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WO2025062362A1 - Anticorps il-5r-alpha pour le traitement de la granulomatose éosinophile avec polyangéite - Google Patents

Anticorps il-5r-alpha pour le traitement de la granulomatose éosinophile avec polyangéite Download PDF

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Publication number
WO2025062362A1
WO2025062362A1 PCT/IB2024/059168 IB2024059168W WO2025062362A1 WO 2025062362 A1 WO2025062362 A1 WO 2025062362A1 IB 2024059168 W IB2024059168 W IB 2024059168W WO 2025062362 A1 WO2025062362 A1 WO 2025062362A1
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weeks
antibody
administration
patient
antigen
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Elizabeth Duncan
Sofia NECANDER
Gina D'ANGELO
Lena BÖRJESSON SJÖ
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AstraZeneca AB
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AstraZeneca AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present disclosure relates to methods of treating Eosinophilic Granulomatosis with Polyangiitis (EGPA) using an anti-interleukin- 5 receptor alpha (IL-5Ra) antibody or an antigen-binding fragment thereof, e.g., benralizumab.
  • EGPA Eosinophilic Granulomatosis with Polyangiitis
  • IL-5Ra anti-interleukin- 5 receptor alpha
  • Eosinophilic granulomatosis with polyangiitis is a rare inflammatory disorder of systemic necrotizing vasculitis of small-to- medium-sized blood vessels.
  • the disease is characterized by potentially life-threatening systemic eosinophilic small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates.
  • Patients with EGPA generally have a greater blood and tissue eosinophil burden than, for example, patients with severe asthma. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. Before the use of corticosteroids for EGPA, more than 50% of patients died within 3 months of diagnosis.
  • corticosteroid therapy is the cornerstone therapy for the treatment of EGPA patients
  • corticosteroids particularly longer term
  • corticosteroids is associated with significant adverse effects, including weight gain, osteoporosis, hyperglycemia, depression, and increased risk of infection, which limit the treatment benefits.
  • remission can be achieved in a proportion of patients with corticosteroid therapy alone, the addition of more potent immunosuppressive therapies (e.g., azathioprine, methotrexate, or mycophenolate mofetil) to maintain remission is commonly required.
  • azathioprine e.g., methotrexate, or mycophenolate mofetil
  • mepolizumab An IL-5 cytokine inhibitor, mepolizumab was recently approved for treatment of EGPA in several countries based on a single Phase III study. Although, mepolizumab increased the time that patients were in remission compared with placebo in this study, 47% of patients treated with mepolizumab did not meet the primary endpoint definition of remission in the study (Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376: 1921-32).
  • a method of treating eosinophilic granulomatosis with polyangiitis (EGPA) in a patient in need thereof comprises administering to the patient a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.
  • the antibody or antigen-binding fragment is a humanized IgGl monoclonal antibody.
  • the antibody is benralizumab.
  • the patient has asthma.
  • the patient has eosinophilia.
  • the patient has at least 2 of the following: (a) a biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation; (b) neuropathy; (c) pulmonary infiltrates; (d) a sino-nasal abnormality; (e) cardiomyopathy; (f) glomerulonephritis; (g) alveolar hemorrhage; (h) palpable purpura; and (i) a positive test for ANCA immunofluorescence, myeloperoxidase (MPO) antibodies, and/or proteinase-3 (PR3) antibodies.
  • MPO myeloperoxidase
  • the patient does not have severe eosinophilic asthma.
  • the patient has had EGPA for at least six months.
  • the patient has ANCA positive EGPA.
  • the patient has ANCA negative EGPA.
  • the patient has a history of relapsing or refractory disease.
  • the patient has a history of relapsing EGPA.
  • the patient has a history of at least 3 EGPA relapses.
  • the patient has a history of refractory
  • the patient uses an oral corticosteroid (OCS) prior to the administration, optionally wherein the patient has been using an OCS for at least 4 weeks prior to the administration.
  • OCS oral corticosteroid
  • the OCS is a glucocorticoid.
  • the OCS is prednisolone or prednisone.
  • the OCS is methylprednisolone.
  • the patient uses at least 7.5 mg/day or about 7.5 mg/day to about 50 mg/day of the OCS prior to the administration.
  • the administration reduces the OCS usage to 7.5 mg/day or less.
  • the administration reduces the OCS usage to 4 mg/day or less.
  • the administration eliminates OCS usage.
  • the OCS daily dose is reduced from at least 7.5 mg/day prior to the administration to 4 mg/day or less after the administration.
  • the administration reduces the OCS daily dose 50% or more.
  • the administration reduces the OCS daily dose by 100%.
  • the reduction in OCS daily dose occurs within 52 weeks of the first administration of the antibody or an antigen-binding fragment thereof to the patient.
  • the reduction in OCS daily dose does not decrease the patient's lung function.
  • the patient's lung function is measured by spirometry.
  • the reduction in OCS daily dose does not increase the severity of the patient's asthma.
  • the severity of the patient's asthma is measured by the asthma control questionnaire-6 (ACQ-6).
  • the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS).
  • the administration reduces the patient's Birmingham Vasculitis Activity Score (BVAS) more than administration of mepolizumab reduces it.
  • BVAS Birmingham Vasculitis Activity Score
  • the administration reduces the patient's BVAS to 0.
  • the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg/day or less. In some aspects, the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg/day or less within 24 weeks of the first administration. In further aspects, the reduction in BVAS to 0 and the OCS dose to 4 mg/day or less is maintained for at least about 52 weeks after the first administration.
  • the method comprises administering at least two doses of the antibody or an antigen-binding fragment thereof to the patient.
  • the administration reduces the patient's BVAS to 0 and the OCS dose to 4 mg/day or less after at least 3 doses, at least 6 doses, at least 9 doses, or at least 12 doses of the antibody or an antigen-binding fragment thereof to the patient.
  • the administration increases the time to EGPA relapse.
  • the administration increases the time to EGPA relapse more than administration of mepolizumab increases it.
  • the administration decreases the annual relapse rate.
  • the administration decreases the annual relapse rate more than administration of mepolizumab decreases it.
  • the administration decreases the likelihood of an EGPA relapse.
  • the administration decreases the likelihood of an EGPA relapse more than administration of mepolizumab decreases it.
  • the administration decreases the likelihood of an increase in the vasculitis damage index (VDI) of the patient.
  • VDI vasculitis damage index
  • the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient.
  • the administration improves the asthma control questionnaire-6 (ACQ-6) score of the patient more than administration of mepolizumab improves it.
  • ACQ-6 asthma control questionnaire-6
  • the administration improves the sino- nasal outcome test-22 (SNOT-22) score of the patient.
  • the administration improves the sino- nasal outcome test-22 (SNOT-22) score of the patient more than administration of mepolizumab improves it.
  • SNOT-22 sino- nasal outcome test-22
  • the administration improves the Patient Global Impression of Severity (PGIS) score.
  • PGIS Patient Global Impression of Severity
  • the administration improves the Patient Global Impression of Severity (PGIS) score more than administration of mepolizumab improves it.
  • PGIS Patient Global Impression of Severity
  • the antibody or antigen-binding fragment thereof is administered at about 30 mg per dose.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for 12 weeks.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for 24 weeks.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for 36 weeks.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for 48 weeks. [0061] In certain aspects of a method provided herein, the antibody or antigen-binding fragment thereof is administered once every four weeks for at least four doses.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for at least eight doses.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for at least twelve doses.
