Methods for treating or preventing asthma by administering il-4r antagonist

Abstract

To provide methods for treating or preventing asthma and associated conditions in a patient.SOLUTION: Methods herein comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 579,120, filed October 30, 2017, U.S. Provisional Patent Application No. 62 / 710,381, filed February 16, 2018, U.S. Provisional Patent Application No. 62 / 647,368, filed March 23, 2018, U.S. Provisional Patent Application No. 62 / 742,736, filed October 8, 2018, and European Application No. EP 18305566.4, filed May 4, 2018. The contents of the foregoing applications are incorporated herein by reference in their entireties.

[0002] The present invention relates to the treatment and / or prevention of asthma and related conditions. More particularly, the present invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists to treat or prevent asthma in patients in need thereof. [Background technology]

[0003] Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. The inflammatory component of asthma is thought to involve many cell types, including mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells, as well as their biological products. Patients with asthma most commonly present with symptoms of wheezing, shortness of breath, cough, and chest tightness. For most asthma patients, long-term controller and bronchodilator treatment regimens provide adequate long-term control. Inhaled corticosteroids (ICS) are considered the "gold standard" for managing asthma symptoms, and inhaled β2-agonists are the most effective bronchodilators currently available. Studies have demonstrated that combination therapy with ICS and inhaled long-acting β2-agonists (LABAs) provides better asthma control than high-dose ICS alone. As a result, combination therapy is recommended for patients not controlled with low-dose ICS alone.

[0004] However, despite maximum recommended treatment with a combination of anti-inflammatory and bronchodilator medications, an estimated 5% to 10% of the asthma population has symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of total healthcare costs due to hospitalizations, emergency service use, and unscheduled physician visits. Because many of these patients are poorly responsive to ICS due to numerous cellular and molecular mechanisms, the need for new therapies in this severe asthma population remains unmet. Additionally, attempts are made to minimize corticosteroid use due to the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and child growth. While the majority of asthma patients are controlled to some degree with current treatments, patients with severe, uncontrolled asthma (e.g., severe corticosteroid-resistant or steroid-intolerant asthma) have few therapeutic treatment options that can adequately manage their disease. The consequence of treatment failure or lack of adherence is loss of asthma control and, ultimately, asthma exacerbations.

[0005] An estimated 45% of patients with severe asthma require systemic glucocorticoids to manage their disease and prevent life-threatening exacerbations associated with increased risk of permanent damage to lung tissue, progressive fixed airway obstruction, and accelerated decline in lung function. However, systemic glucocorticoids act nonselectively and are associated with significant multiorgan toxicity and widespread immunosuppression. There is a need for safer and more effective targeted therapies that prevent exacerbations and lung function impairment, improve asthma symptoms and control, and reduce or eliminate the need for oral glucocorticoids.

[0006] Approximately 20% of patients with asthma are on maximum standard-of-care long-term controller medication. Patients with pulmonary edema have moderate to severe uncontrolled disease with recurrent exacerbations and persistent symptoms despite extensive treatment (including chemotherapy). This population is at increased risk for morbidity, particularly exacerbations, and occupies significant healthcare resources. These patients have substantially reduced lung function despite maximal treatment and are inexorably destined for further loss of lung function. No currently approved treatments have been shown to slow the inexorable decline or consistently and meaningfully increase lung function in these patients. Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is a need in the art for novel targeted therapies for the treatment and / or prevention of asthma. [Means for solving the problem]

[0008] According to one aspect, there is provided a method for treating a subject with severe uncontrolled asthma (e.g., severe steroid-dependent asthma), comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the multiple maintenance doses are administered during a treatment phase comprising an induction phase, an oral corticosteroid (OCS) tapering phase, and an OCS maintenance phase.

[0009] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w). In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0010] In certain embodiments, a subject is administered a loading dose, and the subject is administered a maintenance dose with a dosage regimen of 500 mg q4w or 750 mg q4w.

[0011] In certain embodiments, the loading dose is removed. In certain embodiments, the subject is administered a dose regimen of 500 mg q4w or 750 mg q4w.

[0012] In certain exemplary embodiments, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof, and / or each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

[0013] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks.

[0014] In certain exemplary embodiments, the first maintenance dose of the antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of the antibody or antigen-binding fragment thereof.

[0015] In certain exemplary embodiments, the OCS reduction phase is about 16 weeks in length.

[0016] In certain exemplary embodiments, the subject's OCS use is reduced during the OCS reduction phase. In certain exemplary embodiments, the subject uses 50% or less, 75% or less, or 90% or less of OCS during the maintenance phase compared to the induction phase. In certain exemplary embodiments, the subject's OCS use is reduced to about 5 mg / day or less during the maintenance phase. In other exemplary embodiments, OCS is reduced and / or eliminated, for example, the subject is stopped from their previous OCS dose. In certain exemplary embodiments, OCS administration is completely eliminated from the treatment regimen.

[0017] In certain exemplary embodiments, the subject has a blood eosinophil count of about 150 cells / μL or less. In certain exemplary embodiments, the subject has a blood eosinophil count of greater than about 150 cells / μL. In certain exemplary embodiments, the subject has a blood eosinophil count of greater than about 300 cells / μL.

[0018] In certain exemplary embodiments, the subject experiences a reduction in annualized severe asthma exacerbations. In certain exemplary embodiments, the subject experiences improved lung function as measured by forced expiratory volume (FEV1). In other embodiments, the subject exhibits improved small airway lung function and / or reduced small airway inflammation. In certain embodiments, the improved lung function and reduced inflammation are measured by forced expiratory flow at 25-75% of lung capacity (FEF25-75).

[0019] In certain exemplary embodiments, a subject's OCS use is optimized prior to treatment with the antibody or antigen-binding fragment thereof, hi certain exemplary embodiments, the OCS is prednisone or prednisolone.

[0020] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity-determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0021] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0022] In another embodiment, a method is provided for treating a subject with severe, uncontrolled asthma (e.g., severe steroid-dependent asthma), comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the multiple maintenance doses are administered during a treatment period comprising an induction period, an oral corticosteroid (OCS) reduction period, and a maintenance period, and wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

[0023] In another embodiment, a method is provided for treating a subject with severe, uncontrolled asthma, e.g., severe steroid-dependent asthma, comprising: administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, each maintenance dose being about 300 mg of the antibody or antigen-binding fragment thereof, wherein the multiple maintenance doses are administered during a treatment period comprising an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

[0024] In another aspect, provided is a method for reducing the annualized severe exacerbation rate in a subject with moderate to severe uncontrolled asthma, the method comprising administering to the subject q2w or q4w an antibody or antigen-binding fragment thereof that specifically binds to IL-4R.

[0025] In certain exemplary embodiments, the dosage is 200 mg q2w or 300 mg q2w.

[0026] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0027] In certain embodiments, subjects are administered a loading dose and a maintenance dose, and subjects are administered a dose regimen of 500 mg q4w or 750 mg q4w.

[0028] In certain embodiments, the loading dose is removed. In certain embodiments, the subject is administered a dose regimen of 500 mg q4w or 750 mg q4w.

[0029] In certain exemplary embodiments, the subject has a blood eosinophil count of less than about 150 cells / μl, greater than or equal to about 150 cells / μl, or greater than about 300 cells / μl.

[0030] In certain exemplary embodiments, the subject receives approximately 25×10 -9 (25 ppb) or greater, having an FeNO level of about 50 ppb or greater, or having an FeNO level between about 25 ppb or greater and about 50 ppb.

[0031] In another aspect, there is provided a method for improving FEV1 score in a subject with moderate to severe uncontrolled asthma, the method comprising administering to the subject q2w or q4w an antibody or antigen-binding fragment thereof that specifically binds to IL-4R.

[0032] In certain exemplary embodiments, the dosage is administered at 200 mg q2w or 300 mg q2w, hi certain exemplary embodiments, the dosage is administered at 500 mg q4w or 750 mg q4w.

[0033] In certain exemplary embodiments, the subject has a blood eosinophil count of less than about 150 cells / μl, greater than or equal to about 150 cells / μl, or greater than about 300 cells / μl.

[0034] In certain exemplary embodiments, the subject receives approximately 25×10 -9(25 ppb) or greater, having an FeNO level of about 50 ppb or greater, or having an FeNO level between about 25 ppb or greater and about 50 ppb.

[0035] In another embodiment, the subject exhibits at least a 10%, 15%, 20%, or 25% decrease in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC) at 4, 12, or 24 weeks after administration of the IL-4R antibody or fragment thereof.

[0036] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0037] In another aspect, the present disclosure provides a method for improving the forced expiratory flow rate at 25-75% of lung volume (FEF25-75) score in a subject with moderate to severe uncontrolled asthma, the method comprising administering to the subject q2w or q4w an antibody or antigen-binding fragment thereof that specifically binds to IL-4R.

[0038] In one embodiment, the dosage is 200 mg q2w or 300 mg q2w. In one embodiment, the dosage is 500 mg q4w or 750 mg q4w.

[0039] In one embodiment, the subject has a blood eosinophil count of less than about 150 cells / μl. In one embodiment, the subject has a blood eosinophil count of greater than about 150 cells / μl. In one embodiment, the subject has a blood eosinophil count of greater than about 300 cells / μl.

[0040] In another embodiment, the subject has an FeNO level of about 25 ppb or greater. In another embodiment, the subject has an FeNO level of about 50 ppb or greater. In another embodiment, the subject has an FeNO level of about 25 ppb or greater to about 50 ppb.

[0041] In another embodiment, the subject exhibits at least a 10%, at least a 15%, at least a 20%, or at least a 25% decrease in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC) at 4, 12, or 24 weeks after administration of the IL-4R antibody or fragment thereof.

[0042] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0043] In another aspect, the disclosure provides a method of reducing or eliminating OCS use in a subject suffering from steroid-dependent severe asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds IL-4R; and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein a reduction in OCS use of at least 50% or more, at least 75% or more, or at least 90% or more is achieved 24 weeks after administration of the loading dose.

[0044] In one embodiment, OCS use is reduced to less than 5 mg per day 24 weeks after administration of the loading dose. In another embodiment, the OCS is substantially eliminated after a predetermined period of time (e.g., 1 year) after administration of the loading dose. In certain embodiments, the OCS is substantially eliminated 40 weeks, 45 weeks, 50 weeks, 52 weeks, or more after administration of the loading dose from the first dose.

[0045] In one embodiment, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w). In one embodiment, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof. In one embodiment, each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof. In another embodiment, the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks. In one embodiment, the first maintenance dose of the antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of the antibody or antigen-binding fragment thereof. In one embodiment, the OCS is prednisone or prednisolone.

[0046] In one embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining region (CDR) sequences from the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In one embodiment, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In one embodiment, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0047] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

[0048] In certain embodiments, the subject is administered a loading dose and the subject is given a dose regimen of 500 mg q4w and 750 mg q4w.

[0049] In certain embodiments, the loading dose is removed. In certain embodiments, the subject is administered a dose regimen of 500 mg q4w and 750 mg q4w.

[0050] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is an adult or an adolescent, e.g., 12 years of age or older.

[0051] In another aspect, there is provided a method for treating a subject with moderate to severe oral corticosteroid (OCS)-dependent asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance therapy.

[0052] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity-determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0053] In certain exemplary embodiments, the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

[0054] In certain exemplary embodiments, the loading dose is about 400 mg of the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, each maintenance dose of the antibody or antigen-binding fragment thereof is about 200 mg of the antibody or antigen-binding fragment thereof.

[0055] In certain exemplary embodiments, the subject is 12 years of age or older.

[0056] In certain exemplary embodiments, the OCS is prednisone or prednisolone.

[0057] In another aspect, there is provided a method for treating a subject with moderate to severe asthma and coexisting moderate to severe atopic dermatitis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance therapy.

[0058] In another embodiment, a method for treating a subject with moderate to severe uncontrolled asthma, wherein the onset of asthma occurred at age 40 or older, comprises administering to a subject an interleukin-4 receptor (IL-4R) and administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to the asthma targeting antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

[0059] In another aspect, provided is a method for treating a subject with moderate to severe uncontrolled asthma and one or both of coexisting chronic rhinosinusitis and nasal polyposis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance therapy.

[0060] In another aspect, a method is provided for treating a subject with moderate to severe uncontrolled asthma and coexisting allergic rhinitis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance therapy.

[0061] In another aspect, there is provided a method for improving allergic rhinitis-related quality of life in a subject with moderate to severe uncontrolled asthma and comorbid allergic rhinitis, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

[0062] In another aspect, there is provided a method for improving quality of life associated with allergic rhinitis in a subject with oral corticosteroid-dependent asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

[0063] In certain exemplary embodiments, morning and evening asthma symptoms throughout the day are improved.

[0064] In certain exemplary embodiments, the oral corticosteroid-dependent asthma is oral corticosteroid-dependent severe asthma.

[0065] In another aspect, there is provided a method for improving asthma control in a subject with oral corticosteroid-dependent asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

[0066] In certain exemplary embodiments, the quality of life associated with a health condition is improved.

[0067] In certain exemplary embodiments, the oral corticosteroid-dependent asthma is oral corticosteroid-dependent severe asthma.

[0068] Other embodiments will become apparent from review of the subsequent detailed description, drawings, tables, and appended claims.

[0069] The above and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. The file of this patent contains at least one drawing / photograph executed in color. Copies of this application with color drawing(s) / photograph(s) will be provided by the (U.S. Patent and Trademark) Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0070] [Figure 1] Figure 1 depicts the Venture (EFC13691) study design for the phase 3 clinical trial. EOS is end of study, EOT is end of treatment, OCS is oral glucocorticoid, q2w is every 2 weeks, and R is the randomization visit. a 600 mg (or matching placebo) loading dose on day 1; b Randomization and first study drug administration occurred at this visit; c The screening period can be increased to 10 weeks for patients who experience an asthma exacerbation requiring a change in glucocorticoid dose to allow for 2 weeks of stabilization before randomization. [Figure 2] FIG. 1 is a CONSORT diagram showing patient demographics for the Venture (EFC13691) study. [Figure 3] 1 is a chart showing baseline demographics for the patient population. [Figure 4-1] Figures 4A-4D graphically depict the primary and secondary endpoints during the 24-week treatment period in the intention-to-treat (ITT) population. Figure 4A depicts the primary and secondary oral glucocorticoid endpoints at Week 24. Figure 4B depicts the annualized rate of severe exacerbations. Figure 4C depicts the change in pre-bronchodilator FEV1(L). Figure 4D depicts the change in FeNO (ppb). [Figure 4-2] Continued from Figure 4-1. [Figure 5A] Figure 5A depicts results by baseline blood eosinophil subgroup at week 24. Figure 5A depicts primary endpoint data. [Figure 5B] Figure 5B depicts results by baseline blood eosinophil subgroup at week 24. Figure 5B depicts secondary oral glucocorticoid endpoint data. [Figure 6A] FIG. 6A depicts severe asthma exacerbations during the 24-week treatment period by baseline blood eosinophil subpopulation (FIG. 6A). [Figure 6B] FIG. 6B depicts pre-bronchodilator FEV1(L) during the 24-week treatment period by baseline blood eosinophil subpopulation. [Figure 7] FIG. 1 depicts the Quest study design for the Phase 3 clinical trial. [Figure 8] FIG. 1 shows patient demographics for the Quest study. [Figure 9A] FIG. 9B graphically depicts severe asthma exacerbations in the ITT population and subgroups defined by baseline blood eosinophils ≧150 cells / μl and ≧300 cells / μl (FIG. 9A), and subgroups defined by baseline FeNO levels <25 ppb, 25 ppb≦FeNO levels <50 ppb, and FeNO levels ≧50 ppb (FIG. 9B). [Figure 9B]FIG. 9B graphically depicts severe asthma exacerbations in the ITT population and subgroups defined by baseline blood eosinophils ≧150 cells / μl and ≧300 cells / μl (FIG. 9A), and subgroups defined by baseline FeNO levels <25 ppb, 25 ppb≦FeNO levels <50 ppb, and FeNO levels ≧50 ppb (FIG. 9B). [Figure 10-1] 10A-10C depict the change from baseline in FEV1 over time in the ITT population (FIG. 10A) and in subgroups defined by baseline blood eosinophils ≧150 cells / μl and ≧300 cells / μl (FIG. 10B), and by baseline FeNO levels <25 ppb, 25 ppb≦FeNO levels <50 ppb, and FeNO levels ≧50 ppb (FIG. 10C) at week 12. [Figure 10-2] Continued from Figure 10-1. [Figure 11A] Figure 11A graphically depicts post-hoc analysis of severe asthma exacerbations (Figure 11A) and change from baseline in FEV1 (Figure 11B) in patients with high (≥25 ppb) or low (<25 ppb) baseline FeNO levels and high (≥150 cells / μl) or low (<150 cells / μl) baseline blood eosinophils. [Figure 11B] Figure 11A graphically depicts post-hoc analysis of severe asthma exacerbations (Figure 11A) and change from baseline in FEV1 (Figure 11B) in patients with high (≥25 ppb) or low (<25 ppb) baseline FeNO levels and high (≥150 cells / μl) or low (<150 cells / μl) baseline blood eosinophils. [Figure 12] Figure 1 depicts baseline demographic and clinical characteristics of adolescents (n=107) and adults (n=1795). Bold text highlights significant differences between subgroups. FeNO, exhaled nitric oxide concentration; LABA, long-acting beta-agonists; SD, standard deviation. [Figure 13]Figures 13-13B graphically depict the reduction in severe exacerbations and improvement in FEV1 in the overall intention-to-treat (ITT) population. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; X, 300 mg q2w dupilumab. ***P<0.001 vs. placebo. CI, confidence interval; LS, least squares; SE, standard error; arrow, primary endpoint. [Figure 14A] Graphical depiction of reduction in severe exacerbation rates in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; orange, 200 mg q2w dupilumab; blue, 300 mg q2w dupilumab. ***P<0.001 vs. placebo; NS, not significant. [Figure 14B] Graphical depiction of reduction in severe exacerbation rates in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; orange, 200 mg q2w dupilumab; blue, 300 mg q2w dupilumab. ***P<0.001 vs. placebo; NS, not significant. [Figure 15] 15A-15B graphically depict improvements in FEV1 at weeks 12 and 52 in adolescents and adults. Despite higher baseline levels, adolescents experienced greater increases in FEV1. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 16] 16A-16B graphically depict improvements in FEV1 during the 52-week treatment period in adolescents and adults. *P<0.05, **P<0.01 vs. placebo. [Figure 17] Figure 1 depicts that adverse event profiles were comparable between subgroups (safety populations). Eosinophilia was identified as an AE with an HLT as eosinophilic disorder or a PT as increased eosinophil count. HLT, high-level term; PT, preferred term; SAE, severe adverse event; TEAE, treatment-emergent adverse event. [Figure 18]18A-18B graphically depict the improvement in percent predicted FEV1 over a 52-week treatment period in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; X, 300 mg q2w dupilumab. *P<0.05, **P<0.01 vs. placebo. [Figure 19] 19A-19B graphically depict FeNO levels during the 52-week treatment period in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; X, 300 mg q2w dupilumab. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 20] 20A-20B graphically depict ACQ-5 scores during the 52-week treatment period in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; X, 300 mg q2w dupilumab. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 21] 21A-21B graphically depict AQLQ scores during the 52-week treatment period in adolescents and adults. Light gray circles, 1.14 mL placebo; dark gray circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; X, 300 mg q2w dupilumab. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 22] FIG. 1 depicts TEAEs (PTs) occurring in ≥10% of patients by adolescent and adult subgroup (safety population). [Figure 23] FIG. 1 depicts conjunctivitis TEAE information (safety population). [Figure 24] Figure 1 depicts Eosinophilia TEAE information (safety population). Eosinophilia is identified as an AE with an HLT as Eosinophilic Disorder or a PT as Eosinophil Count Increased. [Figure 25-1]25A-25D depict the effect of dupilumab during the 24-week treatment period on AM symptom scores in the ITT population (FIG. 25A) and the subgroup of patients who reduced OCS use by 100% by week 24 (FIG. 25B), as well as on PM symptom scores in the ITT population (FIG. 25C) and the subgroup of patients who reduced OCS use by 100% by week 24 (FIG. 25D). *P<0.05, ***P<0.001. SE, standard error. Triangles, placebo; circles, 300 mg q2w dupilumab. [Figure 25-2] Continuation of Figure 25-1. [Figure 26] Figures 26A-26B depict the effect of dupilumab on asthma control and HRQoL in patients with OCS-dependent severe asthma, showing ACQ-5 scores (Figure 26A) and AQLQ total scores (Figure 26B). *P<0.05, *P<0.01, ***P<0.001. SE, standard error. The minimum clinically important difference is 0.5 for all scales. Triangles, placebo; circles, 300 mg q2w dupilumab. [Figure 27-1] FIG. 1 depicts the effect of dupilumab on severe exacerbation rate, FEV1, and FEV1 / FVC ratio in patients with moderate to severe uncontrolled asthma who were older than 40 years at the time of asthma onset and had an FEV1 / FVC<0.7 or ≥0.7 after baseline bronchodilator use. [Figure 27-2] Continuation of Figure 27-1. DETAILED DESCRIPTION OF THE INVENTION

