Methods for treating or preventing asthma by administering il-33 antagonist

Abstract

To provide methods for treating or preventing asthma and associated conditions in a patient.SOLUTION: Methods comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-33 (IL-33) antagonist, such as an anti-IL-33 antibody. The methods comprise administering to a subject in need thereof a first therapeutic composition comprising an interleukin-33 (IL-33) antagonist, such as an anti-IL-33 antibody, and a second therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application Nos. 62 / 841,481, filed May 1, 2019, 62 / 848,248, filed May 15, 2019, and 62 / 898,900, filed September 11, 2019, the entire disclosures of each of which are incorporated herein by reference.

[0002] The present invention relates to the treatment and / or prevention of asthma and related conditions. More particularly, the present invention relates to the administration of an interleukin-33 (IL-33) antagonist to treat or prevent asthma in a patient in need thereof. The present invention also relates to the administration of an IL-33 antagonist and an interleukin-4 receptor (IL-4R) antagonist to treat or prevent asthma in a patient in need thereof. [Background technology]

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

[0004] Despite this, despite maximum recommended treatment with a combination of anti-inflammatory and bronchodilator medications, an estimated 5% to 10% of the population with asthma has symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of all healthcare costs due to hospitalizations, emergency service use, and unscheduled visits. Because many of these patients respond poorly to ICS due to numerous cellular and molecular mechanisms, there is an unmet need for new therapies in this severe asthma population. Furthermore, the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and childhood growth motivate attempts to minimize corticosteroid use. While the majority of asthma patients are managed to some extent with current therapies, patients with severe, uncontrolled asthma have few therapeutic treatment options that can adequately control their disease. Nonresponsiveness to therapy or lack of compliance can result in loss of asthma control and ultimately asthma exacerbation.

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

[0006] Approximately 20% of patients with asthma have uncontrolled, moderate-to-severe disease with recurrent exacerbations and persistent symptoms despite maximizing standard-of-care controller therapy. This population is at increased risk for morbidity, particularly exacerbations, and occupies significant healthcare resources. These patients experience substantial declines in lung function despite maximal treatment and are unavoidably destined for further loss of lung function. Currently approved treatments have not been shown to slow this unavoidable decline or consistently and meaningfully increase lung function in these patients.

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

[0008] According to one aspect, there is provided a method for treating asthma in a subject in need thereof, comprising administering to the subject an initial dose of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6 and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, and one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0009] In certain exemplary embodiments, loss of asthma control (LOAC) is reduced in a subject.

[0010] In certain exemplary embodiments, one or more asthma-related parameters are improved in the subject.

[0011] In certain exemplary embodiments, the asthma-related parameter is selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, number or dose of long-acting beta-2 adrenergic agonist (LABA), number or dose of inhaled corticosteroid, and number or dose of systemic steroid.

[0012] In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved.

[0013] In certain exemplary embodiments, the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; between about 150 and 299 cells per μL; or about <150 cells per μL.

[0014] In certain exemplary embodiments, the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl.

[0015] In certain exemplary embodiments, blood eosinophil levels are reduced.

[0016] In certain exemplary embodiments, the subject has high blood periostin levels of about 60 ng / ml or more, about 65 ng / ml or more, about 70 ng / ml or more, about 75 ng / ml or more, about 80 ng / ml or more, or about 74.4 ng / mL or more, or the subject has high blood periostin levels of less than about 80 ng / mL, less than about 75 ng / mL, less than about 70 ng / mL, less than about 65 ng / mL, or less than about 60 ng / mL, or less than about 74.4 ng / mL. is about 60 ng / ml or greater, about 65 ng / ml or greater, about 70 ng / ml or greater, about 75 ng / ml or greater, or about 80 ng / ml or greater. In certain exemplary embodiments, the subject has high blood periostin levels of about 74.4 ng / mL or greater.

[0017] In certain exemplary embodiments, one or both of the asthma control questionnaire 5-question version (ACQ-5) score and the asthma quality of life questionnaire with standardized activities (AQLQ) score are improved.

[0018] In certain exemplary embodiments, the emotional functioning score of the AQLQ is improved.

[0019] In certain exemplary embodiments, the number or dosage of a long-acting beta-2 adrenergic agonist (LABA) is reduced, the number or dosage of an inhaled corticosteroid is reduced, or the number or dosage of a systemic steroid is reduced.

[0020] In certain exemplary embodiments, the asthma is moderate to severe asthma that is not adequately controlled on background therapy.

[0021] In certain exemplary embodiments, the background therapy includes an inhaled corticosteroid (ICS) and a long-acting beta-2 adrenergic agonist (LABA).

[0022] In certain exemplary embodiments, the background therapy includes a moderate to high dose of ICS / LABA.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:10.

[0024] In certain exemplary embodiments, the antibody comprises SAR440340.

[0025] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered every other week.

[0026] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0027] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered as two injections.

[0028] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, needle and syringe, or pen delivery device.

[0029] According to another aspect, there is provided a method for treating asthma in a subject in need thereof, comprising administering to a subject an initial dose of about 300 mg of a first antibody or antigen-binding fragment thereof, wherein the first antibody or antigen-binding fragment thereof specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16; one or more maintenance doses of about 300 mg of the first antibody or antigen-binding fragment thereof; Provided is a method comprising administering to a subject an initial dose of about 300 mg of a second antibody or antigen-binding fragment thereof that specifically binds and comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 21, 22, and 23, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 24, 25, and 26, and one or more maintenance doses of about 300 mg of the second antibody or antigen-binding fragment thereof.

[0030] In certain exemplary embodiments, the LOAC is reduced in a subject.

[0031] In certain exemplary embodiments, one or more asthma-related parameters are improved in the subject.

[0032] In certain exemplary embodiments, the asthma-related parameter is selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, number or dose of long-acting beta-2 adrenergic agonist (LABA), number or dose of inhaled corticosteroid, and number or dose of systemic steroid.

[0033] In certain exemplary embodiments, the post-bronchodilator FEV1 is improved.

[0034] In certain exemplary embodiments, the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; between about 150 and 299 cells per μL; or about <150 cells per μL.

[0035] In certain exemplary embodiments, the subject has high blood periostin levels of about 60 ng / ml or more, about 65 ng / ml or more, about 70 ng / ml or more, about 75 ng / ml or more, about 80 ng / ml or more, or about 74.4 ng / ml or more, or the subject has high blood periostin levels of less than about 80 ng / ml, less than about 75 ng / ml, less than about 70 ng / ml, less than about 65 ng / ml, less than about 60 ng / ml, or less than about 74.4 ng / ml. In certain exemplary embodiments, the subject has high blood periostin levels of about 60 ng / ml or more, about 65 ng / ml or more, about 70 ng / ml or more, about 75 ng / ml or more, about 80 ng / ml or more, or about 74.4 ng / ml or more.

[0036] In certain exemplary embodiments, the asthma is moderate to severe asthma that is not adequately controlled on background therapy.

[0037] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:10.

[0038] In certain exemplary embodiments, the first antibody comprises SAR440340.

[0039] In certain exemplary embodiments, the second antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 28.

[0040] In certain exemplary embodiments, the second antibody comprises dupilumab.

[0041] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered every other week.

[0042] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered subcutaneously.

[0043] In certain exemplary embodiments, the second antibody or antigen-binding fragment thereof is administered to the subject before, after, or simultaneously with the first antibody or antigen-binding fragment thereof.

[0044] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof is administered as two injections and the second antibody or antigen-binding fragment thereof is administered as one injection.

[0045] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered subcutaneously using an autoinjector, a needle and syringe, or a pen delivery device.

[0046] In certain exemplary embodiments, at least one additional therapeutic agent is administered to the subject.

[0047] In certain exemplary embodiments, the at least one additional therapeutic agent comprises one or both of an ICS and a LABA.

[0048] In certain exemplary embodiments, the ICS is fluticasone or budesonide.

[0049] In certain exemplary embodiments, the LABA is salmeterol or formoterol.

[0050] In certain exemplary embodiments, an ICS and a LABA are both administered, the ICS being fluticasone and the LABA being salmeterol.

[0051] In another aspect, a method is provided for treating moderate to severe asthma in a subject in need thereof, comprising administering to the subject an initial dose of about 300 mg of SAR440340, and one or more maintenance doses of about 300 mg of SAR440340, wherein SAR440340 is administered subcutaneously every other week.

[0052] In another aspect, provided is a method for treating moderate to severe asthma in a subject in need thereof, comprising administering to the subject an initial dose of about 300 mg of SAR440340, one or more maintenance doses of about 300 mg of SAR440340, an initial dose of about 300 mg of dupilumab, and one or more maintenance doses of about 300 mg of dupilumab, wherein SAR440340 and dupilumab are administered subcutaneously every other week.

[0053] In another aspect, a method for reducing an asthma patient's dependence on one or both of inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs) for the treatment of one or more asthma exacerbations or the patient's dependence on inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs) is provided, comprising administering to a subject with moderate to severe asthma that is partially controlled or uncontrolled with a baseline asthma therapy comprising an ICS, a LABA, or a combination thereof, at defined times for an initial treatment period, while maintaining the subject's baseline asthma therapy; and administering to the subject at defined times and doses used during the initial treatment period, a defined dose of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33), the antibody or antigen-binding fragment comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16. Methods are provided that include gradually reducing or eliminating the dosage of ICS, LABA, or a combination thereof administered to the subject over the course of a subsequent treatment period, while continuing to administer the antigen-binding fragment.

[0054] In certain exemplary embodiments, the ICS is fluticasone, budesonide, or mometasone and the LABA is salmeterol or formoterol.

[0055] In certain exemplary embodiments, the ICS / LABA combination is selected from the group consisting of fluticasone / salmeterol, budesonide / formoterol, and mometasone / formoterol.

[0056] In certain exemplary embodiments, the doses of one or both of the LABA and ICS are removed at the end of the initial treatment period.

[0057] In certain exemplary embodiments, the dosage of one or both of the LABA and ICS is gradually reduced or eliminated over a period of 2 to 8 weeks.

[0058] In certain exemplary embodiments, the method further comprises administering to the subject a second antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) and comprises three HCDR sequences comprising SEQ ID NOs: 21, 22, and 23, and three LCDR sequences comprising SEQ ID NOs: 24, 25, and 26.

[0059] In another aspect, a method is provided for treating asthma in a subject in need thereof, comprising administering to the subject an approximately 300 mg dose of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16.

[0060] In certain exemplary embodiments, loss of asthma control (LOAC) is reduced in a subject.

[0061] In certain exemplary embodiments, one or more asthma-related parameters are improved in the subject. In certain exemplary embodiments, the asthma-related parameters are selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, long-acting beta-2 adrenergic agonist (LABA) frequency or dose, inhaled corticosteroid frequency or dose, and systemic steroid frequency or dose.

[0062] In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved.

[0063] In certain exemplary embodiments, the subject has a blood eosinophil count of about 300 cells per μL or greater; about 150-299 cells per μL; or about <150 cells per μL. In certain exemplary embodiments, the subject has a blood eosinophil count of about 300 cells per μL or greater. In certain exemplary embodiments, blood eosinophil levels are reduced.

[0064] In certain exemplary embodiments, the subject has high or low blood periostin levels. In certain exemplary embodiments, the subject has high blood periostin levels of about ≧74.4 ng / mL.

[0065] In one particular exemplary embodiment, the Asthma Control Questionnaire 5 question version (A One or both of the Asthma Quality of Life Questionnaire (AQLQ) score with standardized activities and the Asthma Quality of Life Questionnaire (CQ-5) score are improved. In certain exemplary embodiments, the AQLQ emotional function score is improved.

[0066] In certain exemplary embodiments, the number or dosage of a long-acting beta-2 adrenergic agonist (LABA) is reduced, the number or dosage of an inhaled corticosteroid is reduced, or the number or dosage of a systemic steroid is reduced.

[0067] In certain exemplary embodiments, the asthma is moderate to severe asthma that is not adequately controlled on background therapy.

[0068] In certain exemplary embodiments, the background therapy includes an inhaled corticosteroid (ICS) and a long-acting beta-2 adrenergic agonist (LABA).

[0069] In certain exemplary embodiments, the background therapy includes a moderate to high dose of ICS / LABA.

[0070] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, needle and syringe, or pen delivery device.

[0071] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the antibody comprises SAR440340.

[0072] In another aspect, a method for treating asthma in a subject in need thereof is provided, comprising administering to the subject an approximately 300 mg dose of a first antibody or antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, and an approximately 300 mg dose of a second antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 21, 22, and 23, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 24, 25, and 26.

[0073] In certain exemplary embodiments, loss of asthma control (LOAC) is reduced in a subject.

[0074] In certain exemplary embodiments, one or more asthma-related parameters are improved in the subject. In certain exemplary embodiments, the asthma-related parameters are selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, long-acting beta-2 adrenergic agonist (LABA) frequency or dose, inhaled corticosteroid frequency or dose, and systemic steroid frequency or dose.

[0075] In certain exemplary embodiments, the pre-bronchodilator FEV1 is improved.

[0076] In certain exemplary embodiments, the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; between about 150 and 299 cells per μl; or about <150 cells per μl. In certain exemplary embodiments, the subject has a blood eosinophil count of less than or equal to about 300 cells per μl. In certain exemplary embodiments, blood eosinophil levels are reduced.

[0077] In certain exemplary embodiments, the subject has high or low blood periostin levels. In certain exemplary embodiments, the subject has high blood periostin levels of about ≧74.4 ng / mL.

[0078] In certain exemplary embodiments, one or both of the Asthma Control Questionnaire 5 Question Version (ACQ-5) score and the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ) score are improved, hi certain exemplary embodiments, the AQLQ emotional function score is improved.

[0079] In certain exemplary embodiments, the number or dosage of a long-acting beta-2 adrenergic agonist (LABA) is reduced, the number or dosage of an inhaled corticosteroid is reduced, or the number or dosage of a systemic steroid is reduced.

[0080] In certain exemplary embodiments, the asthma is moderate to severe asthma that is not adequately controlled on background therapy.

[0081] In certain exemplary embodiments, the background therapy includes an inhaled corticosteroid (ICS) and a long-acting beta-2 adrenergic agonist (LABA).

[0082] In certain exemplary embodiments, the background therapy includes a moderate to high dose of ICS / LABA.

[0083] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, needle and syringe, or pen delivery device.

[0084] In certain exemplary embodiments, the first antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the first antibody comprises SAR440340.

[0085] In certain exemplary embodiments, the second antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 28. In certain exemplary embodiments, the second antibody comprises dupilumab.

[0086] Other embodiments will become apparent from review of the following detailed description, drawings, tables, and appended claims.

