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: The present invention provides methods that 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 priority to U.S. Provisional Patent Application No. 61 / 943,019, filed February 21, 2014, and U.S. Provisional Patent Application No. 62 / 077,669, filed November 10, 2014. The contents of the foregoing applications are incorporated herein by reference in their entireties for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. Said ASCII copy, created on February 20, 2015, is named 565201-SA9-134PC_SL.txt and is 4,279 bytes in size.

[0003] The present invention relates to the treatment and / or prevention of asthma and related conditions. More specifically, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent asthma in a patient in need thereof. [Background technology]

[0004] 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. Asthma patients most often 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" in 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 doses of ICS alone. As a result, combination therapy has become the recommended treatment for subjects not controlled with low doses of ICS alone.

[0005] However, despite maximum recommended treatment with anti-inflammatory and bronchodilator combinations, it is estimated that 5%-10% of the asthma population has symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of total medical costs due to hospitalizations, use of emergency services, and unscheduled physician visits. The need for new therapies in this severe asthma population remains unaddressed, as many of these patients are poorly responsive to ICS due to a number of cellular and molecular mechanisms. In addition, attempts are made to minimize corticosteroid usage 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 fairly well treated with current treatments, corticosteroid-resistant severe asthma patients have few therapeutic treatment options that can adequately manage their disease. The consequence of non-response or lack of adherence to treatment is loss of asthma control and, ultimately, asthma exacerbation. Summary of the Invention [Problem to be solved by the invention]

[0006] 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]

[0007] According to one aspect, a method of treating asthma in a subject in need thereof is provided.

[0008] In another aspect, a method of increasing forced expiratory volume in 1 second (FEV1) in a subject in need thereof is provided.

[0009] In another aspect, a method of reducing asthma-related exacerbation events in a subject in need thereof is provided.

[0010] In yet another embodiment, a method of improving one or more asthma-related parameters in a subject in need thereof is provided.

[0011] In a further embodiment, a method is provided for reducing or eliminating an asthma patient's dependency on inhaled corticosteroids and / or long-acting beta-agonists for the treatment of one or more asthma exacerbations.

[0012] The method featured in the present invention comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor 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 method featured in the present invention are 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 region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively.

[0013] The present invention also includes the IL-4R antagonists disclosed herein for use in the manufacture of a medicament for the treatment and / or prevention of asthma or for treating any of the other indications or conditions disclosed herein.

[0014] The present invention also includes the IL-4R antagonists disclosed herein for use in the treatment and / or prevention of asthma, and / or for the treatment and / or prevention of any of the other indications or conditions disclosed herein.

[0015] In one embodiment, there is provided a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, comprising administering to the subject a combination therapy, the combination therapy comprising: i) one or more maintenance doses of an inhaled corticosteroid (ICS); and ii) a long-acting beta-blocker (B-10). 2 iii) a loading dose of about 400 to about 600 mg of an interleukin-4 receptor IL-4R antagonist; and iv) one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0016] In a particular embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In yet a further particular embodiment, the antibody is dupilumab. In yet a further particular embodiment, the antibody is a CDR sequence comprising the heavy chain complementarity determining region (HCDR) sequences comprising the heavy chain complementarity determining region (HCDR) sequences comprising the heavy chain complementarity determining region (LCDR) sequences comprising the light ... It has AS number 1190264-60-8.

[0017] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w), hi other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0018] In certain 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 two weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL, and less than 200 cells / μL.

[0019] In certain 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. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0020] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0021] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0022] In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0023] In certain embodiments, the subject has a blood eosinophil count selected from the group consisting of: greater than or equal to 300 cells / μL; between 200 and 299 cells / μL; and less than 200 cells / μL.

[0024] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate.In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol.In a further embodiment, the ICS is mometasone furoate and the LABA is formoterol.In yet a further embodiment, the ICS is budesonide and the LABA is formoterol.In yet a further embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0025] In certain embodiments, the subject is selected from the group consisting of subjects aged 18 years or older, subjects aged between 12 years and less than 18 years, subjects aged between 6 years and less than 12 years, and subjects aged between 2 years and less than 6 years. can be.

[0026] In certain embodiments, the subject is assessed for asthma in accordance with the Global Initiative for Asthma Management (GINA) 2009 guidelines and the following criteria: i) existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; ii) forced expiratory volume (FEV1) 40-80% predicted normal prior to administration of a loading dose of an IL-4R antagonist; iii) a stable ICS / LABA dose prior to administration of a loading dose of an IL-4R antagonist; Juniper Asthma Control Questionnaire, 5-question version (ACQ-5) score of ≥ 1.5 prior to administration; iv) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations) prior to administration of a loading dose of an IL-4R antagonist; or v) any of the following events within 1 year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency / urgent care visit for asthma exacerbation. Having experienced any of the following: Have moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following:

[0027] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 150 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0028] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 175 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0029] In certain 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.

[0030] Certain embodiments include a method of increasing forced expiratory volume in 1 second (FEV1) in a subject in need thereof comprising administering to the subject a combination therapy comprising: i) one or more maintenance doses of an ICS, ii) one or more maintenance doses of a LABA, iii) a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0031] In a particular embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In yet a further particular embodiment, the antibody is dupilumab. It is.

[0032] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w), hi other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0033] In certain 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 two weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0034] In certain 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. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0035] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0036] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0037] In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0038] In certain embodiments, the subject has a blood eosinophil count selected from the group consisting of: greater than or equal to 300 cells / μL; between 200 and 299 cells / μL; and less than 200 cells / μL.

[0039] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In a further embodiment, the ICS is mometasone furoate and the LABA is formoterol. In yet a further embodiment, the ICS is budesonide and the LABA is formoterol. In yet a further embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0040] In certain embodiments, the subject is selected from the group consisting of subjects aged 18 years or older, subjects aged between 12 years and less than 18 years, subjects aged between 6 years and less than 12 years, and subjects aged between 2 years and less than 6 years. can be.

[0041] In certain embodiments, the subject is assessed according to the Global Initiative on Asthma Management (GINA) 2009 guidelines and the following criteria: i) pre-existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; ii) FEV1 40-80% predicted normal; iii) ACQ-5 score of 1.5 or greater before administration of the loading dose of an IL-4R antagonist; iv) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg-400 μg (2-4 inhalations) before administration of the loading dose of an IL-4R antagonist; or v) having moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following events within 1 year prior to administration of the loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency / urgent care visit for asthma exacerbation.

[0042] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 150 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0043] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 175 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0044] In certain 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.

[0045] In one embodiment, there is provided a method of improving one or more asthma-related parameters in a subject in need thereof, comprising administering to the subject a combination therapy comprising: i) one or more maintenance doses of an ICS, ii) one or more maintenance doses of a LABA, iii) a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist; Methods include those in which the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0046] In a particular embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In yet a further particular embodiment, the antibody is dupilumab.

[0047] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w), hi other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0048] In certain 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 two weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0049] In certain 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. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0050] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0051] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0052] In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0053] In certain embodiments, the subject has a blood eosinophil count selected from the group consisting of: greater than or equal to 300 cells / μL; between 200 and 299 cells / μL; and less than 200 cells / μL.

[0054] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate.In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol.In a further embodiment, the ICS is mometasone furoate and the LABA is formoterol.In yet a further embodiment, the ICS is budesonide and the LABA is formoterol.In yet a further embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0055] In certain embodiments, the subject is selected from the group consisting of subjects aged 18 years or older, subjects aged between 12 years and less than 18 years, subjects aged between 6 years and less than 12 years, and subjects aged between 2 years and less than 6 years.

[0056] In certain embodiments, the subject is assessed according to the Global Initiative on Asthma Management (GINA) 2009 guidelines and the following criteria: i) pre-existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; ii) FEV1 40-80% predicted normal; iii) ACQ-5 score of 1.5 or greater before administration of the loading dose of an IL-4R antagonist; iv) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg-400 μg (2-4 inhalations) before administration of the loading dose of an IL-4R antagonist; or v) having moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following events within 1 year prior to administration of the loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency / urgent care visit for asthma exacerbation.

[0057] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 150 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0058] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 175 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0059] In certain 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.

[0060] In certain embodiments, the one or more asthma related parameters include: (1) relative percent change from baseline in forced expiratory volume in 1 second (FEV1) at Week 12; (2) annualized rate of loss of asthma control events during the treatment period; (3) annualized rate of severe exacerbation events during the treatment period; (4) time to loss of asthma control event during the treatment period; (5) time to severe exacerbation event during the treatment period; (6) time to loss of asthma control event over the entire study period; (7) time to severe exacerbation event over the entire study period; (8) healthcare resource utilization; (9) at Week 12: i) morning and evening asthma symptom scores, ii) A (10) At weeks 12 and 24, the following outcomes were selected from the group consisting of: i) the 22-item Sinus Outcome Test (SNOT-22); ii) the Hospital Anxiety and Depression Score (HADS); iii) the EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L).

[0061] In certain embodiments, a loss of asthma control (LOAC) event is defined as any of the following events: i) 6 or more additional puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared to baseline in a 24-hour period on 2 consecutive days, or ii) a 4-fold or greater increase in the dose of corticosteroids at Visit 2, or iii) systemic corticosteroid use for 3 or more days, or iv) requirement of systemic corticosteroids. It is defined as any hospitalization or emergency department visit due to asthma.

[0062] In certain embodiments, a severe exacerbation event is defined as the following events: i) use of systemic corticosteroids for 3 days or more, or ii) hospitalization or emergency department visit for asthma requiring systemic corticosteroids.

[0063] Certain embodiments include a method of reducing an asthma patient's dependency on inhaled corticosteroids (ICS) and / or long-acting beta-agonists (LABAs) for the treatment of one or more asthma exacerbations, the method comprising the steps of: (a) selecting a patient with moderate to severe asthma uncontrolled on background asthma therapy comprising an ICS, a LABA, or a combination thereof; and (b) administering to the patient a combination therapy comprising: i) one or more maintenance doses of an ICS, ii) one or more maintenance doses of a LABA, iii) a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0064] In a particular embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In yet a further particular embodiment, the antibody is dupilumab.

[0065] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w), hi other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0066] In certain 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 two weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0067] In certain 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. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0068] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject is administered a blood serum concentration selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL. Has eosinophil count.

[0069] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0070] In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0071] In certain embodiments, the subject has a blood eosinophil count selected from the group consisting of: greater than or equal to 300 cells / μL; between 200 and 299 cells / μL; and less than 200 cells / μL.

[0072] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate.In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol.In a further embodiment, the ICS is mometasone furoate and the LABA is formoterol.In yet a further embodiment, the ICS is budesonide and the LABA is formoterol.In yet a further embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0073] In certain embodiments, the patient is selected from the group consisting of subjects aged 18 years or older, subjects aged between 12 years and less than 18 years, subjects aged between 6 years and less than 12 years, and subjects aged between 2 years and less than 6 years.

[0074] In certain embodiments, the patient is assessed according to the Global Initiative for Asthma Management (GINA) 2009 guidelines and the following criteria: i) existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; ii) FEV140-80% predicted normal prior to administration of a loading dose of an IL-4R antagonist; iii) ACQ-5 score ≥1.5 prior to administration of a loading dose of an IL-4R antagonist; iv) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg-400 μg (2-4 inhalations) prior to administration of a loading dose of an IL-4R antagonist; or v) having moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following events within 1 year prior to administration of a loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency / urgent care visit for asthma exacerbation.

[0075] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 150 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0076] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is a IL-4R antibody or antigen-binding fragment thereof that is at about 175 mg / mL, 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, wherein the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0077] In certain 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.

[0078] One embodiment is a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, comprising administering to the subject a combination therapy comprising: i) one or more maintenance doses of an ICS, ii) one or more maintenance doses of a LABA, iii) a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and iv) one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist; The methods include, wherein the ICS and LABA are administered during the duration of the administration of the IL-4R antagonist, and the subject has a blood eosinophil count selected from the group consisting of: ≥ 300 cells / μL, 200-299 cells / μL; and < 200 cells / μL.

[0079] In a particular embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In a further particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In yet a further particular embodiment, the antibody is dupilumab.

[0080] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w), hi other embodiments, one or more maintenance doses are administered every four weeks (q4w).

[0081] In certain 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 two weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0082] In certain 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. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0083] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject is administered a blood serum concentration selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL. Has eosinophil count.

[0084] In certain 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 4 weeks. In further embodiments, the one or more maintenance doses are administered for at least 24 weeks. In still further embodiments, the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200-299 cells / μL; and less than 200 cells / μL.

[0085] In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously, or intranasally.

[0086] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate.In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol.In a further embodiment, the ICS is mometasone furoate and the LABA is formoterol.In yet a further embodiment, the ICS is budesonide and the LABA is formoterol.In yet a further embodiment, the ICS is fluticasone propionate and the LABA is salmeterol.

[0087] In certain embodiments, the subject is selected from the group consisting of subjects aged 18 years or older, subjects aged between 12 years and less than 18 years, subjects aged between 6 years and less than 12 years, and subjects aged between 2 years and less than 6 years.

[0088] In certain embodiments, the subject is assessed according to the Global Initiative on Asthma Management (GINA) 2009 guidelines and the following criteria: i) pre-existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; ii) FEV1 40-80% predicted normal; iii) ACQ-5 score of 1.5 or greater before administration of the loading dose of an IL-4R antagonist; iv) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg-400 μg (2-4 inhalations) before administration of the loading dose of an IL-4R antagonist; or v) having moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following events within 1 year prior to administration of the loading dose of an IL-4R antagonist: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) hospitalization or emergency / urgent care visit for asthma exacerbation.

[0089] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 150 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0090] In a particular embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R is administered in a formulation comprising: i) about 175 mg / mL of the 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, vi) about 0.2% (w / v) polysorbate 80, and the pH of the formulation is about 5.9. In a further embodiment, the viscosity of the formulation is about 8.5 centipoise.

[0091] In certain 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.

[0092] Certain embodiments include IL-4R antagonists for use in the treatment and / or prevention of asthma and related conditions.

[0093] Certain embodiments include pharmaceutical compositions comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in the treatment and / or prevention of asthma and related conditions.

[0094] An embodiment includes a formulation 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, wherein the pH of the formulation is about 5.9. In certain embodiments, the viscosity of the formulation is about 8.5 centipoise. In certain 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.

[0095] An embodiment includes a formulation 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, wherein the pH of the formulation is about 5.9. In certain embodiments, the viscosity of the formulation is about 8.5 centipoise. In certain 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.

[0096] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, the subject having low or moderate blood eosinophil levels, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0097] In certain embodiments, the subject has a blood eosinophil count of between about 200 cells / μL and about 299 cells / μL, or the subject has a blood eosinophil count of less than about 200 cells / μL.

[0098] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0099] In certain embodiments, the one or more maintenance doses are administered q2w or q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and the one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered q4w. In certain embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and the one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered q2w. In certain 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 q4w. In certain 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 q2w. In certain embodiments, the one or more maintenance doses are administered for at least 24 weeks.

[0100] In certain embodiments, the subject has elevated levels of one or more of the following biomarkers: periostin, thymus and activation-regulated chemokine (TARC), dipeptidyl peptidase 4 (DPP4), eosinophil cationic protein (ECP), eotaxin-3, total IgE, antigen-specific IgE, and exhaled nitric oxide levels (FeNO).

[0101] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, the subject being between about 12 and about 75 years of age, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0102] In certain embodiments, the subject has a blood eosinophil count between about 200 cells / μL and about 299 cells / μL, or has a blood eosinophil count less than about 200 cells / μL.

[0103] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0104] In certain embodiments, one or more maintenance doses are administered q2w or q4w. In certain 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 q4w. In certain 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 q2w. In certain 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 q4w. In certain 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 q2w. In certain embodiments, the one or more maintenance doses are administered for at least 24 weeks.

[0105] In certain embodiments, the subject has elevated levels of one or more of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0106] In one embodiment, there is provided a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, comprising administering to the subject a combination therapy, the combination therapy comprising one or more of prednisone or The methods include administering a single oral dose of about 100 to about 200 mg of an IL-4R antagonist, a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0107] In certain embodiments, one or more oral doses of about 10 mg or less of prednisone each are administered. In certain embodiments, one or more oral doses of about 5 mg or less of prednisone each are administered. In certain embodiments, the one or more oral doses of prednisone are a daily dose. In certain embodiments, the subject has a blood eosinophil count between about 200 and about 299 cells / μL. In certain embodiments, the subject has a blood eosinophil count less than about 200 cells / μL.