[0071] Before describing the present invention, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0072] 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 invention belongs.

[0073] As used herein, the term "about," when used in reference to a specific recited numerical value, means that the value may vary by 1% or less from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0074] As used herein, the terms "treat," "treating," or similar terms refer to the alleviation of symptoms, the temporary or permanent removal of the cause of symptoms, or the like. or to prevent or delay the onset of symptoms of the named disorder or condition.

[0075] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0076] Methods for reducing the incidence of asthma exacerbations The present invention includes a method for reducing the incidence of asthma exacerbations in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. According to certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. Exemplary anti-IL-4R antibodies that can be used in connection with the methods featured in the present invention are described elsewhere herein. As used herein, the term "asthma exacerbation" refers to an increase in the severity and / or frequency and / or duration of one or more symptoms or signs of asthma. "Asthma exacerbation" also includes any deterioration in a subject's respiratory health that requires and / or is treatable by therapeutic intervention for asthma (e.g., steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.). There are two types of asthma exacerbation events: loss of asthma control (LOAC) events and severe exacerbation events.

[0077] According to certain embodiments, a loss of asthma control (LOAC) event is defined as one or more of the following events: (a) 6 or more additional puffs of salbutamol / albuterol or levosalbutamol / levalbuterol relief medication in a 24-hour period on 2 consecutive days (compared to baseline); (b) a 4-fold or greater increase in the ICS dose at Visit 2; and (c) systemic corticosteroid use for 3 or more days; or (d) asthma hospitalization or emergency department visit requiring systemic corticosteroids.

[0078] In certain cases, an asthma exacerbation may be categorized as a "severe asthma exacerbation event." A severe asthma exacerbation event refers to an incident requiring immediate intervention, where the intervention is in the form of treatment with either systemic or inhaled corticosteroids at four or more times the dose taken prior to the incident. According to certain embodiments, a severe asthma exacerbation event is defined as an asthma worsening requiring the use of systemic corticosteroids for three or more days; or asthma hospitalization or emergency department visit requiring systemic corticosteroids. Thus, the general term "asthma exacerbation" includes and encompasses the more specific subcategory of "severe asthma exacerbation." Accordingly, methods for reducing the incidence of severe asthma exacerbations in patients in need thereof are included.

[0079] A "reduced incidence" of asthma exacerbations means that a subject receiving a pharmaceutical composition comprising an IL-4R antagonist experiences fewer asthma exacerbations (i.e., at least one less exacerbation) after treatment than before treatment, or does not experience an asthma exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14 weeks, or more) after initiation of treatment with the pharmaceutical composition. Alternatively, a "reduced incidence" of asthma exacerbations means that the likelihood of a subject experiencing an asthma exacerbation after administration of the pharmaceutical composition is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) compared to a subject not receiving the pharmaceutical composition.

[0080] The present invention provides a method for reducing the incidence of asthma exacerbations in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist and administering to the subject one or more maintenance doses of an inhaled corticosteroid (ICS) and / or a second long-term controller medication. The method includes administering to the subject one or more maintenance doses of an ICS, such as a long-acting beta-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., Flovent™), budesonide, momentasone (e.g., mometasone furoate, e.g., Asmanex™), flunisolide (e.g., Aerobid™), dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort™), beclomethasone dipropionate HFA (Qvar™), and the like. Suitable LABAs include, but are not limited to, salmeterol (e.g., Serevent™), formoterol (e.g., Foradil™), and the like. Suitable LTAs include, but are not limited to, montelukast (e.g., Singulaire™), zafirlukast (e.g., Accolate™), and the like.

[0081] The present invention includes a method for reducing the incidence of asthma exacerbations in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, and administering to the subject one or more acute treatments to eliminate or reduce one or more asthma-related symptoms. Suitable acute treatments include, but are not limited to, fast-acting β2-adrenergic receptor agonists, such as albuterol (i.e., salbutamol, e.g., Proventil™, Ventolin™, Xopenex™, etc.), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), etc.

[0082] Methods for improving asthma-related parameters The present invention also includes a method for improving one or more asthma-related parameters in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbations (as described above) may be correlated with an improvement in one or more asthma-related parameters; however, such a correlation may not be observed in all cases.

[0083] Examples of "asthma-related parameters" include: (1) the relative percent change from baseline (e.g., at week 12) in forced expiratory flow in 1 second (FEV1); (2) the relative percent change from baseline (e.g., at week 12) as measured by forced expiratory flow at 25-75% of lung capacity (FEF25-75); (3) the annualized rate of asthma control loss events during the treatment period; (4) the annualized rate of severe exacerbation events during the treatment period; (5) the time to asthma control loss events during the treatment period; (6) the time to severe exacerbation events during the treatment period; (7) the time to asthma control loss events during the entire study period; (8) the time to severe exacerbation events during the entire study period; (9 ) Healthcare resource utilization; (10) Change from baseline at Week 12 in: i) morning and evening asthma symptom scores, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations / day of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief, vi) nighttime awakenings; (11) Change from baseline at Weeks 12 and 24 in: i) 22-item Sinus Outcome Test (SNOT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement in asthma-related parameters" means FEV1, AM PEF, or PM PEF. "Baseline" refers to an increase from baseline in one or more of PEF and / or a decrease from baseline in one or more of daily albuterol / levalbuterol use, ACQ5 score, mean number of nighttime awakenings, or SNOT-22 score. As used herein, the term "baseline" with respect to an asthma-related parameter refers to the value of the asthma-related parameter for a patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0084] To determine whether asthma-related parameters are " improved ", the parameters are quantified at baseline and at the time point after administration of pharmaceutical compositions described herein.For example, after the first treatment with pharmaceutical compositions, asthma-related parameters can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th day, or at the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th or more time points. The difference between the parameter value at a particular time point after treatment initiation and the parameter value at baseline is used to establish whether there has been an "improvement" (e.g., an increase or decrease, as the case may be, depending on the specific parameter being measured) in the asthma-related parameter.

[0085] As used herein, the term "obtain" or "obtaining" refers to obtaining a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, such as an asthma-related parameter. "Directly obtaining" means performing a process (e.g., performing a synthesis or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving a physical entity or value from another party or source (e.g., a laboratory of a third party that directly obtained the physical entity or value). Directly obtaining a physical entity includes performing a process that involves a physical change of a physical substance, e.g., a starting material. Exemplary changes include producing a physical entity from two or more starting materials, covalently or fragmenting a material, separating or purifying a material, combining two or more separate entities into a mixture, and performing a chemical reaction that involves the breaking or forming of a covalent or non-covalent bond. Obtaining a value directly includes performing a process that involves a physical change of a sample or another substance, for example, performing an analytical process (sometimes referred to herein as a "physical analysis") that involves a physical change of a substance, such as a sample, analyte, or reagent.

[0086] Indirectly obtained information may be provided in the form of a report, such as from an online database or application ("App"), and may be provided in paper or electronic form, for example. The report or information may be provided, for example, by a medical facility, such as a hospital or clinic; or by a medical provider, such as a doctor or nurse.

[0087] Forced Exhausted Volume in One Second (FEV1). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in forced expiratory volume in one second (FEV1). Methods for measuring FEV1 are known in the art. For example, a patient's FEV1 can be measured using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommended criteria. The ATS / ERS standardization of spirometry may be used as a guideline. Spirometry is typically performed between 6 and 10 AM after abstaining from albuterol for at least six hours. Pulmonary function testing is typically performed in a sitting position, with the highest FEV1 (in liters) measured being recorded.

[0088] The present invention includes methods of treatment that result in an increase in FEV1 from baseline of at least 0.05 L at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof results in an increase in FEV1 from baseline of about 0.05 L, 0.10 L, 0.12 L, 0.14 L, 0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L, 0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L, 0.48 L, 0.50 L, or more at week 12.

[0089] FEF25-75%. According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase in FEF25-75% from baseline. Methods for measuring FEF are known in the art. For example, a patient's FEV1 can be measured using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommended standards. FEF25-75 (forced expiratory flow between 25% and 75%) is the rate (in liters per second) at which a person can empty half of their air during maximal expiration (i.e., forced vital capacity or FVC). This parameter relates to the average flow rate from when 25 percent of the FVC is exhaled to when 75 percent of the FVC is exhaled. A subject's FEF25-75% provides information about peripheral airway function, such as the extent of small airway disease and / or inflammation. Changes in FEF25-75 are an early indicator of obstructive pulmonary disease. In certain embodiments, the improvement and / or increase in the FEF25-75% parameter is at least a 10%, 25%, 50% or more improvement compared to baseline. In certain embodiments, the methods of the invention result in a normal FEF25-75% value in a subject (e.g., a value ranging from 50-60% to 130% of the mean value).

[0090] Morning and Evening Peak Expiratory Flow Rates (AM PEF and PM PEF). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in morning (AM) and / or evening (PM) peak expiratory flow rates (AM PEF and / or PM PEF). Methods for measuring PEF are known in the art. For example, according to one method for measuring PEF, a patient is provided with an electronic PEF meter to record morning (AM) and evening (PM) PEF (as well as daily albuterol use, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring rescue medication). The patient is instructed on the use of the device, and written instructions for using the electronic PEF meter are provided to the patient. In addition, a medical professional may instruct the patient on how to record variables directly relevant to the patient on the electronic PEF meter. AM PEF is typically performed within 15 minutes of waking up (between 6 PM and 10 PM) and before any albuterol intake. PM PEF is typically performed in the evening (between 6:00 AM and 10:00 AM) before any albuterol intake. Subjects should attempt to abstain from albuterol for at least 6 hours before PEF measurement. Three PEF efforts are performed by the patient, and all three values ​​are recorded by an electronic PEF meter. The highest value is typically used for evaluation. Baseline AM PEF can be calculated as the average AM measurements recorded during the 7 days prior to administration of the first dose of a pharmaceutical composition containing an IL-4R antagonist, and baseline PM PEF can be calculated as the average PM measurements recorded during the 7 days prior to administration of the first dose of a pharmaceutical composition containing an IL-4R antagonist.

[0091] The present invention includes methods of treatment that result in an increase from baseline in AM PEF and / or PM PEF of at least 1.0 L / min 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, according to the present invention, administration of an IL-4R antagonist to a subject in need thereof results in an increase in PEF from baseline of about 0.5 L / min, 1.0 L / min, 1.5 L / min, 2.0 L / min, 2.5 L / min, 3.0 L / min, 3.5 L / min, 4.0 L / min, 4.5 L / min, 5.0 L / min, 5.5 L / min, 6.0 L / min, 6.5 L / min, 7.0 L / min, 7.5 L / min, 8.0 L / min, 8.5 L / min, 9.0 L / min, 9.5 L / min, 10.0 L / min, 10.5 L / min, 11.0 L / min, 12.0 L / min, 15 L / min, 20 L / min, or more at week 12.

[0092] Albuterol / levalbuterol use. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in daily albuterol or levalbuterol use. The number of albuterol / levalbuterol inhalations is recorded daily by the patient using a diary, PEF meter, or other recording device. The medical treatments described herein may be used to treat a variety of conditions, including: During treatment with the pharmaceutical composition, albuterol / levalbuterol is typically used as needed for symptoms, rather than regularly or prophylactically. Baseline albuterol / levalbuterol inhalations per day can be calculated based on the average number of inhalations over the 7 days prior to the first dose of the pharmaceutical composition containing an IL-4R antagonist.

[0093] The present invention includes methods of treatment that result in a reduction of albuterol / levalbuterol use from baseline by at least 0.25 puffs per day at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof results in a reduction of albuterol / levalbuterol use from baseline by about 0.25 puffs per day, 0.50 puffs per day, 0.75 puffs per day, 1.00 puffs per day, 1.25 puffs per day, 1.5 puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day, or more at week 12.

[0094] OCS Use. According to certain embodiments, the administration of an IL-4R antagonist to a patient can be combined with an OCS, such as oral prednisone. The number of OCS doses is recorded daily by the patient using a diary, a PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, short-term prednisone use can sometimes be used to manage acute asthma episodes, for example, episodes in which symptoms cannot be controlled by bronchodilators and other anti-inflammatory drugs. In other embodiments, prednisone is used in combination with or as a substitute for ICS. Oral prednisone can be administered in a dosage of approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. OCS can optionally be administered once a day or multiple times a day (e.g., twice a day, three times a day, four times a day, etc.).

[0095] In certain exemplary embodiments, the present invention provides methods for reducing or eliminating a subject's dependence on OCS use. Reducing or eliminating steroid dependence is highly advantageous and desirable. In certain embodiments, a 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or greater) reduction in OCS dosage is achieved after administration of IL-4R antibody treatment for a predetermined period of time (e.g., at week 24). In certain embodiments, OCS is substantially eliminated 40, 45, 50, 52, or more weeks after the initial dose following administration of a loading dose. In other embodiments, OCS use levels are reduced to less than 5 mg per day (e.g., less than 5 mg, less than 4 mg, less than 3 mg, less than 2 mg, or less per day). In other embodiments, dependence on OCS use is substantially eliminated 3 months, 6 months, 9 months, or 1 year after treatment with an IL4R antibody or fragment thereof.

[0096] 5-Item Asthma Control Questionnaire (ACQ) Score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the 5-Item Asthma Control Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[0097] The present invention includes methods of treatment that result in a reduction of at least 0.10 points from baseline in ACQ5 score at Week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof results in a reduction of about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more from baseline in ACQ score at Week 12.

[0098] Nocturnal Awakenings. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the mean number of nocturnal awakenings.

[0099] In certain embodiments, the method reduces the average nighttime awakenings from baseline by at least about 0.10 per night at 12 weeks after starting treatment. For example, administering an IL-4R antagonist to a subject in need thereof reduces the average nighttime awakenings from baseline by about 0.10 per night, 0.15 per night, 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0.50 per night, 0.55 per night, 0.60 per night, 0.65 per night, 0.70 per night, 0.75 per night, 0.80 per night, 0.85 per night, 0.90 per night, 0.95 per night, 1.0 per night, 2.0 per night or more at 12 weeks.

[0100] 22-Item Sinus Outcome Test (SNOT-22) Score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the 22-Item Sinus Outcome Test (SNOT-22). The SNOT-22 is a validated questionnaire for assessing the impact of chronic sinusitis on quality of life (Hopkins et al., 2009, Clin. Otolaryngol. 34:447-454).

