Methods for treating chronic sinusitis with nasal polyps by administering il-4r antagonist

Abstract

To provide methods for decreasing a nasal polyp score in a subject.SOLUTION: Provided are methods including the step for administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist such as an anti-IL-4R antibody or antigen binding fragment thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 080,092, filed November 14, 2014, U.S. Provisional Patent Application No. 62 / 083,821, filed November 24, 2014, U.S. Provisional Patent Application No. 62 / 158,832, filed May 8, 2015, and U.S. Provisional Patent Application No. 62 / 199,305, filed July 31, 2015, as well as European Application No. 15306632.9, filed October 14, 2015, each of which is incorporated by reference herein in its entirety.

[0002] The present invention relates to the field of therapeutic treatment of inflammatory conditions. More particularly, the present invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists to reduce nasal polyps scores and to treat related conditions. [Background technology]

[0003] Chronic rhinosinusitis (CS), an inflammatory condition of the paranasal sinuses, is a common syndrome with an estimated prevalence of 13% in Western populations. The condition is characterized by any combination of specific symptoms, often over many years, including nasal congestion, reduced or lost sense of smell, anterior and / or posterior rhinorrhea, facial pain and / or headaches and their consequences. CS can be clinically classified as CS with or without nasal polyps.

[0004] Nasal polyps (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, arising from the middle meatus natural orifice route. NP is a T helper cell-2 (Th-2) driven inflammatory process affecting the nasal mucosa and paranasal sinuses. Eosinophils and their products are considered to be hallmarks of inflammation associated with nasal polyps, as high levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cationic protein (ECP) and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are typically found in nasal polyps. Eosinophils are the primary inflammatory cells found in the sinuses and nasal polyps, which are also associated with high levels of IgE. NP is characterized by long-lasting symptoms of nasal obstruction and congestion, reduced or lost sense of smell, anterior and posterior rhinorrhea, and facial pain. Current treatment options range from topical or systemic corticosteroids to functional endoscopic sinus surgery.

[0005] Current medical management of chronic rhinosinusitis with nasal polyps / polyps (CSwNP) focuses primarily on managing inflammation, including administration of topical and systemic corticosteroids aimed at reducing polyp burden and number. If unsuccessful, surgical resection is indicated. However, disease recurrence is frequently reported after surgery, with recurrence rates approaching 50% in patients with tissue eosinophilia. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 7,605,237 [Patent Document 2] U.S. Patent No. 7,608,693 Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the present invention provides a method for reducing the nasal polyp score (NPS) in a subject in need thereof. The present invention provides a method for reducing NPS in a subject, the method comprising the steps of determining an NPS of the subject and administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences derived from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 and 2, thereby reducing the NPS of the subject (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%). This aspect may alternatively be stated as follows: A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) for use in reducing nasal polyp score (NPS) in a subject in need thereof (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%), the pharmaceutical composition being for administration to a subject having a determined NPS, the antibody or antigen-binding fragment thereof comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 and 2. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4, and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7, and 8. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises a HCVR having the amino acid sequence of SEQ ID NO: 1 and a LCVR having the amino acid sequence of SEQ ID NO: 2. The antibody can have, for example, a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10.

[0008] In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in U.S. Patent No. 5,933,633 and U.S. Patent No. 5,933,633.

[0009] A subject suitable for treatment with an IL-4R antagonist may have at least five nasal polyps in total, including two or more nasal polyps present in each nostril prior to the administration step, and / or may suffer from one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, and Samter's triad (defined by the presence of nasal polyps, asthma, and aspirin and NSAID hypersensitivity), and / or may have undergone surgery for either or both of nasal polyps and chronic rhinosinusitis. In certain embodiments, a subject suitable for treatment has one or more conditions selected from the group consisting of chronic rhinosinusitis with nasal polyps (CSwNP), chronic rhinosinusitis with bilateral nasal polyps, and rhinosinusitis with nasal polyps (CRSwNP) (e.g., with or without asthma). A subject suitable for treatment may or may not have asthma. In some embodiments, subjects suitable for treatment are indicated for primary functional endoscopic sinus surgery (FESS), are indicated for revision surgery, or have a contraindication to surgery.

[0010] In some embodiments, the IL-4R antagonist is indicated for the long-term treatment of adults with chronic rhinosinusitis with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with intranasal corticosteroids (INCS); for the long-term treatment of adults with bilateral nasal polyps and associated chronic rhinosinusitis and who have persistent signs and symptoms despite treatment with INCS; for the treatment of adults with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with intranasal or oral corticosteroids or who are intolerant to oral corticosteroids; for the treatment of adults with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with intranasal or oral corticosteroids or who are intolerant to oral corticosteroids.

[0011] In some embodiments, the IL-4R antagonist is administered at a dose of between about 100 mg and about 600 mg. In some embodiments, the IL-4R antagonist is administered at an initial dose of between about 400 mg and about 600 mg, and at an initial dose of between about 200 mg and about 400 mg, respectively. In some embodiments, the IL-4R antagonist is administered at an initial dose of about 600 mg and at one or more subsequent doses of about 300 mg each. In other embodiments, the IL-4R antagonist is administered once every seven days (QW). In certain embodiments, the pharmaceutical composition is administered to the subject systemically or locally. For example, the pharmaceutical composition is administered subcutaneously, intravenously, or intranasally. In one embodiment, the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg or a dose of 600 mg.

[0012] In some embodiments, after the administration step, one or more nasal polyp-related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea, and nasal peak inspiratory flow (NPIF) are improved. In some embodiments, the improvement of one or more of loss of smell, runny nose, post-rhinorrhea, and nasal peak inspiratory flow occurs during the day (AM), at night (PM), or both AM and PM. In some embodiments, after the administration step, one or more of serum IgE level, plasma eotaxin-3 level, and serum thymus and activation-regulated chemokine (TARC) level are reduced. In some embodiments, after the administration step, one or more of total IgE level, eotaxin-3 level, and ECP level are reduced in the subject's nasal secretion.

[0013] In another aspect, the present invention provides a method for reducing NPS in a subject in need thereof, comprising the steps of determining the NPS of the subject; administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; and administering to the subject one or more maintenance doses of about 200 to about 300 mg each of the antibody or antigen-binding fragment thereof, thereby reducing the NPS of the subject (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%). This aspect may alternatively be stated as follows: an antibody or antigen-binding fragment thereof that specifically binds IL-4R for use in reducing NPS in a subject in need thereof (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%), wherein the antibody or antigen-binding fragment is for administration to a subject whose NPS has been determined; for administration at a loading dose of about 400 to about 600 mg; comprises heavy and light chain CDR sequences from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; and for administration at one or more maintenance doses of about 200 to about 300 mg each. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4, and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7, and 8. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises a HCVR having the amino acid sequence of SEQ ID NO: 1 and a LCVR having the amino acid sequence of SEQ ID NO: 2. The antibody can have, for example, a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof.

[0014] In some embodiments, the loading dose of the IL-4R antagonist is about 600 mg, and one or more maintenance doses of the IL-4R antagonist are each about 300 mg. In other embodiments, the IL-4R antagonist is administered once every seven days (QW). In certain embodiments, the pharmaceutical composition is administered systemically or locally to the subject. For example, the pharmaceutical composition is administered subcutaneously, intravenously, or intranasally. In one embodiment, the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg or a dose of 600 mg.

[0015] A subject suitable for treatment with an IL-4R antagonist may have a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administration step, and / or may have a condition such as sinusitis, rhinitis, asthma, aspirin hypersensitivity, NSAID hypersensitivity, and / or a condition such as rhinitis, asthma, aspirin hypersensitivity, NSAID hypersensitivity, or ... The subject may suffer from one or more conditions selected from the group consisting of nasal polyps and Samter's triad, and / or may have undergone surgery for either or both of nasal polyps and chronic rhinosinusitis. In certain embodiments, the subject suitable for treatment has one or more conditions selected from the group consisting of CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP (e.g., with or without asthma). The subject suitable for treatment may or may not have asthma. In some embodiments, the subject suitable for treatment is indicated for FESS, indicated for revision surgery, or has a contraindication to surgery.

[0016] In some embodiments, after the administration step, one or more of the parameters related to nasal polyps are improved, selected from the group consisting of loss of smell, runny nose, post-rhinorrhea, and NPIF. In some embodiments, the improvement of one or more of loss of smell, runny nose, post-rhinorrhea, and nasal peak inspiratory flow occurs in AM, PM, or both AM and PM. In some embodiments, after the administration step, one or more of serum IgE level, plasma eotaxin-3 level, and serum TARC level are reduced. In some embodiments, after the administration step, one or more of total IgE level, eotaxin-3 level, and ECP level are reduced in the subject's nasal secretion.

[0017] In another aspect, the present invention provides a method of reducing NPS in a subject in need thereof, comprising the steps of determining the NPS of the subject; administering to the subject one or more maintenance doses of ICS; administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; and administering to the subject one or more maintenance doses of about 200 to about 300 mg each of the antibody or antigen-binding fragment thereof, wherein the ICS is administered during the period of administration of the antibody or antigen-binding fragment thereof, resulting in a reduction in the NPS of the subject (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%). This aspect can alternatively be expressed as follows: an antibody or antigen-binding fragment thereof that specifically binds IL-4R for use in reducing NPS in a subject in need thereof (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%); for administration to a subject whose NPS has been determined; for administration to a subject who has received one or more maintenance doses of ICS; for administration at a loading dose of about 400 to about 600 mg; comprising heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; for administration at one or more maintenance doses of about 200 to about 300 mg each; and for administration during the administration period of the antibody or antigen-binding fragment. For example, in one embodiment, the antibody or antigen-binding fragment comprises the heavy chain CDR sequences of SEQ ID NOs: 3, 4, and 5 and the light chain CDR sequences of SEQ ID NOs: 6, 7, and 8. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. The antibody can have, for example, a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof.

[0018] In some embodiments, the loading dose of the IL-4R antagonist is about 600 mg and one or more maintenance doses of the IL-4R antagonist are each about 300 mg. In other embodiments, the IL-4R antagonist is administered once every seven days (QW). In certain embodiments, the pharmaceutical composition is administered systemically or orally to the subject. For example, the pharmaceutical composition is administered subcutaneously, intravenously, or intranasally. In one embodiment, the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg or a dose of 600 mg. In some embodiments, the ICS is mometasone furoate nasal spray (MFNS). In some embodiments, about 100 mg of MFNS is administered to each nostril of the subject once or twice daily.

[0019] A subject suitable for treatment with an IL-4R antagonist may have at least five nasal polyps in total, including two or more nasal polyps present in each nostril prior to the administration step, and / or may suffer from one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity, NSAID hypersensitivity, and Samter's triad, and / or may have undergone surgery for either or both of nasal polyps and chronic rhinosinusitis. In certain embodiments, a subject suitable for treatment has one or more conditions selected from the group consisting of CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP (e.g., with or without asthma). A subject suitable for treatment may or may not have asthma. In some embodiments, a subject suitable for treatment is indicated for FESS, indicated for revision surgery, or contraindicated for surgery.

[0020] In some embodiments, after the administration step, one or more of the parameters related to nasal polyps are improved, selected from the group consisting of loss of smell, runny nose, post-rhinorrhea, and NPIF. In some embodiments, the improvement of one or more of loss of smell, runny nose, post-rhinorrhea, and nasal peak inspiratory flow occurs in AM, PM, or both AM and PM. In some embodiments, after the administration step, one or more of serum IgE level, plasma eotaxin-3 level, and serum TARC level are reduced. In some embodiments, after the administration step, one or more of total IgE level, eotaxin-3 level, and ECP level are reduced in the subject's nasal secretion.

[0021] In another aspect, the present invention provides a method of reducing NPS and improving one or more additional nasal polyp associated parameters in a subject in need thereof, comprising the steps of determining NPS in the subject; determining a level of the one or more additional nasal polyp associated parameters in the subject; administering to the subject one or more maintenance doses of ICS; and administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2. and administering to the subject one or more maintenance doses of about 200 to about 300 mg each of the antibody or antigen-binding fragment thereof, wherein the ICS is administered during the administration period of the antibody or antigen-binding fragment thereof, such that the subject's NPS is reduced (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%) and one or more additional nasal polyp-related parameters are improved in the subject. This embodiment can alternatively be expressed as follows: an antibody or antigen-binding fragment thereof that specifically binds IL-4R for use in reducing NPS (e.g., by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%) and for use in improving one or more additional nasal polyp-related parameters in a subject in need thereof; for administration to a subject whose NPS has been determined; for administration to a subject whose level of one or more additional nasal polyp-related parameters has been determined; for administration to a subject who has received one or more maintenance doses of ICS; for administration at a loading dose of about 400 to about 600 mg; comprising heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; for administration at one or more maintenance doses of about 200 to about 300 mg each; and for administration during the period of administration of the antibody or antigen-binding fragment thereof. In one embodiment, the antibody or antigen-binding fragment thereof comprises the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5 and the heavy chain CDR sequences of SEQ ID NOs: 6, 7 and a light chain CDR sequence of SEQ ID NO:8. For example, in one embodiment, the antibody or antigen-binding fragment thereof comprises a HCVR having the amino acid sequence of SEQ ID NO:1 and a LCVR having the amino acid sequence of SEQ ID NO:2. The antibody can have, for example, a heavy chain sequence of SEQ ID NO:9 and a light chain sequence of SEQ ID NO:10. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. In one embodiment, the one or more additional nasal polyps-related parameters are selected from the group consisting of loss of smell, runny nose, post-nasal drip, and NPIF.

[0022] In another aspect, the invention provides a method of treating CSwNP in a patient with or without asthma by administering a therapeutically effective amount of an anti-IL-4R antibody or antigen-binding fragment thereof to a subject. This aspect can alternatively be stated as follows: an anti-IL-4R antibody or antigen-binding fragment for use in treating CSwNP in a patient with or without asthma. The antibody can have, for example, a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2. In some embodiments, the antibody or antigen-binding fragment thereof is administered as an initial loading dose of about 400 mg to about 600 mg of the antibody or antigen-binding fragment thereof, followed by one or more maintenance doses of about 200 mg to about 300 mg each, such that one or more symptoms of CSwNP are reduced. In some embodiments, one or more of the endoscopic, radiological and clinical endpoints of CSwNP are improved. In other embodiments, lung function and disease management is improved in patients with comorbid asthma. In other embodiments, the NPS of a subject with CSwNP is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

[0023] Other embodiments will be apparent from the figures, tables, and detailed description provided in this application. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 is a schematic representation of an example of a background therapy holiday in the treatment of asthma patients. [Figure 2-1] FIG. 1 graphically depicts least squares (LS) mean change from baseline in bilateral endoscopic nasal polyp scores by visit in the intent-to-treat (ITT) population. [Figure 2-2] Continued from Figure 2-1. [Figure 2-3] Continued from Figure 2-2. [Diagram 3] FIG. 1 graphically depicts LS mean change from baseline in bilateral endoscopic nasal polyp scores by visit for the subgroup of patients with comorbid asthma in the ITT population. [Figure 4] FIG. 1 graphically depicts LS mean change from baseline in bilateral endoscopic nasal polyp scores by visit for the subgroup of patients without comorbid asthma in the ITT population. [Diagram 5] FIG. 1 graphically depicts LS mean change from baseline in Sinus Oral Test-22 (SNOT-22) total score in the ITT population. [Figure 6] FIG. 1 graphically depicts LS mean change from baseline in visual analog scale (VAS) for rhinosinusitis symptom severity in the ITT population. [Figure 7] FIG. 1 graphically depicts LS mean change from baseline in daytime (AM) symptom scores for loss of smell in the ITT population. [Figure 8] FIG. 1 graphically depicts LS mean change from baseline in nighttime (PM) symptom scores for loss of smell in the ITT population. [Figure 9] FIG. 1 graphically depicts LS mean change from baseline in olfactory testing in the ITT population. [Figure 10] FIG. 1 graphically depicts LS mean change from baseline in AM symptom score for clog / obstruction in the ITT population. [Figure 11] FIG. 1 graphically depicts LS mean change from baseline in PM symptom scores for clogs / obstructions in the ITT population. [Figure 12] FIG. 1 graphically depicts LS mean change from baseline in AM symptom scores for runny nose in the ITT population. [Figure 13] FIG. 1 graphically depicts LS mean change from baseline in PM symptom scores for runny nose in the ITT population. [Figure 14] FIG. 1 graphically depicts LS mean change from baseline in AM symptom scores for posterior rhinorrhea in the ITT population. [Figure 15] FIG. 1 graphically depicts LS mean change from baseline in PM symptom scores for posterior rhinorrhea in the ITT population. [Figure 16] FIG. 1 graphically depicts LS mean change from baseline in AM nasal peak inspiratory flow (NPIF) in the ITT population. [Figure 17] FIG. 13 graphically depicts LS mean change from baseline in PM NPIF in the ITT population. [Figure 18] FIG. 1 graphically depicts serum total immunoglobulin E (IgE) mean percent change from baseline by treatment in the ITT population. [Figure 19] FIG. 1 graphically depicts serum thymus and activation-regulated chemokine (TARC) mean percent change from baseline by treatment in the ITT population. [Figure 20] FIG. 1 graphically depicts Fridericia corrected (QTc) (MS) mean change from baseline by visit in the safety population. [Figure 21-1] FIG. 13 Graphical results from subjective secondary outcomes including smell, assessed by the University of Pennsylvania Smell Identification Test (UPSIT) (A), self-reported morning nasal congestion / blockage (B), and self-reported morning posterior rhinorrhea (C). [Figure 21-2] Continued from Figure 21-1. [Figure 22-1]Figure 1 graphically depicts endpoints in patients with asthma. Compared with placebo, dupilumab was associated with significant improvements in mean forced expiratory volume in 1 second (FEV1) percent predicted (%) and FEV1(L) in liters (A), Asthma Control Questionnaire, 5 Questions (ACQ-5) (B), and Endoscopic Nasal Polyp Score (NPS) (C). [Figure 22-2] Continued from Figure 22-1. [Figure 23-1] FIG. 1 graphically depicts pharmacodynamic biomarkers expressed in serum: least squares mean percent change from baseline for total IgE (A), thymus and activation-regulated chemokine (TARC) (B), eotaxin-3 (C) and blood eosinophil count (D). [Figure 23-2] Continued from Figure 23-1. [Figure 24-1] FIG. 1 graphically depicts pharmacodynamic biomarkers expressed in nasal secretions: least squares mean percent change from baseline for Eotaxin-3 (A), IgE (B), Eosinophil Cationic Protein (ECP) (C). [Figure 24-2] Continued from Figure 24-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0026] 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. As used herein, the term "about" when used in reference to a particular recited numerical value means that the numerical value may vary by no more than 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.).

[0027] All publications mentioned herein are incorporated by reference in their entirety for all purposes.

[0028] Methods for Treating Chronic Sinusitis with Nasal Polyps In certain embodiments, the present invention provides a method for treating chronic sinusitis with nasal polyps / polyps (CSwNP). In other embodiments, the present invention provides a method for treating chronic sinusitis without nasal polyps / polyps. As used herein, "chronic sinusitis" ("CS") refers to an inflammatory condition of the paranasal sinuses characterized by any combination of specific symptoms, often over many years, including but not limited to nasal obstruction, reduced or lost sense of smell, anterior and / or posterior rhinorrhea, facial pain and / or headaches and their consequences. Formal diagnosis is made based on sinus computed tomography (CT) scans and / or sinus endoscopy. Based on endoscopic evaluation, CS can be clinically classified as CS with nasal polyps / polyps (CSwNP) or CS without nasal polyps / polyps.

[0029] In certain embodiments, the IL-4R antagonists described herein are indicated for the long-term treatment of adults with chronic rhinosinusitis with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with intranasal corticosteroids (INCS). In other embodiments, the IL-4R antagonists described herein are indicated for the long-term treatment of adults with chronic rhinosinusitis with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with INCS.

[0030] In certain embodiments, the present invention provides a method for treating nasal polyps. As used herein, "nasal polyps" are overgrowths of tissue in one or more nasal cavities. The condition of having nasal polyps is called "nasal polyps". Approximately 80% of nasal polyps are highly edematous and filled with eosinophils. Nasal polyps may also be present as fibrous, glandular or cystic. Nasal polyps are typically teardrop-shaped growths that form in the nose and / or paranasal sinuses and block the paranasal sinuses and nasal passages.

[0031] In a particular embodiment, the present invention provides a method for treating nasal polyps (NP). NP is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, originating from the middle meatus natural orifice route. NP is a T helper cell-2 (Th-2) driven inflammatory process that affects the nasal mucosa and paranasal sinuses. Eosinophils and their products are considered to be characteristic of the inflammation associated with nasal polyps, since high levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), ECP and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are typically found in nasal polyps. Eosinophils are the main inflammatory cells found in sinuses and nasal polyps, and nasal polyps are also associated with high levels of IgE.