[0108] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0109] In certain embodiments, one or more maintenance doses are administered q2w or q4w. In certain 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 q4w. In certain 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 q2w. In certain 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 q4w. In certain 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 q2w. In certain embodiments, the one or more maintenance doses are administered for at least 24 weeks.

[0110] In certain embodiments, the subject has elevated levels of one or more of the following biomarkers: Eos, periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0111] In one embodiment, there is provided a method of reducing the incidence of one or more asthma exacerbations in a subject in need thereof, comprising administering to the subject a combination therapy comprising one or more maintenance doses of an ICS, one or more maintenance doses of a second long-term controller medication, a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of the IL-4R antagonist, wherein the ICS and the second asthma long-term controller medication are administered during the duration of administration of the IL-4R antagonist.

[0112] In certain embodiments, the asthma exacerbation is selected from the group consisting of the following exacerbation: a 30% or greater decrease from baseline in morning peak expiratory flow (PEF) on two consecutive days; six or more additional bout-medicinal puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on two consecutive days; and an asthma exacerbation requiring: systemic (oral and / or parenteral) steroid treatment, or an increase in inhaled corticosteroids to at least four times the last dose received before discontinuation, or hospitalization.

[0113] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0114] Certain embodiments include a method of improving FEV1 in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the therapeutically effective amount of the pharmaceutical composition comprises a pharmaceutical composition comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0115] In certain embodiments, the improvement in an asthma-related parameter is an increase in FEV1 of at least 0.10 L from baseline.

[0116] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0117] Certain embodiments include a method of reducing the incidence of one or more asthma exacerbations in a subject in need thereof, wherein the subject has low or moderate blood eosinophil levels and / or the subject is between about 12 and about 75 years of age, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0118] In certain embodiments, an asthma exacerbation is an exacerbation of the following: a 30% or greater decrease from baseline in morning peak expiratory flow (PEF) on two consecutive days; Six or more additional puffs of albuterol or levalbuterol (compared to baseline) in 24 hours on 2 consecutive days, and systemic (oral and / or parenteral) steroid treatment, or an increase in inhaled corticosteroids to at least four times the last dose received before discontinuation, or an asthma exacerbation requiring hospitalization.

[0119] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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 ... In the instant case, the antibody is dupilumab.

[0120] Certain embodiments include a method of improving FEV1 in a subject in need thereof, wherein the subject has low or moderate blood eosinophil levels and / or the subject is between 12 and 75 years of age, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0121] In certain embodiments, the improvement in an asthma-related parameter is an increase in FEV1 of at least 0.10 L from baseline.

[0122] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. The antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0123] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, wherein the subject has low or moderate blood eosinophil levels and / or the subject is between 12 and 75 years of age, the method comprising administering to the subject a combination therapy, the combination therapy comprising one or more maintenance doses of an ICS, one or more maintenance doses of a second long term controller medication, a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of the IL-4R antagonist, wherein the ICS and the second asthma long term controller medication are administered during the duration of the administration of the IL-4R antagonist.

[0124] In certain embodiments, the one or more maintenance doses of ICS are medium to high doses. In certain embodiments, the subject has a blood eosinophil count between about 200 and about 299 cells / μL. In certain embodiments, the subject has a blood eosinophil count less than about 200 cells / μL.

[0125] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0126] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof comprising administering to the subject a combination therapy, the combination therapy comprising one or more oral doses of prednisone, one or more maintenance doses of an ICS, one or more maintenance doses of a second inhaled asthma long-term controller, a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of the IL-4R antagonist, wherein the ICS and the second inhaled asthma long-term controller are administered during the duration of the administration of the IL-4R antagonist.

[0127] In certain embodiments, the one or more maintenance doses of ICS are medium to high doses. In certain embodiments, one or more oral doses of about 10 mg or less of prednisone each are administered. In certain embodiments, one or more oral doses of about 5 mg or less of prednisone each are administered. In certain embodiments, the one or more oral doses of prednisone are daily doses.

[0128] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0129] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, the subject being between about 12 and about 17 years of age, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 400 to about 600 mg of an IL-4R antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0130] In certain embodiments, the subject has a blood eosinophil count between about 200 cells / μL and about 299 cells / μL, or has a blood eosinophil count less than about 200 cells / μL.

[0131] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0132] In certain embodiments, one or more maintenance doses are administered q4w. In certain embodiments, one or more maintenance doses are administered for at least 24 weeks. In certain 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 q4w, optionally, said one or more maintenance doses are administered for at least 24 weeks. In certain 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 q2w, optionally, said one or more maintenance doses are administered for at least 24 weeks. In certain 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 q4w, optionally, said one or more maintenance doses are administered for at least 24 weeks. In a particular embodiment, 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 q2w, optionally wherein said one or more maintenance doses are administered for at least 24 weeks.

[0133] In certain embodiments, the subject has elevated levels of one or more of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

[0134] In one embodiment, a method of treating moderate to severe uncontrolled asthma in a subject in need thereof comprises administering to the subject a combination therapy, the combination therapy comprising one or more maintenance doses of an inhaled corticosteroid (ICS) and a long-acting beta-blocker (B-CSF) 2 The method includes administering one or more maintenance doses of an adrenergic stimulant (LABA), a loading dose of about 4 mg / kg of an interleukin-4 receptor (IL-4R) antagonist, and one or more maintenance doses of about 2 mg / kg of the IL-4R antagonist, wherein the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0135] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0136] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w) or every four weeks (q4w).

[0137] Certain embodiments include a method of treating moderate to severe uncontrolled asthma in a subject in need thereof, the subject having low or moderate blood eosinophil levels, the method comprising administering a treatment to the subject, the treatment comprising a loading dose of about 4 mg / kg of an IL-4R antagonist, and one or more maintenance doses of about 2 mg / kg of an IL-4R antagonist.

[0138] In certain embodiments, the subject has a blood eosinophil count between about 200 cells / μL and about 299 cells / μL.In certain embodiments, the subject has a blood eosinophil count less than about 200 cells / μL.

[0139] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three LCDR sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0140] In certain embodiments, one or more maintenance doses are administered q2w. In certain embodiments, one or more maintenance doses are administered q4w.

[0141] In one embodiment, there is provided a method of treating persistent asthma in a subject in need thereof, comprising administering to the subject The combination therapy includes administering a maintenance dose of one or more of an inhaled corticosteroid (ICS), a long-acting beta 2The present invention includes a method comprising administering one or more maintenance doses of an adrenergic stimulant (LABA), a loading dose of about 400 to about 600 mg of an interleukin-4 receptor (IL-4R) antagonist, and one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist, wherein the ICS and the LABA are administered for the duration of the administration of the IL-4R antagonist.

[0142] In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises heavy and light chain CDR sequences from the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NO:3, 4 and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NO:6, 7 and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R 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. In certain embodiments, the antibody is dupilumab.

[0143] In certain embodiments, one or more maintenance doses are administered every two weeks (q2w). In certain embodiments, one or more maintenance doses are administered every four weeks (q4w). In certain embodiments, the antibody or antigen-binding fragment thereof is administered to the subject systemically, intradermally, intravenously or intranasally.

[0144] In certain embodiments, the subject has a blood eosinophil count selected from the group consisting of: greater than or equal to 300 cells / μL; between 200 and 299 cells / μL; and less than 200 cells / μL.

[0145] In certain embodiments, the ICS is selected from the group consisting of mometasone furoate, budesonide and fluticasone propionate. In certain embodiments, the LABA is selected from the group consisting of formoterol and salmeterol. In certain embodiments, the ICS is mometasone furoate and the LABA is formoterol. In certain embodiments, the ICS is budesonide and the LABA is formoterol. In certain embodiments, the ICS is fluticasone propionate and the LABA is salmeterol.

[0146] In certain embodiments, the subject is selected from the group consisting of subjects aged about 18 years or older, subjects aged between about 12 years and about 75 years, subjects aged between about 12 years and about 18 years, subjects aged between about 6 years and about 11 years, and subjects aged between about 2 years and about 5 years.

[0147] In certain embodiments, subjects are assessed for asthma according to the Global Initiative for Asthma Management (GINA) 2009 guidelines and the following criteria: existing treatment with a stable ICS / LABA dose of medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥1 month prior to administration of a loading dose of an IL-4R antagonist; forced expiratory volume (FEV1) 40-80% predicted normal prior to administration of a loading dose of an IL-4R antagonist; Juniper Asthma Management Questionnaire, 5-question version prior to administration of a loading dose of an IL-4R antagonist. have persistent asthma for 12 months or more based on one or more of the following events within 1 year prior to administration of a loading dose of an IL-4R antagonist: treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation; or have been hospitalized or visited an emergency / urgent care facility for asthma exacerbation.

[0148] Other embodiments will become apparent from review of the subsequent detailed description, drawings, tables, and appended claims.

[0149] 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 description of the drawings]

[0150] [Figure 1] FIG. 1 graphically depicts mean serum functional mAb1 concentrations over time for mAb1 dosed qw (once per week) at 300 mg. [Diagram 2] FIG. 1 is a graphical representation of mean serum concentrations over time for various studies of mAb1 administered at 300 mg weekly. Asthma studies are indicated by solid lines and circles. Multinational atopic dermatitis studies are indicated by dashed lines and squares. US atopic dermatitis studies are indicated by dashed lines and circles. [Diagram 3] FIG. 13 graphically depicts least squares mean change in FEV1(L) from baseline over time (mixed effects model repeated measures analysis (MMRM) including measurements through week 12) for the high eosinophil (HEos) intention to treat (ITT) population. Abbreviations: Dup = dupilumab; FEV1 = forced expiratory volume in 1 second; LS = least squares; q2w = once every 2 weeks; q4w = once every 4 weeks; SE = standard error of the mean. FEV1(L) collected from the systemic corticosteroid start date through the systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 4] Figure 13 graphically depicts least squares mean change in FEV1(L) over time for the ITT population (MMRM including measurements through week 12). FEV1(L) collected from the systemic corticosteroid start date through the systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Diagram 5]Figure 13. Least squares mean change from baseline in FEV1(L) by eosinophil category at Week 12 for the ITT population. FEV1(L) collected from systemic corticosteroid start date to systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 6] Figure 1 graphically depicts the cumulative mean fraction of severe exacerbation events versus treatment duration for the HEos ITT population. FEV1(L) collected from systemic corticosteroid start date to systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 7] Figure 1 graphically depicts the cumulative mean fraction of severe exacerbation events versus treatment duration for the ITT population. FEV1(L) collected from the systemic corticosteroid start date to the systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 8] Figure 1 graphically depicts annualized event rates of severe exacerbations during the treatment period by treatment period baseline blood eosinophils (GIGA / L) category for the ITT population.Note: SEs of annualized event rate estimates were calculated from the SEs of log-yearly event rate estimates by the delta method. [Figure 9] FIG. 13 graphically depicts least squares mean percent change from baseline in FEV1(L) at Week 12 for the HEos ITT population. FEV1(L) collected from the systemic corticosteroid start date to the systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 10] FIG. 1 graphically depicts the cumulative mean fraction of treatment-period loss of asthma control events for the HEos ITT population. [Figure 11] FIG. 1 shows a Kaplan-Meier plot of time to first loss of asthma control event during treatment for the HEos ITT population. [Figure 12]FIG. 1 shows a Kaplan-Meier plot of time to first severe progression event during treatment for the HEos ITT population. [Figure 13] FIG. 1 graphically depicts the mean percent change from baseline TARC for the HEos ITT population. TARC=thymus and activation regulated chemokine. [Figure 14] FIG. 1 graphically depicts the mean percent change from baseline TARC for the ITT population. [Figure 15] FIG. 1 graphically depicts the mean percent change from baseline eotaxin-3 for the HEos ITT population. [Figure 16] FIG. 1 graphically depicts the mean percent change from baseline eotaxin-3 for the ITT population. [Figure 17] FIG. 1 graphically depicts the mean percent change from baseline FeNO for the HEos ITT population. FeNO=exhaled nitric oxide concentration. [Figure 18] FIG. 1 graphically depicts mean percent change from baseline FeNO—ITT population. [Figure 19] Figure 13 graphically depicts the least squares (LS) mean change from baseline in FEV1(L) over time (MMRM including measurements through week 12) for the ITT population with moderate blood eosinophils (0.2-0.299 GIGA / L). FEV1(L) collected from the systemic corticosteroid start date through the systemic corticosteroid end date +30 days for each severe exacerbation episode was excluded to reduce the confounding effect of systemic corticosteroids. [Figure 20] Figure 13 graphically depicts LS mean change from baseline in FEV1(L) over time (MMRM including measurements through week 12) for the ITT population with low blood eosinophils (<0.2GIGA / L). FEV1(L) collected from the systemic corticosteroid start date through the systemic corticosteroid end date +30 days for each severe exacerbation episode is excluded to reduce the confounding effect of systemic corticosteroids. [Figure 21]FIG. 1 graphically depicts the cumulative mean fraction of severe exacerbation events over the treatment period for the ITT population with moderate blood eosinophils (0.2-0.299 GIGA / L). [Figure 22] FIG. 1 graphically depicts the cumulative mean fraction of severe exacerbation events over the treatment period for the ITT population with low blood eosinophils (<0.2 GIGA / L). [Figure 23] FIG. 1 shows the asthma interim analysis summary disclosed herein. [Figure 24] FIG. 1 is a table showing demographic and disease baseline characteristics. [Diagram 25] FIG. 1 graphically depicts the percent of the ITT population by subgroup defined by baseline blood eosinophil count. [Figure 26] FIG. 13 graphically depicts LS mean percent change from baseline in FEV1(L) at Week 12 by eosinophil subgroups defined by baseline blood eosinophil counts (GIGA / L). [Figure 27] FIG. 13 is a graphical representation of LS mean percent change in FEV1 comparing ITT and HEos populations. [Figure 28] FIG. 13 graphically depicts LS mean change (MMRM) in FEV1(L) from baseline over time, including measurements through week 12. [Figure 29] FIG. 1 graphically depicts the cumulative mean fraction of severe exacerbation events for available data. [Diagram 30] FIG. 1 graphically depicts LS mean change from baseline in AM asthma symptom scores over time (MMRM including measurements up to week 12). [Diagram 31] FIG. 1 graphically depicts the mean percent change from baseline in blood eosinophils over time. [Diagram 32] FIG. 1 graphically depicts the mean percent change from baseline in eosinophil cationic protein (ECP). [Diagram 33] FIG. 13 graphically illustrates that suppression of total IgE is comparable between the ITT and HEos ITT populations. [Diagram 34] FIG. 1 graphically depicts the mean percent change from baseline TARC. [Diagram 35] FIG. 1 graphically depicts the mean percent change from baseline FeNO. [Diagram 36] FIG. 1 graphically depicts the mean percent change from baseline eotaxin-3. [Figure 37] FIG. 1 shows a scatter plot analysis showing absolute FEV1. [Figure 38] FIG. 1 shows a scatter plot analysis showing percent change in FEV1. [Figure 39] FIG. 1 graphically depicts the cumulative mean fraction of LOAC events for available data. [Diagram 40] FIG. 1 shows a Kaplan-Meier plot of time to first severe exacerbation event over the treatment period. [Diagram 41] FIG. 1 graphically depicts LS mean change (MMRM) from baseline in PM asthma symptoms over time of scoring, including measurements up to week 12. [Diagram 42] FIG. 13 graphically depicts LS mean change from baseline in AM PEF (L / min) over time (MMRM including measurements up to week 12). [Diagram 43] FIG. 13 graphically depicts LS mean change from baseline in PM PEF (L / min) over time (MMRM including measurements up to week 12). [Diagram 44] FIG. 1 graphically depicts LS mean change from baseline over time in the number of inhalations per day of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief (MMRM including measurements up to week 12). [Diagram 45] FIG. 1 illustrates that suppression of total IgE for the ITT population was comparable between low Eos (<0.2 GI / L) and moderate Eos (0.200-0.299 GI / L). [Figure 46] FIG. 1 illustrates the mean percent change from baseline FeNO. [Figure 47]FIG. 1 illustrates periostin levels (pg / mL) for low Eos, moderate Eos, high Eos and ITT populations. [Figure 48] 1 is a table showing that the magnitude of TARC and IgE suppression (mean % change) was greater with dupilumab (patients with high Eos) than with lebrikizumab after 12 weeks of treatment, even for patients retrospectively stratified by high periostin levels. [Figure 49] FIG. 1 shows that TARC and IgE suppression (mean percent change) was greater with dupilumab than with lebrikizumab at week 12. [Figure 50] Figure 1 shows key efficacy results for moderate-severe asthma and high eosinophil / periostin subpopulations. Left column: exacerbations. Right column: FEV1 scores. [Figure 51-1] FIG. 1 shows a description and breakdown of subjects. [Figure 51-2] Continued from Figure 51-1. [Figure 52] FIG. 1 shows the randomization population of the study. [Figure 53-1] FIG. 1 shows subject exposure to dupilumab. [Figure 53-2] Continued from Figure 53-1. [Figure 54] FIG. 1 summarizes the change from baseline in FEV1(L) and annualized rate of severe exacerbations by baseline blood Eos. [Figure 55] FIG. 11 summarizes the percent change at week 12 between the ITT, high Eos (≧300) and low Eos (<300) populations. [Figure 56] FIG. 1 shows mean baseline biomarkers by eosinophil count subpopulations. [Figure 57] FIG. 1 shows Asthma Control Questionnaire 5 (ACQ5) data for the intention to treat (ITT) population. [Figure 58] FIG. 1 shows ACQ5 item analysis for the ITT population. [Figure 59] FIG. 1 shows Asthma Quality of Life Questionnaire (AQLQ) data for the ITT population. [Figure 60] FIG. 1 shows AQLQ ITT data by domain. [Figure 61] FIG. 1 shows European Quality of Life-5 Item-5L (EQ5D-5L) data. [Figure 62] FIG. 1 shows EQ5D-5L data by item. [Figure 63] FIG. 1 shows Hospital Anxiety and Depression Score (HADS) data by domain. [Figure 64] FIG. 1 shows HADS data for the ITT population. [Figure 65] Figure 1 shows HADS data for the ITT high eosinophil (HEos) population. *Derived from an MMRM model with change from baseline score through week 24 as the dependent variable and factors (fixed effects) for treatment, country / region, visit, treatment / visit interaction, baseline score value, and baseline / visit interaction as covariates, using an unstructured correlation matrix. Scores collected from the systemic corticosteroid start date through the systemic corticosteroid end date +30 days for each exacerbation episode are excluded to reduce the confounding effect of systemic corticosteroids. [Figure 66] Figure 1 shows HADS baseline data and change from baseline at Week 12 for the ITT population. *Derived from an MMRM model with change from baseline score to Week 24 as the dependent variable and factors (fixed effects) for treatment, country / region, visit, treatment / visit interaction, baseline score value and baseline / visit interaction as covariates, using an unstructured correlation matrix. Scores collected from the systemic corticosteroid start date to the systemic corticosteroid end date +30 days for each exacerbation episode are excluded to reduce the confounding effect of systemic corticosteroids. [Figure 67] FIG. 1 shows Sino Nasal Outcome Test 22 (SNOT 22) data for the ITT population. [Figure 68] FIG. 1 shows SNOT22 data by domain. [Figure 69] FIG. 1 shows pruritus numerical rating scale (NRS) results. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0151] Before describing the invention, it is to be understood that the 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, since the scope of the invention is limited only by the appended claims.