[0101] The present invention includes methods of treatment that result in at least a 1-point decrease from baseline in SNOT-22 score at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof can result in about a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more point decrease from baseline in SNOT-22 score at week 12.

[0102] Biomarkers. In certain embodiments, the subject experiences improved lung function as measured by a biomarker, for example, a biomarker associated with severe steroid-dependent asthma or severe uncontrolled asthma. For example, the biomarker can be exhaled nitric oxide (FeNO), eotaxin-3, total IgE, periostin, or thymus and activation-regulated chemokine (TARC). In certain embodiments, the improvement in lung function is indicated by a decrease or increase (as appropriate) at 4 weeks, 12 weeks, or 24 weeks after treatment.

[0103] Methods for Treating Asthma In some embodiments, the present invention provides a method for treating asthma (including, for example, moderate to severe uncontrolled asthma or inadequately controlled asthma) in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. In certain embodiments, the method is useful for treating moderate to severe uncontrolled asthma in a subject.

[0104] As used herein, the term "asthma" can be used interchangeably with "intermittent asthma" or "bronchial asthma." "Asthma," "bronchial asthma," and "intermittent asthma" refer to asthma in which one or any combination of the following applies: symptoms occur 2 days or less per week; symptoms do not interfere with daily life; nighttime symptoms occur 2 days or less per month; or one or more pulmonary function tests (e.g., forced expiratory volume in 1 second (FEV1) and / or peak expiratory flow rate (PEF) greater than 80%) are normal when the subject is not experiencing an asthma attack.

[0105] As used herein, the term "persistent asthma" or "persistent bronchial asthma" refers to asthma that is more severe than (bronchial) asthma / intermittent (bronchial) asthma. Subjects suffering from persistent asthma or persistent bronchial asthma experience one or more of the following: symptoms more than 2 days per week; symptoms that interfere with daily life; nighttime symptoms that occur more than 2 days per month; or one or more pulmonary function tests that are not normal when the subject is not experiencing an asthma attack (e.g., forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF) less than 80%); the subject relies on asthma control medications on a daily basis; the subject has taken systemic steroids more than once after a severe asthma exacerbation in the last year; or the use of short-acting beta-2 agonists more than two days per week for relief of asthma symptoms.

[0106] Asthma / intermittent asthma, bronchial asthma / intermittent asthma, and persistent asthma / persistent asthma can be categorized as "mild," "moderate," "severe," or "moderate-severe." "Mild intermittent asthma" or "mild intermittent asthma" is defined as symptoms occurring less than once a week and having a forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF) ≥ 80%. "Mild persistent asthma" or "mild persistent asthma" differs in that symptoms occur more frequently than once a week but less than once a day and that FEV1 or PEF fluctuates by < 20%-30%. "Moderate intermittent asthma" or "moderate intermittent asthma" is defined as symptoms occurring less than once a week and having a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60-80%. "Moderate persistent asthma" or "moderate persistent asthma" is defined as having exacerbations that may affect daily symptoms, activities, and / or sleep, nocturnal symptoms more than once a week, daily use of inhaled short-acting beta-2 agonists, and having a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60-80%. "Severe intermittent asthma" or "severe intermittent asthma" is defined as symptoms occurring less than once a week and having a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60%. "Severe persistent asthma" or "severe persistent asthma" is defined as frequent exacerbations that may affect daily symptoms, activities, and / or sleep, frequent nocturnal symptoms, limited physical activity, daily use of inhaled short-acting beta-agonists, and having a forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF) of 60%. "Moderate-to-severe intermittent asthma" or "moderate-to-severe intermittent asthma" is defined as having symptoms between those of moderate intermittent asthma / moderate intermittent asthma and those of severe intermittent asthma / severe intermittent asthma. "Moderate-to-severe persistent asthma" or "moderate-to-severe persistent bronchial asthma" is defined as having symptoms between those of moderate persistent asthma / moderate persistent bronchial asthma and those of severe persistent asthma / severe persistent bronchial asthma.

[0107] As used herein, the term "inadequately controlled asthma" refers to the condition described in Expert Panel Report 3: Guidelines for the Diagnosis and Treatment of Asthma. Patients with poorly controlled asthma are either "poorly controlled" or "very poorly controlled" as defined by the "Asthma and Management of Asthma," National Heart, Blood and Lung Institute, NIH, August 28, 2007. "Poorly controlled asthma" is defined as symptoms more than 2 days per week, nighttime awakenings 1-3 times per week, some limitation in daily activities, use of short-acting beta-agonists for symptom control more than 2 days per week, FEV1 of 60-80% of best predicted and / or best personal, ATAQ score of 1-2, ACQ score of 1.5 or greater, and ACT score of 16-19. "Severely poorly controlled asthma" is defined as daytime symptoms, nocturnal awakenings four or more times per week, severe limitations in daily activities, use of short-acting beta-agonists several times per day to control symptoms, FEV1 less than 60% of best predicted and / or personal best, ATAQ score of 3-4, ACQ score not applicable, and ACT score of 15 or less.

[0108] In some embodiments, the subject is on a steroid regimen in accordance with the Global Initiative for Asthma Management (GINA) 2009 guidelines and one or more of the following criteria: i) moderate or high dose ICS / LABA (2x propionate fumarate) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist. A patient was defined as having moderate to severe uncontrolled asthma if they had a physician-diagnosed moderate to severe uncontrolled asthma based on one or more of the following events within 1 year prior to the loading dose of an IL-4R antagonist: (a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, or (b) hospitalization or emergency / urgent care visit for asthma exacerbation.

[0109] "Severe asthma" refers to asthma that cannot be adequately controlled by high-dose treatment with inhaled corticosteroids and additional long-term controller medications (e.g., long-acting inhaled beta-agonists, montelukast, and / or theophylline) or by oral corticosteroid treatment (e.g., for at least 6 months per year), or that loses adequate control when treatment is reduced. In certain embodiments, severe asthma includes asthma treated with high-dose ICS and at least one additional long-term controller medication (e.g., LABA, montelukast, or theophylline) or oral corticosteroids for more than 6 months per year, in which at least one of the following occurs or would occur when treatment is reduced: ACT<20 or ACQ>1.5; at least two exacerbations in the last 12 months; at least one exacerbation in the last 12 months that was treated in a hospital or required mechanical ventilation; or FEV1<80% (when FEV1 / FVC is below the lower limit of normal).

[0110] "Steroid-dependent asthma" refers to asthma that requires one or more of the following treatments: frequent short-term oral corticosteroid treatment bursts within the past 12 months; regular use of high-dose inhaled corticosteroids within the past 12 months; regular use of injectable long-acting corticosteroids; daily use of oral corticosteroids; alternate-day oral corticosteroids; or long-term use of oral corticosteroids within the past year.

[0111] "Oral corticosteroid-dependent asthma" refers to a subject with three or more 30-day oral corticosteroid (OCS) prescriptions over a 12-month period and a primary asthma diagnosis within 12 months of the first OCS prescription. Subjects with OCS-dependent asthma may also experience one or any combination of the following: at least three months of physician-prescribed LABA and high-dose IS (total daily dose >500 μg receiving fluticasone propionate dry powder equivalent) (ICS and LABA can be part of a combination product or given in separate inhalers); receiving additional maintenance asthma long-term controller medications according to standard practice, e.g., leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), second-line ICS, and cromone; receiving OCS for the treatment of asthma at a dose of 7.5 mg to 30 mg (prednisone or prednisolone equivalent); receiving an OCS dose every other day (or a different dose every other day); FEV1 < 80% predicted normal before morning bronchodilator (BD) use; FEV1 ≥ 12% and ≥ 200 mL after BD (albuterol / salbutamol) use (albuterol / salbutamol have evidence of asthma as demonstrated by reversibility of the 4-puff dose (15-30 minutes after administration); or have a history of at least one asthma exacerbation event within 12 months.

[0112] In one aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0113] In another aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of 200 to 299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0114] In another aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 200 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0115] In a related aspect, methods of treating asthma are provided that include add-on therapy to background therapy. In certain embodiments, an IL-4R antagonist is administered as add-on therapy to an asthma patient who has been receiving background therapy for a certain period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or more) (also referred to as a "stable period"). In some embodiments, the background therapy includes an ICS and / or a LABA.

[0116] In some embodiments, the present invention provides a method for reducing an asthma patient's dependence on ICS and / or LABA for the treatment of one or more asthma exacerbations, the method comprising: (a) selecting a patient with moderate to severe asthma uncontrolled on background asthma therapy comprising an ICS, a LABA, or a combination thereof; and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0117] In some embodiments, the invention encompasses methods of treating or alleviating conditions or complications associated with asthma, such as chronic sinusitis, allergic rhinitis, allergic fungal sinusitis, allergic bronchopulmonary aspergillosis, unified airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD), and exercise-induced bronchospasm.

[0118] The present invention also includes a method for treating persistent asthma.As used herein, the term "persistent asthma" means that the subject has symptoms at least once a week, during the day and / or at night, and these symptoms last from a few hours to several days.In certain alternative embodiments, persistent asthma is "mild persistent" (for example, more than twice a week but less than every day, symptoms are severe enough to interfere with daily activities or sleep, and / or lung function is normalized or reversible with inhaled bronchodilators), "moderate persistent" (for example, symptoms occur every day, sleep is disturbed at least once a week, and / or lung function is moderately abnormal), or "severe persistent" (for example, symptoms continue despite the correct use of approved medication, and / or lung function is severely affected).

[0119] Interleukin-4 receptor antagonists Methods of interest in the present invention include administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when expressed in cells in vitro or in vivo. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, IL-4R antagonists include anti-IL-4R antibodies that can be configured in the present invention and used in conjunction with the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises heavy and light chain (complementarity determining regions) C1 from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2. Each contains a DR sequence.

[0120] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor, e.g., IL-4Rα, that specifically binds interleukin-4 (IL-4).

[0121] The term "antibody" refers to immunoglobulin molecules comprising four polypeptide chains (two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds), and multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region comprises three domains: C H 1. C H 2 and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence is defined based on parallel analysis of two or more CDRs.

[0122] The term "antibody" also includes antigen-binding fragments of a complete antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained from complete antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering methods involving the manipulation and expression of DNA encoding antibody variable and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains into a suitable conformation, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0123] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking a hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR), e.g., a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment."

[0124] An antigen-binding fragment of an antibody will generally contain at least one variable domain. The variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in-frame with one or more framework sequences. L V associated with domain H For antigen-binding fragments containing domains, V H and V L The domains can be positioned in any suitable arrangement relative to each other. For example, the variable region is , is a dimer, and V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a monomeric V H or V L It may also contain a domain.

[0125] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary conformations of variable and constant domains that may be found in the antigen-binding fragments of antibodies described herein include the following: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -CH 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any conformation of the variable and constant domains, including any of the exemplary conformations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains within a single polypeptide molecule; generally, the hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Furthermore, antigen-binding fragments of antibodies described herein may be linked to each other and / or to one or more monomeric V H Or V L The variable and constant domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain conformations listed above, in which the domains are non-covalently associated (e.g., by disulfide bonds).

[0126] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will generally comprise at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antigen-binding fragments of antibodies described herein using routine techniques available in the art.

[0127] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0128] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of interest herein may, however, contain amino acid residues (e.g., mutations induced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0129] The term "recombinant human antibody" refers to any human antibody that is produced, expressed, generated, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), or antibodies isolated from an animal (e.g., a mouse) that has been transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295). ), or any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when using animals transgenic for human Ig sequences) so that the V and constant regions of the recombinant antibody are not altered. H and V L The amino acid sequence of the region is human germline V H and V L Derived from human germline V sequences H and V L A sequence that is related to the sequence, but that cannot naturally exist within the human antibody germline repertoire in vivo.

[0130] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150–160 kDa, in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds, and approximately 75–80 kDa molecules are formed by covalently coupled light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0131] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for modifying the hinge, C ... H 2 or C HAntibodies with one or more mutations in three regions are included.

[0132] An "isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism or from the tissue or cell in which it naturally occurs or is naturally produced is an "isolated antibody." Isolated antibodies also include antibodies in situ in vivo within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0133] The term "specifically binds" or similar terms means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4R, as of interest in the present invention, has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured by a surface plasmon resonance assay. D and includes antibodies that bind to IL-4R or a portion thereof. However, an isolated antibody that specifically binds to human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0134] Anti-IL-4R antibodies useful in the method may have one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 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, 31, 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, , 6, 7, 8, 9 or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deletions). Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention includes methods involving the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) within one or more framework and / or one or more (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a trimeric antibody, or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) CDR regions are mutated to the corresponding residue in the germline sequence from which the antibody was derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence exchanges are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce a large number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues within a domain are backmutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, e.g., only mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained by this general methodology are encompassed by the present invention.

[0135] The present invention also includes methods that involve the use of anti-IL-4R antibodies that contain variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein that have one or more conservative substitutions. For example, the present invention includes the use of anti-IL-4R antibodies that have HCVR, LCVR, and / or CDR amino acid sequences that have, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0136] The term "surface plasmon resonance" refers to an optical phenomenon that allows real-time interactions to be analyzed by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0137] The term “K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0138] The term "epitope" refers to a specific antigen binding site within the variable region of an antibody molecule known as a paratope. An epitope refers to an antigenic determinant that interacts with a binding site. A single antigen may have more than one epitope. Therefore, different antibodies may bind to different antigenic regions and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are formed by adjacent amino acids from different segments of a linear peptide chain. Linear epitopes are formed by adjacent amino acid residues within a polypeptide chain. In certain circumstances, epitopes may include carbohydrate, phosphoryl, or sulfonyl moieties on the antigen.

[0139] Human antibody production Methods for producing human antibodies in transgenic mice are known in the art. Any such known method can be used to generate human antibodies that specifically bind to human IL-4R.

[0140] Using VELOCIMMUNE® technology (see, e.g., U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, a high-affinity chimeric antibody against IL-4R containing a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the production of transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0141] Generally, VELOCIMMUNE® mice are sensitized with an antigen of interest, and lymphocytes (e.g., B cells) are collected from the mice that express antibodies. These lymphocytes can be fused with a myeloma cell line to produce immortal hybridoma cell lines, which are then screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions can be isolated and linked to the desired heavy and light chain isotype constant regions. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or heavy and light chain variable domains can be isolated directly from antigen-specific lymphocytes.

[0142] High-affinity chimeric antibodies having human variable regions and mouse constant regions are first isolated. Using standard procedures known to those skilled in the art, the antibodies are characterized and selected for desired characteristics, including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with the desired human constant regions to produce the fully human antibodies of interest in the present invention, such as wild-type or modified IgG1 or IgG4. The constant region selected may vary depending on the specific application, but the variable regions possess high-affinity antigen-binding properties and target specificity.

[0143] Generally, antibodies that can be used in this method have high affinity, as described above, as measured by binding to antigen immobilized on a solid phase or in solution. The mouse constant region is replaced with a desired human constant region to produce the fully human antibody of interest in this invention. The constant region selected may vary depending on the specific application, but the variable region possesses high affinity antigen-binding properties and target specificity.

[0144] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and that can be used in connection with the methods featured in the present invention has three heavy chain CDRs (HCDs) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art, and such methods and techniques can be used to identify CDRs within a particular HCVR and / or LCVR amino acid sequence disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, Kabat, "Sequences of Proteins" of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86, 9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0145] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy chain variable region amino acid and light chain variable region amino acid pairs (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0146] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0147] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0148] In one embodiment, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0149] Pharmaceutical Composition The present invention includes methods comprising administering to a patient an IL-4R antagonist contained in a pharmaceutical composition. Pharmaceutical compositions of interest in the present invention are formulated using suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, etc. Many suitable formulations can be found in formularies known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, (cationic or anionic) lipid-containing vehicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See, e.g., Powell et al., "Compendium of Excipients for Parenteral Formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0150] The dose of antibody administered to a patient may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is generally calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. The effective dosage and schedule for administering a pharmaceutical composition containing an anti-IL-4R antibody can be empirically determined; for example, the patient's progress can be monitored by periodic evaluation, and the dosage can be adjusted accordingly. Furthermore, interspecies scaling of dosage can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0151] Various delivery systems are known, such as liposomes, microparticles, encapsulation in microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432), and such delivery systems can be used to administer the pharmaceutical compositions featured in the present invention. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa), and can be administered together with other bioactive agents.

[0152] The pharmaceutical compositions featured in the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. Additionally, for subcutaneous delivery, pen delivery devices (e.g., autoinjector pens) are readily utilized to deliver the pharmaceutical compositions featured in the present invention. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. Disposable pen delivery devices do not have a replaceable cartridge. Rather, disposable pen delivery devices are prefilled with the pharmaceutical composition, which is held in a reservoir of the device. Once the reservoir is emptied of pharmaceutical composition, the entire device is discarded.

[0153] Numerous reusable pen and autoinjector delivery devices are available for the subcutaneous delivery of pharmaceutical compositions. Examples include the AUTOPEN™ (Owen), to name just a few. Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices utilized for subcutaneous delivery of pharmaceutical compositions of interest in the present invention include the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA™ pen (Amgen), to name just a few. Examples of large volume delivery devices (e.g., large volume injectors) include, but are not limited to, bolus injectors such as BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, and the like.

[0154] For direct administration to the sinuses, the pharmaceutical compositions featured in the present invention may be administered using, for example, a microcatheter (e.g., an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. The method includes administering an IL-4R antagonist in an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-4R may be administered to treat asthma in a patient. Aerosolized antibodies can be prepared, for example, as described in U.S. Pat. No. 8,178,098 (incorporated herein in its entirety).