  • the antibody or antigen-binding fragment thereof is administered once every four weeks for three doses and then once every eight weeks.
  • the antibody or antigen-binding fragment thereof is administered parenterally.
  • the antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the administration is into the upper arm, thigh, or abdomen.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra for use in any one of the methods provided herein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.
  • antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra in the preparation of a medicament for use in any one of the methods provided herein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1.
  • Figure 1A shows a flow diagram for a clinical trial demonstrating the efficacy of benralizumab compared to mepolizumab, an IL- 5 cytokine inhibitor, to treat eosinophilic granulomatosis with polyangiitis (EGPA).
  • Figure IB shows the patient disposition throughout the study. (See Examples 1 and 2.)
  • Figure 2 outlines the algorithm for reversibility testing. (See Example 1.)
  • Figure 3A shows patients achieving remission at weeks 36 and 48 following treatment with benralizumab versus mepolizumab.
  • Figure 3B shows the proportion of patients with reduction from baseline in the average daily oral glucocorticoid (OGC) dose during weeks 48- 52 (full analysis set).
  • Figure 3C shows the proportion of patients who achieved remission by time point. Vertical lines represent 95% confidence intervals, calculated using the Clopper- Pearson method.
  • Figure 4 show subgroup analysis of the proportion of patients who achieved remission at both weeks 36 and 48.
  • the remission rates and the difference were estimated using marginal standardization method in a logistic regression model.
  • the covariates in the model include treatment arm, baseline dose of prednisone, baseline BVAS, region, the subgroup and interaction between treatment arm and the subgroup (treatment arm* subgroup).
  • the covariate region is not in the model when the subgroup is geographical region or race, to avoid confounding.
  • Figure 5A shows the average daily dose of OGC (prednisone/prednisolone) during weeks 48-52 in patients following treatment with benralizumab versus mepolizumab.
  • the odds ratios (OR) and 95% confidence intervals (CI) were estimated using a proportional odds model, with treatment arm, baseline dose of OGC, baseline BVAS, and region as covariates.
  • Figure 5B shows the mean average daily OGC dose by time (week). OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration.
  • Figure 6 shows the percentage of patients achieving > 50% reduction in OGC dose and the percentage of patients achieving 100% reduction in OGC dose at weeks 48-52 following treatment with benralizumab versus mepolizumab. Secondary endpoints were not multiplicity protected; p-values are nominal. Rates and difference were estimated using a marginal standardization method in a logistic regression model, with treatment arm, baseline dose of OGC, baseline BVAS, and region, as covariates.
  • Figure 7A shows the percentage of patients achieving accrued remission
  • Figure 7B shows the percentage of patients achieving remission by week 24 and maintaining remission until week 52, following treatment with benralizumab versus mepolizumab.
  • OGC dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration. OR and 95% CI were estimated with a proportional odds model. Covariates included treatment arm, baseline dose of OGC, baseline BVAS, and region.
  • Figure 9 is Kaplan-Meier plot of time to first relapse. The percentage of patients with relapses and time to first relapse for benralizumab versus mepolizumab treatment groups is shown. Relapse was defined as worsening or persistence of active disease characterized by: active vasculitis (BVAS > 0), or active symptoms and/or signs of asthma with a corresponding worsening in Asthma Control Questionnaire (6-item version, ACQ-6) score, or active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions; warranting: an increase of OGCs, or an increased dose or addition of an immunosuppressive therapy, or hospitalization related to worsening of EGPA.
  • active vasculitis BVAS > 0
  • Asthma Control Questionnaire (6-item version, ACQ-6) score
  • active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal
  • the hazard ratios HR (benralizumab vs mepolizumab) and associated 95% CI were estimated using a Cox regression model with Efron method to control for ties.
  • the covariates in the model included treatment arm, baseline dose of OGC (prednisone/prednisolone), baseline BVAS, and region. P-value was calculated using unstratified log-rank test; p-values for secondary endpoints are nominal.
  • Figure 10 shows blood eosinophil count over time in patients following treatment with benralizumab versus mepolizumab.
  • Figure 11 shows Birmingham Vasculitis Activity Score (BVAS) and change from baseline over time in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.
  • BVAS Birmingham Vasculitis Activity Score
  • Figure 12 shows the change from baseline in Vasculitis Damage Index (VDI) in patients following treatment with benralizumab versus mepolizumab.
  • Analysis of covariance used an unstructured variance-covariance matrix. Covariates included treatment group, baseline OGC dose, baseline BVAS score, region, baseline VDI, visit (week 24 and week 52), and visit by treatment group.
  • Figure 13 shows the least-squares change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) over time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.
  • Figure 14A shows the least-squares change from baseline in Asthma Control Questionnaire (6-Item Version (ACQ-6) score over time (weeks) in patients following treatment with benralizumab versus mepolizumab.
  • Figure 14B shows the least-squares change from baseline in Sino-Nasal Outcome Test-22 (SNOT-22) total score over time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.
  • Figure 15 shows the Medical Outcomes Study 36-item Short Form Health Survey version 2 (36v2) least-squares mean change from baseline by time (weeks) in patients following treatment with benralizumab versus mepolizumab. Vertical bars indicate 95% confidence intervals.
  • Figure 16 shows Patient Global Impression of Severity (PGI-S) category at baseline and week 52 in patients following treatment with benralizumab versus mepolizumab.
  • Figure 17 shows Patient Global Impression of Change (PGI-C) category at baseline and week 52 in patients following treatment with benralizumab versus mepolizumab.
  • PKI-C Patient Global Impression of Change
  • Figure 18A shows the time (weeks) to first >50% reduction in OGC use in patients following treatment with benralizumab versus mepolizumab.
  • Figure 18B shows the time (weeks) to first 100% reduction in OGC use in patients following treatment with benralizumab versus mepolizumab.
  • Figure 19 shows a heatmap of OGC dose (average daily dose of prednisolone/prednisone, mg/day) by time and relapse in patients following treatment with benralizumab versus mepolizumab.
  • Figure 20B shows percentage reduction from baseline in average daily dose of OGC during Weeks 48-52.
  • the OR for higher percent reduction and 95% CI were estimated using a proportional odds model, including treatment arm, baseline dose of prednisone, baseline BVAS, and region as covariates.
  • BD pre-bronchodilator
  • antibody refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as IL-5Ra through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
  • a target such as IL-5Ra
  • antibody encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule so long as the antibodies exhibit the desired biological activity.
  • An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgGl, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
  • the different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations.
  • Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.
  • antibody fragment or "antigen-binding fragment” are used interchangeably and refer to a portion of an intact antibody.
  • An "antigen-binding fragment,” “antigen-binding domain,” or “antigen-binding region,” refer to a portion of an intact antibody that binds to a target such as IL-5Ra.
  • An antigen-binding fragment can contain the antigenic determining regions of an intact antibody (e.g., the complementarity determining regions (CDR)).
  • CDR complementarity determining regions
  • antigen-binding fragments of antibodies include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies.
  • An antigen-binding fragment of an antibody can be derived from any animal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced.
  • a "monoclonal” antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants.
  • the term "monoclonal” antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site.
  • monoclonal antibodies or antigen-binding fragments thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.
  • variable region refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen.
  • the variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • variable region is a human variable region.
  • variable region comprises rodent or murine CDRs and human framework regions (FRs).
  • variable region is a primate (e.g., nonhuman primate) variable region.
  • variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).
  • complementarity determining region refers to each of the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops (hypervariable loops) and/or contain the antigen-contacting residues.
  • Antibodies can comprise six CDRs, e.g., three in the VH and three in the VL.
  • VL and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.
  • VH and "VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.
  • Kabat numbering and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof.
  • CDRs can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT ( 1971 ) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3).
  • CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)).
  • the end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).
  • the AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.
  • constant region or “constant domain” are interchangeable and have its meaning common in the art.
  • the constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor.
  • the constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.
  • an antibody or antigen-binding fragment comprises a constant region or portion thereof that is sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the term "heavy chain” when used in reference to an antibody can refer to any distinct type, e.g., alpha (a), delta (8), epsilon (s), gamma (y), and mu (p), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGl, IgG2, IgG3, and IgG4.
  • Heavy chain amino acid sequences are well known in the art.
  • the heavy chain is a human heavy chain.
  • the term "light chain” when used in reference to an antibody can refer to any distinct type, e.g., kappa (K) or lambda (X) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In some aspects, the light chain is a human light chain.
  • humanized antibody or antigen-binding fragment thereof refers to forms of non- human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences.
  • humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g.
  • CDR grafted mouse, rat, rabbit, hamster
  • Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody or fragment from a non-human species that has the desired specificity, affinity, and capability.
  • the humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody or antigen-binding fragment thereof specificity, affinity, and/or capability.
  • the humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.
  • a "humanized antibody” is a resurfaced antibody.
  • the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies or antigen-binding fragments thereof. These terms indicate that the antibody or antigen-binding fragment thereof binds to an epitope via its antigen-binding domain and that the binding entails some complementarity between the antigen binding domain and the epitope.
  • a polypeptide, antibody, polynucleotide, vector, cell, or composition which is "isolated” is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature.
  • Isolated polypeptides, antibodies, polynucleotides, vectors, cell or compositions include those that have been purified to a degree that they are no longer in a form in which they are found in nature.
  • an antibody, polynucleotide, vector, cell, or composition that is isolated is substantially pure.
  • substantially pure refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.
  • treating refers to the administration of a composition to a subject for therapeutic purposes.
  • the terms "patient” and “subject” are used interchangeably and refer to members of the animal kingdom including but not limited to human beings. In some aspects, the patient is human.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • the formulation can be sterile.
  • administer refers to methods that may be used to enable delivery of a drug, e.g., an antibody or antigenbinding fragment thereof (e.g., subcutaneous administration).
  • Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa.
  • terapéuticaally effective amount refers to an amount of a drug, e.g., one or more antibodies or antigen-binding fragments thereof effective to treat a disease or disorder in a subject.
  • relapsing EGPA refers to the recurrence or worsening of EGPA. In some embodiments, relapsing EGPA refers to recurrence or worsening of EGPA following a period of remission.
  • refractory EGPA refers to EGPA in subjects that have been treated for EGPA but have not achieved remission.
  • headers are provided solely for ease of reading, and are not intended to be limiting. Aspects disclosed under one or more headers can be applicable to or combinable with aspects disclosed under one or more other headers.
  • IL-5Ra Anti-interleukin-5 receptor-alpha antibodies and antigen-binding fragments
  • the methods provided comprise administering an effective amount of an antiinterleukin-5 receptor-alpha (IL-5Ra) antibody or antigen-binding fragment thereof such as benralizumab or an antigen-binding fragment thereof.
  • IL-5Ra antiinterleukin-5 receptor-alpha
  • the amino acid sequences of human and mouse IL-5Ra are provided below as SEQ ID NOs: 5 and 6, respectively.
  • the IL-5Ra antibody or antigen-binding fragment thereof is a humanized antibody.
  • the IL-5Ra antibody or antigen-binding fragment thereof is one of the following classes: IgA, IgD, IgE, IgG, or IgM.
  • the IL- 5Ra antibody or antigen-binding fragment thereof is an IgG.
  • the IL-5Ra antibody or antigen-binding fragment thereof is one of the following subclasses IgGl , IgG2, IgG3, IgG4.
  • the IL-5Ra antibody or antigen-binding fragment thereof is an IgGl .
  • the IL-5Ra antibody or antigen-binding fragment thereof has a kappa (K) or lambda (X) type light chain. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof has a K type (K-class) light chain. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is benralizumab or an antigen-binding fragment thereof.
  • the IL-5Ra antibody or antigen-binding fragment thereof can be naturally-occurring or recombinantly produced. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is afucosylated. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced by recombinant DNA technology. In some aspects, the IL-5Ra antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells by recombinant DNA technology.
  • the IL-5Ra antibody or antigen-binding fragment thereof is benralizumab (MEDI-563).
  • Benralizumab is a humanized monoclonal antibody (mAb) that binds to the alpha chain of IL-5R, which is expressed on eosinophils and basophils. It induces apoptosis of these cells via antibody-dependent cell cytotoxicity.
  • Benralizumab and antigen-binding fragments thereof for use in the methods provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
  • benralizumab or an antigen-binding fragment thereof for use in the methods provided herein includes any one of the amino acid sequences of SEQ ID NOs:l-4.
  • benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3.
  • benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:2 and heavy chain comprising the amino acid sequence of SEQ ID NO:4.
  • benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:7-9, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10-12.
  • SEQ ID NOs:l-12 are shown in Table 2 below. Those of ordinary skill in the art would easily be able to identify Chothia-defined, AbM-defined or other CDRs.
  • benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the KM1259 antibody as disclosed in U.S. 6,018,032, which is herein incorporated by reference in its entirety.
  • Table 2 Antibody Sequence Summary Administration
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered only once.
  • the patient is administered additional follow-on doses.
  • follow-on doses can be administered at various time intervals.
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered into the upper arm, thigh, and/or abdomen.
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered about every 1 week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, or longer intervals.
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered every 4 weeks.
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered every 1-5 weeks, every 2-5 weeks, every 3-5 weeks, or every 4-5 weeks.
  • the intervals can be every 1-9 weeks, every 2-9 weeks, every 3-9 weeks, every 4-9 weeks, every 5-9 weeks, every 6-9 weeks, every 7-9 weeks, or every 8- 9 weeks.
  • the IL-5Ra antibody or antigen-binding fragment thereof is administered every 4 weeks.
  • the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered at a frequency sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.
  • IL-5Ra antibody or antigen-binding fragment thereof e.g., benralizumab
  • At least two doses the IL-5Ra antibody or antigen-binding fragment thereof are administered to the patient.
  • the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered over the course of about four weeks, over the course of about eight weeks, over the course of about 12 weeks, over the course of about 24 weeks, over the course of about 28 weeks, over the course of about 52 weeks, over the course of about 76 weeks, or over the course of about 104 weeks.
  • the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered over the course of at least four weeks, over the course of at least eight weeks, over the course of at least 12 weeks, over the course of at least 24 weeks, over the course of at least 28 weeks, over the course of at least 52 weeks, over the course of at least 76 weeks, or over the course of at least 104 weeks.
  • the subject is administered one or more doses of an IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab), wherein the dose is about 2 mg to about 100 mg, for example about 20 mg to about 100 mg, or about 30 mg to about 100 mg.
  • the patient is administered one or more doses of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab), wherein the dose is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.
  • the dose is about 20 mg.
  • the dose is about 30 mg.
  • the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered in an amount sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.
