NZ752224B2 - Methods for treating nasal polyposis by administering an il-4r antagonist - Google Patents

Abstract

Disclosed is the use of an antibody or antigen binding fragment thereof, that specifically binds an interleukin-4 receptor (IL-4R) for the preparation of a pharmaceutical composition for treating nasal polyposis in a subject, and wherein the antibody or antigen-binding fragment thereof comprises three HCDRs and three LCDRs, wherein the HCDR1 comprises SEQ ID NO:3, the HCDR2 comprises SEQ ID NO:4, the HCDR3 comprises SEQ ID NO:5, the LCDR1 comprises SEQ ID NO:6, the LCDR2 comprises SEQ ID NO:7, and the LCDR3 comprises SEQ ID NO:8. In a preferred embodiment the pharmaceutical composition is prepared to treat chronic rhinosinusitis with nasal polyposis. ee HCDRs and three LCDRs, wherein the HCDR1 comprises SEQ ID NO:3, the HCDR2 comprises SEQ ID NO:4, the HCDR3 comprises SEQ ID NO:5, the LCDR1 comprises SEQ ID NO:6, the LCDR2 comprises SEQ ID NO:7, and the LCDR3 comprises SEQ ID NO:8. In a preferred embodiment the pharmaceutical composition is prepared to treat chronic rhinosinusitis with nasal polyposis.

Description

METHODS FOR TREATING NASAL POLYPOSIS BY ADMINISTERING AN |L-4R NIST RELATED APPLICATIONS This ation claims the benefit of US. Provisional Application No. 61/837,912, filed June 21, 2013 and European Application No. 143056703, filed May 7, 2014, each of which is incorporated herein by reference in its ty.

FIELD OF THE INVENTION The present invention relates to the field of therapeutic treatments of inflammatory ions. More specifically, the invention relates to the administration of interleukin-4 or (IL-4R) antagonists to treat nasal polyposis.

BACKGROUND Nasal sis (NP) is a clinical condition characterized by the presence of le polyps in the upper nasal cavity, originating from the ostiomeatal complex. NP is a T helper cell- 2 (Th-2) driven inflammatory process affecting the mucosa of the nose and paranasal sinuses.

Eosinophils and their products are thought to be a hallmark of nasal polyp-associated inflammation as elevated levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cationic protein (ECP), and eotaxin (eosinophil chemoattractant), factors that attract and te eosinophils, are typically found in nasal polyps. Eosinophils are the predominant inflammatory cell found in the sinuses and nasal polyps, and nasal polyps are also associated with elevated levels of lgE. NP is characterized by long-term symptoms of nasal obstruction and congestion, reduction in or loss of sense of smell, anterior and posterior rhinorrhea, and facial pain. Current treatment options range from local or ic corticosteroids to functional endoscopic sinus surgery.

BRIEF SUMMARY OF THE INVENTION

[0004] In one aspect, the invention provides a method for treating nasal polyposis, where the method includes administering to a subject in need thereof a pharmaceutical composition containing an eukin-4 receptor (IL-4R) antagonist, such as an L-4R antibody or n-binding fragment thereof. In one embodiment, the lL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR ces 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 an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid ce of SEQ ID NO:2. In one embodiment, the lL-4R antagonist is dupilumab or an n-binding fragment thereof. Other exemplary anti- IL-4R dies or antigen-binding fragments thereof are bed, for example, in US Patent Nos. 7,605,237 and 7,608,693.

A subject suitable for treatment with an IL-4R antagonist may have one or more of sinusitis, is, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or have previously undergone surgery to treat nasal polyposis. In some embodiments, the subject has c tis or chronic rhinosinusitis. For example, the subject may have nasal polyposis with severe symptoms of sinusitis.

In some embodiments, the IL-4R antagonist is administered at a dose of 0.1 mg to 600 mg (e.g., 100 mg to 400 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg). In n embodiments, the pharmaceutical composition is administered to the subject systemically or locally. For example, the pharmaceutical composition may be administered subcutaneously, intravenously, or asally.

In one embodiment, the pharmaceutical ition is administered to the subject subcutaneously at a dose of 300 mg.

In certain embodiments, one or more additional therapeutic agents are administered to the subject , after or concurrent with the pharmaceutical composition sing the IL-4R antagonist, such as the IL-4R antibody or n-binding fragment thereof. For example, in one ment, the one or more additional agents, such as a second therapeutic agent can be a TNF inhibitor, an lL-1 inhibitor, an lL-5 inhibitor, an lL-8 inhibitor, an lgE inhibitor, an NSAID (non-steroidal nflammatory drug), an otic, an anti-fungal agent, an intranasal corticosteroid, an inhaled corticosteroid, a systemic corticosteroid, a long-acting beta2 agonist, a decongestant, or any combination thereof. In one embodiment, the second therapeutic agent is an inhaled corticosteroid, such as fluticasone or budesonide, or an intranasal corticosteroid, such as mometasone furoate nasal spray (MFNS). In another embodiment, the second therapeutic agent further includes a long-acting beta2 agonist, such as erol or formoterol.

In certain embodiments, administration of the IL-4R antagonist is followed by an improvement in one or more symptoms of nasal polyposis. For example, the administration of the antagonist can be followed by an improvement in one or more nasal polyposis-associated parameters, such as an improvement in a 22—item Sinonasal Outcome Test (SNOT-22) score; a nasal symptom score; number of nocturnal awakenings; a Visual Analog Score (VAS), such as for rhinosinusitis symptom severity; a five-item Asthma Control Questionnaire (ACQS) score; nasal peak inspiratory flow (NPIF); the University of Pennsylvania Smell Identification Test (UPSIT); Lund-McKay Score; and three dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen binding fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3D-Volumetric Score. In some embodiments, administration of the lL-4R antagonist is followed by a decrease in nasal polyp score in the patient.

In one aspect, the ion provides a method for treating nasal polyposis, by sequentially administering to a subject in need thereof a single initial dose of an interleukin-4 receptor (IL-4R) antagonist, such as an lL-4R antibody or an antigen-binding fragment thereof, followed by one or more secondary doses of the lL-4R antagonist. In some embodiments, each secondary dose is administered 1 to 15 weeks after the immediately preceding dose. In other embodiments, at least three secondary doses of the lL-4R antagonist are administered to the subject, and each secondary dose is administered days or weeks (e.g., 1 week or 2 weeks or more) after the immediately preceding dose. In another embodiment, the initial dose and the one or more secondary doses each include 50 mg to 500 mg of the lL-4R antagonist, e.g., 100 mg to 400 mg of the lL-4R antagonist, e.g., 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg of the lL-4R antagonist. In some embodiments, the initial dose and the one or more secondary doses each n the same amount of the lL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the lL-4R antagonist, and the one or more secondary doses each comprise a second amount of the lL-4R antagonist. For example, the first amount of the lL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x or 5x or more than the second amount of lL-4R nist.

[0011] In one embodiment, the subject (e.g., a patient) has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal nflammatory drug (NSAID) hypersensitivity, or has undergone surgery for nasal polyps. In some embodiments, the subject has chronic sinusitis or c rhinosinusitis. For example, the subject may have nasal polyposis with severe symptoms of tis.

[0012] The initial dose and the secondary doses of the lL-4R antagonist can be administered by the same or different routes of administration. For example, the initial dose and the secondary doses can be stered subcutaneously, intravenously, or intranasally.

In certain embodiments, administration of the initial dose and the one or more secondary doses is followed by an improvement in one or more nasal polyposis associated parameters, such as an improvement in a 22—item Sinonasal e Test (SNOT-22) score; a nasal m score; number of nocturnal awakenings; a Visual Analog Score (VAS), such as for rhinosinusitis symptom ty; a tem Asthma Control Questionnaire (ACQ5) score; nasal peak inspiratory flow (NPIF); the sity of Pennsylvania Smell fication Test (UPSIT); Lund-McKay Score; and three dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen g fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3D-Volumetric Score. In some embodiments, administration of the IL-4R antagonist is ed by a decrease in nasal polyp score in the patient.

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after or concurrent with the pharmaceutical composition comprising the IL-4R antagonist, such as the IL-4R antibody or antigen-binding fragment thereof. For example, in one embodiment, the one or more additional , such as a second therapeutic agent can be a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an lgE inhibitor, an NSAID, an antibiotic, an ungal agent, an intranasal corticosteroid, an d corticosteroid, a systemic corticosteroid, a long-acting beta2 agonist, a decongestant, or any combination thereof. In one embodiment, the second therapeutic agent is an inhaled corticosteroid, such as fluticasone or budesonide, or an intranasal corticosteroid, such as mometasone furoate nasal spray (MFNS).

In another embodiment, the second therapeutic agent further includes a long-acting beta2 agonist, such as erol or formoterol.

In one aspect, the invention provides a method for treating nasal polyposis, by selecting a patient with a m bilateral nasal polyp score of 5, or at least two or more of the chronic symptoms of sinusitis selected from the group consisting of: nasal blockade/obstruction/congestion, or or posterior nasal drip, facial pain or pressure, and reduction or loss of smell; and administering to the selected patient a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the patient’s nasal polyp score is reduced or the two or more chronic symptoms of sinusitis are improved. In one embodiment, the IL-4R nist is an antibody or antigen-binding fragment thereof that specifically binds , such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For e, in one ment, the dy or antigen binding fragment f 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 an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid ce of SEQ ID NO:2. In one embodiment, the IL-4R antagonist is mab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments f are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one , the invention provides a method for treating nasal polyposis, by selecting a patient with a minimum bilateral nasal polyp score of 5, or at least two or more of the chronic symptoms of sinusitis selected from the group consisting of: nasal blockade/obstruction/congestion, anterior or posterior nasal drip, facial pain or pressure, and reduction or loss of smell; and sequentially administering to the patient a single initial dose of a pharmaceutical composition an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), followed by one or more secondary doses of the antibody or antigen binding fragment thereof, such that the patient’s nasal polyp score is reduced or the two or more chronic symptoms of tis are improved. In one embodiment, the lL-4R antagonist is an antibody or antigen- binding nt thereof that ically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO: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 dy or antigen-binding fragment f ses 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. In one embodiment, the lL-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 US Patent Nos. 237 and 7,608,693.

In one aspect, the invention provides a method for treating nasal polyposis, by determining in a subject the expression level of one or more genes selected from the group consisting of thymus and activation-regulated chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA), and ; selecting the subject as a candidate for treatment with an interleukin-4 receptor ) nist, such as antibody or n-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), if the subject has an elevated expression level of the one or more genes; and administering to the selected subject a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the level of the one or more genes is reduced. In one embodiment, the lL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one ment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs:3, 4, and 5, and light chain CDR ces of SEQ ID NOs:6, 7 and 8. For example, in one embodiment, the antibody or antigen-binding fragment thereof ses 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. In one ment, the lL-4R antagonist is dupilumab or an antigen-binding nt thereof. Other exemplary L-4R antibodies or antigen- binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention provides a method for treating nasal polyposis, by determining in a subject the expression level of one or more genes ed from the group consisting of thymus and tion-regulated chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA), and YKL-40; selecting the subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment f that specifically binds an interleukin-4 or (IL-4R), if the subject has an elevated expression level of the one or more genes; and sequentially administering to the selected subject a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that ically binds an interleukin-4 receptor (IL-4R), followed by one or more secondary doses of the antibody or antigen binding fragment thereof, such that the level of the one or more genes is reduced. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rd, such as an antibody or antigen g fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For e, 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 ces 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. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment f. Other exemplary anti-IL-4R antibodies or antigen- binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention provides a method for treating nasal polyposis, by determining in a subject the level of blood eosinophils or sputum eosinophils; selecting the t as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as dy or n-binding nt thereof that specifically binds an interleukin-4 receptor (IL- 4R), if the subject has an elevated level of blood eosinophils or sputum eosinophils; and administering to the selected subject a pharmaceutical composition comprising an interleukin-4 receptor ) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the level of blood eosinophils or sputum eosinophils is reduced. In one embodiment, the IL-4R nist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rd, such as an antibody or antigen binding fragment that ses heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain le region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the antibody or n g 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 nt f 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. In one embodiment, the lL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other ary anti- IL-4R antibodies or n-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention es a method for treating nasal polyposis, by determining in a subject the level of blood eosinophils or sputum eosinophils; selecting the subject as a ate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL- 4R), if the subject has an elevated level of blood eosinophils or sputum eosinophils; and sequentially administering to the selected subject a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), followed by one or more secondary doses of the antibody or antigen binding fragment thereof, such that the level of blood phils or sputum eosinophils is d. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL- 4Ror, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain le region (LCVR) of SEQ ID NO: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 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. In one ment, the lL-4R antagonist is dupilumab or an n-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

Other embodiments will become apparent from the below figure and the Detailed Description.

BRIEF DESCRIPTION OF THE FIGURES shows the schematic representation of an example of ound therapy withdrawal time period in the ent of an asthma patient.

DETAILED DESCRIPTION Before the present invention is described, it is to be understood that this invention is not limited to particular s and mental conditions bed, 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.

Unless d otherwise, 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 cal value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

All publications mentioned herein are incorporated herein by reference in their entirety.

Methods for Treating Nasal Polyposis

[0026] The present ion provides s for treating nasal polyposis. As used herein, a "nasal polyp" is an owth of tissue in one or more of the nasal cavities. The condition of nasal polyps is called “nasal polyposis.” About 80% of nasal polyps are highly edematous and filled with eosinophils. Nasal polyps can also present as fibrous, glandular or cystic.

Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal , originating from the ostiomeatal complex. NP is a T helper cell- 2 (Th-2) driven inflammatory process ing the mucosa of the nose and paranasal sinuses.

Eosinophils and their products are t to be a hallmark of nasal polyp-associated inflammation as elevated 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 predominant inflammatory cell found in the sinuses and nasal polyps, and nasal polyps are also associated with ed levels of lgE.

NP is characterized by erm symptoms of nasal obstruction and congestion, reduction in or loss of sense of smell, anterior and ior rhinorrhea, and facial pain. The presence or absence of nasal polyps can be confirmed for example by performing endoscopy, and the presence and extent of sinus and polyp involvement can be confirmed by methods such as coronal computed tomography (CT) scans.

An lL-4R antagonist can be used to treat nasal polyposis associated with a variety of conditions. For example, nasal polyposis is associated with sinusitis, rhinitis (e.g., allergic and non-allergic is), asthma (e.g., moderate-to-severe asthma), NSAID sensitivity (e.g., aspirin sensitivity), and infection, such as bacterial and fungal infection. Bacterial infections include, for example, staphylococcus infections. A subject with nasal polyposis can have a chronic infection, such as a chronic bacterial infection, e.g., a chronic staphylococcus aureus infection.