[0155] In certain circumstances, pharmaceutical compositions can be delivered in controlled release systems. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0156] Injectable preparations include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, and the like. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying the antibody or its salt in a sterile aqueous or oily medium conventionally used for injections. Aqueous media for injections include, for example, saline, isotonic solutions containing glucose and other adjuvants, and the like. These may be used in combination with appropriate solubilizers, such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), and the like. Oily media include, for example, sesame oil and soybean oil, and these may be used in combination with solubilizers, such as benzyl benzoate and benzyl alcohol. The injections prepared in this manner are generally filled into appropriate ampoules.

[0157] Advantageously, the oral or parenteral pharmaceutical compositions described above are prepared in unit dosage forms suitable for containing a dose of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0158] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the present invention are disclosed, for example, in US Patent Application Publication No. 2012 / 0097565.

[0159] Dosage The IL-4R antagonist (e.g., The amount of an IL-4R antagonist (anti-IL-4R antibody) administered is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of an IL-4R antagonist that results in one or more of the following: (a) a reduction in the incidence of asthma exacerbations; (b) an improvement in one or more asthma-related parameters (as defined elsewhere herein), and / or (c) a detectable improvement in one or more symptoms or signs of an upper airway inflammatory condition. A "therapeutically effective amount" also includes an amount of an IL-4R antagonist that inhibits, prevents, relieves, or slows the progression of asthma in a subject.

[0160] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 700 mg of the anti-IL-4R antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 61 mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 1 90mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, About 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400 mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 5 The dose can be 10 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In a specific embodiment, 300 mg of an anti-IL-4R antibody is administered.

[0161] The amount of IL-4R antagonist contained in an individual dose may be expressed in milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of patient body weight. For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0162] In some embodiments, the dose of the IL-4R antagonist may vary depending on the eosinophil count. For example, the subject may have a blood eosinophil count of ≥ 300 cells / μL, or 300-499 cells / μL, or ≥ 500 cells / μL (high blood eosinophils) (HEos), a blood eosinophil count of 200-299 cells / μL (moderate blood eosinophils), or a blood eosinophil count of < 200 cells / μL (low blood eosinophils).

[0163] In certain embodiments, the method includes a loading dose of about 400 to about 600 mg of an IL-4R antagonist.

[0164] In certain embodiments, the method includes one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0165] In certain embodiments, the ICS and LABA are administered during the administration period of the IL-4R antagonist.

[0166] In a specific embodiment, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0167] In a specific embodiment, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0168] In a specific embodiment, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks, which may be increased to 300 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0169] In another embodiment, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0170] In another embodiment, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0171] In another embodiment, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered once weekly.

[0172] In another embodiment, the loading dose comprises 400 mg of an anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered once weekly.

[0173] In another embodiment, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0174] In another embodiment, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0175] In one embodiment, the subject is 6 to under 18 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0176] In another embodiment, the subject is 12 to under 18 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0177] In another embodiment, the subject is between 6 and under 12 years of age, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0178] In another embodiment, the subject is between 2 and under 6 years old, and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0179] In yet another embodiment, the subject is under 2 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0180] Combination treatment Certain embodiments of the methods featured in the present invention may include one or more additional therapeutic agents. The present invention includes administering a therapeutic agent to a subject in combination with an IL-4R antagonist. As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent. The present invention includes methods for treating asthma or related conditions or complications or reducing at least one exacerbation, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0181] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently with" a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0182] The additional therapeutic agent can be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibodies described in U.S. Pat. No. 7,582,298), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal agent, an NSAID, a long-acting beta-2 agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), a methylxanthine, nedocromil sodium, sodium cromoglycate, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered in combination with a combination drug comprising a long-acting beta-agonist and an inhaled corticosteroid (e.g., fluticasone plus salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide plus formoterol [e.g., SYMBICORT® (Astra Zeneca)]).

[0183] Dosing regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined period of time. Such methods include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means administering each dose of an IL-4R antagonist to a subject at different times, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present invention includes methods comprising sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more second doses of the IL-4R antagonist, optionally followed by one or more third doses of the IL-4R antagonist.

[0184] The present invention provides a pharmaceutical composition comprising an IL-4R antagonist at an administration frequency of about 4 times per week, twice per week, once per week (q1w), once every 2 weeks (every other week or q2w), once every 3 weeks (every 3 weeks or q3w), once every 4 weeks (monthly or q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 8 weeks (q8w), once every 12 weeks (q12w), or as directed by a pharmacokinetic profile, ... and administering to a subject less frequently than necessary if a therapeutically effective dose is achieved. In certain embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, weekly administration in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once every two weeks (biweekly administration) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once every three weeks in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once every four weeks (monthly administration) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be administered once every five weeks. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be administered once every six weeks. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be administered once every eight weeks. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be administered once every twelve weeks. In one embodiment, the route of administration is subcutaneous.

[0185] The term "week" refers to a period of (n x 7 days) ± 2 days, e.g., (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0186] The terms "first dose," "second dose," and "third dose" refer to the time sequence of administration of the IL-4R antagonist. Thus, the "first dose" is the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the first dose, and the "third dose" is the dose administered after the second dose. The first, second, and third doses may all contain the same amount of IL-4R antagonist, but will generally differ from each other in terms of administration frequency. However, in certain embodiments, the amount of IL-4R antagonist contained in the first, second, and / or third doses differ from each other during the course of treatment (e.g., adjusted upward or downward as needed). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as "loading doses," followed by subsequent doses (e.g., "maintenance doses") that are administered less frequently. In one embodiment, the maintenance doses may be lower than the loading doses. For example, one or more loading doses of 600 mg of the IL-4R antagonist may be administered, followed by maintenance doses of about 75 mg to about 300 mg.

[0187] In certain embodiments, the loading dose is about 400 to about 600 mg of the IL-4R antagonist. In one embodiment, the loading dose is 400 mg of the IL-4R antagonist. In another embodiment, the loading dose is 600 mg of the IL-4R antagonist.

[0188] In certain embodiments, the maintenance dose is about 200 to about 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist. In another embodiment, the maintenance dose is 300 mg of the IL-4R antagonist.

[0189] In certain embodiments, the loading dose is twice the maintenance dose.

[0190] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 600 mg of the antibody or antigen-binding fragment thereof administered every two weeks. Contains 300mg of fragments.

[0191] In some embodiments, the subject has OCS-dependent asthma, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0192] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0193] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0194] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0195] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every two weeks.

[0196] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0197] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0198] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0199] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0200] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0201] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0202] In one exemplary embodiment, each second and / or third dose is administered 1 to 14 weeks (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5) after the immediately preceding dose. , 12, 12.5, 13, 13.5, 14, 14.5 or more weeks after the first dose of an anti-IL-4R antagonist in a sequence of multiple doses. The phrase "immediately preceding dose" refers to the dose of an anti-IL-4R antagonist administered to a patient prior to the administration of the immediately next dose in the sequence, with no intervening doses.

[0203] The method can include administering any number of second and / or third doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0204] In embodiments comprising multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments comprising multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the second and / or third doses are administered to the patient may vary throughout the course of the treatment regimen. The administration frequency may be adjusted by a physician during the course of treatment according to the needs of an individual patient according to clinical examination.

[0205] The present invention includes methods for treating asthma or a related condition, comprising sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient. In some embodiments, the methods comprise administering one or more doses of an IL-4R antagonist, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more doses) of a second therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-4R antagonist may be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more doses) of a second therapeutic agent (e.g., an inhaled corticosteroid or β2-agonist or other therapeutic agent, as described elsewhere herein) to treat, alleviate, reduce, or ameliorate one or more symptoms of asthma. In some embodiments, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more doses) of an IL-4R antagonist are administered, resulting in an improvement in one or more asthma-related parameters, followed by administration of a second therapeutic agent to prevent the recurrence of at least one symptom of asthma. Alternative embodiments relate to the combined administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more doses) of an IL-4R antagonist are administered, and the second therapeutic agent is administered in a separate dosage amount and at a similar or different frequency compared to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0206] In certain embodiments, the IL-4R antagonist is administered every two weeks for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or more weeks. In other embodiments, the IL-4R antagonist is administered every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or more weeks. In a specific embodiment, the IL-4R antagonist is administered for at least 24 weeks.

[0207] The present invention provides a method for treating a subject with severe, uncontrolled asthma (e.g., severe, steroid-dependent asthma) with The present invention also includes a method for treating IL-4R-associated leukemia, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the method comprises administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, the multiple maintenance doses being administered during a treatment phase. The treatment phase includes an induction phase, an OCS reduction phase, and an OCS maintenance phase.

[0208] In certain exemplary embodiments, the induction phase comprises a period during which the subject receives their OCS dose continuously. In certain exemplary embodiments, the reduction phase comprises a period during which the subject receives a lower OCS dose compared to the dose received during the induction phase. In certain exemplary embodiments, the maintenance phase comprises a period during which the subject receives a constant, stable amount or dose of OCS. Alternatively, the maintenance phase comprises a period during which OCS treatment / administration is reduced / eliminated. In certain embodiments, the patient's OCS use is completely eliminated, and the patient is steroid-free within less than one year of treatment with the IL4R antibody or fragment thereof (e.g., within one year, six months, three months, or one month of initial treatment).

[0209] In another embodiment, a method for treating a subject with severe steroid-dependent asthma and / or severe uncontrolled asthma comprises administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, each maintenance dose being about 300 mg of the antibody or antigen-binding fragment thereof, and the multiple maintenance doses being administered during a treatment period comprising an induction phase, an oral corticosteroid (OCS) tapering phase, and a maintenance phase, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

[0210] Treatment population A method of interest in the present invention involves administering a therapeutic composition containing an IL-4R antagonist to a subject in need thereof. The term "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of asthma (e.g., moderate to severe uncontrolled asthma) or has been diagnosed with asthma. For example, a "subject in need thereof" may include a subject that exhibits (or has exhibited) one or more asthma-related parameters prior to treatment, such as a reduced FEV1 (e.g., less than 2.0 L), a reduced FEF of 25-75%, a reduced AM PEF (e.g., less than 400 L / min), a reduced PM PEF (e.g., less than 400 L / min), an ACQ5 score of at least 2.5, at least one nighttime awakening per night, and / or a SNOT-22 score of at least 20. In various embodiments, the method may be used to treat mild asthma, moderate to severe asthma, and severe asthma in patients in need thereof. In certain embodiments, the methods are used to treat mild, moderate-to-severe, and severe asthma in patients in need thereof, who further exhibit coexisting moderate-to-severe atopic dermatitis.

[0211] In related embodiments, a "subject in need thereof" may be a subject who has been prescribed or is currently taking an ICS / LABA combination prior to receiving an IL-4R antagonist. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABA include formoterol and salmeterol. Examples of ICS / LABA treatment include fluticasone / salmeterol combination treatment and budesonide / formoterol combination treatment. For example, the present invention includes methods comprising administering an IL-4R antagonist to a patient who has been receiving regular ICS / LABA treatment for two or more weeks immediately prior to administration of the IL-4R antagonist (such prior treatment is referred to herein as "background treatment"). The present invention includes methods of treatment in which the background treatment is continued in conjunction with administration of the IL-4R antagonist. In yet other embodiments, The amount of the ICS component, the LABA component, or both is gradually reduced before or after the initiation of administration of the IL-4R antagonist. In some embodiments, the present invention includes a method of treating a patient who has had persistent asthma for at least 12 months or more. In one embodiment, a patient with persistent asthma may be resistant to treatment with therapeutic agents such as corticosteroids, and such a patient may be administered an IL-4R antagonist according to the method.

[0212] In some embodiments, a "subject in need thereof" may be a subject with elevated levels of an asthma-related biomarker. Examples of asthma-related biomarkers include, but are not limited to, IgE, thymus and activation-regulated chemokine (TARC), eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, a "subject in need thereof" may be a subject with blood eosinophils ≥ 300 / μL, 200-299 / μL, or < 200 / μL. In one embodiment, a "subject in need thereof" may be a subject with elevated levels of bronchial or airway inflammation as measured by exhaled nitric oxide (FeNO) levels.

[0213] In some embodiments, the "subject in need thereof" is selected from the group consisting of subjects 18 years of age or older, subjects 12 years of age or older, subjects 12-17 years of age (12-18 years of age), subjects 6-11 years of age (6-12 years of age), and subjects 2-5 years of age (2-6 years of age). In some embodiments, the "subject in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "subject in need thereof" is selected from the group consisting of adults 18 years of age or older, adolescents 12-17 years of age (12-18 years of age), children 6-11 years of age (6-12 years of age), and children 2-5 years of age (2-6 years of age). The subject may be under 2 years of age, e.g., 12-23 months of age, or 6-11 months of age.

[0214] Normal IgE levels in healthy subjects are less than about 100 kU / L (e.g., as measured using the IMMUNOCAP® assay [Phadia, Inc., Portage, MI]). Accordingly, the present invention includes methods comprising selecting a subject exhibiting elevated serum IgE levels, where the serum IgE levels are greater than about 100 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0215] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with a mean value of about 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC quantitative ELISA kit provided by R&D Systems, Minneapolis, MN, under catalog number DDN00.) Accordingly, the present invention includes methods comprising selecting a subject exhibiting elevated TARC levels, where the serum TARC level is greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0216] Eotaxin-3 belongs to a group of chemokines released by airway epithelial cells that are upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al., 1999, J. Allergy Clin. Immunol. 104:786-79). (p. 0). The present invention includes methods comprising administering an IL-4R antagonist to treat a patient with elevated eotaxin-3 levels, e.g., greater than about 100 pg / ml, greater than about 150 pg / ml, greater than about 200 pg / ml, greater than about 300 pg / ml, or greater than about 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0217] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin levels have been found to be upregulated in patients with asthma (Jia et al., 2012, J Allergy Clin Immunol. 130:647-654.e10.doi:10.1016:j.jaci.2012.06.025. Epub 1 Aug. 2012). The present invention includes methods comprising administering an IL-4R antagonist to treat patients with elevated periostin levels.

[0218] Exhaled NO concentration (FeNO) is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines, including IL-4 and IL-13 (Alwing et al., 1993, Eur. Respir. J. 6:1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is by using the NIOX instrument by Aerocrine AB, Solna, Sweden. Assessment can be performed before spirometry and after at least one hour of fasting. The present invention includes methods comprising administering an IL-4R antagonist to a patient with elevated exhaled NO (FeNO) levels, e.g., FeNO levels greater than 30 ppb, greater than about 31 ppb, greater than about 32 ppb, greater than about 33 ppb, greater than about 34 ppb, or greater than about 35 ppb.

[0219] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker that has been shown to correlate with non-neoplastic lung diseases (Marechal et al., 1988, Anticancer Res. 8:677-680). Serum CEA levels can be measured by ELISA. The present invention includes methods comprising administering an IL-4R antagonist to a patient with elevated CEA levels, e.g., greater than about 1.0 ng / ml, greater than about 1.5 ng / ml, greater than about 2.0 ng / ml, greater than about 2.5 ng / ml, greater than about 3.0 ng / ml, greater than about 4.0 ng / ml, or greater than about 5.0 ng / ml.

[0220] YKL-40 (named for its N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L) and having a molecular weight of 40 kD) is a chitinase-like protein that has been shown to be upregulated and correlated with asthma exacerbations, IgE, and eosinophils (Tang et al., 2010, Eur. Respir. J. 35:757-760). Serum YKL-40 levels are measured, for example, by ELISA. The present invention includes methods comprising administering an IL-4R antagonist to a patient with elevated YKL-40 levels, for example, greater than about 40 ng / ml, greater than about 50 ng / ml, greater than about 100 ng / ml, greater than about 150 ng / ml, greater than about 200 ng / ml, or greater than about 250 ng / ml.

[0221] Periostin is a secreted matricellular protein associated with fibrosis, and its expression is upregulated by recombinant IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial fibroblasts (Jia et al., (2012) J. Allergy Clin. Immunol. 130:647). In human asthma patients, periostin expression levels correlate with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Id. The present invention includes methods comprising administering an IL-4R antagonist to a patient with elevated periostin levels.

[0222] Induced sputum eosinophils and neutrophils are established direct markers of airway inflammation (Djukanovic et al., 2002, Eur. Respire. J. 37:1S-2S). Sputum is induced by inhalation of hypertonic saline and processed for cell counting according to methods known in the art, such as the European Respiratory Society guidelines.

[0223] In some embodiments, subjects are stratified into the following groups: blood eosinophil count ≥ 300 cells / μL (high blood eosinophils) (HEos) or 300-499 cells / μL or ≥ 500 cells / μL, blood eosinophil count 200-299 cells / μL (moderate blood eosinophils), or blood eosinophil count < 200 cells / μL (low blood eosinophils) and receive an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dosing regimen based on eosinophil levels.

[0224] In some embodiments, subjects are stratified into the following groups: blood eosinophil count ≧300 cells / μL, 300-499 cells / μL, or ≧500 cells / μL (high blood eosinophils); blood eosinophil count ≧150 cells / μL (moderate blood eosinophils); or blood eosinophil count <150 cells / μL (low blood eosinophils) and are administered an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or administration regimen based on their eosinophil level.

[0225] In some embodiments, the subject has "eosinophilic phenotype" asthma, as defined by a blood eosinophil count of ≥ 150 cells / μL, a blood eosinophil count of ≥ 300 cells / μL, a blood eosinophil count of 300-499 cells / μL, or a blood eosinophil count of ≥ 500 cells / μL, and is administered an anti-IL-4R antibody or antigen-binding fragment thereof.

[0226] Methods for assessing pharmacodynamic asthma-related parameters The present invention also includes methods for assessing one or more pharmacodynamic asthma-related parameters in a subject in need thereof resulting from administration of a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbations (as described above) or an improvement in one or more asthma-related parameters (as described above) may be correlated with an improvement in one or more pharmacodynamic asthma-related parameters, although such a correlation may not be observed in all cases.