[0032] NP is characterized by long-standing symptoms of nasal obstruction and congestion, decreased or lost sense of smell, anterior and posterior rhinorrhea, and facial pain. The presence or absence of nasal polyps is confirmed, for example, by performing an endoscopy, and the presence and extent of sinus and polyp involvement is confirmed by methods such as coronal computed tomography (CT) scans.

[0033] As used herein, "bilateral NP" refers to one or more NPs on both sides of the nasal cavity. Refers to the presence of P.

[0034] IL-4R antagonists can be used to treat nasal polyps associated with various conditions. For example, nasal polyps are associated with infections such as sinusitis (e.g., allergic and nonallergic sinusitis), rhinitis (e.g., allergic and nonallergic rhinitis), rhinosinusitis (e.g., allergic and nonallergic rhinosinusitis), asthma (e.g., moderate to severe asthma), NSAID hypersensitivity (e.g., aspirin hypersensitivity), and bacterial and fungal infections. Subjects with nasal polyps, such as patients with chronic sinusitis with bilateral nasal polyps, may have concurrent Samter's triad (defined by the presence of NP, asthma, and aspirin and SNAID hypersensitivity). Subjects with nasal polyps may also have concurrent asthma, and / or other Th2 concurrent systemic conditions. Bacterial infections include, for example, Staphylococcus aureus infections. The subject with nasal polyps may have a chronic infection, such as a chronic bacterial infection, for example, a chronic Staphylococcus aureus infection. In some embodiments, the subject has recurrent nasal polyps, such as those that may be associated with recurrent sinusitis. In other embodiments, the subject has cystic fibrosis or NARES (non-allergic rhinitis with hypereosinophilic syndrome). In other embodiments, the subject has recurrent nasal polyps after undergoing surgery to treat polyps. Risk factors for nasal polyps include genetic susceptibility, anatomical abnormalities, mucociliary dysfunction, infection, and local immune imbalance.

[0035] IL-4R antagonists can be used to treat nasal polyps associated with various conditions. For example, nasal polyps are associated with infections such as sinusitis (e.g., allergic or nonallergic sinusitis), rhinitis (e.g., allergic and nonallergic rhinitis), rhinosinusitis (e.g., allergic or nonallergic rhinosinusitis), asthma (e.g., moderate to severe asthma), NSAID hypersensitivity (e.g., aspirin hypersensitivity), and bacterial and fungal infections. Subjects with nasal polyps, such as patients with chronic sinusitis with bilateral nasal polyps, may have concurrent Samter's triad (defined by the presence of NP, asthma, and aspirin and SNAID hypersensitivity). Subjects with nasal polyps may also have concurrent asthma, and / or other Th2 concurrent systemic conditions. Bacterial infections include, for example, Staphylococcus aureus infections. The subject with nasal polyps may have a chronic infection, such as a chronic bacterial infection, for example, a chronic Staphylococcus aureus infection. In some embodiments, the subject has recurrent nasal polyps, such as those that may be associated with recurrent sinusitis. In other embodiments, the subject has cystic fibrosis or NARES (non-allergic rhinitis with hypereosinophilic syndrome). In other embodiments, the subject has recurrent nasal polyps after undergoing surgery to treat polyps. Risk factors for nasal polyps include genetic susceptibility, anatomical abnormalities, mucociliary dysfunction, infection, and local immune imbalance.

[0036] As used herein, the term "sinusitis" refers to any inflammatory condition characterized by inflammation of the paranasal sinuses, including inflammation of the maxillary, frontal, ethmoid and / or sphenoid sinuses. IL-4R antagonists are suitable for the treatment of nasal polyps associated with acute sinusitis, subacute sinusitis, chronic sinusitis and recurrent sinusitis. Acute sinusitis is characterized by the sudden onset of cold-like symptoms such as runny nose, nasal congestion and facial pain that do not subside after 10-14 days. Acute sinusitis typically lasts less than 4 weeks. Subacute sinusitis lasts 4-8 weeks. Chronic sinusitis lasts 8 weeks or more, and recurrent sinusitis is characterized by episodes of sinusitis symptoms that occur three or more times a year. More than 80% of patients with CSwNP have eosinophilic upper airway inflammation.

[0037] Many patients with chronic sinusitis have "chronic hyperplastic eosinophilic sinusitis," characterized by significant sinus inflammation, increased eosinophils and mixed mononuclear cells, and relatively few neutrophils. Some of these patients also have one or more of associated nasal polyps, asthma, and aspirin or NSAID sensitivity. In certain embodiments, IL-4R antagonists are used to treat chronic sinusitis. The antagonists are used to treat nasal polyps in subjects with chronic hyperplastic eosinophilic sinusitis.

[0038] As used herein, "allergic sinusitis" refers to sinusitis that occurs when the body's immune system responds to specific non-infectious irritants, such as, for example, plant pollens, molds, dust mites, animal hair, industrial chemicals (including tobacco smoke), foods, medicines, and insect venom.

[0039] As used herein, "non-allergic sinusitis" refers to sinusitis that is not due to an allergic reaction, for example, from colds, allergies, and tissue irritants (e.g., nasal sprays, cocaine, cigarette smoke, etc.). Less commonly, the sinuses may be blocked by a tumor or growth.

[0040] The term "rhinitis" refers to an allergic reaction to common allergens ("allergic rhinitis", e.g., perennial allergic rhinitis) or environmental irritants (non-allergic rhinitis). Symptoms of allergic rhinitis include sneezing; stuffy or runny nose; sinus pressure and pain or throbbing in the cheeks or nose; and itchy nose, throat, eyes, and ears.

[0041] As used herein, "allergic rhinitis" refers to rhinitis that occurs when the body's immune system responds to specific non-infectious irritants.

[0042] As used herein, "non-allergic rhinitis" refers to rhinitis not caused by an allergic reaction, for example, rhinitis induced by factors such as cigarette smoke and other pollutants, strong odors, strong chemical environments, alcoholic beverages, colds, nasal blockage, deviated septum, infections, and overuse of medications such as decongestants and / or nasal sprays. Symptoms of non-allergic rhinitis include narrowing or inflammation of the nasal passages that lead to many of the same symptoms of allergic rhinitis.

[0043] As used herein, the term "rhinosinusitis" refers to a condition that has symptoms of both rhinitis and sinusitis. Rhinosinusitis includes acute rhinosinusitis and chronic rhinosinusitis. Acute rhinosinusitis is caused by infection, such as bacterial, viral or fungal infection, or by chemical irritation. Acute rhinosinusitis induced by cigarette smoke and chronic rhinosinusitis induced by chlorine gas are examples of acute rhinosinusitis. NP is most commonly associated with chronic rhinosinusitis (CRS), characterized by mucosal inflammation of the nasal cavity and paranasal sinuses, with symptoms lasting longer than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps is a condition lasting longer than 8 weeks.

[0044] Chronic sinusitis (CS) and chronic rhinosinusitis (CRS) are conditions that last longer than 8 weeks. The underlying causes of acute sinusitis and acute rhinosinusitis may lead to chronic sinusitis or chronic rhinosinusitis if the resulting inflammation lasts longer than 8 weeks. Chronic rhinosinusitis includes, for example, eosinophilic chronic hyperplastic rhinosinusitis.

[0045] Further subcategories of chronic sinusitis (and chronic rhinosinusitis) include, for example, superantigen-induced eosinophilic chronic sinusitis (e.g., sinusitis induced by exotoxins and endotoxins produced by bacteria such as Staphylococcus aureus); allergic fungal sinusitis (e.g., sinusitis induced by fungi such as Aspergillus or Alternaria); nonallergic fungal eosinophilic chronic sinusitis; and aspirin-exacerbated eosinophilic chronic sinusitis. Rhinosinusitis can be further classified as allergy-induced. They are classified as allergic rhinosinusitis and nonallergic rhinosinusitis.

[0046] As used herein, "allergic rhinosinusitis" refers to rhinosinusitis that occurs in response to exposure to one or more allergens.

[0047] As used herein, "non-allergic rhinosinusitis" refers to rhinosinusitis caused by factors including, but not limited to, pregnancy; thyroid disorders as a side effect of certain blood pressure and / or topical OTC decongestants; structural abnormalities of the nasal septum, nasal filtering structures (nasal turbinates) and / or sinus drainage tracts; nasal polyps; and eosinophils.

[0048] IL-4R antagonists are used to treat nasal polyps in subjects with any of the above disorders.

[0049] Methods for improving parameters related to nasal polyps The present invention includes a method for improving one or more nasal polyp-related parameters in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist. In other words, the present invention includes a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in improving one or more nasal polyp-related parameters in a subject in need thereof. For example, an IL-4R receptor antagonist can reduce the endoscopic nasal polyp score (NPS) in a patient. A nasal polyp score of 0 indicates the absence of polyps. An NPS of 1 indicates the presence of small polyps in the middle meatus that do not reach below the lower edge of the middle turbinate. An NPS of 3 indicates large polyps that reach the lower edge of the inferior turbinate or polyps midway up to the middle turbinate. An NPS of 4 indicates large polyps that cause complete obstruction of the inferior nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nasal cavity). Treatment with an IL-4R antagonist can reduce the NPS by about 1 to about 8 points. For example, treatment with an IL-4R antagonist can reduce the NPS by about 1 point or more, about 2 points or more, or about 3 points or more. In some embodiments, treatment with an IL-4R antagonist can reduce the NPS by about 1 point or fraction; 2 points or fraction; 3 points or fraction; 4 points or fraction; 5 points or fraction; 6 points or fraction; 7 points or fraction; or 8 points or fraction.

[0050] Treatment with an IL-4R antagonist can reduce the patient's NPS compared to the NPS before treatment. In certain embodiments, the NPS is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 82%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about %, about 27%, about 28%, about 29%, about 30, about 31%, about 32%, about 33%, about 34%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%, or any range between these numbers. Thus, in certain embodiments, NPS is about 1% to about 99%, or about 2% to about 98%, or about 3% to about 97%, or about 4% to about 96%, or about 5% to about 95%, or about 6% to about 90%, or about 7% to about 85%, or about 8% to about 80%, or about 9% to about 75%, or about 10% to about 70%, or about 11% to about 65%, or about 12% to about 60%, or about 13% to about 55%, or about 14% to about 50%, or about 15% to about 45%, or about 16% to about 40%, or about 17% to about 35%, or about 18% to about 34%, or about 19% to about 33%, or about 20% to about 32% , or by about 21% to about 31%, or by about 22% to about 30%, or by about 23% to about 29%, or by about 24% to about 28%, or by about 25% to about 27%, or by about 25% to about 26%.

[0051] A decrease in NPS may correlate with an improvement in one or more other nasal polyp-related parameters, however, such a correlation may not be observed in all cases.

[0052] Other examples of "nasal polyp-related parameters" include, but are not limited to: (a) 22-item Sinus Oral Test (SNOT-22) score; (b) subject-assessed nasal congestion / obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip), and loss of smell; (c) number of night awakenings; (d) visual analog scores (VAS) for assessing the severity of patient-assessed rhinosinusitis symptoms; (e) 5-item Asthma Control Questionnaire (ACQ5) score, such as in patients with asthma; (f) nasal peak inspiratory flow (NPIF); (g) olfactory testing (University of Pennsylvania Smell Identification Test (UPSIT)); (h) physiological parameters measured, such as by nasal endoscopy and CT scan; (i) Lund-Mackay score; and (j) three-dimensional volume measurements of the maxillary sinuses.

[0053] 22-item Sinus Oral Test (SNOT-22) score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the 22-item Sinus Oral Test (SNOT-22). SNOT-22 is a questionnaire for assessing the impact of chronic rhinosinusitis (CRS) on quality of life. The questionnaire measures items related to sinus conditions and surgical procedures. Scores range from 0 to 110, with higher scores indicating a greater impact of CRS on health-related quality of life (HRQoL) (Hopkins et al. 2009, Clin. Otolaryngol. 34:447-454).

[0054] The present invention includes a method of treatment that results in a reduction in SNOT-22 score from baseline of at least 1 point at 4 to 16 weeks after administration of an IL-4R antagonist. In other words, the present invention includes an IL-4R antagonist for use in reducing SNOT-22 score from baseline of at least 1 point at 4 to 16 weeks. For example, administration of an IL-4R antagonist results in a reduction in SNOT-22 score at 4, 6, 8, 12 or 16 weeks after the start of treatment. In some embodiments, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more points at 4, 6, 8 or 12 weeks. Thus, in one embodiment, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points or more at week 4. In another embodiment, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points or more at week 6. In a further embodiment, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points or more at week 8. In yet another embodiment, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more points at 12 weeks.

[0055] Individual and total nasal symptom scores. Symptoms were assessed by the subjects on a categorical scale of 0 to 3 ( Here, a scale of 0=no symptoms, 1=mild symptoms, 2=moderate symptoms and 3=severe symptoms is used and assayed by answering individual rhinosinusitis symptom questions in the morning and evening, including symptoms of congestion / obstruction, anterior rhinorrhea, posterior rhinorrhea and loss of smell. Nasal symptoms may be assayed during the day (AM), evening (PM), or both AM and PM.

[0056] The loss of smell can be tracked. The administration of an IL-4R antagonist can result in a reduction in the loss of smell from baseline (i.e., a smaller number on the scale) compared to 4 to 16 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a reduction in the loss of smell from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks, 6 weeks, 8 weeks, 12 weeks or 16 weeks after the start of treatment. Thus, for example, a reduction in the loss of smell from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks after the start of treatment. In a further example, a reduction in olfactory loss from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 6 weeks after the start of treatment. In a further example, a reduction in olfactory loss from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 8 weeks after the start of treatment. In a further example, a reduction in olfactory loss from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 12 weeks after the start of treatment. In a further example, a reduction in olfactory loss from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 16 weeks after the start of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in, for example, a decrease in the loss of smell symptom score from baseline at 4 weeks, 8 weeks, 12 weeks or 16 weeks of about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0.

[0057] The reduction in clogging and / or obstruction can be tracked. Administration of an IL-4R antagonist can result in a reduction in clogging and / or obstruction from baseline (i.e., a smaller number on the scale) compared to, for example, 4 to 16 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks, 6 weeks, 8 weeks, 12 weeks or 16 weeks after the start of treatment. Thus, for example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks after the start of treatment. In a further example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 6 weeks after the start of treatment. In a further example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 8 weeks after the start of treatment. In a further example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 12 weeks after the start of treatment. In a further example, a reduction in clogging and / or obstruction from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 16 weeks after the start of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a reduction in congestion and / or obstruction symptom score from baseline of about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at, for example, 4 weeks, 8 weeks, 12 weeks or 16 weeks.

[0058] The reduction in runny nose can be monitored. Administration of an IL-4R antagonist can be used to treat, for example, Treatment with a pharmaceutical composition comprising an IL-4R antagonist can result in a decrease in runny nose from baseline (i.e., a smaller number on the scale) compared to 4 to 16 weeks after the start of treatment. For example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks, 6 weeks, 8 weeks, 12 weeks or 16 weeks after the start of treatment. Thus, for example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 4 weeks after the start of treatment. In a further example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 6 weeks after the start of treatment. In a further example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 8 weeks after the start of treatment. In a further example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 12 weeks after the start of treatment. In a further example, a decrease in runny nose from baseline (e.g., about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 16 weeks after the start of treatment. Administration of an IL-4R antagonist to a subject in need thereof can cause a decrease in runny nose symptom score from baseline of about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more, for example, at 4 weeks, 8 weeks, 12 weeks or 16 weeks.

[0059] The reduction in posterior rhinorrhea can be tracked. Administration of an IL-4R antagonist can result in a reduction in nasal discharge from baseline (i.e., a smaller number on the scale) compared to 4 to 16 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) can be seen at 4 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after the start of treatment. Thus, for example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) can be seen at 4 weeks after the start of treatment. In a further example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 6 weeks after the start of treatment. In a further example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 8 weeks after the start of treatment. In a further example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 12 weeks after the start of treatment. In a further example, a reduction in posterior rhinorrhea from baseline (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be seen 16 weeks after the start of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in, for example, a reduction in posterior nasal drip symptom score from baseline of about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at 4 weeks, 8 weeks, 12 weeks or 16 weeks.

[0060] Measurement of night awakenings is also tracked. For example, the measurement of night awakenings is evaluated according to the following scores based on the subject's self-assessment: 0 = no symptoms, slept all night; 1 = slept well, but had some symptoms in the morning; 2 = woke up once due to rhinosinusitis symptoms (including early awakening); 3 = woke up several times due to symptoms (including early awakening); 4 = slept restlessly, woke up most of the night due to symptoms. Administration of an IL-4R antagonist may result in a reduction in the average number of night awakenings per night from baseline of at least about 0.10 times per night, for example, 4 to 16 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a reduction in the frequency of night awakenings per night from baseline of at least about 0.10 times per night is observed 4, 6, 8, 12 or 16 weeks after the start of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a reduction in the average number of nighttime awakenings per night from baseline 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, for example, at 4 weeks, 8 weeks, 12 weeks or 16 weeks. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof can cause a decrease in the average number of overnight awakenings from baseline during week 4 by about 0.10 per night, 0.15 per night, 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0.50 per night, 0.55 per night, 0.60 per night, 0.65 per night, 0.70 per night, 0.75 per night, 0.80 per night, 0.85 per night, 0.90 per night, 0.95 per night, 1.0 per night, 2.0 per night or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof can cause a decrease in the average number of overnight awakenings from baseline at week 8 by about 0.10 per night, 0.15 per night, 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0.50 per night, 0.55 per night, 0.60 per night, 0.65 per night, 0.70 per night, 0.75 per night, 0.80 per night, 0.85 per night, 0.90 per night, 0.95 per night, 1.0 per night, 2.0 per night or more.In a further example, administration of an IL-4R antagonist to a subject in need thereof can cause a decrease in the average number of overnight awakenings from baseline at week 12 by about 0.10 per night, 0.15 per night, 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0.50 per night, 0.55 per night, 0.60 per night, 0.65 per night, 0.70 per night, 0.75 per night, 0.80 per night, 0.85 per night, 0.90 per night, 0.95 per night, 1.0 per night, 2.0 per night or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof can cause a decrease in the average number of overnight awakenings from baseline at week 16 by about 0.10 per night, 0.15 per night, 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0.50 per night, 0.55 per night, 0.60 per night, 0.65 per night, 0.70 per night, 0.75 per night, 0.80 per night, 0.85 per night, 0.90 per night, 0.95 per night, 1.0 per night, 2.0 per night or more.

[0061] Visual Analog Score (VAS). The VAS is a scale for assessing the severity of patient-rated rhinosinusitis symptoms on a scale of 1 to 10. Mild symptoms are indicated by a score of 0 to 3, moderate symptoms are indicated by a VAS score of more than 3 to 7, and severe symptoms are indicated by a VAS score of more than 7 to 10. Administration of an IL-4R antagonist to a subject in need thereof causes a reduction in the VAS score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points or more at 4 weeks, 6 weeks or 12 weeks. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in the VAS score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points or more at 4 weeks. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in VAS score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points or more at week 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in VAS score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points or more at week 12. The reduction in VAS score from baseline can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

[0062] Five-item Asthma Control Questionnaire (ACQ) score. The ACQ5 measures both the adequacy of asthma control and changes in asthma control that occur spontaneously or as a result of treatment. The five questions in the ACQ5 represent the top five asthma symptoms: symptoms waking you up at night, symptoms waking you up in the morning, limitation of daily activities, shortness of breath, and wheezing. Patients answered the symptom questions on a 7-point scale (0=no impairment, completely controlled; 6=maximal impairment, very poorly controlled).