In some embodiments, the subject has recurring nasal polyposis, such as may be associated with recurring sinusitis. In other embodiments, the subject as cystic fibrosis or NARES (Non- Allergic Rhinitis with Eosinophilia Syndrome). In other embodiments, the subject has a relapse of nasal polyposis after receiving surgery to treat the polyps. Risk factors for nasal polyposis include genetic susceptibility, anatomic abnormality, mucociliary impairment, infection, and local immunologic imbalance.

An lL-4R nist can also be used to treat nasal polyposis in patients who have never previously received a ent or surgery for NP. An lL-4R antagonist can also be used to treat nasal polyposis in patients who have usly undergone surgery, such as a nasal surgery, such as for treatment of nasal polyps. In certain ments, an lL-4R antagonist is administered to a subject whose nasal polyposis has relapsed after the subject received prior treatment for the polyps, such as a prior nasal surgery.

As used herein, the term “sinusitis” refers to any inflammatory condition characterized by inflammation of the paranasal sinuses, including mation of the ary, frontal, ethmoid and/or sphenoid paranasal sinuses. An lL-4R antagonist is suitable for treatment of nasal polyposis is associated with acute sinusitis, subacute sinusitis, chronic sinusitis and recurrent sinusitis. Acute sinusitis is characterized by a sudden onset of cold-like ms such as runny, stuffy nose and facial pain that does not go away after 10 to 14 days. Acute sinusitis typically lasts less than four weeks. Subacute sinusitis lasts four to eight weeks.

Chronic sinusitis lasts eight weeks or longer, and recurrent sinusitis is characterized by sinusitis es that occur three or more times in one year. More than 80% of patients with c tis with nasal polyps have eosinophilic upper airway inflammation.

Many patients with chronic sinusitis have “chronic hyperplastic eosinophilic sinusitis,” which is terized by marked inflammation of the sinuses, increased eosinophils and mixed mononuclear cells, and a relative paucity of neutrophils. Some of these patients have one or more of ated nasal polyps, asthma, and aspirin or NSAID sensitivity. In certain embodiments, an lL-4R antagonist can be used to treat nasal polyposis in a subject who has chronic hyperplastic eosinophilic sinusitis.

The term “rhinitis” refers to an allergic response, such as to a common allergen (“allergic rhinitis,” e.g., perennial allergic rhinitis) or to an environmental irritant allergic rhinitis”). Symptoms of allergic rhinitis include sneezing; stuffy or runny nose; sinus pressure, and pain or throbbing in the cheeks or nose; and g in the nose, throat, eyes and ears.

Symptoms of non-allergic is include constriction or inflammation in the nasal passages which leads to many of the same symptoms of allergic rhinitis. lergic rhinitis can be caused, for e, by strong chemical or smoky environments, or by erm use of certain medications or dependency on nasal sprays.

As used herein, the term “rhinosinusitis” refers to a condition that has ms of both rhinitis and sinusitis. Rhinosinusitis includes acute rhinosinusitis and chronic rhinosinusitis.

Acute rhinosinusitis can be caused by an infection, such as a bacterial, viral or fungal infection, or by a chemical tion. Cigarette-smoke-induced acute inusitis and chlorine fume- induced chronic rhinosinusitis are examples of acute rhinosinusitis. NP is most commonly associated with chronic rhinosinusitis (CRS), which is characterized by mucosal inflammation of the nasal cavity and paranasal sinuses with symptoms lasting more than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps is a condition that lasts longer than 8 weeks.

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

Additional subcategories of chronic sinusitis (and chronic rhinosinusitis) e, e.g., superantigen-induced eosinophilic chronic sinusitis (e.g., sinusitis induced by exo- and endo- toxins produced by bacteria such as Staphylococcus aureus); allergic fungal sinusitis (e.g., sinusitis induced by fungi such as Aspergil/us or Alternaria); non-allergic fungal eosinophilic chronic sinusitis; and aspirin-exacerbated eosinophilic chronic sinusitis.

An lL-4R antagonist can be used to treat nasal polyposis in subjects having any of the disorders described above.

Methods for Improving Nasal Polyp-Associated Parameters The present invention includes methods for ing one or more nasal polypassociated parameters in a subject in need thereof, wherein the methods include administering a pharmaceutical ition comprising an eukin-4 receptor (IL-4R) antagonist to the subject. For example, an lL-4R or antagonist can reduce endoscopic nasal polyp score in a patient. A nasal polyp score of 0 indicates the presence of no polyps. A nasal polyp score of 1 indicates the presence of small polyps in the middle meatus not reaching below the inferior border of the middle ate. A nasal polyp score of 3 indicates large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate. A nasal polyp score of 4 indicates large polyps causing complete obstruction of the inferior nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nasal ). Treatment with an lL-4R antagonist can decrease nasal polyp score by about 1 to about 8 points. For example, treatment with an lL-4R nist can decrease nasal polyp score by about 1 point or more, by about 2 points or more, or by about 3 points or more. In some embodiments, ent with an lL-4R antagonist can decrease nasal polyp score by about 1 point, or a fraction f; by 2 points, or a on f; by 3 points, or a fraction thereof; by 4 points, or a fraction thereof; by 5 points, or a fraction thereof; by 6 points, or a fraction thereof; by 7 points, or a on thereof; or by 8 points or a fraction thereof. A reduction in nasal polyp score may correlate with an improvement in one or more other nasal polyp-associated parameters. Such a correlation, however, is not necessarily observed in all cases.

Other examples of "nasal polyp-associated parameters" e: (a) 22-item SinoNasal Outcome Test (SNOT-22) score; (b) subject-assessed nasal tion/obstruction, anterior rhea (runny nose), posterior rhinorrhea (post nasal drip) and loss of sense of smell; (c) number of nocturnal awakenings; (d) Visual Analog Score (VAS) to assess t-rated rhinosinusitis symptom severity; (e) five-item Asthma l Questionnaire (ACOS) score, such as in patients with asthma; (f) Nasal Peak lnspiratory Flow (NPIF); (g) smell test (University of Pennsylvania Smell Identification Test (UPSIT)); (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) ackay Score; and (j) Three ional volumetric measurement of the maxillary sinus. 22-ltem Sinonasal Outcome Test 22) Score. According to certain embodiments, administration of an lL-4R antagonist to a patient results in a decrease from baseline of 22-item Sinonasal Outcome Test (SNOT-22). The SNOT-22 is a questionnaire to assess the impact of chronic rhinosinusitis (CRS) on quality of life. The questionnaire measures items d to sinonasal conditions and surgical treatments. The score ranges from 0 to 110, and higher scores imply greater impact of CR8 on Health Related Quality of Life (HROoL) (Hopkins et al 2009, Clin. yngol. 34: 447-454).

The present invention includes therapeutic methods that result in a se in SNOT-22 score from baseline of at least 1 point at week 4 to week 16 following administration of the lL-4R antagonist. For example, administration of an lL-4R antagonist will result in a decrease in SNOT-22 score at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. In some embodiments, administration of an lL-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 13 points, or more at week 4, week 6, week 8 or week 12. , 12, Individual and Total Nasal Symptom Score. Subject-assessed symptoms are assayed by responding to g and evening dual rhinosinusitis symptom questions using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), and including the symptoms of congestion and/or obstruction, anterior rhinorrhea, posterior rhinorrhea, and loss of sense of smell. A measure of night-time ings can also be tracked. For e, a measure of night-time awakenings can be assessed according to the following scores based on subject self-assessment: 0: no symptoms, slept through the night; 1: slept well, but some complaints in the morning; 2: woke up once because of rhinosinusitis symptoms (including early awakening); 3= woke up several times because of symptoms (including early ing); 4: bad night, awake most of the night because of symptoms. Administration of an lL-4R antagonist can result, for example, in a decrease in average number of nighttime awakenings per night from baseline of at least about 0.10 times per night at week 4 to week 16 ing initiation of treatment with a pharmaceutical composition sing an anti-lL-4R antagonist. For example, a decrease in frequency of nighttime awakenings per night from baseline of at least about 0.10 times per night can be detected at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment.

Administration of an lL-4R antagonist to a subject in need thereof can cause a decrease in 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 time per night, 2.0 times per night, or more at week 4, week 8, week 12, or week 16, for example.

Visual Analog Score (VAS). The VAS is a measure to assess patient-related rhinosinusitis symptom severity 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 >3 to 7, and severe symptoms are indicated by a VAS score of >7 to 10. Administration of an lL-4R antagonist to a subject in need thereof causes a decrease in VAS score from baseline of about 0.5 point, 1 point, 1.5 , 2 points, 2.5 points, 3 points, 3.5 points, 4 points, or more at week 4, week 6 or week 12. The decrease in VAS score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist. 5-ltem Asthma Control Questionnaire (ACQ) Score. The A005 measures both the adequacy of asthma l and change in asthma control, which occurs either spontaneously or as a result of treatment. The five questions on the A005 reflect the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, tion of daily activities, shortness of breath and wheeze. ts respond to the symptom questions on a 7-point scale (0=no ment, totally controlled; 6: m impairment, severely uncontrolled).

The present invention includes therapeutic methods which result in a decrease in A005 score from baseline of at least 0.10 point at week 12 following initiation of treatment with a pharmaceutical composition comprising an anti-lL-4R antagonist. For e, according to the present invention, stration of an lL-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 , 0.85 points, or more at week 4, week 6 or week 12. The decrease in ACQ score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

[0047] Nasal Peak atory Flow (NPIF). The Nasal Peak atory Flow (NPIF) represents a physiologic measure of air flow through both nasal cavities during forced inspiration and/or expiration expressed in liters per minute. Nasal inspiration correlates most with the subjective feeling of obstruction and is used to monitor nasal flow. Administration of an lL-4R antagonist to a subject in need thereof causes an increase in NPIF from baseline by about 0.10 liters per , 0.15 liters per minute, 0.20 liters per minute, 0.25 liters per minute, 0.30 liters per minute, 0.35 liters per minute, 0.40 liters per minute, 0.45 liters per minute, 0.50 liters per minute, 0.55 liters per , 0.60 liters per minute, 0.65 liters per minute, 0.70 liters per minute, 0.75 liters per minute, 0.80 liters per , 0.85 liters per minute, or more at week 4, week 6 or week 12. The increase in NPIF score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

University of Pennsylvania Smell fication Test (UPSIT). The UPSIT is a method to quantitatively assess human olfactory function. The test consists of samples of odorants, and the subject has to describe the odor. The score is based on the number of correct answers.

This test can distinguish patients with a normal sense of smell ("normosmia") from those with different levels of reduction ("mild, moderate and severe microsmia") or loss mia").

Administration of an lL-4R antagonist to a subject in need thereof causes an increase in UPSIT score from baseline by about 0.5 points, 1 point, 1.5 , 2 points, 2.5 points, 3 points, 3.5 points or more at week 4, week 6 or week 12. The increase in UPSIT score can be ed as early as week 4, and as late as week 12 or later following administration of the lL-4R nist.

Physiological parameters. Efficacy of an lL-4R antagonist can be assayed by measuring the effect of physiological ters, such as within the nasal cavities, such as by nasal endoscopy or computed tomography (CT) scan.

[0050] Lund-Mackay Score. The Lund-Mackay scoring system is based on localization with points given for degree of opacification: 0 = normal, 1 = partial opacification, 2 = total opacification. These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on each side. The eatal complex is graded as 0 = not occluded, or 2 = occluded ng a maximum score of 12 per side. For patients in whom the osteomeatal complex (00) is missing (because of a previous surgery) the location of the former DC is considered and a score is provided, as if the 00 was there. Administration of an lL-4R antagonist to a subject in need thereof causes a decrease in Lund-Mackay score from baseline by about 0.10 points, 0.15 points, 0.20 points, 0.25 , 0.30 points, 0.35 , 0.40 , 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 4, week 6 or week 12. The decrease in Lund-Mackay score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

Three-Dimensional volumetric measurement of maxillary sinus. This value is used to calculate the volume of air (mL); the volume of mucosa (mL); the percent sinus occupied by disease; and the thickness of lateral wall in the maxillary sinus. Administration of an lL-4R antagonist to a subject in need thereof causes an increase in the Three-Dimensional volumetric measurement.

Quality of Life (QoL) Questionnaires. Various QoL onnaires can be used to r cy of an lL-4R antagonist, including Form-36 (SF-36) Questionnaire, the Euroqol-5D (EQ-5D), nasal polyp related resource use questionnaire, and the patient qualitative self-assessment.

The SF-36 is a 36 item questionnaire that measures eight multi-item dimensions of health: physical functioning (10 items) social functioning (2 items) role tions 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 perception (5 items). For each dimension, item scores are coded, summed, and transformed on 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 summary (MOS).

The EQ-5D is a standardized health-related quality of life questionnaire developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal and inter-disease comparisons. EQ-5D, designed for ompletion by patients, consists of two parts, the EQ-5D ptive system and the EQ VAS. The EQ-5D descriptive system ses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression; and each ion has 3 levels: no m, some problems, severe problems. The EQ Visual Analogue Scale (VAS) s the respondent’s self-rated health on a vertical visual analogue scale. The EQ VAS ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the bottom.

The nasal polyp related resource use questionnaire is a onnaire of health care resource utilization for nasal polyposis, including specialist visits, emergency care visits, sick leaves, days off etc.

[0056] Improvement of a nasal polyp-associated parameter, such as a nasal polyp-associated parameter described above, can be expressed as a percentage. For example, a score can be improved by 30% or more, by 40% or more, by 50% or more, by 60% or more, by 70% or more, or by 80% or more.

An "improvement in a nasal polyp-associated parameter" means an increase from baseline of one or more of NPIF, UPSIT, and/or a decrease from baseline of one or more of SNOT-22 score, subject-assessed nasal congestion/obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post nasal drip) and loss of sense of smell; number of nocturnal awakenings; VAS score; ackay score; and 3D volumetric scores; and ACQ5 score in patients with asthma. As used herein, the term "baseline," with regard to a nasal polyp- associated ter, means the cal value of the nasal polyp-associated parameter for a patient prior to or at the time of administration of a pharmaceutical composition of the present invenfion.

To determine r a nasal polyp-associated parameter has "improved," the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition of the present invention. For example, a nasal polyp-associated parameter may be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11 , day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer, after the initial treatment with a pharmaceutical ition of the present invention. In some embodiments, the ter is measured daily (e.g., once or twice per day), weekly, biweekly, or monthly. In other embodiments, the parameter is measured daily and the mean value determined over the course of a month is compared to baseline.