[0227] Examples of "pharmacodynamic asthma-related parameters" include, for example, (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement of a pharmacodynamic asthma-related parameter" means, for example, a decrease from baseline in one or more biomarkers, such as TARC, eotaxin-3, or IgE, a decrease in sputum eosinophils or neutrophils, FeNO, periostin, or blood eosinophil count. As used herein, the term "baseline" with respect to a pharmacodynamic asthma-related parameter refers to the value of the pharmacodynamic asthma-related parameter in a patient before or at the time of administration of a pharmaceutical composition described herein.

[0228] To evaluate pharmacodynamic asthma-related parameters, these parameters are quantified at baseline and at the time point after administration of pharmaceutical compositions.For example, after first treatment with pharmaceutical compositions, pharmacodynamic asthma-related parameters can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th day, or at the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th week or more. The difference between the value of a parameter at a specific time point after treatment initiation and the value of the parameter at baseline is used to identify a change, such as an "improvement," in a pharmacodynamic asthma-related parameter (e.g., the specific parameter being measured). The purpose of this study is to establish whether there has been a significant change in the variability of the data (increase or decrease, as the case may be, depending on the underlying parameters).

[0229] In certain embodiments, administration of an IL-4R antagonist to a patient results in a change, e.g., a decrease or increase, in the expression of certain biomarkers. Asthma-related biomarkers include, but are not limited to, (a) total IgE; (b) thymus and activation-regulated chemokine (TARC); (c) YKL-40; (d) serum carcinoembryonic antigen; (e) plasma eotaxin-3; and (f) serum periostin. For example, administration of an IL-4R antagonist to an asthma patient may result in one or more of a decrease in TARC or eotaxin-3 levels or a decrease in serum total IgE levels. The decrease can be detected 1, 2, 3, 4, 5, or later weeks after administration of the IL-4R antagonist. Biomarker expression can be assayed by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured, for example, by reverse transcription-linked polymerase chain reaction (RT-PCR).

[0230] Biomarker expression as discussed above can be assayed by detecting protein or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers related to response to treatment with IL-4R antagonists, IL-4 / IL-13 signaling, asthma, atopic or eosinophilic diseases (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, periostin). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., to determine the RNA levels of biomarkers; in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0231] formulation In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 150 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 25 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80. The pH of the formulation is about 5.9, and the viscosity of the formulation is about 8.5 centipoise.

[0232] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 50 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80. In this case, the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 centipoise.

[0233] In a specific embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:2.

[0234] The present invention is further illustrated by the following examples, which should not be construed as further limiting. The contents of the figures and all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0235] Moreover, in accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are fully explained in the literature. See, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed. (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Vols. I and II (D.N. Glover, eds., 1985); Oligonucleotide Synthesis (M.J. Gait, eds., 1984); Nucleic Acid Hybridization [B.D. Hames and S.J. Higgins, eds. (1985)]; Transcription and Translation [B.D. Hames and S.J. Higgins, eds. (1984)]; Animal Cell Culture [R.I. Freshney, ed. (1986)]; Immobilized Cells and Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M.A.usubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). [Example]

[0236] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0237] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1"). [Example]

[0238] VENTURE Phase III Clinical Trial Study (NCT02528214) Severe, uncontrolled asthma can lead to systemic steroid exposure and dependence on oral corticosteroids. This can result in serious short- and long-term adverse effects, including weight gain, diabetes, osteoporosis, glaucoma, anxiety, depression, cardiovascular disease, and immunosuppression. Patients with severe, chronic asthma live with severely reduced lung function, approximately 52 percent of the predicted normal value for the patients in this study at baseline. Reduced lung function affects the ability to breathe normally and can lead to frequent exacerbations requiring acute treatment and hospitalization. These problems occur even in patients treated with long-term OCS.

[0239] A phase 3 clinical trial / study evaluating investigational dupilumab was conducted in adults and adolescents with severe steroid-dependent asthma, with no minimum blood eosinophil requirement, who received an additional 300 mg of dupilumab or placebo every 2 weeks for 24 weeks. The phase 3 trial (VENTURE) enrolled 210 patients (101 in the dupilumab group and 102 in the placebo group; 203 completed the randomized treatment period) with severe asthma and regular use of maintenance OCS during the 6 months prior to the study (Figure 1). In this study, the prescribed OCS was prednisone or prednisolone. Patients were randomized using a 1:1 randomization ratio to receive either 300 mg of dupilumab every 2 weeks with a loading dose of 600 mg or placebo (Figure 2). The median baseline eosinophil count in this study was 260 eosinophils / microliter. The primary endpoint was reduction in glucocorticoid dose at week 24. Key secondary endpoints included the proportion of patients achieving a ≥ 50% reduction in glucocorticoid dose and a reduction in glucocorticoid dose to < 5 mg / day at week 24. Severe exacerbation rate and pre-bronchodilator forced expiratory volume in 1 second (FEV 1) was evaluated in the overall population and in patients with blood eosinophils ≥ 300 cells / μL. Safety was assessed overall.

[0240] The inclusion criteria for this study are shown below in Table 1. The baseline demographics for this study are shown in Figure 3.

[0241] [Table 1] The exclusion criteria for the Venture study were also used; patient exclusion criteria were EOS<150, limited to no more than 25% of the total population.

[0242] The primary endpoint analyzed was the percent reduction in OCS dose at week 24. Key secondary endpoints analyzed included a 50% or greater reduction in OCS dose and a reduction in OCS dose to <5 mg / day. Other secondary endpoints examined included patients achieving the maximum possible reduction per protocol and patients no longer requiring OCS. Disease-specific efficacy measures were used. The measures were annualized reduction in severe exacerbations and improvement in lung function (FEV1). Figure 2 shows the overall breakdown of patients in this study.

[0243] Primary outcome In the intention-to-treat (ITT) population, dupilumab treatment significantly reduced oral glucocorticoid doses compared with placebo while maintaining asthma control: least-squares (LS) mean (standard error [SE]) percentage change from baseline to week 24 (-70.1% (4.90) vs. -41.9% (4.57) from baseline, respectively (P < 0.001; Figure 4A; Table 2). The observed median change from baseline to week 24 in dupilumab-treated patients was 100% (interquartile range (IQR), 62.5% to 100%) compared with 50% (interquartile range (IQR), 0% to 100%) in the placebo group.

[0244] [Table 2] [Table 3]

[0245] Secondary outcomes Outcomes of glucocorticoid reduction For the primary endpoint, at week 24 in the overall population, dupilumab added to standard of care significantly reduced maintenance oral corticosteroid (OCS) use by 70.1% (median 100 percent) compared with 41.9% (median 50 percent) with placebo (p<0.001).

[0246] In a prespecified analysis of patients with a baseline eosinophil count of 300 cells / microliter or greater, adding dupilumab significantly reduced OCS use by a mean of 80 percent (median 100 percent) compared with 43 percent (median 50 percent) for placebo.

[0247] The proportion of patients achieving a ≥50% reduction in oral corticosteroid dose relative to baseline at week 24 was significantly higher for dupilumab versus placebo (80% vs. 50%; P<0.001; observed: 80% for dupilumab, 53% for placebo) (Figure 4A; Table 2). Sensitivity analyses also demonstrated higher proportions of patients with 50%, 75%, and 90% reductions in oral corticosteroids with dupilumab (Table 3). Significantly more patients treated with dupilumab versus placebo achieved a reduction in oral corticosteroid dose to <5 mg / day (69% vs. 33%; P<0.001; observed: 72% for dupilumab, 37% for placebo) (Figure 4A; Table 2).

[0248] [Table 4]

[0249] Notably, 48% of dupilumab-treated patients versus 26% of placebo-treated patients achieved their maximum possible glucocorticoid dose reduction at week 24 (P = 0.002; observed values: 52% for dupilumab, 30% for placebo) (Figure 4A; Table 2). Similarly, 48% of dupilumab-treated patients versus 25% of placebo-treated patients no longer required oral corticosteroids at week 24 (P = 0.002; observed values: 52% for dupilumab, 29% for placebo) (Figure 4A; Table 2). Dupilumab consistently reduced oral corticosteroid outcome measures regardless of baseline blood eosinophil counts (Figures 5A and 5B; Table 4).

[0250] [Table 5] [Table 6]

[0251] Although improvements were observed in all baseline blood eosinophil subgroups, the magnitude of the treatment effect was greatest in subgroups with higher baseline eosinophil counts (e.g., the odds ratios vs. placebo for patients with a ≥ 50% reduction in oral glucocorticoid dose were 6.59 (95% CI, 2.1-20.4) for patients with ≥ 300 cells / μL at baseline and 2.91 (95% CI, 1.3-6.6) for patients with < 300 cells / μL at baseline). In the overall population, 69 percent of patients receiving dupilumab reduced their OCS dose to < 5 mg per day while maintaining asthma control, compared with 33 percent of patients receiving placebo. In the high EOS group, 84 percent of dupilumab patients were able to reduce their OCS dose to less than 5 mg per day compared with 40 percent for placebo (p equal to 0.0002). Half of the patients completely eliminated oral glucocorticoid use. Despite glucocorticoid reduction, dupilumab versus placebo in the overall population and the ≥ 300 cells / μL EOS subgroup reduced severe exacerbations by 59.3% (P < 0.001) and 71.1%, respectively, and improved FEV1 by 0.22 L (P < 0.001) and 0.32 L, respectively.

[0252] Exacerbations and FEV1 In addition to significantly reducing oral glucocorticoid use during the 24-week treatment period, dupilumab significantly (P<0.001) reduced severe asthma exacerbations versus placebo in the overall population by 59.3% (Figure 4B and Table 7) and improved LS mean (SE) FEV1 by 0.22 L (0.05) at week 24 in the overall population (vs. 0.01 L [0.05] with placebo, P<0.001). Dupilumab reduced the annualized rate of severe asthma exacerbations and improved FEV1 versus placebo regardless of baseline eosinophil count (Figures 6A and 6B, Table 5), but these benefits were more pronounced in patients with higher baseline blood eosinophil counts. For example, dupilumab reduced severe exacerbations by 71.1% and improved FEV1 by LS mean (SE) 0.32 L (95% CI 0.10-0.54) in patients with baseline blood eosinophils ≥ 300 cells / µL (both P < 0.001 vs placebo).

[0253] [Table 7] [Table 8]

[0254] Improvements in FEV1 were rapid and sustained, occurring as early as week 2 (LS mean change 0.15 L; 95% CI 0.04-0.26), and further increased through week 24 (P < 0.05 at all time points) (Figure 4C and Table 2). At week 24, dupilumab improved lung function, as assessed by forced expiratory volume in 1 second (FEV1), by 220 ml (15 percent) compared with a 10 ml difference for placebo in the overall population (P equals 0.0007), and by 320 ml (25 percent) compared with a 120 ml difference for placebo in patients with eosinophil counts of 300 cells / microliter or greater (P equals 0.0049).

[0255] Other secondary and exploratory outcomes The phase 3 study enrolled patients with steroid-dependent severe asthma, regardless of eosinophil levels or other biomarkers, and the results showed improvements in lung function and exacerbations compared with placebo across the following patient subgroups: patients with baseline blood eosinophil counts above 300 cells / microliter; above 150 cells / microliter; and below 150 cells / microliter. Dupilumab demonstrated consistent improvements in lung function across the asthma program for patients with severe asthma who suffer from reduced daily breathing ability.

[0256] ACQ-5 scores at week 24 demonstrated a significant improvement in asthma control with dupilumab versus placebo (P = 0.002) (LS mean difference in change from baseline: -0.47 [95% CI, -0.76 to -0.18]). For dupilumab, the LS mean improvement from baseline at week 24 (-1.05) was twice the minimal clinically important difference of 0.5 for the ACQ-5 instrument.

[0257] Dupilumab treatment suppressed FeNO by week 2, which was maintained throughout the 24-week treatment period (P < 0.001 vs. placebo at all time points; Fig. 4D). The percentage of patients with FeNO < 25 ppb (upper limit of normal) (Table 6) increased from 43.6% at baseline to 84.4% in the dupilumab group, whereas no change was observed in the placebo group (44.7% to 45.1%).

[0258] [Table 9]

[0259] Morning and evening daily asthma symptoms in patients with oral corticosteroid-dependent severe asthma Patients' asthma symptoms were recorded in electronic diaries, scored in the morning for nighttime symptoms (AM symptoms) and in the evening for daytime symptoms (PM symptoms), and rated on a scale from 0 (mildest) to 4 (most severe). Changes from baseline in asthma symptom scores during the 24-week treatment period were analyzed using a mixed-effects model with repeated measures.

[0260] The mean baseline AM / PM symptom scores in the dupilumab and placebo groups, respectively, were 1.37 / 1.37 and 1.50 / 1.52 in the ITT population (n=210) and 1.45 / 1.49 and 1.50 / 1.52 in patients (40.5%) who reduced OCS use by 100% by week 24. In the dupilumab group, symptoms improved rapidly (LS mean change from baseline in AM / PM symptom scores at week 2, -0.18 / -0.23; both P<0.05 vs. placebo), continued to improve through week 16 (-0.47 / -0.47, both P<0.05 vs. placebo), and maintained a positive effect through week 24 (Figures 25A and 25C). Patients in the dupilumab group who reduced OCS use by 100% by week 24 showed a similar pattern of response, with greater symptomatic improvement (Figures 25B and 25D). Overall, the most common treatment-emergent adverse event in dupilumab-treated patients versus placebo-treated patients was eosinophilia (14% versus 1%). Injection site reactions occurred in 9% of dupilumab-treated patients versus 4% of placebo-treated patients.

[0261] Dupilumab improved morning and evening daily asthma symptoms in a rapid and sustained manner in patients with OCS-dependent severe asthma, despite OCS withdrawal. Symptom improvement was greatest in patients who achieved a 100% reduction in OCS use by week 24. Dupilumab was generally well tolerated.

[0262] Population: ITT; 100% OCS reduction subgroup. Endpoint: LS mean change from baseline in AM / PM asthma symptoms during treatment. Treatment arm: dupilumab 300 mg q2w; placebo.

[0263] Asthma control and health-related quality of life Asthma control was assessed by weekly electronic diary recording of the validated 5-item Asthma Control Questionnaire (ACQ-5), with higher scores (range 0-6) indicating poorer control. Health-related quality of life (HRQoL) was assessed using the self-administered 7-item Asthma Quality of Life Questionnaire (AQLQ), with higher overall scores (range 0-7) indicating better HRQoL. Changes from baseline in ACQ-5 and AQLQ scores during the 24-week treatment period were analyzed using mixed-effects models with repeated measures.

[0264] In the dupilumab and placebo groups, mean baseline ACQ-5 scores were 2.42 and 2.58, and mean baseline AQLQ scores were 4.38 and 4.31, respectively. In the dupilumab group, asthma control rapidly improved (LS mean change from baseline in ACQ-5 score at week 2, 0.57; P = 0.002 vs. placebo), further improved at week 12 (1.01; P = 0.001 vs. placebo), and remained stable through week 24 (1.05; P = 0.002 vs. placebo) (Figure 26A). In dupilumab-treated patients, a LS mean improvement from baseline in AQLQ score of 0.76 was observed at week 12 (P = 0.14 vs. placebo), which further improved to 0.89 at week 24 (P = 0.008 vs. placebo) (Figure 26B). Overall, the most common treatment-emergent adverse event in dupilumab-treated patients compared with placebo-treated patients was eosinophilia (14% vs. 1%). Injection site reactions occurred in 9% of dupilumab-treated patients compared with 4% of placebo-treated patients.

[0265] Add-on dupilumab versus placebo significantly improved asthma control and improved HRQoL in patients with OCS-dependent severe asthma. Improved asthma control occurred as early as week 2 and was maintained through 24 weeks. Dupilumab was generally well tolerated.

[0266] Population: ITT. Endpoints: LS mean change from baseline in ACQ-5 at weeks 2, 12, and 24; LS mean change from baseline in AQLQ at weeks 12 and 24; safety during treatment. Treatment arms: dupilumab 300 mg q2w; placebo.

[0267] safety The incidence of TEAEs was similar across treatment groups in the safety population (62.1% vs. 64.5% for dupilumab vs. placebo). The most frequent MedDRA Preferred Term TEAEs occurring in ≥5% of dupilumab-treated vs. placebo-treated patients were viral upper respiratory tract infection (8.7% vs. 17.8%), bronchitis (6.8% vs. 5.6%), sinusitis (6.8% vs. 3.7%), influenza (2.9% vs. 5.6%), injection site reaction (8.7% vs. 3.7%), and laboratory measurement of eosinophilia (grouping "eosinophil count increased" and "eosinophilia" preferred terms) (13.6% vs. 0.9%). Per the study protocol, all cases of treatment-emergent eosinophil counts >3,000 cells / μL were to be reported as AEs, occurring in 12.6% of dupilumab-treated patients compared with 0.9% in the placebo group. All reported eosinophilia TEAEs were exclusively laboratory findings without any clinical consequences or related AEs.

[0268] Serious TEAEs were reported in 9 (8.7%) dupilumab-treated patients and 6 (5.6%) placebo-treated patients; none of the serious TEAEs were related to the study drug. There were no deaths in this study. Treatment-emergent antidrug antibody responses were observed in 5 patients in each group (dupilumab 5.0%; placebo 4.7%) and did not significantly affect efficacy or safety.

[0269] [Table 10]

[0270] method Study design and monitoring This phase 3, multinational, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of dupilumab in patients with oral glucocorticoid-dependent severe asthma. Patients completed an 8- to 10-week oral glucocorticoid dose optimization period followed by 1:1 randomization to dupilumab or placebo for a 24-week treatment period. This treatment period consisted of a 4-week induction period during which the optimized oral glucocorticoid dose was continued; a 16-week oral glucocorticoid reduction period (weeks 4 to 20) during which the glucocorticoid dose was tapered every 4 weeks according to a protocol-prespecified algorithm; a 4-week maintenance period during which patients continued on the established glucocorticoid dose at week 20; and a 12-week post-treatment evaluation period. Eligible patients who completed treatment were allowed to enter a long-term, open-label extension study.