[0087] The foregoing 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 invention will contain at least one drawing / photograph executed in color. Copies of this invention with color drawing(s) / photograph(s) will be provided by the Agency upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0088] [Figure 1] FIG. 1 shows the study flow chart for a 12-week proof-of-concept (PoC) study designed to evaluate the efficacy, safety, and tolerability of SAR440340 and co-administration of SAR440340 and dupilumab in patients with moderate to severe asthma not adequately controlled on inhaled ICS / LABA therapy. [Figure 2-1]Figure 1 shows a table corresponding to the flowchart in Figure 1. Abbreviations: ACQ-5, Asthma Control Questionnaire-5; AQLQ(S), Asthma Quality of Life Questionnaire; β-hCG, β-human chorionic gonadotropin; D, day; EOT, end of treatment; FEF, forced expiratory flow rate; FeNO, exhaled nitric oxide; FEV1, forced expiratory volume in one second; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IMP, investigational drug; IL33, interleukin-33; IVRS / IWRS, voice / wave response Automated response system; LABA, long-acting beta-2 adrenergic receptor agonist; LOAC, loss of asthma control; BD, bronchodilator; PARC, lung and activation-regulated chemokine; PEF, peak expiratory flow; PGx, pharmacogenomics; PK, pharmacokinetics; RNA, ribonucleic acid; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SAE, serious adverse events; sST2, soluble IL33 receptor; V, visit; W, week. a Study visits will occur as scheduled and on the planned dates (relative to the first injection). The visit schedule should be adhered to within ±3 days during the screening and randomized IMP treatment periods, and within ±5 days for visits during the post-IMP safety follow-up period. b After 5 weeks of the ICS / LABA treatment withdrawal period, at Visit 2 / Baseline, patients who used high-dose ICS (fluticasone) background therapy will undergo IMP treatment without background therapy for 3 weeks. After 4 weeks of the cICS / LABA treatment withdrawal period, patients who used medium-dose fluticasone background therapy at Visit 2 / baseline will receive IMP treatment without background therapy for 4 weeks. dEnd of IMP Treatment (EOT) Visit: Patients who discontinue the study (i.e., early treatment discontinuation (ETD)) before completing 12 weeks of IMP treatment (e.g., due to a LOAC event or other reason) will be evaluated as soon as possible at their individual EOT visit, using the procedures as planned for the EOT visit at Week 12 (Visit 14). At these EOT visits, all patients will resume their prescreening ICS / LABA background therapy and enter the 20-week IMP post-treatment period (V15-V17). If a patient's asthma cannot be adequately controlled with prescreening ICS / LABA therapy, additional controller therapy may be prescribed based on the investigator's clinical judgment.The eIMP posttreatment period begins at week 12 for patients completing the IMP treatment period and may begin earlier for patients who meet criteria for LOAC or who discontinue IMP treatment early (for other reasons) before completing 12 weeks of IMP treatment. f Visit 16 may be an on-site visit or a telephone visit. g Patients with a reversibility of at least 12% and 200 mL in FEV1 after administration of 2–4 puffs (200–400 mcg) of albuterol / salbutamol or levalbuterol / levosalbutamol during screening, or a documented history of a reversibility test that meets this criterion within the 12 months prior to Visit 1, or a documented positive response to a methacholine challenge (decline of 20% [PC20] of FEV<8 mg / mL) within the 12 months prior to Visit 1 / screening, are considered acceptable for inclusion. If a subject does not meet the eligibility criteria for reversibility at Visit 1 / Screening, they may be attempted up to two more times during the screening period, on different days before Visit 2 / Baseline. If the reversibility assessment is repeated during the screening period, the pre-bronchodilator FEV1 should again meet the inclusion criterion (I 03) of >40% of predicted normal. Patients should be monitored by on-site personnel for at least 30 minutes after administration of all IMP injections. The monitoring period may be extended according to specific country requirements. The electronic diary / PEF meter is a portable device used to record daily data on salbutamol / albuterol or levosalbutamol / levalbuterol use, asthma controller medication use, asthma symptom score numerical rating scale (NRS), asthma symptoms and nighttime awakenings due to AM and PM PEF, and patient responses to the ACQ-5, AQLQ(S), and RQLQ questionnaires between scheduled visits. The portable device (including instructions for use) will be distributed at Visit 1, and recorded information will be downloaded from the device on other indicated dates. If not already done so, the patient will return the electronic device to their site at EOS. The electronic device will be returned to the sponsor at EOS as up-to-date.j After evaluation for LOAC events, all patients who do not meet LOAC criteria at Week 4 / V6 will have LABA (salmeterol) discontinued from their background therapy and will switch from fluticasone / salmeterol combination therapy to a clinically comparable ICS dose of fluticasone monotherapy. k After evaluation for LOAC events, all patients who do not meet LOAC criteria at V8, V9, V10 (and V11) will have ICS (fluticasone) discontinued by a 3- or 4-step dose reduction, depending on their medium- or high-dose ICS (fluticasone) background therapy, at Visit 2 / Baseline, respectively. l A complete physical examination will include the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, gastrointestinal system, nervous system, lymphatic system, and musculoskeletal system. m Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), and respiratory rate (breaths per minute), will be measured at all visits as detailed in the flowchart. Height (cm) will be measured only at screening (Visit 1). Weight (kg) will be measured at Visit 1 / screening, Visit 2 / baseline, and Visit 14 / EOT. Hematology tests will include hemoglobin, hematocrit, platelet count, total white blood cell count, differential white blood cell count, and total red blood cell count. Blood chemistry tests will include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. Urinalysis will include specific gravity, pH, glucose, ketones, occult blood, protein, nitrates, leukocyte esterase, urobilinogen, and bilirubin. If any parameter on the dipstick is abnormal, a urine sample should be sent to a central laboratory for quantitative measurement. If protein and / or red blood cells are positive, microscopic analysis will be performed by a central laboratory.Screening Visit 1 laboratory tests will include hepatitis virus testing, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), hepatitis C virus antibody (HCVAb), human immunodeficiency virus (HIV) testing (anti-HIV-1 and HIV-2 antibodies), and antinuclear antibody (ANA). If results show HBsAg (negative) and HBcAb (positive), HBV DNA testing may be performed prior to randomization to rule out a false positive if the investigator believes the patient is false positive, or to clarify serology if the investigator finds it unclear to interpret in the absence of known HBV infection. If results show HCVAb (positive), HCV RNA testing may be performed to rule out a false positive if the investigator believes the patient is false positive. Note: If ANA is positive (titer ≥ 1:160), anti-dsDNA antibodies will be tested. Blood samples for blood chemistry testing must be collected from patients in a fasting state, meaning they have not consumed any food or drink other than water for at least 8 hours. (If the visit can only be performed at a different time of day and the patient is not fasting, then the patient should be advised to eat a light snack, and the site should document that blood chemistry tests were not obtained under fasting conditions.) QuantiFERON Gold should be collected for all patients at Screening Visit 1. If this result is confirmed to be positive, the patient should be referred to an infectious disease specialist. For further details, refer to the Central Laboratory Manual. pFor women of childbearing potential only: Serum pregnancy test at Screening / V1 and urine pregnancy test at V2, V6, V10, V14 / EOT, and V17 / EOS. Negative results must be obtained at V1 and V2 before randomization. In the case of a positive urine test, study treatment will be withheld, and a serum pregnancy test to confirm pregnancy should be performed as soon as possible. Pregnancy will ultimately result in treatment discontinuation in all cases. If the ADA assessment at week 12 (or analysis of the first post-treatment time point) is positive, further measurements may be performed from a PK sample collected at week 4.Hematology samples will be drawn for eosinophils and neutrophils (with other critical limits reported per laboratory manual). Exhaled nitric oxide assessment will be performed before spirometry and after at least 1 hour of fasting. Spirometry (pre-BD FEV1, post-BD FEV1, and PEF, FVC, FEF) should be performed no earlier than 6 hours after the last dose of albuterol or levalbuterol (if used), withholding at least 12 hours and the last dose of LABA before administration of study drug. Post-bronchodilator spirometry may be repeated several times within 30 minutes after bronchodilator administration. The ACQ-5, AQLQ(S), and RQLQ will be completed on the patient's portable device during the clinic visit. [Figure 2-2] Continued from Figure 2-1. [Figure 2-3] Continued from Figure 2-2. [Figure 3] Figure 1. Summary of efficacy results. SAR440340 demonstrates significant efficacy across multiple endpoints. [Figure 4] Figure 1. Graphical representation of loss of asthma control (LOAC) in the intent to treat (ITT) population. Significant reduction in the proportion of patients with LOAC events in the SAR440340 and dupilumab arms. [Figure 5] Figure 1 shows the distribution of reasons for LOAC in the ITT population. The most common reason for LOAC was not meeting peak expiratory flow (PEF) criteria. [Figure 6] Figure 1 graphically depicts time to LOAC results in the ITT population. There was a significant effect for both SAR440340 and dupilumab on time to LOAC. [Figure 7-1]7A-7C graphically depict LOAC by subgroup: (A) eosinophil subgroup; (B) FeNO subgroup; (C) periostin subgroup. SAR440340 demonstrated balanced reductions in LOAC across eosinophil and FeNO levels. SAR440340 demonstrated greater efficacy in the high periostin subpopulation. [Figure 7-2] Continued from Figure 7-1. [Figure 8] 8A-8D show forest plots of LOAC by baseline blood eosinophil count for SAR440340 (A) and dupilumab (B), and incidence of LOAC by baseline FeNO and periostin for SAR440340 (C) and dupilumab (D). [Figure 9] 9A-9B show baseline pre-bronchodilator (pre-BD) FEV1 change as LS mean (SE) (A) and as percent change from baseline (B). [Figure 10] 1 shows mean change in pre-BD FEV1 over time in the ITT population. Rapid onset and sustained effect in improving FEV1 was observed for both SAR440340 and dupilumab. [Figure 11] Figure 1 shows the mean change from baseline in pre-BD FEV1(L) over time in the ITT population with baseline Eos < 0.3 x 109 / L. No significant effect was observed versus placebo in the low Eos population. [Figure 12] Figure 1 shows the change from baseline in pre-BD FEVl(L) over time in the ITT population with a baseline Eos of 0.3x109 / L or greater. SAR440340 has a rapid onset and sustained effect on FEVl over 12 weeks. [Figure 13] FIG. 1 shows the mean change in FEV1 from baseline to before BD administration by Eos subgroup. [Figure 14]Figure 1 shows the change from baseline in pre-bronchodilator FEV1(L) over time in the ITT population with baseline FeNO <25 ppb. There was no significant effect of FEV1 in the low FeNO population. [Figure 15] Figure 1 shows the change from baseline in pre-bronchodilator FEVl(L) over time in the ITT population with baseline FeNO >= 25 ppb. SAR440340 had a rapid onset and sustained effect on FEVl over the 12-week period. [Figure 16] 1 shows the mean change in FEV1 from baseline to pre-BD administration by FeNO subgroup. SAR440340 demonstrated a significant effect on FEV1. [Figure 17] 1 shows the mean change in FEV1 from baseline to pre-BD administration by periostin subgroup. SAR440340 demonstrated a significant effect on FEV1 in the high periostin group. [Figure 18] Forest plot of change from baseline in pre-bronchodilator FEV1(L) at week 12 by baseline blood eosinophil count in the ITT population. A significant placebo effect was observed in the 150-300 group, which may result in a negative effect on the treatment group. [Figure 19] FIG. 1 shows forest plots of change from baseline in pre-BD FEV1(L) at week 12 by baseline FeNO and periostin subgroups in the modified ITT (mITT) population. [Figure 20] Figure 1 shows absolute change in FEV1 after BD administration from baseline, LS mean. SAR440340 had no significant effect on FEV1 after BD administration. [Figure 21]

[0023] Figure 1 shows the mean change in FEVl after BD administration over time in the ITT population. Both the combination of SAR440340 and dupilumab and dupilumab alone had a rapid effect on FEVl after BD administration, but the effect was sustained only in the dupilumab arm. [Figure 22]

[0023] Figure 1 shows the change from baseline in ACQ-5 in the ITT population. SAR440340 demonstrated significant improvement in ACQ-5 by week 12. [Figure 23] Figure 1 shows the change from baseline in ACQ-5 over time in the mITT population. The effect of SAR440340 on ACQ-5 was rapid and sustained over 12 weeks. [Figure 24] Figure 1 shows AQLQ in the ITT population. SAR440340 demonstrated significant improvement in AQLQ over 12 weeks. [Figure 25] Figure 1 shows the AQLQ, change from baseline in AQLQ(S) total score over time in the ITT population. SAR440340 had an immediate and sustained effect on the AQLQ over the 12-week period. [Figure 26] Figure 1 shows the change from baseline in AQLQ, AQLQ(S) emotional functioning scores over time in the ITT population. SAR440340 demonstrated significant improvements in AQLQ emotional functioning scores. [Figure 27] FIG. 1 shows mean blood eosinophil count (109 / L) over time in the ITT population. [Figure 28] Figure 1 shows the mean and median change from baseline in blood eosinophil counts over time in the ITT population. SAR440340 consistently reduced eosinophils over the 12-week period. [Figure 29] FIG. 1 shows mean FeNO (ppb) over time in the ITT population. [Figure 30]Figure 1 shows the mean and median change from baseline in FeNO (ppb) over time in the ITT population. SAR440340 demonstrated a modest effect on FeNO over the 12-week period. [Figure 31] FIG. 1 shows mean periostin (ng / mL) over time in the ITT population. [Figure 32] 1 shows the mean and median change from baseline in periostin (ng / mL) over time in the ITT population. SAR440340 demonstrated a modest effect on periostin levels over 12 weeks. [Figure 33] FIG. 1 shows mean eotaxin-3 (pg / mL) over time in the ITT population. [Figure 34] 1 shows the mean and median change from baseline in eotaxin-3 (pg / mL) over time in the ITT population. SAR440340 had no apparent effect on eotaxin-3. [Figure 35] FIG. 1 shows mean PARC (pg / mL) over time in the ITT population. [Figure 36] Figure 1 shows the mean and median change from baseline in PARC (pg / mL) over time in the ITT population. SAR440340 had no apparent effect on PARC. [Figure 37] FIG. 1 shows mean total IgE (IU / mL) over time in the ITT population. [Figure 38] Figure 1 shows the mean and median change from baseline in total IgE (IU / mL) over time in the ITT population. SAR440340 had no apparent effect on IgE. [Figure 39] FIG. 1 shows mean total IL33 (pg / mL) over time. [Figure 40] Figure 1 shows the mean and median change from baseline in total IL33 (pg / mL) over time in the safety population. As expected, SAR440340 increased IL-33 levels. [Figure 41] FIG. 1 shows mean sST2 (pg / mL) over time in the ITT population. [Figure 42] Figure 1 shows the mean and median change from baseline in sST2 (pg / mL) over time in the ITT population. SAR440340 had no apparent effect on sST2 levels. [Figure 43] FIG. 1 shows mean calcitonin (pg / mL) over time in the ITT population. [Figure 44] Figure 1 shows the mean change from baseline in calcitonin (pg / mL) over time in the ITT population. SAR440340 had no effect on calcitonin levels. [Figure 45] FIG. 1 shows mean blood neutrophil counts over time in the ITT population. [Figure 46] 1 shows the mean and median change from baseline in blood neutrophil counts over time in the ITT population. SAR440340 demonstrated a modest effect on blood neutrophils. [Figure 47] Figure 1 shows serum concentrations of SAR440340 (ng / mL) over time in the PK population. Concentrations above 17 mg / L were reached at week 2. The lowest concentrations of SAR440340 were achieved in the SAR440340 and dupilumab combination arm at week 12. [Figure 48] 1 shows the mean change in blood Eos per blood Eos stratum. There was a more pronounced decrease in blood Eos in the high blood Eos subgroup. [Figure 49] Figure 1 shows the median change in blood Eos per blood Eos stratum. There was a more pronounced decrease in blood Eos in the high blood Eos subgroup. [Figure 50] 1 shows the mean change in blood Eos per FeNO stratum. There was a more obvious decrease in blood Eos in patients with high FeNO. [Figure 51] Figure 1 shows the median change in blood Eos per FeNO stratum. There was a more pronounced decrease in blood Eos in patients with high FeNO. [Figure 52] 1 shows the mean change in neutrophils per Eos layer. Blood Eos levels were not affected by the trend of neutrophil reduction. [Figure 53] Figure 1 shows the median change in neutrophils per Eos layer. There was no decrease in neutrophils. [Figure 54] Fig. 1 shows the mean change in blood neutrophils per FeNO layer. Neutrophil decline (trend) was not affected by FeNO level. [Figure 55] Figure 1 shows the median change in blood neutrophils per FeNO layer. There was no decrease in neutrophils. [Figure 56] Figure 1 shows the mean change in FeNO per blood Eos layer. There was a slight decrease in FeNO in patients with high blood Eos. [Figure 57] Figure 1 shows the median change in FeNO per blood Eos layer. There was a slight decrease in FeNO in patients with high blood Eos. [Figure 58] Figure 1 shows the mean change in FeNO per FeNO stratum. There was a slight decrease in FeNO in patients with high FeNO. [Figure 59] Figure 1 shows the median change in FeNO per FeNO stratum. There was no significant decrease in FeNO even in patients with high FeNO. [Figure 60] 1 shows the mean change in PARC per blood Eos layer. PARC decreased only in patients with high blood Eos. [Figure 61] Figure 1 shows the median change in PARC per blood Eos layer. There was no significant decrease in PARC in patients with high blood Eos. [Figure 62] Figure 1 shows the mean change in PARC per FeNO layer. There was a decrease in PARC only in patients with high FeNO. [Figure 63] Figure 1 shows the median change in PARC per FeNO layer. There was no significant decrease in PARC. [Figure 64]1 shows the average change in eotaxin-3 per blood Eos layer. There was an increase in eotaxin-3 in patients with low blood Eos, but no change in patients with high blood Eos. [Figure 65] Figure 1 shows the median change in eotaxin-3 per blood Eos layer. There was no significant change in eotaxin-3. [Figure 66] FIG. 1 shows the mean change in eotaxin-3 per FeNO layer. There was a slight increase in eotaxin-3 in patients with high FeNO. [Figure 67] FIG. 1 shows the median change in eotaxin-3 per FeNO layer. There was no significant change in eotaxin-3. [Figure 68] 1 shows the mean change in IgE per blood Eos layer. There was a greater decrease in IgE in patients with high blood Eos. [Figure 69] Figure 1 shows the median change in IgE per Eos layer in the blood. There was no significant decrease in IgE. [Figure 70] Figure 1 shows the mean change in IgE per Eos layer. There was a greater decrease in IgE in patients with high FeNO. [Figure 71] Figure 1 shows the median change in IgE per FeNO layer. There was no significant decrease in IgE. [Figure 72] 1 shows the mean change in periostin per blood Eos layer. Similar decreases in periostin were observed across blood Eos layers. [Figure 73] FIG. 1 shows the median change in periostin per blood Eos layer. [Figure 74] 1 shows the mean change in periostin per FeNO stratum. Only patients with low FeNO had a decrease in periostin. [Figure 75] FIG. 1 shows the median change in periostin per FeNO layer. [Figure 76] FIG. 1 shows a forest plot of the incidence of LOAC by baseline ICS dose level in the mITT population. [Figure 77] FIG. 1 shows the mean change in FEV1 from baseline to pre-BD administration by ICS subgroup. [Figure 78] FIG. 1 shows LOAC by FeNO subgroup. [Figure 79] Figure 1 shows LOAC by ICS subgroup. [Figure 80] FIG. 1 shows LOAC by periostin subgroup. [Figure 81] FIG. 1 shows the percent change (%) in FEV1 after BD administration from baseline in the ITT population. [Figure 82] FIG. 1 shows absolute change in FEV1 after BD administration from baseline by Eos subgroup. [Figure 83] FIG. 1 shows absolute change in FEV1 after BD administration from baseline by FeNO subgroup. [Figure 84] FIG. 1 shows absolute change in FEV1 after BD administration from baseline by FeNO subgroup. [Figure 85] FIG. 1 shows absolute change in FEV1 from baseline after BD administration by periostin subgroup. [Figure 86] FIG. 1 shows a forest plot of the change from baseline in FEV1(L) after bronchodilator administration at week 12 by baseline blood eosinophil count in the ITT population. [Figure 87] FIG. 1 shows a forest plot of the change from baseline in FEV1(L) after bronchodilator administration at week 12 by baseline blood eosinophil count in the ITT population. [Figure 88] FIG. 1 shows forest plot of change from baseline in post-bronchodilator FEV1(L) at week 12 by baseline ICS dose level in the mITT population. [Figure 89] Figure 1 shows LOAC by ICS subgroup. [Figure 90] FIG. 1 shows the AQLQ in the ITT population. [Figure 91] FIG. 1 shows a Bayesian analysis. [Figure 92] Figure 1 shows key inclusion and exclusion criteria for the asthma proof-of-concept. Patients were enrolled across a wide range of baseline eosinophil levels. [Figure 93] Figure outlining patient disposition. *Loss of asthma control (LOAC) was the criterion for discontinuation. **Two patients discontinued due to adverse effects (AS) before the end of the study (EOT). †One patient in the dupilumab group died from ethyl alcohol poisoning during the post-treatment follow-up period (information received after database lock). [Figure 94] FIG. 1 shows baseline demographics that were generally balanced across the three treatment arms and placebo. [Figure 95] FIG. 1 shows baseline disease characteristics generally balanced across treatment arms. [Figure 96A] Graphical representation of baseline Eos (A) and FeNO (B) levels, evenly distributed across active treatment arms. (C) Baseline distribution by ICS. Most patients (65.9%) received high-dose ICS. [Figure 96B] Graphical representation of baseline Eos (A) and FeNO (B) levels, evenly distributed across active treatment arms. (C) Baseline distribution by ICS. Most patients (65.9%) received high-dose ICS. [Figure 96C] Graphical representation of baseline Eos (A) and FeNO (B) levels, evenly distributed across active treatment arms. (C) Baseline distribution by ICS. Most patients (65.9%) received high-dose ICS. [Figure 97]Figure 1 shows mean change in pre-BD FEV1 over time to week 32 in the ITT population. SAR440340 demonstrated sustained efficacy several weeks after discontinuation. [Figure 98] FIG. 1 shows the distribution of ACQ-5 and AQLQ respondents by subgroup at weeks 4 and 12. [Figure 99] 1 shows the change from baseline in AM and PM PEF over time in the ITT population. SAR440340 did not demonstrate improvement in AM or PM PEF. [Figure 100] Figure 1 shows the change from baseline in forced vital capacity (FVC) and forced expiratory flow rate at 25-75% (FEF25-75) over time in the ITT population. SAR440340 did not demonstrate improvement in FVC or FEF25-75. [Figure 101] Figure 1 shows the change from baseline in AM and PM asthma symptom scores over time in the ITT population. SAR440340 did not demonstrate improvement in AM or PM asthma symptom scores. [Figure 102] Figure 1 shows the change from baseline in the number of nighttime awakenings and use of relief medications over time in the ITT population. SAR440340 did not demonstrate a reduction in nighttime awakenings or use of relief medications. [Figure 103] Figure 1 shows the change from baseline in RQLQ(S) overall score over time in the ITT population with comorbid allergic rhinitis. SAR440340 did not demonstrate a reduction in RQLQ score. [Figure 104] Figure 1 shows serum concentrations of SAR440340 (ng / mL) over time. Concentrations of over 17 mg / L (inferred from the house dust mite (HDM) mouse model) were reached at week 2. The lowest concentrations of SAR440340 were observed in the dupilumab combination arm at week 12. [Figure 105] FIG. 1 shows total IL-33 (pg / mL) over time consistent with a Phase 1 study. [Figure 106-1]Figure 1 shows results (median change) for type 2 pharmacodynamic (PD) biomarkers. SAR440340 induced a decrease in blood eosinophils and had modest effects on other type 2 biomarkers. [Figure 106-2] Continuation of Figure 106-1. [Figure 106-3] Continuation of Figure 106-2. [Figure 107] Figure 1 shows the median change in blood Eos levels up to week 32. SAR440340 continued to keep blood Eos levels low after discontinuation. [Figure 108] 1 shows a spaghetti plot of change from baseline in blood Eos levels in the ITT population. Despite a few outliers, SAR440340 demonstrated a consistent reduction in blood Eos levels. [Figure 109-1] Figure 1 shows median changes in blood neutrophil, sST2 and calcitonin biomarkers. SAR440340 induced a modest decrease in blood neutrophils. [Figure 109-2] Continuation of Figure 109-1. [Figure 109-3] Continuation of Figure 109-2. [Figure 110] 1 shows serum concentrations of SAR440340 over time by anti-drug antibody (ADA) status in the SAR440340 monotherapy and combination therapy arms. No patients had positive ADA to SAR440340. [Figure 111] 1 shows a spaghetti plot of serum concentrations of SAR440340 over time by peak post-baseline titer category for SAR440340 in the ADA population. No patients had a positive ADA to SAR440340. [Figure 112] Figure 1 shows a spaghetti plot of serum concentrations of dupilumab over time by peak post-baseline titer category for dupilumab. Dupilumab ADA occurred as expected in the monotherapy arm. There was a numerically greater ADA positivity rate in the combination arm. [Figure 113]Figure 1 shows a spaghetti plot of serum concentrations of dupilumab over time by peak post-baseline titer category for dupilumab in the ADA population. Dupilumab ADA-positive patients have a trend toward lower exposure (ADA-positive and ADA-negative overlap in PK exposure). [Figure 114-1] FIG. 1 shows forest plots of change from baseline in pre-BD FEV1(L) at week 12 by demographic subgroup. [Figure 114-2] Continuation of Figure 114-1. [Figure 115-1] FIG. 1 shows forest plots of change from baseline in pre-BD FEV1(L) at week 12 by disease characteristic subgroup. [Figure 115-2] Continuation of Figure 115-1. [Figure 116-1] FIG. 1 shows forest plots of change from baseline in FEV1(L) after BD administration at week 12 by demographic subgroup. [Figure 116-2] Continuation of Figure 116-1. [Figure 117-1] FIG. 1 shows forest plots of change from baseline in FEV1(L) after BD administration at week 12 by disease characteristic subgroup. [Figure 117-2] Continuation of Figure 117-1. [Figure 118] FIG. 1 shows blood Eos kinetics (mean change) up to 32 weeks. [Figure 119] Figure 1 shows the mean change from baseline in blood Eos counts (109 / L) across visits in patients by baseline blood Eos (cutoffs of <0.5 or >0.5). SAR440340 reduced blood Eos, although the effect was greater in the <0.5 group. [Figure 120] Figure 1 shows the median change in blood Eos per FeNO stratum. There was a more pronounced decrease in blood Eos in patients with high FeNO. [Figure 121]Figure 1 shows the median change in FeNO per blood Eos layer. There was a slight decrease in FeNO in patients with high blood Eos. [Figure 122] Figure 1 shows the median change in periostin per blood Eos layer. There was a decrease in periostin in patients with high blood Eos. [Figure 123] FIG. 1 shows a flow diagram of a multiple ascending dose study of the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of subcutaneously administered SAR440340 in adult patients with moderate asthma. [Figure 124] Figure 1 shows percent change from baseline in eosinophil levels. Eosinophil levels decreased by approximately 35% from baseline at day 29, an effect that persisted through day 197. [Figure 125] FIG. 1 shows mean eosinophil levels over time. [Figure 126] FIG. 1 shows mean eosinophil levels over time excluding outliers for the 75 mg dose. [Figure 127] Figure 1 shows the percent change from baseline in eosinophil levels. The 75 mg and 150 mg doses were not significantly different. [Figure 128] Figure 1 shows the percent change from baseline in eosinophil levels in the 75 mg and 150 mg combined populations. Eosinophil levels decreased by approximately 35% from baseline at day 29, an effect that persisted through day 197. [Figure 129-1] FIG. 1 shows individual eosinophil level profiles aligned with group means. [Figure 129-2] Continuation of Figure 129-1. [Figure 130]