The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" in the nasal associated parameter (e.g., an increase or decrease, as the case may be, depending on the specific parameter being measured).

Interleukin-4 Receptor Antagonists 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 cts with lL-4R and inhibits the normal biological signaling function of lL-4R when lL-4R is expressed on a cell in vitro or in vivo. miting examples of ries of lL-4R antagonists include small molecule lL-4R antagonists, peptide- based lL-4R antagonists (e.g., "peptibody" molecules), and antibodies or n-binding fragments of antibodies that specifically bind human lL-4R.

[0061] The term "human lL-4R" (hlL-4R), as used herein, is ed to refer to the r subunit, which is a component of the lL-4 receptors Type | and Type II, as well as the lL-13 receptor system. An lL-4R antagonist, such as an anti-lL-4Roc antibody or antigen-binding nt thereof, blocks the function of both lL-4 and lL-13 signal transduction.

The term ody", as used herein, is intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter- connected by disulfide bonds, as well as multimers thereof (e.g., lgM). Each heavy chain ses a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant . The heavy chain constant region comprises three domains, CH1, CH2 and CH3.

Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be r subdivided into s of hypen/ariability, termed complementarity determining regions (CDRs), interspersed with regions that are more consen/ed, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDRB, FR4. In some embodiments, the PBS of the anti-Ang-2 antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid sus sequence may be defined based on a side-by-side analysis of two or more CDRs.

The term "antibody," as used herein, also includes antigen-binding nts of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any le standard techniques such as lytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding dy variable and optionally constant s. Such DNA is known and/or is readily ble from, e.g., cial sources, DNA libraries ding, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular y techniques, for example, to arrange one or more le and/or constant domains into a suitable uration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments e: (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 the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3- CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted dies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, nt nanobodies, etc.), small r immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen- binding fragment," as used herein.

[0065] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally se at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers.

Alternatively, the antigen-binding fragment of an dy may contain a monomeric VH or VL domain.

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 that may be found within an nbinding fragment of an antibody include: (i) VH-CHf; (ii) VH-CH2; (iii) VH-CHB; (iv) VH-CHf -CH2; (v) VH-CH1-CH2-CH3; (vi) -CH3; (vii) VH-CL; (viii)VL-CH1; (ix) VL-CH2; (X) VL-CHS; (xi) VL-CH1- CH2; (xii) VL-CHf-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or l hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible e between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and nt domain configurations listed above in non-covalent association with one another and/or with one or more ric VH or VL domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable s, n each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific dy formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an anti-lL-4R antibody using routine techniques available in the art.

The nt region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.

The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human dies featured in the invention may nonetheless include amino acid residues not encoded by human germline globulin ces (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDRB. However, the term "human antibody", as used herein, is not intended to e antibodies in which CDR sequences derived from the germline of another ian species, such as a mouse, have been grafted onto human framework sequences.

The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, d or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further , antibodies isolated from a recombinant, combinatorial human antibody library (described further , antibodies isolated from an animal (e.g., a mouse) that is transgenic for human globulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 7-6295) or antibodies prepared, expressed, created or isolated by any other means that involves 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. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human lg sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human dy ne repertoire in vivo.

Human antibodies can exist in two forms that are associated with hinge heterogeneity.

In one form, an immunoglobulin molecule comprises a stable four chain construct of imately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a ntly d light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.

The frequency of appearance of the second form in various intact lgG 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 the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular logy 30:105) to levels typically observed using a human lng hinge. The instant invention encompasses dies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

An "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 nment. 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 the antibody naturally exists or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular al and/or chemicals.

The term "specifically binds," or the like, means that an antibody or antigen-binding fragment thereof forms a x with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and e, for example, equilibrium dialysis, surface n resonance, and the like. For example, an dy that "specifically binds" lL-4R, as used herein, es antibodies that bind lL-4R or portion thereof with a KB 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 in a surface plasmon resonance assay. An isolated antibody that specifically binds human lL-4R may, however, have cross-reactivity to other antigens, such as lL-4R molecules from other (non-human) species.

The anti-lL-4R antibodies useful for the methods featured herein may include one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable s as compared to the corresponding germline sequences from which the dies were d. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes s involving the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed , wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human ne sequence, or to a consen/ative amino acid substitution of the ponding germline residue(s) (such sequence changes are referred to herein collectively as "germline ons"). A person of ordinary skill in the art, ng with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual ne mutations or combinations thereof. In n embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only n residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FRf or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1,CDR2 or CDRB. In other ments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally d). Furthermore, the antibodies may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual es are mutated to the corresponding residue of a ular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence.

Once ed, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more d property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological ties (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invenfion.

The present invention also includes methods involving the use of anti-lL-4R antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences sed herein having one or more consen/ative substitutions. For example, the present invention includes the use of anti-lL-4R antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. consen/ative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein.

[0077] The term "surface plasmon resonance", as used , refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of tions in protein concentrations within a biosensor matrix, for example using the BlAcoreTM system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

The term "KD as used herein, is intended to refer to the equilibrium dissociation constant of a particular dy-antigen ction.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody le known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatiallyjuxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include es of saccharides, phosphoryl , or sulfonyl groups on the n.

According to n exemplary embodiments of the present invention, the lL-4R antagonist is an anti-lL-4Rd antibody, or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) sing any of the amino acid sequences of the L-4R antibodies as set forth in US Patent Nos. 7,608,693 and 7,605,237. In certain exemplary embodiments, the anti-lL-4Rd antibody or antigen-binding fragment thereof that can be used in the context of the methods of the t invention comprises the heavy chain complementarity determining s (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and the light chain complementarity determining regions ) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-lL-4Rd antibody or antigen-binding fragment thereof comprises three HCDRs(HCDR1, HCDR2 and HCDR3) and three LCDRs(LCDR1, LCDR2 and LCDR3), wherein the HCDRf comprises the amino acid sequence of SEQ ID NO:3; the HCDR2 comprises the amino acid sequence of SEQ ID NO:4; the HCDR3 comprises the amino acid sequence of SEQ ID NO:5; the LCDRf comprises the amino acid sequence of SEQ ID NO:6; the LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and the LCDR3 ses the amino acid sequence of SEQ ID NO:8. In yet other ments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR sing SEQ ID NO:1 and an LCVR comprising SEQ ID NO:2. According to certain exemplary embodiments, the methods of the present ion comprise the use of the anti-lL-4Rd dy ed to and known in the art as dupilumab, or a bioequivalent thereof.

The term “bioequivalent” as used herein, refers to a molecule having similar bioavaiIabiIity (rate and extent of bility) after administration at the same molar dose and under similar ions (e.g., same route of administration), such that the effect, with respect to both efficacy and safety, can be expected to be essentially same as the ator molecule.

Two pharmaceutical compositions comprising an lL-4R nist are bioequivalent if they are pharmaceutically equivalent, meaning they contain the same amount of active ingredient (e.g., lL-4R antagonist), in the same dosage form, for the same route of administration and meeting the same or comparable standards. Bioequivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration time cun/e (AUG).

Other anti-lL-4Rd antibodies that can be used in the context of the methods of the present invention include, e.g., the antibody referred to and known in the art as AMG317 (Corren etal., 2010, Am J Respir Crit Care Med, 181(8):788-796), or any of the anti-IL-4Rd antibodies as set forth in US Patent No. 7,186,809, or US Patent No. 8,092,804.

The anti-lL-4Rd antibodies used in the context of the methods of the present invention may have pH-dependent binding characteristics. For example, an anti-lL-4Rd antibody for use in the methods of the present invention may t reduced binding to lL-4Rd at acidic pH as compared to neutral pH. Alternatively, an L-4Ror antibody of the ion may exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH. The expression "acidic pH" includes pH values less than about 6.2, e.g., about 6.0, 5.95, 5,9, 5.85, 5.8, 5.75, 5.7, 5.65, .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 less. As used herein, the expression "neutral pH" means 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.

In certain instances, "reduced binding to lL-4Rd at acidic pH as compared to neutral pH" is expressed in terms of a ratio of the KB value of the antibody binding to lL-4Rd at acidic pH to the KB value of the antibody g to lL-4Rd at neutral pH (or vice versa). For example, an dy or antigen-binding fragment thereof may be ed as exhibiting "reduced binding to lL-4Rd at acidic pH as compared to neutral pH" for es of the present invention if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral KD ratio of about 3.0 or greater. In certain exemplary embodiments, the acidic/neutral KD ratio for an antibody or antigen-binding fragment of the present invention can 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, .0. 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

Antibodies with pH-dependent g characteristics may be obtained, e.g., by screening a population of dies for d (or enhanced) binding to a particular antigen at acidic pH as compared to l pH. Additionally, modifications of the antigen-binding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain (e.g., within a CDR) with a histidine residue, an antibody with reduced antigen-binding at acidic pH relative to neutral pH may be obtained. As used herein, the expression "acidic pH" means a pH of 6.0 or less.

Pharmaceutical Compositions The present invention includes s which include stering an lL-4R antagonist to a patient, where the lL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions featured in the invention are formulated with suitable carriers, excipients, and other agents that e suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: 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 es (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid es containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of antibody administered to a patient may vary depending upon the age and the size of the patient, ms, conditions, route of administration, and the like. The preferred dose is typically ated according to body weight or body surface area. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted.

Effective dosages and schedules for administering pharmaceutical compositions comprising anti-lL-4R antibodies may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose ed accordingly. Moreover, pecies scaling of dosages can be performed using nown methods in the art (e.g., Mordenti eta/., 1991 Pharmaceut. Res. 8:1351).

Various delivery systems are known and can be used to administer a pharmaceutical composition containing an lL-4R antagonist, including encapsulation in mes, microparticles, apsules, recombinant cells e of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

Methods of administration e, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, al, and oral routes. The composition may be stered by any convenient route, for example by infusion or bolus injection, by absorption through lial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.

A pharmaceutical composition can be delivered aneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition. Such a pen delivery device, including an jection pen delivery device, can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen ry device, there is no replaceable cartridge. Rather, the able pen ry device comes prefilled with the pharmaceutical composition held in a reservoir within the . Once the oir is emptied of the pharmaceutical composition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition. Examples include, but are not d to AUTOPENTM (Owen Mumford, lnc., Woodstock, UK), DlSETRONlCTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and 00., Indianapolis, IN), NOVOPENTM I, II and Ill (Novo Nordisk, Copenhagen, Denmark), NOVOPEN TM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton son, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROT'V', N STARLETTM, and OPTICLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition include, but are not limited to the SOLOSTARTM pen (sanofi- aventis), the NTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly), the ICKTM Autoinjector (Amgen, Thousand Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, y), the EPIPEN (Dey, LP), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL), to name only a few.

For direct administration to the sinuses, the pharmaceutical compositions containing lL- 4R antagonists may be administered using, e.g., a microcatheter (e.g., an endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer or an r.

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14201). In another embodiment, polymeric als can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, a. In yet another embodiment, a controlled release system can be placed in proximity of the compositions target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 8).

Other controlled release systems are discussed in the review by Langer, 1990, Science 27-1533.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular ions, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for ions, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an l (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a lizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is ably filled in an appropriate ampoule.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

Dosage The amount of lL-4R antagonist (e.g., anti-lL-4R antibody, or antigen binding fragment thereof) administered to a subject according to the s featured herein is generally a eutically effective amount. As used herein, the phrase "therapeutically effective " means a dose of lL-4R nist that results in a detectable improvement in one or more ms ated with nasal polyps, or a dose of lL-4R antagonist that inhibits, prevents, lessens, or delays the progression of nasal polyps or a condition associated with nasal polyps.

In the case of an anti-lL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., 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, or about 600 mg, of the anti-lL-4R antibody or antigen binding fragment.

The amount of lL-4R nist ned within the individual doses may be sed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg).

For example, the lL-4R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of patient body weight.

Combination ies

[0097] The methods, according to certain embodiments, include administering to the subject one or more additional therapeutic agents in combination with the lL-4R antagonist. As used herein, the expression "in combination with" means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising the IL- 4R antagonist. For example, when administered "before" the pharmaceutical composition comprising the lL-4R nist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 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 prior to the administration of the ceutical composition sing the lL-4R antagonist. When administered "after" the pharmaceutical composition comprising the lL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the ceutical composition sing the lL-4R antagonist.

Administration "concurrent" with the ceutical composition comprising the lL-4R antagonist means that the additional eutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the lL-4R antagonist, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the lL-4R antagonist.

The additional therapeutic agent may be, e.g., another lL-4R antagonist, an lL-1 antagonist (including, e.g., an lL-1 antagonist as set forth in US Patent No. 6,927,044), an lL-6 antagonist, an lL-6R antagonist (including, e.g., an anti-lL-6R antibody as set forth in US Patent No. 7,582,298), an lL-13 antagonist, a TNF antagonist, an lL-8 antagonist, an lL-9 antagonist, an lL-17 antagonist, an lL-5 antagonist, an lgE nist, a CD48 antagonist, an antibiotic (e.g., doxycycline), an anti-fungal agent, a leukotriene, an antihistamine, an d-adrenergic decongestant, a tic, an NSAID, a long-acting beta2 agonist (e.g., salmeterol or formoterol), a short-acting beta2 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 combinations thereof. For example, in certain ments, the pharmaceutical composition comprising an lL-4R antagonist is administered in combination with a combination comprising a cting beta2 agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., ort® (Astra Zeneca)]).

In some embodiments, the lL-4R antagonist is administered after a subject receives surgery to treat nasal polyposis.

Administration Regimens According to certain ments, multiple doses of an lL-4R antagonist may be administered to a subject over a defined time course. The methods include, for example, sequentially administering to a subject multiple doses of an lL-4R antagonist. As used herein, "sequentially stering" means that each dose of lL-4R antagonist is administered to the subject at a different point in time, e.g., on different days separated by a ermined inten/al (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an lL-4R antagonist, followed by one or more secondary doses of the lL-4R antagonist, and optionally followed by one or more ry doses of the lL-4R antagonist.

[00101] The terms "initial dose," "secondary doses," and "tertiary " refer to the temporal ce of administration of the lL-4R antagonist. Thus, the "initial dose" is the dose which is administered at the beginning of the ent regimen (also referred to as the "baseline ; the "secondary doses" are the doses which are administered after the initial dose; and the ary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of lL-4R antagonist, but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of lL-4R antagonist contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.