[0271] This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, and applicable international treatises. The study was conducted in accordance with applicable regulatory requirements. An independent data safety monitoring committee provided blinded monitoring of patient safety data. Local institutional review or ethics committees at each study center oversaw study conduct and documentation. All patients provided written informed consent before participating in the study.

[0272] patient Patients aged 12 years or older with a physician-diagnosed asthma for ≥12 months based on the 2014 International Guidelines for Asthma Management were eligible to participate. Patients were required to have received regular systemic glucocorticoids (prednisone or prednisolone or equivalent 5–35 mg / day) for the past 6 months and high-dose inhaled glucocorticoids (fluticasone propionate >500 μg total daily dose or equipotent equivalent) in combination with up to two controller medications (e.g., long-acting beta-2 agonists or leukotriene receptor antagonists) for ≥3 months during the 4 weeks prior to screening. Eligible patients had to have a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≤80% of predicted normal (≤90% for adolescents), FEV1 reversibility ≥12% and ≥200 mL, or airway hyperresponsiveness documented in the 12 months prior to Screening Visit 1. Patients were recruited without minimum requirements for baseline blood or sputum eosinophil counts or any other type 2 biomarkers (e.g., FeNO or IgE). Key exclusion criteria included pulmonary disease other than asthma, asthma exacerbation requiring emergency care or hospitalization within 4 weeks after visit 1, and current smokers or smokers who had quit within 6 months prior to screening or had a smoking history of more than 10 pack years.

[0273] Treatments and Procedures Patients were randomized (1:1) to receive subcutaneous dupilumab 300 mg or matching placebo every 2 weeks (q2W) as add-on treatment (after a 600 mg loading dose on day 1). Randomization was performed using interactive voice / web response technology, and patients were stratified by optimized oral glucocorticoid dose (prednisone / prednisolone ≤ 10 mg / day or > 10 mg / day) and country. Patients using other oral glucocorticoids were switched to a clinically equivalent dose of prednisone or prednisolone during the screening period.

[0274] The optimized oral glucocorticoid dose was defined as the lowest dose that a patient could tolerate without experiencing a ≥0.5 increase in the 5-item Asthma Control Questionnaire (ACQ-5) score, a severe exacerbation, or any clinically significant event requiring oral glucocorticoid dose adjustment. During the dose reduction phase, the oral glucocorticoid dose was reduced every 4 weeks to minimize the risk of clinically significant events and carryover effects from the previous dose. No dose adjustments were allowed beyond week 20, except for safety reasons. Background asthma long-term controller medications were continued at stable doses, and short-acting β2-agonists were permitted if needed for asthma symptoms.

[0275] Evaluation items The primary efficacy endpoint was the percentage reduction in oral glucocorticoid dose from baseline to week 24 while maintaining asthma control. Patients were considered to have maintained asthma control between weeks 20 and 24 if they had no clinically significant events (based on investigator judgment) requiring oral glucocorticoid dose adjustment. For patients who experienced an exacerbation, the final oral glucocorticoid dose was considered to be one step higher than the dose they were receiving at the time of the exacerbation.

[0276] Key secondary efficacy endpoints evaluated in patients who maintained asthma control were the proportion of patients achieving a ≥ 50% reduction from baseline in oral glucocorticoid dose and the proportion of patients achieving a reduction in oral glucocorticoid dose to < 5 mg / day. Other secondary endpoints included absolute reduction in oral glucocorticoid dose, proportion of patients achieving the maximum possible oral glucocorticoid dose reduction, and proportion of patients no longer requiring oral glucocorticoids.

[0277] Additional efficacy endpoints included the annualized rate of severe exacerbations during the treatment period (defined as requiring hospitalization, emergency department visit, or treatment with systemic glucocorticoids at least twice the current dose for ≥3 days); absolute change from baseline in pre-bronchodilator FEV1 at weeks 2, 4, 8, 12, 16, 20, and 24; and change from baseline in ACQ-5 score at week 24.

[0278] The exploratory endpoint of absolute change from baseline in FeNO (ppb) was assessed at weeks 2, 4, 8, 12, 16, 20, and 24 using the NIOX instrument (Aerocrine AB, Solna, Sweden).

[0279] statistical analysis It was estimated that 90 randomized patients per treatment group would give the study 94% power (two-sided test at α = 0.05) to detect a 27% treatment difference in daily glucocorticoid dose, assuming a common standard deviation of 50%.

[0280] The primary endpoint was analyzed using an analysis of covariance (ANCOVA) model. The model included the percentage reduction in oral glucocorticoid dose at week 24 as the response variable and treatment group, optimized oral glucocorticoid dose at baseline, region (country), and baseline eosinophil subgroup (≥150 cells / μL, <150 cells / μL) as covariates. Treatment differences were tested at a two-sided significance level of α = 0.05. For patients who discontinued the study or had missing oral glucocorticoid dose data at week 24 (two patients in the dupilumab group and one in the placebo group), the primary missing data approach was pattern mixture modeling with multiple imputation (PMM with MI).

[0281] Key secondary and other binary secondary endpoints were analyzed using logistic regression models. Annualized rates of severe exacerbations during the 24-week treatment period were analyzed using negative binomial regression models. Mixed-effects models with repeated measures were used to analyze the change from baseline in pre-bronchodilator FEV1 at various time points during the 24-week treatment period and the change from baseline in the 5-item Asthma Control Questionnaire (ACQ-5) at week 24.

[0282] Efficacy analyses were performed on the intention-to-treat (ITT) population, defined as all randomized patients analyzed according to their assigned treatment, regardless of the treatment they received. The key secondary endpoint, FEV1, and severe asthma exacerbation rate were also analyzed in patient subgroups defined by baseline blood eosinophil levels (≥300 cells / μL, <300 cells / μL, ≥150 cells / μL, and <150 cells / μL). The safety population included all patients who received one or more doses or partial doses of study treatment and was analyzed according to treatment received.

[0283] All analyses were performed using SAS software, version 9.4 (SAS Institute).

[0284] conclusion This study demonstrated that dupilumab as add-on therapy significantly reduced oral glucocorticoid use in patients with oral glucocorticoid-dependent severe asthma, reduced severe asthma exacerbations by 59.3% and improved FEV1 by 0.22 L in the overall population, and in "eosinophilic" patients with baseline blood eosinophils ≥ 300 cells / μL, reduced exacerbations by 71% and improved FEV1 by 0.32 L. Dupilumab treatment also improved asthma control and reduced FeNO levels, a marker of airway type 2 inflammation.

[0285] Add-on dupilumab 300 mg every 2 weeks (q2w) (vs. placebo) significantly reduced oral corticosteroid (OCS) use at week 24 (least squares [LS] mean 41.9% vs. 70.1%, median 50% vs. 100%), while simultaneously reducing the rate of severe asthma exacerbations during the 24-week treatment period (59%) and improving forced expiratory volume in 1 second (FEV1) at week 24 (LS mean difference 0.22 L) and was generally well tolerated in patients with OCS-dependent severe asthma.

[0286] Dupilumab is the first biologic to demonstrate positive efficacy based on multiple asthma outcome measures in the entire study population, regardless of baseline blood eosinophil count (i.e., ≥300, <300, ≥150, and <150 cells / µL). Indeed, 28.6% of enrolled patients had baseline blood eosinophils <150 cells / µL. In this subgroup, 75% of dupilumab-treated patients reduced their oral glucocorticoid dose by 50%, and 62% of patients reduced their oral glucocorticoid dose <5 mg / day. These data contrast with previous studies of anti-interleukin-5 monoclonal antibodies, including mepolizumab and benralizumab, which showed treatment benefit exclusively in patients with high baseline blood eosinophils.

[0287] In this study, placebo-treated patients also showed a 41.9% reduction in oral glucocorticoid dependence. Better adherence to drug regimens in clinical research settings may have contributed to this observation. However, near the end of the study, Based on these data, these placebo-treated patients showed a mild deterioration in lung function (FEV1), further highlighting the need for treatments that improve lung function in patients with oral glucocorticoid-dependent severe asthma. The ability of dupilumab to increase lung function as significantly as it did in this study, even upon glucocorticoid withdrawal, indicates that it likely inhibits a key driver of pulmonary inflammation that leads to the decline in lung function.

[0288] Dupilumab reduced FeNO levels in a study population with persistent type 2 inflammation (determined by elevated FeNO) despite chronic glucocorticoid use, and in the setting of significant withdrawal of oral glucocorticoids.

[0289] Dupilumab reduced oral glucocorticoid doses by an observed mean of 74% (observed median of 100%) in the broader population without requiring a minimum baseline blood eosinophil count. While not wishing to be bound by scientific theory, these findings indicate that dupilumab, which dually blocks the interleukin-4 and interleukin-13 signaling pathways through interleukin-4 receptor-α blockade, inhibits type 2 inflammation more broadly than targeting eosinophils alone. Interleukin-4 is central to the differentiation and proliferation of type 2 helper T cells, induction of cytokine production, and IgE synthesis, whereas interleukin-13 plays a central role in pathological features of the disease, such as goblet cell hyperplasia, mucus production, smooth muscle contractility, and airway hyperresponsiveness.

[0290] In patients with glucocorticoid-dependent severe asthma, dupilumab was generally well tolerated, and the safety profile was consistent with previous studies in asthma and other indications, such as eosinophilic esophagitis, nasal polyposis, and atopic dermatitis. Dupilumab-treated patients demonstrated a greater mean transient increase from baseline in blood eosinophil counts compared with placebo, with an increased proportion of patients (12.6%) with eosinophil counts >3,000 cells / μL. Patients with transient elevations in blood eosinophil counts did not experience concurrent clinical adverse events or outcomes. The increase in blood eosinophil counts is consistent with the hypothesis that dupilumab blocks interleukin-4 and interleukin-13 function in eosinophil survival, activation, and tissue recruitment, but does not eliminate eosinophils from the bone marrow, resulting in a transient increase in circulating eosinophil counts. The greater reduction in oral glucocorticoids in the dupilumab group may also have contributed to the elevated eosinophils, as glucocorticoids suppress circulating eosinophils. Treatment-related conjunctivitis AEs were not observed between the dupilumab and placebo groups, in contrast to the atopic dermatitis study of dupilumab.

[0291] In conclusion, add-on treatment with dupilumab significantly reduced the need for oral glucocorticoids in patients with glucocorticoid-dependent severe asthma, regardless of baseline blood eosinophil count, while simultaneously reducing severe exacerbations and improving lung function (FEV1), and was generally well tolerated. [Example]

[0292] QUEST Phase III Clinical Trial Study (NCT02414854) method Asthma patients aged 12 years and older with moderate-to-severe asthma not controlled with ICS and one or two long-term controller medications were randomized 2:1 to receive add-on subcutaneous dupilumab 200 mg or 300 mg every 2 weeks (q2w) or matching placebo for 52 weeks in a double-blind, placebo-controlled phase 3 study (NCT02414854). Primary endpoints were the annualized rate of severe asthma exacerbations in the overall study population and the absolute change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 second (FEV1). Secondary endpoints included exacerbations and FEV1 in patients with ≥300 neutrophils / μL. Asthma control and dupilumab safety were also assessed. Co-primary endpoints were the annualized rate of severe exacerbations over 52 weeks and the change from baseline to week 12 in FEV1(L).

[0293] Specific details of this study are described below. This randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy of dupilumab in patients with moderate to severe uncontrolled asthma. Patients completed a 4±1 week screening period, followed by randomization to dupilumab or a matching placebo, a 52-week randomized treatment period, and a 12-week post-treatment follow-up period (see Figure 7).

[0294] patient Patients aged 12 years or older with physician-diagnosed persistent asthma for 12 months or more according to the International Guidelines for Asthma Management 2014 guidelines were eligible to participate, and met the following key criteria: The following criteria were met: current treatment with medium- to high-dose inhaled glucocorticoids (fluticasone propionate >500 μg total daily dose or equipotent equivalent), plus up to two additional long-term controller medications (e.g., long-acting beta-agonists or leukotriene receptor antagonists); pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) ≤80% of predicted normal (≤90% for patients aged 12–17 years); FEV1 reversibility ≥12% and ≥200 mL; 5-item Asthma Control Questionnaire (ACQ-5) score ≥1.5; and asthma exacerbation in the previous year requiring hospitalization, emergency medical care, or treatment with systemic glucocorticoids for ≥3 days. Patients were recruited regardless of baseline blood eosinophil count or type 2 biomarkers (see Figure 8).

[0295] Treatments and Procedures Patients were randomized (2:2:1:1) to receive 52 weeks of additional treatment with subcutaneous dupilumab 200 mg (400 mg loading dose) or 300 mg (600 mg loading dose) every 2 weeks (q2w) or placebo in a volume corresponding to each active dose (delivered in prefilled syringes: 1.14 mL for dupilumab 200 mg and 2.0 mL for dupilumab 300 mg). Randomization was performed using interactive voice / web response technology and stratified by age (<18 years, ≥18 years), peripheral blood eosinophil count at screening (<300 cells / μL, ≥300 cells / μL), inhaled glucocorticoid dose level (intermediate / high), and country. Background asthma long-term control medications were continued at stable doses throughout the study and were recorded daily by patients in an electronic diary. The use of inhaled glucocorticoids, long-acting beta-agonists, long-acting muscarinic antagonists, anti-leukotrienes, and methylxanthines was permitted. Throughout the study, patients were allowed to use short-acting beta-adrenergic receptor agonists as needed for symptomatic relief. Type 2 biomarkers were measured; these included blood eosinophils, FeNO, serum IgE, periostin, TARC, and plasma eotaxin-3.

[0296] Evaluation items The primary efficacy endpoints were the annualized rate of severe exacerbation events during the 52-week treatment period and the absolute change from baseline in pre-BD FEV1 at Week 12 in the overall study population. These endpoints were also included as secondary study endpoints for patients with a blood eosinophil count ≥ 300 eosinophils / μL. Additional secondary study endpoints are summarized in Table 8. A severe asthma exacerbation was defined as a worsening of asthma requiring ≥ 3 days of treatment with systemic glucocorticoids, or hospitalization or emergency department visit requiring systemic glucocorticoids. Safety and tolerability were reported by the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs.

[0297] [Table 11]

[0298] statistical analysis It was estimated that a sample size of approximately 1638 patients would give the study 99% power (two-sided test at α = 0.05) to detect a 55% relative risk reduction in the annualized rate of severe exacerbations (i.e., annualized rates of 0.6 and 0.27 for the placebo and dupilumab groups, respectively). This sample size was also expected to provide 98% power to detect a 0.15 L treatment difference in pre-BD FEV1 change from baseline to week 12. Efficacy analyses were performed on the intention-to-treat (ITT) population, defined as all randomized patients with assigned treatment, regardless of whether treatment was accepted. Covariates The annual rate of severe exacerbations was analyzed using a negative binomial regression model, including the four treatment groups, age, region, baseline eosinophil level, baseline inhaled glucocorticoid dose level, and exacerbations 1 year prior, all included as numbers. Changes from baseline in continuous endpoints such as FEV1 and patient-reported outcomes were analyzed using mixed-effects models for repeated measures (MMRM), which included treatment, age, baseline eosinophil level, baseline inhaled glucocorticoid dose level, visit, treatment / visit interaction, baseline value, and baseline / visit interaction as covariates. Sex and baseline height were included as covariates only in models for spirometry parameters.

[0299] result Baseline demographic and clinical characteristics of the ITT population are shown in Table 4 and were generally similar across the four treatment groups (Table 10). In 1,902 patients, dupilumab 200 / 300 mg q2w reduced the annualized severe exacerbation rate by 48% / 46% (both P<0.0001) compared with placebo during the 52-week treatment period (Figure 9A). Improvements in FEV1 were observed at week 12 in the overall population (LS mean difference 0.14 L / 0.13 L vs. placebo; both P<0.0001).

[0300] Prespecified subgroup analysis by baseline blood eosinophil count showed significant reductions in exacerbation rates (P<0.001) for dupilumab 200 mg and 300 mg compared with matched placebo in patients with ≥300 eosinophils / μL (65.8% and 67.4% reductions vs. placebo) and in patients with ≥150 eosinophils / μL (55.8% and 59.8% reductions vs. placebo). There was a consistent trend, but not significance, for exacerbation and FEV1 outcomes in patients with <300 eosinophils / μL. Prespecified subgroup analysis by baseline FeNO level showed similar effects (P<0.001) (see Figure 9B and Table 9).

[0301] [Table 12] [Table 13]

[0302] In the overall study population, dupilumab 200 mg and 300 mg q2w improved pre-BD FEV1 by 0.32 L and 0.34 L, respectively, at week 12 (differences of 0.14 L and 0.13 L vs. matched placebo, P<0.001) (Figure 10A). In patients with ≥300 eosinophils / μL, FEV1 improvements were greater, with dupilumab improving FEV1 by 0.43 L and 0.47 L, respectively, at week 12 (differences of 0.21 to 0.24 L vs. matched placebo, P<0.001) (see Figure 10B). The FEV1 improvements were rapid (significant differences compared with placebo, evident by the first assessment at week 2 for both regimens) and sustained throughout the 52-week treatment period (P<0.001 for both regimens at week 52). Additionally, post-bronchodilator FEV1 slope analysis between weeks 8 and 52 showed a loss of lung function of 0.04 L / year for placebo and no loss for either dupilumab dose (P<0.05).

[0303] The FEV1 improvement (P<0.05) at week 12 was higher for both dose regimens It was higher in the subgroup of patients with baseline FeNO levels (0.19 L and 0.12 L for 25 ppb≦FeNO<50 ppb; 0.30 L and 0.39 L for FeNO≧50 ppb). (See FIG. 10C and Table 8.)