[0023] Figure 1 shows mean FeNO levels over time. Baseline levels in the 75 mg cohort were higher than in the 150 mg and placebo cohorts. [Figure 131] Figure 1 shows the percent change in FeNO levels over time. There was a moderate effect on FeNO levels in the 150 mg cohort. [Figure 132]Figure 1 shows the percent change in FeNO levels over time for the 75 mg and 150 mg combined populations. There was an approximately 10% decrease in the SAR440340 cohort. [Figure 133] FIG. 1 shows percent change from baseline in FeNO levels over time for the 75 mg and 150 mg combined populations. [Figure 134-1] Figure 1 shows individual changes in FeNO levels aligned with group means. Outliers in the 75 mg cohort rose to mean levels. [Figure 134-2] Continuation of Figure 134-1. DETAILED DESCRIPTION OF THE INVENTION

[0089] Before describing the present invention, it is to be understood that the present invention is not limited to the methods and conditions described, as such methods and conditions may vary. It is to be understood that the present invention is not limited to particular methods and experimental conditions. 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 present invention will be limited only by the appended claims.

[0090] 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.

[0091] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary by up to 1% 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.).

[0092] As used herein, the terms "treat," "treating," and the like mean to alleviate symptoms, temporarily or permanently remove the causal effects of symptoms, or prevent or slow the onset of symptoms of the specified disorder or condition.

[0093] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0094] Methods for reducing the incidence of asthma exacerbations The present invention includes a method for reducing the incidence of asthma exacerbations in a subject in need thereof, comprising administering a pharmaceutical composition comprising an interleukin-33 (IL-33) antagonist. The methods featured in the present invention further comprise administering to a subject in need thereof a first therapeutic composition comprising an interleukin-33 (IL-33) antagonist and a second therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist. According to certain embodiments, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33. Exemplary anti-IL-33 antibodies that can be used in the context of the methods featured in the present invention are described herein. 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 the context of the methods featured in the present invention are described herein.

[0095] 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 worsening of a subject's respiratory health that requires and / or can be treated by therapeutic intervention for asthma (e.g., steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.). There are two types of asthma exacerbation events: loss of asthma control (LOAC) events and severe exacerbation events.

[0096] According to certain embodiments, a loss of asthma control (LOAC) event is defined as one or more of the following: (a) a 30% or greater decrease from baseline in morning PEF for two consecutive days; (b) 6 or more additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in a 24-hour period (compared to baseline) for two consecutive days; (c) an increase in ICS of 4 times or more above the last prescribed ICS dose (or ≥ 50% of the ICS dose prescribed at V2 if discontinuation of background therapy is complete); (d) use of systemic (oral and / or parenteral) corticosteroid therapy; or ( e) Hospitalization or emergency room visit for asthma.

[0097] In certain instances, asthma exacerbation can be classified as "severe asthma exacerbation event." Severe asthma exacerbation event refers to an event requiring immediate intervention in the form of treatment with systemic or inhaled corticosteroids at doses four times or more than those administered before the event. According to certain embodiments, severe asthma exacerbation event is defined as the use of systemic corticosteroids for three days or more; or an asthma exacerbation requiring systemic corticosteroids, requiring hospitalization or emergency room visit for asthma. Thus, the general expression "asthma exacerbation" encompasses and encompasses the more detailed subcategory of "severe asthma exacerbation." Thus, methods for reducing the incidence of severe asthma exacerbation in patients in need thereof are included.

[0098] A "reduced incidence" of asthma exacerbations means that a subject administered a pharmaceutical composition comprising an IL-4R antagonist experiences fewer asthma exacerbations (i.e., at least one fewer exacerbation) after treatment than before treatment, or does not experience an asthma exacerbation at least 4 weeks (e.g., 4, 6, 8, 12, 14 weeks or more) after initiation of treatment with the pharmaceutical composition. Alternatively, a "reduced incidence" of asthma exacerbations means that the likelihood of a subject experiencing an asthma exacerbation after administration of the pharmaceutical composition is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more) compared to a subject not administered the pharmaceutical composition.

[0099] The present invention includes a method for reducing the incidence of asthma exacerbations in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist and one or more maintenance doses of an inhaled corticosteroid (ICS) and / or one or more maintenance doses of a second controller, such as a long-acting beta-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., Flovent™), budesonide, mometasone (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™), etc. Suitable LTAs include, but are not limited to, montelukast (e.g., Singulaire™), zafirlukast (e.g., Accolate™), etc.

[0100] The present invention includes a method for reducing the incidence of asthma exacerbations in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist and administering to the subject one or more reliever agents to eliminate or reduce one or more asthma-related symptoms. Suitable reliever agents include, but are not limited to, fast-acting β2-adrenergic receptor agonists, such as albuterol (i.e., salbutamol, e.g., Proventil™, Ventolin™, Xopenex™, etc.), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), etc.

[0101] 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, the method comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist. and a method for improving a further asthma-related parameter, the method comprising administering to a subject a first pharmaceutical composition comprising an IL-33 antagonist and a second pharmaceutical composition comprising an IL-4R antagonist. Although (as discussed above) a reduced incidence of asthma exacerbations may correlate with an improvement in one or more asthma-related parameters; such a correlation may not be observed in all cases.

[0102] Examples of "asthma-related parameters" include: (1) the relative percent change from baseline (e.g., at week 12) in forced expiratory volume in one second (FEV1); (2) the relative percent change from baseline (e.g., at week 12) as measured by forced expiratory flow at lung capacity 25-75% (FEF25-75); (3) the annualized rate of loss of asthma control events during the treatment period; (4) the annualized rate of severe exacerbation events during the treatment period; (5) the time to loss of asthma control events during the treatment period; (6) the time to severe exacerbation events during the treatment period; (7) the number of loss of asthma control events during the entire study period. (8) time to severe exacerbation event during the entire study period; (9) healthcare resource utilization; (10) i) morning and evening asthma symptom score, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol per day to relieve symptoms, vi) change from baseline at week 12 in nighttime awakenings; (11) i) 22-item Nasal and Sinus Osseous Test (SNOT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) change from baseline at weeks 12 and 24 in the EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement in asthma-related parameters" means 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 nighttime wakefulness, or SNOT-22 score. As used herein, the term "baseline," with respect to asthma-related parameters, means the value of the asthma-related parameter for a patient before or at the time of administration of a pharmaceutical composition comprising an IL-33 antagonist, or the value of the asthma-related parameter for a patient before or at the time of administration to the subject of a first pharmaceutical composition comprising an IL-33 antagonist and a second pharmaceutical composition comprising an IL-4R antagonist.

[0103] To determine whether asthma-related parameters are "improved", the parameters are quantified at baseline and at a time point after administration of the pharmaceutical compositions described herein.For example, asthma-related parameters can be measured on 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, or fourteenth day, or on the third week, fourth week, fifth week, sixth week, seventh week, eighth week, ninth week, tenth week, eleventh week, twelfth week, thirteenth week, fourteenth week, fifteenth week, sixteenth week, seventeenth week, eighteenth week, nineteenth week, twentieth week, twenty-first week, twenty-two weeks, twenty-three weeks, twenty-fourth week, or more. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured) of the asthma-related parameter.

[0104] As used herein, the term "obtain" or "obtaining" means to gain possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, e.g., an asthma-related parameter. "Directly obtaining" means performing a method (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory from which the physical entity or value is obtained directly). Directly obtaining a physical entity includes obtaining the object. Directly obtaining a value includes performing a method that involves a physical change of a qualitative entity, e.g., a starting material. Exemplary changes include creating a physical entity from two or more starting materials, shearing 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. Directly obtaining a value includes performing a method that involves a physical change of a sample or another substance, e.g., performing an analytical method that involves a physical change of a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as "physical analysis").

[0105] Indirectly obtained information can be provided, for example, in the form of a report, provided in written or electronic form, e.g., an online database or application ("App"), etc. The report or information can be provided, for example, by a medical institution, e.g., a hospital or clinic; or a health care provider, e.g., a doctor or nurse.

[0106] Forced Exhausted Volume in One Second (FEV1). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in forced expiratory volume in one second (FEV1). Methods for measuring FEV1 are known in the art. For example, FEV1 can be measured in a patient using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. The ATS / ERS Standardization of Spirometry can be used as a guideline. Spirometry is typically performed between 6 and 10 AM after at least 6 hours of albuterol withdrawal. Pulmonary function tests are typically performed in the sitting position, and the peak reading is recorded as FEV1 (in liters).

[0107] The present invention includes a method of treatment that increases FEV1 from baseline by at least 0.05 L at 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist or a first pharmaceutical composition comprising an IL-33 antagonist and a second pharmaceutical composition comprising an IL-4R antagonist. For example, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist increases FEV1 from baseline by 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.

[0108] FEF 25-75%. According to certain embodiments, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient results in an increase from baseline in FEF of 25-75%. Methods for measuring FEF are known in the art. For example, FEV1 can be measured in a patient using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. FEF 25-75 (forced expiratory rate between 25% and 75%) is the rate (in liters per second) at which a person can empty the middle half of their air (i.e., forced vital capacity or FVC) during maximal expiration. The parameter relates to the average flow from the point at which 25 percent of the FVC is exhaled to the point at which 75 percent of the FVC is exhaled. A subject's FEF 25-75% can be calculated by: Small airwaysIt provides information regarding small airway function, such as the degree of disease and / or inflammation. Changes in FEF25-75 are an early indicator of obstructive pulmonary disease. In certain embodiments, the improvement and / or increase in the FEF25-75% parameter is at least a 10%, 25%, 50% or greater improvement compared to baseline. In certain embodiments, the methods of the present invention result in a normal FEF25-75% value in a subject (e.g., a value ranging from an average of 50-60% to 130%).

[0109] Morning and evening peak expiratory flow (AM PEF and PM PEF). According to certain embodiments, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient results in an increase from baseline in morning (AM) and / or evening (PM) peak expiratory flow (AM PEF and / or PM PEF). Methods for measuring PEF are known in the art. For example, according to one method of measuring PEF, a patient is provided with an electronic PEF meter to record morning (AM) and evening (PM) PEF (as well as daily albuterol use, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring rescue medication). The patient is instructed on the use of the device, and written instructions for use of the electronic PEF meter are provided to the patient. Additionally, a medical professional can instruct the patient on how to record the appropriate variables on the electronic PEF meter. AM PEF is typically performed within 15 minutes of waking (between 6 AM and 10 AM) before any albuterol administration. PM PEF is typically performed in the evening (between 6 PM and 10 PM) before any albuterol administration. Subjects should attempt to withhold albuterol for at least 6 hours before measuring their PEF. Three PEF efforts are performed by the patient, and all three values are recorded using an electronic PEF meter. The highest value is usually used for evaluation. Baseline AM PEF can be calculated as the average AM measurement recorded 7 days prior to administration of the first dose of a pharmaceutical composition comprising an IL-4R antagonist, and baseline PM PEF can be calculated as the average PM measurement recorded 7 days prior to administration of the first dose of a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0110] The present invention includes methods of treatment that result in an increase in AM PEF and / or PM PEF from baseline of at least 1.0 L / min 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist. For example, according to the present invention, administration of an IL-33 antagonist, or an IL-33 antagonist and 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 12 weeks.

[0111] Use of albuterol / levalbuterol. According to certain embodiments, administering an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient results in a reduction in daily albuterol or levalbuterol use from baseline. The number of inhalations of albuterol / levalbuterol can be recorded daily by the patient using a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, albuterol / levalbuterol can generally be used non-regularly or prophylactically as needed for symptoms. The baseline number of inhalations of albuterol / levalbuterol per day can be calculated based on the average of the 7 days prior to administration of the first dose of a pharmaceutical composition containing an IL-4R antagonist.

[0112] The present invention includes methods of treatment that result in a reduction in albuterol / levalbuterol use from baseline of at least 0.25 puffs per day 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist or a first pharmaceutical composition comprising an IL-33 antagonist and a second pharmaceutical composition comprising an IL-4R antagonist. For example, a method of treatment with an IL-33 antagonist or a first pharmaceutical composition comprising an IL-33 antagonist and an IL-4R antagonist can be used. Administration of levalbuterol / levalbuterol to a subject in need thereof results in a reduction in albuterol / levalbuterol use from baseline by about 0.25 puffs per day, 0.50 puffs per day, 0.75 puffs per day, 1.00 puffs per day, 1.25 puffs per day, 1.5 puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day or more at 12 weeks.

[0113] Use of OCS. According to certain embodiments, the administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient can be used in conjunction with an OCS, such as oral prednisone. The number of OCS doses can be recorded daily by the patient using a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, occasional short-term use of prednisone can generally be used to control acute asthma episodes, such as episodes in which bronchodilators and other anti-inflammatory agents fail to control symptoms. In other aspects, prednisone is used simultaneously with or as a substitute for ICS. Oral prednisone can be administered at a dosage of approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. The OCS can be administered once daily or multiple times daily (e.g., twice daily, three times daily, four times daily, etc.), as appropriate.

[0114] In certain exemplary embodiments, the present invention provides methods for reducing or eliminating a subject's dependence on OCS use. Reducing or eliminating steroid dependence is highly advantageous and desirable. In certain embodiments, a 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or greater) reduction in OCS dosage is achieved after administration of IL-4R antibody therapy at a certain time period (e.g., at week 240). In certain embodiments, OCS is substantially eliminated 40, 45, 50, 52, or more weeks after administration of the first dose after administration of the initial dose. In other embodiments, the level of OCS use is reduced to less than 5 mg per day (e.g., less than 5 mg, 4 mg, 3 mg, 2 mg, or less per day). In other embodiments, dependence on OCS use is substantially eliminated 3 months, 6 months, 9 months, or 1 year after treatment with an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0115] 5-item Asthma Control Questionnaire (ACQ) score. According to certain embodiments, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient results in a decrease from baseline in the 5-item Asthma Control Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[0116] The present invention includes methods of treatment that result in a reduction in ACQ5 score from baseline of at least 0.10 points at 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist. For example, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a subject in need thereof results in a reduction in ACQ score from baseline 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 at 12 weeks.

[0117] According to certain embodiments, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient reduces average nighttime wakefulness. Produces a reduction from baseline in the number of wakefulness episodes.

[0118] In certain embodiments, the method reduces the average number of nighttime awakenings from baseline by at least about 0.10-fold per night 12 weeks after initiation of treatment. For example, administration of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a subject in need thereof may result in a decrease from baseline in the mean number of nighttime wakes 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.