[00102] In one exemplary embodiment, each secondary and/or ry dose is administered 1 to 14 (e.g., 1, 11/2, 2, 21/2, 3, 31/2, 4, 41/2, 5, 51/2, 6, 61/2, 7, 71/2, 8, 81/2, 9, 91/2, 10, 101/2, 11,111/2, 12, 121/2, 13, 131/2, 14, 141/2, or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of lL-4R antagonist which is administered to a patient prior to the stration of the very next dose in the sequence with no inten/ening doses.

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

In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the ately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be ed during the course of ent by a ian depending on the needs of the individual patient following clinical examination.

In certain embodiments, the initial dose (e.g., a “loading dose”) is higher than either or both of the secondary and tertiary doses. For example, the initial dose can be a loading dose, which is 1.5x, 2x, 2.5x, 3x or more greater than the secondary dose.

Treatment Populations The methods ed in the present invention including administering to a subject in need thereof a therapeutic composition comprising an lL-4R antagonist. As used , the expression "a subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or indication of nasal polyposis, or who has been sed with nasal polyposis, or c ms of sinusitis. For example, a subject in need f has bilateral nasal polyps, and a nasal polyp score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each nostril. In certain embodiments, the polyps are in the middle meatus. In certain ments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has bilateral mucosal disease, which is confirmed by a method such as CT scan. As used herein “bilateral l disease” is an infection of the mucous lining of the sinus cavities, e.g., the ary sinus cavities. In some embodiments, nasal polyposis (e.g., a nasal polyp score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each nostril) persists even after a treatment regimen of inhaled corticosteroids (INCS), such as where the INCS was administered for at least 6 weeks, at least 7 weeks, at least 8 weeks, or longer.

In certain ments, a subject in need thereof has anterior and/or posterior mucopurulent drainage, nasal obstruction, and a decreased sense of smell. In certain ments, a subject in need thereof has had symptoms of nasal polyposis for 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In yet other embodiments, the subject has received a previous treatment, such as with an intranasal corticosteroid (e.g., MFNS), for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks or longer, prior to ing treatment with an lL-4R antagonist. In some embodiments the subject will continue to receive the INCS while receiving ent with the lL-4R antagonist. In other embodiments, the subject stops receiving the INCS before receiving treatment with the lL-4R antagonist, or the subject stops ing ent with the INCS if administration with the lL-4R antagonist is effective to treat the nasal sis. In some embodiments, the subject tapers the dose of the INCS before stopping treatment completely.

A subject in need thereof may further have been diagnosed with nasal polyposis on the basis of one or more of the following: (a) 22—item sal e Test (SNOT-22) score; (b) subject-assessed nasal congestion/obstruction, anterior rhinorrhea, posterior rhinorrhea and loss of sense of smell; (c) number of nocturnal awakenings; (d) Visual Analog Score (VAS) to assess patient-rated rhinosinusitis m severity; (e) five-item Asthma Control Questionnaire (ACQ5) score in patients with asthma; (f) Nasal Peak lnspiratory Flow (NPIF); (g) smell test rsity 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 volumetric measurement of the maxillary sinus.

For example, in certain embodiments, a “subject in need thereof” is a human t with chronic symptoms of sinusitis, which are the presence of at least two of the following symptoms: nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); facial pain/pressure; and reduction or loss of smell.

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 , 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 who exhibits 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.

In a related ment, a "subject in need thereof" may be a subject who, prior to ing an lL-4R antagonist, has been prescribed or is currently taking another medication, “a background therapy.” The background therapy can be, for example, an asal corticosteroid (INCS, or 108), such as sone furoate nasal spray (MFNS; Nasonex®). In some embodiments, a “subject in need thereof” is an asthma patient who prior to receiving an lL-4R antagonist, has been prescribed or is currently taking an INCS in combination with a long-acting beta2-adronergic antagonist (LABA). Examples of lNCS/LABA therapies e fluticasone/salmeterol combination y and budesonide/formoterol ation therapy. In some embodiments, the background therapy is a nasal saline, a topical decongestant, a topical anesthetic, a leukotriene nist or a systemic antihistamine. In some embodiments, the “subject in need thereof” continues the background therapy after the subject receives the lL-4R nist, and in other ments, the subject in need thereof stops receiving the background therapy (e.g., at once or gradually) before receiving the lL-4R antagonist.

EXAMPLES The following examples are put forth so as to e those of ordinary skill in the art with a complete sure and description of how to make and use the methods and compositions featured in the invention, and are not intended to limit the scope of what the ors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is e molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

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 Hyperplastic Eosinophilic Sinusitis A. Study Objectives and ew A randomized, o-controlled, double-blind, parallel group study was conducted with once-a-week subcutaneous administration of either 300 mg dupilumab (“mAb1”) or placebo for 12 weeks to patients with persistent moderate-to-severe eosinophilic asthma who were partially controlled/uncontrolled by inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) y. Dupilumab is an anti-lL-4R antibody having a heavy chain le region of SEQ ID NO:1, and a light chain variable region of SEQ ID NO:2. Dupilumab is described in US 7,608,693.

The primary objective of the study was to investigate the effects of mAb1 administered subcutaneously once weekly for 12 weeks as compared to placebo on ng the incidence of asthma exacerbations in patients with persistent moderate-to-severe eosinophilic asthma. The secondary objectives of the study were to assess the safety and bility of mAb1 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma, and to assess mAb1 serum concentrations following once weekly subcutaneous dosing for 12 weeks in patients with persistent te to severe eosinophilic asthma.

] Prior to screening, patients were required to be on a stable dose of any of the following doses and formulations of lCS/LABA combination therapy (also called “background therapy”) for at least 1 month: Fluticasone/salmeterol combination therapy - Advair® Diskus — dry powder inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or - Advair® HFA — d dose inhaler (MDI): 230/42 ug BID or 460/42 ug BID; or Budesonide/formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or Mometasone/formoterol combination therapy (Dulera® 200/10 ug BID or 400/10 ug BID) ] Patients who were on budesonide/formoterol or mometasone/formoterol were switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1) and patients who had been on fluticasone/salmeterol remained on the same as background therapy.

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

[00118] The study comprised a 2-week screening period, a 12-week treatment period comprising a 4-week ound therapy stable phase and an 8-week background therapy withdrawal phase post-randomization, ed by an 8-week post-treatment follow-up period.

Algorithm for background therapy (ICS/LABA) withdrawal: Patients remained on BID fluticasone/salmeterol background therapy for 4 weeks after starting add-on therapy or treatment of 300 mg mAb1 (or placebo). At 4 weeks post- randomization, patients were switched from the BID fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone erapy (comprising either Flovent® Diskus — DPI formulation of 250ug or 500 ug BID; or Flovent® HFA — MDI formulation of 220 ug or 440 ug BID). The LABA component (i.e., salmeterol) was discontinued. At subsequent visits, beginning with week 6, the fluticasone dose was d by imately 50%, provided the patient did not meet any of the criteria for an asthma exacerbation (as defined below). If no asthma exacerbations occurred, the ICS withdrawal ded according to the following dosing schedule: ound therapy ound therapy withdrawal phase stable phase Week 4 Week 6 Week 7 Week 8 Week 9 Fluticasone/salmeterol Fluticasone 100 pg 50 ug BID 0 ug BID 0 ug (DPI): 250/50 pg BID (DPI): 250 ug BID BID BID Fluticasone/salmeterol Fluticasone 250 pg 100 pg 50 ug BID 0 ug (DPI): 500/50 pg BID (DPI): 500 ug BID BID BID BID Fluticasone/salmeterol Fluticasone 110 pg 44 ug BID 0 ug BID 0 ug (MDI): 230/42 ug BID (MDI): 220 ug BID BID Fluticasone/salmeterol Fluticasone 220 pg 110 pg 44 ug BID 0 ug (MDI): 460/42 ug BID (MDI): 440 ug BID BID BID Upon completing 12 weeks of treatment with investigational product (or after early discontinuation), patients were placed on their original dose of fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol (dose at study entry) and albuterol or levalbuterol as-needed to control their symptoms for an additional 8 weeks off study medication before a final safety evaluation.

A schematic of the study protocol is provided in Figure 1.

Adult patients were included in the study based on the ing criteria: (1) physician’s diagnosis of tent asthma for at least 2 12 months based on the Global Initiative for Asthma (GINA) 2009 Guidelines, whose y inflammation is likely to be eosinophilic; and (2) whose asthma is partially controlled or uncontrolled in d corticosteroids/long acting gonists combination therapy according to the following ia: (i) stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 pg BID or 500/50 pg BID or MDI formulation: 230/42 pg BID or 460/42 pg BID), or budesonide/formoterol combination therapy (160/9 pg BID or 320/9 pg BID), or sone/formoterol combination therapy (200/10 pg BID or 400/10 pg BID) for at least 1 month prior to screening; (ii) blood eosinophils 2 300 cells/pl or sputum eosinophils 2 3% during the screening phase; (iii) Juniper asthma control questionnaire stion version, ACQ) score of 2 1.5 and s 3.0 at screening; (iv) FEV1 2 50% predicted normal during the screening phase (3 attempts maximum) and on the ization day prior to the first dose (3 attempts maximum); (v) has had within the 2 years prior to ing either treatment with one or more systemic (oral and/or parenteral) steroid bursts for worsening asthma or in-patient hospitalization or an emergency care visit for worsening asthma; and (vi) documented history of reversibility within 12 months of screening that meets the criterion — at least 12% and 200 mL in FEV1 after 200 pg to 400 pg (2 to 4 tions) of albuterol during the screening phase (3 attempts maximum), or documented history of a positive methacholine challenge (PD20 methacholine S 8 mg) within 12 months prior to screening.

Patients with moderate-to-severe asthma that is partially controlled or uncontrolled with moderate to high doses of combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT® or DULERA®) and with blood eosinophils r than or equal to 300 cells per microliter, or sputum eosinophils greater than or equal to 3% during the screening phase, were included in the study.

Patients who met all the inclusion criteria were screened for the following exclusion criteria: (1) patients less than 18 years of age or greater than 65 years of age; (2) clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation; (3) chronic ctive ary disease (COPD) and/or other lung diseases ing ary function tests; (4) patients requiring beta-adrenergic receptor blockers for any reason; (5) current smoker or cessation of smoking within the 6 months prior to screening; (6) previous smoking with a smoking history > 10 tte pack-years; (7) in-patient hospitalization or emergency care visit due to asthma exacerbation in the 2 months prior to screening; (8) plans to begin allergen immunotherapy within the study period; (9) exposure to another investigative antibody within a time period prior to screening that is less than 5 half-lives of the antibody but not less than 30 days, or if the half life of the antibody is not known, then a time period prior to screening that is at least 6 months; (10) previous enrollment into the current study; (11) patient was the igator, his/her family member or an ee at the investigational site; (12) known or suspected non-compliance, alcohol or drug abuse; (13) inability to follow the procedures of the study (e.g., due to language problems or psychological disorders); (14) reversal of sleep pattern (e.g., night shift worker); (15) treatment with drugs known to prolong QTc inten/al; (16) concomitant severe disease(s) for which the use of ICS (e.g., active or inactive pulmonary tuberculosis) or LABA (e.g., diabetes, cardiovascular diseases, hypertension, hyroidism, thyrotoxicosis, etc) are contra-indicated; (17) use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening; (18) pre-treatment with variable doses of ICS, either alone or in combination with a non-steroidal controller (other than fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy, or mometasone/formoterol combination therapy); (19) ts receiving prohibited concomitant medications (listed below); (20) known allergy to doxycycline or d compounds; (21) pregnancy or intention to become pregnant during the course of the study, breast feeding or unwillingness to use an effective method of contraception; and (22) recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to ing.

Patients remained on a constant dose of the background asthma therapy for the first four weeks of the study after which the dose of background therapy was reduced gradually.

First, the long-acting beta agonist component of the background therapy was withdrawn at week 4, and then the inhaled corticosteroid dose was reduced by half every 2 weeks until week 12.

Patients ued on study treatment until the end of the study or until they were withdrawn due to an asthma exacerbation or for any other .

B. Study Treatments igational Product: Sterile mAb1 150 mg/mL solution for SC ion was provided in a 5 mL glass vial. Each vial contained a withdrawable volume of 2 mL. A 300 mg dose was administered subcutaneously at the study site once weekly in the g for 12 weeks.

Placebo: Sterile placebo for SC injection was ed in an identically matched 5 mL glass vial.

Each vial ned a awable volume of 2 mL. Placebo was administered subcutaneously at the study site once weekly in the morning for 12 weeks.

[00126] The following concomitant medications were not allowed during the duration of the study: any other inhaled steroid other than fluticasone/salmeterol combination y or fluticasone administered per the protocol (or budesonide/formoterol or mometasone/formoterol during the screening period); systemic or ocular steroids; LABAs other than the salmeterol component of the fluticasone/salmeterol combination therapy administered per the protocol; any other ICS/LABA combination products other than those given above; any inhaled anti- cholinergic agents (e.g., opium bromide or tiotropium); methylxanthines (theophylline, aminophyllines); cromones; anti-lgE therapy; |ipoxygenase inhibitors; and leukotriene receptor antagonists or leukotriene synthesis inhibitors.

C. Efficacy of treatment The primary nt of this study was the occurrence of an exacerbation of asthma as defined by any of the ing: (1) a 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on two consecutive days; or (2) six or more additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 utive days; or (3) deterioration of , as determined by the Investigator, requiring: (a) systemic (oral and/or eral) steroid treatment, or (b) an increase in ICS 24 times the last dose received prior to discontinuation from the study, or (c) alization.

[00128] Secondary endpoints of the study included mean changes from baseline of the following parameters: (1) Forced expiratory volume in 1 second (FEV1) in liters measured at every visit; (2) Morning and evening peak expiratory flow rate (AM PEF and PM PEF) in /minute measured daily; (3) Daily Albuterol/Levalbuterol use in inhalations/day; (4) Five- item Asthma Control Questionnaire (ACQ5) score at every visit; and (5) Nighttime awakenings (no. of times per night) measured daily and (6) a m Sino-Nasal Outcome Test (SNOT-22), evaluated at baseline and end of ent (at Week 12), to assess upper ainNay symptoms.

Secondary endpoints also included proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on two consecutive days together with 2 6 additional reliever puffs of rol or levalbuterol in a 24-hour period red to baseline) on 2 utive days. PEF, ACQS, asthma symptoms scores, nocturnal awakenings, and reliever medication use were captured in an electronic daily diary.

Mean daily nocturnal awakenings, ranging from 0-10, were averaged from the previous 7 days.

Morning and evening asthma m scores consisted of a non-validated patient-reported outcome assessed on a 5-point Likert-type scale, with higher scores indicating worse outcomes (Table 2). Patients recorded overall symptom scores twice a day prior to measuring PEF. Data were described as the average for the 7 days prior to the specified time point.