[0063] The present invention includes a method of treatment that results in a decrease 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-4R antagonist. For example, according to the present invention, administration of an IL-4R antagonist to a subject in need thereof causes a decrease 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 4 weeks, 6 weeks or 12 weeks. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease 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 4 weeks. In further examples, administration of an IL-4R antagonist to a subject in need thereof causes a decrease 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 6 weeks. In further examples, administration of an IL-4R antagonist to a subject in need thereof causes a decrease 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.A reduction in ACQ scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

[0064] Nasal peak inspiratory flow (NPIF). Nasal peak inspiratory flow (NPIF) represents a physiological measure of airflow through both nasal passages during forced inspiration and / or expiration, expressed in liters / minute. Nasal inspiration correlates, in large part, with a subjective sense of obstruction and is used to monitor rhinorrhea. Administration of an IL-4R antagonist to a subject in need thereof causes an increase in NPIF from baseline of about 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0.25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 liters / minute, 0.65 liters / minute, 0.70 liters / minute, 0.75 liters / minute, 0.80 liters / minute, 0.85 liters / minute or more at 4, 6 or 12 weeks. Thus, in one example, administration of IL- Administration of a 4R antagonist results in an increase in NPIF from baseline of about 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0.25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 liters / minute, 0.65 liters / minute, 0.70 liters / minute, 0.75 liters / minute, 0.80 liters / minute, 0.85 liters / minute or more at 4 weeks. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in NPIF from baseline of about 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0.25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 liters / minute, 0.65 liters / minute, 0.70 liters / minute, 0.75 liters / minute, 0.80 liters / minute, 0.85 liters / minute or more at 6 weeks. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in NPIF from baseline of about 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0.25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 liters / minute, 0.65 liters / minute, 0.70 liters / minute, 0.75 liters / minute, 0.80 liters / minute, 0.85 liters / minute or more at 12 weeks. The increase in NPIF score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

[0065] University of Pennsylvania Smell Identification Test (UPSIT). The UPSIT is a method for quantitatively assessing olfactory function in humans. The test consists of a sample of odorants, and the subject must describe the odor. The score is based on the number of correct answers. The test can distinguish between patients with normal smell ("normosmia") and patients with different levels of reduction ("mild, moderate and severe microsmia") or loss ("anosmia"). Administration of an IL-4R antagonist to a subject in need thereof causes an increase in the UPSIT score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points or more at 4 weeks, 6 weeks or 12 weeks. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in the UPSIT score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points or more at 4 weeks. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in the UPSIT score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points or more at 6 weeks. In a further example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in the UPSIT score from baseline of about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points or more at 12 weeks. The increase in the UPSIT score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

[0066] Physiological parameters. The efficacy of IL-4R antagonists is assayed by measuring the effect of physiological parameters, such as intranasal, such as by nasal endoscopy or computed tomography (CT) scan.

[0067] Lund-Mackay Score. The Lund-Mackay scoring system is based on localization with points given for opacity: 0=normal, 1=partial opacification, 2=complete opacification. These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses on each side. The middle meatal ostium is graded as 0=not obstructed or 2=obstructed. The scores are calculated based on the number of points scored, resulting in a maximum score of 12 per side. For patients with missing middle orifice (OC) (due to previous surgery), the location of the previous OC is taken into account and a score is given as if the OC was there. Administration of an IL-4R antagonist to a subject in need thereof causes a reduction in the Lund-Mackay 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 4 weeks, 6 weeks or 12 weeks. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in Lund-Mackay 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 4 weeks. In further examples, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in Lund-Mackay 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 6 weeks.In a further example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in the Lund-Mackay 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 week 12. The decrease in the Lund-Mackay score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

[0068] Three-dimensional volume measurement of the maxillary sinus. This value is used to calculate air volume (mL); mucosal volume (mL); percent of the sinus occupied by disease; and lateral wall thickness in the maxillary sinus. Administration of an IL-4R antagonist to a subject in need thereof causes an increase in the three-dimensional volume measurement.

[0069] Quality of Life (QoL) Instruments. Various QoL instruments are used to monitor the efficacy of IL-4R antagonists, including the Short-Form-36 (SF-36) instrument, the Euroqol-5D (EQ-5D), a questionnaire using nasal polyp-related materials, and qualitative patient self-assessment.

[0070] The SF-36 is a 36-item questionnaire measuring eight multi-dimensional dimensions of health: physical functioning (10 items), social functioning (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), mental health (5 items), energy / vitality (4 items), pain (2 items) and general health (5 items). For each dimension, item scores were coded, summed and converted to a scale from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). Two standardized summary scores can also be calculated from the SF-36; the Physical Component Summary (PCS) and the Mental Health Component (MCS).

[0071] The EQ-5D was developed by the EuroQol Group to provide a simple, general measure of health for clinical and economic evaluations and inter-disease comparisons. It is a standardized health-related quality of life questionnaire developed by the EQ-5D. Designed for self-administration by patients, the EQ-5D consists of two parts: the EQ-5D Descriptor System and the EQ VAS. The EQ-5D Descriptor System includes five dimensions: mobility, caring for oneself, usual activities, pain / discomfort and anxiety / depression; each dimension has three levels: no problems, some problems and a lot of problems. The EQ Visual Analogue Scale (VAS) records the respondent's self-related health against a vertical visual analogue scale. The EQ VAS "thermometer" has a rating scale of 100 at the highest (best possible health state) and 0 at the lowest (worst possible health state).

[0072] The questionnaire using materials related to nasal polyps was a questionnaire using materials related to health care regarding nasal polyps, including specialist visits, emergency care visits, sick leave, and holidays.

[0073] Biomarkers associated with nasal polyps. Examples of biomarkers associated with nasal polyps include, but are not limited to, one or any combination of IgE, TARC, eotaxin-3 and ECP. In certain embodiments of the present invention, one or more biomarkers associated with nasal polyps are detected from a biological sample from a subject. The biological sample includes, but is not limited to, one or any combination of material collected from a patient, including cultures, cells, tissues, blood, saliva, nasal secretions, cerebrospinal fluid, pleural fluid, milk, lymph, sputum, semen, needle aspirates, etc. The biological sample may be obtained using any method known in the art. For example, nasal secretions are obtained from smears, nasal blows, smears, washes, swabs, brushes, etc.

[0074] Normal IgE levels in a healthy subject are less than about 100 kU / L (e.g., as measured using the IMMUNOCAP® assay [Phadia, Inc. Portage, MI]). Thus, the present invention includes a method of lowering elevated serum IgE levels, which are serum IgE levels of more than about 100 kU / L, more than about 150 kU / L, more than about 500 kU / L, more than about 1000 kU / L, more than about 1500 kU / L, more than about 2000 kU / L, more than about 2500 kU / L, more than about 3000 kU / L, more than about 3500 kU / L, more than about 4000 kU / L, more than about 4500 kU / L, or more than about 5000 kU / L, by administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0075] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with a mean value of about 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC quantification ELISA kit provided by R&D Systems, Minneapolis, MN under catalog number DDN00). Thus, the present invention includes a method of lowering elevated TARC levels, where the serum TARC (e.g., serum TARC) levels are 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, by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0076] Improvement in a nasal polyp-related parameter, such as the nasal polyp-related parameters listed above, can be expressed as a percentage, for example, the score can improve by 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more.

[0077] Biomarker expression as discussed above can be assayed by detection of protein or RNA in serum. In some embodiments, RNA samples are assayed for RNA level determination (non-genetic analysis), e.g., to determine the RNA level of a biomarker. In other embodiments, the RNA sample is used for transcriptome sequencing (eg, genetic analysis).

[0078] "Improvement of nasal polyp-related parameters" refers to an increase from baseline in one or more of NPIF, UPSIT, and / or a decrease from baseline in one or more of SNOT-22 score, subject-assessed nasal congestion / obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post-nasal drip) and loss of smell; number of night awakenings; VAS score; Lund-Mackay score; and 3D volume score; and ACQ5 score in patients with asthma.As used herein, with respect to nasal polyp-related parameters, the term "baseline" refers to the numerical value of the nasal polyp-related parameter for a patient before or at the time of administration of the pharmaceutical composition of the present invention.

[0079] To determine whether a parameter associated with nasal polyps is "improved", the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition of the present invention.For example, the parameter associated with nasal polyps is measured 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, or 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer after the start of treatment with the pharmaceutical composition of the present invention.In some embodiments, the parameter is measured daily (e.g., once or twice a day), weekly, biweekly, or monthly.In other embodiments, the parameter is measured daily, and the average value determined over the course of a month is compared to the baseline.

[0080] The difference between the value of a parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to demonstrate whether the nasal-related parameter has "improved" (e.g., may increase or decrease, depending on the particular parameter being measured).

[0081] Interleukin-4 receptor antagonist In one embodiment, a subject in need thereof is administered a therapeutic composition comprising an interleukin-4 receptor (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 IL-4R is expressed on a cell in vitro or in vivo. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R.

[0082] The term "human IL-4R" (hIL-4R), as used herein, is intended to refer to the IL-4Rα subunit, which is a component of the IL-4 receptor types I and II, as well as the IL-13 receptor system. An IL-4R antagonist, such as an anti-IL-4Rα antibody or antigen-binding fragment thereof, blocks both IL-4 and IL-13 signaling functions.

[0083] The term "antibody", as used herein, is intended to refer 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 HCVR or V H and the heavy chain constant region The heavy chain constant region consists of three domains, C H 1. C H2 and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions are further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), which are interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences or are naturally or artificially modified. An amino acid consensus sequence is defined based on a side-by-side analysis of two or more CDRs.

[0084] The term "antibody" as used herein also includes antigen-binding fragments of a complete antibody molecule. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically accessible, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies are derived, for example, from complete antibody molecules using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding the variable and optionally constant domains of an antibody. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or synthesized. The DNA is sequenced and engineered, for example, chemically or by using molecular biology techniques, to place 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, and the like.

[0085] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity determining regions (CDRs), such as CDR3 peptides), or restricted FR3-CDR3-FR4 peptides. Domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetraspecific antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed within the term "antigen-binding fragment" as used herein.

[0086] Antigen-binding fragments of antibodies typically contain at least one variable domain. A variable domain 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 associated with the domain H In an antigen-binding fragment having a domain, H and V L The domains may be positioned relative to one another in any suitable configuration. For example, the variable region may be a dimer, H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomeric V H or V L It may contain domains.

[0087] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains found in an antigen-binding fragment of an antibody include: (i) a 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;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains are directly linked to each other or are linked by a full-length or partial hinge or linker region. A hinge region consists of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that create a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies can 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 configurations of variable and constant domains listed above non-covalently associated (eg, by disulfide bonds).

[0088] As with complete antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, where each variable domain can specifically bind to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of an antigen-binding fragment of an anti-IL-4R antibody using routine techniques available in the art.

[0089] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody is selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0090] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies featured in the present invention may contain amino acid residues (e.g., mutations introduced by in vitro random or site-specific mutagenesis or in vivo somatic mutation), e.g., in the CDRs and especially in CDR3, that are not encoded by human germline immunoglobulin sequences. However, the term "human antibody", as used herein, is not intended to 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.

[0091] The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are 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) 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 including splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), and thus the V and V regions of the recombinant antibodies are modified. Hand V L The amino acid sequence of the region is H and V L Derived from the human germline V H and V L Related to arrays, but in These sequences may not naturally occur within the human antibody germline repertoire in vivo.

[0092] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa, where the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds, forming a molecule of approximately 75-80 kDa composed of covalently coupled light and heavy chains (half antibodies). These forms have been very difficult to separate, even after affinity purification.

[0093] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for the identification of a hinge, C H 2 or C H Included are antibodies with one or more mutations in three regions, which may be desirable, for example, to improve the yield of the desired antibody form during manufacturing.

[0094] "Isolated antibody" as used herein means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody". An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0095] Terms such as "specifically bind" mean that an antibody or antigen-binding fragment thereof forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4R, as used herein, is an antibody that binds to IL-4R or a portion thereof with a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured by a surface plasmon resonance assay. D Unless otherwise specified, this includes antibodies that bind at K D is determined at a particular temperature, for example, 20° C., 25° C., 30° C., 37° C. or 42° C. An isolated antibody that specifically binds to human IL-4R may, however, have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0096] Anti-IL-4R antibodies useful in the methods featured herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The invention also includes methods that include the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more framework and / or CDR regions are the same or similar to the corresponding residue in the germline sequence from which the antibody is derived, or the corresponding residue in another human germline sequence, or The present invention also includes methods in which V is mutated to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Beginning 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 that contain one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues in the domain are backmutated to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, for example only mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations in the framework and / or CDR regions, for example where certain individual residues are mutated to the corresponding residues in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residues in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0097] The invention also includes methods that include the use of anti-IL-4R antibodies that include variants of any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the invention includes the use of anti-IL-4R antibodies that have HCVR, LCVR and / or CDR amino acid sequences that include, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein.

[0098] The term "surface plasmon resonance," as used herein, refers to an optical phenomenon that allows 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).

[0099] "K D The term "as used herein" is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0100] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes may be either conformational or linear. Conformational epitopes arise from spatially adjacent amino acids from different segments of a linear polypeptide chain. Linear epitopes are those that arise from adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include sugar, phosphoryl or sulfonyl moieties on an antigen.

[0101] According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4R antibody as described in U.S. Pat. Nos. 7,608,693 and 7,605,237. and a light chain variable region (LCVR) and / or complementarity determining region (CDR) comprising any of the amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; LCDR3 comprises the amino acid sequence of SEQ ID NO:8. In yet other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO:1 and a LCVR comprising SEQ ID NO:2. In certain exemplary embodiments of the invention, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain sequence of SEQ ID NO:9 and a light chain sequence of SEQ ID NO:10. According to certain exemplary embodiments, the method of the invention comprises the use of an anti-IL-4Rα antibody, referred to as dupilumab or a biological equivalent thereof, known in the art.

[0102] The term "bioequivalent" as used herein refers to a molecule that has a similar bioavailability (rate and degree of availability) after administration of the same molecular dose and under similar conditions (e.g., same route of administration) such that the effect is considered to be essentially the same as the comparative molecule, both in terms of efficacy and safety. Two pharmaceutical compositions containing an IL-4R antagonist are bioequivalent if they are pharmacologic equivalent, meaning that they contain the same amount of active ingredient (e.g., IL-4R antagonist) in the same dosage form, for the same route of administration, and meet the same or equivalent criteria. Bioequivalence can be determined, for example, by in vivo studies comparing pharmacokinetic parameters for the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (C max ) and area under the plasma drug concentration time curve (AUC).

[0103] Other anti-IL-4Rα antibodies that find use in the context of the methods of the present invention include, for example, the antibody designated AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) and known in the art, or any of the anti-IL-4Rα antibodies described in U.S. Pat. No. 7,186,809 or U.S. Pat. No. 8,092,804.

[0104] Anti-IL-4Rα antibodies used in the context of the methods of the invention may have pH-dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, anti-IL-4Rα antibodies of the invention may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​below about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or lower. As used herein, the term "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0105] In certain cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is the K of antibody binding to IL-4Rα at acidic pH D K value for antibody binding to IL-4Rα at neutral pH vs. D For example, an antibody or antigen-binding fragment thereof may be expressed as a ratio of the acidic / neutral K of about 3.0 or greater. D When a ratio is shown, it is considered for the purposes of the present invention to be indicative of "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K D The ratio may be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0106] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Furthermore, modification of the antigen-binding domain at the amino acid level can result in antibodies with pH-dependent properties. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues, an antibody can be obtained with reduced antigen binding at acidic pH compared to neutral pH. As used herein, the term "acidic pH" refers to a pH of 6.0 or lower.

[0107] Pharmaceutical Compositions The present invention includes a method comprising the step of administering an IL-4R antagonist to a patient, the IL-4R antagonist being contained within a pharmaceutical composition. The pharmaceutical compositions featured in the present invention are formulated with suitable carriers, excipients and other agents that provide suitable transport, delivery, tolerance, etc. A number of 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 (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbowax. Powell et al., "Compendium of Pharmaceuticals and Medical Devices," 1999, pp. 111-114, 2001. See also "PDA" (1998) J Pharm Sci Technol 52:238-311.

[0108] The dose of the antibody administered to the patient may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The preferred dose is typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment are adjusted. The effective dosage and schedule of administering the pharmaceutical composition comprising the anti-IL-4R antibody are empirically determined; for example, the progress of the patient is monitored by regular evaluation, and the dosage is adjusted accordingly. Furthermore, inter-species scaling of dosage is performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0109] A variety of delivery systems are known and may be used to administer pharmaceutical compositions containing IL-4R antagonists, including liposome encapsulation, 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, epidural, and oral routes. The compositions may be administered by any conventional route, for example, by infusion or bolus injection. , by absorption through epithelial or mucocutaneous linings (eg, oral mucosa, rectal and intestinal mucosa, etc.), and may be administered in conjunction with other biologically active agents.

[0110] The pharmaceutical composition can be delivered subcutaneously or intravenously using a standard needle and / or syringe (e.g., a pre-filled needle and / or syringe, or a needle and / or syringe filled from a vial). In addition, for subcutaneous delivery, a pen delivery device has ready utility in delivering the pharmaceutical composition. Such pen delivery devices, including auto-injection pen delivery devices, may be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge is easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device is then reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0111] A number of reusable pen and autoinjector delivery devices have utility in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN™, to name a few. STARLET™ and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices that have utility in subcutaneous delivery of pharmaceutical compositions include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name a few.

[0112] For direct administration to the sinuses, a pharmaceutical composition containing an IL-4R antagonist is administered using, for example, a microcatheter (eg, an endoscope and a microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler.

[0113] In certain circumstances, the pharmaceutical composition is delivered in a controlled release system. In one embodiment, a pump is used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material is used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system is placed in close proximity to the target of the composition, thus preventing systemic delivery. (See, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138.) Other controlled release systems are described in the review by Langer, 1990, Science 249:1527-1533.

[0114] The injectable preparation may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, drip infusion, etc. These injectable preparations are manufactured by known methods. For example, the injectable preparation is manufactured by dissolving, suspending or emulsifying, for example, the above-mentioned antibody or its salt in a sterile aqueous medium or oily medium conventionally used for injection. The aqueous medium for injection includes, for example, isotonic solutions containing physiological saline, glucose and other auxiliary agents, etc., which are used in combination with suitable solubilizing agents such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 20, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, for example, sesame oil, soybean oil, etc. are used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc. The injectable preparation manufactured in this manner is usually filled into a suitable ampoule.

[0115] The pharmaceutical composition can be delivered intranasally. As used herein, "intranasal" administration refers to the administration of pharmaceutical compounds to the nasal cavity. Intranasal delivery can be performed using any method known in the art, including but not limited to inhalation, spraying, lavage, vaporization, atomization, or nasal irrigation. The pharmaceutical composition can be delivered intranasally using a syringe, dropper, squeeze bottle, or spray (atomizer) device (e.g., syringe-driven atomizer or pump-driven atomizer). Suitable pre-filled syringes that can be used for intranasal delivery include, but are not limited to, Carpuject™ (Hospira), Accuspray (BD Pharmaceutical Systems), Direct-Haler (Direct-Haler A / S), Go-Pump, a device that sprays and nebulizes the mucous membrane, Veridoser (Mystic Pharmaceuticals), OptiNose (OptiNose US), ViaNase™ (Kurve technology), Nebu-Laser, and the like.

[0116] Advantageously, the pharmaceutical compositions for oral or parenteral use are prepared into dosage forms with unit doses suitable for the dosage of the active ingredient.Such dosage forms with unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0117] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4R antibody or antigen-binding fragment thereof) administered to a subject according to the methods featured herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to a dose of an IL-4R antagonist that produces a detectable improvement in one or more symptoms associated with nasal polyps, or a dose of an IL-4R antagonist that inhibits, prevents, reduces or delays the progression of nasal polyps or a condition associated with nasal polyps. In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg The amount of the anti-IL-4R antibody or antigen-binding fragment may be about 300 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. For example, a therapeutically effective amount of an anti-IL-4R antibody or antigen-binding fragment may be about 0.1 mg to about 590 mg, or about 1.0 mg to about 580 mg, or about 1.5 mg to about 570 mg, or about 2.0 mg to about 570 mg, or about 10 mg to about 560 mg, or about 20 mg to about 550 mg, or about 30 mg to about 540 mg, or about 40 mg to about 530 mg, or about 50 mg to about 520 mg, or about 60 mg to about 510 mg, or about 70 mg to about 500 mg, or about 80 mg to about 490 mg, or about 90 mg to about 480 mg, or about 100 mg to about 470 mg, or about 110 mg to about 460 mg, or about 120 mg to about 450 mg, or about It may be 130 mg to about 440 mg, or about 140 mg to about 430 mg, or about 150 mg to about 420 mg, or about 160 mg to about 410 mg, or about 170 mg to about 400 mg, or about 180 mg to about 390 mg, or about 190 mg to about 380 mg, or about 200 mg to about 380 mg, or about 210 mg to about 370 mg, or about 220 mg to about 360 mg, or about 230 mg to about 350 mg, or about 240 mg to about 340 mg, or about 250 mg to about 330 mg, or about 260 mg to about 320 mg, or about 270 mg to about 310 mg, or about 280 mg to about 300 mg, or about 290 mg to about 300 mg.

[0118] The amount of IL-4R antagonist contained within an individual dose is expressed as milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist is administered to a patient at a dose of about 0.0001 to about 10 mg / kg of the patient's body weight.