[0152] 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.

[0153] 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.).

[0154] As used herein, the terms "treat," "treating," or similar terms, mean to alleviate symptoms, temporarily or permanently remove the cause of symptoms, or prevent or delay the onset of symptoms of the named disorder or condition.

[0155] Any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. Although typical methods and materials can be used for the present invention, the following describes all publications mentioned herein, all of which are incorporated herein by reference in their entirety.

[0156] Methods for reducing the incidence of asthma exacerbations The present invention includes a method for reducing the incidence of asthma exacerbation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.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 the subject's respiratory health that requires and / or is treatable by therapeutic intervention for asthma (such as, for example, 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.

[0157] 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 bout-medicinal puffs of salbutamol / albuterol or levosalbutamol / levalbuterol (compared to baseline) in a 24-hour period on 2 consecutive days; (b) a 4-fold or greater dose increase in ICS at Visit 2; and (c) systemic corticosteroid use for 3 or more days; or (d) asthma hospitalization or emergency department visit requiring systemic corticosteroids.

[0158] In certain cases, an asthma exacerbation may be categorized as a "severe asthma exacerbation event". A severe asthma exacerbation event refers to an incident that requires immediate intervention, said intervention being in the form of treatment with either systemic or inhaled corticosteroids at four or more times the dose taken prior to said incident. According to certain embodiments, a severe asthma exacerbation event is defined as an asthma exacerbation that requires: use of systemic corticosteroids for three or more days; or hospitalization or emergency department visit due to asthma that requires systemic corticosteroids. Thus, the general expression "asthma exacerbation" includes and encompasses the more specific subcategory of "severe asthma exacerbation". Thus, the present invention includes a method of reducing the incidence of severe asthma exacerbations in patients in need thereof.

[0159] "Reducing the 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 starting treatment with the pharmaceutical composition. Alternatively, "reducing the 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.

[0160] The present invention includes a method of 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 one or more maintenance doses of a second long-term controller medication, such as a long-acting beta agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include 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.

[0161] The present invention includes a method of 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 exacerbation medications to eliminate or reduce one or more asthma-related symptoms. Suitable acute exacerbation medications include fast-acting β 2 Adrenergic receptor stimulants include, but are not limited to, albuterol (i.e., salbutamol, e.g., Proventil™, Ventolin™, Xopenex™, etc.), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), and the like.

[0162] 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. Reduction in the incidence of asthma exacerbations (as described above) may be correlated with improvement in one or more asthma-related parameters; however, such a correlation is not necessarily observed in all cases.

[0163] Examples of "asthma-related parameters" include: (1) relative percent change from baseline in forced expiratory volume in 1 second (FEV1) at Week 12; (2) annualized rate of loss of asthma control events during the treatment period; (3) annualized rate of severe exacerbation events during the treatment period; (4) time to loss of asthma control events during the treatment period; (5) time to severe exacerbation events during the treatment period; (6) time to loss of asthma control events during the entire study period; (7) time to severe exacerbation events during the entire study period. (8) time; (9) at week 12: i) morning and evening asthma symptom scores, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations of salbutamol / albuterol or levosalbuterol / levalbuterol for symptom relief per day, vi) change from baseline in nocturnal awakenings; (10) at weeks 12 and 24: i) change from baseline in the 22-item Sino Nasal Outcome Test (SNOT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement of asthma-related parameters" refers to an increase from baseline in one or more of FEV1, AM PEF, or PM PEF, and / or a decrease from baseline in one or more of daily albuterol / levalbuterol use, ACQ5 score, mean nocturnal 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 in a patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0164] To determine whether an asthma-related parameter is "improved", the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein.For example, the asthma-related parameter may be measured on the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or fourteenth day, or on the third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or more weeks after initial treatment with the pharmaceutical composition.The parameter value at a particular time point after the start of treatment and the parameter at baseline may be compared. The difference between the criterion values ​​is used to establish whether there has been an "improvement" (eg, an increase or decrease, as the case may be, depending on the particular parameter being measured) of the asthma-related parameter.

[0165] The term "obtain" or "obtaining" as used herein refers to obtaining a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" a physical entity or value, such as an asthma-related parameter. "Directly obtaining" refers to 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 substance, separating or purifying a substance, combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming 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, such as 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.

[0166] 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, for example, in paper or electronic form. 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.

[0167] Forced expiratory 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 spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommended criteria can be used to measure FEV1 in a patient. The ATS / ERS standardization of spirometry may be used as a guideline. Spirometry is generally performed between 6-10 am and after abstaining from albuterol for at least 6 hours. Pulmonary function tests are generally performed in a sitting position, and the highest measured value of FEV1 (in liters) is recorded.

[0168] The present invention includes a method of treatment that results 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.

[0169] 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 PEF measurement method, 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 number of nighttime awakenings due to asthma symptoms requiring rescue medication). The patient is instructed on the use of the device, and written instructions on the use of the electronic PEF meter are given to the patient. In addition, a medical professional may be provided with electronic PEF meters to record variables directly relevant to the patient. The AM PEF is typically performed within 15 minutes of waking (between 6 pm and 10 pm) and before taking any albuterol. PEF is typically performed in the evening (between 6:00 AM and 10:00 AM) prior to any albuterol intake. Subjects should attempt to abstain from albuterol for at least 6 hours prior to PEF measurement. Three PEF efforts are performed by the patient and all three values ​​are recorded by the electronic PEF meter. The highest value is usually used for evaluation. The baseline AM PEF can be calculated as the average AM measurements recorded during the 7 days prior to administration of the first dose of the pharmaceutical composition comprising the IL-4R antagonist, and the baseline PM PEF can be calculated as the average PM measurements recorded during the 7 days prior to administration of the first dose of the pharmaceutical composition comprising the IL-4R antagonist.

[0170] 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.

[0171] Albuterol / lev albuterol use. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in daily albuterol or lev albuterol use from baseline. The number of albuterol / lev albuterol inhalations is recorded daily by the patient in a diary, PEF meter or other recording device. The use of albuterol / lev albuterol during treatment with the pharmaceutical composition described herein can be on an as-needed basis for symptoms, rather than regular and prophylactic. The baseline number of albuterol / lev albuterol inhalations / day can be calculated based on the average value over the 7 days prior to administration of the first dose of a pharmaceutical composition comprising an IL-4R antagonist.

[0172] The present invention includes a method of treatment that results in a reduction of at least 0.25 puffs per day from baseline in albuterol / lev albuterol usage 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 0.25 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 from baseline in albuterol / lev albuterol usage at week 12.

[0173] Prednisone Use. According to certain embodiments, the administration of IL-4R antagonist to a patient can be combined with oral prednisone. The number of prednisone doses is recorded by the patient daily in a diary, PEF meter or other recording device. During treatment with the pharmaceutical composition described herein, short-term prednisone use can be used from time to time to manage acute asthma episodes, such as episodes whose symptoms cannot be managed by bronchodilators and other anti-inflammatory drugs. In other aspects, prednisone is used in combination with ICS or as a replacement for ICS. Oral prednisone can be administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg. Oral prednisone can be administered once a day or multiple times a day (e.g., twice a day, three times a day, four times a day, etc.).

[0174] Five-item Asthma Control Questionnaire (ACQ) Score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the five-item Asthma Control Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[0175] The present invention includes a method of treatment that results in a decrease 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 decrease 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.

[0176] 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.

[0177] In certain embodiments, the method reduces the average nighttime awakenings from baseline to at least about 0.10 times per night at 12 weeks after starting treatment.For example, administering IL-4R antagonist to a subject in need thereof causes the average nighttime awakenings from baseline to be reduced by about 0.10 times per night, 0.15 times per night, 0.20 times per night, 0.25 times per night, 0.30 times per night, 0.35 times per night, 0.40 times per night, 0.45 times per night, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night, or more at 12 weeks.

[0178] 22-item Sinus Outcome Test (SNOT-22) score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction 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).

[0179] The present invention includes a method of treatment that results 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.

[0180] Methods for Treating Asthma In some embodiments, the present invention provides a method of treating asthma (including, for example, moderate to severe uncontrolled or inadequately controlled asthma) in a subject in need thereof, 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.

[0181] As used herein, the term "asthma" can be used synonymously with "intermittent asthma". "Asthma" and "intermittent asthma" refer to asthma in which one or any combination of the following applies: symptoms occur less than 2 days per week; symptoms do not interfere with daily life; nighttime symptoms occur less than 2 days 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.

[0182] As used herein, the term "persistent asthma" refers to asthma that is more severe than asthma / intermittent asthma.Subjects suffering from persistent asthma experience one or more of the following: symptoms more than 2 days per week; symptoms that interfere with daily life; nighttime symptoms more than 2 days per month; or one or more pulmonary function tests that are not normal even when the subject is not experiencing an asthma attack (e.g., forced expiratory volume in 1 second (FEV1) and / or maximum expiratory flow (PEF) is less than 80%); the subject relies on asthma management drugs on a daily basis; the subject has taken systemic steroids more than once after severe asthma exacerbation in the last year; or use short-acting β2 agonists more than 2 days per week to relieve asthma symptoms.

[0183] Asthma / intermittent asthma and persistent asthma can be categorized as "mild," "moderate," "severe," or "moderate-severe." "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" 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" 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) of 60-80%. "Moderate persistent asthma" is defined as having exacerbations that may affect daily symptoms, activities, and / or sleep, nighttime 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 maximum expiratory flow (PEF) of 60-80%. "Severe intermittent asthma" is defined as having symptoms less than once a week and having a forced expiratory volume in one second (FEV1) or maximum expiratory flow (PEF) of 60%. "Severe persistent asthma" is defined as having frequent exacerbations that may affect daily symptoms, activities, and / or sleep, frequent nighttime symptoms, limited physical activity, daily use of inhaled short-acting beta-2 agonists, and having a forced expiratory volume in one second (FEV1) or maximum expiratory flow (PEF) of 60%. "Moderate-severe intermittent asthma" is defined as having symptoms between those of moderate intermittent asthma and those of severe intermittent asthma. "Moderate-severe persistent asthma" is defined as having symptoms between those of moderate persistent asthma and those of severe persistent asthma.

[0184] 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 asthma may have 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, and the use of short-acting beta-blockers for symptom control. 2 Stimulant use more than 2 days per week, FEV1 60-80% of best predicted and / or best, ATAQ score of 1-2, ACQ score of 1.5 or greater, and ACT score of 16-19. "Very poorly controlled asthma" is defined as daytime symptoms, nighttime awakenings 4 or more times per week, severe limitations in daily activities, and the use of short-acting beta-blockers for symptom management. 2 It is defined as having stimulant medication use several times per day, an FEV1 less than 60% of best predicted and / or best personal, an ATAQ score of 3-4, an ACQ score of not applicable, and an ACT score of 15 or less.

[0185] In some embodiments, the subject meets the Global Initiative for Asthma Management (GINA) 2009 guidelines and one or more of the following criteria: i) stable IC with medium or high dose ICS / LABA (2 x fluticasone propionate 250 μg twice daily, or a daily dose of equipotent ICS) for ≥ 1 month prior to administration of a loading dose of an IL-4R antagonist; A patient is defined as having moderate to severe uncontrolled asthma if, within 1 year prior to the loading dose of an IL-4R antagonist, he or she has received a physician-provided diagnosis of moderate to severe uncontrolled asthma based on: a) treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbations, b) hospitalization or emergency / urgent care visit for asthma exacerbations.

[0186] In one aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0187] In another aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of between 200 and 299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0188] In another aspect, a method of treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 200 per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0189] In a related aspect, a method of treating asthma is provided that includes an add-on therapy to a background therapy. In certain embodiments, an IL-4R antagonist is administered as an add-on therapy to an asthma patient who has been on 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 called a "stable period"). In some embodiments, the background therapy includes an ICS and / or a LABA.

[0190] In some embodiments, the present invention provides a method of reducing an asthma patient's dependency 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.

[0191] 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.

[0192] 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 the symptoms last from a few hours to several days.In certain alternative embodiments, persistent asthma is "mild persistent" (e.g., symptoms occur more than twice a week but less than every day, and symptoms are severe enough to interfere with daily activities or sleep, and / or lung function is normalized or reversible with inhalation of bronchodilator), "moderate persistent" (e.g., symptoms occur every day, sleep is disturbed at least once a week, and / or lung function is moderately abnormal), or "severe persistent" (e.g., symptoms continue despite correct use of approved medication, and / or lung function is severely affected).

[0193] Interleukin-4 receptor antagonists The method of interest in the present invention includes administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. 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 IL-4R is 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.

[0194] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), e.g., IL-4Rα.

[0195] 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 (referred to herein as HCVR or V HThe heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (herein LCVR or V L The light chain constant region comprises one domain (C L 1) is included. 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 amino terminus to 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 a parallel analysis of two or more CDRs.

[0196] The term "antibody" also includes antigen-binding fragments of complete antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically modified 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 techniques, including the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or can be readily obtained, 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 in a suitable conformation, or to introduce codons, generate cysteine ​​residues, modify, add or delete amino acids, and the like.

[0197] 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) a minimal recognition unit consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR), such as 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, and the like, may also be used. Nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs) and shark variable IgNAR domains are also encompassed by the expression "antigen-binding fragment".

[0198] 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 the domain H For an antigen-binding fragment having a domain, V H and V L The domains can be positioned in any suitable arrangement relative to each other. For example, the variable region is a dimer and the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomeric V H or V L It may also contain a domain.

[0199] 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 within 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 -C H 1;(ix)VL -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, and 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 domains. 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).

[0200] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will generally contain 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.

[0201] 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.

[0202] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, human antibodies of interest in the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations induced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), e.g., 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.