[0119] 22-item Nasal and Sinus Occlusion Test (SNOT-22) score. According to certain embodiments, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient results in a reduction from baseline in the 22-item Nasal and Sinus Occlusion Test (SNOT-22). The SNOT-22 is a validated questionnaire that assesses the impact of chronic rhinosinusitis on quality of life (Hopkins et al., 2009, Clin. Otolaryngol. 34:447-454).

[0120] The present invention includes methods of treatment that result in a reduction in SNOT-22 score from baseline of at least 1 point at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist. For example, administration of an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist to a subject in need thereof may result in about a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more point reduction in SNOT-22 score from baseline at week 12.

[0121] Biomarkers. In certain embodiments, subjects experience improved pulmonary function as measured by a biomarker. For example, the biomarker can be exhaled nitric oxide (FeNO), eotaxin-3, total IgE, periostin, or thymus and activation-regulated chemokine (TARC). In certain embodiments, the improved pulmonary function is indicated by a decrease or increase (as appropriate) at 4 weeks, 12 weeks, or 24 weeks after treatment.

[0122] Methods for treating asthma In some embodiments, the present invention provides a method for treating asthma, including, for example, moderate to severe asthma, in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist. In certain embodiments, the method is useful for treating moderate to severe asthma in a subject.

[0123] As used herein, the term " asthma " can be used interchangeably with " intermittent asthma " or " bronchial asthma ". " Asthma ", " bronchial asthma " and " intermittent asthma " refer to the asthma that one or any combination of the following applies: symptoms occur 2 days or several days per week; symptoms do not interfere with daily activities; nighttime symptoms occur less than 2 days per month; or one or more pulmonary function tests (for example, forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF) greater than 80%) are normal when the subject does not suffer from asthma attacks.

[0124] As used herein, the term "persistent asthma" or "persistent bronchial asthma" refers to a respiratory illness characterized by: Persistent asthma refers to asthma that is more severe than intermittent (bronchial) asthma / intermittent (bronchial) asthma. Subjects suffering from persistent asthma or persistent bronchial asthma experience one or more of the following: symptoms more than 2 days per week; symptoms that interfere with daily activities; nighttime symptoms that occur more than 2 days per month; or one or more pulmonary function tests that are not normal when the subject is not experiencing an asthma attack (e.g., forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF) less than 80%); the subject is dependent on daily asthma control medication; the subject has taken systemic steroids more than once since the last year of severe asthma exacerbation; or the use of short-acting beta-2 agonists to relieve asthma symptoms more than 2 days per week.

[0125] Asthma / intermittent asthma, bronchial asthma / intermittent asthma, and persistent asthma / persistent asthma can be classified as "mild," "moderate," "severe," or "moderate-to-severe." "Mild intermittent asthma" or "mild intermittent asthma" is defined as having symptoms less than once a week and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of ≥ 80%. "Mild persistent asthma" or "mild persistent asthma" differs in that symptoms occur more frequently than once a week but less than once a day, with FEV1 or PEF variability of < 20%-30%. "Moderate intermittent asthma" or "moderate intermittent asthma" is defined as having symptoms less than once a week and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60-80%. "Moderate persistent asthma" or "moderate persistent asthma" is defined as having daily symptoms, exacerbations that may affect activity and / or sleep, nocturnal symptoms more than once a week, daily use of inhaled short-acting beta-2 agonists, and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60-80%. "Severe intermittent asthma" or "severe intermittent asthma" is defined as having symptoms less than once a week and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60%. "Severe persistent asthma" or "severe persistent asthma" is defined as having daily symptoms, frequent exacerbations that may affect activity and / or sleep, frequent nocturnal symptoms, limited physical activity, daily use of inhaled short-acting beta-2 agonists, and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60%. "Moderate to severe intermittent asthma" or "moderate to severe intermittent asthma" is defined as having symptoms between those of moderate intermittent asthma / moderate intermittent asthma and those of severe intermittent asthma / severe intermittent asthma. "Moderate to severe persistent asthma" or "moderate to severe persistent asthma" is defined as having symptoms between those of moderate persistent asthma / moderate persistent asthma and those of severe persistent asthma / severe persistent asthma.

[0126] As used herein, the term "inadequately controlled asthma" refers to patients whose asthma is "inadequately controlled" or "very poorly controlled," as defined by "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma," National Heart, Blood and Lung Institute, NIH, August 28, 2007. "Inadequately controlled asthma" is defined as symptoms more than two days per week, one to three nighttime awakenings per week, some limitation in normal activity, use of short-acting beta-agonists for symptom control more than two days per week, FEV1 between 60% and 80% predicted and / or personal best, ATAQ score of 1 to 2, ACQ score of 1.5 or greater, and ACT score of 16 to 19. "Very poorly controlled asthma" is defined as daytime symptoms, four or more nighttime awakenings per week, severe limitation of normal activities, use of short-acting beta-agonists several times per day for symptom control, FEV1 less than 60% predicted and / or personal best, ATAQ score 3-4, ACQ score N / A, and ACT score 15 or less.

[0127] In some embodiments, the subject meets the Global Initiative for Asthma (GINA) 2009 guidelines and one or more of the following criteria: i) existing treatment with a moderate to high dose of ICS / LABA (fluticasone dipropionate 250 μg twice daily or an equipotent daily dose of ICS) with a stable dose of ICS / LABA for more than one month prior to administration of the first dose of the IL-33 antagonist or the first doses of the IL-33 antagonist and the IL-4R antagonist; ii) an FEV1 of 40-80% of predicted normal prior to administration of the first dose of the IL-33 antagonist or the first doses of the IL-33 antagonist and the IL-4R antagonist; iii) an ACQ-5 score of 1.5 or greater prior to administration of the first dose of the IL-33 antagonist or the first doses of the IL-33 antagonist and the IL-4R antagonist; iv) at least 12% and 200 mL reversibility in FEV1 after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations) prior to administration of the initial dose of the IL-33 antagonist or the initial dose of the IL-33 antagonist and the IL-4R antagonist; or v) a subject is identified as having "moderate to severely uncontrolled" asthma if they have a physician diagnosis based on experiencing any of the following events within one year prior to administration of the initial dose of the IL-33 antagonist or the initial dose of the IL-33 antagonist and the IL-4R antagonist: (a) treatment with one or more systemic (oral or parenteral) steroid bursts for worsening asthma, (b) hospitalization or emergency / urgent medical visit for worsening asthma.

[0128] "Severe asthma" refers to asthma in which adequate control cannot be achieved by high-dose treatment with inhaled corticosteroids and an additional controller (e.g., a long-acting inhaled beta-2 agonist, montelukast, and / or theophylline) or by oral corticosteroid treatment (e.g., for at least 6 months per year), or is lost if treatment is reduced. In certain embodiments, severe asthma includes asthma treated with high-dose ICS and at least one additional controller (e.g., a LABA, montelukast, or theophylline) or oral corticosteroids for more than 6 months per year, and in which at least one of the following occurs or would occur if treatment were reduced: ACT<20 or ACQ>1.5; at least two exacerbations in the past 12 months; at least one exacerbation in the past 12 months requiring hospital treatment or mechanical ventilation; or (if FEV1 / FVC is below the lower limit of normal) FEV1<80%.

[0129] "Steroid-dependent asthma" refers to asthma that requires one or more of the following treatments: frequent, short-term oral corticosteroid treatment bursts in the past 12 months; regular use of high-dose inhaled corticosteroids in the past 12 months; regular use of injected long-acting corticosteroids; daily use of oral corticosteroids; alternate-day oral corticosteroids; or long-term use of oral corticosteroids within the past year.

[0130] "Oral corticosteroid-dependent asthma" refers to subjects with ≥ 3 30-day oral corticosteroid (OCS) fills over a 12-month period and a primary asthma diagnosis within 12 months of the first OCS fill. Subjects with OCS-dependent asthma were defined as those receiving a physician-prescribed LABA and high-dose ICS (total daily dose >500 μg fluticasone propionate dry powder combination equivalent) for at least 3 months (ICS and LABA can be part of a combination product or can be administered by separate inhalers); receiving additional maintenance asthma controller medications per standard medical practice, e.g., leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), second-line ICS, and cromones; receiving an OCS for the treatment of asthma at a dose between ≥7.5 and ≤30 mg (prednisone or prednisolone equivalent); receiving an OCS dose administered every other day (or a different dose every other day); a morning pre-bronchodilator (BD) FEV1 <80% of predicted normal; or a BD (albuterol Evidence of asthma as described by a reversible FEV1 ≥ 12% and ≥ 200 mL (15-30 minutes after 4 puffs of albuterol / salbutamol); or a history of at least one exacerbation of asthma within 12 months.

[0131] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient having a blood eosinophil level of at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0132] In another aspect, a method for treating asthma is provided, comprising: (a) selecting a patient having a blood eosinophil level of 150 to 299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0133] In another aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 150 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0134] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting low levels of periostin; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0135] In another aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting high levels of periostin; and (b) administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0136] As used herein, "high levels of periostin" refers to blood periostin measurements of about 60 ng / mL or more, about 65 ng / mL or more, about 70 ng / mL or more, about 75 ng / mL or more, or about 80 ng / mL or more, about 85 ng / mL or more, about 90 ng / mL or more, about 95 ng / mL or more, or about 100 ng / mL or more. In specific exemplary embodiments, high levels of periostin are about 75.0 ng / mL or more or about 74.4 ng / mL or more.

[0137] As used herein, "low levels of periostin" refers to blood periostin measurements of less than about 100 ng / mL, less than about 95 ng / mL, less than about 90 ng / mL, less than about 85 ng / mL, less than about 80 ng / mL, less than about 75 ng / mL, less than about 70 ng / mL, less than about 65 ng / mL, or less than about 60 ng / mL. In specific exemplary embodiments, low levels of periostin are less than about 75.0 ng / mL or less than about 74.4 ng / mL.

[0138] In a related aspect, methods for treating asthma are provided that include add-on therapy to baseline therapy. In certain embodiments, an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist are administered as add-on therapy to an asthma patient who is receiving baseline therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months or more) (also referred to as a "stable phase"). In some embodiments, the baseline therapy includes an ICS and / or a LABA.

[0139] In some embodiments, the present invention comprises a method for reducing an asthma patient's dependence on ICS and / or LABA for the treatment of one or more asthma exacerbations, comprising: (a) selecting a patient with moderate to severe asthma that is not adequately controlled with background asthma therapy comprising an ICS, a LABA, or a combination thereof; and administering to the patient a pharmaceutical composition comprising an IL-33 antagonist or an IL-33 antagonist and an IL-4R antagonist.

[0140] In some embodiments, the present invention encompasses methods of treating or alleviating conditions or complications associated with asthma, such as chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, allergic bronchopulmonary aspergillosis, unified airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD), and exercise-induced bronchospasm.

[0141] The present invention also includes a method for treating persistent asthma.As used herein, the term "persistent asthma" means that the subject experiences symptoms at least once a week during the day and / or at night, and these symptoms last from a few hours to several days.In certain alternative embodiments, persistent asthma is "mild persistent" (for example, symptoms that are severe enough to interfere with daily activities or sleep occur more than twice a week, but less than every day, and / or lung function is normal or reversible by inhaling bronchodilators), "moderate persistent" (for example, symptoms that interfere with sleep at least once a week and / or moderately abnormal lung function occur every day), or "severe persistent" (for example, symptoms persist despite the correct use of approved medications and / or lung function is seriously affected).

[0142] Interleukin-33 (IL-33) antagonist and interleukin-4 receptor (IL-4R) antagonist The methods featured in the invention include administering to a subject in need thereof a therapeutic composition comprising an IL-33 antagonist. As used herein, an "IL-33 antagonist" is any agent that binds to or interacts with IL-33 and inhibits the normal biological signaling function of IL-33 when expressed in cells in vitro or in vivo.

[0143] The methods featured in the present invention optionally include administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when expressed in cells in vitro or in vivo.

[0144] Non-limiting examples of categories of IL-33 antagonists and IL-4R antagonists include small molecule IL-33 antagonists, small molecule IL-4R antagonists, anti-IL-33 aptamers, anti-IL-4R aptamers, peptide-based IL-33 antagonists or peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-33 or human IL-4R.

[0145] According to certain embodiments, the IL-33 antagonist comprises an anti-IL-33 antibody or antigen-binding fragment thereof that can be used in the context of the methods featured in the present invention, as described elsewhere herein. For example, in one embodiment, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and comprises a heavy chain variable region (HCVR) and a light chain variable region (HCVR) of SEQ ID NOs: 2 and 10. In another embodiment, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and comprises the heavy and light chain CDR sequences of SEQ ID NOs: 4, 5, and 6 and SEQ ID NOs: 12, 14, and 16, respectively. In another embodiment, the IL-33 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and comprises the HCVR / LCVR pairs of SEQ ID NOs: 2 and 10, respectively.

[0146] aggtgcagct ggtggagtct gggggaaact tggaacagcc tggggggtcc cttagactct cctgtacagc ctctggattc acctttagca gatctgccat gaactgggtc cgccgggctc cagggaaggg gctggagtgg gtctcaggaa ttagtggtag tggtggtcga acatactacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaat acgctatatc tgcaaatgaa cagcctgagc gccgaggaca cggccgcata ttactgtgcg aaagattcgt atactaccag ttggtacgga ggtatggacg tctggggcca cgggaccacg gtcaccgtct cctca (SEQ ID NO: 1), SAR440340 HCVR, DNA sequence.

[0147] VQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMDVWGHGTTVTVSS (SEQ ID NO: 2), SAR440340 HCVR, amino acid sequence.

[0148] gattcacctt tagcagatct gcc (SEQ ID NO: 3), SAR440340 HCDR1, DNA sequence.

[0149] FTFSRSA (SEQ ID NO: 4), SAR440340 HCDR1, amino acid sequence.

[0150] ttagtggtag tggtggtcga aca (SEQ ID NO: 5), SAR440340 HCDR2, DNA sequence.

[0151] SGSGGRT (SEQ ID NO: 6), SAR440340 HCDR2, amino acid sequence.

[0152] cgaaagattc gtatactacc agttggtacg gaggtatgga cgtc (SEQ ID NO: 7), SAR440340 HCDR3, DNA sequence.

[0153] KDSYTTSWYGGMDV (SEQ ID NO: 8), SAR440340 HCDR3, amino acid sequence.

[0154] acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac agagtcacca tcacttgtcg ggcgagtcag ggtattttca gctggttagc ctggtatcag cagaaaccag gaaaagcccc taagctcctg atctatgctg cttccagttt acaaagtggg gtcccatcaa gattcagcgg cagtggatct gggacagatt tcactctcac catcagcagc ctgcagcctg aggattttgc aatttactat tgtcaacagg ctaacagtgt cccgatcacc ttcggccaag ggacacgact ggagattaaa cga (SEQ ID NO: 9), SAR440340 LCVR, DNA sequence;

[0155] IQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEIKR (SEQ ID NO: 10) SAR440340 LCVR, amino acid sequence.

[0156] agggtatttt cagctgg (SEQ ID NO: 11), SAR440340 LCDR1, DNA sequence.

[0157] GIFSW (SEQ ID NO: 12), SAR440340 LCDR1, amino acid sequence.

[0158] ctgcttcc (SEQ ID NO: 13), SAR440340 LCDR2, DNA sequence.

[0159] AS (SEQ ID NO: 14), SAR440340 LCDR2, amino acid sequence.

[0160] aacaggctaa cagtgtcccg atcacc (SEQ ID NO: 15), SAR440340 LCDR3, DNA sequence.

[0161] QANSVPIT (SEQ ID NO: 16), SAR440340 LCDR3, amino acid sequence.

[0162] aggtgcagct ggtggagtct gggggaaact tggaacagcc tggggggtcc cttagactct cctgtacagc ctctggattc acctttagca gatctgccat gaactgggtc cgccgggctc cagggaaggg gctggagtgg gtctcaggaa ttagtggtag tggtggtcga acatactacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaat acgctatatc tgcaaatgaa cagcctgagc gccgaggaca cggccgcata ttactgtgcg aaagattcgt atactaccag ttggtacgga ggtatggacg tctggggcca cgggaccacg gtcaccgtct cctcagcctc caccaagggc ccatcggtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg ggctgcctgg tcaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacccttcccggct gtcctacaggcta cccggact tgaccgtgcc ctccagcagc tgggcacga agacctacac ctgcaacgta gatcacaagc ccagcacac caggtggac agagagttg agtccaata tggccccca tgcccacct gcccagcacc agagttccctg gggggaccac gcggatccccacct acccctgagg tcacgtgcgt gtggtggac gtgagccagg agaccccga ggtccagttc aactgtacg tggatgcgt ggaggtgcat aatgccaga aaagccgcg ggaggagcag ttcacagca cgtaccgtgt ggtcagcgtc ctcacctcc aggcacctcc tgcaccagga ctcaggcagcaacacac aaaggcctcc cgtcctccat cgagaaaacc atctccaag ccaagggca gccccgagag ccacaggtgt acac cctgcc cccatcccag gaggagatga ccagaacca ggtcagcctg acctgcctgg tcaaggctt ctaccccagc gatacgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc ctctacagca ggctcaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac tacacacaga agtccctctc cctgtctctg ggtaaatga (SEQ ID NO: 17), SAR440340 heavy chain DNA sequence.

[0163] VQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTYYADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMDVWGHGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 18), SAR440340 heavy chain amino acid sequence.

[0164] acatccagat gacccagtct ccatcttccg tgtctgcatc tgtaggagac agagtcacca tcacttgtcg ggcgagtcag ggtattttca gctggttagc ctggtatcag cagaaaccag gaaaagcccc taagctcctg atctatgctg cttccagttt acaaagtggg gtcccatcaa gattcagcgg cagtggatct gggacagatt tcactctcac catcagcagc ctgcagcctg aggattttgc aatttactat tgtcaacagg ctaacagtgt cccgatcacc ttcggccaag ggacacgact ggagattaaa cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag(SEQ ID NO: 19), the light chain DNA sequence of SAR440340.

[0165] IQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), SAR440340 heavy chain amino acid sequence.

[0166] According to certain embodiments, the IL-4R antagonist comprises an anti-IL-4R antibody or antigen-binding fragment thereof that can be used in the context of the methods featured in the present invention, as 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 the 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: 27 and 28, respectively. In another embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises the heavy and light chain CDR sequences of SEQ ID NOs: 21, 22, and 23 and SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises the HCVR / LCVR pairs of SEQ ID NOs: 27 and 28, respectively.

[0167] GFTFRDYA (SEQ ID NO: 21), dupilumab HCDR1 amino acid sequence.

[0168] ISGSGGNT (SEQ ID NO: 22), dupilumab HCDR2 amino acid sequence.

[0169] AKDRLSITIRPRYYGL (SEQ ID NO: 23), dupilumab HCDR3 amino acid sequence.

