.006% (w / v) of polysorbate 20.

[0159] In some aspects, the formulation comprises an uncharged excipient, such as trehalose. In some aspects, the uncharged excipient (e.g., trehalose dihydrate) is present in the formulation in an amount from about 1 mM to about 500 mM. In some aspects, the formulation comprises about 1 mM to about 250 mM of an uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 100 mM to about 400 mM of an uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 200 mM to about 300 mM of an 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 an uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 0.25 M of trehalose dihydrate.

[0160] In some respects, the formulation is sterile and preservative-free.

[0161] In some respects, the formulation contains 30 mg / mL of anti-IL5R antibody, 20 mM histidine / histidine HCl and 250 mM trehalose dihydrate (pH 6.0), and is either surfactant-free or contains 0.0004% polysorbate 80, 0.0012% PS80, 0.02% poloxamer 188 or 0.08% poloxamer 188.

[0162] In some respects, the formulation contains an aqueous solution of 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 α,α-trehalose dihydrate.

[0163] Eosinophilic granulomatous polyangiitis (EGPA)

[0164] This article presents methods for treating EGPA. In all respects, the methods presented in this article can significantly reduce the severity of EGPA disease.

[0165] EGPA is only partially understood, but in approximately 40% of patients, it is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCA) on enzyme-linked immunosorbent assays (ELISA), typically targeting myeloperoxidase (MPO) or proteinase-3 (PR3). Two distinct phenotypes of EGPA are described: ANCA-positive and ANCA-negative. The data show differences in clinical disease presentation based on ANCA status and suggest that ANCA-positive patients should be treated more aggressively (Soko). owska B, SzczeklikW, W udarczyk A, Kuczia P, Jakie A 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 Polishcentre. Clin Exp Rheumatol. 2014; 32 (Supplement 82): S41-7). In some respects, subjects treated with IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein were ANCA-positive. In some respects, subjects treated with IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein were ANCA-negative. In some respects, subjects treated with IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein were either ANCA-positive or ANCA-negative.

[0166] In all respects, EGPA is defined based on the following medical history or presence: asthma plus documented eosinophilia (> 1.0 × 10⁻⁶). 9 / liters and / or > 10% white blood cells).

[0167] Additional features of EGPA may include:

[0168] (a) Histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation on biopsy.

[0169] (b) Mononeuropathy or polyneuropathy (motor defects or abnormal nerve conduction)

[0170] (c) Non-fixed pulmonary infiltration

[0171] (d) Sinus abnormalities

[0172] (e) Cardiomyopathy (diagnosed by echocardiography or magnetic resonance imaging)

[0173] (f) Glomerulonephritis (hematuria, red blood cell casts, proteinuria)

[0174] (g) Alveolar hemorrhage (via bronchoalveolar lavage)

[0175] (h) Palpable purpura

[0176] (i) Positive ANCA immunofluorescence assay and / or positive MPO and / or PR3 antibody assay.

[0177] In all respects, EGPA is defined based on the following medical history or presence: asthma plus documented eosinophilia (>1.0×10⁻⁶). 9 ( / liter and / or >10% white blood cells) plus at least two additional features from the additional features listed in (a) to (i) above.

[0178] In all respects, subjects with EGPA did not have severe eosinophilic asthma.

[0179] In several respects, the subject had a history of recurrent or refractory EGPA. In some respects, the subject had a history of recurrent EGPA when the subject had increased the dose of oral corticosteroids (OCS), started or increased the dose of immunosuppressive therapy, and / or been hospitalized. In some respects, the subject had a history of at least one, two, or three EGPA relapses.

[0180] In various respects, a history of refractory EGPA is defined as a subject's failure to achieve remission after at least 1, 2, or 3 months of induction therapy with administered corticosteroids. In some respects, a history of refractory EGPA is defined as a subject's failure to achieve remission after at least 3 months of induction therapy with administered corticosteroids. In some respects, a history of recurrent EGPA is defined as a subject's relapse of EGPA symptoms during a gradual decrease in OCS. In some respects, a history of recurrent EGPA is defined as a subject's relapse of EGPA symptoms during a gradual decrease in OCS at any dose level of prednisolone or its equivalent at ≥7.5 mg / day.

[0181] EGPA treatment

[0182] In some respects, methods of treating EGPA in subjects include administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to IL5Rα (e.g., benazepril). EGPA can be relapsed or refractory EGPA. Subjects may be those receiving corticosteroid therapy prior to administration of the antibody or its antigen-binding fragment.

[0183] In some respects, this article provides for the treatment of EGPA with immune-specific binding to IL5Rα antibodies or antigen-binding fragments thereof (e.g., benazepril). EGPA can be relapsed or refractory EGPA. Subjects may be those receiving corticosteroid therapy prior to administration of the antibody or its antigen-binding fragment.

[0184] In some respects, this article provides for the preparation of a medicament for the treatment of EGPA that specifically binds to IL5Rα or its antigen-binding fragment (e.g., benazepril). EGPA can be relapsed or refractory EGPA. Subjects can be those receiving corticosteroid therapy prior to administration of the antibody or its antigen-binding fragment.

[0185] In some respects, this article provides the use of antibodies or antigen-binding fragments thereof that specifically bind to IL5Rα (e.g., benalizumab) for the treatment of EGPA.

[0186] In some respects, this article provides the use of antibodies or antigen-binding fragments thereof that specifically bind to IL5Rα (e.g., benalizumab) for the treatment of relapsed or refractory EGPA.

[0187] In some respects, this article provides the use of antibodies or antigen-binding fragments thereof that specifically bind to IL5Rα (e.g., benalizumab) for the treatment of relapsed or refractory EGPA in subjects receiving corticosteroid therapy.

[0188] Efficacy of EGPA therapy

[0189] This article presents methods for treating EGPA. In all respects, the methods presented in this article can significantly reduce EGPA disease activity.

[0190] In some respects, one or more clinical outcome assessments may be used to measure EGPA disease activity. In some respects, clinical outcome assessments include, but are not limited to, the Birmingham Vasculitis Activity Score (BVAS), EGPA relapse / remission, the Vasculitis Injury Index (VDI), patient-reported outcomes (PRO) assessment, and / or vital capacity measurement.

[0191] In some respects, clinical outcome assessment can be used at approximately 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 weeks after initiation of treatment with an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein. EGPA disease activity was measured at approximately 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 weeks.

[0192] In all respects, the methods presented in this paper reduced the Birmingham Vasculitis Activity Score (BVAS). In some respects, the BVAS decreased by 1, 2, 3, 4 or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31 points. 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63. In some cases, BVAS drops to 0.

[0193] In all respects, EGPA remission includes, but is not limited to, BVAS=0 and an OCS dose of prednisolone / prednisolone ≤4 mg / day. In some respects, EGPA remission includes, but is not limited to, BVAS=0 plus an OCS dose of prednisolone / prednisolone ≤7.5 mg / day. In all respects, the methods provided herein reduce the time to achieve remission. In all respects, the methods provided herein increase the duration of EGPA remission. In all respects, the methods provided herein increase the cumulative duration of EGPA remission. In all respects, the methods provided herein increase the frequency of EGPA remission.

[0194] In some respects, approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, and 31 weeks after the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein. At approximately 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 weeks, the methods described herein were used to reduce the patient's BVAS to 0 and the OCS dose to 4 mg / day or less.

[0195] In some respects, approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, and 27 weeks after initiating treatment with IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, Remission is expected around 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 weeks later.