[0203] The term "recombinant human antibody" includes all human antibodies that are produced, expressed, generated or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (discussed further below), antibodies isolated from recombinant, combinatorial human antibody libraries (discussed further below), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, generated or isolated by any other means including splicing of human immunoglobulin gene sequences to 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 animals transgenic for human Ig sequences are used), so that the V and V regions of the recombinant antibodies may be modified. H and V L The amino acid sequence of the region is human germline V H and V L Derived from the human germline V H and V L A sequence that is related to the sequence, but which may not naturally exist within the human antibody germline repertoire in vivo.

[0204] 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 a molecule of approximately 75-80 kDa is formed and composed of covalently coupled light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0205] 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 hinge region isotype of the antibody. 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 human IgG1 hinges (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for the determination of the frequency of occurrence of the second form in the hinge, C ... H 2 or C H Antibodies with one or more mutations in three regions are included.

[0206] An "isolated antibody" refers to 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 a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ in a recombinant cell. 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.

[0207] 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 noted in the present invention, has a specific binding affinity 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 K less than 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 D and includes antibodies that bind to IL-4R or a portion thereof. However, an isolated antibody that specifically binds human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0208] Anti-IL-4R antibodies useful in the methods may contain one or more amino acid substitutions, insertions and / or deletions (e.g., 1, 2, 3, 4, 5, 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) in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. 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 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, 10, 11, or 12 for a trimeric antibody, or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) within one or more framework and / or one or more CDR regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) 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, the VH and / or V L All of the framework and / or CDR residues in the domain are backmutated to the 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 the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the 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 different from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations in the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residues in a particular germline sequence, while certain other residues that differ from the original germline sequence may be maintained or mutated to the corresponding residues 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 agonist biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present invention.

[0209] The invention also includes methods that include the use of anti-IL-4R antibodies that include 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 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 less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein.

[0210] The term "surface plasmon resonance" refers to an optical phenomenon that allows analysis of real-time interactions by detection of changes in protein concentration within a biosensor matrix, for example using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0211] The term “K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0212] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Different antibodies may therefore bind to different antigenic regions and have different biological effects. Epitopes may be conformational or linear. Conformational epitopes are generated by spatially adjacent amino acids from different segments of a linear peptide chain. Linear epitopes are those generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include sugar, phosphoryl or sulfonyl moieties on the antigen.

[0213] 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.

[0214] Using VELOCIMMUNE™ technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals), or any other known method for producing monoclonal antibodies, a high affinity chimeric antibody against IL-4R is first isolated, having a human variable region and a mouse constant region. VELOCIMMUNE® technology involves the production of a transgenic mouse with a genome that includes human heavy and light chain variable regions operably linked to an endogenous mouse constant region locus, such that the mouse produces an antibody that includes a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[0215] In general, VELOCIMMUNE® mice are sensitized with an antigen of interest, and lymphoid cells (e.g., B cells) are collected from the mice that express antibodies. The lymphoid cells can be fused with a myeloma cell line to produce immortal hybridoma cell lines, which are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light chains can be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the heavy and light chains can be directly isolated from antigen-specific lymphocytes.

[0216] A high affinity chimeric antibody with human variable regions and mouse constant regions is first isolated. Using standard procedures known to those skilled in the art, the antibody is characterized and selected for desired characteristics, including affinity, selectivity, epitope, etc. The mouse constant region is replaced with the desired human constant region to produce the fully human antibody 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 region has high affinity antigen binding properties and target specificity.

[0217] Generally, the antibodies that can be used in the method have high affinity as described above, as measured by binding to antigen immobilized on a solid phase or in solution phase. The mouse constant region is replaced with the desired human constant region to produce the fully human antibody of interest in the present invention. The constant region selected may vary depending on the specific application, but the variable region has high affinity antigen binding properties and target specificity.

[0218] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R that can be used in connection with the methods featured in the present invention comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) 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 also 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 specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence diversity, 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. 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.

[0219] 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 pair and light chain variable region amino acid pair (HCVR / LCVR) of SEQ ID NO:1 / 2.

[0220] 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.

[0221] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2.

[0222] In one embodiment, the antibody is dupilumab comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2.

[0223] Pharmaceutical Compositions The present invention includes a method comprising administering to a patient an IL-4R antagonist contained in a pharmaceutical composition. The pharmaceutical compositions of interest in the present invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, etc. Many suitable formulations can be found in a formulary known to every pharmacist: 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 absorption paces, and the like. Excipients for parenteral formulations include, for example, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also, e.g., Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0224] The dose of the 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. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. The effective dosage and schedule for administering a pharmaceutical composition containing an anti-IL-4R antibody can be empirically determined; for example, the progress of the patient 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).

[0225] Various delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., 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. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions may 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, etc.), and may be administered together with other bioactive agents.

[0226] The pharmaceutical compositions featured in the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, for subcutaneous delivery, pen delivery devices are easily 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 that contains the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and easily replaced with a new cartridge that contains 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 pre-filled with the pharmaceutical composition, which is held in a reservoir of the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0227] A large number of 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 P Examples of disposable pen delivery devices utilized for subcutaneous delivery of pharmaceutical compositions of interest in the present invention include, but are not limited to, SOLOSTAR pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk) and KWIKPEN (Eli Lilly), SURECLICK autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA pen (Abbott Labs, Abbott Park IL), to name just a few.

[0228] For direct administration to the sinuses, the pharmaceutical composition of interest in the present invention may be administered, for example, using a microcatheter (e.g., endoscope and 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. The aerosolized antibody may be prepared, for example, as described in U.S. Pat. No. 8,178,098, which is incorporated herein in its entirety.

[0229] In certain circumstances, pharmaceutical compositions can be delivered in controlled release systems. In one embodiment, pumps 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 Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be located in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, for example, 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.

[0230] The injectable preparations include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, and the like. These injectable preparations can be manufactured by known methods. For example, the injectable preparations can be manufactured by dissolving, suspending or emulsifying the above-mentioned antibody or its salt in a sterile aqueous or oily medium conventionally used for injections. The aqueous medium for the injections includes, for example, physiological saline, isotonic solutions containing glucose and other auxiliary agents, and these may be used in combination with suitable solubilizers, such as alcohol (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. As the oily medium, for example, sesame oil and soybean oil are used, and these may be used in combination with solubilizers, such as benzyl benzoate, benzyl alcohol, and the like. The injections manufactured in this manner are generally filled into suitable ampoules.

[0231] Advantageously, the above-described oral or parenteral pharmaceutical compositions are prepared in unit dose forms suitable for combining a dose of the active ingredient. Such unit dose forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0232] 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.

[0233] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject according to the method of interest in the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of IL-4R antagonist that results in one or more of the following: (a) a reduction in the incidence of asthma exacerbation; (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 upper airway inflammatory conditions. "Therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, alleviates, or slows the progression of asthma in a subject.

[0234] In the case of an anti-IL-4R antibody, a therapeutically effective amount is about 0.05 mg to about 700 mg of an 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, or about 100 mg. 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 about 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.

[0235] 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 may be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0236] 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 >= 300 cells / μL (high blood eosinophils) (HEos); a blood eosinophil count between 200 and 299 cells / μL; or a blood eosinophil count < 200 cells / μL (low blood eosinophils).

[0237] In certain embodiments, the method includes a loading dose of about 400 to about 600 mg of an IL-4R antagonist.

[0238] In certain embodiments, the method includes one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0239] In certain embodiments, the ICS and LABA are administered during the administration of the IL-4R antagonist.

[0240] 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.

[0241] 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.

[0242] In other embodiments, 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.

[0243] In other embodiments, 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.

[0244] In other embodiments, 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.

[0245] In other embodiments, 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 once weekly.

[0246] In other embodiments, 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.

[0247] In other embodiments, 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.

[0248] In one embodiment, the subject is between 6 and 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.

[0249] In another embodiment, the subject is between 2 and under 6 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0250] 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.

[0251] Combination treatment Certain embodiments of the method of interest in the present invention include administering one or more additional therapeutic agents to a subject in combination with an IL-4R antagonist. As used herein, the term "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 a method of 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.

[0252] 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.

[0253] The additional therapeutic agent may 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 The IL-4R antagonist may be a stimulant (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, the pharmaceutical composition comprising the IL-4R antagonist is a long-acting β 2 It is given in combination with a combination drug containing a stimulant and an inhaled corticosteroid (e.g., fluticasone plus salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide plus formoterol [e.g., SYMBICORT® (Astra Zeneca)]).

[0254] Dosing regimen According to certain embodiments, multiple doses of IL-4R antagonist may be administered to a subject over a defined period of time. Such methods include sequentially administering multiple doses of IL-4R antagonist to a subject. As used herein, "sequentially administering" means administering each dose of IL-4R antagonist to a subject at different times, e.g., on different days separated by a predefined interval (e.g., hours, days, weeks or months). The present invention includes methods that include sequentially administering a single initial dose of IL-4R antagonist, followed by one or more second doses of IL-4R antagonist, optionally followed by one or more third doses of IL-4R antagonist to a patient.

[0255] The present invention includes methods comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about 4 times per week, twice per week, once per week, once per 2 weeks (biweekly), once per 3 weeks, once per 4 weeks (monthly), once per 5 weeks, once per 6 weeks, once per 8 weeks, once per 12 weeks, or less frequently if a therapeutic response is obtained. In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a weekly dose in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 2 weeks dose in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving 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 administered once every three weeks may be used. In another embodiment involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 4 weeks administration (once a month administration) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In another embodiment involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 5 weeks administration in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In another embodiment involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 6 weeks administration in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In another embodiment involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 8 weeks administration in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In another embodiment involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once every 12 weeks administration in an amount of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg can be used. In one embodiment, the route of administration is subcutaneous.

[0256] 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.

[0257] 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 the treatment regimen (also called 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 frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the first, second and / or third dose differs from each other during the course of treatment (e.g., adjusted upwards or downwards as necessary). In certain embodiments, two or more doses (e.g., 2, 3, 4 or 5) are administered at the beginning of the 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.

[0258] 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.

[0259] In a specific embodiment, 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.

[0260] In certain embodiments, the loading dose is twice the maintenance dose.

[0261] 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 two weeks.

[0262] 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.

[0263] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses of the antibody or antigen-binding fragment thereof administered every four weeks. Contains 300mg of fragments.

[0264] 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.

[0265] 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, 12, 12.5, 13, 13.5, 14, 14.5 or more weeks) after the immediately preceding dose. The phrase "immediately preceding dose" refers to, in relation to a sequence of multiple administrations, the dose of anti-IL-4R antagonist administered to a patient prior to administration of the very next dose in that sequence with no intervening doses.

[0266] 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.

[0267] In embodiments comprising multiple second doses, each second dose may be administered with 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 with 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 frequency of administration may be adjusted during the course of treatment by the physician according to the needs of the individual patient according to clinical examination.

[0268] The present invention includes methods comprising sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient for treating asthma or a related condition. In some embodiments, the methods comprise administration of one or more doses of an IL-4R antagonist, followed by administration of one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) 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 doses, or more) of a second therapeutic agent (e.g., an inhaled corticosteroid or a β2 agonist or other therapeutic agent as described elsewhere herein) for treating, alleviating, reducing, or ameliorating one or more symptoms of asthma. In some embodiments, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 doses, or more) 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 doses, or more) of an IL-4R antagonist are administered, and the second therapeutic agent is administered in a different dosage amount, 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.

[0269] 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 weeks, or more. In other embodiments, the IL-4R antagonist is administered every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks, or more. In a specific embodiment, the IL-4R antagonist is administered for at least 24 weeks.

[0270] Treatment population The method of interest in the present invention comprises administering a therapeutic composition comprising 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" can include a subject that exhibits (or has exhibited) one or more asthma-related parameters prior to treatment, such as, for example, a reduced FEV1 (e.g., less than 2.0 L), 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 a patient in need thereof.

[0271] In related embodiments, the "subject in need thereof" may be a subject who has been prescribed or is currently taking a combination ICS / LABA 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 treatments include fluticasone / salmeterol combination treatment, and budesonide / formoterol combination treatment. For example, the present invention includes a method comprising administering an IL-4R antagonist to a patient who has been receiving regular treatment with an ICS / LABA 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 a method 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 tapered before or after initiation of IL-4R antagonist administration. 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.

[0272] In some embodiments, the "subject in need thereof" may be a subject with elevated asthma-related biomarker levels. 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, the "subject in need thereof" may be a subject with blood eosinophils ≧300 / μL, 200-299 / μL, or <200 / μL. In one embodiment, the "subject in need thereof" may be a subject with elevated bronchial or airway inflammation levels as measured by exhaled nitric oxide (FeNO).

[0273] In some embodiments, the "subject in need thereof" is selected from the group consisting of subjects aged 18 years or older, subjects aged 12-17 years (12-18 years), subjects aged 6-11 years (6-12 years), and subjects aged 2-5 years (2-6 years). 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 aged 18 years or older, adolescents aged 12-17 years (12-18 years), children aged 6-11 years (6-12 years), and children aged 2-5 years (2-6 years). The subject may be under 2 years of age, e.g., 12-23 months, or 6-11 months.

[0274] 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]). Thus, the present invention includes a method comprising the steps of selecting a subject exhibiting an elevated serum IgE level, where the serum IgE level is 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.

[0275] TARC levels in healthy subjects range from 106ng / L to 431ng / L, with a mean value of about 239ng / 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.) Thus, the present invention includes a method comprising the steps of selecting a subject exhibiting elevated TARC levels, where the serum TARC level is greater than about 431ng / L, greater than about 500ng / L, greater than about 1000ng / L, greater than about 1500ng / L, greater than about 2000ng / L, greater than about 2500ng / L, greater than about 3000ng / L, greater than about 3500ng / L, greater than about 4000ng / L, greater than about 4500ng / L, or greater than about 5000ng / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0276] 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. 104:786-790). The present invention includes methods that include administering an IL-4R antagonist to treat patients with elevated eotaxin-3 levels, for example, eotaxin-3 levels 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.

[0277] 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 Aug. 1, 2012). The present invention includes methods comprising administering an IL-4R antagonist to treat patients with elevated periostin levels.

[0278] 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 use of the NIOX instrument by Aerocrine AB, Solna, Sweden. Assessment is performed prior to spirometry and at least Both can be performed after a one hour fast. The present invention includes methods comprising administering an IL-4R antagonist to a patient having 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.

[0279] 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 diseases of the lung (Marechal et al., 1988, Anticancer Res. 8:677-680). CEA levels in serum can be measured by ELISA. The present invention includes methods that include administering an IL-4R antagonist to a patient with elevated CEA levels, e.g., CEA levels 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.

[0280] YKL-40, named for its N-terminal amino acids tyrosine (Y), lysine (K) and leucine (L) and with 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.

[0281] 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 invention includes methods comprising administering an IL-4R antagonist to a patient having elevated periostin levels.

[0282] Induced sputum eosinophils and neutrophils are well-established direct markers for 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.

[0283] In some embodiments, subjects are stratified into the following groups: blood eosinophil count >= 300 cells / μL (high blood eosinophils) (HEos), 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.

[0284] Methods for assessing pharmacodynamic asthma-related parameters The present invention also includes a method for evaluating 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 is not necessarily observed in all cases.

[0285] 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" refers to, for example, a reduction from baseline in one or more biomarkers, such as TARC, eotaxin-3, or IgE, a reduction 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.

[0286] To evaluate pharmacodynamic asthma-related parameters, the parameters are quantified at baseline and at the time point after administration of pharmaceutical composition.For example, pharmacodynamic asthma-related parameters can be measured at the first day, second day, third day, fourth day, fifth day, sixth day, seventh day, eighth day, ninth day, tenth day, eleventh day, twelfth day, fourteenth day, or at the third week, fourth week, fifth week, sixth week, seventh week, eighth week, nineteenth week, tenth week, eleventh week, twelve weeks, thirteenth week, fourteenth week, fifteenth week, sixteenth week, seventeenth week, eighteenth week, nineteenth week, twentieth week, twenty-first week, twenty-second week, twenty-third week, twenty-fourth week, or more time points after first treatment with pharmaceutical composition. The difference between the parameter value at a particular time point after the start of treatment and the parameter value at baseline is used to establish whether there has been a change, such as an "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured), in the pharmacodynamic asthma-related parameter.

[0287] In certain embodiments, administration of an IL-4R antagonist to a patient results in a change in the expression, e.g., a decrease or an increase, of a particular biomarker. Asthma-related biomarkers include, but are not limited to: (a) total IgE; (b) thymus and activation-regulated chemokine (TARC); (c) YKL-40; (d) carcinoembryonic antigen in serum; (e) eotaxin-3 in plasma; and (f) periostin in serum. 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 more 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).