[0170] QSLLYSIGYNY (SEQ ID NO: 24), dupilumab LCDR1 amino acid sequence.

[0171] LGS (SEQ ID NO: 25), dupilumab LCDR2 amino acid sequence.

[0172] MQALQTPYT (SEQ ID NO: 26), dupilumab LCDR3 amino acid sequence.

[0173] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 27), the dupilumab HCVR amino acid sequence.

[0174] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 28), the dupilumab LCVR amino acid sequence.

[0175] The term "human IL-33" (hIL-33) refers to a human cytokine receptor that specifically binds interleukin-33 (IL-33). The term "human IL-4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), e.g., IL-4Rα.

[0176] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region is made up of three domains: C H 1. C H 2, and C HEach light chain comprises a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The region can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). H and V L The following order: FR1 Each CDR is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus as follows: CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of an anti-IL-33 antibody, an anti-IL-4R antibody, or an antigen-binding portion thereof, may be identical to the human germline sequence or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on side-by-side analysis of two or more CDRs.

[0177] The term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, for example, from intact antibody molecules using any appropriate standard technique, for example, proteolytic digestion or recombinant genetic engineering techniques employing the manipulation and expression of DNA-encoded antibody variable and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated, for example, by using chemical or molecular biology techniques to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine residues, modify, add, or delete amino acids.

[0178] Non-limiting examples of antigen-binding fragments include, but are not limited to: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the scope of the term "antigen-binding fragment."

[0179] Antigen-binding fragments of antibodies generally contain at least one variable domain, which may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. L V related to domain H In an antigen-binding fragment having a domain, V H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody contains a monomeric V dimer. H or V L It may include a domain.

[0180] In certain embodiments, an antigen-binding fragment of an antibody comprises at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found within the antigen-binding fragments of antibodies described herein include: (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)V L -C H 2;(x)VL -C H 3;(xi)V L -C H 1-C H 2;(xi i)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 arrangement of variable and constant domains, including any of the exemplary arrangements 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 connection between adjacent variable and / or constant domains in a single polypeptide molecule; typically, the hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Furthermore, antigen-binding fragments of antibodies described herein may be linked to each other and / or to one or more monomeric V H Or V L The domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above in non-covalent association (e.g., via disulfide bonds).

[0181] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally comprise at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antigen-binding fragments of antibodies described herein using routine techniques available in the art.

[0182] 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.

[0183] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies featured in the present invention may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0184] The term "recombinant human antibody" includes all human antibodies produced, expressed, created, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, created, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) to thereby modify the V and V regions of the recombinant antibody. Hand V L The amino acid sequence of the region is human germline V H and V L When derived from and related to sequences, they are sequences that cannot naturally occur within the human antibody germline repertoire in vivo.

[0185] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a suitable four-chain construct of approximately 150-160 kDa in which dimers are linked by interchain heavy chain disulfide bonds. In the second form, dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75-80 kDa composed of covalently linked light and heavy chains (half-antibodies) is formed. These forms are extremely difficult to separate, even after affinity purification.

[0186] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level commonly observed with human IgG1 hinges. The present invention provides a method for the detection of the second form by using a single amino acid substitution in the hinge region of a human IgG4 hinge. H 2, or C H Antibodies with one or more mutations in the three regions are included, which may be desirable, for example, to improve the yield of the desired antibody form in manufacturing.

[0187] 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 an antibody that has been separated or removed from the tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0188] The term "specifically binds" or the like 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" IL-33 or IL-4R as characterized in the present invention includes an antibody, or a portion thereof, that binds to IL-33 or IL-4R, respectively, and is capable of binding to K. D is less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-33 or human IL-4R may have cross-reactivity to other antigens, for example, IL-33 or IL-4R molecules obtained from other (non-human) species.

[0189] Anti-IL-33 and anti-IL-4R antibodies useful for the present 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 antibodies are derived. Such mutations can be readily identified 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, including those that contain one or more framework mutations. and / or one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) within one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a tetrameric antibody or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) CDR regions are mutated to the corresponding residue in the germline sequence from which the antibody is 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 changes 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 numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, the V H and / or V LAll of the framework and / or CDR residues within a domain are mutated back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, and certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0190] The present invention also includes methods involving the use of anti-IL33 or anti-IL-4R antibodies that contain variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the present invention includes the use of anti-IL-4R antibodies that have HCVR, LCVR, and / or CDR amino acid sequences with, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0191] The term "surface plasmon resonance" refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0192] The term “K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0193] 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 can have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acids in a polypeptide chain. In certain circumstances, an epitope can include a sugar, phosphoryl, or sulfonyl moiety on an antigen.

[0194] Human antibody production Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to generate human antibodies that specifically bind human IL-33 or human IL-4R.

[0195] Using VELOCIMMUNE® technology (see, e.g., U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, high-affinity chimeric antibodies to IL-33 or IL-4R having human variable regions and mouse constant regions are first isolated. VELOCIMMUNE® technology involves the generation of transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0196] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphoid cells (e.g., B cells) are harvested from the mice that express the antibody. The lymphoid cells can be fused with a myeloma cell line to produce an immortal hybridoma cell line, which is screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions can be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells, e.g., CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0197] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for desired characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody characterized in the present invention, such as a wild-type or modified IgG1 or IgG4. The constant region selected can vary depending on the particular use, with the characteristics of high-affinity antigen binding and target specificity residing in the variable region.

[0198] Generally, antibodies that can be used in this method have high affinity, as measured by binding to an antigen immobilized in a solid phase or in a solution phase, as described above. The mouse constant region is replaced with a desired human constant region to produce a fully human antibody characterized in this invention. The constant region selected may vary depending on the specific use, and the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0199] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds IL-33 that can be used in the context of the methods featured in the 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: 2. The antibody or antigen-binding fragment can 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: 10. In another embodiment, a human antibody or antigen-binding fragment thereof that specifically binds IL-4R that can be used in the context of the methods featured in the invention can 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: 10. The heterologously binding human antibody or antigen-binding fragment thereof 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: 27. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 28.

[0200] Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the designated HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence 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. See, e.g., 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.

[0201] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) derived from the heavy and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 2 and 10.

[0202] 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: 4 / 5 / 6 / 12 / 14 / 16.

[0203] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:2 and 10.

[0204] In one embodiment, the antibody is SAR440340, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 2 and 10.

[0205] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) derived from the heavy chain and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 27 and 28.

[0206] 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: 21 / 22 / 23 / 24 / 25 / 26.

[0207] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:27 and 28.

[0208] In one embodiment, the antibody is dupilumab, comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 27 and 28.

[0209] Pharmaceutical Composition The present invention includes methods comprising administering to a patient an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, wherein the IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, is contained within a pharmaceutical composition. The pharmaceutical compositions featured in the present invention are formulated with suitable carriers, additives, and other agents that provide suitable transport, delivery, tolerance, etc. Many suitable formulations can be found in formularies known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J. Pharm. Sci. Technol. 52:238-311.

[0210] The dose of an antibody administered to a patient may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. Doses are 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. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-33 antibodies or anti-IL-4R antibodies can be determined empirically. For example, the patient's progress can be monitored by periodic evaluation, and the dosage adjusted as appropriate. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0211] Various delivery systems are known and can be used to administer the pharmaceutical compositions featured in the present invention, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). 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.

[0212] The pharmaceutical compositions featured in the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, pen delivery devices (e.g., pen autoinjectors) are easily adapted to deliver the pharmaceutical compositions featured in the present invention. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, disposable pen delivery devices are pre-filled with the pharmaceutical composition, which is held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0213] A number of reusable pen and autoinjector delivery devices find use in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, AUTOPEN™ (Owen 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 Noirdisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Noirdisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN, to name just a few. STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices that find use in subcutaneous delivery of the pharmaceutical compositions featured in the present invention include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (vodka), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name just a few. Examples of large-volume delivery devices (e.g., large-volume injectors) include, but are not limited to, bolus injectors, e.g., BD Libertas West These include SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, and Bespak Lapas.

[0214] For direct administration to the sinuses, the pharmaceutical compositions featured in the present invention may be administered using, for example, a microcatheter (e.g., an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. The method includes administering an IL-33 antagonist or an IL-4R antagonist in the form of an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-33 or IL-4R may be administered to treat asthma in a patient. Aerosolized antibodies can be produced, for example, as described in U.S. Patent No. 8,178,098, the entire contents of which are incorporated herein by reference.

[0215] 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 other embodiments, controlled release systems can be placed near the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, 2:115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0216] Injectable preparations include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, intravenous drip infusions, etc. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying an antibody or a salt thereof as described above in a sterile aqueous or oily medium commonly used for injections. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose, and other adjuvants, which can be used in combination with appropriate solubilizers, such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. Oily media include, for example, sesame oil and soybean oil, which may be used in combination with solubilizers, such as benzyl benzoate and benzyl alcohol. The injections prepared in this manner are generally filled into appropriate ampoules.

[0217] Advantageously, the aforementioned pharmaceutical compositions for oral or parenteral use are prepared in dosage forms with unit doses suitable for the dose of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0218] 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.

[0219] Dosage The amount of an IL-33 antagonist (e.g., an anti-IL-33 antibody or antigen-binding fragment thereof) or an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) administered to a subject according to the methods featured in the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of an IL-33 antagonist or an IL-4R antagonist that results in one or more of the following: (a) a reduction in the incidence of asthma exacerbations; (b) an improvement in one or more asthma-related parameters (as defined elsewhere herein); and / or (c) a detectable improvement in one or more symptoms or signs of an upper airway inflammatory condition. A "therapeutically effective amount" also includes an amount of an IL-33 antagonist or an IL-4R antagonist that suppresses, prevents, reduces, or delays the progression of asthma in a subject.

[0220] In the case of an anti-IL-33 antibody or an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 700 mg of the anti-IL-33 antibody or 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 700 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 2 mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, 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 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about The dose may be 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 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 certain embodiments, 300 mg of an anti-IL-33 antibody is administered. In certain embodiments, 300 mg of an anti-IL-33 antibody and 300 mg of an anti-IL-4R antibody are administered.

[0221] The amount of IL-33 antagonist or IL-4R antagonist contained within a particular dose range can be expressed in terms of 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 per kg of patient body weight. For example, the IL-33 antagonist or IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, or 4 mg / kg.

[0222] In some embodiments, the dose of the IL-4R antagonist may vary depending on the eosinophil count. For example, the subject may have a blood eosinophil count of ≥ 300 cells / μL (high blood eosinophils), or 300-499 cells / μL, or ≥ 500 cells / μL (HEos); a blood eosinophil count of 200-299 cells / μL (moderate blood eosinophils); or a blood eosinophil count of < 200 cells / μL (low blood eosinophils).

[0223] In some embodiments, the dose of the IL-4R antagonist can vary depending on periostin levels. For example, a subject can have high periostin levels (e.g., ≥ 75.0 ng / mL or 74.4 ng / mL) or low periostin levels (e.g., < 75.0 ng / mL or < 74.4 ng / mL).

[0224] In certain embodiments, the methods include an initial dose of about 200 to about 600 mg of an IL-33 antagonist, e.g., about 300 mg of an IL-33 antagonist. In certain embodiments, the methods include an initial dose of about 200 to about 600 mg of an IL-4R antagonist, e.g., about 300 mg of an IL-4R antagonist.

[0225] In certain embodiments, the methods include one or more maintenance doses of about 200 to about 300 mg of an IL-33 antagonist. In certain embodiments, the methods include one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0226] In certain embodiments, the ICS and LABA are administered for the duration of administration of the IL-33 antagonist. In certain embodiments, the ICS and LABA are administered for the duration of administration of the IL-4R antagonist.

[0227] In certain embodiments, the initial dose comprises 300 mg of the anti-IL-33 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 other week.

[0228] In certain embodiments, the initial dose comprises 300 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 other week.

[0229] In other embodiments, the initial dose comprises 300 mg of the anti-IL-33 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.

[0230] In other embodiments, the initial dose comprises 300 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.

[0231] In other embodiments, the initial dose comprises 300 mg of the anti-IL-33 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.

[0232] In other embodiments, the initial dose comprises 300 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.

[0233] In other embodiments, the initial dose comprises 300 mg of the anti-IL-33 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.

[0234] In other embodiments, the initial dose comprises 300 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.

[0235] In one embodiment, the subject is 6 to <18 years old and the IL-33 antibody or antigen-binding fragment thereof or IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0236] In one embodiment, the subject is 12 to <18 years of age and the IL-33 antibody or antigen-binding fragment thereof or IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0237] In one embodiment, the subject is 6 to <12 years old and the IL-33 antibody or antigen-binding fragment thereof or IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0238] In one embodiment, the subject is 2 to <6 years old and the IL-33 antibody or antigen-binding fragment thereof or IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0239] In still other embodiments, the subject is <2 years old and the IL-33 antibody or antigen-binding fragment thereof or IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0240] Combination therapy Certain embodiments of the methods featured in the present invention include administering to a subject one or more additional therapeutic agents in combination with an IL-33 antagonist, or one or more additional therapeutic agents in combination with an IL-33 antagonist and 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 an IL-4R antagonist or a pharmaceutical composition comprising an IL-33 antagonist and an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, and an additional therapeutic agent. The present invention includes a method of treating asthma or a related condition or complication or reducing at least one exacerbation, comprising administering an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, in combination with an additional therapeutic agent for additive or synergistic activity.

[0241] For example, when administered "before" a pharmaceutical composition comprising an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, the additional therapeutic agent may inhibit IL-3 The 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 a pharmaceutical composition comprising an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist. When administered "after" the administration of the IL-33 antagonist, or the pharmaceutical composition comprising an IL-33 antagonist and 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 IL-33 antagonist, or the pharmaceutical composition comprising an IL-33 antagonist and an IL-4R antagonist. Administration "concurrently with" an IL-33 antagonist, or a pharmaceutical composition comprising an IL-33 antagonist and 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 IL-33 antagonist, or the pharmaceutical composition comprising an IL-33 antagonist and an IL-4R antagonist, or is administered to the subject as a combined single-dose formulation comprising the additional therapeutic agent and the IL-33 antagonist, or the IL-33 antagonist and the IL-4R antagonist.

[0242] The additional therapeutic agent can be, for example, another IL-33 antagonist, 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, or the like. The therapeutic agent may be an agonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal, an NSAID, a long-acting beta-2 agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), a methylxanthine, nedocromil sodium, cromolyn sodium, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist, or an IL-33 antagonist and an IL-4R antagonist, is administered in a combination that includes a long-acting β2 agonist and an inhaled corticosteroid (e.g., fluticasone plus salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide plus formoterol [e.g., SYMBICORT® (Astra Zeneca)]).

[0243] Dosing regimen According to certain embodiments, multiple doses of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, may be administered to a subject over a defined time course. Such methods include sequentially administering multiple doses of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a subject. As used herein, "sequentially administered" means that each dose of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, is administered to a subject at different time points, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Included are methods comprising sequentially administering to a patient a single initial dose of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, followed by one or more second doses of the IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, optionally followed by one or more third doses of the IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.

[0244] The present invention provides a method for administering the drug about 4 times a week, twice a week, once a week (q1w), or every other week (once every two weeks or q2w). , once every 3 weeks (every 3 weeks or q3w), once every 4 weeks (monthly or q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 8 weeks (q8w), once every 12 weeks (q12w), or less frequently until a therapeutic effect is achieved. In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, weekly dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, biweekly dosing (dosing once every two weeks) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, once every three weeks in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, once every four weeks (dosing every month) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, a once-every-five-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 the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, a once-every-six-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 the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, a once-every-eight-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 the administration of a pharmaceutical composition comprising an anti-IL-33 antibody or an anti-IL-4R antibody, a once-every-twelve-weekly dose 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.

[0245] 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 weeks or more.

[0246] The terms "initial dose," "second dose," and "third dose" refer to the time sequence of administration of an IL-4R antagonist. Thus, the "initial dose" refers to the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"); the "second dose" refers to the dose administered after the initial dose; and the "third dose" refers to the dose administered after the second dose. The initial dose, the second dose, and the third dose can all contain the same amount of IL-33 antagonist or IL-4R antagonist, but generally may differ from each other in terms of the number of administrations. However, in certain embodiments, the amount of IL-33 antagonist or IL-4R antagonist contained in the initial dose, the second dose, and / or the third dose varies from each other during treatment (e.g., adjusted up or down as needed). In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of a treatment regimen as a "loading dose" or "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the maintenance dose may be less than the loading dose or the initial dose. For example, one or more loading doses of 600 mg of an IL-4R antagonist may be administered, followed by maintenance doses of about 75 mg to about 300 mg.

[0247] In certain embodiments, the initial dose is about 400 to about 600 mg of the IL-33 antagonist or IL-4R antagonist. In one embodiment, the initial dose is 400 mg of the IL-33 antagonist or IL-4R antagonist. In another embodiment, the initial dose is 400 mg of the IL-33 antagonist or IL-4R antagonist. The amount is 600 mg of IL-33 antagonist or IL-4R antagonist.

[0248] In certain embodiments, the maintenance dose is about 200 to about 300 mg of the IL-33 antagonist or IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-33 antagonist or IL-4R antagonist. In another embodiment, the maintenance dose is 300 mg of the IL-33 antagonist or IL-4R antagonist.

[0249] In certain embodiments, the loading dose is twice the maintenance dose. In some embodiments, the initial dose is the same as the maintenance dose.

[0250] In some embodiments, the initial dose comprises 300 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 other week.

[0251] In some embodiments, the subject has moderate to severe asthma, and the initial dose comprises 300 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 other week.

[0252] In some embodiments, the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0253] In some embodiments, the subject has moderate to severe asthma, and the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0254] In an exemplary embodiment, each second and / or third dose is administered 1 to 14 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" refers to a dose of an IL-33 antagonist or an IL-4R antagonist administered to a patient prior to administration of the next dose in a series of multiple doses in a sequence that does not interrupt that dose.

[0255] The method can include administering multiple second and / or third doses of an IL-33 antagonist or 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. For example, 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.

[0256] In embodiments including multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments including multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency at which the second and / or third doses are administered to the patient may vary during the treatment regimen. The frequency of administration may also be adjusted during treatment by a physician based on the individual patient's needs after clinical testing.

[0257] The present invention includes methods for treating asthma or a related condition, comprising sequentially administering to a patient an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, and an additional therapeutic agent. In some embodiments, the method comprises administering one or more doses of an IL-33 antagonist, or one or more doses of an IL-33 antagonist and an IL-4R antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of the additional therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-33 antagonist, or one or more doses of an IL-33 antagonist and an IL-4R antagonist, can be administered, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of an additional therapeutic agent (e.g., an inhaled corticosteroid or a β2-agonist or any other therapeutic agent, as described elsewhere herein) to treat, alleviate, reduce, or ameliorate one or more symptoms of asthma. In some embodiments, the IL-33 antagonist or the IL-33 antagonist and the IL-4R antagonist are administered in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses that result in improvement in one or more asthma-related parameters, followed by administration of the second therapeutic agent to prevent recurrence of at least one symptom of asthma. An alternative embodiment involves simultaneous administration of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, and an additional therapeutic agent, for example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, are administered, and the additional therapeutic agent is administered in a separate dosage at similar or different times relative to the IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.In some embodiments, the additional therapeutic agent is administered before, after, or simultaneously with the IL-33 antagonist, or the IL-33 antagonist and the IL-4R antagonist.