  • the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered in an amount and at a frequency sufficient to ensure blood eosinophil depletions in EGPA including in patients with higher eosinophil burden.
  • a dose is about 30 mg of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) is administered once every four weeks (Q4W).
  • administration of the IL-5Ra antibody or antigen-binding fragment thereof is through parenteral administration.
  • the IL-5Ra antibody or antigen-binding fragment thereof e.g., benralizumab
  • the IL-5Ra antibody or antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection.
  • the IL-5Ra antibody or antigen-binding fragment thereof is administered by subcutaneous injection.
  • the IL-5Ra antibody or antigen-binding fragment thereof is administered via a syringe.
  • the IL-5Ra antibody or antigenbinding fragment thereof is administered via an accessorized prefilled syringe (APFS).
  • APFS accessorized prefilled syringe
  • the syringe is glass.
  • the syringe (e.g., prefilled syringe) contains about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 15 ml, or about 20 ml of a formulation provided herein.
  • the syringe (e.g., prefilled syringe) contains about 1 ml a formulation provided herein.
  • the IL-5Ra antibody or antigen-binding fragment thereof is administered according to the methods provided herein in combination or in conjunction with additional Eosinophilic Granulomatosis with Polyangiitis (EGPA) therapies.
  • EGPA Eosinophilic Granulomatosis with Polyangiitis
  • the IL-5Ra antibody or antigen-binding fragment thereof is administered according to the methods provided herein in combination or in conjunction with additional EGPA therapies that are standard of care for treating EGPA.
  • standard of care therapies include, without limitation, immunosuppressive therapies and biologies.
  • the immunosuppressive therapy is azathioprine, methotrexate, or mycophenolate mofetil.
  • the immunosuppressive therapy is a corticosteroid.
  • the corticosteroid is a glucocorticoid.
  • the corticosteroid is delivered orally.
  • the corticosteroid is prednisolone/prednisone.
  • the corticosteroid is methylprednisolone.
  • the corticosteroid dose is ⁇ 4 mg/day.
  • the corticosteroid dose is ⁇ 7.5 mg/day.
  • the corticosteroid dose is > 7.5 mg/day In certain aspects, the corticosteroid dose is > 7.5 mg/day but not > 50 mg/day.
  • the subject has been using a corticosteroid (e.g., prednisone/prednisolone) for at least 4 weeks prior to administration of the IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • a corticosteroid e.g., prednisone/prednisolone
  • the IL-5Ra antibody or antigen-binding fragment thereof e.g., benralizumab
  • the IL-5Ra antibody or antigen-binding fragment thereof for use according to the methods provided herein, is present in a formulation, e.g., a pharmaceutical formulation.
  • a formulation e.g., a pharmaceutical formulation.
  • the IL-5Ra antibody or antigen-binding fragment thereof e.g., benralizumab
  • the IL-5Ra antibody or antigen-binding fragment thereof is present in the formulation at a concentration of about 1 mg/mL to about 200 mg/mL.
  • the IL-5Ra antibody or antigen-binding fragment thereof is present in the formulation at a concentration of about 30 mg/mL.
  • the formulation comprising IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) for methods and uses of the present disclosure comprise various other components.
  • the formulation comprises histidine.
  • the formulation comprises from about 1 mM to about 100 mM histidine, for example, from about 5 mM to about 80 mM histidine, from about 10 mM to about 60 mM histidine, from about 15 mM to about 50 mM histidine, from about 15 mM to about 30 mM histidine, or about 20 mM histidine.
  • the formulation comprises about 20 mM histidine/histidine hydrochloride monohydrate.
  • the formulation comprises a surfactant, for example, a polysorbate such as polysorbate 20 (PS20).
  • a surfactant for example, a polysorbate such as polysorbate 20 (PS20).
  • the formulation comprises about 0.001% to about 0.02%, about 0.002% to about 0.015%, about 0.002% to about 0.01%, about 0.004% to about 0.009%, about 0.005% to about 0.008%, about 0.007%, or about 0.006% PS20.
  • the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.010%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, or about 0.020% (w/v) polysorbate 20. In some aspects, the formulation comprises about 0.006% (w/v) polysorbate 20.
  • the formulation comprises an uncharged excipient, for example, trehalose.
  • the uncharged excipient e.g., trehalose dihydrate
  • the formulation comprises about 1 mMto about 250 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate).
  • the formulation comprises about 100 mM to about 400 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate).
  • the formulation comprises about 200 mM to about 300 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 100 mM, about 150 mM, about 200 mM, about 250 mM, about 300 mM, about 350 mM, or about 400 mM of the uncharged excipient (e.g., trehalose or trehalose dihydrate). In some aspects, the formulation comprises about 0.25 M trehalose dihydrate.
  • the formulation is sterile and preservative-free.
  • the formulation comprises 30 mg/mL anti-IL5R antibody, 20 mM histidine/histidine HC1, and 250 mM trehalose dihydrate, pH 6.0 with either no surfactant or 0.0004% polysorbate 80, 0.0012% PS80, 0.02% poloxamer 188, or 0.08% poloxamer 188.
  • the formulation comprises 30 mg/mL anti-IL5R antibody, 1.4 mg L- histidine, 2.3 mg L- histidine hydrochloride monohydrate, 0.06 mg polysorbate 20, and 95 mg a,a-trehalose dehydrate in water.
  • Eosinophilic Granulomatosis with Polyangiitis EGPA
  • kits for treating EGPA are provided herein.
  • the methods provided herein can significantly reduce EGPA disease severity.
  • EGPA remains only partly understood, but it is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs) usually directed against myeloperoxidase (MPO) or proteinase-3 (PR3) on enzyme-linked immunosorbent assay in approximately 40% of patients.
  • ANCAs anti-neutrophil cytoplasmic antibodies
  • MPO myeloperoxidase
  • PR3 proteinase-3
  • ANCA positive and ANCA negative Two different phenotypes of EGPA are described: ANCA positive and ANCA negative. Data show differences in clinical disease presentation based on ANCA status and indicate that ANCA-positive patients should be treated more aggressively (Sokolowska B, Szczeklik W, Wludarczyk A, Kuczia P, Jakiela B, Gasior J, et al.
  • a subject treated with IL-5Ra antibody or antigenbinding fragment thereof e.g., benralizumab
  • a subject treated with IL-5Ra antibody or antigen-binding fragment thereof e.g., benralizumab
  • ANCA negative e.g., a subject treated with IL-5Ra antibody or antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein is ANCA positive or ANCA negative.
  • EGPA is defined based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x 10 9 /liter and/or > 10% of leukocytes).
  • Additional features of EGPA can include:
  • EGPA is defined based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x 10 9 /liter and/or > 10% of leukocytes) plus at least 2 of the additional features listed as (a) to (i) above.
  • subjects with EGPA do not have severe eosinophilic asthma.
  • subjects have a history of relapsing or refractory EGPA.
  • history of relapsing EGPA is present when a subject has had an increase in oral corticosteroid (OCS) dose, initiation or increased dose of immunosuppressive therapy, and/or hospitalization.
  • OCS oral corticosteroid
  • subjects have a history of at least 1, 2, or 3 EGPA relapses.