[0288] Biomarker expression as discussed above can be assayed by detection of 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 disease (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 RNA levels of biomarkers; in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0289] 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 20 mM glycerol; about 5% (w / v) sucrose, v) about 25 mM arginine hydrochloride, 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.

[0290] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of the 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.

[0291] In a specific 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.

[0292] 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.

[0293] 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 being fully explained in the literature. See, e.g., 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, volumes 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. Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). EXAMPLES

[0294] The following examples are presented to give those of ordinary skill in the art 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 pressure.

[0295] 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").

[0296] Example 1: Pharmacokinetics of mAb1 in asthma patients A pharmacokinetic study was conducted in patients with asthma. Each patient was administered 300 mg of mAb1 once a week for 12 weeks. max , AUC,t last , C last and t 1 / 2 Various medications, including Pharmacokinetic parameters were measured and the results are shown in Table 1 below.

[0297] [Table 1]

[0298] Average t over 458 hours (19.1 days) 1 / 2 is consistent with the half-life of an IgG molecule, further supporting that target-mediated clearance was not the primary elimination route for mAb1 at the concentrations observed in this study.

[0299] A graph of the mean serum functional mAb1 concentration over time is shown in Figure 1. As shown in Figure 1, after 12 weekly doses of 300 mg / week mAb1 in asthma patients, C trough Concentrations appeared to reach a plateau between weeks 10 and 12. C was significantly higher after the 12th dose compared to after the first dose. trough The cumulative cumulative PK response rate, as assessed by PK loading, was 5.88 at the 300 mg weekly dose. In the majority of patients, mAb1 was still detectable in serum at the time of the last PK sample (7-9 weeks after the last drug administration). The results of this study suggest a benefit that may be obtained from a loading dose.

[0300] Serum concentrations of mAb1 were measured during a 300 mg weekly dosing regimen in patients with atopic dermatitis or asthma. As shown in Figure 2, mAb1 systemic exposure was similar in patients with atopic dermatitis and asthma during the first 4 weeks of a 300 mg weekly dose.

[0301] Example 2: A randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the anti-IL-4R antibody dupilumab in patients with moderate to severe uncontrolled asthma A. Research objectives and overview A randomized, double-blind, placebo-controlled, dose-ranging study was conducted to evaluate mAb1 (dupilumab) in patients with moderate to severe uncontrolled asthma. The primary objective of the study was to evaluate the efficacy of different doses and regimens of mAb1 in patients with moderate to severe uncontrolled asthma. A secondary objective of the study was to evaluate the efficacy of different doses and regimens of mAb1 in patients with moderate to severe uncontrolled asthma. The objectives of this study were to evaluate different doses and regimens of mAb1 in patients with refractory leukemia with relapsed or refractory leukemia in terms of: safety and tolerability, mAb1 systemic exposure and anti-drug antibodies, and patient-reported outcomes (PROs); assess baseline biomarkers for their potential value in predicting response to treatment; assess on-treatment biomarkers for their potential value in associating with response to treatment; and assess genetic profiles for their potential value in predicting response to treatment.

[0302] B. Study Design The study is a multinational, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study comparing different doses and regimens of mAb1 administered subcutaneously (SC) for 24 weeks in patients with moderate-to-severe uncontrolled asthma. Approximately 770 patients were randomly assigned to five treatment arms, 150 patients per arm.

[0303] The trial, using an add-on treatment approach to inhaled corticosteroid / long-acting beta-agonist combination therapy (ICS / LABA), consisted of three periods: a screening period (14-21 days) to determine whether patients met the entry criteria and to establish the level of asthma control before the randomized treatment period; a randomized treatment period (24 weeks); and a post-treatment period (16 weeks) to monitor patients after treatment.

[0304] C. Patient Selection Patients aged 18-65 years with physician-diagnosed moderate-to-severe uncontrolled asthma for ≥12 months based on the Global Initiative on Asthma Management (GINA) 2009 guidelines and the following criteria were eligible for inclusion in the study: (1) existing treatment with medium- or high-dose ICS / LABA (2 × fluticasone propionate 250 μg twice daily, or equivalent potency daily dose of ICS) at a stable ICS / LABA dose for ≥1 month prior to Visit 1; (2) FEV1 before the first dose of study drug at Visit 1 and Visit 2; 40-80% predicted normal; (3) ACQ-5 score ≥ 1.5 at Visit 1 and Visit 2; (4) reversibility of FEV1 of at least 12% and 200 mL after salbutamol / albuterol 200 μg to 400 μg (2-4 inhalations) at Visit 1; and (5) any of the following events experienced within the year prior to Visit 1: treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, or hospitalization or emergency / urgent care visit for asthma exacerbation.

[0305] Patients who met all of the above inclusion criteria were screened for the following exclusion criteria: (1) patients <18 years of age; (2) chronic obstructive pulmonary disease (COPD) or other lung disease that would impair pulmonary function tests (e.g., emphysema, idiopathic pulmonary fibrosis, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis); (3) clinically significant evidence of lung disease other than asthma within 12 months of the screening visit or chest x-ray at the time of the screening visit; (4) current smokers or those who had quit smoking within 6 months prior to Visit 1; (5) former smokers with a smoking history >10 pack / year; (6) comorbidities that might interfere with the assessment of IMP(mAb1); (7) non-adherence, alcohol abuse or drug known or suspected abuse;(8) inability to comply with study procedures (e.g., due to speech problems or psychological disorders);(9) reversal of sleep patterns (e.g., night shift personnel);(10) patients requiring beta-adrenergic receptor blocking drugs (beta-blockers) for any reason;(11) anti-immunoglobulin E (IgE) treatment (omalizumab) within 130 days prior to Visit 1; biologic treatment within 6 months prior to Visit 1;(12) initiation of allergen immunotherapy within 3 months prior to Visit 1, or plans to initiate or change dose of treatment during the screening or randomized treatment period;(13) exposure to another investigational antibody within less than 5 half-lives of that antibody (if known) prior to Visit 1. If the half-life is not known, the minimum interval from previous exposure to the investigational antibody is 6 months. The minimum interval from exposure to any other (non-antibody) investigational study drug is 30 days prior to Visit 1; (14) Patients receiving prohibited concomitant medications; (15) Previous enrollment in this or any other mAb1 study (16) the patient is a principal investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff member, or a relative of the patient, directly involved in the implementation of the protocol; (17) non-compliance with required background treatment, use of ICS / LABA combination products during the screening period (this non-compliance was defined as: less than 80% of the total number of prescribed "stable dose" puffs taken during the screening period. Compliance was verified based on ICS / LABA use recorded in the patient's electronic diary during the screening period); ( 18) Concurrent serious illnesses or diseases that contraindicate the use of ICS (e.g., active and inactive pulmonary tuberculosis) or the use of LABA (e.g., diagnosis of significant cardiovascular disease, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, corrected QT interval prolongation (men > 450 ms, women > 470 ms) or history of tachyarrhythmia); (19) Treatment with drugs associated with clinically significant corrected QT interval prolongation / torsades de pointes ventricular tachycardia; (20) Women of childbearing potential (reproductive tract infections) Women who are premenopausal women of biological childbearing potential, without a negative serum β-hCG test at Visit 1 or who are not protected during the study by one of the following accepted forms of effective contraception: established use of oral, injectable, or implantable hormonal contraception; copper-containing intrauterine device (IUD) or progestogen-containing intrauterine system (IUS); barrier contraceptive device (condom, diaphragm, or cervical / vaginal cuff) used in conjunction with a spermicide (foam, gel, film, cream, or suppository). cap); female sterilization (e.g., tubal occlusion, hysterectomy, or bilateral oophorectomy); male sterilization with documentation of post-vasectomy absence of sperm in the ejaculate; for studies of female patients, the vasectomized male partner should be the woman's only partner; true abstinence; cyclical abstinence (e.g., calendar, ovulation, symptomatic temperature, postovulation methods) is not an acceptable method of contraception; or no additional contraception is required for menopausal women (defined as the absence of menses for at least 12 consecutive months); (21) diagnosed with an active parasitic infection;(21) Suspected parasitic infection or high risk for parasitic infection (unless active infection was ruled out by clinical and (if appropriate) laboratory evaluation prior to randomization); (22) History of human immunodeficiency virus (HIV) infection or positive HIV test (anti-HIV-1 and HIV-2 antibodies) at Visit 1; (23) History of invasive, opportunistic infection, including history of infection (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), despite resolution of infection (24) evidence of acute or chronic infection requiring treatment with an antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal agent within 4 weeks prior to Visit 1; significant viral infection within 4 weeks prior to Visit 1 that could not receive antiviral treatment (e.g., influenza that was only treated symptomatically); (25) vaccination with live attenuated vaccine within 12 weeks prior to Visit 1 or during the study - Prohibited live attenuated vaccines include Bacillus Calmette-Guerin (BCG) antituberculosis vaccine; Chickenpox (Chickenpox / Varicella); Intranasal influenza (FluMist Influenza); Inactivated influenza vaccine delivered by injection is acceptable; Measles (Measles / Rubeola); Combined measles-mumps-rubella (MMR); Combined measles-mumps-rubella-varicella (MMRV); Mumps; Oral polio (Sabin); Transoral typhoid; rotavirus; rubella; smallpox (vaccinia); varicella zoster (shingles); and yellow fever; (26) patients with active autoimmune disease or using immunosuppressive treatment for an autoimmune disease (e.g., Hashimoto's thyroiditis, Brave's disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris); and (27) patients who are hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody positive or indeterminate at Visit 1;

[0306] Only patients who met all the inclusion criteria and none of the exclusion criteria were included in the study.

[0307] D. Study Procedures Various concentrations of sterile mAb1 were supplied in 5 mL glass vials; each vial had an expellable volume of 2 mL: 150 mg / mL solution (300 mg dose / 2 mL) or 100 mg / mL solution (200 mg dose / mL).

[0308] Patients were randomly assigned to one of the following treatments for 24 weeks receiving subcutaneous (SC) administration of mAb1 or placebo every 2 weeks (q2w) according to one of the following doses and regimens: ● mAb1 300 mg every 2 weeks (D) with a 600 mg loading dose (LD); ● mAb1 200 mg every 2 weeks (D) with a 400 mg loading dose (LD); ● mAb1 300 mg every 4 weeks (D) with a 600 mg loading dose (LD); ● mAb1 200 mg every 4 weeks (D) with a 400 mg loading dose (LD); or - Placebo every 2 weeks with a placebo loading dose (P).

[0309] Dosing every two weeks is also known as biweekly dosing. Dosing every four weeks is also known as monthly dosing.

[0310] Prior to screening, patients had been on a stable dose of medium- or high-dose ICS / LABA (≥250 μg fluticasone propionate twice daily, or an equipotent ICS dosage) for ≥1 month prior to Visit 1. The combination products acceptable during the treatment period in this study were: mometasone furoate / formoterol; budesonide / formoterol; and fluticasone propionate / salmeterol. If patients were using an alternative combination product (e.g., fluticasone / formoterol) prior to the randomization visit, the investigator switched them to one of the equivalent dosages of the three acceptable treatment-period combination products at randomization Visit 2 (Day 1).

[0311] During the randomized treatment period, patients continued on a stable dose of ICS / LABA at the equivalent dosage as they were using during the screening period. See Table 2 for acceptable ICS / LABA combination products and acceptable dosage forms, strengths, and schedules required during the treatment period to meet background treatment requirements for a daily dose of medium- to high-dose ICS.

[0312] [Table 2]

[0313] Upon completion of the randomized treatment period (or after early discontinuation of study drug), patients continued treatment with the stable dose of ICS / LABA that was maintained throughout the randomized treatment period (or treatment was changed based on medical judgment).

[0314] Patients were allowed to receive salbutamol / albuterol hydrofluoroalkane pressurized MDIs or levosalbutamol / levalbuterol hydrofluoroalkane pressurized MDIs for seizure medication as needed throughout the study. Nebulized liquids were sometimes used as an alternative delivery method.

[0315] The following concomitant treatments were not allowed during the screening or randomized treatment periods: systemic (oral or injectable) corticosteroids (unless used to treat an asthma exacerbation); methylxanthines (e.g., theophylline, aminophylline); lipoxygenase inhibitors (e.g., azelastine, zileuton); chromones; anti-immunoglobulin E (IgE) therapy (e.g., omalizumab); biologic therapy; methotrexate; initiation of allergen immunotherapy (allergen immunotherapy in place for 3 months or more prior to Visit 1 was allowed); and intravenous immunoglobulin (IVIG) therapy.

[0316] Permitted concomitant medications included the following: leukotriene antagonists / modifiers were permitted during the study, but patients had to have been on a stable dose for 30 days or more prior to Visit 1; in-situ allergen immunotherapy was permitted for 3 months or more prior to Visit 1; antihistamines were permitted as concomitant medications; ophthalmic or intranasal corticosteroids were permitted during the study, but patients had to have been on a stable dose for 30 days or more prior to Visit 1; I had to.

[0317] Patients were randomized using a randomization ratio of 1:1:1:1:1 to mAb1 300 mg every 2 weeks, mAb1 200 mg every 2 weeks, mAb1 300 mg every 4 weeks, mAb1 200 mg every 4 weeks, and placebo. Randomization was stratified by visit 1 central laboratory blood eosinophil count (high blood eosinophils ≥ 300 cells / μL (HEos); blood eosinophil cells 200–299 cells / μL; blood eosinophils < 200 cells / μL) and country.

[0318] Approximately 40 percent of patients had high eosinophils across dose groups, and approximately 77 percent of randomized patients had a history of atopic disease, including atopic dermatitis, allergic conjunctivitis, allergic rhinitis, chronic sinusitis, nasal polyposis, food allergies, and / or a history of urticaria.

[0319] E. Treatment Efficacy The primary endpoint of the study was FEV 1 The change from baseline in FEV1 was measured using a spirometer. Spirometry was performed between 6 and 10 am, 6 hours after withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after withholding the last dose of ICS / LABA. Pulmonary function tests were performed in the sitting position, and peak FEV1 readings were recorded in liters.

[0320] Secondary efficacy outcomes evaluated: (1) percent relative change from baseline in FEV1 at Week 12; (2) annualized rate of loss of asthma control events during the treatment period; (3) annualized rate of severe exacerbation events during the treatment period; (4) time to loss of asthma control event during the treatment period; (5) time to severe exacerbation event during the treatment period; (6) time to loss of asthma control event during the entire study period; (7) time to severe exacerbation event during the entire study period; (8) healthcare resource utilization; (9) baseline at Week 12 for the following: (10) Changes from baseline at weeks 12 and 24 for: morning and evening asthma symptom scores, ACQ-5, AQLQ score, morning and evening PEF, number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief / day, and nighttime awakenings; (11) Changes from baseline at weeks 12 and 24 for: SNOT-22, Hospital Anxiety and Depression Scale (HADS), and EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). Changes from baseline at other time points (e.g., 24 weeks) for the above measures were also analyzed.

[0321] Two types of asthma exacerbation events were defined: loss of asthma control (LOAC) events and severe exacerbation events. A loss of asthma control (LOAC) event during the study was defined as any of the following: 6 or more additional puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in 24 hours (compared to baseline) on 2 consecutive days; or a 4-fold or greater dose increase in ICS at visit 2; or systemic corticosteroid use for 3 or more days; or asthma hospitalization or emergency department visit requiring systemic corticosteroids. A severe exacerbation event during the study was defined as a worsening of asthma requiring the following: systemic corticosteroid use for 3 or more days; or asthma hospitalization or emergency department visit requiring systemic corticosteroids.

[0322] Three disease-specific efficacy measures were used in this study: ACQ-5 (Asthma Control Questionnaire, 5-question version), AQLQ (Asthma Quality of Life Questionnaire), and the 22-item Sinus Outcome Test.

[0323] The ACQ-5 is designed to measure both the adequacy of asthma control and changes in asthma control that occur spontaneously or as a result of treatment. It has five questions reflecting point asthma symptoms: waking at night with symptoms, waking in the morning with symptoms, limitation of daily activities, shortness of breath, and wheezing. Patients are asked to recall how their asthma has been during the previous week and to answer the symptom questions on a 7-point scale (0=no interference, 6=maximal interference). A global score is calculated: the questions are weighted equally and the ACQ-5 score is the average of the five questions and is therefore between 0 (completely controlled) and 6 (severely uncontrolled). Higher scores indicate poorer asthma control. Patients with a score below 1.0 have their asthma well controlled and those with a score above 1.0 have their asthma poorly controlled. On the 7-point scale of the ACQ-5, a change or difference in score of 0.5 is the minimum that can be considered clinically important.