[0258] In certain embodiments, the IL-33 antagonist, or the IL-33 antagonist and the IL-4R antagonist, are administered every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or more weeks. In other embodiments, the IL-33 antagonist, or the IL-33 antagonist and the IL-4R antagonist, are administered once every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or more weeks. In particular embodiments, the IL-33 antagonist, or the IL-33 antagonist and the IL-4R antagonist, are administered for at least 24 weeks.

[0259] The present invention includes a method for treating a subject with moderate to severe asthma, comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, or an antibody or antigen-binding fragment thereof that specifically binds to IL-33 and an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the method comprises administering to the subject multiple maintenance doses of one or more antibodies or antigen-binding fragments thereof, wherein the multiple maintenance doses are administered during a treatment phase. The treatment phase includes an induction phase, an OCS reduction phase, and an OCS maintenance phase.

[0260] In certain exemplary embodiments, the induction phase comprises a period during which the subject is continuously administered their OCS dose. In certain exemplary embodiments, the decline phase comprises a period during which the subject is administered a lower OCS dose relative to the dose administered during the induction phase. In an exemplary embodiment, the maintenance phase includes a period during which the subject is administered a particular appropriate amount or dose of OCS. Alternatively, the maintenance phase includes a period during which OCS therapy / administration is reduced or eliminated. In certain embodiments, the patient's use of OCS is completely eliminated, and the patient does not use steroids within less than one year of treatment with the IL4R antibody or fragment thereof (e.g., within one year, six months, three months, or one month of initial treatment).

[0261] In another aspect, a method for treating a subject with moderate to severe asthma includes administering to the subject an initial dose of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-33), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, each maintenance dose being about 300 mg, and the multiple maintenance doses being administered during a treatment period that includes an induction phase, an oral corticosteroid (OCS) tapering phase, and a maintenance phase, wherein the antibody or antigen-binding fragment comprises heavy and light chain CDR sequences, and the heavy and light chain CDR sequences comprise SEQ ID NOs: 4, 5, 6, 12, 14, and 16.

[0262] Treatment population The methods featured in the present invention include administering a therapeutic composition comprising an IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist to a subject in need thereof. The term "subject in need thereof" refers to a human or non-human animal exhibiting one or more symptoms or signs of asthma (e.g., moderate to severe asthma) or a human or non-human animal that has been diagnosed with asthma. For example, a "subject in need thereof" may include a subject who, prior to treatment, exhibits (or exhibits) one or more asthma-related parameters, such as a reduced FEV1 (e.g., less than 2.0 L), a reduced FEF of 25-75%, a reduced AM PEF (e.g., less than 400 L / min), a reduced PM PEF (e.g., less than 400 L / min), an ACQ5 score of at least 2.5, at least one nocturnal awakening per night, and / or a SNOT-22 score of at least 20. In various embodiments, the methods can be used to treat mild, moderate to severe, and severe asthma in patients in need thereof.

[0263] In related embodiments, a "patient in need thereof" may be a subject who was prescribed or is currently receiving an ICS / LABA combination prior to receiving an IL-4R antagonist or an IL-33 antagonist and 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 therapy include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. For example, the present invention includes methods comprising administering an IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist to a patient who has been receiving a regular course of ICS / LABA for two weeks or more immediately prior to administration of the IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist (such prior treatment is referred to herein as "basal therapy"). The present invention includes methods of treatment in which the basal therapy is continued in combination with administration of the IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist. In yet other embodiments, the amount of the ICS component, the LABA component, or both, is tapered before or after initiation of administration of the IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist. In some embodiments, the present invention includes methods of treating patients with persistent asthma for at least 12 months. In one embodiment, patients with moderate to severe persistent asthma may be resistant to treatment with therapeutic agents, e.g., corticosteroids, and may be administered an IL-4R antagonist or an IL-33 antagonist and an IL-4R antagonist according to the present method.

[0264] In some embodiments, a "patient in need thereof" may be a subject with elevated levels of asthma-associated biomarkers. Examples of asthma-associated biomarkers include, but are not limited to, IgE, thymus- and activation-regulated chemokine (TARC), eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, a "patient in need thereof" may be a subject with blood eosinophils ≥ 300 cells / μL, 150-299 cells / μL, or < 150 cells / μL. In one embodiment, a "patient in need thereof" may be a subject with elevated levels of bronchial or airway inflammation as measured by exhaled nitric oxide (FeNO).

[0265] In some embodiments, the "patient in need thereof" is selected from the group consisting of subjects 18 years of age or older, subjects 12 years of age or older, subjects 12-17 years of age (12 to <18 years of age), subjects 6-11 years of age (6 to <12 years of age), and subjects 2-5 years of age (2 to <6 years of age). In some embodiments, the "patient in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "patient in need thereof" is selected from the group consisting of adults 18 years of age or older, adolescents 12-17 years of age (12 to <18 years of age), children 6-11 years of age (6 to <12 years of age), and children 2-5 years of age (2 to <6 years of age). The subject may be under 2 years of age, e.g., 12-23 months of age, or 6-11 months of age.

[0266] In some embodiments, a "patient in need thereof" is a subject who is a habitual smoker. In some embodiments, the subject is a habitual smoker who smokes, for example, cigarettes, cigars, pipes, hookahs, and / or vaporizers (i.e., "vapes"). In some embodiments, the subject is a habitual smoker with a smoking history of 10 or more packs of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of fewer than 10 packs of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a habitual smoker with a smoking history of 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more.

[0267] In some embodiments, a "patient in need thereof" is a subject who is a former smoker. In some embodiments, the subject is a former smoker with a history of smoking cigarettes, cigars, pipes, hookahs, and / or vapes. In some embodiments, the subject is a former smoker with a history of smoking 10 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking fewer than 10 packs per year. In some embodiments, the subject is a former smoker with a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking for 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or more. In some embodiments, the subject is a former smoker who has stopped smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the subject is a former smoker who has quit smoking for at least six months. In some embodiments, the subject is a former smoker who intends to quit smoking permanently.

[0268] In some embodiments, a "patient in need thereof" is a subject who is a non-smoker. In some embodiments, the subject is a non-smoker with no history of smoking cigarettes, cigars, pipes, hookahs, and / or vapes. In some embodiments, the subject is a non-smoker with no history of tobacco smoking.

[0269] Normal IgE levels in healthy subjects (as measured, for example, using the IMMUNOCAP® assay [Phadia, Inc. Portage, MI]) are approximately Thus, the present invention includes methods comprising selecting a subject exhibiting elevated serum IgE levels of greater than about 100 kU / L, greater than 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-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.

[0270] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with a mean of approximately 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC quantitative ELISA kit provided by R&D Systems, Minneapolis, MN, catalog number DDN00.) Accordingly, the present invention includes methods comprising selecting a subject exhibiting an elevated serum TARC level of greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L; and administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.

[0271] 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 comprising administering an IL-4R antagonist to treat a patient with elevated eotaxin-3 levels, e.g., greater than about 100 pg / ml, greater than about 150 pg / ml, greater than about 200 pg / ml, greater than about 300 pg / ml, or greater than about 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA.

[0272] Exhaled nitric oxide (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 the Aerocrine By using a NIOX device by AB, Solna, Sweden. Assessment is performed before spirometry and after at least one hour of fasting. Included herein is a method comprising administering an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a patient with elevated exhaled NO (FeNO) levels, e.g., greater than about 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.

[0273] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker found in association with non-neoplastic diseases of the lung (Marechal et al., 1988, Anticancer Res. 8:677-680). Serum CEA levels can be measured by ELISA. The present invention provides a method for administering an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to patients with elevated CEA levels, for example, 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. The present invention also includes a method comprising the step of administering.

[0274] YKL-40 (derived from its N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L) and having a molecular weight of 40 kD) is a chitinase-like protein that has been found to be upregulated and associated 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-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a patient with elevated YKL-40 levels, e.g., 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.

[0275] 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. Included herein are methods comprising administering an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a patient with elevated periostin levels (e.g., ≥ 74.4 ng / mL).

[0276] Eosinophils and neutrophils in induced sputum are well-established direct markers of airway inflammation (Djukanovic et al., 2002, Eur. Respire. J. 37:1S-2S). Sputum is induced by inhalation of hypertonic saline and processed for cell counts according to methods known in the art, e.g., according to the European Respiratory Society guidelines.

[0277] In some embodiments, subjects are stratified into the following groups: blood eosinophil count >= 300 cells / μL (HEos) or 300-499 cells / μL or >= 500 cells / μL, blood eosinophil count 200-299 cells / μL (intermediate blood eosinophils), or blood eosinophil count < 200 cells / μL (low blood eosinophils) and receive an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, at a dose or dosing regimen based on eosinophil levels.

[0278] In some embodiments, subjects are stratified into the following groups: blood eosinophil count >= 300 cells / μL, 300-499 cells / μL, or >= 500 cells / μL (high blood eosinophils); blood eosinophil count >= 150 cells / μL (intermediate blood eosinophils); or blood eosinophil count < 150 cells / μL (low blood eosinophils) and receive an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, at a dose or dosing regimen based on eosinophil levels.

[0279] In some embodiments, the subject has "eosinophilic phenotype" asthma defined by a blood eosinophil count >= 150 cells / μL, a blood eosinophil count >= 300 cells / μL, a blood eosinophil count between 300 and 499 cells / μL, or a blood eosinophil count >= 500 cells / μL, and is administered an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.

[0280] In some embodiments, the subject has "periostin phenotype" asthma, as defined herein by high blood periostin levels, and is administered an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist.

[0281] Methods for assessing pharmacodynamic asthma-related parameters The present invention also includes methods for assessing one or more pharmacodynamic asthma-related parameters in a subject in need thereof caused by administration of an IL-33 antagonist, or a pharmaceutical composition comprising an IL-33 antagonist and an IL-4R antagonist. While a reduced incidence of asthma exacerbations (as described above) or an improvement in one or more asthma-related parameters (as described above) may correlate with an improvement in one or more pharmacodynamic asthma-related parameters; such a correlation may not be observed in all cases.

[0282] 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, for example, to a decrease from baseline in one or more biomarkers, such as periostin, TARC, eotaxin-3, or IgE, a decrease in sputum eosinophils or neutrophils, FeNO, periostin, or blood eosinophil count. As used herein, the term "baseline" with respect to a pharmacodynamic asthma-related parameter refers to the value of the pharmacodynamic asthma-related parameter for a patient before or at the time of administration of a pharmaceutical composition described herein.

[0283] To evaluate pharmacodynamic asthma-related parameters, parameters are quantified at baseline and at the time point after administration of pharmaceutical compositions.For example, pharmacodynamic asthma-related parameters can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th day after the first treatment with pharmaceutical compositions, or on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th or more weeks. The difference between the parameter value at a particular time point after initiation of treatment and the parameter value at baseline is used to establish whether there is a change, e.g., "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.

[0284] In certain embodiments, administration of an IL-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to a patient results in a change, e.g., a decrease or increase, in the expression of certain biomarkers. Asthma-related biomarkers include, but are not limited to, the following: (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-33 antagonist, or an IL-33 antagonist and an IL-4R antagonist, to an asthma patient can result in one or more of a decrease in TARC or eotaxin-3 levels, or a decrease in total serum IgE levels. The reduction can be detected 1, 2, 3, 4, 5 or more weeks after administration of an IL-33 antagonist, or an IL-33 antagonist and an 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 coupled to polymerase chain reaction (RT-PCR).

[0285] As discussed above, biomarker expression can be assayed by detection of protein or RNA in serum. Serum samples can be used to measure the expression of IL-33 antagonists, Alternatively, additional protein or RNA biomarkers associated with response to treatment with IL-33 antagonists and IL-4R antagonists, IL-4 / IL-13 signaling, asthma, atopy, or eosinophilic disorders (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, periostin, etc.) can be monitored. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers, while in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis). [Example]

[0286] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0287] An exemplary IL-33 antagonist used in the following examples is a human anti-IL-33 antibody designated SAR440340. An exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody designated dupilumab. [Example]

[0288] A randomized, double-blind, placebo-controlled, multiple-ascending-dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of subcutaneously administered SAR440340 in adult patients with moderate asthma. The primary objective of this study was to evaluate the safety and tolerability of multiple ascending SC doses of SAR440340 administered to patients with moderate asthma.

[0289] Secondary objectives of this study were to characterize the pharmacokinetics of SAR440340 after multiple SC administration in patients with moderate asthma; to evaluate the immunogenicity of SAR440340 after multiple SC administration in patients with moderate asthma; to evaluate the in-clinic airway response (forced expiratory volume in one second [FEV1]) of multiple SC administration of SAR440340 in patients with moderate asthma; and to evaluate changes in biomarkers (exhaled nitric oxide [FeNO] and calcitonin, a putative marker of circulating interleukin-33 (IL-33) activity) after multiple SC administration of SAR440340 in patients with moderate asthma.

[0290] The exploratory objectives of this study were to evaluate the effect of SAR440340 on potential circulating PD markers of IL-33 pathway activation, including, but not limited to, circulating concentrations of soluble IL-33 receptor (sST2); to evaluate the effect of SAR440340 on measures of daily FEV1 as measured by an ambulatory home spirometry monitoring device; to evaluate the effect of SAR440340 on measures of asthma symptom scores as measured by the paper Asthma Control Questionnaire (ACQ-6); and to evaluate total circulating IL-33 before and after treatment with SAR440340.

[0291] Study design This was a first-in-patient study of SAR440340 aimed to elucidate the safety and pharmacokinetic / pharmacodynamic (PK / PD) profile of repeated subcutaneous (SC) dosing of this monoclonal antibody (mAb) in patients with asthma.

[0292] Twenty-three patients were enrolled in this study and randomized to receive SAR440340 or placebo in one of two sequentially escalating SC dosing cohorts: SAR440340 75 mg SC QW (6 patients) or placebo SC QW (2 patients) in Cohort 1, and SAR440340 150 mg SC QW (11 patients) or placebo SC QW (4 patients) in Cohort 2 (Figure 123).

[0293] For each cohort, the study consists of a screening period (days -28 to -1, with clinical visits occurring between days -28 and -14), a baseline visit (day 1), a treatment period (days 8 to 22), and a follow-up period (days 29 to 250), with an end of study visit on day 250. The planned total duration of patient participation in the study is approximately 40 weeks (including a screening period of up to 4 weeks).

[0294] Summary of results A total of 23 patients with moderate asthma were enrolled: 6 in placebo, 6 in SAR440340 75 mg SC QW x 4W, and 11 in SAR440340 150 mg SC QW x 4W. SAR440340 was well tolerated.

[0295] Circulating EOS was reduced by SAR440340 treatment (Figures 124-129). Active treatment with SAR440340 (75 mg and 150 mg) resulted in an approximately 35% reduction from baseline observed at Day 29, which was sustained through Day 197. The data are consistent with preclinical data demonstrating that treatment with SAR440340 reduces IL-5 levels.

[0296] The biomarker FeNO demonstrated high variability in a small number of patients, but with potential modest benefit from active treatment (Figures 130-134).

[0297] SAR440340 PK was similar in asthmatic patients compared to healthy subjects, as demonstrated by the dose-proportional AUC, t 1 / 2 The total IL-33 concentration showed linear clearance kinetics with a mean clearance of 30 days. No clear dose response was observed in the total IL-33 concentration over time after administration, ranging from 75 mg to 150 mg SC.

[0298] Treatment-emergent adverse events There were no deaths. There were no treatment discontinuations due to adverse events (AEs). There were no serious treatment-emergent adverse events (TEAEs). There were no severe TEAEs.

[0299] The frequency of the number of patients with at least one TEAE was similar between SAR440340 and placebo.

[0300] The most frequent TEAEs were headache (one patient [16.7%] in placebo and four patients [23.5%] in SAR440340), upper respiratory tract infection (one patient [16.7%] in placebo and two patients [11.8%] in SAR440340), gastroenteritis (two patients [33.3%] in placebo and one patient [5.9%] in SAR440340), and nasopharyngitis (two patients [33.3%] in placebo and one patient [5.9%] in SAR440340).

[0301] The frequency of the number of patients with at least one drug-related TEAE was similar between SAR440340 and placebo. The only drug-related TEAE reported in this study was headache (1 patient [16.7%] in placebo and 1 patient [5.9%] in SAR440340).

[0302] Laboratory parameters, vital signs and ECG Treatment-emergent potentially clinically significant values (PCSV) for laboratories, vital signs, and ECGs were similar between the placebo and SAR440340 treatment groups, except that a higher percentage of patients had at least one treatment-emergent PCSV hematology test in the placebo group (83.3%) than in the SAR440340 group (29.4%). [Example]

[0303] A randomized, double-blind, placebo-controlled, parallel-group, 12-week proof-of-concept (PoC) study to evaluate the efficacy, safety, and tolerability of SAR440340 and coadministration of SAR440340 and dupilumab in patients with moderate-to-severe asthma inadequately controlled on long-acting beta-2 adrenergic agonist (LABA) therapy plus inhaled corticosteroids (ICS) (NCT03387852) Main goal: To assess the effect of SAR440340, with or without dupilumab, compared with placebo in reducing the incidence of 'loss of asthma control' (LOAC) events.

[0304] The protocol defined criteria for LOAC included the occurrence of at least one of the following: 1) a 30% or greater decrease from baseline in morning PEF on 2 consecutive days; ≥6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in 24 hours (compared to baseline) on 2 consecutive days; a ≥4-fold increase in the last prescribed ICS dose (or ≥50% of the prescribed ICS dose at V2 if cessation of background therapy was complete); requiring the use of systemic (oral and / or parenteral) steroid therapy; and requiring hospitalization or an emergency room visit.

[0305] Secondary goal: To assess the effect of SAR440340 and co-administration of SAR440340 and dupilumab on FEV1 compared to placebo.To estimate the effect of co-administration of SAR440340 and dupilumab on FEV1 compared to SAR440340 and compared to dupilumab.To determine the safety and tolerability of SAR440340 alone and co-administered with dupilumab.

[0306] Methodology:

[0307] This randomized, double-blind, placebo-controlled, parallel-group (four-arm), 12-week proof-of-concept (PoC) study evaluated the efficacy, safety, and tolerability of SAR440340 300 mg q2w and coadministration of SAR440340 300 mg q2w and dupilumab 300 mg q2w in patients with moderate-to-severe asthma inadequately controlled on long-acting beta-2 adrenergic agonist (LABA) therapy plus inhaled corticosteroids (ICS). Background therapy (ICS and LABA) was gradually discontinued, and patients were free of any background therapy for 3 to 4 weeks at the end of the treatment period. SAR440340 was administered as two subcutaneous injections. Dupilumab was administered as a single subcutaneous (SC) injection.