[0119] Combination Therapy The method according to certain embodiments includes administering one or more additional therapeutic agents to a subject in combination with an IL-4R antagonist. In other words, certain embodiments include one or more additional therapeutic agents in combination with an IL-4R antagonist for use in treating a subject. As used herein, the term "in combination with" refers to administering the additional therapeutic agent before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent is 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-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent is administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently" with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or simultaneously) of administration of the pharmaceutical composition comprising an IL-4R antagonist, or is administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0120] The additional therapeutic agent may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 7, No. 582,298), IL-13 antagonists, TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists, IL-5 antagonists, IgE antagonists, CD48 antagonists, antibiotics (e.g., doxycycline), antifungals, leukotrienes, antihistamines, alpha-adrenergic decongestants, mucolytics, NSAIDs, long acting The therapeutic agent may be a long-acting beta 2 agonist (e.g., salmeterol or formoterol), a short-acting beta 2 agonist, a steroid (e.g., an oral steroid), a corticosteroid such as an intranasal corticosteroid (e.g., mometasone furoate (MFNS; e.g., Nasonex®)) or an inhaled corticosteroid (e.g., fluticasone or budesonide), an allergen immunotherapy, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered in combination with a combination comprising a long-acting beta 2 agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., Symbicort® (Astra Zeneca)]).

[0121] In some embodiments, the IL-4R antagonist is administered after the subject has undergone surgery to treat nasal polyps.

[0122] Dosing regimen According to certain embodiments, multiple doses of IL-4R antagonist are administered to the subject over a defined time course. The method includes, for example, sequentially administering multiple doses of IL-4R antagonist to the subject. As used herein, "sequentially administering" means that each dose of IL-4R antagonist is administered to the subject at different time points, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes a method that includes sequentially administering to the patient a single initial dose of IL-4R antagonist, followed by one or more secondary doses of IL-4R antagonist, optionally followed by one or more tertiary doses of IL-4R antagonist.

[0123] The terms "initial dose", "secondary dose" and "tertiary dose" refer to the time sequence of administration of IL-4R antagonist. Thus, an "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is the dose administered after the initial dose; and a "tertiary dose" is the dose administered after the secondary dose. The initial, secondary and tertiary doses may all contain the same amount of IL-4R antagonist, but generally differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, secondary and / or tertiary doses varies from each other during the course of treatment (e.g., adjusted upwards or downwards as necessary).

[0124] In one exemplary embodiment, the secondary and / or tertiary doses are each administered 1 to 14 weeks (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 or more) after the immediately preceding dose. For example, each secondary dose is administered between 1 and 14.5 weeks, or between 1.5 and 14 weeks, or between 2 and 13.5 weeks, or between 2.5 and 13 weeks, or between 3 and 12.5 weeks, or between 3.5 and 12 weeks, or between 4 and 11.5 weeks, or between 4.5 and 11 weeks, or between 5 and 10.5 weeks, or between 5.5 and 10 weeks, or between 6 and 9.5 weeks, or between 6.5 and 9 weeks, or between 7 and 8.5 weeks, or between 7.5 and 8 weeks after the immediately preceding dose. For example, each tertiary dose is administered between 1 and 14.5 weeks, or between 1.5 and 14 weeks, or between 2 and 13.5 weeks, or between 2.5 and 13 weeks, or between 3 and 12.5 weeks after the immediately preceding dose. or between 3.5 and 12 weeks, or between 4 and 11.5 weeks, or between 4.5 and 11 weeks, or between 5 and 10.5 weeks, or between 5.5 and 10 weeks, or between 6 and 9.5 weeks, or between 6.5 and 9 weeks, or between 7 and 8.5 weeks, or between 7.5 and 8 weeks. The phrase "immediately preceding dose" as used herein refers to a dose of an IL-4R antagonist administered to a patient prior to administration of the immediately next dose in the sequence, without any intervening doses, in a series of multiple doses.

[0125] These methods may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered to the patient.

[0126] In embodiments involving multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose is administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration is also adjusted during the course of treatment by the physician depending on the needs of the individual patient after clinical testing.

[0127] In certain embodiments, the initial dose (e.g., a "loading dose") is greater than either or both of the secondary and tertiary doses. For example, the initial dose may be a loading dose, which is 1.5 times, 2 times, 2.5 times, 3 times, or more, of the secondary dose.

[0128] Treatment population The method featured in the present invention comprises administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. As used herein, the term "subject in need thereof" refers to a human or non-human animal exhibiting one or more symptoms or indications of (i) nasal polyps, (ii) chronic sinusitis with nasal polyps, (iii) allergic or non-allergic rhinitis, or (iv) allergic or non-allergic rhinosinusitis, or a subject diagnosed with one of these conditions. For example, in one embodiment, the subject in need thereof has bilateral nasal polyps and a nasal polyp score of at least 2 for each nostril and at least 4 to a maximum of 8 for both nostrils. In certain embodiments, the polyps are in the middle meatus. In certain embodiments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has bilateral mucosal disease, confirmed by methods such as CT scan. As used herein, "bilateral mucosal disease" is an infection of the mucosal lining of the nasal cavity, e.g., the maxillary nasal cavity. In some embodiments, bilateral nasal polyps (e.g., a nasal polyp score of at least 4 to a maximum of 8 for both nostrils with a score of at least 2 for each nostril) persists even after a treatment regimen of inhaled corticosteroids (INCS), such as when the INCS is administered for at least 6 weeks, at least 7 weeks, at least 8 weeks or more.

[0129] A subject in need thereof may further be diagnosed with nasal polyps or a condition related to nasal polyps, such as chronic sinusitis with nasal polyps, allergic or non-allergic rhinitis, or allergic or non-allergic rhinosinusitis. Diagnosis may be based on one or more of the following: (a) the Sinus and Nasal Osseous Test 22 (SNOT-22) score; (b) the subject's (c) number of night awakenings; (d) visual analogue score (VAS) to assess the severity of patient-assessed rhinosinusitis symptoms; (e) 5-item Asthma Control Questionnaire (ACQ5) score in patients with asthma; (f) Nasal Polyp Score (NPS); (g) Nasal Peak Inspiratory Flow (NPIF); (h) olfaction testing (University of Pennsylvania Smell Identification Test (UPSIT)); (i) physiological parameters measured such as by nasal endoscopy and CT scan; (j) Lund-Mackay score; and (k) three-dimensional volumetric measurements of the maxillary sinuses.

[0130] The subject in need thereof has been further diagnosed with chronic rhinosinusitis with nasal polyps based on one or more of the following: (a) 22-item Sinus Oral Test (SNOT-22) score; (b) subject-assessed nasal congestion / obstruction, anterior rhinorrhea, posterior rhinorrhea, and loss of smell; (c) number of night awakenings; (d) visual analog score (VAS) for assessing patient-assessed severity of rhinosinusitis symptoms; (e) 5-item Asthma Control Questionnaire (ACQ5) score in patients with asthma; (f) nasal peak inspiratory flow (NPIF); (g) olfactory testing (University of Pennsylvania Smell Identification Test (UPSIT)); (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) Lund-Mackay score; and (k) three-dimensional volume measurement of the maxillary sinuses.

[0131] For example, in certain embodiments, a "subject in need thereof" is a human patient with chronic symptoms of sinusitis in which at least two of the following symptoms are present: nasal blockage / obstruction / stuffiness or runny nose (anterior / posterior rhinorrhea); facial pain / pressure; and reduced or lost sense of smell.

[0132] In certain embodiments, a "subject in need thereof" is a human patient with a SNOT-22 score of greater than about 7, greater than about 10, greater than about 15, greater than about 20, greater than about 25, greater than about 30, greater than about 35, greater than about 40, greater than about 45, or greater than about 50. A "subject in need thereof" may also be a human patient exhibiting a Lund-Mackay score of greater than about 4, greater than about 5, greater than about 6, greater than about 7, greater than about 8, greater than about 9, greater than about 10, greater than about 11, greater than about 12, or greater than about 13.

[0133] In related embodiments, the "subject in need thereof" may be a subject who has not yet received an IL-4R antagonist, or who has been prescribed or is currently receiving another pharmaceutical "background therapy." The background therapy may be, for example, an intranasal corticosteroid (INCS or ICS), such as mometasone furoate nasal spray (MFNS; Nasonex®). In some embodiments, the "subject in need thereof" is an asthma patient who has not yet received an IL-4R antagonist, or who has been prescribed or is currently receiving an INCS in combination with a long-acting beta2-adrenergic antagonist (LABA). Examples of INCS / LABA therapy include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. In some embodiments, the background therapy includes nasal saline, a topical decongestant, a topical anesthetic, a leukotriene antagonist, or a systemic antihistamine. In some embodiments, a "subject in need thereof" continues background therapy after the subject receives an IL-4R antagonist, while in other embodiments, a subject in need thereof stops (e.g., once or gradually) receiving background therapy before receiving an IL-4R antagonist. EXAMPLES

[0134] 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 the present 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 must be taken into account. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0135] Example 1: Clinical Trial of Subcutaneously Administered Anti-IL-4R Antibody (mAb1) in Patients with Persistent Moderate to Severe Eosinophilic Asthma, Including Asthma Patients with Chronic Hypertrophic Eosinophilic Sinusitis A. Research objectives and overview A randomized, placebo-controlled, double-blind, parallel-group study was conducted in patients with persistent moderate to severe eosinophilic asthma partially / uncontrolled by inhaled corticosteroids (ICS) and long-acting beta2 agonist (LABA) therapy with either 300 mg dupilumab ("mAb1") or placebo administered subcutaneously once weekly for 12 weeks. Dupilumab is an anti-IL-4R antibody having a heavy chain variable region of SEQ ID NO: 1 and a light chain variable region of SEQ ID NO: 2. In certain exemplary embodiments, dupilumab comprises a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. Dupilumab is described in U.S. Patent No. 7,608,693.

[0136] The primary objective of the study was to examine the effect of mAb1 administered subcutaneously once weekly for 12 weeks compared with placebo in reducing the incidence of asthma exacerbations in patients with persistent moderate-to-severe eosinophilic asthma.Secondary objectives of the study were to evaluate the safety and tolerability of mAb1 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate-to-severe eosinophilic asthma, and to evaluate mAb1 serum concentrations after 12 weeks of subcutaneous dosing once weekly in patients with persistent moderate-to-severe eosinophilic asthma.

[0137] Prior to screening, patients had to have been on a stable dose of one of the following doses and regimens of ICS / LABA combination therapy (also called "background therapy") for at least 1 month: Fluticasone / salmeterol combination therapy - Advair® Diskus-Dry Powder Inhaler (DPI): 250 / 50 μg BID or 500 / 50 μg BID; or - Advair® HFA-Metered-Dose Inhaler (MDI): 230 / 42 μg BID or 460 / 42 μg BID; or Budesonide / formoterol combination therapy (Symbicort® 160 / 9 μg BID or 320 / 9 μg BID); or Mometasone / formoterol combination therapy (Dulera® 200 / 10 μg BID or 400 / 10 μg BID).

[0138] Patients continuing budesonide / formoterol or mometasone / formoterol were switched to equivalent doses of fluticasone / salmeterol at the time of randomization (day 1), and patients continuing fluticasone / salmeterol remained on the same background treatment.

[0139] Patients who met the inclusion and exclusion criteria (see below) were randomized to one of the following treatments: mAb1 300 mg subcutaneously once weekly for 12 weeks; or placebo subcutaneously once weekly for 12 weeks.

[0140] The study included a 2-week screening period, a 12-week treatment period including a 4-week background treatment stabilization period and an 8-week background treatment washout period after randomization, followed by an 8-week post-treatment follow-up period.

[0141] Algorithm for withdrawal of background medication (ICS / LABA): Patients remained on BID fluticasone / salmeterol background therapy for 4 weeks after starting add-on therapy or treatment with 300 mg mAb1 (or placebo). Four weeks after randomization, patients were switched from BID fluticasone / salmeterol combination therapy to equivalent ICS doses of fluticasone monotherapy (containing either 250ug or 500μg BID of FLOVENT® Diskus-DPI formulation; or 220μg or 440μg BID of FLOVENT® HFA-MDI formulation). The LABA component (i.e., salmeterol) was discontinued. If, at subsequent visits, the patient did not meet any criteria for asthma exacerbation (as defined below), the fluticasone dose was reduced by approximately 50% starting at week 6. If no asthma exacerbation occurred, ICS withdrawal proceeded according to the schedule described in Table 1.

[0142] [Table 1]

[0143] Upon completion of 12 weeks of treatment with study medication (or after early discontinuation), patients were set on their original doses of fluticasone / salmeterol, budesonide / formoterol, or mometasone / formoterol (at study entry dose) and albuterol or levalbuterol as needed to manage symptoms for an additional 8 weeks of off-study medication before the final safety evaluation.

[0144] An outline of the study protocol is given in FIG.

[0145] Adult patients were included in the study based on the following criteria: (1) a physician diagnosis of persistent asthma for at least 12 months according to the Global Initiative for Asthma (GINA) 2009 guidelines, whose airway inflammation may be eosinophilic; and (2) whose asthma was related to inhaled airways according to the following criteria: Partially or not managed with corticosteroid / long-acting beta-agonist combination therapy: (i) fluticasone / salmeterol combination therapy (DPI formulations: 250 / 50 μg BID or 500 / 50 μg BID or MDI formulations: 230 / 42 μg BID or 460 / 42 μg BID) for at least 1 month prior to screening (ii) a stable dose of either budesonide / formoterol combination therapy (160 / 9 μg BID or 320 / 9 μg BID), or mometasone / formoterol combination therapy (200 / 10 μg BID or 400 / 10 μg BID) during the screening period; (iii) a Juniper Asthma Control Questionnaire (5-Question version, ACQ) score of 1.5 or greater and 3.0 or less at screening; (iv) a FEV1 during the screening period (up to three attempts) and at randomization on the day before the first dose (up to three attempts). 50% or greater predicted normal; (v) either one or more treatments with systemic (oral and / or parenteral) steroid bursts for asthma exacerbations or hospitalization or emergency room visit for asthma exacerbations within 2 years prior to screening; and (vi) a documented history of reversibility meeting at least 12% and 200 mL (maximum of 3 attempts) in FEV1 after albuterol 200 μg to 400 μg (2 to 4 inhalations) during the baseline-screening phase within 12 months prior to screening, or a documented history of a positive methacholine challenge (PD20 ≤ 8 mg methacholine) within 12 months prior to screening. Patients with moderate to severe asthma partially controlled or not controlled on medium to high dose combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT®, or DULERA®) and who had blood eosinophils equal to or greater than 300 cells per microliter or sputum eosinophils equal to or greater than 3% during the screening phase were included in the study.

[0146] Patients who met all inclusion criteria were screened for the following exclusion criteria: (1) patients younger than 18 years or older than 65 years; (2) clinically relevant abnormal laboratory values ​​suggesting unknown disease and requiring further evaluation; (3) chronic obstructive pulmonary disease (COPD) and / or other lung disease impairing pulmonary function tests; (4) patients who require beta-adrenergic receptor blockers for any reason; (5) current smokers or those who had quit within 6 months prior to screening; (6) past smoking history of more than 10 packs per year; (7) smoking due to an asthma exacerbation within 2 months prior to screening. (8) hospitalization or emergency care visit; (9) planned initiation of allergen immunotherapy within the study period; (10) exposure to another test antibody within the prescreening period of less than 5 half-lives of the antibody but more than 30 days, or at least 6 months if the half-life of the antibody is not known; (11) previous enrollment in the current study; (12) the patient was an employee of the investigator, a family member of the patient, or the testing laboratory; (13) known or suspected nonadherence, alcohol or drug abuse; (14) inability to follow study procedures (e.g., language problems or psychological disorders); (14) inversion of sleep patterns (e.g., night workers); (15) treatment with drugs known to prolong the QTc interval; (16) concomitant severe illness contraindicating the use of ICS (e.g., active or inactive pulmonary tuberculosis) or LABA (e.g., diabetes mellitus, cardiovascular disease, hypertension, hyperthyroidism, thyrotoxicosis, etc.); (17) use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within 6 months prior to screening; (18) use of nonsteroidal anticoagulants alone or (19) patients receiving prohibited concomitant medications (listed below); (20) known allergy to doxycycline or related compounds; (21) pregnancy or intention to become pregnant during the course of the study, breast-feeding, or not attempting to use an effective method of contraception; and (22) recent history of parasitic infection or infection within 6 months prior to screening. Travel to areas within the region where the parasite is endemic.

[0147] During the first 4 weeks of the study, patients maintained a stable dose of background asthma therapy, after which the dose of background therapy was gradually tapered. First, the long-acting beta-agonist component of the background therapy was discontinued at week 4, and then the inhaled corticosteroid dose was reduced by half every 2 weeks until week 12. Patients continued study treatment until the end of the study or until discontinuation due to an asthma exacerbation or any other reason.

[0148] B. Study Procedures Investigational Medicinal Product: Dupilumab or matching placebo. Formulation: Sterile dupilumab 150 mg / mL solution for SC injection was provided in 5 mL glass vials. Each vial contained a withdrawable volume of 2 mL. Sterile placebo was provided in identically matched glass 5 mL vials. Route of Administration: Subcutaneous (SC) injection. Dose Regimen: Dupilumab 600 mg SC (loading dose) on D1, followed by 300 mg SC injections weekly for 15 weeks. Placebo SC loading dose on D1, followed by SC injections weekly for 15 weeks.

[0149] Non-investigational Medicinal Product (if applicable): Formulation: Mometasone furoate (NASONEX®) 50 micrograms / actuation of nasal spray contained in a bottle that contained 18 g of formulation (140 actuations). Route of Administration: Nasal spray. Dosage Regimen: Following the Screening Visit (V1), all patients received two actuations (50 μg / actuation) of Mometasone furoate (NASONEX®) 50 μg / actuation of nasal spray in each nostril twice daily (total daily dose of 400 μg) or once daily (total daily dose of 200 μg) until the end of the post-treatment observation period.

[0150] The following concomitant medications were not allowed during the study period: fluticasone / salmeterol combination therapy administered according to the protocol or any other inhaled steroids other than fluticasone (or budesonide / formoterol or mometasone / formoterol during the screening period); systemic or ocular steroids; LABAs other than the salmeterol component of fluticasone / salmeterol combination therapy administered according to the protocol; any other ICS / LABA combination products other than those indicated above; any inhaled anticholinergics (e.g., ipratropium bromide or tiotropium); methylxanthines (theophylline, aminophylline); chromones; anti-IgE therapy; lipoxygenase inhibitors; and leukotriene receptor antagonists or leukotriene synthesis inhibitors.

[0151] C. Treatment Efficacy The primary endpoint of this study was the occurrence of asthma exacerbations, defined as any of the following: (1) a 30% or greater decrease from baseline in morning peak expiratory flow (PEF) for 2 consecutive days; or (2) six or more additional exacerbation puffs of albuterol or levalbuterol (compared to baseline) in a 24-hour period for 2 consecutive days; or (3) an investigator-determined worsening of asthma requiring (a) systemic (oral and / or parenteral) steroid treatment, or (b) a 4-fold or greater increase in the last dose of ICS received before discontinuation from the study, or (c) hospitalization.

[0152] Secondary study endpoints included the mean change from baseline in the following parameters: (1) forced expiratory volume in 1 second (FEV1) in liters measured at each visit; (2) morning and evening peak expiratory flow rates (AM PEF and PM PEF) in liters / min measured daily; (3) daily albuterol / levalbuterol use in inhalations / day; (4) 5-item Asthma Control Questionnaire (ACQ5) score at each visit; and (5) nocturnal awakenings (number per night) measured daily, and (6) 22-item Sinus Assessment Examination (SNO) score at each visit, assessed at baseline and at the treatment endpoint (week 12) to evaluate upper respiratory tract symptoms. Secondary outcomes also included the proportion of patients with a composite asthma event, defined as a 30% or greater decrease from baseline in morning PEF for 2 consecutive days, together with 6 or more additional paroxysmal medication puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) for 2 consecutive days. PEF, ACQ5, asthma symptom score, nighttime awakenings, and paroxysmal medication treatment use were obtained via electronic diaries. Mean daily nighttime awakenings, ranging from 0 to 10, were averaged from the previous 7 days. Morning and evening asthma symptom scores consisted of non-validated patient-reported outcomes rated on a 5-point Likert scale, with higher scores indicating worse outcomes (Table 2). Patients recorded their global symptom scores twice daily before measuring PEF. Data were reported as the average of the 7 days preceding the specified time point.

[0153] [Table 2]

[0154] D. Adverse Event Monitoring Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

[0155] An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal product or in a clinical investigational subject. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally related to the use of a medicinal product, whether or not it is considered related to the medicinal product. AEs also include: any worsening of a pre-existing condition (i.e., a clinically significant change in either frequency and / or intensity) that is temporally related to the use of the study drug; an abnormal laboratory finding that is considered clinically significant by the investigator; and any adverse medical occurrence.

[0156] A serious adverse event (SAE) is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires hospitalization or an extension of an existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a major medical event.