[0304] In addition, dupilumab 200 mg and 300 mg significantly improved the percentage change from baseline to week 12 in pre-bronchodilator FEV1 compared with placebo: 12.11% vs. 21.34%, and 13.67% vs. 23.08%, respectively (P<0.001). The rate of severe exacerbations resulting in hospitalization or emergency department visits during the 52-week treatment period was 0.065 vs. 0.035 for combined dupilumab-treated patients compared with combined placebo-treated patients (P=0.004). This resulted in a 46.8% relative risk reduction for dupilumab compared with placebo. (See Table 9.)

[0305] Dupilumab significantly improved ACQ-5 as early as week 2, and the effect persisted over the course of treatment (P<0.01). Similarly, Asthma Quality of Life Questionnaire, Standardized Version score, AM and PM asthma symptom scores, and AM and PM peak expiratory flow rates improved at weeks 24 and 52. (See Table 9.)

[0306] Patients treated with dupilumab demonstrated greater decreases from baseline in FeNO, total IgE, periostin, eotaxin-3, and TARC over the course of treatment compared with placebo (Table 13). Transient increases in blood eosinophil counts were observed in both treatment groups, decreasing to near baseline levels by week 52.

[0307] To better understand the effect of dupilumab on patients with evidence of type 2 inflammation, analyses were performed to assess biomarker efficacy associations. Each biomarker was tested in unpenalized spline models for biomarker / treatment interactions with respect to exacerbations and FEV1. In these analyses, eosinophilia was associated with a significant reduction in eosinophilic ... The interaction between eosinophils and FeNO was significant when exacerbations were the outcome measure (P<0.005), but eosinophils, FeNO, periostin, ECP, IgE, and eotaxin-3 were significant for FEV1 at week 12 (Table 11). The dupilumab effect on exacerbations was similar for IgE levels above and below the median (167 IU / mL) at baseline, with greater FEV1 improvement for IgE levels above the median.

[0308] Baseline blood eosinophils ≥ 150 cells / μL and FeNO ≥ 25 ppb (type 2 - Dupilumab-treated patients with baseline blood eosinophils <150 cells / μL and FeNO<25 ppb (type 2 - low) experienced a greater treatment benefit than placebo for both reduced severe exacerbation rate and improved FEV1. (See Figures 11A and 11B.) No treatment effect was observed in patients with baseline blood eosinophils <150 cells / μL and FeNO>=25 ppb (type 2 - low). However, dupilumab-treated patients with either baseline blood eosinophils <150 cells / μL and FeNO>=25 ppb or baseline blood eosinophils>=150 cells / μL and FeNO<25 ppb experienced a numerical reduction in severe exacerbation rate.

[0309] The most common adverse event in dupilumab-treated patients compared with placebo was injection site reactions (5% / 10% vs. 15% / 18%, respectively). In contrast to dupilumab studies in atopic dermatitis, conjunctivitis rates were similar between dupilumab and placebo.

[0310] [Table 14] [Table 15] [Table 16] [Table 17]

[0311]

Table 18

[0312] Table 22 Table 23 Table 24 Table 25

[0313] Table 26 Table 27 Table 28 Table 29

Table 30

[0314] [Table 33] [Table 34]

[0315] Consideration Dupilumab significantly reduced the annualized rate of severe exacerbations in the intention-to-treat population, with greater treatment effects observed with increasing baseline levels of blood eosinophils and FeNO Dupilumab also significantly reduced the rate of the most severe asthma exacerbations, those requiring hospitalization or emergency department visits. Assessment of FEV1 and asthma control over time demonstrated rapid efficacy of dupilumab, with significant differences versus placebo evident as early as the first assessment at week 2 for both dose regimens and maintained throughout the 52-week treatment period. A significant and clinically meaningful improvement in FEV1 of 0.32 to 0.34 L was observed at week 12, regardless of baseline blood eosinophil count, with an even larger increase of 0.43 to 0.47 L in patients with baseline blood levels of ≥300 eosinophils / µL.

[0316] Furthermore, post-bronchodilator FEV1 slope analysis showed that no loss of lung function was observed in dupilumab-treated patients compared with placebo patients, suggesting a potential effect of dupilumab on airway tissue repair. Slope analysis showed that placebo patients lost an average of approximately 40 mL per year, which is consistent with data from other asthma cohorts. Furthermore, because IL-4Rα is expressed on smooth muscle cells, there may be a direct bronchodilatory effect of the drug in addition to its anti-type 2 inflammatory effects.

[0317] The consistent and significant improvements seen with dupilumab are likely attributable to its unique mechanism of action. With the asthma community's recent increased focus on exacerbations, driven by payer cost-effectiveness concerns, emphasis has shifted away from the significant morbidity and quality of life issues associated with the substantial loss of lung function seen in patients with moderate to severe asthma. Despite current therapies, these patients with moderate to severe asthma are destined to continue to lose more lung function and decline over time. Therefore, the possibility that a new treatment could provide a clinically meaningful level of substantial recovery of lung function, and perhaps halt further future deterioration, could provide a significant benefit to these patients.

[0318] The results of this study confirm that interleukin-4 and interleukin-13 are important proximal drivers of type 2 inflammation in asthma. Dupilumab is the first biologic to significantly reduce FeNO levels, in addition to other systemic type 2 biomarkers such as IgE, confirming its biological activity on airway inflammation. Without wishing to be bound by scientific theory, dupilumab's unique mechanism of action, with dual blockade of interleukin-4 and interleukin-13 signaling, may explain why dupilumab demonstrates significant treatment efficacy in a broader patient population and unprecedented effects on improving lung function, suggesting a potential direct bronchodilatory effect in addition to its anti-inflammatory effects. It is noteworthy that this study, compared with two other important studies of dupilumab, showed the most significant association of benefit with baseline blood eosinophil levels. While we cannot clearly explain why the association was more pronounced in this study, it suggests that blood eosinophils may be an insufficient measure of type 2 inflammation and that other biomarkers of type 2 inflammation, such as FeNO, may be important. That said, overall, across all three studies, dupilumab appears to address a broader range of asthma populations than those defined solely by elevated blood eosinophil or IgE levels, as required for other approved biologics.

[0319] Dupilumab activity has been demonstrated against several atopic / allergic conditions, which are often comorbid in asthma patients. In this study, more than 80% of patients had comorbid atopic or allergic conditions, including atopic dermatitis (approximately 10% of the population), nasal polyposis (approximately 20% of the population), and allergic rhinitis (more than 65% of the population). The high rate of comorbid atopic / allergic conditions suggests that these patients suffer from systemic hyperactivity of the type 2 inflammatory axis, and therefore, treatment of asthma with dupilumab may help simultaneously alleviate these associated conditions.

[0320] Dupilumab was generally well tolerated and had an acceptable safety profile. With the exception of injection site reactions, the incidence of TEAEs was similar across treatment groups. Consistent with its mechanism of action and similar to that observed in atopic dermatitis trials, dupilumab-treated patients demonstrated a greater mean transient increase from baseline in blood eosinophil counts compared with placebo. Per the study protocol, all cases of treatment-emergent eosinophil counts >3,000 cells / μL were to be reported as AEs in this study. The majority of observed increases in eosinophil counts were laboratory findings without clinical consequences or related AEs. The increase in blood eosinophil counts is consistent with the hypothesis that dupilumab blocks the functions of interleukin-4 and interleukin-13 in eosinophil survival, activation, and recruitment to tissues, but does not eliminate eosinophils from the bone marrow, which is influenced by IL-5. Consequently, initial treatment with dupilumab may result in a transient increase in circulating eosinophil counts. Treatment-related conjunctivitis AEs were not observed between the dupilumab and placebo groups, in contrast to the dupilumab atopic dermatitis study.

[0321] In conclusion, this largest study to date of dupilumab in patients with moderate-to-severe uncontrolled asthma demonstrates that dual blockade of interleukin-4 and interleukin-13 with dupilumab effectively treats a broad range of asthma populations, resulting in significant reductions in severe exacerbation rates, rapid and sustained improvements in lung function and asthma control, and symptom relief. The most robust results were observed in patients with elevated type 2 immune signatures, including eosinophil counts and FeNO. Dupilumab is the only biologic to demonstrate efficacy across multiple studies of moderate-to-severe asthma patients, regardless of baseline type 2 biomarker levels. Dupilumab was generally well tolerated and had an acceptable safety profile. These data support the use of dupilumab as an effective add-on treatment for this population of asthma patients with significant unmet medical needs. [Example]

[0322] QUEST Phase III Clinical Trial Study - Dupilumab Reduces Severe Exacerbation Rates and Improves Lung Function in Adolescents with Moderate-to-Severe Uncontrolled Asthma The prevalence of asthma in children and adolescents has increased over the past 30 years (Asher (2014) Int. J. Tuberc. Lung Dis.). In 2011, approximately 11.4% of adolescents (ages 12-17) in the USA reported currently having asthma (Bloom (2011) Vital and Health Statistics Series).

[0323] Although morbidity from asthma is as high (or often higher) in adolescents as in younger children, adolescents are less likely to seek medical help (Couriel (2003) J. Pediatric Resp. Rev.). Many adolescents underestimate the severity of their asthma and overestimate their response to bronchodilators (Rhee (2008) J. Asthma; Andersson (2013) Pediatrics). Asthma profoundly affects adolescents' physical, psychological, and social health, negatively impacting their health-related quality of life (Cui (2016) J. Pediatrics).

[0324] This study evaluated the efficacy and safety of dupilumab in subgroups of adolescents (12-17 years) and adults (≥18 years) with moderate-to-severe uncontrolled asthma. Endpoints evaluated during the 52-week treatment period were the annualized rate of severe exacerbations and the change from baseline in pre-bronchodilator FEV1(L). Baseline demographic and clinical characteristics are shown in Figure 12.

[0325] Inclusion criteria: Uncontrolled asthma for 12 months or more (GINA Guidelines for the Management of Asthma) 12 years of age or older with physician-diagnosed asthma (asthma asthma) in 2014; receiving treatment with medium-to-high doses of inhaled corticosteroids (ICS) plus up to two additional controller medications; pre-bronchodilator FEV1 (forced expiratory volume in 1 second) ≤ 80% (adults) and ≤ 90% (adolescents) of predicted normal at screening and baseline; bronchodilator reversibility ≥ 12% and ≥ 200 mL; ACQ-5 (5-item Asthma Control Questionnaire) score ≥ 1.5 at screening and baseline; ≥ 1 exacerbation in the previous year; no minimum requirement for baseline blood eosinophil count or any other type 2 biomarker.

[0326] Exclusion criteria: chronic obstructive pulmonary disease or other lung disease that may impair lung function; severe asthma exacerbation within 1 month of the enrollment visit or during the screening period; current smokers or smokers who had quit within 6 months prior to screening or had a smoking history of more than 10 pack years; comorbid illnesses that may interfere with the evaluation of the study drug.

[0327] Statistical Analysis: Efficacy analyses were performed on the ITT population, defined as all randomized patients with assigned treatment, regardless of whether they received treatment.

[0328] The annualized rate of severe asthma exacerbations during the 52-week treatment period was analyzed using a negative binomial regression model. Changes from baseline in FEV1 at various time points during the 52-week treatment period were analyzed using a mixed-effects model with repeated measures.

[0329] The primary endpoints, severe asthma exacerbation rate and FEV1, were also analyzed in patient subgroups defined by age (<18 years and >18 years). The safety population included all patients who received ≥1 dose or partial dose of study treatment and was analyzed according to treatment received.

[0330] Dupilumab reduced severe exacerbations and improved FEV1 in the overall ITT population (Figures 13A and 13B), reduced the severe exacerbation rate in adolescents and adults (Figures 14A and 14B), and improved FEV1 in adolescents and adults at weeks 12 (Figure 15A) and 52 (Figure 15B), as well as throughout the 52-week treatment period (Figures 16A and 16B).

[0331] Dupilumab improved percent predicted FEV1 in adolescents and adults over 52 weeks of treatment (Figures 18A and 18B). FeNO levels (Figures 19A and 19B), ACQ-5 scores (Figures 20A and 20B), and AQLQ scores (Figures 21A and 21B) were assessed.

[0332] Adolescents were enrolled in 107 of 1,902 patients (34 in the dupilumab group and 21 in the matched placebo group); 35.5% were female. The mean baseline FEV1 was 2.33 L, the mean %predicted FEV1 was 0.45%, and the mean number of severe exacerbations in the previous year was 1.91. Adolescents receiving placebo experienced fewer severe exacerbations (0.36 / 0.33) than adults (0.89 / 1.00). In adolescents, dupilumab 200 mg reduced the annualized exacerbation rate by 46.4%, while dupilumab 300 mg produced no treatment effect versus placebo (without wishing to be bound by scientific theory, this was likely due to the small sample size and disproportionate number of prior events (mean 1.53 vs. 2.22, respectively)). The unadjusted exacerbation rates were 0.46 (dupilumab 300 mg) and 0.76 (placebo).A significant improvement in change from baseline in FEV1(L) versus placebo was seen in adolescents (dupilumab 200 mg: least-squares mean 0.36 [95% CI 0.12 to 0.61]; 300 mg: 0.27 [0.02 to 0.52]) (P<0.05), which was numerically higher versus adults (200 mg and 300 mg: 0.12 [0.07 to 0.18]).

[0333] Adverse event profiles were comparable between subgroups (Figures 17, 22, 23, and 24). The most common treatment-emergent adverse events (TEAEs) occurring more frequently in the combined dupilumab groups were: Adolescents - respiratory tract infection (viral) (placebo, 2 [5.1%]; dupilumab, 7 [10.3%]); Adults - injection site erythema (placebo, 34 [5.7%]; dupilumab, 168 [14.1%]). Eosinophilia was observed only in the adult population.

[0334] Dupilumab significantly reduced the annual rate of severe exacerbations and improved lung function in adults with moderate-to-severe uncontrolled asthma. Improvements in FEV1 were rapid and sustained throughout the 52-week treatment period. Dupilumab also significantly improved lung function in adolescents with moderate-to-severe uncontrolled asthma, with a numerical reduction in severe exacerbations observed.

[0335] As in adults, improvements in FEV1 in adolescents were rapid and sustained throughout the 52-week treatment period. The magnitude of improvement in FEV1 was greater in adolescents. Dupilumab was generally well tolerated. [Example]

[0336] QUEST Phase III Clinical Trial Study - Dupilumab Improves Health-Related Quality of Life, Improves Lung Function, and Reduces Severe Exacerbation Rates in Patients with Moderate-to-Severe Asthma Health-related quality of life in patients with comorbid allergic rhinitis Allergic rhinitis (AR), a common type 2 comorbidity in asthma patients, contributes to an increased overall disease burden. Phase 3 LIBERTY trial in patients with moderate-to-severe uncontrolled asthma This analysis of the ASTHMA QUEST study (NCT02414854) evaluated the effect of dupilumab on the Standardized Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ(S)+12] in patients with self-reported comorbid AR.

[0337] Patients aged 12 years and older with asthma not controlled with medium- to high-dose ICS plus ≤2 additional long-term controller medications received add-on dupilumab 200 / 300 mg or matching placebo every 2 weeks (q2w) for 52 weeks. Patients with a self-reported history of AR (63.5%; n / N = 1,207 / 1,902) completed the validated RQLQ(S)+12 at weeks 12 and 25. No clinical AR diagnoses were recorded.

[0338] Overall RQLQ(S)+12 scores (baseline mean [SD] 1.90 [1.12] to 2.01 [1.16]) were significantly improved with dupilumab 200 / 300 mg q2w versus placebo at week 52 (least squares mean difference [95% CI] -0.42 [-0.61, -0.24] / -0.39 [-0.56, -0.21]; P < 0.0001). Dupilumab 200 / 300 mg significantly (P<0.001) improved activity (0.44 [0.68, 0.21] / 0.39 [0.61, 0.16]), sleep (0.47 [0.69, 0.25] / 0.38 [0.59, 0.17]), and ocular symptoms (0.37 [0.58, 0.16] / 0.39 [0.59, 0.19]) domain scores from baseline to week 52 versus placebo; and dupilumab 300 mg improved by week 12 (0.23 [0.42, 0.04], 0.26 [0.45, 0.07], and 0.26 [0.45, 0.08], respectively; P<0.05). Nasal symptom domain scores improved significantly with dupilumab 200 / 300 mg versus placebo by week 12 (0.36 [0.56, 0.16] / 0.32 [0.51, 0.13]; P<0.001) and week 52 (0.61 [0.84, 0.39] / 0.55 [0.76, 0.33]; P<0.0001). The most common adverse event, which occurred more frequently with dupilumab versus placebo, was injection-site reactions (15% / 18% versus 5% / 10%).

[0339] Dupilumab significantly improved rhinoconjunctivitis-specific health-related quality of life in patients with moderate-to-severe uncontrolled asthma and comorbid AR and was generally well tolerated.

[0340] Population: Patients with comorbid AR. Endpoints / Visits: LS mean change from baseline during the 52-week treatment period for RQLQ domains (nasal symptoms, ocular symptoms, activity, sleep); safety (ITT). Treatment Arms: Dupilumab 200 mg and 300 mg q2w and matching placebo.

[0341] Improved pulmonary function and reduced severe exacerbations in patients with or without comorbid allergic rhinitis A post-hoc analysis of the Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in asthma patients (ages 12 years and older, not controlled with moderate-to-high doses of ICS plus ≤2 additional long-term controller medications) with a self-reported history of comorbid AR (63.5%; n / N=1,207 / 1,902) or without comorbid AR evaluated the effect of add-on dupilumab 200 mg or 300 mg every 2 weeks (q2w) or matching placebo on annualized rate of severe exacerbations and forced expiratory volume in 1 second (FEV1). Clinical diagnosis of AR was not recorded.