[0308] Diagnostic and inclusion criteria: 1. Adult patients with a physician-diagnosed asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2017 guidelines. 2. Patients receiving a second controller on a stable dose for at least 3 months ≥ 1 month prior to Visit 1. 1. Current treatment with medium- to high-dose ICS (fluticasone propionate twice daily (BID) ≥ 250 mcg or a daily dose of ICS equipotent to fluticasone propionate up to 2000 mcg / day or a clinically equivalent dose) in combination with a LABA as a primary agonist. 2. Pre-bronchodilator forced expiratory volume in one second (FEV1) > 40% of predicted normal at Visit 1 / Screening. 3. Pre-bronchodilator FEV1 ≥ 50% but ≤ 85% of predicted normal at Visit 2 / Baseline. 5. Reversibility of at least 12% and 200 mL in FEV1 after administration of 2-4 puffs (200-400 mcg) of albuterol / salbutamol or levalbuterol / levosalbutamol during screening OR a documented history of a reversibility test meeting this criterion within the 12 months prior to Visit 1 OR a documented positive response to a methacholine challenge (decline to 20% [PC20] of FEV<8 mg / mL) within the 12 months prior to Visit 1 / screening. 6. At least one hospitalization or emergency department visit for an asthma exacerbation or treatment with systemic corticosteroids (oral or parenteral) for an asthma exacerbation within the year prior to Visit 1. (See also Figures 92-96.)

[0309] Primary and key ranked secondary endpoints: efficacy: The primary endpoint was the proportion of patients with LOAC. Secondary endpoints were the change in FEV1 from baseline to week 12 (pre- and post-bronchodilator administration).

[0310] Safety: Adverse events (AEs), standard hematology and blood chemistry, vital signs, physical examination, and electrocardiogram (ECG).

[0311] Statistical methods: The efficacy analysis population was the modified intent-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. Patients were analyzed by treatment group to which they were randomized. Randomization was stratified by blood eosinophil count at the screening visit (<0.15 Giga / L, 0.15 to <0.3 Giga / L, ≥0.3 Giga / L) and by country.

[0312] The primary endpoint of LOAC incidence was analyzed using a logistic regression model. Covariates included in the model were treatment, baseline eosinophil level, region (combined country), background ICS dose level at randomization, and number of exacerbation events within 1 year before screening.

[0313] The secondary endpoint, change from baseline in FEV1 before and after BD treatment at week 12, was analyzed using a mixed-effect model with repeated measures (MMRM) approach. The model included change from baseline to week 12 as the response variable and treatment, gender, baseline height, baseline eosinophil level, region, background ICS dose level at randomization, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as covariates. For patients who experienced rescue medication LOAC, FEV1 collected at and after the start of the event were set as missing values for the primary analysis. Missing data were not imputed.

[0314] All pairwise treatment comparisons in efficacy analyses were tested at a two-sided 5% significance level. The population included all patients exposed to IMP, regardless of exposure. Patients were analyzed by the treatment actually received. The safety summary was descriptive and no hypothesis testing was performed.

[0315] summary: Population characteristics: At the time of core database lock, of the 296 randomized patients, 228 patients (77.0%) were in the post-treatment follow-up period, 58 patients (19.6%) completed the study as planned, and 10 patients (3.4%) discontinued follow-up. Of the 295 randomized and treated patients, 199 patients (67.5%) completed treatment as planned, and 96 patients (32.5%) discontinued treatment prematurely.

[0316] Seventy-eight patients permanently discontinued treatment due to loss of asthma control (protocol requirement), five due to adverse events, one due to poor compliance, and five due to other reasons unrelated to safety. Seven patients discontinued treatment at patient request. More patients in the placebo arm discontinued treatment due to LOAC. Premature discontinuation due to adverse events was low, with two patients discontinuing in the SAR440340 + dupilumab group and three in the placebo group.

[0317] Patient demographics, other characteristics, and baseline disease characteristics were generally similar across the four treatment arms, with an overall mean number of asthma exacerbations in the previous year of 1.3, a mean pre-bronchodilator FEV1 of 2.02 L, a mean pre-bronchodilator FEV1 percent predicted of 64.69%, a mean FEV1 reversibility of 14.9%, a mean ACQ-5 score (Asthma Control Questionnaire 5-question version) of 2.16, a mean eosinophil count of 0.37 10^9 / L, and a mean exhaled nitric oxide (FeNO) of 29.2 ppb. A higher proportion of patients in the SAR440340 plus dupilumab group experienced two or more exacerbations or an exacerbation resulting in hospitalization than in the other treatment groups. More patients in this treatment group were ever smokers.

[0318] Efficacy Results: The proportion of patients with LOAC was 21.9% in the SAR440340 group, 27% in the SAR440340 + dupilumab group, 18.9% in the dupilumab group, and 40.5% in the placebo group. SAR440340 monotherapy reduced the odds of experiencing LOAC compared with placebo (p=0.02). The reduction in odds ratio for the SAR440340 + dupilumab group was not significant (p=0.07). The odds ratio (95% CI) for SAR440340 vs. placebo was 0.423 (0.203-0.880) and for the combination vs. placebo was 0.520 (0.256-1.057).

[0319] Although there was no evidence of a differential treatment effect across subgroups defined by baseline eosinophil count (p=0.5365 for treatment by subgroup interaction), the number of patients in each subgroup was small. In general, the greatest effect versus placebo was observed in the subgroup of patients with baseline eosinophil counts ≥ 300 / mm3 for both SAR440340 and the combination of SAR440340 with dupilumab.

[0320] The LS mean change from baseline in pre-bronchodilator FEV1 at week 12 was 0.10 L for SAR440340, 0.06 L for SAR440340 plus dupilumab, 0.12 L for dupilumab, and -0.04 L for placebo. Compared with placebo, the LS mean difference in change from baseline to week 12 in pre-bronchodilator FEV1 was significant for the SAR440340 group (0.14 [0.01 to 0.27], p=0.03) but not for the SAR440340 plus dupilumab group (0.10 [-0.04]). 03~0.23], p=0.13) was not significant.

[0321] Although there was no evidence of a differential treatment effect across subgroups defined by baseline eosinophil count (p=0.1111 for treatment by subgroup interaction), the number of patients in each subgroup was small. In general, the greatest effect versus placebo was observed in the subgroup of patients with baseline eosinophil counts ≥ 300 / mm3 for both SAR440340 and the combination of SAR440340 with dupilumab.

[0322] The LS mean change from baseline in post-bronchodilator FEV1 at week 12 was -0.00 L for SAR440340, 0.07 L for SAR440340 plus dupilumab, 0.09 L for dupilumab, and -0.05 L for placebo. Compared with placebo, the LS mean difference in change from baseline to week 12 in post-bronchodilator FEV1 was significant for the SAR440340 plus dupilumab group (0.13 [0.01 to 0.25], p = 0.04) but not for the SAR440340 group (0.05 [-0.07 to 0.17], p = 0.41).

[0323] Safety results (incidence reported for all cases of SAR440340, SAR440340 + dupilumab, dupilumab, and placebo): Cumulative exposure to SAR440340 alone or in combination with dupilumab was 30.2 patient-years. The incidence of treatment-emergent adverse events (TEAEs) was balanced across treatment groups (60.3%, 66.2%, 55.4%, and 64.9%). Most TEAEs were mild or moderate in intensity. The most frequent TEAEs were system organ classes (SOCs) of infections and infestations (primarily due to nasopharyngitis and viral upper respiratory tract infections).

[0324] The incidence of treatment-emergent serious adverse events (SAEs) was low. One patient (1.4%) in each of the SAR440340, SAR440340 plus dupilumab, and dupilumab treatment groups had a treatment-emergent SAE compared with three patients (4.1%) in the placebo group. One patient died from ethyl alcohol poisoning during the post-treatment follow-up period (information received after database lock).

[0325] The overall rate of treatment discontinuation due to TEAEs was low (2 patients (2.7%) discontinued in the SAR440340 + dupilumab group and 3 patients (4.1%) discontinued in the placebo group).

[0326] Preliminary conclusions: SAR440340 monotherapy was effective in patients with moderate-to-severe persistent asthma. Compared with placebo, SAR440340 monotherapy significantly reduced the proportion of patients with LOAC in the overall population and improved pre-bronchodilator FEV1 at week 12. No treatment effect was observed in improving post-bronchodilator FEV1 at week 12. Subgroup analysis based on baseline blood eosinophil count showed a trend toward a reduced incidence of LOAC across eosinophil subgroups. However, a trend toward improved pre-bronchodilator FEV1 at week 12 was primarily observed in the ≥300 / mm3 subgroup compared with placebo.

[0327] SAR440340 in combination with dupilumab showed no efficacy in reducing patients with LOAC and improving pre-bronchodilator FEV1 at week 12 compared with placebo in the overall population. However, efficacy was observed in improving post-bronchodilator FEV1 at week 12. Subgroup analysis based on baseline blood eosinophil count showed a significant improvement in patients with baseline EOS counts ≥ 300 / mm3 compared with placebo. Certain patient subgroups generally showed the greatest treatment effect for both LOAC and pre-bronchodilator FEV1.

[0328] The dupilumab arm was included in the study as a standard. In terms of LOAC and FEV1, dupilumab performed as expected.

[0329] SAR440340 alone and in combination with dupilumab was generally well tolerated with an acceptable safety profile.

[0330] result Patient breakdown Of 498 patients screened, 296 patients were randomized (screen failure rate 41%). The main reasons for screen failure were a positive tuberculosis screen and a pre-bronchodilator FEV1 outside the pre-specified range for inclusion. The breakdown of patients by randomized treatment group is shown in Table 1. Allocation to treatment groups conformed to the planned randomization scheme of 1:1:1:1.

[0331] The final distribution by baseline eosinophil count strata (used for statistical analysis) was 0.15 × 10 9 / L in 63 patients (21.4%), ≥ 0.15 × 10 9 / L and <0.3 × 10 9 / L in 92 patients (31.2%), ≥ 0.3 × 10 9 / L in 140 patients (47.5%) (Table 12). This differed slightly from the IVRS stratification based on eosinophil count screening (Table 3).

[0332] Of the 295 randomized and treated patients, 199 patients (67.5%) completed treatment as planned, and 96 patients (32.5%) discontinued treatment prematurely. At the core database lock, of the 296 randomized patients, 228 patients (77.0%) were in post-treatment follow-up; 58 patients (19.6%) completed the study as planned, and 10 patients (3.4%) were discontinued from follow-up.

[0333] Seventy-eight patients permanently discontinued treatment due to loss of asthma control (protocol requirement), five due to adverse events, one due to poor compliance, and five due to other reasons unrelated to safety. Seven patients discontinued treatment at patient request. More patients in the placebo group discontinued treatment due to LOAC. Premature discontinuation due to adverse events was low, with two patients discontinuing in the SAR440340 plus placebo group and three in the placebo group.

[0334] One patient in the dupilumab treatment group was reported as lost to follow-up. After database lock, we received additional information that the patient died from an SAE of ethyl alcohol intoxication during post-treatment follow-up in this study. The event was assessed as not related to IMP.

[0335] [Table 1]

[0336] Demographics and baseline characteristics Patient demographics and baseline characteristics were well balanced across treatment groups (Table 2). The mean age of the overall population was 49 years, ranging from 18 to 70 years. Approximately two-thirds of patients were women (63.9%). 94.9% of patients were white, 2.0% were black, 1.4% were Asian, 1.4% were American Indian or Alaska Native, and 0.3% were multiracial.

[0337] [Table 2] [Table 3]

[0338] Baseline patient disease characteristics were generally similar across treatment groups in the overall population (Table 3). A higher proportion of patients in this treatment group had experienced two or more exacerbations or exacerbations resulting in hospitalization in the previous year than patients in the control group. More patients in this treatment group were former smokers.

[0339] Overall, 27.4% of patients were <18 years of age, 36.5% were 18-40 years of age, and 36.1% developed asthma at age ≥40 years. Overall, 65.9% of patients were receiving high-dose ICS at baseline, and most (85.5%) had ongoing atopic disease. The mean number of asthma exacerbations in the previous year was similar between treatment groups (1.3-1.4), and 26.4% (78) of all randomized patients experienced more than one asthma exacerbation in the previous year.

[0340] Asthma-specific baseline characteristics as well as biomarker baseline characteristics (Table 12) included an overall mean pre-bronchodilator FEV1 of 2.02 L, a mean pre-bronchodilator FEV1 percent predicted of 64.69%, a mean FEV1 reversibility of 14.9%, a mean ACQ-5 score (Asthma Control Questionnaire, 5 question version) of 2.16, a mean AQLQ global score (Asthma Quality of Life Questionnaire with Standardized Activities) of 4.68, and a mean eosinophil count of 0.37 x 10 9 / L, and mean exhaled nitric oxide (FeNO) was 29.2 ppb, which were similar between treatment groups.

[0341] Because baseline medians were comparable, there were observed differences between treatment groups in mean baseline total IgE levels that may be caused by outliers.

[0342] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0343] Dosage and duration The range of exposure to investigational medication (IMP) in the safety population is summarized in Table 13. The mean duration of treatment exposure was 77.3 days in the SAR440340 group, 72.7 days in the SAR440340 + dupilumab group, 76.2 days in the dupilumab group, and 70.6 days in the placebo group. The lower exposure observed in the placebo arm was caused by a higher discontinuation rate due to LOAC. The cumulative exposure to SAR440340 alone and in combination with dupilumab was 30.2 patient-years.

[0344] efficacy Primary Efficacy Endpoint The primary endpoint of this study was the proportion of patients with loss of asthma control (LOAC). The incidence of LOAC was lower for patients in the SAR440340 and SAR440340 + dupilumab groups compared with the placebo group: 21.9% and 27% vs. 40.5%. SAR440340 monotherapy significantly reduced the odds of experiencing LOAC compared with placebo; p = 0.02. The reduction in odds ratio for the SAR440340 + dupilumab arm compared with placebo was not significant (p = 0.07). The odds ratio (95% CI) for SAR440340 vs. placebo was 0.423 (0.203-0.880) and for the combination vs. placebo was 0.520 (0.256-1.057) (Table 4).

[0345] SAR440340 in combination with dupilumab did not reduce the odds of experiencing LOAC compared with SAR440340 (p = 0.60) or compared with dupilumab (p = 0.25). The odds ratios (95% CI) were 1.231 (0.571 to 2.653) compared with SAR440340 and 1.589 (0.723 to 3.492) compared with dupilumab (Table 14). Sensitivity analyses confirmed the conclusions of the primary analysis.

[0346] [Table 9]

[0347] Overall, 80 LOAC events were reported across treatment groups in the study. Per protocol, 78 patients discontinued due to LOAC. Two patients had simultaneous LOAC and adverse events, and the investigator considered the adverse events to be the primary reason for treatment discontinuation. The majority of LOAC was due to a decrease from baseline in morning PEF, followed by an increase in asthma reliever puffs and the use of systemic corticosteroids (Table 15).

[0348] There was no evidence of a differential treatment effect across subgroups defined by baseline eosinophil count (p=0.5365 for treatment by subgroup interaction), although the number of patients in each subgroup was small. SAR440340 monotherapy demonstrated a reduction in LOAC across all subgroups based on baseline eosinophil count, with odds ratios of <150 / mm 3 0.401 (0.072~2.239), ≧150~<300 / mm 3 0.473 (0.099~2.270) and ≥ 300 / mm 3 In the case of

[0349] SAR440340 in combination with dupilumab reduces baseline eosinophil counts to <150 / mm 3 and ≥ 300 / mm 3A numerical reduction in LOAC was demonstrated in the subgroup of patients with baseline eosinophil counts of 150 to <300 / mm3, with odds ratios of 0.623 (0.122 to 3.182) and 0.298 (0.102 to 0.868), respectively. 3 For the subgroup of patients with ≥ 1, there was no observed reduction, with an odds ratio of 1.086 (0.270 to 4.372) (Table 16).

[0350] Key secondary efficacy endpoints Change in pre-bronchodilator FEV1 from baseline to week 12 The LS mean difference (95% CI, p-value) in the change from baseline to week 12 in pre-bronchodilator FEV1 was significant in the SAR440340 group (0.14 [0.01 to 0.27], p = 0.03) but not in the SAR440340 + dupilumab group (0.10 [-0.03 to 0.23], p = 0.13) (Table 5).

[0351] The LS mean difference in the change from baseline to week 12 in pre-bronchodilator FEV1 in the SAR440340 + dupilumab group vs. the SAR440340 group was -0.04 ([-0.17 to 0.09], p=0.53).The LS mean difference in the change from baseline to week 12 in pre-bronchodilator FEV1 in the SAR440340 + dupilumab group vs. the dupilumab group was -0.06 ([-0.19 to 0.06], p=0.33).

[0352] The change from baseline in pre-bronchodilator FEV1 at week 12 for all comparisons is shown in Table 17.

[0353] [Table 10]

[0354] Sensitivity and per-protocol analyses confirmed the conclusions of the primary analysis. There was no evidence of a differential treatment effect across subgroups defined by baseline eosinophil count (p = 0.1111 for treatment-by-subgroup interaction), but the number of patients in each subgroup was small.

[0355] Baseline eosinophil count ≥ 300 / mm 3 For the subgroup of patients with FEV1, the LS mean difference (0 The LS mean (LS mean) was 0.22 (0.02 to 0.41) and was significant for SAR440340 alone versus placebo. SAR440340 in combination with dupilumab showed a trend toward improvement, with a LS mean of 0.19 (-0.01 to 0.40).

[0356] Baseline eosinophil count ≥150 to <300 / mm 3 For the subgroup of patients with bronchodilator FEV1, the LS mean difference in change from baseline to week 12 in pre-bronchodilator FEV1 was not significant for SAR440340 alone or in combination with dupilumab. High FEV1 in the placebo group may lead to a negative FEV1 trajectory across all treatment groups.

[0357] Baseline eosinophil count <150 / mm 3 In the subgroup of patients with bronchodilator-associated pulmonary embolism, the LS mean difference in change from baseline to week 12 in pre-bronchodilator FEV1 showed a trend toward improvement: 0.17 (-0.12 to 0.45) in the SAR440340 group and 0.11 (-0.17 to 0.39) in the SAR440340 + dupilumab group (Table 18).

[0358] Change in FEV1 after bronchodilator administration from baseline to week 12 The LS mean difference in the change from baseline to week 12 in post-bronchodilator FEV1 was significant in the SAR440340 + dupilumab group (0.13 [0.01 to 0.25], p = 0.04) but not in the SAR440340 group (0.05 [-0.07 to 0.17], p = 0.41) (Table 6).

[0359] The LS mean difference in the change from baseline to week 12 in post-bronchodilator FEV1 in the SAR440340 plus dupilumab group vs. the SAR440340 group was (0.08 [-0.04 to 0.19], p=0.19). The LS mean difference in the absolute change from baseline to week 12 in post-bronchodilator FEV1 in the SAR440340 plus dupilumab group vs. the dupilumab group was (-0.02 [-0.13 to 0.10], p=0.78). Sensitivity and per-protocol analyses confirmed the conclusions of the primary analysis.