Table 2: Asthma Symptom Score Assessment A) Morning symptom score: 0 = No asthma symptoms, slept through the night 1 = Slept well, but some complaints in the morning. No ime awakenings 2 = Woke up once because of asthma (including early awakening) 3 = Woke up several times because of asthma ding early awakening) 4 = Bad night, awake most of the night because of asthma B) Evening symptom score: 0 = Very well, no asthma symptoms 1 = One episode of wheezing, cough, or breathlessness 2 = More than one episode of wheezing, cough, or breathlessness without interference of normal activities 3 = Wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities 4 = Asthma very bad. Unable to carry out daily activities as usual D. Adverse Events Monitoring Safety was assessed throughout the study by ring Adverse Events and Serious Adverse Events.

An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product. An AE can, therefore, be any unfavorable and unintended sign (including al laboratory finding), symptom, or e ally associated with the use of a medicinal product, whether or not considered related to the medicinal (investigational) product. AEs also include: any worsening (i.e., any clinically icant change in frequency and/or ity) of a pre-existing condition that is temporally associated with the use of the study drug; abnormal laboratory findings considered by the Investigator to be clinically significant; and any untoward medical occurrence.

A Serious e Event (SAE) is any untoward medical occurrence that at any dose results in death; is life-threatening; requires ient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or is an important medical event.

E. tical methods

[00132] For the primary analysis of proportion of patients experiencing an asthma exacerbation, a logistic regression model was used to compare SAR group with o. The model included terms for treatment and stratification factor (prior lCS/LABA combination therapy dose). The primary analysis was performed based on modified -to-treat (mlTT) population which included all randomized patients who received at least one dose of mAb1. A stratified chi- square test was also used to corroborate the primary analysis.

For secondary efficacy endpoints except SNOT-22, the change from baseline was ed using a mixed-effect model with repeated measures (MMRM) approach. The model included change from baseline values up to week 12 as response variables, and factors (fixed effects) for treatment, fication factor, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction. Statistical inferences on treatment comparisons for the change from ne at week 12 were derived from the mixed-effect model. Change from ne in SNOT- 22 was ed using an analysis of covariance (ANCOVA), with end of treatment measurements used to impute missing data. Pharmacodynamic effects were evaluated using MMRM models in a post hocfashion. No ments were made for multiplicity, since there was only one primary nt and analysis. Safety variables including AEs, laboratory parameter, vital signs, ECG, clinical laboratory observations and physical examinations were ized using descriptive statistics.

Demographic and clinical characteristics were summarized using descriptive characteristics. Plots of secondary and pharmacodynamic variables are presented as mean change from baseline over time with standard error. Comparison of treatment effects from the MMBM analyses are based on least square mean change (95% ence inten/als [Cl]) from baseline at Week 12.

F. Results The results obsen/ed with all 104 ized patients (from 491 screened) who either completed or discontinued the treatment phase of the study are summarized below. All randomized patients were exposed to study treatment and included in the mlTT tion.

Baseline characteristics were r between groups. The demographic and clinical characteristics were also similar between the two groups (Table 3). As noted above, patients were treated either with 300 mg subcutaneous mAb1 once a week, or with placebo. The study treatment period was completed by 86.5% and 67.3% of the mAb1 and placebo patients, respectively. The most common cause of tinuation was lack of efficacy, which was more frequent with placebo (21.2%) than mAb1 (1.9%).

Table 3. Baseline Demographic and Clinical Characteristics of Treatment Groups.* Variable Placebo mAb1 300 mg (N : 52) (N : 52) Age (yr) 41.6 i 13.1 37.8 i 13.2 Male sex, no. (%) 26 (50.0) 26 (50.0) Race or ethnic group, no. (%) White 38 (73.1) 45 (86.5) Black or African American 9 (17.3) 5 (9.6) Asian 3 (5.8) 1 (1.9) Other 2 (3.8) 1 (1.9) Body mass index Mean (kg/m2) 31.6 i 7.0 31.3 i 8 0 2 30, no. (%) 25 (48.1) 24 (46.2) Duration of asthma (yr) 26.9 :r 14.8 24.2 :r 12.6 Number of asthma exacerbations in prior 2 years 1.4 :r 1.3 1.4 :r 1.0 Prior lCS/LABA combination therapy dose, no. (%) High Dose 41 (78.8) 42 (80.8) Low Dose 11 (21.2) 10 (19.2) Blood eosinophils (x10'/|) 0.47 i 0.21 0.55 i 0.19 FEV, (l) 2.54 i 0.66 2.47 i 0.65 FEV, (% of ted value) 72.0 :r 12.7 72.0 :r 12.6 PEF (l/min) Morning 406.9 i 110.7 393.0 i 101.1 Variable Placebo mAb1 300 mg (N : 52) (N : 52) Evening 416.6 1r 116.8 414.6 1r 102.3 ACQ5 score 2.1 :r 0.5 2.1 :r 0.5 Asthma symptom score Morning 0.73 i 0.63 0.75 i 0.81 Evening 1.12 1r 0.73 0.92 1r 0.71 Nocturnal ings per day 0.21 :r 0.50 0.44 :r 0.80 SNOT-22 26.2 1r 15.6 30.9 1r 14.8 Inhalations of albuterol or levalbuterol/24-hour period 2.0 :r 1.8 2.2 :r 2.4 FeNO (ppb) 35.0 1r 27.1 37.6 1r 28.1 TARC (pg/ml) 470.5 1r 204.7 496.1 1r 342.4 Eotaxin-3 (pg/ml) 117.3 i 349.2 75.4 i 44.0 lgE (lU/ml) 694.7 1r 1837.8 657.7 1r 1482.3 *Plus—minus values are means i SD, except as otherwise noted. ACQ5 denotes the Asthma Control Questionnaire (5 question version), FeNO fraction of d nitric oxide, FEV, forced expiratory volume in 1 second, IgE immunoglobulin E, PEF peak expiratory volume, SNOT-22 the 22-item Sinonasal Outcome Test, and TARC thymus and tion regulated chemokine. (i) Primary Efficacy Endpoint The incidence of asthma exacerbations in the placebo and mAb1 treatment groups is presented in Table 4.

Table 4. Incidence of Asthma Exacerbations in mlTT population Placebo (N=52) mAb1 (N=52) Patients With No Asthma 29 ) 49 (94.2%) Exacerbations Patients With Asthma Exacerbations 23 (44.2%) 3 (5.8%) Odds Ratio vs Placebo (95% Cl) -- 0.077 (0.021, 0.279) There were a total of 26 asthma exacerbations during the treatment period, and no patients were hospitalized for asthma bations. There were 23 patients (44.2%) who experienced an asthma exacerbation in the placebo group, whereas only 3 patients (5.8%) experienced an asthma exacerbation in the mAb1 treatment group. The odds ratio is 0.077 (p <0.0001) and the relative risk reduction is approximately 87%.

Out of the 26 asthma bations experienced during this study, 9 were considered severe as demonstrated by a need for immediate inten/ention in the form of treatment with either ic corticosteroids or with inhaled osteroids at 4 or more times the dose taken prior to the event. A y of the incidence of severe asthma exacerbations is presented in Table 5.

Table 5. Incidence of Severe Asthma Exacerbations in mlTT population Placebo (N=52) mAb1 (N=52) Patients With No Asthma Exacerbations 29 (55.8%) 49 (94.2%) Patients WIth Severe Asthma 8 (154%) 1 (1.9%) Exacerbations Patients With Non-Severe Asthma (28's /°)o 2 (3'8 /°)o bations As shown in Table 5, eight severe asthma bations were observed in the placebo group, and only 1 severe asthma exacerbation was observed in the mAb1 treatment group. The remaining 15 asthma exacerbations in the placebo group and 2 in the mAb1 group met the protocol definition of exacerbation based on sed morning PEF and/or increased albuterol/levalbuterol use. Within the active treatment group, a sustained improvement versus baseline was observed during the course of the study for all parameters, despite steroid withdrawal.

Table 6. bation Events Outcome Placebo mAb1 (N : 52) ( N : 52) 2 30% reduction from baseline 10* (19.2) 1 (1.9) in morning PEF in a 24-hr period on 2 consecutive days 2 6 additional inhalations of 10 (19.2) 1 (1.9) albuterol/levalbuterol in a 24-hr period on 2 consecutive days Systemic steroid treatment 5 (9.6) 1 (1.9) 2 4-fold increase in 108 from 3 (5.8) 0 the us dose Hospitalization *4 Placebo patients met both PEF and systemic steroid treatment criteria, and 1 placebo patient met both PEF and additional albuterol/levalbuterol use.

With mAb1, the time to exacerbation was longer, and the risk of exacerbation was reduced relative to placebo (hazard ration 0,10; 95% Cl 0.03, 0.34; P< 0.001 ). An analysis of the time to asthma exacerbation by Kaplan-Meier Plot revealed that the effect of treatment with mAb1 is sustained over time, including after 8 weeks when ts are at higher risk of ping bations due to steroid withdrawal.

Only 1 patient from the placebo group had a composite asthma event. A composite asthma event is d as a 30% or greater reduction from baseline in morning PEF on 2 utive days together with 26 additional reliever puffs of albuterol or Ievalbuterol in a 24- hour period (compared to baseline) on 2 consecutive days. (ii) Other Efficacy nts Lung 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, the SNOT-22 score was assessed at baseline and at the end of treatment. For all parameters, the baseline and Week 12 (LOCF) mean values along with the mean difference between ent groups (ANOVA model for SNOT-22) are summarized in Table 7. In Table 7, the column labeled rence vs. Placebo" reflects the placebo-corrected value from baseline which takes into account changes that are observed in the value of the parameter as compared to the changes that were observed for that parameter in the placebo- treated group.

Table 7. Secondary Parameters of Lung Function and Symptom Scores Least-Squared Baseline Mean Difference vs.

(SD) MeaI:SC[h)ange Placebo p value FEV1 (L) Placebo 52 2.54 (0.66) -0.22 (0.06) -- mAb1 52 2.47 (0.65) 0.05 (0.06) 0.27 (0.11, 0.42) 0.0009 AM PEF (L/min) Placebo 52 406.9 (110.7) -20.7 (9.1) -- mAb1 51 393.0 (101.1) 13.9 (8.8)f 34.6 (10.6, 58.5) 0.0051 PM PEF (L/min) o 51 416.6 (116.8) -18.4 (8.9)1' -- mAb1 52 414.6 (102.3) 4.3 (8.5) 22.7 (-0.7, 46.0) 0.0567 rol Use (Puffs/Day) Placebo 52 2.0 (1.8) 0 7 (0.3 -- mAb1 50 2.2 (2.4) -1 3 (0.3): -2.0 (-2.9, -1.2) <0.0001 ACQ Score Placebo 52 2.08 (0.52) -0.27 (0.16) -- mAb1 52 2.09 (0.46) -1.00 (0.16) -0.73 , -0.30) 0.0011 Night-time Awakenings (No. of times/night) Placebo 52 0.2 (0.5) 0.1 (0.1) -- mAb1 52 0.4 (0.8) -0.2 (0.1) -0.2 (-0.5, -0.0) 0.0518 SNOT22 Average Score Placebo 51 26.24 (15.62) 0.23 (2.15)‘I' -- mAb1 50 30.92 (14.77) -8.26 (2.20): -8.49 (-13.96, -3.03) 0.0027 T 51 ts with at least 1 post-baseline assessment. 1; 50 patients with at least 1 post-baseline assessment.

] Treatment with mAb1 ed in a significant change from baseline in FEV1 at Week 1, which was ined through Week 12 despite LABA and ICS withdrawal, with a small decrease in FEV1 at Week 5 ding with LABA awal. Similar improvements were observed in g PEF, but less so in evening PEF. The least-squared (LS) mean change from baseline to week 12 in FEV1 was -0.22 L for placebo and 0.05 L for the mAb1 group. (p=0.0009).

ACQ5 score improved in both treatment groups at Week 1. However, while ACQ5 improved further with mAb1 between Weeks 1 and 4, the placebo effect ized, ining the difference through Week 12.

[00145] Morning symptom scores increased from baseline to Week 12 with placebo. With mAb1, there was an initial decrease which remained below baseline through Week 12. A similar pattern (with greater variability) was observed for evening asthma symptom scores.

Nocturnal awakenings were stable from the placebo group through Week 6, then increased from Weeks 6 to 12. In contrast, nocturnal awakenings decreased in the mAb1 group by Week 1 and remained improved versus baseline through Week 12.

Changes in albuterol/levalbuterol use were similar to other secondary endpoints: an initial decrease ed by a return towards ne with placebo. With mAb1, the initial decrease was maintained over time.

There was a non-significant difference at ne between the SNOT-22 values with the mean placebo score at 26.24 and the mean mAb1 score at 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 represented a magnitude of improvement of 8.49 points for the mAb1 group (p=0.0027).

Table 8. Secondary Endpoints Outcome Placebo mAb1 Difference vs P Value (N = 52) ( N = 52) Placebo (95% Cl)** Kaplan-Meier estimate at 46.0 (31.8, 60.2) 5.8 0.10 (0.03 to 0.34) <0.001 12 weeks (0.0, 2.1) Change in morning 0.3 i 0.1 -0.4 i 0.1 -0.7 (-0.9 to -0.4) <0.001 asthma symptom scores, baseline to week 12 Change in evening 0.1 i 0.1 -0.6 i 0.1 -0.7 (-0.9 to -0.4) <0.001 asthma symptom , baseline to week 12 Table 9. Change From Baseline at Week 12 in SNOT-22 Items Relevant to Upper Airway Disease.

SNOT-22 Subscale Least-Squares Mean Difference vs Placebo P Value Change 1 Standard Error (95% Cl) Placebo mAb1 (N : 52) ( N : 52) Need to blow nose -0.70 (-1.13, -0.26) 0.002 Nasal blockage -0.20 i 0.19* -0.94 : 0.19T 0.75 (-1.22, -0.28) 0.002 Decreased sense of 0.04 i 0.18* -1.13 : 0.18T -1.16 , -0.71) < 0.001 smell/taste *51 and f50 patients with at least 1 post-baseline assessment respectively For all secondary endpoints, Week 12 measurements favored mAb1 treatment and were significant except for evening PEF and nal awakenings (Table 7 and 8). icant ements with mAb1 were also observed for the three SNOT-22 items relevant to upper ainNay disease (Table 9) (iii) Safety mAb1 was generally safe and well tolerated. Treatment-emergent adverse events (TEAEs) were reported rly by 40 (76.9%) of placebo-treated patients and by 42 (80.8%) of mAb1-treated patients (Table 10). TEAEs were non-specific, generally mild to te in intensity and the majority recovered by the end of the study. An increased reporting of the following TEAEs was observed for mAb1 in comparison with placebo: ion site reactions were reported by 15 (28.8%) mAb1 patients and by 5 (9.6%) placebo patients; aryngitis 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 ts and 1 (1.9%) placebo patients.