[0196] In some respects, after the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, a remission is achieved for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, at least 96 weeks, at least 108 weeks, at least 120 weeks, or longer.

[0197] In some respects, after the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, the remission is maintained for at least 12 weeks, lasting for at least 24 weeks, lasting for at least 36 weeks, lasting for at least 48 weeks, lasting for at least 52 weeks, lasting for at least 60 weeks, lasting for at least 72 weeks, lasting for at least 84 weeks, lasting for at least 96 weeks, lasting for at least 108 weeks, lasting for at least 120 weeks, or longer.

[0198] In some respects, after the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, the BVAS decreases to 0 and the OCS dose is reduced to 4 mg / day or less and maintained for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, at least 96 weeks, at least 108 weeks, at least 120 weeks or longer.

[0199] In some respects, within 24 weeks following the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, the patient's BVAS is reduced to 0 and the OCS dose is reduced to 4 mg / day or less using the methods provided herein. In other respects, following the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, the BVAS is reduced to 0 and the OCS dose is reduced to 4 mg / day or less and maintained for at least about 52 weeks.

[0200] In all respects, the methods presented in this paper reduced the EGPA recurrence rate. In all respects, the methods presented in this paper reduced the annual EGPA recurrence rate. In all respects, the methods presented in this paper prolonged the time to EGPA recurrence.

[0201] In some respects, the methods presented in this paper reduce the annual recurrence rate of EGPA to less than 40%. In other respects, the methods presented in this paper reduce the annual recurrence rate of EGPA to less than 30%.

[0202] In some respects, subjects who received an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) did not experience a relapse for at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, at least 96 weeks, at least 108 weeks, or at least 120 weeks after their first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0203] In some respects, subjects who received IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) had BVAS=0 and a prednisolone / prednisolone dose ≤4 mg / day after administration of IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0204] In some respects, subjects receiving an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) experienced a ≥50% reduction in their daily prednisolone / prednisolone dose within 52 weeks following the first administration of the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein. In some respects, subjects receiving an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) experienced a ≥50% reduction in their daily prednisolone / prednisolone dose within 4 weeks following the first administration of the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0205] In some respects, subjects receiving an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) were EGPA-free for at least 48 weeks following their first administration of the IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods described herein. In some respects, subjects receiving an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab):

[0206] (1) Individuals with BVAS=0 and a prednisolone / prednisolone dose ≤4 mg / day after administration of IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril) according to the methods provided herein.

[0207] (2) Within 52 weeks following the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, there is a ≥50% reduction in the daily prednisolone / prednisolone dose, and

[0208] (3) No EGPA relapse for at least 52 weeks following the first administration of IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril) according to the methods provided herein.

[0209] In some respects, subjects receiving IL-5Rα antibodies or their antigen-binding fragments (e.g., benalizumab):

[0210] (1) Individuals with BVAS=0 and a prednisolone / prednisolone dose ≤4 mg / day after administration of IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril) according to the methods provided herein.

[0211] (2) Within 4 weeks following the first administration of an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein, there is a ≥50% reduction in the daily prednisolone / prednisolone dose, and

[0212] (3) No EGPA relapse after the first administration of IL-5Rα antibody or its antigen-binding fragment (e.g., benazepril) according to the methods provided herein, for at least 48 weeks.

[0213] In some respects, PRO assessments include, but are not limited to, corticosteroid use, Asthma Control Questionnaire (6-item version, ACQ-6), Sinus Symptom Questionnaire (SSQ), Sinus Outcome Test-22 (SNOT-22), Short Form-36 version 2 (Acute Recall, SF-36v), Patient Global Severity Impression (PGIS), Patient Global Change Impression (PGIC), and Work Productivity and Activity Impairment Questionnaire (WPAI).

[0214] In all respects, the methods presented in this paper reduce the likelihood of an increase in the vasculitis injury index (VDI).

[0215] In various respects, the methods provided herein have reduced the daily dose of oral corticosteroids (OCS). In some respects, the daily OCS dose has been reduced by approximately 100%, approximately 95%, approximately 90%, approximately 85%, approximately 80%, approximately 75%, approximately 70%, approximately 65%, approximately 60%, approximately 55%, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, or approximately 5%. In some respects, the daily OCS dose has been reduced to ≤7.5 mg / day. In some respects, the daily OCS dose has been reduced to ≤4.0 mg / day. In some respects, the daily OCS dose has been reduced by 50% or more. In some respects, the use of OCS has been eliminated. In all respects, the daily OCS dose reduction has occurred for 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 an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0216] In various respects, the methods provided herein have reduced the daily dose of oral glucocorticoids (OGCs). In some respects, the daily OGC dose has been reduced by approximately 100%, approximately 95%, approximately 90%, approximately 85%, approximately 80%, approximately 75%, approximately 70%, approximately 65%, approximately 60%, approximately 55%, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, or approximately 5%. In some respects, the daily OGC dose has been reduced to ≤7.5 mg / day. In some respects, the daily OGC dose has been reduced to ≤4.0 mg / day. In some respects, the daily OGC dose has been reduced by 50% or more. In some respects, the use of OGCs has been eliminated. In all respects, the daily OGC dose has been reduced for 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 an IL-5Rα antibody or its antigen-binding fragment (e.g., benalizumab) according to the methods provided herein.

[0217] In various respects, the methods presented in this paper reduced ACQ-6 scores. In some respects, scores were 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 some respects, scores were reduced by 0.5. In some respects, scores were reduced to <1.5. In various respects, the methods presented in this paper reduced SSQ scores to 3, 2, 1, or 0.

[0218] In all respects, the methods presented herein reduced the SNOT-22 score. In some respects, the SNOT-22 score was reduced by at least 8.90 points. In some respects, the SNOT-22 score was reduced by approximately 100%, approximately 95%, approximately 90%, approximately 85%, approximately 80%, approximately 75%, approximately 70%, approximately 65%, approximately 60%, approximately 55%, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, approximately 10%, or approximately 5%.

[0219] In all aspects, the methods presented in this paper are used to augment SF-36v2. In all aspects, the methods presented in this paper are used to augment the psychometrically based Physical Health Component Pooled Score (PCS) and Mental Health Component Pooled Score (MCS).

[0220] In all respects, the methods presented in this paper reduced the patient overall severity impression (PGIS). In some respects, the PGIS was reduced to 4, 3, 2, 1, or 0.

[0221] In all respects, the methods presented in this article reduced the patient's overall impression of change (PGIC). In some respects, PGIC was reduced to 6, 5, 4, 3, 2, or 1.

[0222] In all respects, the methods presented in this paper reduced the percentage of work productivity and activity impairment (WPAI).

[0223] In various respects, the methods provided in this paper improve one or more of the following vital capacity measurements: forced expiratory volume in one second (FEV1), percentage of reversibility, and forced expiratory volume in one second after bronchodilator administration.

[0224] Example

[0225] Example 1: Efficacy of Benalizumab in Human Patients with EGPA

[0226] A clinical trial, MANDARA, was conducted to demonstrate the efficacy of benalizumab in treating human patients with eosinophilic granulomatous polyangiitis (EGPA) compared to mepolizumab.

[0227] (a) Subjects

[0228] Participants in this study were ≥18 years old and met the following inclusion criteria for patient type and disease characteristics.

[0229] Subjects must have a history of or a confirmed diagnosis of EGPA for at least 6 months prior to the screening visit (Visit 1) based on the following medical history: asthma plus documented eosinophilia (>1.0×10⁻⁶). 9 A record of EGPA with at least two of the following additional characteristics: ( / liter and / or >10% white blood cells) plus EGPA:

[0230] (a) Histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation on biopsy.