[0342] Baseline characteristics of patients with and without AR were generally similar. The annualized rate of severe exacerbations was reduced with dupilumab 200 mg q2w versus placebo (relative risk with AR: 0.606 [95% CI, 0.451 to 0.814]; P = 0.0009; without AR: 0.406 [95% CI, 0.273 to 0.605]; P < 0.0001), with similar results for 300 mg q2w. FEV1 improved with dupilumab 200 mg q2w at week 12 (LS mean difference vs. placebo with AR: 0.14 L [95% CI, 0.07 to 0.21]; P<0.0001; without AR: 0.13 L [95% CI, 0.05 to 0.22]; P=0.0023) and persisted through week 52 (both with and without AR: P<0.0001), with similar results for 300 mg q2w at week 52. The most common adverse event in the dupilumab-treated groups (vs. placebo) was injection-site reaction (200 mg / 300 mg vs. matched placebo: 15% / 18% vs. 5% / 10%).

[0343] In this difficult-to-control asthma population with comorbid AR, and also in patients without comorbid AR, dupilumab significantly improved FEV1 and reduced annualized severe exacerbation rates.

[0344] Population: Patients with and without concomitant AR (AR defined according to CSR). Endpoints: LS mean change from baseline in FEV1 at weeks 12 and 52; severe exacerbations during the 52-week treatment period. Safety: ITT. [Example]

[0345] QUEST Phase III Clinical Trial Study - Dupilumab suppresses type 2 biomarkers in patients with moderate-to-severe asthma, with and without comorbid chronic rhinosinusitis with nasal polyposis (CRS+NP) or chronic rhinosinusitis without nasal polyposis (CRS-NP) In the Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200 / 300 mg every 2 weeks versus matching placebo suppressed type 2 biomarkers in patients with moderate-to-severe uncontrolled asthma and improved health-related quality of life, as assessed by SNOT-22, in the hard-to-treat subgroups with comorbid chronic rhinosinusitis with nasal polyposis (CRS+NP) or (CRSwNP) and in the hard-to-treat subgroups with chronic rhinosinusitis without nasal polyposis (CRS-NP). This post-hoc analysis evaluated the effect of dupilumab on type 2 biomarkers in this subgroup.

[0346] Baseline / change from baseline over time was assessed for exhaled nitric oxide concentration (FeNO), total IgE, and eotaxin-3.CRS with or without NP was self-reported by 20.1% (n / N=382 / 1,897) of patients. Baseline FeNO and eotaxin-3 levels were numerically higher in patients with CRS-NP or CRS+NP than in those without. Biomarker suppression was evident in all dupilumab-treated patients by week 12. At week 52, significant biomarker suppression was observed in patients with and without CRS-NP or CRS+NP, as demonstrated by the following median percentage changes from baseline (dupilumab 200 / 300 mg vs. matched placebo): With CRS-NP or CRS+NP: FeNO 46.2 / 37.7 vs. 5.5 / 6.4, IgE 74.8 / 76.8 vs. 0.0 / 2.0, eotaxin-3 47.7 / 50.9 vs. 1.5 / 5.4 (all, P ≤ 0.0001); Without CRS-NP or CRS+NP: FeNO 31.0 / 35.9 vs. 5.9 / 10.1, IgE 67.3 / 67.7 vs. 3.3 / 6.6, eotaxin-3 31.8 / 37.2 vs. 0.0 / 0.8 (all, P<0.0001). The most common adverse event, which occurred more frequently with dupilumab than with placebo, was injection site reactions (15% / 18% vs. 5% / 10%).

[0347] Dupilumab suppressed local and systemic type 2 biomarkers in patients with and without CRS+ / -NP.

[0348] Population: Patients with and without comorbid CRS or NP. Endpoints: Percent change from baseline serum total IgE, plasma eotaxin-3, and FeNO over the 52-week treatment period. Safety: ITT. Treatment arms: Dupilumab 200 mg and 300 mg q2w and matching placebo. [Example]

[0349] QUEST Phase III Clinical Trial Study - Dupilumab Reduces Severe Exacerbations and Improves Lung Function in Patients with Moderate-to-Severe Late-Onset Uncontrolled Asthma In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), this post-hoc analysis evaluated the efficacy of dupilumab in patients with late-onset asthma (>40 years of age) and a baseline pre-bronchodilator FEV1 / forced vital capacity [FVC] ratio <0.7 (suggesting fixed airway obstruction) or ≥0.7.

[0350] The annualized rate of severe exacerbations during the 52-week treatment period was assessed using negative binomial regression models. Changes from baseline in pre- and post-bronchodilator FEV1(L) and pre-bronchodilator FEV1 / FVC ratio at weeks 12 and 52 were analyzed using mixed-effects models with repeated measures.

[0351] Dupilumab 200 mg and 300 mg q2w versus placebo significantly reduced the annualized rate of severe exacerbations in patients with late-onset asthma and fixed airway obstruction (68.8% and 75.7%, respectively, P<0.0001 for both) and in patients without fixed airway obstruction (55.1% and 50.7%, respectively, P<0.05 for both) (Figure 27). At week 12, pre- and post-bronchodilator FEV1 and FEV1 / FVC ratio improved in dupilumab-treated patients with late-onset asthma and fixed airway obstruction (P<0.05 versus placebo for either or both doses). Similar improvements were observed at week 52 (dupilumab 200 mg q2w pre- and post-bronchodilator FEV1 and FEV1 / FVC ratio). P<0.05 for pre-bronchodilator FEV1P = 0.09, post-bronchodilator FEV1P = 0.06; dupilumab 300 mg q2w (pre-bronchodilator FEV1P = 0.09, post-bronchodilator FEV1P = 0.06). Patients with late-onset asthma without fixed airway obstruction had more modest improvements in pre-bronchodilator FEV1 versus placebo at weeks 12 and 52 than patients with late-onset asthma with fixed airway obstruction (P≥0.05). The most frequent adverse event in dupilumab-treated groups versus matched placebo was injection site reactions (15% / 18% vs. 5% / 10%).

[0352] Dupilumab significantly reduced the rate of severe exacerbations in patients with late-onset asthma with or without fixed airway obstruction. Furthermore, improvements in lung function were observed at weeks 12 and 52 in patients with late-onset asthma and fixed airway obstruction, who typically experience worse asthma outcomes than patients with late-onset asthma without fixed airway obstruction.

[0353] Populations: ITT population with age at onset of asthma >40 years and FEV1 / FVC<0.7 after BD use; ITT population with age at onset of asthma >40 years and FEV1 / FVC≥0.7 after BD use.

[0354] Endpoints / visits (data included in abstract): severe exacerbations during the 52-week treatment period; LS mean change from baseline in pre-BD FEV1(L) at weeks 12 and 52; LS mean change from baseline in post-BD FEV1(L) at weeks 12 and 52; LS mean change from baseline in FEV1 / FVC ratio at weeks 12 and 52; safety.

[0355] Treatment arms: dupilumab 200 mg q2w, dupilumab 300 mg q2w, and matching placebo groups.

Claims

1. 1. A method for treating a subject with severe uncontrolled asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the multiple maintenance doses are administered during a treatment period comprising an induction period, an oral corticosteroid (OCS) tapering period, and an OCS maintenance period.

2. 10. The method of claim 1, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

3. 10. The method of claim 1, wherein the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof.

4. 10. The method of claim 1, wherein each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

5. 10. The method of claim 1, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

6. 10. The method of claim 1, wherein the maintenance dose is about 500 mg of the antibody or antigen-binding fragment thereof.

7. 10. The method of claim 1, wherein each maintenance dose of the antibody or antigen-binding fragment thereof is about 750 mg of the antibody or antigen-binding fragment thereof.

8. 10. The method of claim 1, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks.

9. 10. The method of claim 1, wherein the first maintenance dose of the antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of the antibody or antigen-binding fragment thereof.

10. 10. The method of claim 1, wherein the OCS reduction phase is about 16 weeks in length.

11. 10. The method of claim 1, wherein OCS use by the subject is reduced during the OCS reduction period.

12. 12. The method of claim 11, wherein the subject uses 50% or less OCS during the maintenance phase compared to the induction phase.

13. 12. The method of claim 11, wherein the subject uses 75% or less OCS during the maintenance phase compared to the induction phase.

14. 12. The method of claim 11, wherein the subject uses 90% or less OCS during the maintenance phase compared to the induction phase.

15. 12. The method of claim 11, wherein OCS use by the subject is reduced to about 5 mg / day or less during the maintenance phase.

16. The method according to claim 11, wherein the administration of OCS is reduced and / or eliminated during the maintenance phase. The method described.

17. 10. The method of claim 1, wherein the subject has a blood eosinophil count of less than about 150 cells / μl.

18. 10. The method of claim 1, wherein the subject has a blood eosinophil count of about 150 cells / μl or greater.

19. 10. The method of claim 1, wherein the subject has a blood eosinophil count greater than about 300 cells / μl.

20. 10. The method of claim 1, wherein the subject experiences a reduction in annualized severe asthma exacerbations.

21. The subjects were randomly assigned to the forced expiratory volume (FEV １ 10. The method of claim 1, wherein the patient experiences improvement in lung function as measured by forced expiratory flow at 25-75% of lung capacity (FEF25-75) or forced expiratory flow at 25-75% of lung capacity (FEF25-75).

22. 10. The method of claim 1, wherein OCS use by the subject is optimized prior to treatment with the antibody or antigen-binding fragment thereof.

23. 10. The method of claim 1, wherein the OCS is prednisone or prednisolone.

24. 2. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity-determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2.

25. 25. The method of claim 24, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

26. 26. The method of claim 25, wherein the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO:

2.

27. 1. A method for treating a subject with severe uncontrolled asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the multiple maintenance doses are administered during a treatment period comprising an induction period, an oral corticosteroid (OCS) tapering period, and a maintenance period; The above method, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

28. 1. A method for treating a subject with severe uncontrolled asthma, comprising: administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject, wherein each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof. wherein the multiple maintenance doses are administered during a treatment period comprising an induction period, an oral corticosteroid (OCS) tapering period, and a maintenance period; The above method, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

29. 1. A method for reducing the annualized severe exacerbation rate in a subject with moderate to severe uncontrolled asthma, comprising administering to the subject q2w or q4w an antibody or antigen-binding fragment thereof that specifically binds to IL-4R.

30. 30. The method of claim 29, wherein the dosage is about 200 mg q2w, about 300 mg q2w, about 500 mg q4w, or about 750 mg q4w.

31. 30. The method of claim 29, wherein the subject has a blood eosinophil count of less than about 150 cells / μl.

32. 30. The method of claim 29, wherein the subject has a blood eosinophil count of about 150 cells / μl or greater.

33. 30. The method of claim 29, wherein the subject has a blood eosinophil count greater than about 300 cells / μl.

34. The target is approximately 25 x 10 －９ 30. The method of claim 29, wherein the patient has an exhaled nitric oxide (FeNO) level of 25 ppb or greater.

35. 30. The method of claim 29, wherein the subject has an FeNO level of greater than about 25 ppb to between about 50 ppb.

36. 30. The method of claim 29, wherein the subject has an FeNO level of about 50 ppb or greater.

37. FEV1 in subjects with moderate to severe uncontrolled asthma １ The method for improving the score includes administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to IL-4R q2w or q4w, such that the subject has an FEV1 score 4, 12, or 24 weeks after administration of the antibody or antigen-binding fragment thereof. １ The method shows an improvement in the score.

38. 38. The method of claim 37, wherein the dosage is about 200 mg q2w, about 300 mg q2w, about 500 mg q4w, or about 750 mg q4w.

39. 38. The method of claim 37, wherein the subject has a blood eosinophil count of less than about 150 cells / μl.

40. 38. The method of claim 37, wherein the subject has a blood eosinophil count of about 150 cells / μl or greater.

41. 38. The method of claim 37, wherein the subject has a blood eosinophil count greater than about 300 cells / μl.

42. 38. The method of claim 37, wherein the subject has an FeNO level of 25 ppb or greater.

43. 38. The method of claim 37, wherein the subject has an FeNO level of greater than about 25 ppb to between about 50 ppb.

44. 38. The method of claim 37, wherein the subject has an FeNO level of about 50 ppb or greater.

45. The subject is administered IL-4R antibody or fragment thereof at week 4, week 12, or week 24.

38. The method of claim 37, wherein the patient exhibits at least a 10% or 25% decrease in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC).

46. 1. A method for improving the forced expiratory flow at 25-75% of lung capacity (FEF25-75) score in a subject with moderate to severe uncontrolled asthma, comprising administering to the subject q2w or q4w an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, such that the subject exhibits an improvement in the FEF25-75 score at week 4 or week 24 after administration of the antibody or antigen-binding fragment thereof.

47. 47. The method of claim 46, wherein the dosage is about 200 mg q2w, about 300 mg q2w, about 500 mg q4w, or about 750 mg q4w.

48. 47. The method of claim 46, wherein the subject has a blood eosinophil count of less than about 150 cells / μl.

49. 47. The method of claim 46, wherein the subject has a blood eosinophil count of about 150 cells / μl or greater.

50. 47. The method of claim 46, wherein the subject has a blood eosinophil count greater than about 300 cells / μl.

51. 47. The method of claim 46, wherein the subject has an FeNO level of 25 ppb or greater.

52. 47. The method of claim 46, wherein the subject has an FeNO level of greater than about 25 ppb to between about 50 ppb.

53. 47. The method of claim 46, wherein the subject has an FeNO level of about 50 ppb or greater.

54. 47. The method of claim 46, wherein the subject exhibits at least a 10% or at least a 25% decrease in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin, and thymus and activation-regulated chemokine (TARC) at 4, 12, or 24 weeks after administration of the IL-4R antibody or fragment thereof.

55. 1. A method of reducing or eliminating oral corticosteroid (OCS) use in a subject suffering from steroid-dependent severe asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein at least a 50% reduction in OCS use is achieved 24 weeks after administration of the loading dose.

56. 56. The method of claim 55, wherein OCS use is reduced to less than 5 mg per day at week 24 after administration of the loading dose.

57. 56. The method of claim 55, wherein the dependence on OCS use is substantially eliminated after a predetermined period of time following administration of the loading dose.

58. 58. The method of claim 57, wherein the period is after 40 weeks, after 45 weeks, after 50 weeks, after 52 weeks, or more.

59. 56. The method of claim 55, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

60. 56. The method of claim 55, wherein the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof.

61. 61. The method of claim 60, wherein each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

62. 56. The method of claim 55, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered for at least 24 weeks.

63. 56. The method of claim 55, wherein the first maintenance dose of the antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of the antibody or antigen-binding fragment thereof.

64. 56. The method of claim 55, wherein the OCS is prednisone or prednisolone.

65. 56. The method of claim 55, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity-determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2.

66. 56. The method of claim 55, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

67. 56. The method of claim 55, wherein the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO:

2.

68. 56. The method of claim 55, wherein the maintenance dose of the antibody or antigen-binding fragment thereof is administered every four weeks (q4w).

69. 56. The method of claim 55, wherein the maintenance dose is about 500 mg of the antibody or antigen-binding fragment thereof.

70. 56. The method of claim 55, wherein each maintenance dose of the antibody or antigen-binding fragment thereof is about 750 mg of the antibody or antigen-binding fragment thereof.

71. 56. The method of claim 55, wherein at least a 75% reduction in OCS use is achieved.

72. 56. The method of claim 55, wherein at least a 90% reduction in OCS use is achieved.

73. 73. The method of any one of claims 1 to 72, wherein the loading dose is removed.

74. 74. The method of any one of claims 1 to 73, wherein the subject is an adult.

75. 74. The method of any one of claims 1 to 73, wherein the subject is an adolescent.

76. 74. The method of any one of claims 1 to 73, wherein the subject is 12 years of age or older.

77. 1. A method for treating a subject with moderate to severe oral corticosteroid (OCS) dependent asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

78. 78. The method of claim 77, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity-determining region (CDR) sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs: 1 and 2.

79. 78. The method of claim 77, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

80. 78. The method of claim 77, wherein the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO:

2.

81. 78. The method of claim 77, wherein the loading dose is about 600 mg of the antibody or antigen-binding fragment thereof.

82. 82. The method of claim 81, wherein each maintenance dose of the antibody or antigen-binding fragment thereof is about 300 mg of the antibody or antigen-binding fragment thereof.

83. 78. The method of claim 77, wherein the subject is 12 years of age or older.

84. 78. The method of claim 77, wherein the OCS is prednisone or prednisolone.

85. 1. A method for treating a subject with moderate to severe asthma and coexisting moderate to severe atopic dermatitis, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

86. 1. A method for treating a subject with moderate to severe uncontrolled asthma, wherein the onset of asthma occurred at age 40 or older, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

87. 1. A method for treating a subject with moderate to severe uncontrolled asthma and one or both of coexisting chronic sinusitis and nasal polyposis, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

88. 1. A method for treating a subject with moderate to severe uncontrolled asthma and coexisting allergic rhinitis, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

89. 1. A method for improving allergic rhinitis-related quality of life in a subject with moderate to severe uncontrolled asthma and comorbid allergic rhinitis, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

90. 1. A method for improving quality of life associated with allergic rhinitis in a subject with oral corticosteroid-dependent asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

91. 91. The method of claim 90, wherein daily morning and evening asthma symptoms are improved.

92. 1. A method for improving asthma control in a subject with oral corticosteroid-dependent asthma, comprising: administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and administering multiple maintenance doses of the antibody or antigen-binding fragment thereof to the subject. wherein the loading dose and the multiple maintenance doses are administered as additional asthma maintenance treatment.

93. 93. The method of claim 92, wherein health-related quality of life is improved.

94. 93. The method of claim 90 or 92, wherein the oral corticosteroid-dependent asthma is oral corticosteroid-dependent severe asthma.

Images