[0157] E. Statistical methods For the primary analysis of the proportion of patients who experienced an asthma exacerbation, a logistic regression model was used to compare the SAR group with placebo. The model included terms for treatment and stratification factors (prior ICS / LABA combination treatment dose). The primary analysis was based on the modified intent-to-treat (mITT) population, which included all randomized patients who received at least one dose of mAb1. Stratified chi-square tests were also used to support the primary analysis.

[0158] For secondary efficacy endpoints, except for SNOT-22, changes from baseline were analyzed using a mixed-effects model with repeated measures (MMRM) approach. The model included change from baseline value through week 12 as the response variable, and factors for treatment (fixed effect), stratification factors, visit, interaction between visit and treatment, baseline value, and interaction between visit and baseline. Statistical inferences for treatment comparisons for change from baseline at week 12 were derived from the mixed-effects model. Change from baseline in SNOT-22 was analyzed using analysis with covariance (ANCOVA), with end-of-treatment measurements to impute missing data. Pharmacodynamic effects were assessed using MMRM models in a post-hoc manner. As there was only one primary endpoint and analysis, no adjustment was made for multiplicity. Safety variables, including AEs, laboratory parameters, vital signs, ECG, clinical laboratory findings, and physical examinations, were summarized using descriptive statistics.

[0159] Demographic and clinical characteristics were summarized using descriptive characteristics. Plots of secondary and pharmacodynamic variables are shown as mean change from baseline over time with standard error. Comparisons of treatment effects from MMRM analysis are based on least squares mean change from baseline at week 12 (95% confidence interval [CI]).

[0160] F. Results The results observed in all 104 randomized patients (screened out of 491) who completed or discontinued the treatment phase of the study are summarized below. All randomized patients were exposed to the study treatment and were included in the mITT population. Baseline characteristics were similar between the groups. Demographic and clinical characteristics were also similar between the two groups (Table 3). As shown above, patients were treated with either 300 mg subcutaneous mAb1 or placebo once weekly. The study treatment period was completed by 86.5% and 67.3% of mAb1 and placebo patients, respectively. The most common reason for discontinuation was lack of efficacy, which was more frequent with placebo (21.2%) than with mAb1 (1.9%).

[0161] [Table 3]

[0162] (i) Primary efficacy endpoint The incidence of asthma exacerbations in the placebo and mAb1 treatment groups is shown in Table 4.

[0163] [Table 4]

[0164] There were a total of 26 asthma exacerbations during the treatment period, and no patients were hospitalized for an asthma exacerbation. Twenty-three patients (44.2%) in the placebo group experienced an asthma exacerbation, whereas only three patients (5.8%) in the mAb1-treated group experienced an asthma exacerbation. The odds ratio was 0.077 (p<0.0001), a relative risk reduction of approximately 87%.

[0165] Of the 26 asthma exacerbations experienced during the study, 9 were considered severe, as demonstrated by the need for immediate intervention in the form of treatment with either systemic corticosteroids or inhaled corticosteroids at four or more times the dose taken prior to the event. An overview of the incidence of severe asthma exacerbations is shown in Table 5.

[0166] [Table 5]

[0167] As shown in Table 5, eight severe asthma exacerbations were observed in the placebo group and only one severe asthma exacerbation was observed in the mAb1-treated group. The remaining 15 in the placebo group and two in the mAb1 group met the protocol definition of an exacerbation based on decreased morning PEF and / or increased albuterol / levalbuterol use. Within the active treatment group, sustained improvements versus baseline were observed during the course of the study for all parameters despite steroid withdrawal.

[0168] [Table 6]

[0169] mAb1 was associated with a longer time to exacerbation and a reduced risk of exacerbation compared with placebo (hazard ratio 0.10; 95% CI 0.03, 0.34; P<0.001). Analysis of time to asthma exacerbation by Kaplan-Meier plots revealed that the effect of treatment with mAb1 persisted for a long period of time, including after 8 weeks, when patients were at higher risk of developing an exacerbation due to steroid withdrawal.

[0170] Only one patient in the placebo group had a complex asthma event, defined as a 30% or greater decrease from baseline in morning PEF for 2 consecutive days together with 6 or more additional puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days.

[0171] (ii) Other efficacy endpoints Pulmonary function parameters (FEV1, AM PEF and PM PEF), asthma symptom-based endpoints (ACQ score, nighttime awakenings), and albuterol use were assessed for each patient at each visit. In addition, SNOT-22 scores were assessed at baseline and at the end of treatment. The mean values ​​for all parameters at baseline and 12 weeks (LOCF) are summarized in Table 7, along with the mean difference between treatment groups (ANOVA model for SNOT-22). In Table 7, the column labeled "Difference to Placebo" shows the placebo-adjusted value from baseline, taking into account the observed change in the value of the parameter compared to the observed change for that parameter in the placebo treatment group.

[0172] [Table 7]

[0173] Treatment with mAb1 produced a significant change from baseline in FEV1 at week 1 that was maintained through week 12 despite LABA and ICS withdrawal, with a slight decrease in FEV1 at week 5 concomitant with LABA withdrawal. Similar improvements were observed in morning PEF, but less in evening PEF. The least squares (LS) mean change from baseline in FEV1 through week 12 was -0.22 L for placebo and 0.05 L for the mAb1 group (p=0.0009).

[0174] ACQ5 scores improved in both treatment groups at week 1. However, ACQ5 improved further with mAb1 between weeks 1 and 4, whereas the placebo effect stabilized and maintained the difference through week 12.

[0175] Morning symptom scores increased with placebo from baseline to week 12. With mAb1, there was an initial decrease that remained below baseline through week 12. A similar pattern (greater variation) was observed in evening asthma symptom scores.

[0176] Nighttime awakenings remained stable in the placebo group through week 6, then increased from week 6 to week 12. In contrast, nighttime awakenings decreased in the mAb1 group by week 1 and remained improved versus baseline through week 12.

[0177] Changes in albuterol / levalbuterol use were similar to other secondary endpoints: with placebo, there was an initial decrease followed by a return to baseline; with mAb1, the initial decrease was maintained over time.

[0178] There was a non-significant difference between SNOT-22 values ​​at baseline, with a mean placebo score of 26.24 and a mean mAb1 score of 39.02. At week 12, the LS mean change was a slight increase of 0.23 points for the placebo group and a mean decrease (improvement) of 8.26 points for the mAb1 group. This corresponded to a magnitude of improvement of 8.49 points for the mAb1 group (p=0.0027).

[0179] [Table 8]

[0180] [Table 9]

[0181] For all secondary endpoints, except for nocturnal PEF and nocturnal awakenings, the 12-week measurements were significant in favor of mAb1 treatment (Tables 7 and 8). Significant improvements with mAb1 were also observed for the three SNOT-22 items related to upper respiratory tract disease (Table 9).

[0182] (iii) Safety mAb1 was generally safe and well tolerated. Treatment-emergent adverse events Similar adverse events (TEAEs) were reported by 40 (76.9%) placebo-treated patients and 42 (80.8%) mAb1-treated patients (Table 10). TEAEs were nonspecific, generally mild to moderate in intensity, and most resolved by the end of the study. Increased reporting of the following TEAEs was observed for mAb1 compared to placebo: injection site reactions were reported by 15 (28.8%) mAb1 patients and 5 (9.6%) placebo patients; nasopharyngitis was reported by 7 (13.5%) mAb1 patients and 2 (3.8%) placebo patients; headache was reported by 6 (11.5%) mAb1 patients and 3 (5.85) placebo patients, and nausea was reported by 4 (7.7%) mAb1 patients and 1 (1.9%) placebo patient.

[0183] [Table 10]

[0184] No deaths were reported during the study period. Four treatment-emergent serious adverse events (SAEs) were reported: one mAb1 patient experienced bipolar disorder and three placebo patients experienced SAEs of asthma with pneumonia, gunshot wound with left pneumothorax, and right ankle fracture. None of these SAEs were considered related to mAb1, and all resolved by the end of the study except for the new ankle fracture. There were no deaths.

[0185] A total of six patients discontinued the study due to TEAEs: three patients in the mAb1 group (bipolar disorder, wheezing asthma, and angioedema) and three patients in the placebo group (upper respiratory tract infection, psoriasis, and asthma). The TEAE of angioedema occurred in a 42-year-old African-American woman after the ninth study treatment dose as a pruritic generalized rash observed at and away from the injection site. This persisted for 1 week and resolved after discontinuation of study treatment and treatment with prednisone and diphenhydramine. This was considered treatment related. The AEs were followed by a milder rash at the injection site after the first and sixth doses of study treatment.

[0186] Among the most common AEs occurring in three or more patients in either treatment group (Table 10), injection site reactions, nasopharyngitis, nausea, and headache occurred more frequently with mAb1 than with placebo. No clinically significant changes in vital signs, physical examination, laboratory tests, or ECG findings were reported in either group.

[0187] G. Conclusion Significant improvements were observed in lung function and other asthma control parameters. Efficacy was observed early and sustained despite background treatment withdrawal. A relative reduction of approximately 87% (p<0.0001) in the primary endpoint of incidence of asthma exacerbations in patients with persistent moderate-to-severe asthma with eosinophilia was observed after 12 weeks of treatment with 300 mg mAb1 once weekly (5.8%) compared to placebo (44.2%). As shown in Table 7, clinically meaningful and statistically significant (not multiplicity adjusted) improvements with treatment compared to placebo were observed in lung function parameters (FEV1, PEF AM), asthma symptom score (ACQ), and albuterol use. Beneficial trends were observed for PEF PM (p=0.0567) and nighttime awakenings (p=0.0518). Statistically significant (not multiplicity adjusted) improvements were also observed for SNOT-22 scores. Within the active treatment group, sustained improvements versus baseline were observed during the course of the study for all parameters, despite withdrawal of LABA and ICS. mAb1 was generally safe and well tolerated.

[0188] Example 2: Biomarker studies Biomarker analysis was performed on samples obtained from subjects who participated in a clinical trial of mAb1 (see Example 1 above). In particular, serum / plasma biomarkers related to TH2 inflammation, such as thymus and activation chemokine (TARC; CCL17), immunoglobulin E (IgE), eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils, were measured in samples from patients at baseline and at different time points after the start of study treatment. The baseline levels of these biomarkers were evaluated for their potential predictive value for treatment response. In addition, exhaled NO concentration (FeNO) and induced sputum eosinophils and neutrophils were measured as biomarkers of bronchial inflammation. Exhaled nitric oxide assessment was performed using a NIOX instrument (Aerocrine AB, Solna, Sweden) before spirometry and after at least 1 hour of fasting. Biomarkers were analyzed using a mixture model and least squares means derived from the model are reported below.

[0189] Asthmatic subjects (N=104) were administered either mAb1 (300 mg) or placebo subcutaneously on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (i.e., 12 weekly doses) of the study (see Example 1 above). Samples for biomarker analysis were taken from antibody-treated and placebo-treated subjects at weeks 0, 1, 4, 8, and 12. Antigen-specific IgE was detected using the Phadiatop® test.

[0190] TARC, eotaxin-3 and IgE remained unchanged in response to placebo. In contrast, rapid declines in TARC (mean % change +0.3% vs -22.7%; p=0.0003) and eotaxin-3 (mean % change 12.69% vs -39.62%; p<0.0001) were observed within 1 week in patients treated with mAb1 and sustained through 12 weeks: TARC: +7.6% vs -26.0% (p=0.0005); eotaxin-3: +5.13% vs -45.67% (p<0.0001).

[0191] TARC levels responded within 1 week after exposure to mAb1 administered subcutaneously at 300 mg. TARC levels stabilized at approximately 50% of baseline levels in subjects treated with mAb1, despite ICS withdrawal. This data indicates that TARC expression is more directly related to IL-4R signaling than FEV1 changes (which declined in parallel with ICS withdrawal [after 4 weeks]) and that IL-4R blockade induces a shift toward TH1 characteristics, as observed, for example, with IFNγ administration. It may be possible to titrate mAb1 doses using TARC (and, for example, CXCL10), especially in patients who require long-term treatment and are at risk for TH1-type immune disorders.

[0192] Total serum IgE was also decreased after mAb1 treatment. Total serum IgE responses were more heterogeneous and delayed compared to the TARC response. Mean (SD) baseline IgE levels were 694.68 IU / L (1837.82) for the placebo group (n=52) and 657.66 (1482.25) for the mAb1 group (n=52), while medians were 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend for decreased IgE in mAb1-exposed patients compared to placebo was observed, but only beginning at week 4. Serum IgE was significantly decreased in the mAb1 group compared to placebo (mean % change, 10.1% versus +13.5%; p=0.0325), beginning at week 4 and continuing to decrease through week 12 (mean % change, -36.8% for mAb1 versus -5.5% for placebo; p<0.0001).

[0193] Changes from baseline and placebo at week 12 for FeNO, TARC, eotaxin-3, and IgE were all in favor of mAb1 (all P<0.001) (Table 11). No differences from baseline or between treatments were observed for YKL-40 or CEA.

[0194] [Table 11]

[0195] There was a transient decrease in periostin levels, followed by an increase with LABA / ICS withdrawal. Administration of mAb1 delayed the increase but did not prevent the increase above baseline. No consistent treatment effect was observed for CEA and YKL-40. Blood eosinophil counts remained unchanged through 6 weeks, then increased at 8 and 12 weeks. Peripheral blood eosinophil counts were unchanged with placebo throughout treatment. Differences between treatments were not significant, with borderline increases driven by larger blood eosinophil elevations in only a few patients treated with mAb1. Little or no increase was observed in the majority of patients.

[0196] [Table 12]

[0197] Since only three mAb1 patients experienced asthma exacerbations during the study, no conclusions could be drawn regarding the association between baseline biomarker levels and asthma exacerbations.

[0198] mAb1 treatment was also associated with a significant decrease from baseline in FeNO at week 4, and despite ICS withdrawal, FeNo remained below baseline through week 12 (mean % change at week 12: 35.0 for placebo vs. -28.7 for mAb1; p<0.0001). In contrast, placebo FeNo values ​​remained stable through week 8 and then increased at week 12, consistent with ICS withdrawal.

[0199] Improvement in forced expiratory volume in 1 second (FEV1) was significantly correlated with FeNO reduction (r=-0.408, p=0.009) at week 12. Similarly, improvements in AM-PEF and PM-PEF were correlated with FeNO reduction. Other correlations with FeNO were not significant. See Table 13.

[0200] [Table 13]

[0201] Scatterplot analysis of baseline eosinophils vs. change from baseline in FEV1 at week 12 did not appear to indicate an association between baseline eosinophils and treatment effect as measured by change from baseline in FEV1 at week 12 in the study population (baseline eosinophils ≥ 0.3 Giga / L). Baseline eosinophils correlated with decreased ACQ and decreased albuterol / levalbuterol use. Periostin and YKL-40 at baseline correlated with decreased ACQ.

[0202] Change in FEV1 from baseline at week 12 worsened with ICS withdrawal (starting at week 4). Similar analyses did not suggest an association between baseline TARC or IgE and change in FEV1 from baseline at week 12 in the study population (baseline eosinophils ≥ 0.3 giga / L).

[0203] summary These results show that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, eotaxin-3 and IgE) and bronchial inflammation (FeNO) in adult asthmatics. The correlation between FeNO reduction and FEV1 improvement suggests a relationship between IL-4 / IL-13-mediated anti-inflammatory activity and improved lung function in moderate-to-severe uncontrolled asthma.

[0204] Example 3. Clinical trial of subcutaneously administered anti-IL-4R antibody (mAb1) in patients with chronic symptoms of bilateral nasal polyps and sinusitis A. Research objectives and overview The positive effect of mAb1 on the SNOT-22 study described in Example 1 suggested that anti-IL-4R antibodies may also be effective in treating chronic rhinosinusitis with nasal polyps. Furthermore, nasal polyps are most commonly driven by eosinophilic / TH2, and mAb1 significantly reduced biomarkers related to Th2 inflammation (see Example 2). Therefore, a clinical trial was designed to test the therapeutic effect of mAb1 on chronic rhinosinusitis with nasal polyps.

[0205] A randomized, double-blind, phase 2, placebo-controlled, two-arm study was conducted to evaluate mAb1 administered subcutaneously (SC) once weekly (QW) for 16 weeks in patients with chronic rhinosinusitis with nasal polyposis (chronic symptoms of bilateral nasal polyps and sinusitis).

[0206] The primary efficacy assessment was the change from baseline in bilateral endoscopic nasal polyp score (NPS) at week 16 in the intent-to-treat (ITT) population using MMRM analysis. Key secondary efficacy analyses included SNOT-22 score, loss of smell (daily AM / PM assessments), olfactory testing (UPSIT), subject-rated rhinitis symptoms (daily AM / PM assessments), Lund-Mackay sinus CT scan score (central reading), nasal peak inspiratory flow (daily AM / PM assessments) and responder analysis (defined as a 1 or 2 point improvement in total NPS at week 16 compared to baseline).

[0207] mAb1 was administered concomitantly with mometasone furoate nasal spray (MFNS) (NASONEX® 50 micrograms / actuation twice daily, two actuations per nostril). Because there was a high prevalence of NP comorbidity with asthma, aspirin / nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, and previous surgery, patients were allowed to enroll in the study unless they presented with any of the exclusion criteria listed below. Sixty patients were randomized into two treatment groups, 30 patients per group. To ensure that at least 30 patients with comorbid asthma were included in the study, recruitment of NP patients without comorbid asthma was stopped when randomizing approximately 30 patients without asthma. Finally, there were 35 patients with asthma who participated in the study, and 25 patients without asthma who participated. Both patients and investigators were blinded to the assigned treatment group.

[0208] The study consisted of three periods: (1) a 4-week screening period with the MFNS (Visit 1); (2) a 16-week randomized mAb1 or placebo treatment period (Visits 2-18); and (3) a 16-week post-treatment period to assay pharmacokinetics, immunogenicity, safety, and efficacy (Visits 19-22). The total duration of the study was up to 36 weeks.

[0209] The primary endpoint was change from baseline in bilateral NPS at 16 weeks.

[0210] A number of secondary efficacy endpoints were measured to more comprehensively evaluate the efficacy of mAb1. The study included SNOT-22 scores, loss of smell (daily AM / PM assessment), olfactory sensation test (UPSIT), subject-rated rhinitis symptoms (daily AM / PM assessment), Lund-Ma Improvements in ckay sinus CT scan scores (central reading), nasal peak inspiratory flow (daily AM / PM assessment) and responder analysis (defined as a 1 or 2 point improvement in total NPS at 16 weeks compared to baseline) were examined.

[0211] Together with exploratory subgroup analyses and biomarkers, these endpoints informed the therapeutic value of mAb1 in reducing nasal polyp scores and improving symptoms in NP and its subsets. Duration of efficacy was also examined through a 4-month post-treatment evaluation period.

[0212] The 300mg QW dose regimen met apparent target-mediated clearance levels (10-15mg / L). This regimen has been tested and provided statistically significant and clinically relevant responses in two previous proof of concept studies conducted with mAb1 in asthma and atopic dermatitis (see, e.g., Example 1 above, USSN61 / 805797 and USSN61 / 816191). The first dose utilized a 600mg loading dose to achieve steady state concentrations more rapidly. This loading dose range was supported by the acceptable safety profile of the highest loading dose (600mg) demonstrated in previous studies conducted in healthy Japanese subjects.

[0213] Additionally, the Cmax after a 600 mg loading dose was approximately 70 mg / L, the steady-state Ctrough of 300 mg QW was approximately 150 mg / L, and the Cmax after the proposed dosing regimen (i.e., 600 mg loading dose followed by 300 mg QW) was approximately 12 mg / kg. Given that the mean Cmax was less than that of the IV dose (421 mg / L), the highest single dose tested in well-tolerated healthy subjects provided further confidence that this dosing regimen should have an acceptable safety profile.

[0214] Patient inclusion criteria included (i) physician-initiated endoscopic diagnosis of bilateral nasal polyps for at least 8 weeks prior to screening (i.e., a minimum bilateral nasal polyp score of 5 to a maximum score of 8 for both nostrils, with a score of at least 2 for each nostril, despite completion of previous intranasal corticosteroid (INCS) treatment), and (ii) chronic symptoms of sinusitis with at least two of the following symptoms present prior to screening: nasal blockage / obstruction / stuffiness or runny nose (anterior / posterior rhinorrhea); facial pain / pressure; and diminished or lost sense of smell.