  • a history of refractory EGPA is present when a subject has not attained remission following induction treatment with corticosteroid therapy administered for at least 1 month, 2 months, or 3 months. In some aspects, a history of refractory EGPA is present when a subject has not attained remission following induction treatment with corticosteroid therapy administered for at least 3 months. In some aspects, a history of relapsing EGPA is present when a subject has a recurrence of symptoms of EGPA while tapering OCS. In some aspects, a history of relapsing EGPA is present when a subject has a recurrence of symptoms of EGPA while tapering OCS occurring at any dose level > 7.5 mg/day prednisolone or equivalent.
  • a method of treating EGPA in a subject comprises administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab).
  • the EGPA can be relapsing or refractory EGPA.
  • the subject can be a subject that is receiving corticosteroid therapy prior to the administration of an antibody or antigen-binding fragment thereof.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of EGPA.
  • the EGPA can be relapsing or refractory EGPA.
  • the subject can be a subject that is receiving corticosteroid therapy prior to the administration of an antibody or antigen-binding fragment thereof.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for use in the preparation of a medicament for the treatment of EGPA.
  • the EGPA can be relapsing or refractory EGPA.
  • the subject can be a subject that is receiving corticosteroid therapy prior to the administration of an the antibody or antigen-binding fragment thereof.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of EGPA.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra (e.g., benralizumab) for the treatment of relapsing or refractory EGPA.
  • an antibody or an antigen-binding fragment thereof that immunospecifically binds to IL5Ra e.g., benralizumab
  • IL5Ra e.g., benralizumab
  • kits for treating EGPA are provided herein.
  • the methods provided herein can significantly reduce EGPA disease activity.
  • EGPA disease activity of can be measured using one or more clinical outcome assessments.
  • the clinical outcome assessments include, but are not limited to, Birmingham Vasculitis Activity Score (BVAS), EGPA relapse/remission, Vasculitis Damage Index (VDI), Patient-Reported Outcome (PRO) Assessments, and/or Spirometry.
  • BVAS Birmingham Vasculitis Activity Score
  • VDI Vasculitis Damage Index
  • PRO Patient-Reported Outcome
  • Spirometry Spirometry
  • the clinical outcomes assessments can be used to measure EGPA disease activity at about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks following initiation of treatment the
  • BVAS Birmingham Vasculitis Activity Score
  • the BVAS is reduced by 1 point, 2 points, 3 points, 4 points, or 5 points. 6 points, 7 points, 8 points, 9 point, 10 points, 11 points, 12 points, 13 points, 14 points, 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points, 24 points, 25 points, 26 points, 27 points, 28 points, 29 points, 30 points, 31 points, 32 points, 33 points, 34 points, 35 points, 36 points, 37 points, 38 points, 39 points, 40 points, 41 points, 42 points, 43 points 44 points, 45 points, 46 points, 47 points, 48 points, 49 points, 50 points, 51 points, 52 points, 53 points, 54 points, 55 points, 56 points, 57 points, 58 points, 59 points, 60 points, 61 points, 62 points, or 63 points.
  • the BVAS is reduced to 0.
  • use of the methods provided herein reduces the time to achieve remission. In aspects, use of the methods provided herein increases EGPA remission duration. In aspects, use of the methods provided herein increases accrued EGPA remission duration. In aspects, use of the methods provided herein increases EGPA remission frequency.
  • use of the methods provided herein reduces the patient's BVAS to 0 and the OCS dose to 4 mg/day or less within about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58
  • remission is achieved after about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks following initiation of treatment the IL- 5Ra antibody or an
  • remission is achieved for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • remission is maintained for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 52 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • the reduction in BVAS to 0 and the OCS dose to 4 mg/day or less is maintained for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 52 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, for at least 120 weeks, or longer after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • use of the methods provided herein reduces the patient's BVAS to 0 and the OCS dose to 4 mg/day or less within 24 weeks after the first administration of the IL- 5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the reduction in BVAS to 0 and the OCS dose to 4 mg/day or less is maintained for at least about 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • use of the methods provided herein reduces the EGPA relapse rate.
  • use of the methods provided herein reduces the annual EGPA relapse rate.
  • use of the methods provided herein increases the time to EGPA relapse.
  • use of the methods provided herein reduces the EGPA annualized relapse rate to less than 40%. In some aspects, use of the methods provided herein reduces the EGPA annualized relapse rate to less than 30%.
  • subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof do not experience a relapse for at least 12 weeks, for at least 24, weeks, for at least 36 weeks, for at least 48 weeks, for at least 60 weeks, for at least 72 weeks, for at least 84 weeks, for at least 96 weeks, for at least 108 weeks, or for at least 120 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof have > 50% reduction in their daily prednisolone/prednisone dose within 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • 5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • subjects receiving an IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab:
  • BVAS 0 and prednisolone/prednisone dose ⁇ 4 mg/day) after administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein,
  • [0197] (2) have > 50% reduction in their daily prednisolone/prednisone dose within 4 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein, and
  • 5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • the PRO assessments include, but are not limited to, Corticosteroid Medication Usage, Asthma Control Questionnaire (6-Item Version, ACQ-6), Sino-nasal Symptom Questionnaire (SSQ), Sino-Nasal Outcome Test-22 (SNOT-22), Short Form-36 Version 2 (Acute Recall, SF-36v), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Work Productivity and Activity Impairment Questionnaire (WPAI).
  • Corticosteroid Medication Usage Asthma Control Questionnaire (6-Item Version, ACQ-6), Sino-nasal Symptom Questionnaire (SSQ), Sino-Nasal Outcome Test-22 (SNOT-22), Short Form-36 Version 2 (Acute Recall, SF-36v), Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Work Productivity and Activity Impairment Questionnaire (WPAI).
  • VDI Vasculitis Damage Index
  • use of the methods provided herein reduces the daily oral corticosteroid (OCS) dose.
  • OCS daily oral corticosteroid
  • the daily OCS dose is reduced by about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%.
  • the daily OCS dose is reduced to ⁇ 7.5 mg/day.
  • the daily OCS dose is reduced to ⁇ 4.0 mg/day.
  • the daily OCS dose is reduced by 50% or more.
  • use of OCS is eliminated.
  • the daily OCS dose is reduced at least 12 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, or at least 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • use of the methods provided herein reduces the daily oral glucocorticoid (OGC) dose.
  • the daily OGC dose is reduced by about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%.
  • the daily OGC dose is reduced to ⁇ 7.5 mg/day.
  • the daily OGC dose is reduced to ⁇ 4.0 mg/day.
  • the daily OGC dose is reduced by 50% or more.
  • use of OGC is eliminated.
  • the daily OGC dose is reduced at least 12 weeks, at least 16 weeks, at least 24 weeks, at least 32 weeks, or at least 52 weeks after the first administration of the IL-5Ra antibody or an antigen-binding fragment thereof (e.g., benralizumab) according to the methods provided herein.
  • the IL-5Ra antibody or an antigen-binding fragment thereof e.g., benralizumab
  • use of the methods provided herein reduces the ACQ-6 score.
  • the score is reduced to 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, or 0.5.
  • the score is reduced by 0.5.
  • the score is reduced to ⁇ 1.5.
  • use of the methods provided herein reduces the SSQ score to 3, 2, 1, or 0.
  • use of the methods provided herein reduces the SNOT-22 score.
  • the SNOT-22 score is reduced by at least 8.90 points.
  • the SNOT- 22 score is reduced by by about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%.
  • use of the methods provided herein increases the SF-36v2.
  • the use of the methods provided herein increases the psychometrically-based physical health component summary score (PCS) and mental health component summary score (MCS).