Table 10. Adverse Events.

Adverse event Placebo mAb1 300 mg (N : 52) (N : 52) no. ofpatients (%) Any adverse event 40 (76.9) 42 (80.8) Any serious adverse event 3 (5.8) 1 (1.9) Study discontinuation owing to adverse event 3 (5.8) 3 (5.8) Death 0 0 Most common AEs* Injection site reactionsf 5 (9.6) 15 (28.8) Nasopharyngitis 2 (3.8) 7 (13.5) Adverse event Placebo mAb1 300 mg (N : 52) (N : 52) no. ofpatients (%) Upper respiratory tract infection 9 (17.3) 7 (13.5) he 3 (5.8) 6 (11.5) Nausea 1 (1.9) 4 (7.7) Arthropod bite 0 3 (5.8) Muscle spasms 0 3 (5.8) Nasal congestion 1 (1.9) 3 (5.8) Rash 1 (1.9) 3 (5.8) Urticaria 0 3 (5.8) Viral upper atory tract infection 0 3 (5.8) *2 3 patients in any ent group by Preferred Term Tlnjection site reaction includes events reported as: injection site pain, injection site reaction, injection site erythema, injection site rash, injection site haematoma, injection site urticaria, injection site dermatitis, injection sites inflammation, injection site nodule, injection site pruritus and injection site ng.

There were no deaths reported during the study period. Of the 4 treatment emergent serious adverse events (SAEs) reported: 1 mAb1 t experienced bipolar disorder and 3 placebo patients experienced SAEs of asthma with pneumonia, gunshot wound with left pneumothorax, and right ankle fracture. None of these SAEs were ered as related to the mAb1 and all but the recent ankle fracture were recovered by the end of the study. There were no deaths.

A total of 6 patients discontinued the study due to a TEAE: 3 patients in the mAb1 group (bipolar disorder, asthma with wheezing, and angioedema) and 3 patients in the placebo group (upper respiratory tract infection, psoriasis and asthma). The TEAE of angioedema occurred in a 42-year old African-American female after the ninth study treatment dose as a pruritic, popular rash observed at, and distant to, the ion site. It persisted for one week, resolved after study treatment discontinuation, and prednisome and diphenhydramine treatment. It was deemed treatment-related. This AE was subsequent to milder rashes at the injection site after the first and sixth study treatment doses.

] Among the most common AEs occurring in 23 patients in any treatment group (Table ), ion site reactions, nasopharyngitis, nausea, and headache occurred more frequently with mAb1 than placebo. No clinically icant changes in vital signs, physical examination, clinical laboratory or ECG gs were reported in either group.

G. Conclusion Significant improvements were ed for lung function and other asthma control parameters. Efficacy was observed early and sustained despite background y withdrawal. A relative reduction of approximately 87% (p <0.0001) in the primary endpoint of the incidence of asthma exacerbations in persistent, moderate-to-severe asthma patients with eosinophilia was observed after 12-week treatment with 300mg of mAb1 once weekly (5.8%) ed with placebo (44.2%). As shown in Table 7, ally meaningful and statistically significant ut multiplicity adjustment) improvements with treatment ed with o were observed in lung function parameters (FEV1, PEF AM), asthma symptom scores (A00) and albuterol use. Positive trends were obsen/ed for PEF PM 567) and nocturnal awakenings (p=0.0518). A statistically significant (without multiplicity adjustment) improvement was also observed for the SNOT-22 score. Within the active treatment group, a sustained improvement versus baseline was observed during the course of study for all parameters, despite LABA and ICS awal. mAb1 was generally safe and well tolerated. e 2: Biomarker studies Biomarker is was conducted on samples taken from subjects who participated in clinical trials of mAb1 (see Example 1 above). In particular, serum/plasma biomarkers associated with TH2 inflammation such as thymus and activation chemokine (TARC; , lmmunoglobulin E (lgE), n-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils were measured in samples from patients at baseline and at different time points following initiation of study treatment(s). Baseline levels of these biomarkers were assessed for potential predictive value for treatment response. In addition, the fraction of exhaled NO (FeNO) and induced sputum eosinophils and neutrophils were measured as biomarkers of bronchial mation. Exhaled nitric oxide assessment was conducted prior to spirometry and following a fast of at least 1 hour using a NIOX ment (Aerocrine AB, Solna, Sweden). Biomarkers were analyzed using a mixed model and the least square mean d from the model are reported below.

[00156] Asthma 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 of the study (i.e., 12 weekly doses) (see Example 1, above). Samples for biomarker analysis were collected from the antibody- and placebo-treated subjects at week 0, 1, 4, 8 and 12. Antigen-specific lgE was detected using the Phadiatop® test.

[00157] TARC, eotaxin-3 and lgE remained unchanged in se to placebo. In contrast, a rapid reduction in TARC (mean % change -22.7% vs +0.3%; p: 0.0003) and eotaxin-3 (mean % change -39.62% vs 12.69%; p<0.0001) was obsen/ed within one week in ts treated with mAb1 and persisted until week 12: TARC: -26.0% vs +7.6% placebo (p=0.0005); Eotaxin-3: - 45.67% vs +5.13% placebo (p<0.0001).

[00158] TARC levels responded within a week following exposure to mAb1 at 300 mg administered subcutaneously. TARC levels plateau at approximately 50% of the baseline level in mAb1-treated subjects, regardless of ICS awal. The data suggest that TARC expression is more directly linked to lL-4R signaling, than FEV1 changes (which drop in parallel to ICS withdrawal [after Week 4]) and that lL-4R blockage induces a shift towards a TH1 signature, as observed with, for example, lFNgamma administration. It might be possible to titrate the mAb1 dose using TARC (and for example CXCL10) in particular in patients requiring long term treatment and at risk for TH1 type immune diseases.

Total serum lgE also decreased following mAb1 ent. Total serum lgE response was more heterogeneous and delayed compared to TARC response. Mean (SD) baseline lgE levels were 694.68 lU/L (1837.82) for the placebo group (n=52) and 657.66 (1482.25) for the mAb1 group (n=52), whereas median was 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend towards lgE decrease in xposed patients compared with placebo was obsen/ed — however, ng at week 4 only. Serum lgE was significantly reduced in the mAb1 group compared with placebo (mean % change, -10.1% vs +13.5%; p=0.0325) starting from week 4 and continued to decrease until week 12 (mean % change, -36.8% for mAb1 vs -5.5% for o; p<0.0001).

Changes from baseline and placebo at Week 12 for FeNO, TARC, eotaxin-3, and lgE all favored mAb1 (all P< 0.001) (Table 11). No differences from ne or n treatments were observed in YKL-40 or CEA.

Table 11. Percent Change From Baseline at Week 12 in Pharmacodynamic Endpoints.

Least-Squares Mean Percent Change 1 Standard Error e P Value Placebo mAb1 (N : 52) (N : 52) FeNO 35.0 i 10.8 28.7 i 11.2 < 0.001 TARC 7.6 i 6.9 -26.0 i 6.9 < 0.001 Eotaxin-3 5.1 i 4.7 -45.7 i 4.7 < 0.001 lgE 5.5 i 3.6 -36.8 i 3.6 < 0.001 Blood phils 2.7 i 15.8 41.6 i 15.7 0.078 There was a transient decrease in tin 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 with CEA and YKL-40.

The number of blood eosinophils remained unchanged through Week 6, but then increased at Weeks 8 and 12. Peripheral blood eosinophil numbers were ged on placebo throughout treatment. The difference between the treatments was not significant, with the borderline increase driven by larger blood phil elevations in only a few ts treated with mAb1.

Little or no increases were obsen/ed in the majority of patients.

Table 12. Proportions of Patients Achieving Thresholds of Change in Blood Eosinophil Levels.

Change in phils Number (%) of patients Placebo (n = 52) mAb1 (n = 52) > 15% Decrease 13 (30.2) 21 (47.7) % Decrease — 0% change 7 (16.3) 6 (13.6) 0%-15% Increase 8 (18.6) 4 (9.1) % - 100% Increase 13 (30.2) 6 (13.6) 100% - 200% increase 2 (4.7) 3 (6.8) > 200% increase 0 4 (9.1) Since only 3 mAb1 patients experienced asthma exacerbation during the study, no conclusion could be drawn regarding the association n baseline biomarker levels and asthma exacerbations. mAb1 treatment was also associated with a significant decrease from baseline in FeNO at Week 4, and FeNo remained below baseline through Week 12, regardless of lCS withdrawal (mean % change at week 12: -28.7 for mAb1 vs 35.0 for placebo; p<0.0001). In contrast, placebo FeNo values remained stable through Week 8, followed by an increase at Week 12 coincident with lCS withdrawal.

Forced expiratory volume in 1 second (FEV1) ement significantly correlated with FeNO reduction ( =-0.408, 9) at week 12. Similarly, improvements in AM-PEF and PM- PEF correlated with FeNO reduction. Other correlations with FeNO were not significant. See Table 13.

Table 13. Correlation between FEV1 and PD Endpoints.

Outcome Correlation P Value FeNO -0.408 <0.009 TARC -0.248 0.10 Eotaxin-3 -0.146 0.34 lgE -0.279 0.06 Blood eosinophils 0.165 0.28 ] Scatter plot analysis of baseline phils versus change from baseline in FEV1 at week 12 did not seem to suggest association of baseline eosinophils and ent effect, as measured by change from baseline in FEV1 at week 12 in the study tion (baseline eosinophils 2 0.3 Giga/L). Baseline eosinophils correlated with decreased ACQ and sed albuterol/levalbuterol use. Periostin and YKL-40 at baseline correlated with decreased ACQ.

The FEV1 change from baseline at week 12 was compounded by the withdrawal of lCS (starting at week 4). Similar analyses did not suggest ation between baseline TARC or lgE and change from baseline in FEV1 at week 12 in the study population (baseline eosinophils 2 0.3 Giga/L).

H. Summary ] These results show that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, eotaxin-3 and lgE) and bronchial mation (FeNO) in adult asthma ts. The correlation between FeNO reduction and FEV1 improvement suggests a onship between lL-4/lL-13 mediated anti-inflammatory activity and ement in pulmonary function in moderate-to-severe, uncontrolled asthma.

Example 3. Clinical Trial of Subcutaneously Administered Anti-lL-4R Antibody (mAb1) In Patients with Bilateral Nasal Polyposis and Chronic Symptoms of Sinusitis A. Study Objectives and Overview ] The positive effect of mAb1 on the SNOT-22 test described in e 1 suggested that the anti-lL-4R antibody might also be effective for treating nasal polyposis. Further, nasal polyps are most commonly philic/TH2 driven, and mAb1 significantly reduced biomarkers associated with Th2 inflammation (see Example 2). A clinical trial was therefore designed to test the therapeutic effect of mAb1 on nasal polyposis.

[00169] A randomized, double-blind, phase 2, placebo controlled, 2 arm study will be performed to evaluate mAb1 administered once a week (QW) subcutaneously (SC) for 16 weeks in patients with bilateral nasal polyposis and c symptoms of tis. The primary objective of the study will be to evaluate the efficacy of mAb1 in the treatment of bilateral nasal polyposis (NP) by assessment of the endoscopic nasal polyp score in ison to placebo. Secondary objectives of the study include evaluation of mAb1 in patients with bilateral nasal polyps with regards to symptoms of sinusitis, Computed Tomography (CT) scan changes, Nasal polyp score in the sub-group of patients with co-morbid asthma, safety and bility, pharmacodynamic responses based on suppression of TH2 biomarkers, concentrations of mAb1 in serum, immune response to mAb1 (Anti-drug antibodies (ADA)), and effect of mAb1 in patient reported outcomes and Quality of Life (QoL) scales. mAb1 will be administered concomitantly with Mometasone furoate nasal spray (MFNS). Also, there is high co-morbidity of NP with asthma, aspirin/ roidal anti- matory drug (NSAID) hypersensitivity and previous surgeries, and therefore ts will be allowed to enter the study unless they present any of the exclusion criteria described below.

Approximately 56 patients will be ized into 2 treatment groups of 28 patients per group.

To ensure at least 28 patients with co-morbid asthma are included in the study, recruitment of NP patients without co-morbid asthma will stop when approximately 28 patients without asthma are randomized. Both the patient and the investigator will be blinded to the assigned treatment group.

[00171] The study will consist of three periods: 1) a four week screening run in period on MFNS (Visit 1); (2) a 16 week randomized mAb1 or placebo treatment period (Visits 2-18); and (3) a 16 week reatment period to assay cokinetics, immunogenicity, safety and efficacy (Visits 19-22). The total duration of the study is up to 36 weeks.

The primary endpoint will be the change from baseline at Week 16 in bilateral nasal polyp score (NPS).

Numerous secondary efficacy endpoints will be measured to more comprehensively evaluate the efficacy of mAb1. The study will e improvement of nasal polyposis and associated sinus mation in CT scan, improvement in condition specific and general medical questionnaires in order to obtain a better understanding of the impact of severe nasal polyposis on the t's quality of life (QOL).

These endpoints, together with exploratory sub-group analysis and biomarkers will provide the information on the therapeutic value of mAb1 to reduce nasal polyp score and to improve ms in NP and its subsets. The sustainability of the effect will be also explored through the 4-month post-treatment evaluation period.

The 300 mg QW dose n is anticipated to saturate apparent target mediated clearance level (10-15 mg/L). This regimen has been tested and ed statistically significant and clinically relevant response in two previous proof of concept studies med with mAb1 in asthma and atopic dermatitis (see, e.g., Example 1 above, USSN 61/805797 and USSN 61/816191). The first dose will employ a loading dose of 600 mg in order to achieve faster steady-state concentration. This loading dose range is supported by the acceptable safety profile of the highest loading dose (600 mg) trated in a prior study conducted in Japanese healthy subjects.

[00176] In addition, given that the Cmax after 600 mg loading dose is around 70 mg/L and that the steady state h of 300 mg QW is around 150 mg/L, the Cmax after the proposed dosing regimen (ie, 600 mg loading dose followed by 300 mg QW) will be below the mean Cmax of 12 mg/kg lV dose (421 mg/L), the highest single dose tested in healthy ts that was well ted, providing additional confidence that this dose regimen should have an able safety profile.