[0215] Patients who met these criteria were screened for the following exclusion criteria: age <18 or >65 years; any technical / administrative reasons that prevented the patient from being randomized in the study; previous participation in any clinical trial of mAb1; SNOT22 score <7; receipt of any other investigational drug or treatment prohibited for this study within 2 months or 5 half-lives prior to screening, whichever is longer; receipt of oral corticosteroids (OCS) or intranasal corticosteroid drops within 2 months or 1 month prior to screening, or planned to receive OCS for the duration of the study for another condition; treatment with mAb or immunosuppressive therapy; anti-immunoglobulin E (IME) within 130 days of Visit 1. treatment with IgE) therapy (e.g., omalizumab); treatment with leukotriene antagonists / modifiers for patients who have not continued continuous treatment for ≥30 days prior to Visit 1; initiation of allergen immunotherapy within 3 months prior to Visit 1 or plans to initiate treatment during the screening or randomized treatment period; any nasal surgery within 6 months prior to screening or more than five previous sinus surgeries, up to two of which were surgeries that altered the nasal side wall structure; or any condition / comorbidity that would make the patient evaluable for the primary efficacy endpoint (e.g., choanal polyps; deviated nasal septum obstructing at least one nostril; acute sinusitis, nasal infection, or upper respiratory tract infection at or within 2 weeks prior to screening; ongoing rhinitis medicamentosa; Churg-Strauss syndrome syndrome, Young's syndrome, Kartagener's or ciliary dyskinesia syndrome, cystic fibrosis; signs or CT scan suggestion of allergic fungal rhinosinusitis. Patients with comorbid asthma were excluded if: the patient had a forced expiratory volume (FEV1) less than 60%; an exacerbation requiring systemic (oral and / or parenteral) steroid treatment or hospitalization (>24 hours) for the treatment of asthma occurred within 3 months prior to screening; or the patient was receiving a dose of fluticasone greater than 1000 μg or an equivalent amount of inhaled corticosteroids. Other exclusion criteria included patients with a predicted short life expectancy (<6 months); patients receiving concomitant treatments prohibited in the study; women who were pregnant or intending to become pregnant during the study or women who were breastfeeding. Other exclusion criteria included concurrent severe illness (e.g., active and inactive pulmonary tuberculosis, diabetes, etc.); diagnosed active parasitic infection; suspected or high risk for parasitic infection; history of human immunodeficiency virus (HIV) infection or positive HIC screen at Visit 1; evidence of acute or chronic infection; known or suspected immunosuppression, including history of invasive opportunistic infection (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystiosis, aspergillosis), regardless of whether the infection was cured; patients with active autoimmune disease or using immunosuppressive therapy for autoimmune disease (e.g., Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis); patients with positive or indeterminate hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibody at Visit 1; and patients with liver damage-associated criteria (e.g., underlying hepatobiliary disease or ALT>3ULN).

[0216] B. Study Procedures Investigational Medications: Various concentrations of sterile mAb1 were provided in 5 mL glass vials, each containing 2 mL of withdrawable volume: 150 mg / mL solution (300 mg dose / 2 mL). Sterile placebo was provided in identically matched glass 5 mL vials, each containing 2 mL of deliverable volume.

[0217] mAb1 was administered every 7±2 days (QW). Doses of mAb1 were spaced at least 5 days apart to avoid overdosing. At Visit 2 (V2), two injections were administered. After V2, one injection of mAb1 was administered once a week at the investigational site throughout the randomized treatment period. mAb1 was administered after clinical procedures and blood draws. After each administration, patients were monitored for at least 1 hour for any signs or symptoms of local site injection or hypersensitivity reactions. Subcutaneous injection sites were alternated between the abdominal quadrants (avoiding the navel and lower back) or upper thighs to ensure that the same site was not injected 2 times / week consecutively.

[0218] Each day during the study, subjects recorded their daily use of mometasone furoate (MFNS) using an electronic diary. MFNS (NASONEX®) 50 micrograms / actuation of nasal spray was contained in a bottle, which contained 18 g (140 actuations) of the formulation.

[0219] Screening Period: Prior to screening and ≥2 months prior to Visit 1 (V1), subjects continued on a stable dose of intranasal corticosteroids (INCS). If the patient used an alternative INCS formulation other than MFNS at V1 and prior to the screening visit, the patient was switched to MFNS. After V1, all patients entered a 4-week run-in period during which they received MFNS: 2 actuations (50 μg / actuation) in each nostril twice daily (BID) (total daily dose of 400 μg) unless they could not tolerate BID INCS, in which case the patient remained on a low-dose (QD) regimen. To be accepted into the study, patients must have had the following symptoms prior to screening: nasal blockage / obstruction / stuffiness or runny nose (pre / post rhinorrhea); + / - facial pain / pressure or had at least two of the following symptoms: + / - hyposmia or loss of smell.

[0220] Treatment Period: The treatment period proceeded as shown in the study flow chart in Table 14.

[0221] [Table 14]

[0222] [Table 15]

[0223] [Table 16]

[0224] During the treatment period, patients continued on a stable dose of mometasone furoate: 2 actuations of the MFNS in each nostril BID or QD (if the patient could not tolerate the higher dose). At visit 2, patients underwent the SNOT-22 test, VAS and QoL questionnaires (SF-36, EQ-5D, questionnaire using materials related to nasal polyps in patients with asthma), olfactory testing and ACQ-5.

[0225] Clinical laboratory testing at Visit 2 was limited to hematology, pharmacokinetics, anti-drug antibodies, biomarkers in serum and plasma, and allergen-specific IgE panel sampling. Blood samples were obtained before administration of mAb1. Nasal secretion sampling for biomarkers. For those patients who signed specific informed consent forms, blood samples were taken for DNA and RNA sampling (during the randomized treatment period, before administration of study drug).

[0226] Temporary treatment interruptions due to suspected adverse events (AEs) were considered by the investigator. Once the investigator, according to his or her best medical judgment, considered mAb1 unlikely to have caused the relevant event, treatment with mAb1 was reinstated under close and appropriate clinical and / or laboratory monitoring if the study inclusion criteria were still met.

[0227] An AE was any adverse medical occurrence in a patient or clinical trial patient to whom a medicinal product was administered that did not necessarily have a causal relationship to this treatment.

[0228] Serious Adverse Events (SAEs) were, at any dosage, death or life-threatening (the term "life-threatening" in the definition of "serious" refers to an event where the patient is at risk of death at the time of the event; not an event that is hypothesized to cause death if more severe); any untoward medical occurrence resulting in permanent or significant impairment / incapacity that required hospitalization for treatment or an extended period of hospitalization, or a congenital anomaly / birth defect, or was a medically significant event. Medical and scientific judgment was used in determining whether urgent reporting was appropriate in other situations, such as a significant medical event that is not immediately life-threatening and will not result in death or hospitalization, but may endanger the patient or may require intervention (i.e., specific measures or corrective procedures) to prevent one of the other outcomes described in the definition above (the following list of medically significant events is intended to serve as a guideline for determining which conditions must be considered medically significant events). The list was not intended to be comprehensive: intensive treatment in the emergency room or at home: allergic bronchospasm, anaphylaxis, blood dyscrasias (i.e., agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia, etc.), convulsions (seizures, epilepsy, epileptic fits, absence, etc.), development of drug dependence or abuse; ALT > 3 × ULN + total bilirubin > 2 × ULN or asymptomatic ALT increase > 10 × ULN; suicide attempt or any event suggestive of suicidal tendencies; syncope, loss of consciousness (unless documented as a result of blood sampling); bullous skin rash; cancer diagnosed during the study or worsened during the study; chronic neurodegenerative disease (newly diagnosed) or worsened during the study (only if judged abnormal / significant by the investigator specifically in studies evaluating the effect of the study drug on these diseases).

[0229] Post-Treatment Period: Upon completion of the randomized treatment period (or after early discontinuation of mAb1), patients continued treatment with a stable dose of MFNS maintained for the randomized treatment period or had treatment modified based on medical judgment.

[0230] The following concomitant treatments were not allowed during the screening and randomized treatment periods: use of intranasal medications that interfere with symptoms of the disease (antihistamines, nasal atropine, ipratropium bromide, nasal cromolyn) except for nasal saline; INCS drops; systemic corticosteroids; decongestants (topical or systemic) except for previous endoscopy; prolonged use of systemic antibiotics (2 weeks or longer); lipoxygenase inhibitors; any immunosuppressive treatment, including but not limited to methotrexate, cyclosporine, mycophenolate, tacrilomus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (IgE) treatment (omalizumab); and aspirin or NSAIDs in patients with hypersensitivity to aspirin.

[0231] The following concomitant treatments were permitted: MFNS during screening and throughout the entire study; nasal saline; topical decongestants (e.g., oxymetazoline hydrochloride to reduce distension and open the passageway for the endoscope), and topical anesthetics (e.g., lidocaine prior to endoscopy). were permitted); short-term (<2 weeks) use of antibiotics; and SABA, LABA and methylxanthines (e.g., theophylline, aminophylline) for patients with asthma. The following inhaled corticosteroids were permitted for patients continuing a stable dose of 1000 μg or less of fluticasone (or an equivalent dose of another inhaled CS; see Table 16) and only for patients who had continued a stable dose for ≥30 days prior to Visit 1: leukotriene antagonists / modifiers were permitted during the study only for patients who had continued continuous treatment for ≥30 days prior to Visit 1; synthetic antihistamines; and initiation of allergen immunotherapy (routine allergen immunotherapy was permitted for ≥3 months prior to Visit 1).

[0232] C. Treatment Efficacy The primary endpoint of this study was the change from baseline in bilateral endoscopic nasal polyp scores at week 16 (see Table 15).

[0233] [Table 17]

[0234] Nasal endoscopy was performed at the end of the scheduled visit and preceded the topical administration of anaesthetic in combination with a decongestant. Standard video sequences were downloaded or transmitted to the centralized reader. Centralized image data evaluation and scoring by an independent physician reviewer of the image data was performed for all endoscopies. Only V1 centralized readings were made available to sites to confirm eligibility in V2. Final results of centralized readings were made available after the study.

[0235] For the analysis of the primary endpoint, the central reading of V2 was used for comparison with the end-of-treatment (EOT) reading. Sites removed subject-identifying information from the image data header before transmitting the image data to the central reader.

[0236] Secondary study endpoints included patient-reported symptoms (including SNOT-22); subject-rated nasal congestion / obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post-nasal drip) and loss of smell, (daily AM and PM electronic diaries) monthly averages; number of nocturnal awakenings; patient-relevant severity of rhinosinusitis symptoms using a visual analogue scale (VAS); the 5-item Asthma Control Questionnaire (ACQ-5) in the asthma subgroup; nasal peak inspiratory flow (NPIF); olfaction test (UPSIT); NPS in patients with comorbid asthma; CT scan assessment; spirometry (overall and subgroup with asthma); time to first response in NPS (improvement of ≥1 point); time to discontinuation of study treatment; and change from baseline at 16 weeks in the occurrence of treatment discontinuation due to need for OCS or nasal surgery.

[0237] Quality of life (QoL) outcomes included change from baseline at 16 weeks in the 36-item Short Form Health Survey (SF36); the European Quality of Life Scale (EQ-5D); and questionnaires using nasal polyp-related materials.

[0238] Disease-specific efficacy measures included: computed tomography (CT). Sinus CT was performed at EOT in front of V2. For both Lund-Mackay score and 3D volumetric measurements of maxillary sinuses, the same acquisition (sequence) was used for centered image data assessment, and image data was scored by an independent physician reviewer. The centered reading of V2 was used for comparison with EOT. Final results of the centered reading were made available after the study.

[0239] For 3D volumetric measurements of the maxillary sinus, a central reading before V2 was used for comparison with the EOT reading. Sites removed subject-identifying information from the image data header before sending the image data to the central reader. The % change in opacification from BL to EOT was calculated.

[0240] At screening (Visit 1), patients submitted NPIF measurements to record morning (AM) and evening (PM) NPIF. Patients were instructed to record the following changes in their daily electronic diary: AM NPIF performed within 15 minutes of occurrence (between 6am and 10am) before receiving MFNS; and PM NPIF performed in the evening (between 6pm and 10pm) before receiving MFNS.

[0241] Three NPIF attempts were performed by the patient; all three values ​​were recorded by the patient in an electronic diary and the highest value was used for evaluation. The baseline for AM NPIF was the mean AM measurements recorded during the 28 days prior to the first dose of study medication, and the baseline for PM NPIF was the mean PM measurements recorded during the 28 days prior to the first dose of study medication.

[0242] To assess disease-specific daily symptoms, patients used an electronic diary to answer questions about individual morning and evening rhinosinusitis symptoms, including symptoms of congestion and / or blockage, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip) and loss of smell, using a categorical scale of 0 to 3 (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). The number of nighttime awakenings was also recorded.

[0243] The same safety assessments were applied across all treatment groups. Adverse events, including SAEs and adverse events of special interest (AESIs), were collected at every visit.

[0244] Pre-dose blood samples were taken to determine serum functional mAb1 and anti-mAb1 antibodies as specified in Table 14.

[0245] Optional sampling for preliminary DNA and RNA analysis required separate pharmacogenetic informed consent.

[0246] Pharmacokinetics. Serum functional mAb1 and anti-mAb1 antibodies were assayed by ELISA. Serum pre-dose functional mAb1 concentrations at Visit 2 (day 1), mAb1 trough concentrations at weeks 2, 4, 8, 12, 16, and follow-up serum mAb1 at weeks 20, 24, 28, and 32 were provided. Anti-mAb1 antibody status (negative or titer value) at Visit 2 (day 1), weeks 2, 4, 8, 12, 16, and 32 were also provided. Patients with ADA titers of 1000 or greater at the end of the study visit were scheduled to return approximately 6 months later for further evaluation of ADA titers. Further follow-up was considered based on overall evaluation of antibody titers and clinical findings.

[0247] Pharmacodynamics. Because the secretion of certain proteins is at least partially dependent on Th2 cytokines and associated with chronic inflammation of the airway mucosa, including sinus tissue, the expression of certain biomarkers was assayed to monitor the therapeutic effect of mAb1. These biomarkers were also used to predict toxicity. These values ​​were assessed when measuring the drug response and / or recording the time course of the drug response. Values ​​used as baseline were those collected on Day 1 (pre-dose assessment).

[0248] Nasal secretions were obtained by inserting a nasal swab into each nasal cavity for 5 min. The secretions were saved for possible analysis of further biomarkers related to nasal polyps and response to mAb1 treatment.

[0249] At selected clinical sites, nasal polyp tissue was optionally obtained by biopsy with specific informed consent. A baseline biopsy was obtained at V2 of the study. After randomization, another biopsy of nasal polyp tissue was obtained at the end of treatment visit (week 16).

[0250] Biopsied nasal polyp tissue was evaluated for various biomarkers of inflammation and disease process or response, for example, RNA was extracted and used for expression profiling (e.g., microarray, transcriptome sequencing or quantitative RT-PCR, etc.).

[0251] DNA and RNA samples were used to determine possible relationships between the genes and response to treatment with mAb1 and possible side effects to mAb1.

[0252] Analysis of the proportion of patients with binary events. The proportion of patients with binary events was assessed: ≥1 point improvement (decrease) in NPS at 16 weeks (centrally read); 10% or greater improvement in CT opacification from baseline at 16 weeks; decline due to oral CS or surgery; or increase in INCS after 8 weeks, analyzed using a logistic model with the above responses as response variables and treatment group, pooled country / territory, and pre-study stratification factors as covariates, respectively.

[0253] Time-to-event change analysis. Time-to-event (e.g., first response with ≥1 point improvement (decrease) in NPS, study treatment discontinuation, etc.) were analyzed using Cox regression models with time-to-event and treatment as dependent variables, pooled country / territory, and pre-study asthma comorbidity as a covariate. Kaplan-Meier methods were used to derive the proportion of patients with an event specific to each treatment group at 4, 8, 12 and 16 weeks. For analyses during the treatment period, patients were considered event-free until the end of the treatment period (day of last dose + 7 days) if they did not have an event before treatment discontinuation / completion.

[0254] Analysis of change from baseline for continuous variables. NPS for patients with comorbid asthma; Lund Mackay score; SNOT-22; subject-assessed clogging and / or obstruction score; NPIF; ACQ-5 in patients with comorbid asthma; change from baseline in QoL measures (SF36, EQ-5D) and VAS at 16 weeks were analyzed using the same MMRM as the primary endpoint. Descriptive statistics including number of patients, mean, standard error and LS mean were provided. Additionally, difference in LS mean, corresponding 95% Cl and p-values ​​were provided for comparison of each dose against placebo.

[0255] Analysis of efficacy in baseline biomarkers of characteristic-defined subsets. To examine baseline biomarkers for their potential value for predicting treatment response, an analysis of change in NPS was also performed for the entire ITT population and selected pooled dose groups by the following subsets and each dose group:

[0256] Subgroup Analysis. To assess the consistency of treatment effects across subgroup levels and to examine baseline biomarkers for their potential value for predicting treatment response, exploratory subgroup analyses were performed on age group, sex, region, race, INCS dose level, and baseline biomarkers. Changes from baseline in NPS for baseline NPS, baseline CT scan scores, asthma comorbidities, and pre-study selected biomarkers were assessed.

[0257] Anti-mAb1 antibody results (negative or antibody titer) were listed by patient, time point, and treatment group. ADA titer levels were classified into categories: low, medium, and high. Low ADA titer was defined as a titer less than 1000; medium ADA titer was defined as a titer between 1000 and 10,000; high ADA titer was defined as a titer greater than 10,000.

[0258] Anti-mAb1 antibody assay results were described by category. The following summary was provided for patients with any positive ADA assay response during the TEAE period; and patients with treatment-induced positive ADA assay response during the TEAE period. Patients with treatment-induced positive ADA assay response during the TEAE period were further described as patients with transient positive response and patients with persistent positive response. Patients with any positive ADA assay response during the TEAE period were defined as those with at least one sample positive in the ADA assay.

[0259] A treatment-induced positive ADA assay response was defined as: patients without a positive assay response at baseline but with a positive assay response during the TEAE period or patients with a positive ADA assay response at baseline and who also experienced at least a 4-fold increase in titer during the TEAE period.

[0260] A sustained positive response was a treatment-induced positive ADA assay response in which at least two consecutive post-baseline samples from the patient were positive in the ADA assay or the last post-baseline sample taken was positive in the ADA assay. A transient positive response was defined as any treatment-induced positive ADA assay response that was not considered sustained.

[0261] [Table 18]

[0262] statistical analysis A prespecified primary analysis was performed at the end of the 16-week treatment period. Efficacy analyses were performed using the predefined intent-to-treat (ITT) population as all randomized patients, regardless of whether they ever received study treatment. Safety analyses were performed using the predefined safety population as all randomized patients exposed to study drug, regardless of the amount of treatment received.

[0263] The primary efficacy variable, change in endoscopic NPS over the intervention period, was analyzed using a mixed-effects model with repeated measures (MMRM) approach. The model included change from baseline value through week 16 as the response variable, included factors incorporated for stratification variables, and included treatment, visit, interaction between visit and treatment, baseline NPS value, and interaction between visit and baseline as covariates. Statistical inferences for treatment comparisons of change from baseline in NPS at week 16 were derived from the model. A similar analytical approach was utilized for all continuous secondary endpoints, except for CT scan data.

[0264] CT scan data were collected at both baseline and week 16. Changes in Lund-Mackay total score (left and right sinuses combined) from baseline to week 16 were analyzed using an ANCOVA model. Factors in this model included treatment, stratification factors, and baseline values ​​as covariates. To further evaluate the effect of dupilumab treatment on nasal polypoid disease, responder analyses were performed using logistic regression analysis that included terms for treatment and stratification variables. Two categories of response were predefined; a decrease in NPS of ≥1.0 or ≥2.0 units versus baseline at week 16.

[0265] Descriptive statistics were used for demographics, baseline characteristics, and safety variables (including adverse events, vital signs, physical examination, laboratory tests, and ECG findings). Plots of secondary and pharmacodynamic variables were presented as mean or percent change from baseline over time with standard errors. Comparisons of treatment effects from MMRM analysis were based on least-squares mean changes (95% confidence intervals [CI] and P values) from baseline to week 16.

[0266] D. Data Demographics and baseline clinical characteristics were similar between the two groups (Table 51). The 16-week treatment period was completed by 23 of 30 placebo and 28 of 30 dupilumab patients, respectively. In the placebo group, 5 of 7 patients discontinued the study early due to one or more adverse events, and 2 of 7 patients discontinued early due to lack of efficacy. In the dupilumab group, 2 of 30 patients did not complete the treatment period due to both adverse events.

[0267] Primary endpoint: The primary analysis compared dupilumab-treated groups with placebo. The primary efficacy assessment was change from baseline in bilateral endoscopic NPS at week 16 in the intention-to-treat population using mixed-effects model with repeated measures (MMRM) analysis.