  • PCS physical health component summary score
  • MCS mental health component summary score
  • use of the methods provided herein reduces the Patient Global Impression of Severity (PGIS).
  • PGIS Patient Global Impression of Severity
  • the PGIS is reduced to 4, 3, 2, 1, or 0.
  • use of the methods provided herein reduces Patient Global Impression of Change (PGIC).
  • PGIC Patient Global Impression of Change
  • the PGIC is reduced to 6, 5, 4, 3, 2, or 1.
  • use of the methods provided herein reduces the Work Productivity and Activity Impairment (WPAI) percentage.
  • Subjects have an EGPA diagnosis for at least 6 months before screening visit (Visit 1) date based on the history or presence of: asthma plus documented eosinophilia (> 1.0 x l 0 9 /liter and/or > 10% of leukocytes) plus documentation of at least 2 of the following additional features of EGPA:
  • Relapsing disease Subjects must have a history of at least one confirmed EGPA relapse (i.e., requiring increase in oral corticosteroid (OCS) dose, initiation/increased dose of immunosuppressive therapy or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of > 7.5 milligram per day (mg/day).
  • OCS oral corticosteroid
  • patients For study sites in Japan, patients must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of IV prednisolone or equivalent, initiation/increased dose of immunosuppressive therapy, initiation/increased dose of IV immunoglobulin or hospitalization) within the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or equivalent) of > 7.5 mg/day.
  • EGPA relapse i.e., requiring increase in OCS dose, initiation of IV prednisolone or equivalent, initiation/increased dose of immunosuppressive therapy, initiation/increased dose of IV immunoglobulin or hospitalization
  • subjects who have received cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed intravenous (IV) CYC prior to baseline (Visit 2), if their total WBC is > 4 X 10 9 /L prior to randomization;
  • subjects who have received an azathioprine, methotrexate, or my cophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to baseline (Visit 2);
  • subjects who have received an induction regimen comprising corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment and the corticosteroids dose is > 15 mg/day prednisolone for the 4 weeks prior to baseline (Visit 2).
  • the prescribed dose of oral prednisolone or prednisone must be stable (i.e., no adjustment of the dose) and must be > 7.5 mg/day but not > 50 mg/day) for at least 4 weeks prior to baseline (Visit 2). Stable doses of OCS other than prednisolone or prednisone may be acceptable.
  • Subjects are required to have electrocardiogram (ECG) evaluation at screening (Visit 1) within the following range: QT interval corrected by Fredericia’s (QTcF) ⁇ 450 msec or QTcF ⁇ 480 msec for patients with bundle branch block.
  • the QT interval corrected (QTc) was based on averaged QTc values of triplicate ECGs obtained over a brief recording period.
  • Imminently life-threatening EGPA disease defined as any of the following within
  • Liver disease unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
  • Cardiovascular subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:
  • Infectious disease chronic or ongoing active infectious disease requiring systemic treatment.
  • Parasitic infection a helminth parasitic infection diagnosed within 6 months prior to screening (Visit 1) and through randomization (Visit 2) that has not been treated with or had failed to respond to standard of care therapy.
  • Hepatitis status chronic stable hepatitis B and C (including positive testing for
  • HBsAg or hepatitis C antibody are acceptable if the subject otherwise meets the eligibility criteria.
  • Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.
  • Immunodeficiency a history of known immunodeficiency disorder including a positive HIV test.
  • IV Intravenous
  • IM intramuscular
  • SC subcutaneous corticosteroids
  • Alcohol/substance abuse a history (or suspected history) or alcohol misuse or substance abuse within 2 years prior to screening (Visit 1).
  • Other investigational non-biologic product receipt of any investigational nonbiologic product within 30 days or 5 half-lives prior to screening (Visit 1), whichever is longer.
  • Adherence subjects who have known evidence of lack of adherence to prescribed medications and/or ability to follow physician's recommendations.
  • ALT Alanine transaminase
  • AST aspartate transaminase level > 3 times the upper limit of normal (ULN) confirmed during screening period, confirmed by repeated testing (if applicable) during screening period. Subjects who have transient increase of AST/ALT level that resolves by the time of randomization is acceptable if the patient did not have an active liver disease and meets other eligibility criteria.
  • This study is a Phase III randomized, double blind, active-controlled, parallel group, multicenter study comparing the efficacy and safety of benralizumab 30 mg versus mepolizumab 300 mg administered by SC injection Q4W in patients with relapsing or refractory EGPA on corticosteroid therapy with or without stable immunosuppressive therapy.
  • the dosing regimen (30 mg Q4W) was selected to ensure blood eosinophil depletions in EGPA, including in patients with higher eosinophil burden.
  • This study comprises 2 distinct periods: (i) a 52- week double-blind (DB) treatment period, during which patients will be randomized to receive either benralizumab or mepolizumab, and (ii) an open-label extension (OLE), during which all patients will receive benralizumab alone.
  • DB double-blind
  • OOE open-label extension
  • Study treatment in this study refers to benralizumab, mepolizumab, placebo to benralizumab, and placebo to mepolizumab. Placebo to mepolizumab and placebo to benralizumab are used only to ensure blinding for the study treatments.
  • the study treatments are shown in Table 3 below.
  • Table 3 Study Treatments a Mepolizumab is sourced locally in Japan. b Mepolizumab/placebo to mepolizumab in Japan will be administrated with a 2-3 mL polypropylene syringe and 21-27 gauge needle. [0283] Potentially eligible subjects will enter a screening period of up to 4 weeks (minimum of one week) and are be required to be on a stable dose of OCS > 7.5 mg/day prednisolone/prednisone (but not > 50 mg/day), for at least 4 weeks prior to baseline (Visit 2). If dose adjustment is necessary during the screening period, or the subject has not maintained a stable dose, the subject will be screen failed.
  • Subjects on immunosuppressive therapy will be required to be on a stable dose for at least 4 weeks prior to baseline (Visit 2) and to remain on the same dose until the end of the DB period (if the patient does not enter the OLE) or until completion of the first 6 months of the OLE period (if the patient continues into the OLE). Dose reductions for safety reasons will be permitted. All eligible subjects will be randomized 1 : 1 at baseline (Visit 2), to receive study treatments Q4W for a 52- week DB treatment period. The number of patients with ANCA-positive status or an eosinophil count ⁇ 150 cells/pL ( ⁇ 0.15 x 10 9 /L) will be restricted to approximately 10% and 40%, respectively, of the total number of randomized patients.
  • the final dose of the DB treatment period will be given at Week 48, and the DB treatment period will be completed at Week 52. All patients who complete the 52-week DB treatment period will be eligible to continue into the OLE period.
  • the OLE period allows each patient at least one year of treatment with open-label benralizumab 30 mg administered SC every fourth week (earlier enrolled patients were therefore be in the OLE for longer than one year).
  • BVAS Birmingham Vasculitis Activity Score
  • VDI Vasculitis Damage Index
  • Visit 17 is the last double-blind visit and the first OLE visit. All assessments at Visit 17 to be performed BEFORE administration of open-label benralizumab.
  • Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits.
  • assessments may be performed as clinically indicated.
  • OCS dose will be recorded in the eCRF at each study visit and check compliance against subject reported use between study visits.
  • Visit 2 will be confirmed on the handheld device prior to baseline ePRO questionnaires completion by the subject. Sites will ensure subjects complete all baseline ePRO assessments. For subsequent visits, confirm is performed either on the web portal Study Works or on the device.