Patient inclusion criteria include (i) a physician endoscopic diagnosis of bilateral nasal polyposis (ie, a minimum bilateral nasal polyp score of 5 out of a maximum score of 8 for both nostrils, with at least a score of 2 for each nostril, despite completion of a prior INCS (intranasal corticosteroid) treatment) for at least 8 weeks before ing, and (ii) chronic symptoms of sinusitis, which are the presence of at least two of the following ms prior to screening: nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); facial ressure; and reduction or loss of smell.

Patients who have met these criteria will be screened for the following exclusion criteria: age <18 or >65 years; any technical/administrative reason that makes it impossible to randomize the patient in the study; previous participation in any clinical trial of mAb1 ; a SNOT22 score <7; receipt of any other investigational drug or prohibited therapy for this study within 2 months before screening or 5 half-lives, whichever is longer; receipt of oral corticosteroids (008) or intranasal corticosteroid drops within 2 months or 1 month before screening or scheduled to receive OCS during the study period for another condition; treatment with mAB or immunosuppressive therapy; treatment with an anti-immunoglobulin E (IgE) therapy (e.g., omalizumab) within 130 days of Visit 1; treatment with a leukotriene antagonist / modifier for patients who were not on a continuous treatment for 230 days prior to Visit 1; initiation of en immunotherapy within 3 months prior to Visit 1 or a plan to begin y during the Screening Period or the Randomized ent Period; any nasal surgery within six months before screening or have had more than five sal surgeries in the past of which maximal two were surgeries changing the lateral wall structure of the nose; or a condition/concomitant e that makes a patient non-evaluable for the primary efficacy endpoint (e.g., antrochoanal polyps; nasal septal deviation that would occlude at least one nostril; acute sinusitis, nasal infection or upper respiratory infection at screening or in the 2 weeks before screening; ongoing rhinitis medicamentosa; Churg-Strauss syndrome, Young’s syndrome, Kartagener’s syndrome or dyskinetic ciliary syndromes, Cystic fibrosis; signs or a CT scan suggestive of Allergic fungal rhinosinusitis). Patients with co-morbid asthma are excluded if: the patient has a forced expiratory volume (FEV1) of 60% or less; an exacerbation requiring systemic (oral and/or parenteral) steroid treatment or Hospitalization (>24h) for treatment of , has occurred within 3 months prior screening; or the patient is receiving a dose higher than 1000 pg fluticasone or the equivalent of d osteroids. Other exclusion criteria include patients with short life expectancy (less than 6 ); patients receiving concomitant treatment prohibited in the study; women who are pregnant or intend to become pregnant during the study, or breast-feeding women. Other exclusion criteria include concomitant severe diseases (e.g., active and inactive pulmonary tuberculosis, es mellitus etc.); diagnosed active parasitic infection; suspected or high risk of parasitic infection; history of human immunodeficiency virus (HIV) ion or positive HlV screen at Visit 1 ; evidence of acute or chronic infection; known or suspected immunosuppression, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite ion resolution; live vaccinations within 12 weeks prior to Visit 1 or planned vaccinations during the study; patients with active autoimmune disease or patients using immunosuppressive therapy for autoimmune disease (eg, Hashimoto’s thyroiditis, Graves’ disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematous, le sclerosis, psoriasis vulgaris, toid arthritis); patients with positive or indeterminate hepatitis B e n (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at Visit 1; patients with liver injury related criteria ( e.g., underlying hepatobiliary disease, or ALT>3 ULN).

B. Study ents lnvestigational Product: Sterile mAb1 of various trations will be provided in 5 mL glass vials. Each vial will n a withdrawable volume of 2 mL: 150 mg/mL solution (300 mg dose/ 2 mL). Sterile placebo will be provided in cally matched glass 5 mL vials, where each vial contains a deliverable volume of 2 mL. mAb1 will be administered every 7 :r 2 days (QW). The doses of mAb1 will be separated by 25 days to avoid an overdose. At Visit 2 (V2), 2 injections will be performed. After V2 one ion of mAb1 will be performed weekly at the investigational site throughout the randomized treatment period. The mAb1 will be administered following clinic procedures and blood collection. ts will be monitored for at least 1 hour after each administration for any signs or symptoms of a local site injection or hypersensitivity reaction. Subcutaneous injection sites will be alternated between the 4 quadrants of the abdomen (avoiding navel and waist areas) or upper thighs so that the same site is not injected for two consecutive times/weeks.

On a daily basis throughout the study, the subject will use an onic diary to record daily use of MFNS. Mometasone furoate (NASONEX ®) 50 rams/actuation Nasal Spray, is contained in a bottle, that contains 18 g (140 actuations) of product formulation.

[00182] Screening Period: Prior to ing, subjects must be on a stable dose of intranasal osteroids (INCS) for 22 month prior to Visit 1. If the patient is using an alternative INCS product other than MFNS prior to the screening visit, at V1, the patient will be switched to MFNS. After V1 all ts will enter a run-in period of 4 weeks where they will receive MFNS: 2 actuations (50 ug/actuation) in each l twice daily (BID) (total daily dose of 400 pg), unless they are intolerant to BID INCS in which case, they can stay on the lower dose (QD) regimen. To be accepted for the study, patients must also have presence of at least two of the following symptoms prior to screening: Nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); +/- facial pain/pressure or +/- reduction or loss of smell

[00183] Treatment Period: The treatment period will proceed as indicated in the Study Flow- chart at Table 14.

Table 14.

Screenin Randomized ent period Post-treatment 9 period period Inclusion Criteria X X including Informed Consent s Exclusion Criteria Screenin ized treatment period Post-treatment g period penod RDN E VISIT 1 2 15 16 17 18 19 20 21 Week (DAY) W-4(D- W0 14 4 28) (D1) Medical/Surgical X History Prior Medication X Historyb Physical X X Examination Spirometryc X X Treatment: mAb1 weekly SC administrationd Call IVRS Dispense or x x download onic diary/NPIFe NIMP (MFNS) Record concomitant medication Efficacy CT scan9 Smell test (UPSIT) SNOT- 22 Visual analogue scale (VAS) QoL (SF-36, EQ- Nasal polyp related resource use questionnaire ACQ-5h Safet AE /SAE recording (if any) Vital Si 0 ns Laboratory Testing Screenin Randomized treatment period Post-treatment g period period VISIT 1 l\) oo 4> \l 15 16 17 18 19 20 l\) _\ Week (DAY) w-4( UI Eo l\) coo-I 4; O) 13-1614 20 l\)4; l\) 00 28) (D1) Clinical laboratory x >< >< testingi ysis X diostick Pregnancy test (for X x >< WOCBPJ' PK/Anti-drug >< >< >< antibody sampling PKk .->< Serum Biomarker >< >< >< sampling Archival nasal X >< secretion samplingm -I---E— -uuuuumm Polyp biopsyn - Stored DNA sampling I- Stored whole blood X >< X RNA ng0 E The Screening Period is 28 days in duration to run in any patient on MFNS, and to collect baseline data. V2 will take place 28days+/-2 day window after V1 3 No mAb1 administration during this visit. ts who discontinue treatment early will be assessed as soon as possible using the procedures normally planned for the -treatment Visit and the 4 Post- treatment Period Visits. b Prior to screening, patients must be on a stable dose of INCS for more than 8 weeks 0 Spirometry: all patients should have FEV1 anytime during Screening Period (before V2) and at the other scheduled visits during the Randomized treatment period d Weekly mAb1 administrations ng from V2 at the site investigational site must be separated by at least 5 days. 9 Electronic diary/NPIF meter is used for daily recording of MFNS use, nocturnal awakenings, morning and evening NPIF and rhinosinusitis m scores 1) nasal congestion/obstruction 2) anterior rhinorrhea (runny nose), 3) posterior rhinorrhea (post nasal drip), and 4) loss of sense of smell, scored using a 0-3 categorical scale where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms); This device is sed at Visit 1 and information is downloaded from this device on the other indicated days. The e of the last 7 days before V2 is needed to ine the baseline value f Nasal endoscopy: endoscopy (including use of decongestants before the procedure) will be performed after all other efficacy assessments have been completed for each visit; Standard video sequences will be downloaded by the investigator to the central reader’s secured Internet site. For eligibility central reading of V1 will be used. At V2 investigator review V1 results from central reader to confirm entry criteria and reconfirm eligibility based on review of Inclusion/Exclusion Criteria and the V2 opy local reading g CT scan should be performed e during Screening Period before a first administration of mAb1 and at EOT. Central reading will be used for comparison baseline (BL) to EOT h Only for patients with co-morbid asthma, ACQ-5 is completed in the patient’s electronic diary during clinic visits. i Hematology: hemoglobin, hematocrit, et count, total white blood cell count with five-part differential count, differential count, and total red blood cell count. Serum chemistry (Obtain fasting at planned visits but V2): creatinine, blood urea nitrogen, e, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes m, potassium, chloride), bicarbonate, and creatine phosphokinase. Clinical laboratory testing at Visit 1 includes hepatitis screen (hepatitis B surface antigen (HBsAg), Hepatitis B lgM core antibody (HBcAb-lgM), hepatitis C antibodies (HC Ab), HIV screen (Anti-HlV-1 and HIV-2 antibodies), anti-nuclear antibody (ANA). al laboratory testing at Visit 2 is limited to hematology and a separate hematology sample obtained for local analysis. Note: Anti-ds DNA antibody will be tested if ANA is ve (21:160 titer). Clinical lab testing at Visit 2 consists of hematology only j Serum pregnancy test at Visit 1 and urine pregnancy tests at other . A negative result must be obtained at Visits 1 and 2 prior to randomization visits k Serum pharmacokinetic samples, immune response assessment (ADA) samples and optional whole blood RNA samples will be ted prior to administration of investigational product during the Randomized Treatment . During the post-treatment period PK samples will be collected at all visits and ADA s only at EOS visit. Patients with titers >1000 of the ADA at last visit may be followed after the study. Blood samples for PK and ADA ment will be collected at any time iln case an SAE occurs. m Nasal secretion samples will be collected and stored for potential future discovery efforts to identify tors of treatment response n Optional polyp biopsies will be collected in selected clinical s 0 Samples will be collected prior to administration of investigational product during the Randomized ent Period

[00184] During the Treatment , patients will ue the stable dose of mometasone furoate: two actuations of MFNS in each nostril BID or QD (in case patient cannot tolerate the high dose). At Visit 2, patients will be administered the SNOT-22 test, VAS and QoL questionnaires , EQ-5D, Nasal polyp related resource use questionnaire), the smell test, and the ACQ-5 in patients with asthma.

[00185] al laboratory testing at Visit 2 is limited to hematology, pharmacokinetics, anti- drug antibodies, biomarkers in serum and plasma, allergen-specific lgE panel sampling. Blood samples are taken prior to administration of mAb1. Nasal secretion sampling for biomarkers.

For those ts who have signed a specific informed consent form, collect blood sample for DNA and RNA sampling (prior to administration of investigational product during the 40 Randomized ent Period).

Temporary treatment discontinuation may be considered by the Investigator because of suspected AEs. Reinitiation of treatment with mAb1 will be done under close and appropriate clinical/and or laboratory monitoring once the igator will have considered according to his/her best medical judgment that the responsibility of mAb1 in the occurrence of the concerned 45 event was unlikely and if the selection criteria for the study are still met.

An adverse event (AE) is any rd medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

A serious e event (SAE) is any untoward medical occurrence that at any dose: results in death, or is life-threatening, (the term threatening” in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe); requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect; is a medically important event Medical and scientific judgment should be exercised in deciding whether expedited reporting is riate in other situations, such as important medical events that may not be immediately life-threatening or result in death or alization but may jeopardize the patient or may require ention (ie, specific measures or corrective treatment) to prevent one of the other outcomes listed in the definition above (he following list of medically important events is intended to sen/e as a guideline for determining which condition has to be considered as a medically important event. The list is not ed to be exhaustive: intensive treatment in an emergency room or at home for: Allergic bronchospasm, anaphylaxis, blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia, etc), convulsions (seizures, epilepsy, epileptic fit, absence, etc), pment of drug dependency or drug abuse); ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT se >10 x ULN; Suicide attempt or any event suggestive of suicidality; syncope, loss of ousness (except if documented as a consequence of blood sampling); bullous cutaneous eruptions; Cancers diagnosed during the study or aggravated during the study; c neurodegenerative diseases (newly diagnosed) or aggravated during the study (only if judged unusual/significant by the Investigators in s assessing specifically the effect of a study drug on these diseases).

Post-treatment Period: Upon completing the Randomized ent Period (or following early discontinuation of mAb1), ts will continue treatment with the stable dose of MFNS maintained over the randomized treatment period, or modify ent based on medical judgment.

The following concomitant treatments are not permitted during the Screening Period and the Randomized treatment period: use of intranasal medication that would interfere with the symptoms of diseases (antihistamines, nasal ne, ipratropium bromide, nasal cromolyn), except nasal saline; INCS drops; systemic corticosteroid; decongestion (topical or ic), except before endoscopy; long term use of systemic antibiotics (for 2 weeks or more); lipoxygenase tors; any immunosupressive treatment including but not limited to rexate, cyclosporine, mycophenolate, tacrilomus, gold, llamine, sulfasalazine, hydroxychloroquine, oprine, cyclophosphamide; anti-immunoglobulin E (lg E) therapy (omalizumab); and aspirin or NSAID in patients with hypersensitivity to aspirin.

] The following concomitant treatments are allowed: MFNS during the screening and throughout the whole study; Nasal normal saline; Topical decongestants (e.g., Oxymetazoline hydrochloride to reduce the swelling and widen the path for the endoscope), as well as a topical anesthetic e.g. Lidocaine are allowed before endoscopy; short term use of Antibiotics ks); and for patients with asthma, SABA, LABA, and Methylxanthines (e.g., theophylline, aminophyllines). The following inhaled corticosteroids are allowed for patients on a stable dose $1000 pg Fluticasone (or the equivalent dose of another inhaled CS; see Table 16) and only for ts that were on a stable dose 230 days prior to Visit 1 : Leukotriene antagonists / ers are permitted during the study, only for patients that were on a continuous treatment for 230 days prior to Visit 1; Systemic antihistamines; and Initiation of allergen immunotherapy (allergen immunotherapy in place for 23 months prior to Visit 1 is permitted).

C. Efficacy of treatment The primary endpoint of this study is the change from baseline at week 16 in bilateral endoscopic Nasal Polyp Score.

Table 15.