[0324] The AQLQ was designed to measure the most bothersome functional impairments for adults (aged 17-70 years) as a result of asthma. The instrument consists of 32 items, each rated on a 7-point Likert scale ranging from 1 to 7. The AQLQ has four domains. These domains, and the number of items within each domain, are as follows: symptoms (12 items), activity limitations (11 items), emotional functioning (5 items) and environmental stimuli (4 items). A global score ranging from 0 to 7 and scores per domain are calculated. Higher scores indicate better quality of life.

[0325] The SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on quality of life.

[0326] Three disease-specific routine efficacy assessments were used in the study: peak expiratory flow rate, asthma symptom score, and exacerbation medication use. Routinely throughout the study, patients used an electronic diary / PEF meter to: measure morning and evening PEF, answer morning and evening Asthma Symptom Scale questions, indicate number of inhalations / day of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief, record number of inhalations / day of background combined ICS / LABA product used, and record number of nocturnal awakenings.

[0327] At screening (Visit 1), patients were provided with an electronic PEF meter to record morning (AM) and evening (PM) PEF, daily salbutamol / albuterol or levosalbutamol / levalbuterol, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring acute medication. In addition, the investigator instructed patients on how to record the following variables on the electronic PEF meter: AM PEF to be performed within 15 minutes of waking (between 6:00 AM and 10:00 AM) before taking any albuterol or levalbuterol; PM PEF to be performed in the evening (between 6:00 PM and 10:00 PM) before taking any albuterol or levalbuterol; patients should attempt to abstain from albuterol or levalbuterol for at least 6 hours prior to PEF measurement; three PEF efforts would be performed by the patient; all three values ​​would be recorded by the electronic PEF meter, and the highest value would be used for evaluation. The baseline AM PEF will be the average AM measurement recorded during the 7 days prior to the first dose of study medication, and the baseline PM PEF will be the average PM measurement recorded during the 7 days prior to the first dose of study medication.

[0328] Patients recorded a total symptom score twice on the day before the PEF was measured. All asthma symptoms experienced by patients during waking hours were recorded in the evening (PM symptom score). Symptoms experienced during the night were recorded upon waking (AM symptom score). The baseline symptom score was the average AM and average PM scores recorded during the 7 days prior to randomization. Patients were instructed to record the severity of their symptoms as follows: AM Symptom Score: 0 = no asthma symptoms, slept through the night; 1 = slept well but had some symptoms in the morning; no night-time awakenings; 2 = 1 awakening due to asthma (including early morning awakenings); 3 = several awakenings due to asthma (including early morning awakenings); and 4 = not sleeping well and awake most of the night due to asthma. PM Symptom Score: 0 = very well, no asthma symptoms; 1 = no wheezing, coughing or 1 = one episode of shortness of breath; 2 = does not interfere with daily activities, more than one episode of wheezing, coughing or shortness of breath; 3 = interferes somewhat with daily activities, wheezing, coughing or shortness of breath most of the day; and 4 = asthma worst, unable to carry out normal daily activities.

[0329] The number of salbutamol / albuterol or levosalbutamol / levalbuterol inhalations was recorded daily by the patient in an electronic diary / PEF meter. Each patient was reminded that salbutamol / albuterol or levosalbutamol / levalbuterol should only be used when needed for symptoms and should not be used routinely or prophylactically. Baseline salbutamol / albuterol or levosalbutamol / levalbuterol inhalations / day were based on the average of the 7 days before randomization.

[0330] The same safety assessments will be applied across all arms, including adverse events, vital signs, physical examination, electrocardiogram variables, laboratory safety variables and pregnancy testing.

[0331] Adverse events were monitored and documented for each patient from when the subject provided informed consent at Visit 1 until the end-of-study visit, with the exception of the following: SAEs and AEs ongoing at the time of database lock. Adverse events (Ae), adverse events of special interest (AESI), and serious adverse events (SAE) were reported.

[0332] Vital signs were measured at each visit, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), temperature (degrees Celsius), and weight (kg). Height (cm) was measured only at screening (Visit 1). Vital signs were measured in a sitting position using the same arm at each visit and were measured at each visit before receiving study medication.

[0333] Pharmacokinetic and anti-drug antibody endpoints were studied. Pre-dose blood samples were collected for determination of serum functional dupilumab and anti-dupilumab antibodies. Pre-dose serum mAb1 concentrations were obtained at Visit 2 (Day 1), mAb1 trough levels at Weeks 2, 4, 8, 12, 16, 20, and 24, and follow-up serum mAb1 at Weeks 28, 32, 36, and 40. Anti-mAb1 antibody status (negative or titer) was obtained at Visit 2 (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, and 40. Patients with ADA titers ≥ 240 at the end-of-study visit were scheduled to return in approximately 6 months for further evaluation of ADA titers. Further follow-up was considered based on antibody titers and overall clinical evaluation.

[0334] Several biomarkers related to asthma inflammation and Th2 polarization (whole blood biomarkers, plasma biomarkers, serum biomarkers, and exhaled nitric oxide) were evaluated for their value in predicting treatment response and / or demonstrating the time course of drug response.

[0335] Blood eosinophil counts were measured as part of a standard 5-differential white blood cell count on an automated hematology analyzer.

[0336] Eotaxin-3 was assayed using a validated enzyme immunoassay (human eotaxin-3 The levels were measured in heparinized plasma using a Quantikine ELISA kit (R&D Systems).

[0337] Eosinophil cationic protein (ECP) and Staphylococcus aureus enterotoxin IgE concentrations were measured using the quantitative ImmunoCAP assay (Phadia). Antigen-specific IgE was detected using an antigen panel appropriate for the site location (Phadiatop test; Phadia). Quantitative methods approved for diagnostic testing (e.g. Total IgE was measured using a validated enzyme-linked immunosorbent assay (e.g., ImmunoCAP). Thymus and activation-regulated chemokine (TARC) was assayed using a validated enzyme-linked immunosorbent assay (Human TARC Quantikine ELISA kit; R&D Systems). Periostin was measured using a validated immunoassay (Human Periostin DuoSet ELISA Development kit; R&D Systems).

[0338] Exhaled nitric oxide was analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden) or similar analyzer with a flow rate of 50 mL / s and reported in parts per billion (ppb). This assessment was performed before spirometry and after at least 1 hour of fasting.

[0339] Pharmacogenetic testing was optional and voluntary. Participants provided blood samples at study visits, which were stored for future analysis. Blood was collected for DNA and RNA. DNA and RNA samples can be used to determine the possible relationship between genes and response to treatment with mAb1 and possible side effects to mAb1. Genes that can be studied include genes for IL4R receptor, IL-4, IL-13, and STAT6, as well as additional genes that may be elements of the IL4R signaling pathway or asthma.

[0340] Patient-reported outcomes and healthcare resource utilisation were assessed using the Hospital Anxiety and Depression Scale (HADS), EQ-5D-3L or EQ-5D-5L, and healthcare resource utilisation.

[0341] The HADS is a general scale for detecting anxiety and depression, already used and validated in asthma. The instrument consists of 14 items: 7 items for anxiety and 7 items for depression. Each item in the questionnaire is scored from 0 to 3; either anxiety or depression can be scored between 0 and 21. A score of 11 or more on any subscale is considered to be a significant "case" of psychological morbidity, while a score of 8 to 10 represents "borderline" and 0 to 7 "normal."

[0342] The EQ-5D-3L or EQ-5D-5L is a standardized questionnaire of health-related quality of life developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic evaluation. The EQ-5D is designed for self-administration by patients. The EQ-5D essentially consists of two pages (EQ-5D descriptor system and EQ VAS). The EQ-5D descriptor system includes five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each item has three levels: no problems, some problems, and severe problems. The EQ visual analog scale (VAS) records the responder's self-assessed health status using a vertical visual analog scale. The EQ The VAS "thermometer" has a rating scale ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).

[0343] Questionnaires on healthcare resource utilization (eg, seizure medications, specialist visits, hospitalizations, emergency or urgent care facility visits, outcomes, sick leave) were administered at Visit 2 and monthly thereafter.

[0344] F. Study Procedures The trial uses an add-on treatment approach to inhaled corticosteroid / long-acting beta-agonist combination therapy (ICS / LABA) and consists of 3 periods: a screening period (14-21 days; Visit 1), a randomized treatment period (24 weeks; Visits 2-11), and a post-treatment period (16 weeks; Visits 12-15).

[0345] The following procedures were performed at Visit 1: (1) Patients were interviewed to collect demographic information, asthma history (including smoking habits), other medical and surgical history, and prior and concomitant medications; (2) Inclusion criteria were reviewed to assess eligibility, with particular attention to verifying that: (a) prescribed combination product ICS / LABA dosage met the pre-prescription call definition of medium- to high-dose ICS requirement with a stable dose of ICS / LABA for the month prior to Visit 1 (i.e., fluticasone propionate 250 μg twice daily or equipotent ICS); (a) met the 12-hour daily dose requirement; and (b) patients had experienced the following within 1 year prior to Visit 1: 1) treatment with a single systemic (oral or parenteral) steroid burst for an asthma exacerbation and / or 2) hospitalization or emergency / urgent care visit for an asthma exacerbation; (3) vital signs [blood pressure, heart rate, respiratory rate, temperature, weight (kg), height (cm)] were measured; (4) a physical examination was performed; (5) the ACQ-5 was administered and verified to have an ACQ-5 score of 1.5; (6) exhaled nitric oxide was measured and exhaled nitric oxide assessment was performed before spirometry and after a 1-hour fast; (7) spirometry was performed. Inclusion criteria at Visit 1 included specific FEV1 requirement and demonstration of reversibility. Spirometry was first performed between 6 and 10 am, 6 hours after the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol had been withheld and 12 hours after the last dose of ICS / LABA had been withheld. FEV1 had to be between 40 and 80% predicted normal and 3 attempts during the screening period had to meet the eligibility criteria for spirometry; (8) reversibility had been established.Reversibility should be at least 12% and 200 mL for FEV1 after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; (9) a 12-lead electrocardiogram (ECG) was performed; (10) a chest x-ray was performed if one was not available within the past 12 months; (11) a (fasting) blood sample was taken for screening clinical laboratory determinations: a) hematology: this included hemoglobin, hematocrit, platelet count, total white blood cell count (including 5-element percentile count), and total red blood cell count; b) a separate blood sample was collected for local analysis. (12) Hepatitis tests (Hepatitis B surface antigen (HBsAg), Hepatitis B IgM core antigen (HBcAb-IgM), Hepatitis C antibody (HCAb-IgM), Hepatitis B antibody (HC ... (13) blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1–4, IgM, and IgA); (14) serum β-HCG pregnancy test results were obtained for women of childbearing potential; (15) urine was collected for urinalysis (urine dipsticks); (16) blood was collected for sampling of biomarker set A and serum total IgE; (17) specific informed consent was obtained. For patients who signed the intake form; optional blood RNA sampling was performed; (18) an electronic diary / PEF meter was dispensed, instructions for diary use were provided, and patients were reminded to bring the device to their next visit; (19) patients were reminded to continue on a stable dose of ICS / LABA and instructed to record daily usage in the electronic diary; (20) salbutamol / albuterol or levosalbutamol / levalbuterol were dispensed and resupplied for use as seizure medication throughout the study. Patients were instructed to record usage in the electronic diary.(21) Patients were reminded to withhold their last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for 6 hours and their last dose of ICS / LABA for 12 hours before their next visit; and (22) AE reporting was initiated.

[0346] The following procedures were performed at Visit 2 (Week 0): (1) All medication use was recorded in the eCRF with start date and dose; AEs / SAEs and background asthma treatment tolerability were reviewed. (2) Based on the review of inclusion / exclusion criteria, the inclusion criteria were reviewed and eligibility was reconfirmed; (3) ACQ-5 and AQLQ were administered; (4) the following were verified: a) an ACQ-5 score of 21.5 at Visit 2, and b) adherence to mandatory background treatment, the use of ICS / LABA combination products (this adherence was defined as: 80% of the total number of prescribed "stable dose" puffs were taken during the screening period. Adherence was verified based on ICS / LABA use recorded in the patient's electronic diary during the screening period); (5) vital signs were measured (blood pressure, heart rate, respiratory rate, temperature, weight); (6) spirometry was performed: the inclusion criteria at Visit 1 were specific FEV 1 The spirometry test included a spirometry test with a spirometry requirement of 10 mg / kg / day and a spirometry test with a spirometry test of 10 mg / kg / day, 6 hours after the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after the last dose of ICS / LABA, and before administration of any study drug. FEV1 must be 40-80% predicted normal, and patients must also meet criteria for spirometry before randomization at Visit 2.

[0347] If the patient met all inclusion criteria and did not meet any of the exclusion criteria, the following procedures were also performed at Visit 2: (1) The IVRS / IWRS was called to register the visit, and if the inclusion criteria were met, the patient was randomized and received their first procedure kit number assignment. By reference to the central laboratory blood eosinophil count at Visit 1, patients were stratified into the correct high blood eosinophil tier (>300 cells / μL), moderate blood eosinophil tier (200-299 cells / μL) or low blood eosinophil tier (<200 cells / μL) at the time of this IVRS / IWRS call; (2) if the patient's background combination ICS / LABA prior to Visit 2 was an alternative combination product (e.g., fluticasone / formoterol), the patient was switched to the equivalent dosage of one of the three acceptable treatment-period combination products listed below: fluticasone propionate / salmeterol, or budesonide / formoterol, or mometasone furoate / formoterol. Note that the acceptable ICS / LABA combination products as well as the acceptable dosage forms, strengths and schedules required during the treatment period to meet the background treatment requirement for a daily dose of medium- to high-dose ICS were discussed above. (3) SNOT-22 was administered; (4) HADS and EQ-5D-3L or EQ-5D-5L questionnaires were administered; (5) the Health Resource Utilization Questionnaire was administered; (6) a urine pregnancy test was performed (for women of childbearing potential); and (7) blood was drawn for clinical laboratories (before administration of IMP(mAb1)).Note that clinical laboratory testing at Visit 2 was limited to hematology (including a separate hematology sample taken for local analysis), pharmacokinetics, anti-drug antibodies, biomarker set A, periostin, serum total IgE, biomarker set B, and archival serum samples; (8) For patients who signed a specific informed consent form, blood samples were collected for DNA and RNA sampling (during the randomized treatment period, prior to administration of study drug); (9) Electronic diary / PEF meter was downloaded, The patient was reminded to bring the device to her next visit; (10) IMP (mAb1) was dispensed and administered; (11) the patient was reminded to continue a stable dose of ICS / LABA and record daily use in an electronic diary; and (12) the next visit was scheduled and the patient was reminded to refrain from taking her last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for 6 hours and from taking her last dose of ICS / LABA for 12 hours before her next visit.

[0348] The following procedures were performed at Visit 3 (Week 2): (1) all concomitant medications used were recorded; AEs / SAEs and background asthma treatment tolerability were asked; (2) vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) ACQ-5 was administered; (4) exhaled nitric oxide was measured. Exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (5) spirometry was performed. Spirometry was performed between 6 and 10 a.m., 6 hours after the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after the last dose of ICS / LABA, and before administration of any study drug. (6) a 12-lead electrocardiogram (ECG) was performed; (7) blood was drawn (prior to administration of IMP(mAb1)) for pharmacokinetics, anti-drug antibodies, and biomarker set A; (8) optional blood RNA sampling was performed; (9) an electronic diary / PEF meter was downloaded and the patient was reminded to bring the device to their next visit; (10) IMP(mAb1) was dispensed and administered; and (11) the next visit was scheduled and the patient was reminded to refrain from taking their last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for 6 hours and from taking their last dose of ICS / LABA for 12 hours before their next visit.

[0349] These same procedures were performed at Visit 4 (Week 4). In addition, patients completed a health resource utilization questionnaire.

[0350] The following procedures were performed at Visit 5 (Week 6): (1) all concomitant medications used were recorded; AEs / SAEs and background asthma treatment tolerability were inquired about; (2) vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) the electronic diary / PEF meter was downloaded and the patient was reminded to bring the device to the next visit; (4) IMP (mAb1) was dispensed and administered; (5) the patient was reminded to continue a stable dose of ICS / LABA and to record daily usage in the electronic diary; and (6) the next visit was scheduled and the patient was reminded to refrain from taking the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking the last dose of ICS / LABA 12 hours before the next visit.