  • 9 ePRO assessments include: Corticosteroid medication usage, Asthma Control Questionnaire (6-item version), Sino-nasal questionnaire, Sino- nasal Outcome Test-22, Short Form 36-Item Health Survey (version 2, acute recall), Patient Global Impression of Change, Patient Global Impression of Severity, and Work Productivity and Activity Impairment Questionnaire (General Health version 2.0).
  • 11 eGFR will be calculated according to the CKD-EPI formula at each visit where serum chemistry is collected.
  • Subject must be in fasting state. If subject has not fasted, he/she may return to collect this sample as soon as possible. The period of fasting may be adjusted for subjects with relevant metabolic conditions (e.g., diabetes mellitus).
  • relevant metabolic conditions e.g., diabetes mellitus
  • PK will be collected pre-dose.
  • ADA/nAb analysis will only be done on samples from patients who received benralizumab. Neutralizing antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
  • Sample collection is recommended at baseline (Visit 2) but may be drawn at any time after the subject is randomized.
  • Each participating subject will be interviewed twice. The first interview will take place at least 7 and up to 21 days after Visit 2. The second will take place at least 7 and up to 21 days after Visit 16.
  • ADA Anti-drug antibodies
  • AE adverse event(s)
  • ANCA anti-neutrophil cytoplasmic antibodies
  • BD bronchodilator
  • BVAS Birmingham Vasculitis Activity Score
  • CRP C-reactive protein
  • CSP clinical study protocol
  • ECG electrocardiogram
  • eCRF electronic case report form
  • eGFR estimated glomerular filtration rate
  • EGPA eosinophilic granulomatosis with polyangiitis
  • ePRO electronic patient reported outcome
  • ESR erythrocyte sedimentation rate
  • FEIA fluorenzyme immunoassay
  • FEV1 forced expiratory volume in 1 second
  • FSH follicle stimulating hormone
  • HIV human immunodeficiency virus
  • IgE Immunoglobulin E
  • IWRS Interactive Web Response System
  • min minimum
  • MPO myeloperoxidase
  • nAb myeloperoxidase
  • nAb myeloperoxidase
  • the BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis.
  • the form is designed to record features that are attributable to current vasculitis, after exclusion of other causes such as infection, hypertension, etc.
  • the scoring sheet records the presence or absence of each item. Each item is weighted, and a maximum total score applied to each system. The total score on all 9 organ systems gives an indication of the disease activity of each subject at the time of scoring and reflects the need for therapy.
  • EGPA relapse/remission EGPA relapse/remission.
  • EGPA remission at any visit will be defined as a BVAS score of 0 with OCS dose of prednisolone/prednisolone ⁇ 4 mg/day.
  • BVAS 1 which does not require an increase in corticosteroid dose above 4 mg/day or 7.5 mg/day (in accordance with the relevant remission definition), or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.
  • EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by:
  • Control Questionnaire (6-item version) (ACQ-6) score (compared to the most recent previous score); OR
  • the time of onset of a relapse will be defined as:
  • BVAS 0 and prednisolone/prednisone dose ⁇ 4 mg/day
  • BVAS 1, which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, this will not be considered a relapse.
  • a major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS > 6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever > 38°C or weight loss > 2 kg]); OR an asthma relapse requiring hospitalization; OR sino-nasal relapse requiring hospitalization.
  • the minimally effective dose of OCS for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0 to 3.5 mg prednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0 to 4.0 mg range are permitted without being considered a relapse.
  • the management of subjects who relapse will be according to standard of care and may involve increasing the dose of corticosteroids or adjustment in immunosuppressive therapy.
  • VDI Vasculitis Damage Index
  • VDI is divided into 11 organ systems and records items of damage, due to vasculitis, treatment or unrelated, that have occurred since the onset of vasculitis. Completion of the form provides a numerical score. VDI sores are compared between subjects receiving benralizumab and mepolizumab treatment.
  • PRO Patient-Reported Outcome Assessments.
  • the patient-reported outcome (PRO) assessments including Corticosteroid Medication Usage, Asthma Control Questionnaire (6- Item Version), Sino-Nasal Symptom Questionnaire, Sino-Nasal Outcome Test-22, Short Form-36 Version 2 (Acute Recall), Patient Global Impression of Severity, Patient Global Impression of Change, Work Productivity and Activity Impairment Questionnaire, were completed as shown in Table 4.
  • Corticosteroid Medication Usage The subject will be asked to report the daily dosage of OCS taken over the past 24 hours throughout the 52-week DB period. The daily OCS usage assessment will be completed by the subject each evening prior to going to sleep. The number of subjects on an OCS dose ⁇ 4.0 mg/day is compared between subjects receiving benralizumab and mepolizumab treatment to demonstrate that benralizumab reduces OCS dose. The proportion of subjects with > 50% reduction in OCS average daily dose from baseline based on the average daily prednisolone/prednisone dose during Weeks 48 through 52 is assessed. [0311] Asthma Control Questionnaire (6-Item Version, ACQ-6).
  • the ACQ-6 is an assessment of 5 asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and short-acting beta-agonist use.
  • the ACQ-6 was developed for self-administration by adults and adolescents by omitting the forced expiratory volume in 1 second (FEV1) % predicted question (Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-7).
  • the ACQ-6 score is calculated by taking the mean of the 6 equally weighted items.
  • the ACQ-6 score range is 0 (well controlled) to 6 (extremely poorly controlled).
  • Individual score change of at least 0.5 is meaningful and is used to support the responder definition
  • Mean ACQ scores ⁇ 0.75 indicate well-controlled asthma, scores between 0.75 and 1.5 indicate partly controlled asthma, and a score > 1.5 indicates poorly controlled asthma. See Juniper EF, Svensson K, Mork AC, Stahl E.
  • SSQ Sino-Nasal Symptom Questionnaire
  • SNOT-22 Sino-Nasal Outcome Test-22
  • the SNOT-22 is a condition-specific health status/health- related quality of life (HRQoL) assessment that captures subject- reported physical problems, functional limitations, and emotional consequences of sino-nasal conditions.
  • the total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes).
  • a Minimal Clinical Importance Difference of 8.90 has been established for individual score change. See, Piccirillo JF, Merritt Jr. MG, Richards ML.
  • the SF-36v2 is a 36-item, selfreport survey of functional health and well-being, with a one-week recall period (Lincoln, RI. QualityMetric, I. User's manual for the SF-36v2 Health Survey (3 ed.). 2011).
  • the 8-domain profile consists of the following subscales: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health.
  • Psychometrically-based physical health component summary score (PCS) and mental health component summary score (MCS) are computed from subscale scores.
  • PGIS Patient Global Impression of Severity
  • the PGIS is a single item designed to capture the subject's perception of overall symptom severity. PGIS results are compared between subjects receiving benralizumab and mepolizumab treatment.
  • PGIC Patient Global Impression of Change
  • WPAI Work Productivity and Activity Impairment Questionnaire
  • the WP A I general health version 2.0 is a self-administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity (Reilly Associates. Scoring of WPAI. Available from URL: http://www.reillyassociates.netAVPAI_Scoring.html. Accessed on May 16, 2012). WPAI results are compared between subjects receiving benralizumab and mepolizumab treatment.
  • Spirometry Lung function (forced expiratory volume in 1 second (FEV1) and forced vital capacity) will be measured by spirometry. Spirometry will be performed according to American Thoracic Society /European Respiratory Society guidelines (Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38) according to the Schedule of Assessments shown in Table 4. Spirometry testing will be initiated in the morning between 0600 and 1100 at the baseline visit (Visit 2).