[0268] The least squares (LS) mean (SE) change from baseline at week 16 was -0.30 (0.34) in the placebo group and -1.85 (0.30) in the dupilumab group, resulting in an LS mean difference of -1.55 (95% CI, -2.43 to -0.67, p = 0.0009) in favor of dupilumab (Table 17, Table 52, and Figure 2A). A prespecified responder analysis demonstrated that a change of 1 or more points in NPS (NPS1 score) was observed in 70% of patients receiving dupilumab versus 20% of patients receiving placebo, with an odds ratio (OR) of 9.5 (95% CI, 2.8 to 31.8, p = 0.0003). A change of 2 points (NPS2 score) or more was observed in 10% of patients receiving placebo and 53.3% of patients receiving dupilumab, yielding an OR = 10.6 (2.6 to 43.6, p = 0.001) (Table 19). The change in NPS was sustained at the end of the 16-week follow-up period, when patients received only MFNS (Table 53).

[0269] [Table 19]

[0270] The effect of dupilumab on bilateral NPS was observed from week 4 (LS mean difference -1.03; 95% CI [-1.58, -1.03]; p = 0.004) through week 16. However, at week 12, no statistical significance was demonstrated for the difference in NPS (LS mean [SE] -0.30 [0.34]; -1.08 [0.33] placebo vs. dupilumab; p = 0.1011) (Figure 2).

[0271] The mean change from baseline in bilateral NPS at week 16 was assessed by the following subgroups: sex, race, age, weight, previous nasal polyp surgery, baseline NPS, comorbid asthma, and region (Europe and United States) (Table 18). A mean reduction in NPS in the general range of 1 in favor of dupilumab was demonstrated across most subgroup analyses, except for the subgroup of patients without comorbid asthma.

[0272] For patients with comorbid asthma, the mean (SD) difference in NPS at week 16 was 0.27 (0.88) vs. -2.40 (2.03) for the placebo and dupilumab treatment groups, respectively (Table 18 and Figure 3). For patients without comorbid asthma, the mean (SD) difference in NPS was -1.25 (1.49) vs. -1.36 (1.28) for the placebo and dupilumab treatment groups, respectively (Table 18 and Figure 4).

[0273] Baseline weight less than 90 kg or greater than 90 kg did not affect dupilumab treatment benefit (Table 18).

[0274] [Table 20]

[0275] [Table 21]

[0276] [Table 22]

[0277] [Table 23]

[0278] To further evaluate the effect of dupilumab treatment on nasal polyposis disease, a responder analysis was performed. Two categories of response were predefined: NPS decrease of ≥ 1.0 from baseline at week 16 (NPS1 response) and NPS decrease of ≥ 2.0 from baseline at week 16 (NPS2 response).

[0279] [Table 24]

[0280] For patients with comorbid asthma, the responder analysis demonstrated a statistically significant NPS1 response at week 16 in the dupilumab treatment group (75%) compared to placebo (10.5%), p=0.0009. NPS2 responses were also significantly greater in the dupilumab treatment group compared to placebo (0). The results were numerically favorable to the US Army Corps (56.3%) (Table 20).

[0281] [Table 25]

[0282] For patients without comorbid asthma, the responder analysis was similarly numerically in favor of dupilumab for both NPS1 and NPS2 responses (64.3% and 50%, respectively), while the placebo group showed responder rates of 36.4% and 27.3%, respectively (Table 21); therefore, the numerical difference between the two treatment groups for NPS1 and NPS2 responders was smaller in patients without comorbid asthma compared to patients with comorbid asthma.

[0283] [Table 26]

[0284] Sinus Oral Test (SNOT-22) SNOT-22 was used by patients to assess the impact of rhinosinusitis on quality of life during the study. Higher scores indicated worse disease; the total maximum score was 110. Results demonstrated a significant difference in favor of dupilumab at week 16; the LS mean (SE) change from baseline at week 16 was -9.17 (2.96) in the placebo group and -27.28 (2.71) in the dupilumab group, resulting in a LS mean difference of -18.11 (95% CI, -25.62 to -10.60, p<0.0001) (Table 22). The effect of dupilumab on SNOT-22 scores was observed from week 4 to week 16 (Figure 5).

[0285] [Table 27]

[0286] Further patient-reported outcomes included the visual analogue scale (1–10 cm) that patients used to grade the severity of their rhinosinusitis symptoms, their rating of daily (AM / PM) loss of smell (0–3 point scale), the olfactory sensation test (UPSIT), and their rating of typical rhinitis symptoms (nasal obstruction / stuffiness, runny nose, and posterior rhinorrhea) (0–3 point scale).

[0287] Visual analog scale (VAS) results for rhinosinusitis symptom severity demonstrated statistical significance at week 16; the LS mean (SE) change from baseline at week 16 was -2.19 (0.65) in the placebo group and -4.32 (0.55) in the dupilumab group, resulting in a LS mean difference of -2.13 (95% CI, -3.68 to -0.58, p = 0.0082) (Table 23). The effect of dupilumab on VAS scores was observed from week 4 to week 16 (Figure 6).

[0288] [Table 28]

[0289] Results of patient-reported assessments of smell loss (daily AM / PM electronic diary records, and olfactory test scores using the University of Pennsylvania Smell Identification Test (UPSIT)) demonstrated statistical significance in favor of dupilumab at 16 weeks (Tables 24-26). The dupilumab-treated arm demonstrated better olfactory ability at the earliest assessment time point in this study for each of these patient-reported outcomes (Figures 7-9). Significant improvements were also observed in the secondary endpoints of morning anterior rhinorrhea, subjective smell, evening symptoms, and nighttime awakenings (Table 54). Changes in symptom-based endpoints were sustained at the end of the 16-week follow-up period (Table 53).

[0290] [Table 29]

[0291] [Table 30]

[0292] [Table 31]

[0293] Typical symptoms of rhinitis (nasal obstruction / stuffiness, runny nose, and post-rhinorrhea) were assessed daily by patients (AM / PM electronic records). Results demonstrated statistical significance in favor of dupilumab at week 16 across all these assessments (Tables 27-32). Improvements in rhinosinusitis symptoms were observed from week 4 to week 16 for each of these patient-reported outcomes in the dupilumab-treated arm (Figures 10-15).

[0294] [Table 32]

[0295] [Table 33]

[0296] [Table 34]

[0297] [Table 35]

[0298] [Table 36]

[0299] [Table 37]

[0300] Nasal peak inspiratory flow (NPIF) was assessed with an NPIF meter to evaluate the effect of nasal polyp disease on forced AM / PM inspiration and expiration via the nasal passages (L / min). Normal NPIF flow rates were approximately 140 L / min or greater, whereas very limited flows ranged from 110-120 L / min. AM / PM NPIF flow rate results demonstrated statistical significance (p=0.0073 and p=0.0064, respectively) in favor of dupilumab at 16 weeks (Tables 33 and 34). The effect of dupilumab on AM / PM NPIF was observed from weeks 4 to 16 (Figures 16 and 17). Changes in AM NPIF were sustained at the end of the 16-week follow-up period (Table 53).

[0301] [Table 38]

[0302] [Table 39]

[0303] CT scans of the sinuses were used to assess nasal polyps and associated sinus inflammation. The Lund-Mackay total score assesses the patency of each sinus using a scale of 0 to 2 (0 = completely transparent and 2 = completely opaque; range 0 to 24 points). CT results demonstrated statistically significant differences in favor of dupilumab at week 16; the LS mean (SE) change from baseline at week 16 was -0.23 (0.95) in the placebo group and -9.07 (0.81) in the dupilumab group, resulting in a LS mean difference of -8.84 (95% CI, -11.07 to -6.61, p < 0.0001) (Table 24).

[0304] [Table 40]

[0305] Pharmacodynamic measures included serum total immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, and blood eosinophils.Safety and tolerability assessments were based on the incidence of adverse events (AEs) and serious AEs (SAEs), as well as vital signs, physical examination, clinical laboratory assessments, and 12-lead electrocardiogram (ECG) findings.

[0306] Serum total IgE, TARC and eotaxin-3 levels (Figures 23A-23D) decreased in patients receiving dupilumab and mometasone but remained unchanged in patients receiving placebo and mometasone. The observed IgE decline progressed over the 16-week treatment period, while TARC and eotaxin-3 levels were significantly decreased by week 2 and remained decreased throughout the treatment period. Mean peripheral blood eosinophil levels remained unchanged throughout the treatment period for both placebo and dupilumab (Figure 23D).

[0307] Serum total IgE at baseline was generally normal or slightly elevated in the study population (mean, 140 IU / mL for dupilumab group vs. 195 IU / mL for placebo group). Total IgE progressively decreased during treatment with dupilumab (mean percent change from baseline at week 16: -48.0% dupilumab vs. +7.6% placebo) (Figure 18).

[0308] Baseline mean (SD) thymus and activation-regulated chemokine (TARC) levels for placebo and dupilumab were 449.31 (376.77) pg / mL and 469.65 (298) pg / mL, respectively. During dupilumab treatment, serum TARC levels were 449.31 (376.77) pg / mL and 469.65 (298) pg / mL, respectively. C concentrations decreased by week 4 and remained suppressed through week 16 (mean percent change from baseline at week 4: -26.5% dupilumab vs. +5.0 placebo, and at week 16: -23.0% dupilumab vs. -2.5% placebo) (Figure 19).

[0309] Th2 biomarkers in nasal secretions (saline eluates) were significantly (or borderline significantly) lower after dupilumab (DPL) vs. placebo (PBO) treatment (mean % change from baseline): eotaxin-3 from week 8 (-32.4 DPL vs. +74.4 PBO p=0.017) to week 16 (-38.5 DPL vs. +183.0 PBO p=0.040), ECP at weeks 12 (-2.5 DPL vs. +102.6 PBO p=0.055) and 16 (+7.2 DPL vs. +120.2 PBO p=0.072), and eotaxin-3 from week 8 (-15.7 DPL vs. +60.1 PBO p=0.043) to week 16 (-15.9 DPL vs. +43.8 PBO p=0.043). p=0.025) for total IgE (Figures 24A, 24C, and 24D, respectively). Mean serum ECP, unlike mean NS ECP, showed no decrease during dupilumab treatment. There was a transient increase (mean percent change from baseline) in blood eosinophil counts (Eos) after dupilumab (W4: +49 DPL vs. +0.2 PBO), which resolved during treatment (W16: -5.8 DPL vs. +3.8 PBO) (Figure 23D). The mean absolute change from baseline in nasal biomarkers at week 16 is shown in Table 56 below.

[0310] Study endpoints are summarized in Table 52.

[0311] Safety was assessed by evaluation of AE reports, physical examination findings, ECGs, and clinical trial results.

[0312] Twenty-nine of 30 patients in the dupilumab treatment group reported treatment-emergent adverse events (TETAs), with two dupilumab and four placebo patients each reporting serious TEAEs, compared with 25 of 30 patients in the placebo group. No patients died during the treatment period. One patient in the dupilumab group and five patients in the placebo group discontinued treatment due to TEAEs (Table 36).

[0313] [Table 41]

[0314] The most common system organ classes (SOCs) were: infections and infestations (56.7% for placebo and 70.0% for dupilumab); general disorders and administration site conditions (6.7% for placebo and 43.3% for dupilumab); respiratory, thoracic, and mediastinal disorders (33.3% for placebo and 43.3% for dupilumab); nervous system disorders (20.0% for placebo and 36.7% for dupilumab); gastrointestinal disorders (20.0% for placebo and dupilumab, respectively); and musculoskeletal and connective tissue disorders (3.3% for placebo and 26.7% for dupilumab) (Table 37).

[0315] [Table 42]

[0316] [Table 43]

[0317] [Table 44]

[0318] [Table 45]

[0319] The most frequently reported TEAEs were nasopharyngitis (10 (33.3%) for placebo and 11 (36.7%) for dupilumab) and headache (5 (16.7%) for placebo and 6 (20.0%) for dupilumab), both of which were balanced between the two treatment groups, while injection site reactions were reported predominantly in the dupilumab group (2 (6.7%) for placebo and 12 (40.0%) for dupilumab). In addition, two patients each reported injection and puncture site pain (overall 6.7%). Other commonly reported TEAEs, also reported at a higher percentage with dupilumab than with placebo, were oropharyngeal pain (2 (6.7%) in the placebo group and 7 (23.3%) in the dupilumab group), nosebleed (2 (6.7%) in the placebo group and 6 (20.0%) in the dupilumab group), and upper respiratory tract infection and back pain (both 0 in the placebo group and 3 (10.0%) in the dupilumab group). There were only a few events that were more frequently reported by patients in the placebo group or by 2 or 3 patients overall. The majority of TEAEs were reported by only one patient in either the placebo or dupilumab groups.

[0320] Four patients in the placebo group and two in the dupilumab group reported serious TEAEs. There was no pattern of TEAEs. No patients died during the treatment period. One patient died during screening due to a ruptured aortic aneurysm (non-TEAE) but did not receive study drug (Table 38).

[0321] [Table 46]

[0322] [Table 47]

[0323] A total of six patients (five in the placebo group and one in the dupilumab group) discontinued the study due to TEAEs. With the exception of asthma, which was reported by two placebo patients, all other terms were reported only once (Table 39).

[0324] [Table 48]

[0325] [Table 49]

[0326] Adverse events of special interest (AESI) were defined as: ALT increase; anaphylactic and acute allergic reactions requiring emergency treatment; severe injection site reactions lasting longer than 24 hours; serious infections, including parasitic infections; pregnancy; and overdose (Table 40).

[0327] [Table 50]

[0328] Only a small number of laboratory values ​​met the criteria for potentially clinically significant abnormalities. Although balanced across the two treatment groups, a greater number of patients had documented elevated basophil and eosinophil counts (Tables 41-46).

[0329] [Table 51]

[0330] [Table 52]

[0331] [Table 53]

[0332] [Table 54]

[0333] [Table 55]

[0334] [Table 56]

[0335] There were no clinically meaningful differences between treatment groups with respect to vital signs, ECGs, or physician findings (Table 47, Table 48, and Figure 20).

[0336] [Table 57]

[0337] [Table 58]

[0338] [Table 59]

[0339] For patients with available anti-drug antibody (ADA) results at baseline, 7 / 28 and 7 / 30 in the placebo and dupilumab treatment groups, respectively, had pre-existing ADA titers. Except for one patient in the dupilumab group, pre-existing ADA titers did not increase during treatment (Table 49).

[0340] [Table 60]

[0341] During the study treatment period, three placebo and two dupilumab patients each had positive treatment-emergent ADA titers. One dupilumab-treated patient was transiently ADA positive and had a negative ADA titer 8 weeks later. Placebo patients had low titers ranging from 30 to 60, whereas dupilumab-treated patients had titers ranging from 480 to 1920 (Table 50).

[0342] [Table 61]

[0343] [Table 62]

[0344] As this study was ongoing at the interim analysis stage, no definite conclusions could be drawn regarding ADA response. Final assessment of ADA response will be performed at the end of the study.

[0345] D. Summary of Results Baseline characteristics were similar between groups. The least squares (LS) mean change in NPS was -0.30 in the placebo / mometasone group and -1.85 in the dupilumab / mometasone group (LS mean difference (95% CI) -1.55; p=0.0009). Significant changes in favor of dupilumab were also observed for Lund-Mackay CT score (difference -8.84; p<0.0001), percent of maxillary sinus volume affected (difference -32.24; p<0.0001), SNOT-22 (difference -18.1; p<0.0001), smell, and all other secondary endpoints. In patients with asthma (n=16), dupilumab improved FEV1% predicted (increase of 7.2%, p=0.04) and improved asthma control (reduction of ACQ5 by 1.1 units; p<0.0001). Injection site reactions, headache, and nasopharyngitis were the most frequently reported adverse events with dupilumab.

[0346] For patients refractory to intranasal corticosteroids, the addition of dupilumab improved endoscopic, radiographic, and clinical endpoints in chronic rhinosinusitis with nasal polyps (CSwNP), as well as improved lung function and disease control in patients with comorbid asthma.

[0347] Dupilumab has demonstrated positive results in proof-of-concept studies for patients with nasal polyps and chronic symptoms of sinusitis. For CSwNP, robust efficacy of dupilumab 300mg QW versus placebo was observed when added to NASONEX®. Rapid and clinically significant reductions in nasal polyp size were observed. Consistent improvements in CT scan measurements of sinusitis, nasal airflow, and patient-reported symptoms were observed.

[0348] The most frequently reported TEAEs were nasopharyngitis, headache, and injection site reactions, with injection site reactions being reported more frequently in the dupilumab-treated group. Other frequently reported TEAEs that were similarly more frequently reported in the dupilumab-treated group compared with the placebo group were oropharyngeal pain, epistaxis, upper respiratory tract infection, and back pain. There were no other clinically relevant safety findings or differences in safety parameters between the treatment groups.

[0349] A low incidence of treatment-emergent anti-drug antibody responses was observed in both dupilumab and placebo treatment groups. The study was ongoing at the interim analysis stage, so no definite conclusions could be drawn regarding ADA responses. Final evaluation of ADA responses will occur at the end of the study.

[0350] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to be within the scope of the appended claims.

[0351] [Table 63]

[0352] [Table 64]

[0353] [Table 65]

[0354] [Table 66]

[0355] Outcomes in patients with and without comorbid asthma. In the subset of patients with comorbid asthma, treatment with dupilumab was associated with improvements in lung function (Figure 22A) and asthma control (Figure 22B), with an LS mean difference between treatment groups in FEV1(%) of 7.2% (95% CI, 0.4 to 13.9; p=0.04) and a reduction in ACQ-5 of 0.3 (0.3) units in the placebo group and 1.4 (0.4) units in the dupilumab group, resulting in an LS mean difference in ACQ score of -1.1 units (95% CI, -1.5 to -0.6; p<0.0001). In addition, in this subgroup, the mean change in bilateral endoscopic nasal polyp score from baseline to week 16 was 0.3 (0.9) in the placebo group and -2.4 (2.0) in the dupilumab group, resulting in a LS mean difference of -2.3 (95% CI, -3.4 to -1.2, p = 0.0002) in favor of dupilumab. Patients with asthma also experienced improvements in UPSIT, SNOT-22, and congestion symptoms with dupilumab / MFNS (Table 55).

[0356] A change of ≥1 point in NPS was observed in 75% of patients receiving dupilumab versus 10.5% of patients receiving placebo, with an odds ratio (OR) of 26.1 (95% CI, 3.8 to 179.3; p = 0.0009). A change of ≥2 points was not observed in any patients receiving placebo and in 56.3% of patients receiving dupilumab. It was observed in the

[0357] Analysis of the effect of dupilumab / MFNS in patients without asthma did not reveal a significant effect of dupilumab versus placebo on endoscopic NPS, however, effects of dupilumab on UPSIT, SNOT-22, symptoms of congestion, and other clinical and radiographic endpoints were observed in this subgroup (Table 55).

[0358] [Table 67]

[0359] [Table 68]

[0360] safety Adverse events were reported by 25 of 30 patients in the placebo group and 29 of 30 in the dupilumab group (Table 37). Injection site reactions (ISRs), headache, and nasopharyngitis were the most frequent adverse events across the entire study population, with ISRs being more frequent with dupilumab treatment. These events were generally nonspecific and mild to moderate in intensity.

[0361] Six patients had serious adverse events: four in the placebo group (uterine cancer, transient ischemic attack, asthma, and nasal polyps) and two in the dupilumab group (shingles in one patient, and arrhythmia and upper extremity pain / numbness in the other); none were considered related to study drug by the investigator. Five patients in the placebo group experienced adverse events leading to discontinuation of study drug (otitis media, bronchitis, hypersensitivity, headache, hypertension, asthma, and abdominal pain), although one patient in the dupilumab group also experienced one (constipation). No clinically significant changes in vital signs or findings on physical examination, clinical laboratory tests, or ECG were reported in either group.

[0362] There were no deaths during the active treatment period; one patient died of aortic aneurysm rupture during the screening period before randomization to study treatment.

[0363] Rapid and significant improvements in endoscopic, clinical, radiographic and pharmacodynamic endpoints were observed following administration of dupilumab to patients with chronic rhinosinusitis with nasal polyps, indicating the important role of IL-4 and IL-13 in the pathogenesis and clinical manifestations of this disease. A significant benefit of dupilumab on CSwNP outcomes was also observed in an analysis restricted to a subset of patients with comorbid asthma; these patients further experienced improvements in lung function and asthma control (important asthma outcomes). These data indicate that attenuation of IL-4 and IL-13-mediated signaling pathways can have broad therapeutic effects in patients with multiple coexisting Th-2-mediated diseases.

[0364] Compared with other approaches, dupilumab treatment led to sustained clinical improvement over time that exceeded that observed with systemic glucocorticoids. Furthermore, this study added dupilumab or placebo to current standard of care for CSwNP and asthma. 3 When added to current standard of care, dupilumab treatment was associated with broad and significant improvements in multiple clinically relevant CSwNP and asthma parameters.