[0231] (b) Mononeuropathy or polyneuropathy (motor defects or abnormal nerve conduction)

[0232] (c) Non-fixed pulmonary infiltration

[0233] (d) Sinus abnormalities

[0234] (e) Cardiomyopathy (diagnosed by echocardiography or magnetic resonance imaging)

[0235] (f) Glomerulonephritis (hematuria, red blood cell casts, proteinuria)

[0236] (g) Alveolar hemorrhage (via bronchoalveolar lavage)

[0237] (h) Palpable purpura

[0238] (i) Positive ANCA immunofluorescence assay and / or positive MPO and / or PR3 antibody assay

[0239] Subjects also need to have a history of relapsed or refractory diseases as defined below:

[0240] Recurrent disease: Subjects must have a history of at least one confirmed EGPA relapse within the past 2 years and at least 12 weeks prior to screening (Visit 1) while receiving prednisolone (or equivalent) at a dose of ≥7.5 mg / day (i.e., requiring an increase in the dose of oral corticosteroids (OCS), initiation / increase in the dose of immunosuppressive therapy, or hospitalization.

[0241] For the study site in Japan, patients must have a history of at least one confirmed EGPA relapse within the past 2 years and at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of ≥7.5 mg / day (i.e., requiring an increase in OCS dose, initiation of IV prednisolone or equivalent, initiation / increase in the dose of immunosuppressive therapy, initiation / increase in the dose of IV immunoglobulin, or hospitalization).

[0242] Intractable diseases :

[0243] Defined as: Subjects who, after induction therapy with a standard regimen (administered for at least 3 months), did not achieve remission within 6 months prior to Visit 1 (BVAS [scale 0-63] = 0 and OCS dose ≤ 7.5 mg / day prednisolone or equivalent). Alternatively: Subjects who, within 6 months prior to screening (Visit 1), experienced a relapse of EGPA symptoms at any dose level of ≥ 7.5 mg / day prednisolone or equivalent during a gradual reduction in OCS (not necessarily meeting the regimen definition for relapse).

[0244] It is noteworthy that (a) subjects receiving the cyclophosphamide (CYC) induction regimen, if their total WBC was ≥4 × 10⁻⁶ before randomization, were eligible for inclusion. 9 / L, then at least 2 weeks after the last dose of daily oral CYC or 3 weeks after the last dose of pulsatile intravenous (IV) CYC before baseline (Visit 2); (b) subjects receiving azathioprine, methotrexate or mycophenolate mofetil induction regimens, if administered at a stable dose for at least 4 weeks before baseline (Visit 2); and (c) subjects receiving only induction regimens containing corticosteroids, only if they have failed to achieve remission after 3 months of treatment and have received a corticosteroid dose of ≥15 mg / day prednisolone within 4 weeks before baseline (Visit 2).

[0245] The prescribed dose of oral prednisolone or prednisone must be stable (i.e., without dose adjustment) 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.

[0246] If receiving immunosuppressive therapy (excluding CYC), the dose must be stable for 4 weeks prior to baseline (Visit 2). The dose of immunosuppressive therapy must not exceed the maximum dose used in clinical practice.

[0247] Subjects must have an electrocardiogram (ECG) assessment within the following range at screening (Visit 1): for patients with bundle branch block, a Fredericia-corrected QT interval (QTcF) <450 ms or a QTcF <480 ms. The corrected QT interval (QTc) is based on the average QTc value of three ECGs obtained over a short recording period.

[0248] If any of the following criteria apply, the participant will be excluded from the study:

[0249] (1) Diagnosed as granulomatous polyangiitis (formerly known as Wegener's granulomatosis) or microscopic polyangiitis.

[0250] (2) Organ-risk EGPA: According to the European League Against Rheumatism guidelines (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.), organ failure due to active vasculitis, within 3 months prior to screening (visit 1) to randomization (visit 2), with creatinine >5.8 mg / dL (>513 μmol / L).

[0251] (3) Life-threatening EGPA disease: defined as any of the following conditions occurring within 3 months prior to screening (visit 1) and during randomization (visit 2).

[0252] -Requires intensive care

[0253] - Severe alveolar hemorrhage or hemoptysis requiring blood transfusion or ventilation, or hemoglobin levels <8 g / dL (<80 g / L) or a decrease in hemoglobin >2 g / dL (>20 g / L) within 48 hours due to alveolar hemorrhage.

[0254] - Rapidly progressive glomerulonephritis, characterized by creatinine levels >2.5 mg / dL (>221 μmol / L) or creatinine levels >2 mg / dL (>177 μmol / L) within a 48-hour period.

[0255] - Severe gastrointestinal involvement, such as gangrene or bleeding requiring surgery.

[0256] - Severe central nervous system involvement

[0257] - Severe cardiac involvement, such as life-threatening arrhythmias, heart failure: ejection fraction <20%, NYHA Class III / IV (American Heart Association, Classes of Heart Failure, available at URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart-Failure_UCM_306328_Article.jsp, accessed August 14, 2012), acute myocardial infarction.

[0258] (4) Malignant tumors: Current malignant tumors or history of malignant tumors, except for the following: Subjects who have basal cell carcinoma, local squamous cell carcinoma of the skin or cervical carcinoma in situ are eligible if they are in remission and have completed curative therapy at least 12 months prior to screening (visit 1); and subjects who have other malignant tumors are eligible if they are in remission and have completed curative therapy at least 5 years prior to the date of informed consent.

[0259] (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 (excluding Gilbert's syndrome or asymptomatic gallstones).

[0260] (6) Cardiovascular: Subjects with severe or clinically significant cardiovascular disease that is not controlled with standard treatment, including but not limited to:

[0261] - Known ejection fraction <30%, or

[0262] - Severe heart failure meeting NYHA Class IV (American Heart Association, a category of heart failure, available at URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart-Failure_UCM_306328_Article.jsp, accessed August 14, 2012), or

[0263] - Hospitalization within the 12 months prior to screening (Visit 1) for severe heart failure meeting NYHA Class III (American Heart Association, a category of heart failure, available at URL: http: / / www.heart.org / HEARTORG / Conditions / HeartFailure / AboutHeartFailure / Classesof-Heart-Failure_UCM_306328_Article.jsp, accessed August 14, 2012), or

[0264] - Angina pectoris diagnosed within 3 months prior to screening (Visit 1) to randomization (Visit 2).

[0265] (7) Infectious diseases: Chronic or persistent active infectious diseases that require systemic treatment.

[0266] (8) Parasitic infection: helmintic parasitic infection diagnosed within 6 months prior to screening (visit 1) to randomization (visit 2) that was not treated with standard care or did not respond to standard care.

[0267] (9) Hepatitis Status: Chronic stable hepatitis B and hepatitis C (including positive tests for HBsAg or hepatitis C antibodies), or other stable chronic liver disease, are acceptable if the subject meets the eligibility criteria by other means. Stable chronic liver disease is generally defined as the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis.

[0268] (10) Immunodeficiency: History of known immunodeficiency conditions, including a positive HIV test.

[0269] (11) History of known allergy, intolerance or anaphylactic reaction to any biological therapy or vaccine.

[0270] (12) A known history of allergy or reaction to any component of any research treatment.

[0271] (13) Other concurrent medical conditions: Subjects with known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological, respiratory, or other systemic abnormalities that are unrelated to EGPA and cannot be controlled with standard treatment. Subjects with any clinically significant abnormalities found in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during the screening / introduction period that may put the subject at risk due to their participation in the study, or may affect the study outcome or the patient's ability to complete the entire study duration.