[0360] [Table 11]

[0361] The trial was well-conducted, the four treatment arms were balanced in baseline characteristics, and the dupilumab arm, used as the standard, demonstrated expected safety and efficacy outcomes (ITT: LOAC: 53% RR; FEV1: 160 mL; better efficacy in Eos ≥ 300 / μL: LOAC: 72% RR; FEV1: 340 mL).

[0362] SAR440340 demonstrated a favorable safety profile and demonstrated significant efficacy across all endpoints (ITT:LOAC 42% RR; FEV1:140 mL; ACQ5 and AQLQ, mean change vs. placebo, −0.42 and 0.45, respectively).

[0363] While the LOAC data show a more uniform efficacy profile across the low / high blood Eos* strata (SAR: 42% / 45%; dupilumab: 30% / 72%) and FeNO* strata (SAR: 48% / 39%; dupilumab: 43% / 67%), the FEV1 data profile resembled that of dupilumab, with superior efficacy in Type 2 high (220 mL in high Eos* vs. 20 mL in low Eos; 200 mL in high FeNO* vs. 70 mL in low FeNO).

[0364] Beyond the expected reduction in circulating Eos, there was no significant effect on all other type 2 biomarkers.

[0365] safety Safety findings indicated that SAR440340 may be used safely in patients with moderate to severe asthma. SAR440340 alone and in combination with dupilumab was safe and generally well tolerated. Overall, the rate of treatment discontinuation due to AEs was low. The total AESI rate or other selected AE grouping events was low. The most frequent events were hypersensitivity and injection site reactions. ISRs were less frequent in the SAR440340 monotherapy arm.

[0366] Treatment-emergent adverse events (TEAEs) The incidence of TEAEs was similar across treatment groups. The number of treatment-emergent SAEs and TEAEs leading to discontinuation was low (Table 7). One patient died from ethyl alcohol intoxication during post-treatment follow-up in the dupilumab group (information received after database lock).

[0367] [Table 12]

[0368] The majority of TEAEs were mild or moderate in intensity. The number of severe TEAEs was low. Of the four events, three were treatment-emergent SAEs and one was a severe injection site reaction (AESI).

[0369] Table 8 shows the number (%) of patients with TEAEs occurring with a frequency of ≥3% in any treatment group by major SOC and preferred term (PT). The most frequent TEAEs were primarily due to nasopharyngitis and viral upper respiratory tract infections, and nervous system disorders, primarily due to headache, in the Infections and Infestations SOC. Slightly more patients in the SAR440340 group experienced nasopharyngitis compared with the other treatment groups, but other upper respiratory tract infections were less frequent in that arm compared with the other arms. The incidence of injection site reactions (PT injection site erythema and injection site rash) was less frequent in the SAR440340 group compared with the other treatment groups.

[0370] There were three patients with PT rash pruritic reported in the SAR440340 + dupilumab group compared with no patients in the other treatment arms. Two of these events were assessed as hypersensitivity AESIs.

[0371] As per e-CRF reporting rules, the relationship to SAR440340 / matching dose placebo and dupilumab / matching dose placebo should be evaluated separately for each adverse event. In most cases of these events, with the exception of injection site reactions, evaluation can be difficult, and investigators may be inclined to associate the adverse event with both study medications. With this database setting, there were two patients in the dupilumab group with TEAEs that were evaluated as related to both dupilumab / matching dose placebo and SAR440340 / matching dose placebo. One patient experienced nausea and tachycardia on the day of IMP administration, and the other patient experienced neutropenia. Additionally, there was one patient in the SAR440340 group with an injection site reaction erroneously reported as associated with dupilumab / matching dose placebo, and one patient in the dupilumab group experienced an injection site reaction at the SAR440340 / matching dose placebo site in addition to an injection site reaction at the dupilumab injection site.

[0372] [Table 13]

[0373] Deaths and serious treatment-emergent adverse events One patient in the dupilumab group died during post-treatment follow-up. The patient was considered lost to follow-up at the time of database lock. After database lock, new information was received that the patient died of ethyl alcohol poisoning, which was not reported to be related to IMP. The patient was a 62-year-old man from Russia with a history of arterial hypertension. At screening, the man reported drinking more than two drinks of alcohol at least once a week. After the fourth IMP dose, the patient discontinued treatment due to LOAC (a 30% or greater decrease in morning PEF for two consecutive days). The man died approximately 40 days after his last IMP dose. The patient reported no adverse events during the study, and the patient's ECG and laboratory results were unremarkable.

[0374] The incidence of treatment-emergent SAEs was low: only one patient reported a treatment-emergent SAE with PT (Table 9).

[0375] [Table 14]

[0376] Adverse events leading to discontinuation

[0377] The overall treatment discontinuation rate due to AEs was low (Table 10). Only five patients discontinued treatment due to TEAEs (two in the SAR440340 + dupilumab group and three in the placebo group). Per protocol, two patients discontinued IMP due to systemic hypersensitivity (PT pruritic rash and urticaria) that was considered related to IMP and required treatment.

[0378] [Table 15]

[0379] Other significant adverse events (including AESIs and laboratory) Table 11 provides an overview of the number (%) of patients with treatment-emergent AESI or other selected AE grouping events. The overall AESI rate or other selected AE grouping events was low. The most frequent events were hypersensitivity and injection site reactions.

[0380] [Table 16]

[0381] Adverse Events of Special Interest (AESI) Anaphylactic reactions / systemic hypersensitivity The incidence of hypersensitivity was slightly higher in the SAR440340 and SAR440340 + dupilumab groups compared with the placebo and dupilumab groups. Hypersensitivity was reported in three patients (4.1%) in the SAR440340 and SAR440340 + dupilumab groups, respectively, and in one patient (1.4%) in the dupilumab and placebo groups, respectively. Hypersensitivity events included lip swelling, pruritus, and generalized pruritus in the SAR440340 group; pruritic rash and hypersensitivity in the SAR440340 + dupilumab group; conjunctivitis in the dupilumab group; and urticaria in the placebo group. All hypersensitivity-related TEAEs were mild or moderate in severity, and there were no SAEs.

[0382] injection site reactions Injection site reactions consisted primarily of injection site erythema and were of mild severity. One patient had a severe non-serious injection site reaction (AESI) in the SAR440340 + dupilumab group that led to permanent treatment discontinuation. The incidence of injection site reactions was slightly lower in the SAR440340 group compared with the other treatment groups.

[0383] Severe and serious infections One patient in the dupilumab group had a severe treatment-emergent SAE of a jaw abscess, which was reported to have resolved after corrective treatment. Two patients in the placebo group had moderate-intensity non-serious infections (two cases of pneumonia), which were reported to have resolved after corrective treatment.

[0384] Potential drug-related liver injury One treatment-emergent SAE of elevated alanine aminotransferase was reported in a patient in the SAR440340 plus dupilumab group and was assessed as moderate in severity. The patient's ALT increased to 431 U / L (13.33 × ULN); baseline ALT was 11 U / L (normal range: 10-33 U / L). The ALT elevation was reported to be due to alcohol consumption (two beers and one liquor). No corrective treatment was administered. IMP treatment was temporarily discontinued. The event resolved.

[0385] pregnancy One patient in the SAR440340 treatment group was reported to be pregnant. The patient's last menstrual period was 8 days after the last IMP dose. At 6 weeks gestation, the patient underwent elective termination of the pregnancy.

[0386] Other selected adverse event groupings Eosinophilia Two patients reported eosinophilia. One patient in the SAR440340 group experienced a worsening of moderate-severity eosinophilic colitis. The patient had ongoing eosinophilic colitis since 2017. The patient's eosinophil count levels remained consistently low (<0.3 GI / L) throughout the study. The patient recovered with corrective treatment. One patient in the placebo group experienced asymptomatic eosinophilia of mild severity with an eosinophil count >3 GI / L and no recurrence (per protocol, any eosinophil count increase >3 GI / L should be reported as an AE). The patient recovered without corrective treatment.

[0387] Lab Values, ECG and Vital Signs There were no clinically significant differences between groups regarding potentially clinically significant abnormal (PCSA) test results.

[0388] There were no significant differences in all vital sign parameters, weight, and ECG between the treatment groups. One 62-year-old male patient had an increase in QTCF interval from baseline of >60 milliseconds in the SAR440340-treated group. The patient had a history of hypertension. The ECG showed left ventricular hypertrophy. No TEAEs related to QTCF prolongation were reported.

[0389] [Table 17] [Table 18]

[0390] [Table 19]

[0391] Table 20

[0392] Table 21

[0393] Table 22

[0394] Table 23

[0395] Table 24 Table 25

[0396] Table 26 Table 27

Claims

1. 1. A method for treating asthma in a subject in need thereof, comprising: an initial dose of about 300 mg of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16; and one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof to a subject.

2. 10. The method of claim 1, wherein loss of asthma control (LOAC) is reduced in the subject.

3. 10. The method of claim 1, wherein one or more asthma-related parameters are improved in the subject.

4. 4. The method of claim 3, wherein the asthma-related parameter is selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25% to 75%, the number or dose of long-acting beta-2 adrenergic receptor agonists (LABA), the number or dose of inhaled corticosteroids, and the number or dose of systemic steroid drugs.

5. 5. The method of claim 4, wherein the FEV1 before administration of a bronchodilator is improved.

6. 10. The method of claim 1, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; between about 150 and 299 cells per μL; or less than about 150 cells per μL.

7. 7. The method of claim 6, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl.

8. 10. The method of claim 1, wherein blood eosinophil levels are reduced.

9. 10. The method of claim 1, wherein the subject has high or low blood periostin levels.

10. 10. The method of claim 9, wherein the subject has an elevated blood periostin level of about ≧74.4 ng / mL.

11. 10. The method of claim 1, wherein one or both of the Asthma Control Questionnaire 5 Question Version (ACQ-5) score and the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ) score are improved.

12. 12. The method of claim 11, wherein the AQLQ emotional function score is improved.

13. 5. The method of claim 4, wherein the frequency or dosage of a long-acting beta-2 adrenergic agonist (LABA) is reduced, the frequency or dosage of an inhaled corticosteroid is reduced, or the frequency or dosage of a systemic steroid is reduced.

14. 10. The method of claim 1, wherein the asthma is moderate to severe asthma that is not adequately controlled with basic therapy.

15. 15. The method of claim 14, wherein the background therapy comprises inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs).

16. 16. The method of claim 15, wherein the basal therapy comprises a moderate to high dose of ICS / LABA.

17. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

18. 18. The method of claim 17, wherein the antibody comprises SAR440340.

19. 10. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered every other week.

20. 20. The method of claim 19, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

21. 21. The method of claim 20, wherein the antibody or antigen-binding fragment thereof is administered as two injections.

22. 21. The method of claim 20, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, a needle and syringe, or a pen delivery device.

23. 1. A method for treating asthma in a subject in need thereof, comprising: an initial dose of about 300 mg of a first antibody or antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16; one or more maintenance doses of about 300 mg of the first antibody or antigen-binding fragment thereof; an initial dose of about 300 mg of a second antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 21, 22, and 23, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 24, 25, and 26; and The method further comprising administering to the subject one or more maintenance doses of about 300 mg of a second antibody or antigen-binding fragment thereof.

24. 24. The method of claim 23, wherein LOAC is reduced in the subject.

25. 24. The method of claim 23, wherein one or more asthma-related parameters are improved in the subject.

26. 26. The method of claim 25, wherein the asthma-related parameter is selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25% to 75%, the number or dose of long-acting beta-2 adrenergic receptor agonists (LABA), the number or dose of inhaled corticosteroids, and the number or dose of systemic steroid drugs.

27. 27. The method of claim 26, wherein the post-bronchodilator FEV1 is improved.

28. Subjects were randomly assigned to have a blood eosinophil count of approximately 300 cells per μL or greater; approximately 150-200 cells per μL; 99 cells; or about <150 cells per μL.

29. 29. The method of claim 28, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; or between greater than or equal to about 150 cells per μl and less than about 300 cells per μl.

30. 24. The method of claim 23, wherein the subject has high or low blood periostin levels.

31. 31. The method of claim 30, wherein the subject has an elevated blood periostin level of about ≧74.4 ng / mL.

32. 24. The method of claim 23, wherein the asthma is moderate to severe asthma that is not adequately controlled on baseline therapy.

33. 33. The method of claim 32, wherein the background therapy comprises inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs).

34. 24. The method of claim 23, wherein the first antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

35. 35. The method of claim 34, wherein the first antibody comprises SAR440340.

36. 24. The method of claim 23, wherein the second antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

28.

37. 37. The method of claim 36, wherein the second antibody comprises dupilumab.

38. 24. The method of claim 23, wherein the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered every other week.

39. 39. The method of claim 38, wherein the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered subcutaneously.

40. 40. The method of claim 39, wherein the second antibody or antigen-binding fragment thereof is administered to the subject before, after, or simultaneously with the first antibody or antigen-binding fragment thereof.

41. 40. The method of claim 39, wherein the first antibody or antigen-binding fragment thereof is administered as two injections and the second antibody or antigen-binding fragment thereof is administered as one injection.

42. 42. The method of claim 41, wherein the first antibody or antigen-binding fragment thereof and the second antibody or antigen-binding fragment thereof are each administered subcutaneously using an autoinjector, a needle and syringe, or a pen delivery device.

43. The method of any one of claims 1 to 42, wherein at least one additional therapeutic agent is administered to the subject.

44. The at least one additional therapeutic agent comprises one or both of an ICS and a LABA.

44. The method of claim 43.

45. 45. The method of claim 44, wherein the ICS is fluticasone or budesonide.

46. 45. The method of claim 44, wherein the LABA is salmeterol or formoterol.

47. 45. The method of claim 44, wherein an ICS and a LABA are both administered, wherein the ICS is fluticasone and the LABA is salmeterol.

48. 1. A method for treating moderate to severe asthma in a subject in need thereof, comprising: an initial dose of about 300 mg of SAR440340; and One or more maintenance doses of approximately 300 mg of SAR440340 to a subject, The method, wherein SAR440340 is administered subcutaneously every other week.

49. 1. A method for treating moderate to severe asthma in a subject in need thereof, comprising administering an initial dose of about 300 mg of SAR440340; one or more maintenance doses of about 300 mg of SAR440340; an initial dose of dupilumab of about 300 mg; and One or more maintenance doses of dupilumab of approximately 300 mg to a subject, The method, wherein SAR440340 and dupilumab are administered subcutaneously every other week.

50. 1. A method for reducing dependence in an asthma patient on one or both of inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs) for the treatment of one or more asthma exacerbations or asthma exacerbations, comprising: administering, at defined times for an initial treatment period, to a subject with moderate to severe asthma that is partially controlled or uncontrolled with a baseline asthma therapy comprising ICS, LABA, or a combination thereof, a defined dose of an antibody or antigen-binding fragment thereof that specifically binds interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16, while maintaining the subject's baseline asthma therapy; and Continue administering the antibody or antigen-binding fragment thereof to the subject at the defined frequency and dose used during the initial treatment period, while gradually reducing or eliminating the dose of ICS, LABA, or combination administered to the subject over subsequent treatment periods. The method comprising:

51. 51. The method of claim 50, wherein the ICS is fluticasone, budesonide, or mometasone and the LABA is salmeterol or formoterol.

52. 51. The method of claim 50, comprising an ICS / LABA combination selected from the group consisting of fluticasone / salmeterol, budesonide / formoterol, and mometasone / formoterol.

53. 51. The method of claim 50, wherein the dosage of one or both of the LABA and ICS is removed at the end of the initial treatment period.

54. 51. The method of claim 50, wherein the dosage of one or both of the LABA and ICS is gradually reduced or eliminated over a period of 2 to 8 weeks.

55. 51. The method of claim 50, further comprising administering to the subject a second antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) and comprises three HCDR sequences comprising SEQ ID NOs: 21, 22, and 23, and three LCDR sequences comprising SEQ ID NOs: 24, 25, and 26.

56. 1. A method for treating asthma in a subject in need thereof, comprising: A dose of approximately 300 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16. to a subject.

57. 1. A method for treating asthma in a subject in need thereof, comprising: a dose of about 300 mg of a first antibody or antigen-binding fragment thereof that specifically binds to interleukin-33 (IL-33) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 4, 5, and 6, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 12, 14, and 16; and A dose of approximately 300 mg of a second antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) and comprises three heavy chain complementarity-determining region (HCDR) sequences comprising SEQ ID NOs: 21, 22, and 23, and three light chain complementarity-determining region (LCDR) sequences comprising SEQ ID NOs: 24, 25, and 26. The method comprises administering to a subject.

58. 58. The method of claim 56 or 57, wherein loss of asthma control (LOAC) is reduced in the subject.

59. 58. The method of claim 56 or 57, wherein one or more asthma-related parameters are improved in the subject.

60. 60. The method of claim 59, wherein the asthma-related parameter is selected from the group consisting of forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25%-75%, number or dose of long-acting beta-2 adrenergic receptor agonists (LABA), number or dose of inhaled corticosteroids, and number or dose of systemic steroid drugs.

61. 61. The method of claim 60, wherein the FEV1 before administration of a bronchodilator is improved.

62. 58. The method of claim 56 or 57, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl; between about 150 and 299 cells per μL; or about <150 cells per μL.

63. 63. The method of claim 62, wherein the subject has a blood eosinophil count of greater than or equal to about 300 cells per μl.

64. 58. The method of claim 56 or 57, wherein blood eosinophil levels are reduced.

65. 58. The method of claim 56 or 57, wherein the subject has high or low blood periostin levels.

66. 66. The method of claim 65, wherein the subject has an elevated blood periostin level of about ≧74.4 ng / mL.

67. 58. The method of claim 56 or 57, wherein one or both of the Asthma Control Questionnaire 5 Question Version (ACQ-5) score and the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ) score are improved.

68. 68. The method of claim 67, wherein the emotional functioning score on the AQLQ is improved.

69. 61. The method of claim 60, wherein the frequency or dosage of a long-acting beta-2 adrenergic agonist (LABA) is reduced, the frequency or dosage of an inhaled corticosteroid is reduced, or the frequency or dosage of a systemic steroid drug is reduced.

70. 58. The method of claim 56 or 57, wherein the asthma is moderate to severe asthma that is not adequately controlled on baseline therapy.

71. 71. The method of claim 70, wherein the background therapy comprises inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic agonists (LABAs).

72. 72. The method of claim 71, wherein the basal therapy comprises moderate to high doses of ICS / LABA.

73. 57. The method of claim 56, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

74. 74. The method of claim 73, wherein the antibody comprises SAR440340.

75. 58. The method of claim 57, wherein the first antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

76. 76. The method of claim 75, wherein the first antibody comprises SAR440340.

77. 58. The method of claim 57, wherein the second antibody or antigen-binding fragment comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

28.

78. 78. The method of claim 77, wherein the second antibody comprises dupilumab.

79. 58. The method of claim 56 or 57, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously using an autoinjector, needle and syringe, or pen delivery device.

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