  • FEV1 % of PNV (FEV1 measured/FEVl PNV) X 100
  • Percent reversibility (post- bronchodilator FEV - pre- bronchodilator (BD) FEV1) x 100%/pre- bronchodilator FEV1.
  • the reversibility test and post-bronchodilator (BD) FEV1 efficacy assessment will be performed only at baseline (Visit 2). Endpoint maximal bronchodilation will be induced using albuterol (90 pg metered dose), salbutamol (100 pg metered dose), or levalbuterol (45 pg metered dose) 4 inhalations within 30 ⁇ 15 minutes of the final pre-BD spirometry measurement.
  • Post-BD spirometry is preferably performed 15 to 30 minutes after the short acting [32 agonist (SABA) dosing. It is preferable to use a spacer device for this procedure, and a nebulizer should not be used.
  • SABA short acting [32 agonist
  • Clinical Benefit Any clinical benefit is a composite endpoint that is defined as any of the following 3 component endpoints (Steinfeld I, Bradford ES, Brown I, Mallett S, 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.):
  • Complete response is a composite endpoint, and subjects meet complete response if all of the three components above are met.
  • Standard Deviation (SD); Body Mass Index (BMI); oral glucocorticoid (OGC) dose was calculated as the daily dose of prednisone or prednisolone, regardless of the reason for administration
  • a Patients with ANCA-positive status at screening were capped at 10%.
  • b Patients with blood eosinophil count ⁇ 150 cells/pL were capped at ⁇ 40% at recruitment.
  • c A biopsy showing histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation.
  • Mono- or polyneuropathy (motor deficit or nerve conduction abnormality) e Established by echocardiography or magnetic resonance imaging (b) EFFICACY
  • OGC oral glucocorticoid
  • EULAR European Alliance of Associations for Rheumatology
  • the adjusted rate of EULAR-defined remission at both weeks 36 and 48 was 79.0% for the benralizumab group and 73.6% for the mepolizumab group (difference in rates: 5.44%; 95% CI: -7.46, 18.34; Figure 3A).
  • Pre-specified subgroup analyses showed that remission rates were similar between the benralizumab and mepolizumab groups regardless of patient clinical and disease characteristics, including ANCA-positivity status (Figure 4).
  • Table 6 Proportion of patients who achieved remission at both weeks 36 and 48, treatment comparison between benralizumab vs historical placebo (from MIRRA trial), and mepolizumab versus historical mepolizumab (from MIRRA trial)
  • the mean (SD) change from baseline in daily OGC dose was -8.12 (4.536) mg in the benralizumab group and -7.52 (7.070) mg in the mepolizumab group, at weeks 49-52 ( Figure 5A).
  • Table 9 shows the proportion of patients who achieved any clinical benefit and complete response.
  • Clinical benefit was defined as any of the following and complete response was defined as all of the following: remission at any time, >50% and >100% reduction in average daily OGC (prednisone/prednisolone) dose during weeks 48-52, EGPA relapse free during the double-blind treatment period.
  • OGC prednisone/prednisolone
  • the annualized relapse rate was 0.50 (95% CI: 0.30, 0.83) versus 0.49 (95% CI: 0.28, 0.86) in the benralizumab and mepolizumab groups, respectively (rate ratio: 1.03; 95% CI: 0.56, 1.90).
  • rate ratio 1.03; 95% CI: 0.56, 1.90.
  • the proportion of patients with relapses, and time to first relapse was similar between the benralizumab and mepolizumab groups (40.43 vs 38.57 weeks, respectively; Figure 9).
  • ADA anti-drug antibody
  • nAb neutralizing antibodies a A positive post-baseline result and either treatment-induced ADA positive or treatment-boosted ADA positive.
  • Treatment-induced ADA positive is defined as ADA negative at baseline and at least one post-baseline ADA positive assessment.
  • Treatment-boosted ADA positive is defined as ADA positive at baseline and the baseline titre is boosted by greater than the variability of the assay (i.e., > 4-fold) at >1 post-baseline assessment.
  • Non-treatment-emergent ADA positive is defined as ADA positive but not fulfilling the conditions above for treatment-emergent ADA positive.
  • e Persistently positive ADA is defined as ADA negative at baseline and having >2 post-baseline ADApositive assessments (with >16 weeks between first and last positive) or positive at the last available post baseline assessment.
  • Transiently positive ADA is defined as ADA negative at baseline and >1 post-baseline ADA positive assessment but not fulfilling the conditions of persistently positive.
  • nAb prevalence is defined as nAb positive at any visit including baseline and/or post-baseline.
  • nAb incidence is defined as nAb negative at baseline (or ADA negative at baseline) and nAb positive at any post-baseline visit.
  • Figure 19 shows a heatmap of OGC dose by time and relapse during the study.
  • Figure 20B shows the percentage reduction from baseline in average daily dose of OGC during Weeks 48-52.
  • Benralizumab-treated patients tapered OGCs faster than mepolizumab-treated patients and maintained the reduction in dose through to Week 52.
  • a higher proportion of benralizumab-treated patients fully tapered off OGCs.
  • This data indicates that benralizumab enables oral glucocorticoid sparing in patients with EGPA, confirming that anti-IL-5/Ra treatment is beneficial.
  • Time to first reduction was defined from the date of randomization to the first 4-weekly period when the reduction threshold was met during the double-blind period. For patients who did not reach the threshold, the time to first reduction was right censored at the date of their last visit and at the date of last contact for patients lost-to-follow-up.
  • the hazard ratio (HR, benralizumab vs mepolizumab) and 95% Cis were estimated using a Cox regression model with Efron method to control for ties.
  • the covariates in the model included treatment arm, baseline dose of prednisone, baseline BVAS, and region.
  • the p-value was from the unstratified log-rank test;
  • Benralizumab was well tolerated. During the double-blind phase, adverse events (AEs) were reported in 90.0% of benralizumab patients and 95.7% of mepolizumab patients (Table 16). The most commonly reported AEs were coronavirus disease 2019 (COVID-19; 21.4% vs 27.1%), headache (17.1% vs 15.7%), and arthralgia (17.1% vs 11.4%) in the benralizumab versus mepolizumab groups, respectively (Table 16). SAEs were reported in 5.7% of benralizumab and 12.9% of mepolizumab recipients (Table 16).
  • This study provides evidence for the efficacy and utility of benralizumab in this population, confirming that anti-IL-5 treatment is beneficial for patients with EGPA.
  • This Phase 3 randomized study comparing the efficacy of benralizumab and mepolizumab in patients with refractory/relapsing EGPA receiving standard of care, met the primary objective with regard to remission rates over 52 weeks in patients with relapsing/refractory EGPA receiving standard of care. There were few S AEs, and no new safety signals with benralizumab therapy.

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Abstract

L'invention concerne des méthodes de traitement de la granulomatose éosinophile avec polyangéite (GEPA) comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un anticorps anti-récepteur alpha de l'interleukine-5 (IL-5Rα) ou d'un fragment de liaison à l'antigène de celui-ci tel que le benralizumab.
PCT/IB2024/059168 2023-09-21 2024-09-20 Anticorps il-5r-alpha pour le traitement de la granulomatose éosinophile avec polyangéite Pending WO2025062362A1 (fr)

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