[0272] (14) Prohibited drugs: Subjects receiving any of the following prohibited drugs:

[0273] -Prednisolone / prednisolone dose >50 mg / day for a period of 4 weeks prior to baseline (Visit 2).

[0274] - Intravenous (IV), intramuscular (IM), or subcutaneous (SC) corticosteroids administered during the 4-week period prior to baseline (Visit 2).

[0275] -Omalizumab within 130 days prior to screening (Visit 1)

[0276] - Oral CYC within 2 weeks prior to baseline (Visit 2) and IV CYC within 3 weeks prior to baseline (Visit 2)

[0277] - Rituximab within 6 months prior to screening (Visit 1); additionally, the subject must have shown a return to normal peripheral B-cell count.

[0278] -IV or SC immunoglobulin within 30 days prior to screening (Visit 1)

[0279] - Interferon alpha within 6 months prior to screening (Visit 1)

[0280] - Anti-tumor necrosis factor therapy within 12 weeks prior to screening (Visit 1)

[0281] - Anti-CD52 (alemumab) within 6 months prior to screening (Visit 1)

[0282] - Any prior or current treatment with mepolizumab, relizumab, dupilumab, or benalizumab as a commercially available or investigational biologic.

[0283] - Accept any other commercially available or investigational biological product, whether commercially available or investigational, within 4 months or 5 half-lives (whichever is longer) prior to screening.

[0284] Other exclusions include:

[0285] (15) Exclusion of other laboratory parameters during screening (Visit 1) and during repeat testing prior to Visit 2 (if applicable):

[0286] Creatinine > 2.5 mg / dL (221 μmol / L)

[0287] - White blood cell count (WBC) < 4 × 10 9 / L

[0288] - Platelet count <120,000 / mm 3

[0289] - Hemoglobin <8g / dL (<80g / L)

[0290] (16) Subjects with a history (or suspected history) of alcohol abuse or substance abuse within 2 years prior to screening (Visit 1).

[0291] (17) Alcohol / substance abuse: a history (or suspected history) of alcohol or substance abuse within 2 years prior to screening (visit 1).

[0292] (18) Other investigational non-biological products: Any investigational non-biological product received within 30 days or 5 half-lives (whichever is longer) prior to screening (Visit 1).

[0293] (19) Adherence: Subjects with known evidence of a lack of adherence to prescription medications and / or the ability to follow physician advice.

[0294] (20) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times the upper limit of normal (ULN) confirmed during the screening period were confirmed by repeat testing (if applicable) during the screening period. Transient elevations in AST / ALT levels that recovered by randomization were acceptable in patients without active liver disease and who met other eligibility criteria.

[0295] (21) Subjects with any clinically significant abnormalities in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during the screening / introduction period that would put the patient at risk due to their participation in the study, or could affect the study outcome or the patient's ability to complete the entire study duration. Subjects with any other medical condition that would impair their participation in the study.

[0296] (22) Subjects who received blood products within 30 days prior to screening (Visit 1).

[0297] (23) Subjects who received the live attenuated vaccine 30 days prior to screening (Visit 1).

[0298] (b) Research Design

[0299] This phase III randomized, double-blind, active-controlled, parallel-group, multicenter study compared the efficacy and safety of benazepril 30 mg administered via SC Q4W versus mepolilimumab 300 mg in patients with relapsed or refractory EGPA with corticosteroid therapy, with or without stable immunosuppressive therapy. The dosing regimen (30 mg Q4W) was chosen to ensure eosinophil depletion in the blood, including in patients with high eosinophil load, within the context of EGPA.

[0300] The study consisted of two distinct phases: (i) a 52-week double-blind (DB) treatment period during which patients were randomized to receive either benalizumab or mepolizumab, and (ii) an open-label extension (OLE) period during which all patients received only benalizumab.

[0301] The study treatments in this study refer to benalizumab, mepolizumab, benalizumab placebo, and mepolizumab placebo. The mepolizumab placebo and benalizumab placebo were used solely to ensure blinding of the study treatments. The study treatments are shown in Table 3 below.

[0302] Table 3: Research Treatment

[0303]

[0304] a Mepocillinumab has been approved in Japan.

[0305] b In Japan, mepolizumab / mepolizumab placebo is administered using a 2-3 mL polypropylene syringe and a 21-27 gauge needle.

[0306] Potentially eligible subjects will enter a screening period of up to 4 weeks (minimum 1 week) and must receive a stable dose of prednisolone / prednisolone (≥7.5 mg / day) at baseline (Visit 2) for at least 4 weeks prior to baseline. Subjects will fail screening if dose adjustments are required during the screening period or if they do not maintain a stable dose. Subjects receiving immunosuppressive therapy will need to receive a stable dose for at least 4 weeks prior to baseline (Visit 2) and maintain the same dose until the end of the DB period (if the patient has not entered OLE) or until the first 6 months of the OLE period are completed (if the patient continues to enter OLE). Dose reduction will be permitted for safety reasons. All eligible subjects will be randomized 1:1 at baseline (Visit 2) to receive study treatment Q4W for a 52-week DB period. ANCA positivity or an eosinophil count <150 cells / μL (< 0.15 × 10⁻⁶) is required. 9 The number of patients ( / L) will be limited to approximately 10% and 40% of the total number of randomized patients, respectively.

[0307] Between baseline (Visit 2) and week 4, patients will require a stable oral prednisolone / prednisolone dose of ≥7.5 mg / day (but not >50 mg / day). Upward adjustments to the patient's clinical management are permitted if necessary. From week 4 onward, if the patient's BVAS=0, their oral prednisolone / prednisolone dose will be gradually reduced according to standard of care practice using the recommended gradual reduction protocol, which reduces the OCS dose every 2 weeks to achieve a prednisolone / prednisolone dose of 4 mg / day or less.

[0308] The final dose of the DB treatment period will be administered 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 proceed to the OLE period. The OLE period allows each patient to be treated with open-label benalizumab 30 mg every four weeks via SC for at least one year (therefore, earlier recruited patients remain in the OLE for more than one year).

[0309] The research flowchart is shown in Figure 1.

[0310] (c) Proof of validity

[0311] Clinical outcome assessment

[0312] The following assessments will be completed according to the assessment schedule, as shown in Table 4: Birmingham Vasculitis Activity Score (BVAS), EGPA Relapse / Remission and Vasculitis Injury Index (VDI).

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] Birmingham Vasculitis Activity Score (BVAS). BVAS is a validated, clinician-executed tool used for a comprehensive multi-system 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. QJ Med. 1994; 87:671-8; Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. Baillieres Clin Rheumatol. 1997; 11(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 nine organ-based systems, with each section including typical symptoms / signs of specific organ involvement in systemic vasculitis. The form is designed to record features attributable to current vasculitis after excluding other causes such as infection, hypertension, etc. The scoring table records the presence or absence of each item. Each item is weighted, and the maximum total score is applied to each system. The total score for all nine organ systems provides an indication of disease activity for each subject at the time of scoring and reflects the need for therapy.