[0351] The following procedures were performed at Visit 6 (Week 8): (1) All concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) ACQ-5 was administered; (4) Healthcare Resource Utilization Questionnaire was administered; (5) Exhaled nitric oxide was measured, and exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (6) Spirometry was performed, and spirometry was Between 6 and 10 a.m., after 12 hours withholding the last dose of ICS / LABA and before administration of the study drug; (7) blood was drawn for clinical laboratories, pharmacokinetics, anti-drug antibodies, biomarker set A, and serum total IgE; (8) an electronic diary / PEF meter was downloaded and patients were reminded to bring the device to their next visit and to record their daily usage in the electronic diary; and (9) IMP (mAb1) was dispensed and administered.

[0352] The following procedures were performed at Visit 7 (Week 10): (1) all concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) the electronic diary / PEF meter was downloaded and the patient was reminded to bring the device to the next visit; (4) IMP (mAb1) was dispensed and administered; (5) the next visit was scheduled and the patient was reminded to continue on a stable dose of ICS / LABA and record daily usage in the electronic diary, to arrive at the next visit in a fasting state, and to refrain from the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from the last dose of ICS / LABA 12 hours before the next visit.

[0353] The following procedures were performed at Visit 8 (Week 12): (1) all concomitant medications used were recorded; AEs / SAEs and background asthma treatment tolerability were asked; (2) vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) a physical examination was performed; (4) ACQ-5 and AQLQ were administered; (5) SNOT-22 was administered; (6) HADS and EQ-5D-3L or EQ-5D-5L questionnaires were administered; (7) a health resource utilization questionnaire was administered; (8) exhaled nitric oxide was measured, and the exhaled nitric oxide assessment was performed on the pulmonary (9) Spirometry was performed before and after fasting for at least 1 hour; (10) 12-lead electrocardiogram (ECG) was performed; (11) blood was drawn (fasting) for clinical laboratory tests, pharmacokinetics, anti-drug antibodies, biomarker set A, periostin, archival serum samples, and serum total IgE; (12) blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM, and IgA); (13) urinalysis (urine dipsticks) (14) downloaded an electronic diary / PEF meter and reminded the patient to bring the device to their next visit and to record their daily usage in the electronic diary; (15) dispensed and administered IMP (mAb1); (16) distributed a home administration diary to the patient; (17) reminded the patient to continue on a stable dose of ICS / LABA and to record their daily usage in the electronic diary; and (18) scheduled the next visit and reminded the patient to refrain from taking their last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking their last dose of ICS / LABA 12 hours before their next visit.

[0354] The following procedures were performed at Visit 9 (Week 16): (1) IMP (mAb1) adherence was checked; all concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) Patients' home medication diaries were reviewed for content and completeness; (3) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (4) ACQ-5 was administered; (5) Healthcare Resource Utilization Questionnaire was administered; (6) Exhaled nitric oxide was measured, and exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (7) Spirometry was performed, and spirometry was performed between 6 and 10 a.m., after 6 hours withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours withholding the last dose of ICS / LABA, and before administration of study drug; (8) blood was drawn for clinical laboratories, pharmacokinetics, anti-drug antibodies, biomarker set A, and serum total IgE; (9) electronic diary / PEF meter was downloaded and patient was reminded to bring the device to the next visit; (10) self-injection and administration instructions were outlined and the patient was given a home administration diary; (11) IMP (mAb1) was dispensed and administered; (12) patient was reminded to continue on a stable dose of ICS / LABA and record daily usage in the electronic diary; and (13) next visit was scheduled and patient was reminded to refrain from taking the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking the last dose of ICS / LABA 12 hours before the next visit.

[0355] The same procedure was performed at Visit 10 (Week 20), except that patients were reminded to continue the stable dose of ICS / LABA used during the screening period for their next visit, to come to their next visit in a fasting state, and to refrain from taking their last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking their last dose of ICS / LABA 12 hours before their next visit.

[0356] The following procedures were performed at Visit 11 (Week 24 / End of Treatment Visit): (1) Adherence to IMP (mAb1) was checked; all concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) Patients' home medication diaries were reviewed for content and completeness; (3) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (4) Physical examination was performed; (5) ACQ-5 and AQLQ were administered; (6) SNOT-22 was administered; (7) HADS and EQ-5D-3L or EQ-5D-5L questionnaires were administered; (8) Healthcare Resource Utilization Questionnaire was administered; (9) Exhaled nitric oxide was measured, and exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (1 0) Spirometry was performed between 6 and 10 a.m., 6 hours after the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours after the last dose of ICS / LABA, and before administration of study drug; (11) 12-lead electrocardiogram (ECG) was performed; (13) blood was drawn (fasting) for clinical laboratories, pharmacokinetics, anti-drug antibodies, biomarker set A, periostin, biomarker set B, archival serum samples, and serum total IgE; (14) blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM, and IgA); (15) urinalysis (urine dipstick) (16) downloaded the electronic diary / PEF meter and reminded the patient to bring the device to the next visit and to record the daily usage in the electronic diary; (17) reminded the patient to continue the stable dose of ICS / LABA and record the daily usage in the electronic diary; (18) scheduled the next visit and reminded the patient to refrain from taking the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking the last dose of ICS / LABA 12 hours before the next visit; and (19) called the IVRS / IWRS to register the EOT (end of treatment) date.

[0357] At each of Visits 12, 13, and 14 (Weeks 28, 32, and 36 of the post-treatment period), the following was done: (1) all concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) the ACQ-5 was administered; (4) the Healthcare Resource Utilization Questionnaire was administered; (5) exhaled nitric oxide was measured, and exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (6) spirometry was performed, and spirometry was performed between 6 and 10 a.m., after 6 hours withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol and 12 hours withholding the last dose of ICS / LABA, and before administration of study drug; (7) pharmacokinetics, biomarker set A, and spirometry were performed. (8) for Visit 13, blood was drawn for serum total IgE; (9) the electronic diary / PEF meter was downloaded and patients were reminded to bring the device to their next visit; (10) patients were reminded to continue the stable dose of ICS / LABA maintained over the randomized treatment period (unless treatment was changed based on medical judgment) and to record daily dose in the electronic diary; (11) the next visit was scheduled and patients were reminded to refrain from taking their last dose of salbutamol / albuterol or levosalbutamol / levalbuterol 6 hours and from taking their last dose of ICS / LABA 12 hours before their next visit; and (12) for Visit 14, patients were reminded to come to the visit in a fasting state.

[0358] The following procedures were performed at Visit 15 (Week 40 Study Termination Visit): (1) All concomitant medication use was recorded; AEs / SAEs and background asthma treatment tolerability were queried; (2) Vital signs (blood pressure, heart rate, respiratory rate, temperature, weight) were measured; (3) Physical examination was performed; (4) ACQ-5 was administered; (5) SNOT-22 was administered; (6) Healthcare Resource Utilization Questionnaire was administered; (7) Exhaled nitric oxide was measured, and exhaled nitric oxide assessment was performed before spirometry and after at least 1 hour of fasting; (8) Spirometry was performed, and spirometry was performed after salbutamol / albuterol or levosalbutamol / levosalbutamol were administered between 6 and 10 a.m. (9) a 12-lead electrocardiogram (ECG) was performed; (10) blood was drawn for (fasting) clinical laboratories, pharmacokinetics, anti-drug antibodies, biomarker set A, serum total IgE, periostin, and biomarker set B; (11) blood samples were collected for serum immunoglobulin electrophoresis (IgG, IgG subclasses 1-4, IgM, and IgA); (12) electronic diary / PEF meter was downloaded; and (13) the IVRS / IWRS was called to register the EOS (end of study) date.

[0359] Study participant baseline biomarker values ​​were as follows (Table 3):

[0360] [Table 3]

[0361] [Table 4]

[0362] G. Dosage and Duration A summary of treatment exposure is provided in Table 4. Cumulative treatment exposure ranged from 61.4 to 65.3 patient-years across placebo and dupilumab treatment arms. The mean duration of study treatment ranged from 146.4 to 151.7 days in the five treatment arms.

[0363] [Table 5]

[0364] [Table 6]

[0365] H. Efficacy Primary efficacy endpoint The primary analysis compared dupilumab treatment with placebo. The primary efficacy outcome was change in FEV1 from baseline to week 12 for the HEos ITT population. A mixed-effects model for repeated measures (MMRM) approach was used to analyze the primary efficacy variable. Assessment of absolute change from baseline in FEV1 at week 12, performed during the interim analysis, was the final analysis of the primary outcome.

[0366] Figure 3 presents the least squares (LS) mean change in FEV1 over time for the HEos ITT population. The LS mean change in FEV1 from baseline at week 12 was 0.18 L in the placebo group and ranged from 0.26 L (200 mg q4w dose) to 0.43 (200 mg q2w dose) in the four dupilumab treatment arms (Table 5). The LS mean differences between dupilumab and placebo were 0.08 L (200 mg q4w), 0.017 L (300 mg q4w), 0.25 L (200 mg q2w), and 0.20 L (300 mg q2w). The LS mean difference compared to placebo was statistically significant for the 300 mg q4w (p=0.024), 200 mg q2w (p=0.0009), and 300 mg q2w doses (p=0.0073). Statistical significance was not achieved for the lowest dose (200 mg q4w; p=0.2966). The change in FEV1 from baseline to week 12 for the ITT population was analyzed to determine the treatment effect of dupilumab on FEV1 for the entire study population.

[0367] Figure 4 represents the LS mean change in FEV1 over time for the ITT population. The LS mean change in FEV1 from baseline to week 12 for the ITT population was 0.12 L in the placebo group and ranged from 0.21 L (200 mg q4w dose) to 0.31 L (200 mg q2w dose) in the four dupilumab treatment arms (Table 6). The LS mean differences between dupilumab and placebo were 0.09 L (200 mg q4w), 0.012 L (300 mg q4w), 0.19 L (200 mg q2w), and 0.16 L (300 mg q2w). The LS mean differences compared to placebo were statistically significant for all dupilumab doses.

[0368] [Table 7]

[0369] [Table 8]

[0370] For the primary endpoint, change in FEV1 from baseline to week 12 for the HEos ITT population, two sets of sensitivity analyses were performed: 1) sensitivity analysis 1 was the same as the main statistical model but included all FEV1 measurements (i.e., no FEV1 measurements were censored +30 days from the date of systemic corticosteroid initiation, as was done for the primary endpoint analysis); 2) sensitivity analysis 2 was the same as the main statistical model but excluded all FEV1 measurements collected after the first day of systemic corticosteroid use. Both sensitivity analyses (Tables 7 and 8) compared favorably to the primary endpoint analysis provided above.

[0371] [Table 9]

[0372] [Table 10]

[0373] Changes in FEV1 from baseline to week 12 were analyzed by eosinophil category in the ITT population to differentiate patients with low baseline peripheral blood eosinophil counts from those with high baseline peripheral blood eosinophil counts. The effect of dupilumab treatment on FEV1 was determined across a range of patients with peripheral blood eosinophil counts from ≥0 to ≥0.300 (Table 9). As patient categories of peripheral blood eosinophil count increased from ≥0 to ≥0.300, in general, the change from baseline in FEV1 response increased somewhat in all treatment groups, including placebo (Figure 5).

[0374] [Table 11]

[0375] [Table 12]

[0376] [Table 13]

[0377] [Table 14]

[0378] [Table 15]

[0379] [Table 16]

[0380] [Table 17]

[0381] I. Annualized rate of severe exacerbations during treatment The cumulative number of severe exacerbation events (including all events through the data cutoff date) for the HEos ITT population during the treatment period is shown by treatment arm in Figure 6. The annualized rate of severe asthma exacerbation events was analyzed using negative binomial regression models. The number of patients in the HEos ITT population with ≥1 severe exacerbation event during the 24-week treatment period was 16 patients in the placebo group and 5, 5, 7, and 10 patients in the dupilumab 200 mg q4w, 200 mg q2w, 300 mg q2w, and 300 mg q2w groups, respectively (Table 10). The relative risks compared with placebo for severe asthma exacerbation based on adjusted annualized severe exacerbation event rates were 0.257 (200 mg q4w), 0.739 (300 mg q4w), 0.356 (200 mg q2w), and 0.254 (300 mg q2w). Statistical significance (unadjusted for multiplicity) was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0382] The annualized rate of severe asthma exacerbation events for the ITT population was analyzed. The cumulative number of severe exacerbation events for the ITT population during the treatment period is shown by treatment arm in Figure 7. Similar to the HEos ITT population analysis, fewer patients using dupilumab experienced severe exacerbation events during the 24-week treatment period (Table 11), and the relative risk for severe asthma exacerbation compared with placebo was reduced based on the adjusted annualized severe exacerbation event rate. Statistical significance was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0383] The annualized rate of severe asthma exacerbations was analyzed by eosinophil category in the ITT population to determine the effect of dupilumab treatment on severe exacerbation rates across the range of patients with low to high baseline peripheral blood eosinophil counts (Table 12). As shown in Figure 8, as patient categories of peripheral blood eosinophil counts increased from ≧0 to ≧300, the adjusted annualized severe image event rate compared to placebo was reduced in dupilumab-treated patients regardless of eosinophil category. In the placebo group, patients with eosinophil counts <0.250 experienced a higher severe exacerbation rate compared to placebo patients with eosinophil counts ≧0.250.

[0384] [Table 18]

[0385] [Table 19]

[0386] [Table 20]

[0387] [Table 21]

[0388] [Table 22]

[0389] [Table 23]

[0390] [Table 24]

[0391] [Table 25]

[0392] [Table 26]

[0393] [Table 27]

[0394] J. Relative change (%) of FEV1 from baseline to week 12 The percent change from baseline in FEV1 for the HEos ITT population was analyzed at week 12. Figure 9 shows the LS mean percent change from baseline to week 12 in FEV1. The LS mean percent change in FEV1 from baseline to week 12 was 10.44% in the placebo group and ranged from 17.98% (200 mg q4w dose) to 25.92% (200 mg q2w dose) in the four dupilumab treatment arms (Table 13). The LS mean differences between dupilumab and placebo were 7.54% (200 mg q4w), 11.14% (300 mg q4w), 15.48% (200 mg q2w), and 15.37% (300 mg q2w). The LS mean differences compared with placebo were statistically significant for the 300 mg q4w, 200 mg q2w, and 300 mg q2w doses. The lowest dose (200 mg q4w) did not show statistical significance.

[0395] [Table 28]

[0396] FEV1 collected from the date of systemic corticosteroid initiation to the date of systemic corticosteroid end + 30 days for each exacerbation episode was excluded to reduce the confounding effect of systemic corticosteroids.

[0397] K. Annualized Rate of Loss of Asthma Control (LOAC) Events During Treatment Figure 10 depicts the cumulative mean fractional change in number of LOAC events by treatment arm through 24 weeks. During the 24-week treatment period, the number of patients in the HEos ITT population with ≥1 LOAC event was 23 patients in the placebo group and 6, 12, 7, and 10 patients in the dupilumab 200 mg q4w, 300 mg q4w, 200 mg q2w, and 300 mg q2w groups, respectively (Table 14). The relative risks for LOAC compared with placebo based on adjusted annualized LOAC event rates were 0.232 (200 mg q4w), 0.626 (3 00mg q4w), 0.413 (200mg q2w) and 0.311 (300mg Statistical significance was demonstrated for all dupilumab doses except the 300 mg q4w dose.

[0398] [Table 29]

[0399] L. Time to treatment-period loss of asthma control and severe exacerbation events Time to first LOAC event and first severity for HEos ITT population during treatment The time to first severe progression event is shown by treatment arm in Figure 11 and Figure 12, respectively. These two Kaplan-Meier plots show comparable results for time to first severe progression event and time to first LOAC event. All dupilumab arms demonstrated delayed events.

[0400] M. Serum Thymus and Activation-Regulated Chemokine Dupilumab treatment was associated with a significant reduction in mean serum TARC concentrations (relative to baseline) (Figures 13 and 14). Near-maximal effect was reached by week 4, and this effect was similar for all four dose regimens. This effect was maintained, except for a partial loss of effect for the HEos ITT population treated with the two q4w regimens. Serum TARC gradually increased over time in the placebo group.

[0401] N. Plasma eotaxin-3 Mean plasma eotaxin-3 concentrations declined for all four dupiluma regimens, with near maximal effects observed by weeks 4-8 of treatment, although increases in plasma eotaxin-3 were observed in patients receiving placebo (Figures 15 and 16). The mean percent increases in plasma eotaxin-3 were dose-dependent, with smaller effects in the 200 mg q4w group. The distinction between the three higher dose regimens was less clear. Group mean percent decreases in eotaxin-3 were generally greater in the HEos ITT population than those observed in the ITT population.