[0365] Levels of biomarkers of Th2 inflammation, including serum IgE, eotaxin-3, and TARC, were reduced with dupilumab, which correlated with clinical improvement and confirmed the drug's biological activity in many of these pathways. In this study, patients with CSwNP who also reported a diagnosis of asthma generally exhibited impaired pulmonary function, suboptimal disease control, and had disease that was of adult-onset. The clinical benefit observed in patients with both CSwNP and asthma illustrates that in at least one subset of patients, a common set of Th2-related inflammatory pathways appears to be shared between asthma and CSwNP, demonstrating that targeting these pathways can lead to clinical improvement in both diseases.

[0366] In summary, this example demonstrates that in patients with CSwNP refractory to intranasal corticosteroids, treatment with dupilumab was associated with improvement in endoscopic, radiographic and clinical measures of disease. The efficacy of dupilumab was augmented in patients with comorbid asthma, who also experienced concomitant improvements in lung function and disease control. Further studies will be conducted to fully elucidate the impact of targeting IL-4 and IL-13 in patients with multiple comorbid atopic diseases.

Claims

1. 1. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) for use in reducing nasal polyp score (NPS) in a subject in need thereof, comprising: a pharmaceutical composition for administration to a subject in whom NPS has been determined; The pharmaceutical composition, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences of SEQ ID NOs: 3, 4 and 5, derived from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 and 2.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nasal cavity.

3. 3. The pharmaceutical composition according to claim 1 or 2 for use in reducing NPS by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

4. 4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity.

5. 5. The pharmaceutical composition for use according to claim 4, wherein the subject has one or more conditions selected from the group consisting of nasal polyps, chronic rhinosinusitis with nasal polyps (CSwNP), chronic rhinosinusitis with bilateral nasal polyps, and chronic rhinosinusitis with nasal polyps (CRSwNP).

6. The pharmaceutical composition for use according to claim 5, wherein the subject has asthma.

7. 6. The pharmaceutical composition for use according to claim 5, wherein the subject does not have asthma.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the subject has had surgery for either or both of nasal polyps and chronic rhinosinusitis.

9. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein initial functional endoscopic sinus surgery (FESS) is indicated, revision surgery is indicated or surgery is contraindicated.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof is for administration at a dose of between about 100 mg to about 600 mg.

11. 11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is for administration at an initial dose of between about 400 mg and about 600 mg, and one or more subsequent doses each of between about 200 mg and about 400 mg.

12. 12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the antibody or antigen-binding fragment thereof is for administration in an initial dose of about 600 mg, and in one or more subsequent doses of about 300 mg each.

13. 13. The pharmaceutical composition for use according to claim 12, wherein the one or more subsequent doses are for administration once every seven days (QW).

14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the antibody or antigen-binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

16. The pharmaceutical composition for use according to any one of claims 1 to 15, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

17. The pharmaceutical composition for use according to any one of claims 1 to 16, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

18. 18. The pharmaceutical composition for use according to any one of claims 1 to 17, further for use in improving one or more nasal polyps related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow (NPIF).

19. 19. The pharmaceutical composition for use according to claim 18 for use in improving one or more of daytime (AM), nighttime (PM) or both AM and PM loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow.

20. 20. The pharmaceutical composition for use according to any one of claims 1 to 19, further for use in decreasing one or more of serum IgE levels, plasma eotaxin-3 levels and serum thymus and activation regulated chemokine (TARC) levels.

21. The pharmaceutical composition for use according to any one of claims 1 to 20, further for use in decreasing one or more of total IgE levels, eotaxin-3 levels and eosinophil cationic protein (ECP) levels in the nasal secretion of a subject.

22. 1. An antibody or antigen-binding fragment thereof that specifically binds to IL-4R for use in reducing NPS in a subject in need thereof, comprising: The NPS is for administration to a determined subject; For administration at a loading dose of about 400 to about 600 mg; comprising heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; and The antibody or antigen-binding fragment is for administration in one or more maintenance doses of about 200 to about 300 mg each.

23. 23. The antibody or antigen-binding fragment thereof for use according to claim 22, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administration step.

24. The antibody or antigen-binding fragment thereof for use according to claim 22 or 23 for use in reducing NPS by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

25. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 24, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity and NSAID hypersensitivity.

26. The antibody or antigen-binding fragment thereof for use according to claim 25, wherein the subject has one or more conditions selected from the group consisting of nasal polyps, CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP.

27. 27. The antibody or antigen-binding fragment thereof for use according to claim 26, wherein the subject has asthma.

28. 27. The antibody or antigen-binding fragment thereof for use according to claim 26, wherein the subject does not have asthma.

29. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 28, wherein the subject has undergone surgery for one or both of nasal polyps and chronic rhinosinusitis.

30. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 29, wherein FESS is indicated, revision surgery is indicated or surgery is contraindicated.

31. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 30, wherein the loading dose is about 600 mg and the one or more maintenance doses are each about 300 mg.

32. The antibody or antigen-binding fragment thereof for use according to claim 31 , wherein the one or more maintenance doses are administered QW.

33. 33. An antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 32, comprising the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

34. An antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 33, comprising an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

35. 35. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 34, comprising the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

36. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 35, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

37. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 36, further for use in improving one or more nasal polyps-related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and NPIF.

38. The antibody or antigen-binding fragment thereof for use as described in claim 37 for use in improving one or more of the following: loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow in AM, PM or both AM and PM.

39. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 38 for use in reducing one or more of serum IgE levels, plasma eotaxin-3 levels and serum TARC levels.

40. The antibody or antigen-binding fragment thereof for use according to any one of claims 22 to 39 for use in reducing one or more of total IgE levels, eotaxin-3 levels and ECP levels in the nasal secretion of a subject.

41. 1. An antibody or antigen-binding fragment thereof that specifically binds to IL-4R for use in reducing NPS in a subject in need thereof, comprising: The NPS is for administration to a determined subject; For administration to a subject who has received one or more maintenance doses of an ICS; For administration at a loading dose of about 400 to about 600 mg; comprising heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; for administration in one or more maintenance doses each of about 200 to about 300 mg; The antibody or antigen-binding fragment, wherein the ICS is for administration during the period of administration of the antibody or antigen-binding fragment.

42. 42. The antibody or antigen-binding fragment thereof for use according to claim 41, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administration step.

43. The antibody or antigen-binding fragment thereof for use according to claim 41 or 42 for use in reducing NPS by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

44. 44. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 43, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity and NSAID hypersensitivity.

45. The antibody or antigen-binding fragment thereof for use according to claim 44, wherein the subject has one or more conditions selected from the group consisting of nasal polyps, CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP.

46. 46. ​​The antibody or antigen-binding fragment thereof for use according to claim 45, wherein the subject has asthma.

47. 46. ​​The antibody or antigen-binding fragment thereof for use according to claim 45, wherein the subject does not have asthma.

48. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 47, wherein the subject has undergone surgery for one or both of nasal polyps and chronic rhinosinusitis.

49. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 48, wherein initial functional endoscopic sinus surgery (FESS) is indicated, revision surgery is indicated, or surgery is contraindicated.

50. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 49, wherein the loading dose is about 600 mg and the one or more maintenance doses are each about 300 mg.

51. 51. The method of claim 50, wherein the one or more maintenance doses are administered QW. The antibody or antigen-binding fragment thereof.

52. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 51, wherein the ICS is mometasone furoate nasal spray (MFNS).

53. 53. The antibody or antigen-binding fragment thereof for use according to claim 52, wherein the MFNS is for administration once or twice daily at a dose of about 100 mg in each nostril of a subject.

54. 54. An antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 53, comprising the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

55. 55. An antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 54, comprising an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

56. 56. An antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 55, comprising the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

57. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 56, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

58. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 57, further for use in improving one or more nasal polyps-related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and NPIF.

59. The antibody or antigen-binding fragment thereof for use as described in claim 58 for use in improving one or more of loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow in AM, PM or both AM and PM.

60. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 59 for use in reducing one or more of serum IgE levels, plasma eotaxin-3 levels and serum TARC levels.

61. The antibody or antigen-binding fragment thereof for use according to any one of claims 41 to 60 for use in reducing one or more of total IgE levels, eotaxin-3 levels and ECP levels in the nasal secretion of a subject.

62. An antibody or antigen-binding fragment thereof that specifically binds to IL-4R for use in reducing NPS and for use in improving one or more additional nasal polyps related parameters in a subject in need thereof; The NPS is for administration to a determined subject; for administration to a subject in which the level of one or more additional nasal polyps-related parameters has been determined; For administration to a subject who has received one or more maintenance doses of an ICS; For administration at a loading dose of about 400 to about 600 mg; comprising heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; for administration in one or more maintenance doses each of about 200 to about 300 mg; The antibody or antigen-binding fragment, wherein the ICS is for administration during the period of administration of the antibody or antigen-binding fragment.

63. The antibody or antigen-binding fragment thereof for use according to claim 62, wherein the one or more additional nasal polyps related parameters are selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and NPIF.

64. 1. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R for use in treating nasal polyps in a subject in need thereof, comprising: The above pharmaceutical composition, wherein the antibody or antigen-binding portion thereof comprises heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2.

65. 65. The pharmaceutical composition of claim 64 for use in reducing NPS in a subject by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

66. 66. The pharmaceutical composition for use according to claim 64 or 65, wherein the subject has asthma.

67. 67. The pharmaceutical composition for use according to claim 66, wherein one or both of lung function and asthma control are improved.

68. 66. The pharmaceutical composition for use according to claim 64 or 65, wherein the subject does not have asthma.

69. 69. The pharmaceutical composition for use according to any one of claims 64 to 68 for use in improving one or more nasal polyp endpoints selected from the group consisting of endoscopic endpoints, radiological endpoints and clinical endpoints.

70. 70. The pharmaceutical composition for use according to any one of claims 64 to 69, wherein the antibody or antigen-binding fragment thereof is for administration at an initial dose of between about 400 mg and about 600 mg, and one or more maintenance doses each of between about 200 mg and about 300 mg.

71. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R for use in treating CSwNP in a subject in need thereof, The above pharmaceutical composition, wherein the antibody or antigen-binding portion thereof comprises heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2.

72. 72. The pharmaceutical composition of claim 71 for use in reducing NPS in a subject by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

73. 73. The pharmaceutical composition for use according to claim 71 or 72, wherein the subject has asthma.

74. 74. The pharmaceutical composition for use according to claim 73, wherein one or both of lung function and asthma control are improved.

75. 73. The pharmaceutical composition for use according to claim 71 or 72, wherein the subject does not have asthma.

76. The pharmaceutical composition for use according to any one of claims 71 to 75 for use in improving one or more CSwNP evaluation items selected from the group consisting of endoscopic evaluation items, radiological evaluation items and clinical evaluation items.

77. The antibody or antigen-binding fragment thereof may be administered at an initial dose of between about 400 mg and about 600 mg, and and one or more maintenance doses of between about 200 mg and about 300 mg each.

78. 1. A method of reducing nasal polyp score (NPS) in a subject in need thereof, comprising: (i) determining the NPS of the subject; (ii) administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising heavy and light chain CDR sequences of SEQ ID NOs: 3, 4 and 5, derived from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 and 2; so that the subject's NPS is reduced.

79. 80. The method of claim 78, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administering step.

80. 80. The method of claim 78 or 79, wherein the NPS is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

81. 81. The method of any one of claims 78-80, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity, and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity.

82. 82. The method of claim 81, wherein the subject has one or more conditions selected from the group consisting of nasal polyps, chronic rhinosinusitis with nasal polyps (CSwNP), chronic rhinosinusitis with bilateral nasal polyps, and chronic rhinosinusitis with nasal polyps (CRSwNP).

83. 83. The method of claim 82, wherein the subject has asthma.

84. 83. The method of claim 82, wherein the subject does not have asthma.

85. 85. The method of any one of claims 78 to 84, wherein the subject has had surgery for one or both of nasal polyps and chronic rhinosinusitis.

86. 86. The method of any one of claims 78 to 85, wherein initial functional endoscopic sinus surgery (FESS) is indicated, revision surgery is indicated, or surgery is contraindicated.

87. The method of any one of claims 78 to 86, wherein the antibody or antigen-binding fragment thereof is administered at a dose of between about 100 mg and about 600 mg.

88. 88. The method of any one of claims 78-87, wherein the antibody or antigen-binding fragment thereof is administered in an initial dose of between about 400 mg and about 600 mg, and in one or more subsequent doses each of between about 200 mg and about 400 mg.

89. 89. The method of any one of claims 78-88, wherein the antibody or antigen-binding fragment thereof is administered in an initial dose of about 600 mg, and in one or more subsequent doses of about 300 mg each.

90. 90. The method of claim 89, wherein the one or more subsequent doses are administered once every seven days (QW).

91. The method of any one of claims 78 to 90, wherein the antibody or antigen-binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

92. The method of any one of claims 78 to 91, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

93. The method of any one of claims 78 to 92, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

94. The method of any one of claims 78 to 93, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

95. 95. The method of any one of claims 78 to 94, wherein after the administering step, there occurs an improvement in one or more nasal polyps related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow (NPIF).

96. 96. The method of claim 95, wherein the improvement in one or more of loss of smell, runny nose, post-rhinorrhea, and nasal peak inspiratory flow occurs during the day (AM), at night (PM), or both AM and PM.

97. 97. The method of any one of claims 78 to 96, wherein after the administering step, there is a decrease in one or more of serum IgE levels, plasma eotaxin-3 levels, and serum thymus and activation-regulated chemokine (TARC) levels.

98. The method of any one of claims 78 to 97, wherein after the administering step, there is a decrease in one or more of total IgE levels, eotaxin-3 levels and eosinophil cationic protein (ECP) levels in the subject's nasal secretion.

99. 1. A method for reducing NPS in a subject in need thereof, comprising: (i) determining the NPS of the subject; (ii) administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; (iii) administering to the subject one or more maintenance doses of the antibody or antigen-binding fragment thereof, each of about 200 to about 300 mg; thereby reducing NPS in the subject.

100. 100. The method of claim 99, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administering step.

101. 101. The method of claim 99 or 100, wherein the NPS is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

102. 102. The method of any one of claims 99-101, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity and NSAID hypersensitivity.

103. 103. The method of claim 102, wherein the subject has one or more conditions selected from the group consisting of CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP.

104. 104. The method of claim 103, wherein the subject has asthma.

105. 104. The method of claim 103, wherein the subject does not have asthma.

106. The method of any one of claims 99 to 105, wherein the subject has had surgery for one or both of nasal polyps and chronic rhinosinusitis.

107. 107. The method of any one of claims 99 to 106, wherein FESS is indicated, revision surgery is indicated, or surgery is contraindicated.

108. 108. The method of any one of claims 99-107, wherein the loading dose is about 600 mg and the one or more maintenance doses are each about 300 mg.

109. The method of claim 108, wherein the one or more maintenance doses are administered QW.

110. The method of any one of claims 99 to 109, wherein the antibody or antigen-binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

111. The method of any one of claims 99 to 110, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

112. The method of any one of claims 99 to 111, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

113. The method of any one of claims 99 to 112, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

114. 114. The method of any one of claims 99 to 113, wherein after the administration step, there occurs an improvement in one or more nasal polyps-related parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and NPIF.

115. The method of claim 114, wherein improvement in one or more of loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow occurs in AM, PM, or both AM and PM.

116. 116. The method of any one of claims 99 to 115, wherein after the administering step, there is a decrease in one or more of serum IgE levels, plasma eotaxin-3 levels and serum TARC levels.

117. 117. The method of any one of claims 99 to 116, wherein after the administering step, there is a decrease in one or more of total IgE levels, eotaxin-3 levels and ECP levels in the subject's nasal secretion.

118. 1. A method for reducing NPS in a subject in need thereof, comprising: (i) determining the NPS of the subject; (ii) administering to the subject one or more maintenance doses of an ICS; (iii) administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; (iv) administering to the subject one or more maintenance doses of about 200 to about 300 mg each of the antibody or antigen-binding fragment thereof, wherein the ICS is administered during the period of administration of the antibody or antigen-binding fragment thereof; thereby reducing NPS in the subject.

119. 119. The method of claim 118, wherein the subject has a total of at least five nasal polyps, including two or more nasal polyps present in each nostril prior to the administration step.

120. 120. The method of claim 118 or 119, wherein the NPS is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

121. 121. The method of any one of claims 118-120, wherein the subject further has one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity and NSAID hypersensitivity.

122. 122. The method of claim 121, wherein the subject has one or more conditions selected from the group consisting of nasal polyps, CSwNP, chronic rhinosinusitis with bilateral nasal polyps, and CRSwNP.

123. 123. The method of claim 122, wherein the subject has asthma.

124. 123. The method of claim 122, wherein the subject does not have asthma.

125. The method of any one of claims 118 to 124, wherein the subject has had surgery for one or both of nasal polyps and chronic rhinosinusitis.

126. 126. The method of any one of claims 118 to 125, wherein initial functional endoscopic sinus surgery (FESS) is indicated, revision surgery is indicated, or surgery is contraindicated.

127. 127. The method of any one of claims 118-126, wherein the loading dose is about 600 mg and the one or more maintenance doses are each about 300 mg.

128. 128. The method of claim 127, wherein the one or more maintenance doses are administered QW.

129. The method of any one of claims 118 to 128, wherein the ICS is mometasone furoate nasal spray (MFNS).

130. 130. The method of claim 129, wherein about 100 mg of MFNS is administered to each nostril of the subject once or twice daily.

131. The method of any one of claims 118 to 130, wherein the antibody or antigen-binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.

132. The antibody or antigen-binding fragment thereof according to any one of claims 118 to 131, comprising an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2. The method described.

133. The method of any one of claims 118 to 132, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:

10.

134. The method of any one of claims 118 to 133, wherein the antibody is dupilumab or an antigen-binding fragment thereof.

135. The method of any one of claims 118 to 134, wherein after the administration step, there occurs an improvement in one or more nasal polyps associated parameters selected from the group consisting of loss of smell, runny nose, post-rhinorrhea and NPIF.

136. The method of claim 135, wherein improvement in one or more of loss of smell, runny nose, post-rhinorrhea and nasal peak inspiratory flow occurs in AM, PM, or both AM and PM.

137. 137. The method of any one of claims 118 to 136, wherein after the administering step, there is a decrease in one or more of serum IgE levels, plasma eotaxin-3 levels and serum TARC levels.

138. The method of any one of claims 118 to 137, wherein after the administering step, there is a decrease in one or more of total IgE levels, eotaxin-3 levels and ECP levels in the subject's nasal secretion.

139. 1. A method of reducing NPS and improving one or more additional nasal polyps associated parameters in a subject in need thereof, comprising: (i) determining the NPS of the subject; (ii) determining the level of one or more additional nasal polyp-related parameters in the subject; (iii) administering to the subject one or more maintenance doses of an ICS; (iv) administering to the subject a loading dose of about 400 to about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2; (v) administering to the subject one or more maintenance doses of about 200 to about 300 mg each of the antibody or antigen-binding fragment thereof, wherein the ICS is administered during the period of administration of the antibody or antigen-binding fragment thereof; such that the subject's NPS is reduced and one or more additional nasal polyp-related parameters are improved in the subject.

140. 140. The method of claim 139, wherein the one or more additional nasal polyps related parameters are selected from the group consisting of loss of smell, runny nose, post nasal drip and NPIF.

141. 1. A method of treating nasal polyps in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDRs derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2, such that one or more symptoms of nasal polyps in the subject are reduced.

142. 142. The method of claim 141, wherein the subject's NPS is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

143. 143. The method of claim 141 or 142, wherein the subject has asthma.

144. 144. The method of claim 143, wherein one or both of lung function and asthma control are improved.

145. 143. The method of claim 141 or 142, wherein the subject does not have asthma.

146. The method of any one of claims 141 to 145, wherein one or more nasal polyp endpoints selected from the group consisting of endoscopic endpoints, radiological endpoints, and clinical endpoints are improved.

147. 147. The method of any one of claims 141-146, wherein the antibody or antigen-binding fragment thereof is administered at an initial dose of between about 400 mg and about 600 mg, and one or more maintenance doses each of between about 200 mg and about 300 mg.

148. A method of treating CSwNP in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs derived from the HCVR and LCVR sequence pair of SEQ ID NOs: 1 and 2, such that one or more symptoms of CSwNP in the subject are reduced.

149. 149. The method of claim 148, wherein the subject's NPS is reduced by about 10% to about 50%, about 20% to about 40%, or about 25% to about 30%.

150. The method of claim 148, wherein the subject has asthma.

151. 151. The method of claim 150, wherein one or both of lung function and asthma control are improved.

152. 149. The method of claim 148, wherein the subject does not have asthma.

153. The method of claim 148, wherein one or more CSwNP evaluation items selected from the group consisting of endoscopic evaluation items, radiological evaluation items, and clinical evaluation items are improved.

154. The method of claim 148, wherein the antibody or antigen-binding fragment thereof is administered at an initial dose of between about 400 mg and about 600 mg, and one or more maintenance doses each of between about 200 mg and about 300 mg.

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