[0319] EGPA relapse / remission. EGPA remission at any visit will be defined as a BVAS score of 0, with an OCS dose of prednisolone / prednisolone ≤4 mg / day. Subjects who have achieved remission and have a BVAS of 1 at any subsequent visit (where no increase in corticosteroid dose to above 4 mg / day or 7.5 mg / day (according to the relevant definition of remission)) or any other significant clinical intervention or investigation will be considered to be in sustained remission. EGPA relapse will be defined as a worsening or persistence of active disease since the last visit, characterized by:

[0320] - Active vasculitis (BVAS>0); or

[0321] - Having corresponding worsening of active asthma symptoms and / or signs on the Asthma Control Questionnaire (6-item version) (ACQ-6) score (compared to the most recent previous score); or

[0322] - Active nasal and / or sinus disease, with a corresponding worsening of at least one of the sinus symptoms (compared to the most recent previous assessment).

[0323] Guarantee any of the following:

[0324] - The dose of OCS therapy is increased to >4 mg / day of prednisolone total daily dose; or

[0325] - Increase the dosage or add immunosuppressive therapy; or

[0326] - Hospitalization associated with worsening EGPA.

[0327] In cases of suspected EGPA relapse, subjects will attend unplanned visits and will undergo BVAS assessment at the time of relapse or as soon as possible after relapse.

[0328] The recurrence time will be defined as:

[0329] - The timing of dose increases in OCS therapy, and / or

[0330] - Increase the dosage or add immunosuppressive therapy, and / or

[0331] - Hospitalization associated with worsening of BVAS, asthma, or sinus symptoms.

[0332] If a subject has achieved remission (i.e., BVAS=0 and prednisolone / prednisolone dose ≤4 mg / day) and has BVAS=1 at a subsequent visit, and does not require an increase in corticosteroid dose to above 4 mg / day, or any other significant clinical intervention or study, this will not be considered a relapse.

[0333] A major relapse (a subset of all 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 present [myalgia, arthralgia / arthritis, fever > 38°C or weight loss > 2 kg]); or an asthma relapse requiring hospitalization; or a sinus relapse requiring hospitalization.

[0334] The minimum effective dose of OCS (prednisolone / prednisolone) for each subject will be defined as an OCS dose one step higher than the OCS dose at the time of the first relapse. If the subject has already reached an OCS dose of 0 mg to 3.5 mg prednisolone / prednisolone, the minimum effective dose will be defined as 4.0 mg / day. Upward dose adjustments within the range of 0 mg to 4.0 mg are permitted and will not be considered a relapse.

[0335] The management of relapsed subjects will be based on standard care and may involve increasing the dose of corticosteroids or adjusting immunosuppressive therapy.

[0336] If a subject's first relapse is controlled by increasing the dose of corticosteroids, then according to standard care practice, once the relapse has been properly controlled, a gradual reduction in dose will be recommended. Any reduction below the minimum effective dose of the OCS once that level is reached will be based on the subject's clinical condition.

[0337] If relapse is controlled by increasing the dose of immunosuppressive therapy or starting immunosuppressive therapy, the subject can be withdrawn from further investigational treatment and, where possible, continue to be followed up.

[0338] If a subject experiences an organ-threatening or life-threatening relapse, he / she may withdraw from further study treatment and, where possible, continue follow-up.

[0339] The Vasculitis Damage Index (VDI). The 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 record those characteristics of vasculitis caused by persistent damage in which there is no current disease activity. Damage is defined as the presence of non-healing scarring and does not give any indication of current disease activity. The VDI is divided into 11 organ systems and records items of damage caused by vasculitis, treatment, or unrelated factors since the onset of vasculitis. A numerical score is provided upon completion of the table. VDI scores were compared between subjects treated with benazepril and mepolizumab.

[0340] Patient-reported outcome (PRO) assessment. Complete the patient-reported outcome (PRO) assessment as shown in Table 4, including corticosteroid use, asthma control questionnaire (6-item version), sinus symptoms questionnaire, sinus outcome test-22, short form-36 version 2 (acute recall), patient overall severity impression, patient overall change impression, work productivity and activity impairment questionnaire.

[0341] Corticosteroid Use. Subjects will be asked to report their daily dose of OCS taken in the past 24 hours throughout the 52-week DB period. Daily OCS use assessment will be completed by subjects before bedtime each night. The number of subjects receiving benalizumab and mepolizumab at an OCS dose ≤4.0 mg / day will be compared to demonstrate that benalizumab reduces OCS dose. The proportion of subjects who, based on the mean daily prednisolone / prednisolone dose, had a mean daily OCS dose reduction of ≥50% relative to baseline during weeks 48 to 52 will be assessed.

[0342] The Asthma Control Questionnaire (6-item version, ACQ-6) is used to assess five asthma symptoms (nighttime awakening, symptoms upon waking, activity limitation, shortness of breath, and wheezing) and the use of short-acting beta-agonists. The ACQ-6 was developed to predict the use of a question by omitting forced expiratory volume in one second (FEV1) % by self-administered questions in adults and adolescents (uniper 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). Participants were asked to use a 7-point scale (0 = no impairment; 6 = maximum impairment) to record their experience with five symptoms (nighttime awakening, symptoms upon waking, activity limitation, shortness of breath, and wheezing) and the use of a short-acting beta-2 agonist (SABA) in the previous week. The ACQ-6 score was calculated by averaging the six equally weighted items. The ACQ-6 score ranged from 0 (good control) to 6 (very poor control). Individual score variations of at least 0.5 were significant and used to support the responder definition that a mean ACQ score ≤0.75 indicated well-controlled asthma, a score between 0.75 and 1.5 indicated partially controlled asthma, and a score ≥1.5 indicated poorly controlled asthma. See Juniper EF, Svensson K, Mörk AC, Ståhl 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. Comparison of ACQ-6 scores between subjects treated with benazepril and mepolizumab.

[0343] The Sinus Symptom Questionnaire (SSQ) captures the severity of five sinus and nasal symptoms. Specifically, the SSQ asks participants to report the severity of their symptoms from the previous week: “Given your sinus and nasal symptoms from the previous week, rate each symptom according to the following categories: very severe, severe, moderate, mild, none.” Symptoms include runny nose, postnasal discharge (feeling liquid in your throat), facial pain / pressure, loss or reduction of taste / smegma, and nasal congestion / redness. Higher scores indicate higher severity (0 = none to 4 = very severe). SSQ scores were compared between participants receiving benazepril and mepolizumab treatment.

[0344] The Sinus Outcomes Test-22 (SNOT-22) is a symptom-specific health status / health-related quality of life (HRQoL) assessment that captures the emotional consequences of subjects' reported physical problems, functional limitations, and sinus conditions. A 6-point scale (0 = no problem to 5 = problem severe to the extreme) captures the severity and impact of symptoms reported by subjects over the past 2 weeks. The total score is the sum of item scores and ranges from 0 to 110 (higher scores indicate poorer outcomes). For individual score variation, a minimum clinically significant difference of 8.90 has been determined. 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. Comparison of SNOT-22 scores between subjects treated with benazepril and mepolizumab.

[0345] Short Form-36 Version 2 (Acute Memory, SF-36v2). SF-36v2 is a 36-item self-report survey of functional health and well-being with a one-week memory period (Lincoln, RI. QualityMetric, I. User's manual for the SF-36v2 Health Survey (3rd edition). 2011). The 8-domain profile consists of the following subscales: physical functioning, role limitations due to physical health, physical pain, general health perception, vitality, social functioning, role limitations due to emotional problems, and mental health. The psychometrically based Physical Health Component Pooled Score (PCS) and Mental Health Component Pooled Score (MCS) are calculated from the subscale scores.

[0346] Patient Global Severity Impression (PGIS). PGIS is a single item designed to capture a subject's perception of the overall severity of their symptoms. PGIS results were compared between subjects treated with benazepril and mepolipril.