Pol score Polyp size 0 No polyps 1 Small polyps in the middle meatus not reaching below the inferior border of the middle ate 2 Polyps ng below the lower border of the middle turbinate 3 Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate 4 Large polyps causing complete obstruction of the inferior nasal cavity Nasal endoscopy will be performed at the end of the scheduled visits and preceded by local administration of anaesthetic drugs in combination with a decongestant. rd video sequences will be downloaded or sent to a centralized reader. Centralized imaging data assessments and scoring by an independent physician reviewer for the imaging data will be performed for all endoscopies. To confirm eligibility at V2, only the V1 central reading will be made ble to the site. The final results of central reading will be made available after the study.

For the analysis of the primary nt, central reading of V2 will be used for comparison with EOT reading. The sites will remove subject-identifying information from the imaging data header prior to sending the imaging data to the l reader.

Secondary nts of the study will include change from baseline at Week 16 in: patient reported symptoms (including 22-item Sinonasal Outcome Test (SNOT-22)); t- assessed nasal congestion/obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post nasal drip), and loss of sense of smell, (daily AM and PM e-diary) month average; number of nocturnal awakenings; patient-rated rhinosinusitis ms severity using a visual analog scale (VAS); 5-item Asthma control questionnaire ) in asthma sub-group); nasal peak atory flow (NPIF); smell test (UPSIT); NPS in patients with co-morbid asthma; CT scan assessments; Spirometry (overall and in sub-group with ); time to first response (21 point improvement) in NPS; time to study treatment discontinuation; and incidence of treatment discontinuation due to need for OCS or nasal y.

Quality of life (QoL) end points will include change from baseline at Week 16 in: 36- item short form health sun/ey (SF36); European y of life scale (EQ-5D); and Nasal polyp d resource use questionnaire.

Disease-specific efficacy es include: Computed tomography (CT). CT of the sinuses should be performed before V2 and at EOT. For both Lund-Mackay scores and 3D volumetric measurement of the maxillary sinus, the same acquisitions nces) will be used for centralized imaging data assessments and scoring by an independent physician reviewer for the imaging data. Central reading of V2 will be used for comparison with EDT. The final results of l reading will be made available after the study.

[00220] For Three-Dimensional volumetric measurement of the maxillary sinus, central reading before V2 will be used for ison with EOT reading. The sites will remove subject- identifying information from the imaging data header prior to sending the imaging data to the central reader. The % change in opacification from BL to EOT will be calculated.

At screening (Visit 1), patients will be issued an NPIF meter for recording morning (AM) and evening (PM) NPIF. The patients will be instructed to record the following variables in the e-diary on a daily basis: AM NPIF performed within 15 minutes after arising (between 6 am and am) prior to taking MFNS; and PM NPIF performed in the evening (between 6 pm and 10 pm) prior to taking MFNS.

Three NPIF efforts will be med by the patient; all 3 values will be recorded by the patient in the e-diary, and the highest value will be used for evaluation. The baseline AM NPIF will be the mean AM measurement recorded for the 28 days prior to the first dose of investigational product, and baseline PM NPIF will be the mean PM measurement recorded for the 28 days prior to the first dose of investigational product.

To assess disease-specific, daily symptoms, the patient will use an electronic diary to: respond to the morning and evening individual rhinosinusitis symptom questions using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe ms), and including the ms of tion and/or obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post-nasal drip), and loss of sense of smell. The number of nal awakenings will also be recorded.

The same safety ments will be d across all arms. e events, including serious adverse events (SAEs) and adverse events of special interest (AESI), will be collected at every visit.

[00225] e blood samples will be collected for determination of serum functional mAb1 and anti-mAb1 antibodies as designated in Table 14.

Optional ng for exploratory analysis of DNA and RNA, requiring separate pharmacogenetics informed consent.

[00227] cokinetics. Functional mAb1 and anti-mAb1 antibodies in serum will be assayed by ELISA. Predose functional mAb1 concentrations in serum at Visit 2 (Day 1), mAb1 trough concentrations at Week 2, Week 4, Week 8, Week 12, Week 16, and follow-up serum mAb1 at Week 20, Week 24, Week 28 and Week 32 will be ed. Anti-mAb1 antibody status (negative or titer value) at Visit 2 (Day 1), Week 2, Week 4, Week 8, Week 12, Week 16, and Week 32 will also be provided. Patients with ADA titers 21000 at the end of study visit will be scheduled to return approximately 6 months later for an additional assessment of ADA titer.

Further follow-up will be considered based on the overall assessment of antibody titers and clinical presentation.

[00228] Pharmacodynamics. Since the secretion of certain proteins is dependent, at least in part, on Th2 cytokines and is associated with chronic mation of the ainNay mucosa, including sinus tissue, expression of certain biomarkers will be assayed to monitor a therapeutic effect of mAb1. These biomarkers also will be assessed for their value in predicting toxicity and/or in documenting the time course of drug se. The values to be used as baselines will be those collected on Day 1 (predose assessments).

Nasal secretions will be obtained by inserting nasal swabs bilaterally into the nasal cavity for five minutes. The nasal secretions will be presen/ed for possible analysis of additional biomarkers related to nasal polyposis and responses to mAb1 treatment.

At selected clinical site (s) and with ic informed t, nasal polyp tissue will be optionally obtained by biopsy. A baseline biopsy will be obtained at V2 of the study. After randomization, another biopsy of nasal polyp tissue will be obtained at the end of treatment visit (Week 16).

The biopsied nasal polyp tissue will be assessed for various biomarkers of inflammation and disease process or se. For example, RNA will be extracted and used for expression profiling (e.g., microarray, transcriptome sequencing or quantitative ).

DNA and RNA samples may be used to determine a possible relationship between genes and response to treatment with mAb1 and possible side s to mAb1.

[00236] Analysis of proportion of patients with binary events. Proportion of patients with binary events will be assessed for : 21 point improvement (reduction) in NPS at week 16 (as read lly); 10% or more improvement in CT opacification from baseline at week 16; drop-out due to oral CS or surgery; or INCS increase after 8 weeks will be analyzed using a logistic model with the above responses, respectively, as the response variable, and treatment group, pooled countries /regions and the stratification factor(s) prior to the study as ates.

Analysis of time to event variables. Time to event (e.g., the first se with 21 point improvement (reduction) in NPS, study treatment discontinuation, etc) will be analyzed suing a Cox regression model with time to event as the dependent variable, and ent, pooled countries/regions, asthma comorbidity prior to the study as covariates. The Kaplan-Meier method will be used to derive the proportion of patients with an event at Week 4, 8, 12 and 16 specific to each treatment group. For is during the treatment period, if a patient has no event before treatment discontinuation/completion, then the patient will be considered as free of event till the end of treatment period (last dose date + 7 days).

Analysis of change from baseline for continuous variables. The change from baseline at week 16 in: NPS for patients with co-morbid asthma; Lund Mackay score; 22-item Sinonasal Outcome Test (SNOT-22); Subject-assessed congestion and/or ction score; nasal peak inspiratory flow (NPIF); ACQ-5 in patients with co-morbid asthma; QoL measures (SF36, EQ- 5D), and VAS will be analyzed using MMRM same as the primary endpoints. Descriptive statistics including number of patients, mean, standard error and LS means will be provided. In addition, differences in LS means, the corresponding 95% Cl and the p-value will be provided for comparisons of each dose against o. is of cy in baseline biomarker of characteristics defined subsets. To e baseline biomarkers for their potential value to predict ent response, es of change in NPS will also be performed for the following subsets and the entire lTT population by each dose group and selected pooled dose group.

Subgroup analysis. To assess the consistency treatment effects across the subgroup levels and to examine baseline biomarkers for their potential value to predict treatment response, exploratory subgroup analyses will be conducted for the change from baseline in NPS with respect to age group, gender, region, race, INCS dose level, baseline NPS, baseline CT scan score, asthma comorbidity, and selected biomarkers prior to the study.

Listings of anti-mAb1 antibody results (Negative or titer value) will be presented by patient, time point and treatment groups. ADA titer levels will be classified into categories: Low, moderate and high. Low levels of ADA titers are defined as titers below 1000; moderate levels of ADA titers are d as titers n 1000 and 10,000; high levels of ADA titers are defined as titers >10,000.

Anti-mAb1 antibody assay s will be described categorically. The following y will be provided for: Patients with any positive ADA assay response during the TEAE period; Patients with treatment induced positive ADA assay response during the TEAE period; Patients with treatment induced ve ADA assay se during the TEAE period will be further described as patients with transient positive se and patients with persistent positive response. Patients with any positive ADA assay se during the TEAE period is defined as those having at least one sample positive in the ADA assay.

[00243] The treatment induced positive ADA assay response is defined as: ts with no ve assay response at baseline but with a positive assay response during the TEAE period or ts with a positive ADA assay response at baseline and also have at least a 4-fold increase in titer during the TEAE period.

A persistent positive response is a treatment induced positive ADA assay response in which at least 2 consecutive post-baseline samples from a patient are positive in the ADA assay or the last post-baseline sample collected is positive in the ADA assay. A transient positive response is defined as any treatment induced positive ADA assay response that is not considered persistent.

Table 16. Allowable lnhaled Glucocorticosteroid / Long-Acting Beta2 Agonist Combination Products and Acceptable Dosage Form, Strength and Dosage Schedule Generic Name Brand Name Acceptable Acceptable Dosage Form, Strength Product and Dosage le Fluticasone propionate and Advair®/ DPI (250/50 or DPI: 1 puff twice daily (500/50) salmeterol de® 500/50) DPI: 1 puffs twice daily (250/50) 115/210r MDI: 2 puffs twice daily (115/21) 230/21) MDI: 2 puffs twice daily (230/21) Budesonide and formoterol Symbicort® DPI (200/6 or DPI: 1 puff twice daily (400/12) 400/12 DPI: 2 puffs twice daily (200/6) MDI (160/4-5) MDI: 2 puffs twice daily 5) Mometasone furoate and Dulera® MDI ( 100/5 or MDI: 2 puffs twice daily (200/5) formoterol 200/5) MDI: 2 puffs twice daily (100/5) The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various cations in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the anying figure. Such modifications are intended to fall within the scope of the appended claims.

Claims (30)

What is claimed 1. is:

1. Use of an antibody, or antigen binding fragment thereof, that specifically binds an interleukin-4 receptor (IL-4R) for the preparation of a pharmaceutical composition for treating chronic rhinosinusitis with nasal polyposis (CRSwNP) in a subject, and wherein the antibody, or antigen-binding fragment thereof, comprises: three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 ses the amino acid sequence of SEQ ID NO:3, the HCDR2 ses the amino acid ce of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 ses the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence of SEQ ID NO:7, and the LCDR3 comprises the amino acid ce of SEQ ID NO:8.

2. The use of claim 1, wherein the subject has chronic rhinosinusitis with bilateral nasal polyposis.

3. The use of claims 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (HCVR) having the amino acid ce of SEQ ID NO: 1; and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

4. The use of any one of claims 1-3, wherein the t has one or more of asthma, aspirin hypersensitivity, or hypersensitivity to a non-steroidal anti-inflammatory drug (NSAID).

5. The use of any one of claims 1-4, wherein the subject has severe nasal polyposis.

6. The use of any one of claims 1-5, wherein the composition is formulated for administration as a single initial dose and one or more secondary doses.

7. The use of claim 6, wherein the initial dose and one or more secondary doses are each about 300 mg. 06_1 (GHMatters) P39476NZ01

8. The use of claim 6 or78, wherein the ceutical composition is formulated for administration every two weeks.

9. The use of any one of claims 1-8, wherein the pharmaceutical ition is ated for subcutaneous, intravenous or intranasal administration to the t.

10. The use of any one of claims 1-9, wherein the subject has nasal polyposis which persists after a treatment regimen with inhaled corticosteroids (INCS) or after the subject stops receiving INCS.

11. The use of any one of claims 1-10, wherein the subject is selected based on one or more of the following criteria: i) a m bilateral nasal polyp score of 5; ii) an elevated level of one or more genes selected from the group consisting of thymus and activation-regulated chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA), and YKL-40; and iii) an elevated level of blood eosinophils or sputum eosinophils.

12. The use of any one of claims 1-11, for improving one or more of: a) 22-item sinonasal outcome test (SNOT-22) score; b) nasal symptom score; c) number of nocturnal awakenings; d) visual analog score (VAS); e) five-item asthma l questionnaire (ACQ5) score; f) nasal peak inspiratory flow (NPIF); g) University of Pennsylvania Smell identification test (UPSIT); h) Lund-McKay Score; and 17032506_1 (GHMatters) P39476NZ01 i) three-dimensional tric measurement of the maxillary sinus, in particular an increase in one or both of NPIF and UPSIT and/or a decrease in in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3DVolumetric Score.

13. The use of any one of claims 1-12, for decreasing a nasal polyp score.

14. The use of any one of claims 1-13, for increasing one or both of NPIF and UPSIT.

15. The use of any one of claims 9-14, wherein the pharmaceutical composition is formulated for aneous administration to the subject with a pen delivery device or an autoinjector, or formulated for subcutaneous or intravenous administration with a standard e and needle.

16. The use of any one of claims 1-15, wherein the dy is mab.

17. The use of any one of claims 1-16, wherein the ceutical composition is formulated for administration with a second therapeutic agent before, after or concurrently with the second therapeutic agent.

18. The use of claim 17, wherein the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic agent, and an anti-fungal agent.

19. The use of claim 17, wherein the second therapeutic agent comprises an intranasal corticosteroid, optionally wherein the intranasal corticosteroid is mometasone furoate nasal spray (MFNS).

20. The use of claim 19, n the second therapeutic agent comprises an inhaled corticosteroid, optionally n the inhaled corticosteroid is fluticasone or budesonide.

21. The use of claim 17, wherein the second therapeutic agent comprises a long-acting beta2 agonist, optionally wherein the long-acting beta2 agonist is salmeterol or formoterol. 17032506_1 (GHMatters) P39476NZ01

22. The use of any one of claims 1-16, wherein the subject has been prescribed or is currently taking a background therapy for nasal polyposis.

23. The use of claim 22, wherein the background therapy is an intranasal corticosteroid.

24. The use of claim 23, wherein the intranasal corticosteroid is mometasone furoate nasal spray (MFNS).

25. The use of claim 22, wherein the background therapy is an intranasal osteroid and a long-acting beta2 agonist.

26. The use of claim 25, wherein the background therapy is fluticasone/salmeterol combination therapy.

27. The use of claim 25, n the ound therapy is budesonide/formoterol combination therapy.

28. The use of claim 22, wherein the background therapy is selected from the group consisting of a nasal saline, a topical decongestant, a topical anesthetic, a leukotriene antagonist, and a systemic antihistamine.

29. The use of any one of claims 6-28, wherein the initial dose is about 400 mg and the one or more ary doses are each about 200 mg.

30. The use of any one of claims 6-28, n the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg.