JP7216122B2 - Methods of treating chronic sinusitis associated with nasal polyps by administering an IL-4R antagonist - Google Patents

Description

RELATED APPLICATIONS This application is based on U.S. Provisional Application No. 62/080,092 filed November 14, 2014; U.S. Provisional Application No. 62/158,832 filed May 8, 2015 and U.S. Provisional Application No. 62/199,305 filed July 31, 2015 and October 2015 It claims the benefit of European Application No. 15306632.9 filed on 14th, each of which is hereby incorporated by reference in its entirety.

The present invention relates to the field of therapeutic treatment of inflammatory conditions. More particularly, the invention relates to administration of interleukin-4 receptor (IL-4R) antagonists to reduce nasal polyp score and to treat associated conditions.

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

Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, arising from the natural oral route of the middle meatus. NP is a T helper cell-2 (Th-2) driven inflammatory process that affects the nasal mucosa and sinuses. High levels of interleukin-5 (IL-5; promotes survival and differentiation of eosinophils), eosinophil cationic protein (ECP) and eotaxin (a factor that attracts and activates eosinophils) Since acidophil chemoattractants) are typically found in nasal polyps, eosinophils and their products are thought to be a hallmark of inflammation associated with nasal polyps. Eosinophils are the major inflammatory cells found in sinuses and nasal polyps, which are also associated with high levels of IgE. NP is characterized by long-lasting symptoms of nasal obstruction and congestion, decreased or lost sense of smell, anterior and posterior rhinorrhea, and facial pain. Current treatment options range from topical or systemic corticosteroids to functional endoscopic sinus surgery.

Current medical management of chronic sinusitis with nasal polyps/polyps (CSwNP) is primarily focused on managing inflammation, including administration of topical and systemic corticosteroids aimed at reducing polyp burden and number. Emphasis is placed on If unsuccessful, surgical resection is indicated. However, disease recurrence is often reported after surgery, with recurrence rates approaching 50% in patients with tissue eosinophilia.

U.S. Patent No. 7,605,237 U.S. Patent No. 7,608,693

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

In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, eg, in US Pat.

Subjects suitable for treatment with an IL-4R antagonist may have a total of at least 5 nasal polyps, including 2 or more nasal polyps present within each nostril prior to the administering step, and/or from the group consisting of rhinitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity and Samter's triad (defined by the presence of nasal polyps, asthma, and aspirin and NSAID hypersensitivity) They may suffer from one or more selected conditions and/or may have undergone surgery for one or both of nasal polyps and chronic rhinosinusitis. In certain embodiments, subjects suitable for treatment are chronic sinusitis with nasal polyps (CSwNP), chronic sinusitis with bilateral nasal polyps, and rhinosinusitis with nasal polyps (CRSwNP) (e.g., , with or without asthma). Subjects suitable for treatment may or may not have asthma. In some embodiments, subjects suitable for treatment are indicated for initial functional endoscopic sinus surgery (FESS), are indicated for revision surgery, or are contraindicated for surgery.

In some embodiments, the IL-4R antagonist is administered to adults with chronic sinusitis with bilateral nasal polyps and who have persistent signs and symptoms despite treatment with intranasal corticosteroids (INCS). Indicated for long-term treatment in adults with bilateral nasal polyps and associated chronic sinusitis with persistent signs and symptoms despite treatment with INCS, or bilateral nasal polyps with persistent signs and symptoms despite treatment with intranasal or oral corticosteroids or who are intolerant to oral corticosteroids or who have bilateral nasal polyps and have persistent signs and symptoms despite treatment with intranasal or oral corticosteroids, or are intolerant to oral corticosteroids.

In some embodiments, the IL-4R antagonist is administered in doses between about 100 mg and about 600 mg. In some embodiments, the IL-4R antagonist has an initial dose of between about 400 mg to about 600 mg and about 200 mg to about 40 mg each.
One or more subsequent doses between 0 mg are administered. In some embodiments, the IL-4R antagonist is administered in an initial dose of about 600 mg and one or more subsequent doses of about 300 mg each. In other embodiments, the IL-4R antagonist is administered once every seven days (QW). In certain embodiments, the pharmaceutical composition is administered to the subject systemically or locally. For example, pharmaceutical compositions are administered subcutaneously, intravenously, or intranasally. In one embodiment, the pharmaceutical composition is administered subcutaneously to a subject at a dose of 300 mg or a dose of 600 mg.

In some embodiments, after the administering step, improvement in one or more nasal polyp-related parameters selected from the group consisting of loss of smell, runny nose, posterior rhinorrhea and nasal peak inspiratory flow (NPIF). break out. In some embodiments, the improvement in one or more of loss of smell, runny nose, posterior rhinorrhea, and peak nasal inspiratory flow is achieved during the day (AM), at night (PM), or between AM and PM. occurs in both In some embodiments, the administering step is followed by a decrease in one or more of serum IgE levels, plasma eotaxin-3 levels, and serum thymic and activation-regulated chemokine (TARC) levels. In some embodiments, a reduction in one or more of total IgE levels, eotaxin-3 levels and ECP levels in the subject's nasal secretions occurs after the administering step.

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

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

A subject suitable for treatment with an IL-4R antagonist may have a total of at least 5 nasal polyps, including 2 or more nasal polyps present within each nostril prior to the administering step, and/or may suffer from one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity, NSAID hypersensitivity and Samter's triad; You may have had surgery for one or both sinusitis. In certain embodiments, the subject amenable to treatment is one or more selected from the group consisting of CSwNP, chronic sinusitis with bilateral nasal polyps, and CRSwNP (e.g., with or without asthma) has a state of Subjects suitable for treatment may or may not have asthma. In some embodiments, subjects suitable for treatment are indicated for FESS, indicated for revision surgery, or contraindicated for surgery.

In some embodiments, the administering step is followed by improvement in one or more nasal polyp-related parameters selected from the group consisting of loss of smell, runny nose, postnasal drip and NPIF. In some embodiments, the improvement in one or more of loss of smell, runny nose, posterior rhinorrhea, and peak nasal inspiratory flow occurs in AM, PM, or both AM and PM. In some embodiments, a reduction in one or more of serum IgE levels, plasma eotaxin-3 levels, and serum TARC levels occurs after the administering step. In some embodiments, a decrease in one or more of total IgE levels, eotaxin-3 levels and ECP levels in the subject's nasal secretions occurs after the administering step.

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

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

A subject suitable for treatment with an IL-4R antagonist may have a total of at least 5 nasal polyps, including 2 or more nasal polyps present within each nostril prior to the administering step, and/or may suffer from one or more conditions selected from the group consisting of sinusitis, rhinitis, asthma, aspirin hypersensitivity, NSAID hypersensitivity and Samter's triad; You may have had surgery for one or both sinusitis. In certain embodiments, the subject amenable to treatment is one or more selected from the group consisting of CSwNP, chronic sinusitis with bilateral nasal polyps, and CRSwNP (e.g., with or without asthma) has a state of Subjects suitable for treatment may or may not have asthma. In some embodiments, subjects suitable for treatment are indicated for FESS, indicated for revision surgery, or contraindicated for surgery.

In some embodiments, the administering step is followed by improvement in one or more nasal polyp-related parameters selected from the group consisting of loss of smell, runny nose, postnasal drip and NPIF. In some embodiments, the improvement in one or more of loss of smell, runny nose, posterior rhinorrhea, and peak nasal inspiratory flow occurs in AM, PM, or both AM and PM. In some embodiments, a reduction in one or more of serum IgE levels, plasma eotaxin-3 levels, and serum TARC levels occurs after the administering step. In some embodiments, a decrease in one or more of total IgE levels, eotaxin-3 levels and ECP levels in the subject's nasal secretions occurs after the administering step.

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

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

Other embodiments will become apparent from the drawings, tables and detailed description provided in this application.

FIG. 2 is a schematic representation of an example of a background treatment washout period in the treatment of an asthmatic patient. FIG. 2 graphically depicts the least squares (LS) mean change from baseline in bilateral endoscopic nasal polyp scores by visit in the intent-to-treat (ITT) population. Continuation of Figure 2-1. Continued from Figure 2-2. FIG. 2 graphically depicts the LS mean change from baseline in bilateral endoscopic nasal polyp scores by visit for a subgroup of patients with comorbid asthma in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in bilateral endoscopic nasal polyp scores by visit for the subgroup of patients without comorbid asthma in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in the 22-Item Sinus Assessment Test (SNOT-22) total score in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in the visual analogue scale (VAS) for severity of rhinosinusitis symptoms in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in daytime (AM) symptom scores for loss of smell in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in nighttime (PM) symptom scores for loss of smell in the ITT population. FIG. 4 graphically illustrates the LS mean change from baseline in the olfactory test in the ITT population. FIG. 4 graphically illustrates the LS Mean Change from Baseline in AM Symptom Score for blockage/obstruction in the ITT population. FIG. 4 graphically illustrates the LS mean change from baseline in PM symptom scores for blockage/obstruction in the ITT population. FIG. 2 graphically illustrates the LS mean change from baseline in AM symptom scores for runny nose in the ITT population. FIG. 2 graphically illustrates the LS mean change from baseline in PM symptom scores for runny nose in the ITT population. FIG. 2 graphically depicts the LS mean change from baseline in AM symptom scores for posterior nasal drip in the ITT population. FIG. 2 graphically illustrates the LS mean change from baseline in PM symptom scores for posterior nasal drip in the ITT population. FIG. 2 graphically illustrates the LS mean change from baseline in AM nasal peak inspiratory flow (NPIF) in the ITT population. FIG. 2 graphically depicts LS mean change from baseline in PM NPIF in the ITT population. FIG. 2 graphically depicts the mean percent change in serum total immunoglobulin E (IgE) from baseline with treatment in the ITT population. FIG. 2 graphically depicts serum thymic and activation-regulated chemokine (TARC) mean percent change from baseline with treatment in the ITT population. FIG. 2 graphically depicts the Fridericia-corrected (QTc) (MS) mean change from baseline by visit in the safety population. Subjective collaterals, including olfactory, as assessed by the University of Pennsylvania Olfactory Discrimination Test (UPSIT) (A), self-reported morning nasal congestion/blockage (B), and self-reported morning post-nasal drip (C). FIG. 2 graphically illustrates the results from the objective evaluation items. Continuation of Figure 21-1. FIG. 1 graphically illustrates endpoints in patients with asthma. Compared to placebo, dupilumab improved mean forced expiratory volume in liters (FEV1) percent (%) predicted and FEV1(L) (A), Asthma Control Questionnaire, 5 question version (ACQ-5) (B ), as well as significant improvement in endoscopic nasal polyp score (NPS) (C). Continuation of Figure 22-1. FIG. 2 graphically depicts pharmacodynamic biomarkers expressed in serum. Least-squares mean percent change from baseline in total IgE (A), thymic and activation-regulated chemokines (TARC) (B), eotaxin-3 (C) and blood eosinophil counts (D). Continuation of Figure 23-1. FIG. 2 graphically depicts pharmacodynamic biomarkers expressed in nasal secretions. Least square mean percent change from baseline in eotaxin-3 (A), IgE (B), eosinophil cationic protein (ECP) (C). Continuation of Figure 24-1.

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

Unless defined 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 with respect to a particular numerical value, means that the numerical value may vary from the stated value by no more than 1%. For example, as used herein, the phrase "about 100" includes 99 and 101 and all values between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

All publications mentioned herein are hereby incorporated by reference in their entirety for all purposes.

Methods of Treating Chronic Sinusitis with Nasal Polyps In certain aspects, the present invention provides methods of treating chronic sinusitis with nasal polyps/polyps (CSwNP). In another aspect, the present invention provides a method of treating chronic sinusitis without nasal polyps/polyps. As used herein, "chronic sinusitis"("CS") includes, but is not limited to, nasal obstruction, decreased or lost sense of smell, anterior and/or posterior rhinorrhea, facial pain and/or headache. Refers to an inflammatory condition of the sinuses characterized by any combination of specific symptoms, often over a period of years, including and its consequences. Formal diagnosis is based on sinus computed tomography (CT) scans and/or sinus endoscopy. Based on endoscopic evaluation, CS can be classified clinically as CS with nasal polyps/nasal polyps (CSwNP) or CS without nasal polyps/polyps.

In certain embodiments, an IL-4R antagonist described herein has chronic sinusitis with bilateral nasal polyps and persistent symptoms despite treatment with intranasal corticosteroids (INCS). and indicated for long-term treatment of symptomatic adults. In other embodiments, the IL-4R antagonists described herein can be used for long-term treatment of adults with bilateral nasal polyps and associated chronic sinusitis who have persistent signs and symptoms despite treatment with INCS. Adapted for treatment.

In certain aspects, the present invention provides methods of treating nasal polyps. As used herein, a "nasal polyp" is an overgrowth of tissue in one or more nasal cavities. The condition with nasal polyps is called "nasal polyps." About 80% of nasal polyps are highly edematous and filled with eosinophils. Nasal polyps may also present as fibrous, glandular, or cystic. Nasal polyps are teardrop-shaped growths that typically form within the nose and/or sinuses and block the sinuses and nasal passages.

In certain aspects, the invention provides methods of treating nasal polyps (NP). NP is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, arising from the natural oral route of the middle meatus. NP is a T helper cell-2 (Th-2) driven inflammatory process that affects the nasal mucosa and sinuses. High levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), ECP and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are typical. Commonly found in nasal polyps, eosinophils and their products are thought to be a hallmark of inflammation associated with nasal polyps. Eosinophils are the major inflammatory cells found in sinuses and nasal polyps, which are also associated with high levels of IgE.

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

As used herein, "bilateral NPs" means one or more N
refers to the presence of P.

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

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

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

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

As used herein, "allergic sinusitis" refers to a condition in which the body's immune system reacts to, for example, plant pollen, mold, dust mites, animal hair, industrial chemicals (including cigarette smoke), food , refers to sinusitis that occurs in response to specific non-infectious irritants such as medications and insect venoms.

As used herein, "non-allergic sinusitis" does not result from allergic reactions, e.g., from colds, allergies and tissue irritants (e.g., nasal sprays, cocaine, cigarette smoke, etc.) , refers to sinusitis. Less commonly, sinuses can also be blocked by tumors or growths.

The term "rhinitis" refers to allergic reactions such as to common allergens ("allergic rhinitis", eg, perennial allergic rhinitis) or to environmental irritants (non-allergic rhinitis). Symptoms of allergic rhinitis include sneezing; nasal congestion or runny nose; sinus pressure and pain or throbbing of the cheeks or nose; and itching of the nose, throat, eyes and ears.

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

As used herein, "non-allergic rhinitis" is rhinitis that is not caused by an allergic reaction, e.g., cigarette smoke and other pollutants, strong odors, harsh chemical environments, alcoholic beverages, colds, etc. , refers to rhinitis induced by factors such as nasal blockage, septal deviation, infection, and overuse of medications such as decongestants and/or nasal sprays. Symptoms of non-allergic rhinitis include narrowing or inflammation of the nasal passages leading to many of the same symptoms of allergic rhinitis.

As used herein, the term "rhinosinusitis" refers to a condition that has symptoms of both rhinitis and sinusitis. Rhinosinusitis includes acute rhinosinusitis and chronic rhinosinusitis. Acute rhinosinusitis is caused by infections, such as bacterial, viral or fungal infections, or by chemical irritation. Cigarette smoke-induced acute rhinosinusitis and chlorine gas-induced chronic rhinosinusitis are examples of acute rhinosinusitis. NP is most commonly associated with chronic rhinosinusitis (CRS), characterized by mucosal inflammation of the nasal and sinus cavities, with symptoms lasting longer 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 lasting longer than 8 weeks. The underlying causes of acute sinusitis and acute rhinosinusitis can lead to chronic sinusitis or chronic rhinosinusitis if the resulting inflammation persists for longer than 8 weeks. Chronic rhinosinusitis includes, for example, eosinophilic chronic hyperplastic rhinosinusitis.

Additional subcategories of chronic sinusitis (and chronic rhinosinusitis) include, for example, superantigen-induced eosinophilic chronic sinusitis (e.g., bacteriologically-produced diseases such as Staphylococcus aureus). allergic fungal sinusitis (e.g., sinusitis induced by fungi such as Aspergillus or Alternaria); Non-allergic fungal chronic eosinophilic sinusitis; and chronic eosinophilic sinusitis exacerbated by aspirin. Rhinosinusitis is further classified as allergic rhinosinusitis and non-allergic rhinosinusitis.

As used herein, "allergic rhinosinusitis" refers to rhinosinusitis that develops in response to exposure to one or more allergens.

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

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

Methods of Improving Parameters Associated with Nasal Polyps The present invention provides methods of improving one or more parameters associated with nasal polyps in a subject in need thereof, comprising interleukin-4 receptor (IL- 4R) A method comprising administering to a subject a pharmaceutical composition comprising an antagonist. In other words, the present invention provides interleukin-4 receptor (IL-4R) for use in improving one or more nasal polyp-related parameters in a subject in need thereof. ) including pharmaceutical compositions comprising the antagonist. For example, IL-4R receptor antagonists can reduce endoscopic nasal polyp score (NPS) in patients. A nasal polyp score of 0 indicates the absence of polyps. An NPS of 1 indicates the presence of a small polyp in the middle meatus that does not reach below the inferior margin of the middle turbinate. An NPS of 3 indicates a large polyp reaching the inferior margin of the inferior turbinate or an intermediate polyp to the middle turbinate. NPS of 4 shows a large polyp causing complete obstruction of the inferior nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nostril). Treatment with an IL-4R antagonist can reduce NPS by about 1 to about 8 points. For example, treatment with an IL-4R antagonist can reduce NPS by about 1 point or more, about 2 points or more, or about 3 points or more. In some embodiments, treatment with an IL-4R antagonist reduces NPS by about 1 point or percentage thereof; 2 points or percentage thereof; 3 points or percentage thereof; 4 points or percentage thereof; or a percentage thereof; 7 points or a percentage thereof; or 8 points or a percentage thereof.

Treatment with an IL-4R antagonist can decrease a patient's NPS compared to pretreatment NPS. In certain embodiments, NPS is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21% , about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30, about 31%, about 32%, about 33%, about 34 %, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, Reduced by about 95%, about 96%, about 97%, about 98% or about 99%, or any range between these numbers. Thus, in certain embodiments, NPS is about 1% to about 99%, or about 2% to about 98%, or about 3% to about 97%, or about 4% to about 96%, or about 5% to about 95%, or about 6% to about 90%, or about 7% to about 85%, or about 8% to about 80%, or about 9% to about 75%, or about 10% to about 70%, or about 11% to about 65%, or about 12% to about 60%, or about 13% to about 55%, or about 14% to about 50%, or about 15% to about 45%, or about 16% to about 40%, or about 17% to about 35%, or about 18% to about 34%, or about 19% to about 33%, or about 20% to about 32%
, or about 21% to about 31%, or about 22% to about 30%, or about 23% to about 29%, or about 24% to about 28%, or about 25% to about 27%, or about 25% ~26% reduction.

Reduction in NPS can be correlated with improvement in one or more other nasal polyp-related parameters. However, such correlation is not observed in all cases.

Other examples of "parameters associated with nasal polyps" include, but are not limited to: (a) 22-Item Sinus Assessment Test (SNOT-22) score; Rhinorrhea (runny nose), posterior nasal drip (postnasal drip) and loss of sense of smell; (c) number of nocturnal awakenings; (d) visual analogue score to assess severity of patient-rated rhinosinus symptoms. (VAS); (e) 5-Item Asthma Control Inventory (ACQ5) score, such as in patients with asthma; (f) Nasal Peak Inspiratory Flow (NPIF); (g) Olfactory test (University of Pennsylvania Olfactory Discrimination Test (UPSIT)) (h) physiological parameters measured such as by nasal endoscopy and CT scan; (i) Lund-Mackay score; and (j) three-dimensional volumetric measurements of the maxillary sinuses.

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

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

Individual and total nasal symptom scores. Symptoms as assessed by the subject were evaluated using a 0-3 classification scale (where 0=no symptoms, 1=mild symptoms, 2=moderate symptoms and 3=severe symptoms), blockage/obstruction, It is assayed by answering individual rhinosinusitis symptom questions in the morning and evening, including symptoms of anterior rhinorrhea, posterior rhinorrhea and loss of smell. Nasal symptoms may be assayed during the day (AM), night (PM), or both AM and PM.

Loss of smell can be tracked. Administration of an IL-4R antagonist is associated with, for example, a decrease in loss of smell from baseline compared to weeks 4-16 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist (i.e. acquisition of a smaller number). For example, a decrease (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline is the beginning of treatment. It can be seen at 4, 6, 8, 12 or 16 weeks later. Thus, for example, a reduction (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline may be associated with treatment can be seen at 4 weeks after the onset of . In a further example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline is associated with treatment can be seen at 6 weeks after the onset of In a further example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline is associated with treatment can be seen at 8 weeks after the onset of In a further example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline is associated with treatment can be seen at 12 weeks after the onset of In a further example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in loss of smell from baseline is associated with treatment can be seen at 16 weeks after the onset of Administration of an IL-4R antagonist to a subject in need thereof, e.g. , about 1.5, about 2.0, about 2.5 or about 3.0 reduction.

Reduction of clogs and/or blockages can be tracked. Administration of an IL-4R antagonist reduces clogging and/or occlusion from baseline compared to, for example, 4-16 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist (i.e., the Acquisition of smaller numbers on the scale). For example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in clogging and/or occlusion from baseline is associated with treatment. can be seen at 4, 6, 8, 12 or 16 weeks after the start of . Thus, for example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in clogging and/or occlusion from baseline is , can be seen at 4 weeks after the start of treatment. In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in clogging and/or occlusion from baseline is , can be seen at 6 weeks after the start of treatment. In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in clogging and/or occlusion from baseline is , can be seen at 8 weeks after the start of treatment. In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in clogging and/or occlusion from baseline is , can be seen at 12 weeks after the start of treatment. In a further example, a reduction in clogging and/or occlusion (e.g., from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) from baseline is Visible at 16 weeks after initiation of treatment. Administration of an IL-4R antagonist to a subject in need thereof reduces the blockage and/or obstructive symptom score from baseline at, for example, 4, 8, 12, or 16 weeks, by about 0.5, about 1.5, 1.5, 1.2, 1.2, 1.2, 1.2, 1.3, 1.3, 1.3, 1.3, 1.3, 1.3, 1.3, 1.3, 1.3, and 1.3. A reduction of 0, about 1.5, about 2.0, about 2.5, or about 3.0 or more can be caused.

A reduction in runny nose can be tracked. Administration of an IL-4R antagonist results in, for example, a reduction in nasal discharge from baseline (ie, less on the scale) compared to weeks 4-16 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. number acquisition). For example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) of nasal discharge from baseline is 4 days after initiation of treatment. It can be seen at weeks, 6 weeks, 8 weeks, 12 weeks or 16 weeks. Thus, for example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) of runny nose from baseline indicates initiation of treatment. See you in the next 4 weeks. In a further example, a decrease (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in nasal discharge from baseline is associated with initiation of treatment. Can be seen in 6 weeks later. In a further example, a decrease (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in nasal discharge from baseline is associated with initiation of treatment. Can be seen in 8 weeks later. In a further example, a decrease (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in nasal discharge from baseline is associated with initiation of treatment. Can be seen in the next 12 weeks. In a further example, a decrease (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in nasal discharge from baseline is associated with initiation of treatment. Can be seen at 16 weeks later. Administration of an IL-4R antagonist to a subject in need thereof, e.g. .5, about 2.0, about 2.5, or about 3.0 or more.

A reduction in posterior nasal drip can be tracked. Administration of an IL-4R antagonist results in, for example, a reduction in nasal discharge from baseline (ie, less on the scale) compared to weeks 4-16 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. number acquisition). For example, a reduction (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline is the beginning of treatment. It can be seen at 4, 6, 8, 12 or 16 weeks later. Thus, for example, a reduction (eg, from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline may be associated with treatment. can be seen at 4 weeks after the onset of . In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline is associated with treatment can be seen at 6 weeks after the onset of In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline is associated with treatment can be seen at 8 weeks after the onset of In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline is associated with treatment can be seen at 12 weeks after the onset of In a further example, a reduction (eg, from about 0.5 to about 1.0, about 1.5, about 2.0, about 2.5, or about 3.0) in postnasal drip from baseline is associated with treatment can be seen at 16 weeks after the onset of Administration of an IL-4R antagonist to a subject in need thereof, e.g. A reduction of about 1.5, about 2.0, about 2.5, or about 3.0 or more can be caused.

A measure of nighttime awakening is also tracked. For example, nocturnal awakening measures are rated according to the following scores based on the subject's self-assessment: 0 = no symptoms, slept through the night; 1 = slept well, but some discomfort in the morning; 2 = Awakened once due to symptoms of rhinosinusitis (including early awakening); 3 = woke several times due to symptoms (including early awakening); 4 = had trouble sleeping, due to symptoms Stay awake most of the night. Administration of an IL-4R antagonist, e.g., at least about 0.10 nocturnal awakenings per night from baseline in weeks 4 to 16 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist may result in a decrease in the average number of For example, a reduction in the frequency of overnight nocturnal awakenings from baseline of at least about 0.10 times per night can be seen at 4, 6, 8, 12 or 16 weeks after initiation of treatment. . Administration of an IL-4R antagonist to a subject in need thereof is, for example, about 0.10 times per night, 0.15 times per night, 0.15 times per night, at 4, 8, 12 or 16 weeks. 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night, 0 per night .50 0.55 per night 0.60 per night 0.65 per night 0.70 per night 0.75 per night 0.80 per night times, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night or more; It can cause a reduction in the average number of nocturnal awakenings in the evening. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof reduces the average number of nocturnal awakenings from baseline at week 4 to about 0.10 times per night per night. 0.15 times per night, 0.20 times per night, 0.25 times per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.1 per night 45 times per night 0.50 per night 0.55 per night 0.60 per night 0.65 per night 0.70 per night 0.75 per night , 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 per night, 2.0 per night or more more can cause a decrease. In a further example, administration of an IL-4R antagonist to a subject in need thereof reduces the average number of nocturnal awakenings per night from baseline to about 0.10 per night, 0 per night from baseline at week 8. 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night times, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night or more can cause a decrease in In a further example, administration of an IL-4R antagonist to a subject in need thereof reduces the average number of nocturnal awakenings per night from baseline at week 12 to about 0.10 per night and 0 per night. 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night times, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night or more can cause a decrease in In a further example, administration of an IL-4R antagonist to a subject in need thereof reduces the average number of nocturnal awakenings per night from baseline to about 0.10 per night, 0 per night from baseline at week 16. 0.20 per night, 0.25 per night, 0.30 per night, 0.35 per night, 0.40 per night, 0.45 per night times, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night or more can cause a decrease in

Visual Analogue Score (VAS). The VAS is a scale for assessing the severity of patient-rated rhinosinus symptoms on a scale of 1 to 10. Mild symptoms are indicated by a score of 0 to 3, moderate symptoms are indicated by a VAS score of >3 to 7, and severe symptoms are indicated by a VAS score of >7 to 10. Administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4, 6 or 12 weeks , causes a decrease in VAS score from baseline of 3.5 points, 4 points or more. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3 points in 4 weeks. Cause a decrease in VAS score from baseline of .5 points, 4 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3 points at 6 weeks. Cause a decrease in VAS score from baseline of 5 points, 4 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points at 12 weeks, 1
Cause a decrease in VAS score from baseline of points, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points or more. A decrease in VAS scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

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

The present invention includes therapeutic methods that result in a reduction in ACQ5 score from baseline of at least 0.10 points at 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, according to the present invention, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, at 4 weeks, 6 weeks or 12 weeks. 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, Cause a decrease in ACQ score from baseline of 0.75 points, 0.80 points, 0.85 points or more. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, Cause a decrease in ACQ score from baseline of 0.85 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0 points at 6 weeks. .35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0 Cause a decrease in ACQ score from baseline of .85 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0 points at 12 weeks. .35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0 Cause a decrease in ACQ score from baseline of .85 points or more. A decrease in ACQ scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

Nasal Peak Inspiratory Flow (NPIF). Nasal peak inspiratory flow (NPIF) represents a physiological measure of airflow through both nasal cavities during forced inspiration and/or expiration, expressed in liters/minute. Nasal inspiration largely correlates with the subjective sensation of obstruction and is used to monitor rhinorrhea. Administration of the IL-4R antagonist to a subject in need thereof is at about 0.10 liters/minute, 0.15 liters/minute, 0.20 liters/minute, 0.15 liters/minute, 0.20 liters/minute, at 4, 6 or 12 weeks. 25 l/min, 0.30 l/min, 0.35 l/min, 0.40 l/min, 0.45 l/min, 0.50 l/min, 0.55 l/min, 0.60 Increase in NPIF from baseline by liters/min, 0.65 liters/min, 0.70 liters/min, 0.75 liters/min, 0.80 liters/min, 0.85 liters/min or greater cause. Thus, in one example, IL-
Dosing of the 4R antagonist was about 0.10 liters/minute, 0.15 liters/minute, 0.20 liters/minute, 0.25 liters/minute, 0.30 liters/minute, 0.35 liters/minute over four weeks. min, 0.40 l/min, 0.45 l/min, 0.50 l/min, 0.55 l/min, 0.60 l/min, 0.65 l/min, 0.70 l/min , 0.75 liters/minute, 0.80 liters/minute, 0.85 liters/minute, or more causes an increase in NPIF from baseline. In further examples, administration of the IL-4R antagonist to a subject in need thereof is about 0.10 liters/minute, 0.15 liters/minute, 0.20 liters/minute, 0.25 liters/minute in 6 weeks. min, 0.30 l/min, 0.35 l/min, 0.40 l/min, 0.45 l/min, 0.50 l/min, 0.55 l/min, 0.60 l/min , 0.65 L/min, 0.70 L/min, 0.75 L/min, 0.80 L/min, 0.85 L/min or more in NPIF from baseline. In further examples, administration of the IL-4R antagonist to a subject in need thereof is about 0.10 liters/minute, 0.15 liters/minute, 0.20 liters/minute, 0.25 liters/minute in 12 weeks. min, 0.30 l/min, 0.35 l/min, 0.40 l/min, 0.45 l/min, 0.50 l/min, 0.55 l/min, 0.60 l/min , 0.65 L/min, 0.70 L/min, 0.75 L/min, 0.80 L/min, 0.85 L/min or more in NPIF from baseline. Increases in NPIF scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

University of Pennsylvania Olfactory Discrimination Test (UPSIT). UPSIT is a method for quantitatively evaluating human olfactory function. The test consists of a sample of odorants and the subject must describe the odor. Scores are based on the number of correct answers. The test distinguishes between patients with normal sense of smell (“normosmia”) and those with different levels of loss (“mild, moderate and severe microsmia”) or loss (“anosmia”). can be discerned. Administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4, 6 or 12 weeks , causing an increase in UPSIT score from baseline of 3.5 points or more. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3 points in 4 weeks. Cause an increase in UPSIT score from baseline of .5 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3 points at 6 weeks. Cause an increase in the UPSIT score from baseline of 5 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3 points at 12 weeks. Cause an increase in the UPSIT score from baseline of 5 points or more. Increases in UPSIT scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

physiological parameters. Efficacy of IL-4R antagonists is assayed by measuring the effect of intranasal and other physiological parameters, such as by nasal endoscopy or computed tomography (CT) scans.

Lund-Mackay score. The Lund-Mackay scoring system is based on localization with points given for opacity: 0=normal, 1=partial opacity, 2=complete opacity. These points are then applied to the maxilla, anterior ethmoid, posterior ethmoid, sphenoid and frontal sinus on each side. The middle meatus ostium route is graded as 0 = no obstruction or 2 = obstruction, yielding a maximum score of 12 per side. For patients with a missing middle meatus ostium (OC) (due to previous surgery), the location of the previous OC is considered and scored as if the OC was there. Administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points at 4, 6 or 12 weeks. 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 Cause a decrease in Lund-Mackay score from baseline of 0.85 points or more. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, Cause a decrease in Lund-Mackay score from baseline of 0.85 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0 points at 6 weeks. .35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0 Cause a decrease in Lund-Mackay score from baseline of 0.85 points or more. In a further example, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0 points at 12 weeks. .35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0 Cause a decrease in Lund-Mackay score from baseline of 0.85 points or more. A decrease in Lund-Mackay scores can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

Three-dimensional volumetric measurements of the maxillary sinuses. This value is used to calculate air volume (mL); mucosal volume (mL); percentage of sinus occupied by disease; and sidewall thickness in the maxillary sinus. Administration of an IL-4R antagonist to a subject in need thereof causes an increase in three-dimensional volumetric measurements.

Quality of life (QoL) questionnaire. Various QoL questionnaires, including Short-Form-36 (SF-36) questionnaire, Euroqol-5D (EQ-5D), questionnaire using materials related to nasal polyps and patient qualitative self-assessment are used to monitor the efficacy of IL-4R antagonists.

The SF-36 is a 36-item questionnaire that measures eight multi-item measures of health: physical functioning (10 items), social functioning (2 items), role limitations due to physical problems (4 items), Role limitation due to emotional problems (3 items), mental health (5 items), energy/energy (4 items), pain (2 items) and overall well-being (5 items). For each degree, the item scores were coded, summed and converted to a scale from 0 (worst considered health as measured by questionnaire) to 100 (best considered health). Two standardized summary scores can also be calculated from the SF-36; physical component summary (PCS) and mental health component (MCS).

The EQ-5D was developed by the EuroQol Group to provide a simple, universal measure of health for clinical and economic evaluation and inter-disease comparisons.
It is a standardized health-related quality of life questionnaire developed by Designed for self-completion by the patient, the EQ-5D consists of two parts, the EQ-5D Writing System and the EQ VAS. The EQ-5D writing system includes 5 degrees: mobility, self-care, usual activities, pain/discomfort and anxiety/depression; each degree has 3 levels: no problem, some problem, very much problem. can be. The EQ Visual Analog Scale (VAS) records the respondent's self-related health against a vertical visual analog scale. The EQ VAS "thermometer" has endpoints of 100 highest (highest possible health condition) and 0 lowest (worst possible health condition).

A questionnaire using materials related to nasal polyps is a questionnaire utilizing health care materials about nasal polyps, including specialist visits, emergency medical visits, sick leave, holidays, and the like.

Biomarkers associated with nasal polyps. Examples of biomarkers associated with nasal polyps include, but are not limited to, one or any combination of IgE, TARC, Eotaxin-3 and ECP. In certain embodiments of the invention, one or more nasal polyp-associated biomarkers are detected from a biological sample derived from a subject. A biological sample is any substance taken from a patient, including cultures, cells, tissues, blood, saliva, nasal secretions, cerebrospinal fluid, pleural fluid, milk, lymph, sputum, semen, needle aspirate, etc. One or any combination are included without limitation. Biological samples may be obtained using any method known in the art. For example, nasal secretions may be obtained from smears, nasal discharges, stamps, washes, swabs, brush scrapes, and the like.

Normal IgE levels in healthy subjects are less than about 100 kU/L (eg, as measured using the IMMUNOCAP® assay [Phadia, Inc. Portage, Mich.]). Accordingly, the present invention provides a The elevated serum IgE level, which is greater than about 3500 kU/L, greater than about 3500 kU/L, greater than about 4000 kU/L, greater than about 4500 kU/L, or greater than about 5000 kU/L, is treated with a therapeutically effective amount of IL-4R It includes methods of reducing by administering to said subject a pharmaceutical composition comprising an antagonist.

TARC levels in healthy subjects range from 106 ng/L to 431 ng/L, with a mean value of approximately 239 ng/L. (An exemplary assay system for measuring TARC levels is the TARC quantitative ELISA kit provided by R&D Systems, Minneapolis, Minn. as catalog number DDN00). Accordingly, the present invention provides a Serum TARC (e.g., serum TARC) levels of greater than /L, greater than about 4000 ng/L, greater than about 4500 ng/L, or greater than about 5000 ng/L are treated with a therapeutically effective amount of IL-4R It includes methods of reducing by administering to said subject a pharmaceutical composition comprising an antagonist.

Improvement in nasal polyp-related parameters, such as the nasal polyp-related parameters described above, can be expressed as a percentage. For example, scores can be improved by 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more.

Biomarker expression as discussed above can be assayed by detection of protein or RNA in serum. In some embodiments, the RNA sample is used to determine RNA levels (non-genetic analysis), e.g., to determine RNA levels of biomarkers; in other embodiments, the RNA sample is used for transcriptome sequencing. Used for sequencing (eg genetic analysis).

"Improvement in parameters associated with nasal polyps" includes an increase from baseline in one or more of NPIF, UPSIT, and/or SNOT-22 score, subject-assessed nasal congestion/obstruction, anterior Rhinorrhea (runny nose), posterior nasal drip (postnasal drip) and loss of smell; number of nocturnal awakenings; VAS score; Lund-Mackay score; and 3D volume score; or more decrease from baseline. As used herein, with respect to parameters associated with nasal polyps, the term "baseline" refers to numerical values of parameters associated with nasal polyps for a patient prior to or at the time of administration of the pharmaceutical composition of the present invention. means.

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

The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline indicates that the nasal-related parameter is "improving" (e.g., in some cases, the particular parameter being measured can be increased or decreased accordingly).

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" binds to or interacts with IL-4R when IL-4R is expressed on cells in vitro or in vivo Any agent that inhibits the normal biological signaling function of IL-4R. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, peptide-based IL-4R antagonists (eg, "peptibody" molecules), and IL-4R antagonists specific for human IL-4R. Antibodies or antigen-binding fragments of antibodies that bind are included.

The term "human IL-4R" (hIL-4R), as used herein, refers to IL-4 receptors type I and II, and IL-4Rα, a component of the IL-13 receptor system. Intended to refer to subunits. IL-4R antagonists, such as anti-IL-4Rα antibodies or antigen-binding fragments thereof, block the function of both IL-4 and IL-13 signaling.

The term "antibody" as used herein refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds; as well as multimers thereof (eg, IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or _VH ) and a heavy chain constant region. The heavy chain constant region comprises three domains, C _H 1, C _H 2 and C _H 3. 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 contains one domain (C _L 1). The V _H and V _L regions are further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each _VH and _VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences, or are naturally or artificially modified. Amino acid consensus sequences are defined based on side-by-side analysis of two or more CDRs.

The term "antibody" as used herein also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., as used herein, are any naturally occurring or , enzymatically available, synthetic or genetically engineered polypeptides or glycoproteins. Antigen-binding fragments of antibodies are prepared using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of the DNA encoding the variable and optionally constant domains of an antibody, e.g. , derived from the complete antibody molecule. Such DNAs are known and/or readily available, eg, from commercial sources, DNA libraries (including, eg, phage-antibody libraries), or synthesized. The DNA may be modified, for example, to place one or more variable and/or constant domains in an appropriate configuration, or to introduce codons, create cysteine residues, or alter, add or delete amino acids. For example, it is sequenced and manipulated chemically or by using molecular biology techniques.

(ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single chain Fv (scFv). (vi) a dAb fragment; and (vii) a minimal recognition unit consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or restriction. Included are the FR3-CDR3-FR4 peptides that are defined. Domain specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, bispecific antibodies, trispecific antibodies, tetraspecific antibodies, minibodies, nanobodies (e.g. Other engineered molecules such as monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also referred to herein as "antigen Included within the phrase "binding fragment".

An antigen-binding fragment of an antibody typically contains at least one variable domain. A variable domain can be of any size or amino acid composition and generally has at least one CDR flanked by, or in-frame with, one or more framework sequences. including. In antigen-binding fragments having a _VH domain associated with a _VL domain, the _VH and _VL domains are positioned relative to each other in any suitable arrangement. For example, the variable region may be dimeric and may contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, an antigen-binding fragment of an antibody 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 found within an antigen-binding fragment of an antibody include: (i) V _H −
(ii) _VH - _CH2 ; (iii) _VH - _CH3 ; ( _iv ) _VH - _CH1 - _CH2 ; (v) _VH - _CH1 - _CH 2-C _H 3; (vi) V _H -C _H 2-C _H 3; (vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _L -C _H 2; (xi) V _L -C _H 1-C _H 2; (xii) V _L -C _H 1-C _H 2- _{C H} 3; (xiii) _{V L -C H} 2 -C _H 3; and (xiv) V _L -C _L. In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains are either directly linked to each other or linked by a full-length or partial hinge or linker region. be. The hinge region comprises at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids. In addition, antigen-binding fragments of antibodies include the variable and constant fragments listed above that are non-covalently linked (e.g., by disulfide bonds) to each other and/or to one or more monomeric _VH or _VL domains. It may comprise homodimers or heterodimers (or other multimers) of any of the domain configurations.

As with whole antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). A multispecific antigen-binding fragment of an antibody typically comprises at least two different variable domains, wherein each variable domain can specifically bind a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be prepared using routine techniques available in the art to generate antigen-binding fragments of an anti-IL-4R antibody. adapted for use in the context of

The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype is selected based on 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. Nonetheless, the human antibodies featured in the present invention are subject to amino acid residues not encoded by human germline immunoglobulin sequences (e.g., random or site-directed mutagenesis in vitro or in vivo mutations introduced by somatic mutation of ). However, the term "human antibody" as used herein includes antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been grafted onto human framework sequences. not intended.

The term "recombinant human antibody" as used herein refers to any human antibody that is produced, expressed, produced or isolated by recombinant means, e.g. Antibodies expressed using vectors (described further below), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), animals transgenic for human immunoglobulin genes (described further below) antibodies isolated from, e.g., mice (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or splicing of human immunoglobulin gene sequences to other DNA sequences. It is intended to include antibodies produced, expressed, produced or isolated by any other means. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if animals transgenic for human Ig sequences are used) and therefore The amino acid sequences of the _VH and _VL regions of the recombinant antibody are derived from and related to human _{germline VH and VL sequences} , but in
A sequence that may not be naturally present in the human antibody germline repertoire in vivo.

Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construction of about 150-160 kDa, wherein the dimer is held together by interchain heavy chain disulfide bonds. In a second form, the dimer is not linked via an interchain disulfide bond, and a molecule of approximately 75-80 kDa composed of covalently coupled light and heavy chains (half-antibodies). It is formed. These forms were very difficult to separate even after affinity purification.