[0347] Patient Global Impression of Change (PGIC). PGIC is a single item designed to capture an overall assessment of a subject's response to treatment. PGIC results were compared between subjects treated with benazepril and mepolipril.

[0348] Work Productivity and Activity Impairment Questionnaire (WPAI). The WPAI General Health Version 2.0 is a self-management tool consisting of six questions covering absences, attendance (reduced productivity at work), overall work productivity loss (absences plus attendance), and activity impairment. This validation tool captures data from the past 7 days. WPAI results are scored as a percentage of impairment, with higher percentages indicating greater impairment and lower productivity (Reilly Associates, WPAI scoring, available at URL: http: / / www.reillyassociates.net / WPAI_Scoring.html, accessed May 16, 2012). WPAI results were compared between subjects receiving benazepril and mepolizumab.

[0349] Vital capacity measurement. Lung function (forced expiratory volume in one second (FEV1) and forced vital capacity) will be measured by vital capacity measurement. Vital capacity measurement will be performed according to the 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), following the assessment schedule shown in Table 4. Vital capacity measurement tests will begin at the baseline visit (Visit 2) between 06:00 and 11:00 in the morning. Where possible, all randomized vital capacity assessments will be performed within ±2 hours of the time of day during which the baseline (Visit 2) vital capacity measurement was performed. Predicted normal values ​​(PNV) will be determined using the global active equation of lung function pre-programmed into the spirometer.

[0350] Forced expiratory volume in one second (FEV1), expressed as a percentage of PNV, will be calculated as follows:

[0351] PNV FEV1% = (Measured FEV1 / FEV1) PNV )×100

[0352] The percentage of reversibility will be calculated as follows:

[0353] Reversibility percentage = (FEV1 after bronchodilator administration - FEV1 before bronchodilator (BD)) × 100% / FEV1 before bronchodilator administration. Reversibility testing and FEV1 efficacy assessment after bronchodilator (BD) will be performed only at baseline (Visit 2). Maximum bronchial dilation will be induced by four inhalations of albuterol (90 μg dose), salbutamol (100 μg dose), or levosalbutamol (45 μg dose) within 30 ± 15 minutes of the last pre-BD vital capacity measurement. Post-BD vital capacity measurement is preferably performed 15 to 30 minutes after administration of a short-acting β2 agonist (SABA). Preferably, an interval device is used for this procedure, and a nebulizer should not be used. Figure 2 The algorithm used for reversibility testing is outlined in this paper.

[0354] The study compared lung capacity measurements between subjects treated with benazepril and mepolipril.

[0355] Clinical benefit. Any clinical benefit is a composite endpoint, defined as any one of the following three component endpoints (Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, 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):

[0356] (1) Remission at any time during the double-blind treatment period (defined as BVAS=0 and prednisolone / prednisolone dose ≤4mg / day).

[0357] (2) During weeks 48 to 52, the average daily prednisolone / prednisolone dose was reduced by ≥50%.

[0358] (3) No recurrence of EGPA during the double-blind treatment period.

[0359] A complete response is a composite endpoint, and a subject is considered to have a complete response if all three of the above components are met.

[0360] Example 2: Results

[0361] (a) Registration and baseline characteristics

[0362] Baseline characteristics of all 140 patients randomized to benazepril zumab (n=70) or mepolilizumab (n=70) are presented in Table 5 below. Demographic, baseline disease characteristics and concomitant drug use were generally balanced between treatment groups (Table 5; 60.0% were female, mean [standard deviation]; SD] age 52.3 [14.1] years).

[0363] Table 5: Demographic and Baseline Clinical Characteristics

[0364]

[0365]

[0366] Standard deviation (SD); Body mass index (BMI); Oral glucocorticoid (OGC) dosage is calculated as a daily dose of prednisone or prednisolone, regardless of the reason for administration.

[0367] aThe maximum number of patients with ANCA positivity during screening is 10%.

[0368] b Patients with a blood eosinophil count <150 cells / μL are limited to approximately 40% at the time of recruitment.

[0369] c Histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation via biopsy.

[0370] d Mononeuropathy or polyneuropathy (motor deficits or abnormal nerve conduction)

[0371] e Diagnosis is made via echocardiography or magnetic resonance imaging.

[0372] (b) Efficacy

[0373] The primary endpoint was compared in patients receiving benazepril and mepolipril, specifically, oral glucocorticoid (OGC) dose ≤4 mg / day, and European Union of Rheumatology Societies (EULAR) defined remission at weeks 36 and 48. Figures 3A to 3C and Figure 4 ; Response: BVAS=0 and OGC dose ≤4 mg / day, and EULAR-defined response: BVAS=0 and OGC dose ≤7.5 mg / day). At both weeks 36 and 48, the adjusted primary endpoint of response rate was 59.2% for the benalizumab group and 56.5% for the mepolizumab group (difference in rate: 2.71%; 95% CI: -12.54, 17.96; p=0.7278); Figures 3A-3C And 4). At both weeks 36 and 48, the adjusted rate of response as defined by EULAR was 79.0% for the benazepril group and 73.6% for the mepolizumab group (difference in rate: 5.44%; 95% CI: –7.46, 18.34). Figure 3A Pre-specified subgroup analyses showed that response rates were similar between the benazepril and mepolizumab groups, regardless of patient clinical and disease characteristics, including ANCA-positive status. Figure 4 ).

[0374] The external efficacy of this study was assessed using a method that compared the benalizumab rate observed in this study with the historical placebo response rate observed in 2 out of 68 patients (2.9%) in 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. NEngl J Med. 2017; 376:1921-32.). Comparisons with response rates in the historical placebo and historical mepolizumab groups from the MIRRA trial are shown in Table 6 below.

[0375] Table 6: Proportion of patients achieving remission at both week 36 and week 48, with benalizumab versus historical placebo. Between different formulations (from the MIRRA trial) and between mepolizumab and historical mepolizumab formulations (from the MIRRA trial). Treatment Comparison

[0376]

[0377] Historical placebo response rates and historical mepolizumab response rates were collected from subjects observed in the phase 3 trial MIRRA.

[0378] The benazepril and mepolilizumab groups had similar mean daily doses at OGC levels during weeks 48–52 (OR 1.42; 95% CI: 0.77, 2.62; p = 0.2618). Figure 5A and Figure 5B During weeks 49–52, the mean (SD) change in daily OGC dose relative to baseline was -8.12 (4.536) mg in the benalizumab group and -7.52 (7.070) mg in the mepolizumab group. Figure 5A During weeks 48–52, 86.1% and 73.9% of patients achieved a ≥50% reduction in OGC use, respectively (ratio difference: 12.26; 95% CI: -0.57, 25.10). A higher proportion of patients treated with benalizumab achieved a complete and gradual reduction in OGC compared to mepolizumab (41.4% vs. 25.8%); ratio difference: 15.69; 95% CI: 0.67, 30.71. Figure 3B and Figure 6 (And Table 7). The daily dose of OGC is shown in Table 7 below.

[0379] Table 7. Daily dose of OGC during weeks 48–52

[0380]

[0381] The secondary endpoint of total cumulative duration of response was similar in both the benazepril and mepolizumab groups (odds ratio [OR] 1.36; 95% CI: 0.75, 2.48; Table 8). A similar proportion of patients achieved response within the first 24 weeks of treatment and maintained response at week 52 (42.1% vs. 36.5%; difference in response rate: 5.54; 95% CI: -9.30, 20.37). Figure 7A and Figure 7B The cumulative duration of relief is shown in Table 8 below.

[0382] Table 8. Cumulative duration of remission during the double-blind phase

[0383]

[0384] Similar clinical benefits and clinical response rates were observed in both treatment groups. Figure 8 (and Table 9). Table 9 shows the proportion of patients who achieved any clinical benefit and a complete response. Clinical benefit was defined as any of the following, and a complete response was defined as all of the following: remission at any time, a mean daily OGC (prednisone / prednisolone) dose reduction of ≥50% and ≥100% during weeks 48 to 52, and no relapse of EGPA during the double-blind treatment period.

[0385] Table 9. Percentage of patients who achieved any clinical benefit and a complete response

[0386]

[0387] In addition, 30.0% of patients experienced relapse in both groups, 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 summary, 34 and 30 relapses were observed in the benalizumab and mepolizumab groups, respectively, and these relapses occurred in similar relapse categories (any vasculitis: 30.0% vs. 25.7%; any asthma: 17.1% vs. 12.9%; and any sinus: 10.0% vs. 11.4%, respectively). The yearly relapse rates in the benalizumab and mepolizumab groups were 0.50 (95% CI: 0.30, 0.83) and 0.49 (95% CI: 0.28, 0.86), respectively (ratio ratio: 1.03; 95% CI: 0.56, 1.90). No severe relapses were observed in the benalizumab group, and three patients (4.3%) in the mepolizumab group experienced four severe relapses. Between the benalizumab group and the mepolizumab group, the proportion of patients who relapsed and the time to first relapse were similar (40.43 weeks vs. 38.57 weeks, respectively). Figure 9 ).

[0388] In both treatment groups, a significant reduction in blood eosinophil counts was observed early after treatment initiation and was maintained throughout the double-blind period. At week 1, the mean LS change in blood eosinophil counts relative to baseline was 0.15 (95% CI: 0.12, 0.18) and 0.39 (95% CI: 0.32, 0.47) in benalizumab 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 counts in benalizumab and mepolizumab recipients were 32.4 (40.8) and 71.8 (54.4) cells / μL, respectively.

[0389] Data on other secondary outcomes (BVAS; VDI; lung function [FEV1]; scores on ACQ-6, Sinus Outcomes Test-22, Sinus Symptom Questionnaire (SSQ), Medical Outcomes Study Brief - 36 Health Survey Version 2, Patient Overall Severity Impression, Patient Overall Change Impression, and Work Productivity and Activity Impairment General Health Questionnaire (WPAI); and immunogenicity) are provided below. Figures 11 to 17 And Tables 10 to 12.

[0390] Table 10. SSQ scores and changes relative to baseline at each time point.

[0391]

[0392] Table 11. WPAI Absence and Attendance Scores at Baseline and Week 52 and Changes Relative to Baseline

[0393]

[0394] Table 12. Anti-drug antibody response to benazepril 1ab

[0395]

[0396] ADA, anti-drug antibody; nAb, neutralizing antibody

[0397] a Positive baseline results, as well as treatment-induced ADA positivity or treatment-enhanced ADA positivity.

[0398] b Treatment-induced ADA positivity was defined as ADA negative at baseline and at least one positive ADA assessment after baseline.

[0399] c Treatment-enhanced ADA positivity was defined as ADA positivity at baseline, with the baseline titer increasing by more than the measured variability (i.e., ≥4-fold) after baseline assessment at a baseline level of ≥1.

[0400] d ADA positivity occurring without treatment is defined as ADA positivity but does not meet the above criteria for ADA positivity occurring with treatment.

[0401] e Persistent positive ADA is defined as negative ADA at baseline and having ≥2 positive ADA assessments after baseline (with ≥16 weeks between the first and last positive assessment) or a positive assessment after the last available baseline.

[0402] f Transient positive ADA is defined as negative ADA at baseline and positive ADA assessment ≥1 baseline time, but not meeting the criteria for persistent positive.

[0403] g The median of the maximum post-baseline titer was calculated based on the maximum post-baseline titer for each ADA-positive patient.

[0404] h The nAb prevalence rate is defined as nAb positivity at any visit (including baseline and / or post-baseline).

[0405] i The incidence of nAb was defined as nAb negative at baseline (or ADA negative at baseline) and nAb positive at any post-baseline visit.

[0406] The reduction in OGC use in patients with EGPA was further evaluated in the benalizumab and mepolizumab groups (see Tables 13-15 and 14). Figures 18A to 21B During the study, the mean cumulative oral glucocorticoid use was similar between groups (approximately 2,000 mg); however, patients treated with benalizumab were more complete in gradually reducing OGC (i.e., achieving a 100% reduction in OGC use) than those treated with mepolizumab, and they were able to do so more quickly (see, for example, Table 14 and...). Figures 18B to 20B Table 15 shows the complete remissions at weeks 36 and 48 (i.e., BVAS=0 + OCS=0 mg / day + no relapse). Specifically, a higher proportion of patients treated with benalizumab achieved complete remission compared to those treated with mepolizumab.

[0407] Figure 19 A heatmap showing OGC dose over time and recurrence during the study period is presented. Figure 20A The total cumulative duration (weeks) of OGC=0 mg / day for both groups is shown, and Figure 20BThe mean daily dose reduction of OGC relative to baseline is shown during weeks 48–52. Patients treated with benalizumab had a faster rate of OGC reduction than those treated with melphalan, and maintained this dose reduction until week 52. A higher proportion of patients treated with benalizumab had a complete rate of OGC reduction. Despite the rate of OGC reduction, lung function did not deteriorate (i.e., FEV1 before BD). Figure 21A And there was no loss in asthma control score (ACQ-6). Figure 21B This data suggests that benalizumab allows for the reduction of oral glucocorticoids in patients with EGPA, thus confirming the benefit of anti-IL-5 / Rα therapy.

[0408] Table 13. Cumulative OGC usage during the study period

[0409]

[0410] Table 14. Time of OGC Reduction During the 52-Week Treatment Period

[0411]

[0412] The time to first reduction was defined as the first 4 weeks from the date of randomization to when the reduction threshold was met during the double-blind period. For patients who did not meet the threshold, the time to first reduction was properly reviewed on the date of their last visit and on the date of the last contact for patients who lost follow-up.

[0413] a Calculated using Kaplan-Meier techniques;

[0414] b The hazard ratio (HR, benalizumab vs. mepolizumab) and 95% CI were estimated using a Cox regression model with the Efron method to control for the endpoints. Covariates in the model included the treatment group, baseline prednisone dose, baseline BVAS, and region. A hazard ratio >1 favored benalizumab. p-values ​​were derived from an unstratified log-rank test.

[0415] c The p-value was calculated using a two-sided, unstratified log-rank test; the p-value is nominal.

[0416] Table 15. Complete remission at weeks 36 and 48

[0417]

[0418] a Marginal standardization was used in the logistic regression model to estimate the remission rate and difference (benalizumab-mepolizumab).

[0419] The covariates in the model included the treatment group, baseline prednisone dose, baseline BVAS, and region (North America, Western Europe, and Japan). The baseline was defined as the last measurement taken on or before the randomization date.

[0420] b Nominal p-value

[0421] (c) Security

[0422] Benalizumab was well tolerated. During the double-blind phase, adverse events (AEs) were reported in 90.0% of patients receiving benalizumab and 95.7% of patients receiving mepolizumab (Table 16). The most frequently 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 benalizumab group and the mepolizumab group (Table 16). SAEs were reported in 5.7% of benalizumab recipients and 12.9% of mepolizumab recipients (Table 16). The most common SAEs were infectious and invasive (2.9% in the benalizumab group vs. 5.7% in the mepolizumab group). Patients without benalizumab treatment and two patients receiving mepolizumab experienced AEs leading to treatment discontinuation. Two patients treated with meplezumab experienced serious prostate cancer events; however, these events were considered unrelated to meplezumab. There were no deaths during the double-blind period. Safety profiles for the benalizumab and meplezumab groups are shown in Table 16 below.