[0402] O. Exhaled nitric oxide concentration Exhaled nitric oxide levels were assessed at baseline for approximately half of the patients (median 28 ppb vs. upper norm 25 ppb), and exhaled nitric oxide levels were higher in the HEos ITT population (median 40 ppb). Group mean FeNO levels decreased in a roughly dose-dependent manner for all dupilumab dose regimens, with maximal effects achieved by 4 weeks of treatment (Figures 17 and 18). The greater effects observed with the two q2w dose regimens were maintained throughout dupilumab treatment.

[0403] [Example 3] Subgroup analysis FEV1 values ​​were determined for the population with moderate blood Eos (Table 15). Figure 19 shows a graphical representation of these results.

[0404] [Table 30]

[0405] FEV1 values ​​were determined for the population with low blood Eos (Table 16). Figure 20 shows a graphical representation of these results.

[0406] [Table 31]

[0407] An analysis of change over time in baseline FEV1 was performed for the ITT population (Table 17).

[0408] [Table 32]

[0409] An analysis of the number of severe exacerbation events for the ITT population with moderate blood Eos was performed (Table 18). Figure 21 presents these results graphically.

[0410] [Table 33]

[0411] An analysis of the number of severe exacerbation events for the ITT population with low blood Eos was performed (Table 19). Figure 22 shows a graphical representation of these results.

[0412] [Table 34]

[0413] The most common adverse events were injection site reactions, which were more frequent in the four dupilumab dose groups (13-25 percent) compared with placebo (12 percent). Other common adverse events in the study included upper respiratory tract infections (dupilumab, 10-13 percent; placebo, 13 percent), headache (dupilumab, 5-10 percent; placebo, 8 percent), nasopharyngitis (dupilumab, 3-10 percent; placebo, 6 percent), and bronchitis (dupilumab, 5-8 percent; placebo, 8 percent). The incidence of infections was balanced across treatment groups (dupilumab, 42-45 percent; placebo, 46 ​​percent), as were the rates of serious adverse events (dupilumab, 3-7 percent; placebo, 5 percent).

[0414] P. Patient-reported outcomes interim analysis ACQ Patient-reported outcomes (PRO) data were obtained. Figures 57 and 58 show the results of the Asthma Control Questionnaire (ACQ). The effect was not stabilized at 12 weeks. A higher treatment effect was observed for the high eosinophil (HEos) population compared to the ITT population (-0.46 (-0.79,-0.12)) (Figure 57). The first two domains (arousal, morning symptoms) were highly significant versus placebo (PBO).

[0415] AQLQ Asthma Quality of Life Questionnaire (AQLQ) data was obtained (Figures 59 and 60). Results showed that dupilumab (DUPI) was superior to placebo (PBO) in all domains.

[0416] EQ5D-5L European Quality of Life Five Item-5L (EQ5D-5L) data were obtained (Figures 61 and 62). A significant effect was observed in the HEos population (0.10 (0.04, 0.16)).

[0417] HADS Hospital Anxiety and Depression Score (HADS) data were obtained (Figures 63-66). Statistically significant effects were observed in the HEos population for both anxiety (-1.54 (-2.58,-0.50)) and depression (-1.88 (-2.88,-0.88)). Anxiety was more affected than depression at baseline. A greater treatment effect was observed for depression compared to anxiety. A significant improvement was observed in the HEos population for the overall HADS (-3.47 (-5.29,-1.65)).

[0418] At baseline, the 300 mg q2w arm was significantly worse than the other treatment arms.

[0419] Patients were worse off in the depression environment than in the anxiety domain. At week 12, the 200mg q4w, 200mg q2w, and 300mg q2w arms demonstrated a high significance compared to placebo and improved across the different treatment arms. The same trends were observed for each subscore. HADS anxiety demonstrated the same trends for change, but arm 1 demonstrated the highest risk of response compared to placebo (based on analysis on responder profile). HADS depression demonstrated the same trends for change, but arm 1 demonstrated the highest risk of response compared to placebo (based on analysis on responder profile). Responders: ORs demonstrated a significant risk of treatment versus placebo for response (arms 1, 3, 4). This risk improved in arm 3 (OR 200mg q2w=4.61) Responders (%): placebo (39.7%) vs. 200mg q2w (66.2%) (Figure 65).

[0420] At baseline, the 300 mg q2w arm was worse than the other treatment arms (except for depression). Patients were worse in the depression setting than in the anxiety domain. At week 12, only the 200 mg q2w demonstrated a significant effect compared to placebo, and this effect was improved between the different treatment arms. Different trends were observed for each subscore. HADS anxiety - no significant effect was observed for placebo; HADS depression - arms 3 and 4 were significant. (Figure 66).

[0421] SNOT-22 Sinus Outcome Test-22 (SNOT-22) data was obtained (Figures 67 and 68). Results showed that dupilumab (DUPI) was superior to placebo (PBO) (Figure 67), nasal scores drove the treatment effect, and DUPI was superior to PBO for nasal, sleep, and general scores.

[0422] NRS Pruritus Numeric Rating Scale (NRS) data was obtained (Figure 69).

[0423] Example 3 Summary of Results Overall, high efficacy was demonstrated with dupilumab, resulting in reduced exacerbations, improved lung function, and improved asthma control. Dupilumab was very well tolerated (Table 20 ). Dupilumab was superior to placebo for nasal, sleep and general scores. The safety profile was consistent with observations in previous studies. A dose response was observed, with the biweekly regimen being superior. There was a dose-dependent imbalance between dupilumab and placebo for injection site reactions, but not for nasopharyngitis, as previously observed with other treatments. Efficacy was observed across the entire population, indicating that it is possible to distinguish between one or more subpopulations that will respond to treatment without the need for biomarkers. Importantly, significant efficacy was demonstrated in the ITT population compared to the efficacy of other treatments known in the art at the time of filing. Comparable or superior efficacy was observed in the biomarker-rich population compared to the efficacy of other treatments for biomarker-rich populations known in the art at the time of filing.

[0424] [Table 35]

[0425] The three highest doses of dupilumab in combination with standard of care met the primary endpoint of a statistically significant improvement from baseline in FEV1 at week 12 in patients with high blood eosinophils (≥300 cells / μL) compared to placebo in combination with standard of care. In addition, the two highest dupilumab doses demonstrated a reduction in severe exacerbations as well as a statistically significant improvement in the mean percent change in FEV1 in both the high eosinophil population and the overall study population.

[0426] Regarding the high eosinophil patient population: The primary (and secondary) endpoints of the study, the mean improvement from baseline in FEV1 (and mean percent change in FEV1) at week 12, were: 390 ml (26 percent) dupilumab 300 mg Q2W; 430 ml (26 percent) dupilumab 200 mg Q2W; 180 ml (10 percent) placebo. (p less than 0.01).

[0427] For the entire population: The mean improvement from baseline in FEV1 (and mean percent change in FEV1) at week 12 was: 280 ml (18 percent) dupilumab 300 mg Q2W; 310 ml (18 percent) dupilumab 200 mg Q2W; 120 ml (6 percent) placebo. (p less than 0.001).

[0428] For both the high eosinophil patient group and the total patient group: Dupilumab demonstrated a reduction in the adjusted annualized rate of severe exacerbations compared with placebo (64-75 percent reduction, p less than 0.05 for the high eosinophil group and p less than 0.01 for the overall population).

[0429] These results were based on a prespecified interim analysis that was performed when all patients had reached week 12 of the 24-week treatment period. The mean treatment duration at the time of this analysis was 21.5 weeks.

[0430] label Dupilumab is indicated in adults and adolescents (ages 12 years or older) as an add-on to medium- to high-dose inhaled corticosteroids (ICS) and a second controller medication for the treatment of persistent asthma.

Claims

1. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 600 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds interleukin-4 receptor (IL-4R) for use in treating severe uncontrolled asthma in a subject in need thereof, in a method comprising administering to the subject one or more maintenance doses of about 300 mg of an antibody that specifically binds IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is an add-on treatment.

3. The pharmaceutical composition according to claim 1, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

4. The pharmaceutical composition of claim 3, wherein the antibody that specifically binds to IL-4R is dupilumab.

5. 2. The pharmaceutical composition of claim 1, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

6. The one or more maintenance doses of the antibody that specifically binds to IL-4R comprise at least 6. The pharmaceutical composition of claim 5, which is administered for 24 weeks.

7. The pharmaceutical composition of claim 1, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

8. 8. The pharmaceutical composition of claim 7, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

9. The pharmaceutical composition of claim 1 , wherein the subject has an eosinophilic phenotype.

10. 10. The pharmaceutical composition of claim 1, wherein the subject is at least 12 years old.

11. 2. The pharmaceutical composition of claim 1, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for asthma exacerbations prior to treatment with the antibody that specifically binds to IL-4R.

12. 2. The pharmaceutical composition of claim 1, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second (FEV1) at 12 weeks of treatment in the subject.

13. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 400 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds interleukin-4 receptor (IL-4R) for use in treating severe uncontrolled asthma in a subject in need thereof, in a method comprising administering to the subject one or more maintenance doses of about 200 mg of an antibody that specifically binds IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is an add-on treatment.

15. The pharmaceutical composition according to claim 13, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

16. The pharmaceutical composition of claim 15, wherein the antibody that specifically binds to IL-4R is dupilumab.

17. The pharmaceutical composition of claim 13, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

18. 18. The pharmaceutical composition of claim 17, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

19. The pharmaceutical composition of claim 13, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

20. 20. The pharmaceutical composition of claim 19, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

21. The pharmaceutical composition of claim 13 , wherein the subject has an eosinophilic phenotype.

22. 14. The pharmaceutical composition of claim 13, wherein the subject is at least 12 years old.

23. 14. The pharmaceutical composition of claim 13, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for asthma exacerbations prior to treatment with the antibody that specifically binds to IL-4R.

24. The pharmaceutical composition of claim 13, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second in liters (FEV1) at 12 weeks of treatment in the subject.

25. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 600 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R) for use in increasing forced expiratory volume in one second in liters (FEV1) in a subject with severe uncontrolled asthma, in a method comprising administering to the subject one or more maintenance doses of about 300 mg of an antibody that specifically binds to the IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

26. 26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is an add-on treatment.

27. The pharmaceutical composition of claim 25, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

28. The pharmaceutical composition of claim 27, wherein the antibody that specifically binds to IL-4R is dupilumab.

29. 26. The pharmaceutical composition of claim 25, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

30. 30. The pharmaceutical composition of claim 29, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

31. The pharmaceutical composition of claim 25, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

32. 32. The pharmaceutical composition of claim 31, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

33. 26. The pharmaceutical composition of claim 25, wherein the subject has an eosinophilic phenotype.

34. 26. The pharmaceutical composition of claim 25, wherein the subject is at least 12 years old.

35. 26. The pharmaceutical composition of claim 25, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for asthma exacerbations prior to treatment with the antibody that specifically binds to IL-4R.

36. 26. The pharmaceutical composition of claim 25, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second in liters (FEV1) at 12 weeks of treatment in the subject.

37. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 400 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R) for use in increasing forced expiratory volume in one second in liters (FEV1) in a subject with severe uncontrolled asthma, in a method comprising administering to the subject one or more maintenance doses of about 200 mg of an antibody that specifically binds to the IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

38. 38. The pharmaceutical composition of claim 37, wherein the pharmaceutical composition is an add-on treatment.

39. The pharmaceutical composition of claim 38, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

40. The pharmaceutical composition of claim 39, wherein the antibody that specifically binds to IL-4R is dupilumab.

41. 38. The pharmaceutical composition of claim 37, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

42. The pharmaceutical composition of claim 41, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

43. The pharmaceutical composition of claim 37, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

44. 44. The pharmaceutical composition of claim 43, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

45. 38. The pharmaceutical composition of claim 37, wherein the subject has an eosinophilic phenotype.

46. 38. The pharmaceutical composition of claim 37, wherein the subject is at least 12 years old.

47. 38. The pharmaceutical composition of claim 37, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for an asthma exacerbation prior to treatment with the antibody that specifically binds to IL-4R.

48. 38. The pharmaceutical composition of claim 37, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second in liters (FEV1) at 12 weeks of treatment in the subject.

49. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 600 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds interleukin-4 receptor (IL-4R) for use in reducing the annual rate of severe asthma exacerbations in a subject with severe, uncontrolled asthma, in a method comprising administering to the subject one or more maintenance doses of about 300 mg of an antibody that specifically binds IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

50. 50. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition is an add-on treatment.

51. The pharmaceutical composition of claim 49, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

52. The pharmaceutical composition of claim 51, wherein the antibody that specifically binds to IL-4R is dupilumab.

53. 50. The pharmaceutical composition of claim 49, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

54. 54. The pharmaceutical composition of claim 53, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

55. The pharmaceutical composition of claim 49, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

56. 56. The pharmaceutical composition of claim 55, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

57. 50. The pharmaceutical composition of claim 49, wherein the subject has an eosinophilic phenotype.

58. 50. The pharmaceutical composition of claim 49, wherein the subject is at least 12 years old.

59. 50. The pharmaceutical composition of claim 49, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for asthma exacerbations prior to treatment with the antibody that specifically binds to IL-4R.

60. 50. The pharmaceutical composition of claim 49, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second in liters (FEV1) at 12 weeks of treatment in the subject.

61. one or more maintenance doses of inhaled corticosteroids (ICS); long-acting beta 2 one or more maintenance doses of adrenergic stimulants (LABAs); an initial dose of about 400 mg of an antibody that specifically binds to IL-4R, and 1. A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R) for use in reducing the annual rate of severe asthma exacerbations in a subject with severe, uncontrolled asthma, in a method comprising administering to the subject one or more maintenance doses of about 200 mg of an antibody that specifically binds to the IL-4R, The pharmaceutical composition, wherein the antibody that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

62. 62. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is an add-on treatment.

63. The pharmaceutical composition of claim 62, wherein the antibody that specifically binds to IL-4R comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

64. The pharmaceutical composition of claim 63, wherein the antibody that specifically binds to IL-4R is dupilumab.

65. 62. The pharmaceutical composition of claim 61, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered every two weeks (q2w).

66. 66. The pharmaceutical composition of claim 65, wherein the one or more maintenance doses of the antibody that specifically binds to IL-4R are administered for at least 24 weeks.

67. The pharmaceutical composition of claim 61, wherein the antibody that specifically binds to IL-4R is administered subcutaneously to the subject.

68. 68. The pharmaceutical composition of claim 67, wherein the antibody that specifically binds to IL-4R is administered using an autoinjector, a needle and syringe, or a pen delivery device.

69. 62. The pharmaceutical composition of claim 61, wherein the subject has an eosinophilic phenotype.

70. 62. The pharmaceutical composition of claim 61, wherein the subject is at least 12 years old.

71. 62. The pharmaceutical composition of claim 61, wherein the subject was treated with medium or high dose ICS / LABA and required one or more systemic steroids for asthma exacerbations prior to treatment with the antibody that specifically binds to IL-4R.

72. 62. The pharmaceutical composition of claim 61, wherein treatment with the antibody that specifically binds to IL-4R results in a reduction from baseline in severe exacerbation events at 24 weeks of treatment and / or an increase from baseline in forced expiratory volume in 1 second in liters (FEV1) at 12 weeks of treatment in the subject.

73. 1. A pharmaceutical composition comprising dupilumab for use in treating severe uncontrolled asthma in a subject, in a method comprising administering to the subject by subcutaneous injection an initial dose of about 600 mg of dupilumab and one or more maintenance doses of about 300 mg of dupilumab, wherein the subject is at least 12 years of age, the subject has an eosinophilic phenotype, and The composition may further comprise one or more maintenance doses of an inhaled corticosteroid (ICS) and a long-acting beta-lactam. 2 The pharmaceutical composition comprises one or more maintenance doses of an adrenergic stimulant (LABA).

74. 74. The pharmaceutical composition of claim 73, wherein the one or more maintenance doses of dupilumab are administered every two weeks (q2w).

75. 1. A pharmaceutical composition comprising dupilumab for use in treating severe uncontrolled asthma in a subject in need thereof, the method comprising administering to the subject by subcutaneous injection an initial dose of about 400 mg of dupilumab and one or more maintenance doses of about 200 mg of dupilumab, wherein the subject is at least 12 years of age, the subject has an eosinophilic phenotype, and the pharmaceutical composition further comprises one or more maintenance doses of an inhaled corticosteroid (ICS) and a long-acting beta-lactam agonist. 2 The pharmaceutical composition comprises one or more maintenance doses of an adrenergic stimulant (LABA).

76. 76. The pharmaceutical composition of claim 75, wherein the one or more maintenance doses of dupilumab are administered every two weeks (q2w).

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