[0423] Table 16: Security Overview

[0424]

[0425]

[0426] (d) Discussion

[0427] This study provides evidence of the efficacy and utility of benalizumab in this population, confirming the benefit of anti-IL-5 therapy for patients with EGPA. This phase 3 randomized study compared the efficacy of benalizumab and mepolizumab in patients with refractory / relapsed EGPA receiving standard of care, and met the primary endpoint of response rate within 52 weeks in patients with relapsed / refractory EGPA receiving standard of care. SAEs were minimal with benalizumab therapy, and no new safety signals were reported.

[0428] More patients treated with benalizumab were able to eliminate OCS, and they eliminated OCS faster than patients treated with melphalan. The time to the first 100% reduction in OCS was observed shorter in patients treated with benalizumab compared to those treated with melphalan. Furthermore, during the 52-week double-blind period, more patients treated with benalizumab were OCS-free for at least 24 weeks compared to those treated with melphalan. Patients treated with benalizumab were more likely than those treated with melphalan to eliminate OCS and remain OCS-free during the double-blind period. Additionally, a similar proportion of patients achieved 100% OCS reduction regardless of ANCA status and immunosuppressive medication.

[0429] Consistent efficacy of benalizumab was observed across all secondary endpoints. Results demonstrated comparable control and durability of response to disease activity with both benalizumab and mepolizumab, as well as similar cumulative duration and sustained remission. Similar annual relapse rates and time to first relapse were observed between the treatment groups. Most patients treated with both benalizumab and mepolizumab experienced clinical benefit, reflected in the low number of discontinuations during the trial. More patients treated with benalizumab achieved a mean daily OGC dose reduction of ≥50% and complete gradual reduction of their OGC use compared to mepolizumab.

[0430]

[0431] The scope of this invention is not limited to the aspects described herein. In fact, various modifications to the invention, in addition to those described, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

[0432] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein in their entirety by reference and for all purposes, to the extent that each individual reference (e.g., publications, patents, or patent applications) is specifically and individually indicated as incorporated herein in its entirety by reference for all purposes.

[0433] Some aspects are covered by the appended claims.

Claims

1. A method for treating eosinophilic granulomatous polyangiitis (EGPA) in a patient in need, the method comprising administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to IL5Rα, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

1.

2. The method according to claim 1, wherein the antibody or antigen-binding fragment is a humanized IgG1 monoclonal antibody.

3. The method according to claim 1 or 2, wherein the antibody is benazepril.

4. The method according to any one of claims 1 to 3, wherein the patient suffers from asthma.

5. The method according to any one of claims 1 to 4, wherein the patient suffers from eosinophilia.

6. The method according to any one of claims 1 to 5, wherein the patient has at least two of the following characteristics: (a) Histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation from biopsy. (b) Neuropathy; (c) Pulmonary infiltration; (d) Sinus abnormalities; (e) Cardiomyopathy; (f) Glomerulonephritis; (g) Alveolar hemorrhage; (h) palpable purpura; and (i) ANCA immunofluorescence, myeloperoxidase (MPO) antibody and / or protease-3 (PR3) antibody tests were positive.

7. The method according to any one of claims 1 to 6, wherein the patient does not suffer from severe eosinophilic asthma.

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

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

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

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

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

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

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

15. The method according to any one of claims 1 to 14, wherein the patient uses an oral corticosteroid (OCS) prior to the administration, optionally wherein the patient has used 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 prednisolone.

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

19. The method according to any one of claims 15 to 18, wherein the patient uses the OCS at least 7.5 mg / day or about 7.5 mg / day to about 50 mg / day prior to the administration.

20. The method according to any one of claims 15 to 19, wherein the administration reduces OCS usage to 7.5 mg / day or less.

21. The method according to any one of claims 15 to 20, wherein the administration reduces the use of the OCS to 4 mg / day or less.

22. The method according to any one of claims 15 to 21, wherein the application eliminates the use of OCS.

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

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

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

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

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

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

29. The method according to any one of claims 24 to 28, wherein the reduction in the daily dose of OCS 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 according to any one of claims 1 to 30, wherein the administration reduces the Birmingham Vasculitis Activity Score (BVAS) of the patient.

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

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

34. The method according to 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 of BVAS to 0 and the reduction of the OCS dose to 4 mg / day or less occur within 24 weeks of the first administration of the antibody or its antigen-binding fragment to the patient.

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

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

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

39. The method according to any one of claims 1 to 38, wherein the application prolongs the time to EGPA recurrence.

40. The method according to any one of claims 1 to 39, wherein the degree to which the administration prolongs the time to EGPA relapse is greater than the degree to which the administration of mepolizumab prolongs the time.

41. The method according to any one of claims 1 to 40, wherein the application reduces the annual recurrence rate.

42. The method according to any one of claims 1 to 41, wherein the reduction in the annual relapse rate by the administration is greater than the reduction by the administration of mepolizumab.

43. The method according to any one of claims 1 to 42, wherein the application reduces the likelihood of EGPA recurrence.

44. The method according to any one of claims 1 to 43, wherein the degree to which the application reduces the likelihood of EGPA relapse is greater than the degree to which the application of mepolizumab reduces the likelihood.

45. The method according to any one of claims 1 to 44, wherein the administration reduces the likelihood of an increase in the patient's vasculitis injury index (VDI).

46. ​​The method according to any one of claims 1 to 45, wherein the administration improves the patient's Asthma Control Questionnaire-6 (ACQ-6) score.

47. The method according to any one of claims 1 to 46, wherein the degree to which the administration improves the patient's Asthma Control Questionnaire-6 (ACQ-6) score is greater than the degree of improvement resulting from the administration of mepolizumab.

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

49. The method according to any one of claims 1 to 48, wherein the degree of improvement in the patient's Sinus Outcome Test-22 (SNOT-22) score by administration is greater than the degree of improvement by administration of mepolizumab.

50. The method according to any one of claims 1 to 49, wherein the administration improves the patient's overall severity impression (PGIS) score.

51. The method according to any one of claims 1 to 50, wherein the degree of improvement in the Patient Overall Severity Impression (PGIS) score from administration is greater than the degree of improvement from administration of mepolizumab.

52. The method according to any one of claims 1 to 51, wherein the antibody or its antigen-binding fragment is administered at a dose of about 30 mg.

53. The method according to any one of claims 1 to 52, wherein the antibody or its antigen-binding fragment is administered once every four weeks.

54. The method according to any one of claims 1 to 53, wherein the antibody or its antigen-binding fragment is administered once every four weeks for a period of 12 weeks.

55. The method according to any one of claims 1 to 54, wherein the antibody or its antigen-binding fragment is administered once every four weeks for 24 weeks.

56. The method according to any one of claims 1 to 55, wherein the antibody or its antigen-binding fragment is administered once every four weeks for 36 weeks.

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

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

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

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

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

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

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

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

65. An antibody or antigen-binding fragment thereof that specifically binds to IL5Rα, for use in the method according to any one of claims 1 to 64, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

1.

66. Use of an antibody or antigen-binding fragment thereof that specifically binds to IL5Rα in the preparation of a medicament for use in the method according to any one of claims 1 to 64, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 1.

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