The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with antibody hinge region isotypes. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed using the human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The invention encompasses antibodies with one or more mutations in the hinge, C _H 2 or C _H 3 regions, which are desirable, for example, to improve the yield of the desired antibody form during manufacturing.

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

Terms such as "binds specifically" mean that an antibody or antigen-binding fragment thereof forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4R, as used herein, has less than about 1000 nM, less than about 500 nM, less than about 500 nM, less than about 500 nM, as measured by a surface plasmon resonance assay, of IL-4R or portions thereof 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 Antibodies that bind with a K _D of less than, 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. Unless otherwise specified, KD is determined at a specified temperature, eg 20° _C , 25°C, 30°C, 37°C or 42°C. An isolated antibody that specifically binds human IL-4R may, however, have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

An anti-IL-4R antibody useful for the methods characterized herein will have a sequence in the framework and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody is derived. , may contain one or more amino acid substitutions, insertions and/or deletions. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention is a method comprising the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more framework and/or CDR regions is the corresponding residue in the germline sequence from which the antibody was derived, or the corresponding residue in another human germline sequence, or a conservative amino acid substitution of the corresponding germline residue (such sequence alterations are collectively referred to herein as "germline mutations"). One skilled in the art can readily produce large numbers of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof starting from the heavy and light chain variable region sequences disclosed herein. can do. In certain embodiments, all framework and/or CDR residues within the V _H and/or V _L domains are backmutated to those residues found in the germline sequence from which the antibody was derived. In other embodiments, only certain residues, such as only mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or found within CDR1, CDR2 or CDR3 Only mutated residues are backmutated to the original germline sequence. In other embodiments, one or more of the framework and/or CDR residues are corresponding residues in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). mutated into. Furthermore, an antibody may contain any combination of two or more germline mutations in the framework and/or CDR regions, e.g. Certain other residues that are mutated to the corresponding residue but differ from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations have improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties. It can be readily tested for one or more desired properties, such as (optionally) reduced immunogenicity. The use of antibodies and antigen-binding fragments obtained in this general fashion is encompassed within the invention.

The invention also includes the use of anti-IL-4R antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. Also includes For example, the present invention provides, for example, 10 or less, 8 or less, 6 or less, 4 or less, compared to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein. Includes use of anti-IL-4R antibodies that have HCVR, LCVR and/or CDR amino acid sequences that contain conservative amino acid substitutions such as.

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

The term "K _D ", as used herein, is intended to refer to the equilibrium dissociation constant for a particular antibody-antigen interaction.

The term "epitope" refers to antigenic determinants that interact with specific antigen-binding sites in the variable regions of antibody molecules known as paratopes. A single antigen may have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes arise from spatially adjacent amino acids from different segments of a linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain situations, epitopes may include sugar, phosphoryl or sulfonyl moieties on the antigen.

According to certain exemplary embodiments of the invention, the IL-4R antagonist is an anti-IL-4R antibody amino acid sequence described in US Pat. Nos. 7,608,693 and 7,605,237. An anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR) and/or a complementarity determining region (CDR) comprising any of the sequences. In certain exemplary embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof used in the context of the methods of the invention comprises a heavy chain complement of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1. A sex determining region (HCDR) and a light chain complementarity determining region (LCDR) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 is HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; contains the amino acid sequence of SEQ ID NO:8. In still other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises HCVR comprising SEQ ID NO:1 and LCVR comprising SEQ ID NO:2. In certain exemplary embodiments of the invention, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10. According to certain exemplary embodiments, the methods of the invention comprise the use of an anti-IL-4Rα antibody known in the art, termed dupilumab or a biological equivalent thereof.

The term "biological equivalent" as used herein refers to administration of the same molecule dose such that the effect is considered essentially the same as the comparable molecule, both in terms of efficacy and safety. It refers to molecules that have similar bioavailability (percentage and degree of availability) after administration, and under similar conditions (eg, same route of administration). Two pharmaceutical compositions comprising an IL-4R antagonist are bioequivalents if they are pharmaceutically equivalent, and they contain the same amount of active ingredient in the same dosage form for the same route of administration (e.g. , IL-4R antagonist) and meets the same or equivalent criteria. Bioequivalence can be determined, for example, by in vivo studies comparing pharmacokinetic parameters for two compositions. Commonly used parameters in bioequivalence studies include peak plasma concentration (C _max ) and area under the plasma drug concentration time curve (AUC).

Other anti-IL-4Rα antibodies of use in the context of the methods of the invention include, for example, AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), Antibodies known in the art or any of the anti-IL-4Rα antibodies described in US Pat. No. 7,186,809 or US Pat. No. 8,092,804 are included.

Anti-IL-4Rα antibodies used in the context of the methods of the invention may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use in the methods of the invention can exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody of the invention may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" refers to a pH of less than about 6.2, e.g. .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 including pH values below or below. 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 cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH"
is expressed as the ratio of the KD value for antibody binding to IL- _4Rα at acidic pH to the KD value for antibody binding to IL- _4Rα at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof is defined as "acidic relative to neutral pH" for purposes of the present invention if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral _KD ratio of about 3.0 or greater. It is considered to show reduced binding to IL-4Rα at pH. In certain exemplary embodiments, the acidic/neutral _KD ratio for an antibody or antigen-binding fragment of the invention is about 3.0, 3.5, 4.0, 4.5, 5.0, 5. 5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0. It may be 0, 70.0, 100.0 or more.

Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Furthermore, alteration of the antigen-binding domain at the amino acid level can give rise to antibodies with pH-dependent properties. For example, substitution of one or more amino acids in an antigen binding domain (e.g., within a CDR) with a histidine residue can result in an antibody with reduced antigen binding at acidic pH compared to neutral pH. can. As used herein, the expression "acidic pH" means a pH of 6.0 or less.

Pharmaceutical Compositions The present invention includes methods comprising administering an IL-4R antagonist to a patient, wherein the IL-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 provide for proper transport, delivery, tolerance, and the like. Suitable formulations can be found in formularies known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, Included are oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbowax. Powell et al.
of excipients for parental formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of antibody administered to a patient may vary according to the patient's age and size, symptoms, condition, route of administration, and the like. Preferred doses are typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment are adjusted. Effective dosages and schedules for administering pharmaceutical compositions comprising anti-IL-4R antibodies are determined empirically; eg, patient progress is monitored by periodic assessment and dosages are adjusted accordingly. Additionally, interspecies scaling of dosage is performed using methods well known in the art (eg, Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

Various delivery systems are known to administer pharmaceutical compositions containing IL-4R antagonists, including liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis. (see, eg, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The compositions are administered by any conventional route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (eg, oral mucosa, rectal and intestinal mucosa, etc.), and other biologically active agents. Administered with drugs.

Pharmaceutical compositions can be delivered subcutaneously or intravenously using standard needles and/or syringes (e.g., prefilled needles and/or syringes or needles and/or syringes filled from vials). . Additionally, for subcutaneous delivery, pen-type delivery devices readily have utility in delivering pharmaceutical compositions. Such pen delivery devices, including auto-injection pen delivery devices, may be reusable or disposable. Reusable pen delivery devices generally utilize replaceable cartridges containing pharmaceutical compositions. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge is easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device is then reused. There are no replaceable cartridges in disposable pen delivery devices. Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir within the device. When the reservoir is emptied of pharmaceutical composition, the entire device is discarded.

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

For direct administration to the sinus, pharmaceutical compositions containing IL-4R antagonists can be administered using, for example, microcatheters (eg, endoscopes and microcatheters), aerosolizers, powder dispensers, nebulizers or inhalers. administered as

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

Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, infusion, and the like. These injectable preparations are manufactured by known methods. For example, injectable formulations are prepared by dissolving, suspending or emulsifying the antibody or salt thereof in a sterile aqueous or oily medium conventionally used for injection. Aqueous vehicles for injection include, for example, isotonic solutions containing saline, glucose and other adjuvants, which include alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol). ), nonionic surfactants [e.g. Polysorbate 20, Polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. . Oily media include, for example, sesame oil and soybean oil, which are used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. Injections thus produced are usually filled into suitable ampoules.

The pharmaceutical composition can be delivered intranasally. As used herein, “intranasal” administration refers to administration of a pharmaceutical compound into the nasal cavity. Intranasal delivery can be accomplished using any method known in the art including, but not limited to, inhalation, spraying, stream irrigation, evaporative inhalation, nebulizing spray or nasal irrigation. Pharmaceutical compositions can be delivered intranasally using a syringe, dropper, squeeze bottle or spray (atomizer) device (eg, a syringe-driven atomizer or a pump-driven atomizer). Suitable pre-filled syringes that can be used for intranasal delivery include, but are not limited to, Carpuject™ (Hospira), Accuspray (BD Pharmaceutical Systems), Direct-Haler (Direct-Haler A/S), Go- Pumps, devices that atomize and spray mucous membranes, Veridoser (Mystic Pharmaceuticals), OptiNose (OptiNose US), ViaNase™ (Kurve technology), Nebu-Laser, and the like.

Advantageously, the pharmaceutical compositions for oral or parenteral use as described above are prepared in unit dosage forms suitable to suit the dosage of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

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

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

Combination Therapy Methods according to certain embodiments comprise administering to the subject one or more additional therapeutic agents in combination with the IL-4R antagonist. In other words, certain embodiments include one or more additional therapeutic agents in combination with an IL-4R antagonist for use in treating a subject. As used herein, the term "in combination with" means that the additional therapeutic agent is administered before, after, or at the same time as the pharmaceutical composition comprising the IL-4R antagonist. For example, when administered “prior to” a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent is administered at about 72 hours, about 60 hours, about 48 hours, after administration of the pharmaceutical composition comprising the IL-4R antagonist. About 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes before administration be done. When administered “after” a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent is administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 minute after administration of the pharmaceutical composition comprising the IL-4R antagonist. hours, 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 later. Administration "simultaneously" with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is a separate agent within less than 5 minutes (before, after, or at the same time) administration of the pharmaceutical composition comprising the IL-4R antagonist. or as a single combined dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

Additional therapeutic agents include, for example, another IL-4R antagonist, IL-1 antagonists (including, for example, IL-1 antagonists described in US Pat. No. 6,927,044), IL-6 antagonists, IL-1 antagonists, IL-1 antagonists, 6R antagonists (e.g. US Pat. No. 7,
582,298), IL-13 antagonists, TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists, IL-5 antagonists, IgE antagonists, CD48 Antagonists, antibiotics (eg, doxycycline), antifungals, leukotrienes, antihistamines, alpha-adrenergic decongestants, mucolytics, NSAIDs, long-acting beta- ₂ agonists (eg, salmeterol or formoterol), short term active β2 agonists, steroids (e.g. oral steroids), intranasal corticosteroids (e.g. mometasone furoate ( _MFNS ; e.g. Nasonex®)) or inhaled corticosteroids (e.g. fluticasone or budesonide) corticosteroids, such as allergen immunotherapy, or combinations thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is a combination comprising a long-acting beta- ₂ agonist and an inhaled corticosteroid (eg, fluticasone + salmeterol [eg, Advair® (GlaxoSmithKline )]; or in combination with budesonide plus formoterol [eg Symbicort® (Astra Zeneca)]).

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

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

The terms "initial dose," "secondary dose," and "tertiary dose" refer to the timeline of administration of the IL-4R antagonist. Thus, the "initial dose" is the dose administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary dose" is the dose administered after the initial dose; ' is the dose administered after the second dose. The initial, secondary and tertiary doses may all contain the same amount of IL-4R antagonist, but generally differ from each other in terms of frequency of administration. However, in certain embodiments, the amounts of IL-4R antagonist included in the initial, secondary and/or tertiary doses are varied relative to one another during the course of treatment (eg, adjusted upwards or downwards as needed). ).

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

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

In embodiments comprising multiple secondary doses, each secondary dose is administered with the same frequency as the other secondary doses. For example, each secondary dose is administered to the patient 1-2 weeks after the previous dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose is administered with the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient 2-4 weeks after the previous dose. Alternatively, the frequency with which the secondary and/or tertiary doses are administered to the patient may vary over the course of the treatment regimen. Dosage frequency is also adjusted during the course of treatment by the physician after clinical examination, depending on the individual patient's needs.

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

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

The subject in need thereof is further diagnosed with nasal polyps or a condition associated with nasal polyps, such as chronic sinusitis with nasal polyps, allergic or non-allergic rhinitis, or allergic or non-allergic rhinosinusitis. may be Diagnosis is based on one or more of the following: (a) 22-item sinus assessment test (SNOT-22) score; (b) nasal congestion/blockage, anterior rhinorrhea, posterior rhinorrhea as assessed by subject. (c) number of nocturnal awakenings; (d) visual analogue score (VAS) to assess severity of patient-assessed rhinosinus symptoms; (e) 5 items in patients with asthma (f) Nasal Polyp Score (NPS); (g) Nasal Peak Inspiratory Flow (NPIF); (h) Olfactory Test (University of Pennsylvania Olfactory Identification Test (UPSIT)); (i) Nasal Physiological parameters, such as measured by endoscopy and CT scan; (j) Lund-Mackay score; and (k) three-dimensional volumetric measurements of the maxillary sinuses.

The subject in need thereof is further diagnosed with chronic sinusitis with nasal polyps based on one or more of the following: (a) 22-Item Sinus Assessment Test (SNOT-22) score; (b) nasal congestion/obstruction, anterior rhinorrhea, posterior rhinorrhea, and loss of smell as assessed by subject; (c) number of nocturnal awakenings; (d) patient-assessed severity of rhinosinus symptoms (e) 5-item Asthma Control Inventory (ACQ5) score in patients with asthma; (f) Nasal Peak Inspiratory Flow (NPIF); (g) Olfactory test (University of Pennsylvania) (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) Lund-Mackay score; and (k) three-dimensional volumetric measurements of the maxillary sinuses.

For example, in certain embodiments, a "subject in need thereof" is a human patient with chronic symptoms of sinusitis in which at least two of the following symptoms are present: nasal blockage/obstruction/blockage. or nasal discharge (front/rear rhinorrhea); facial pain/pressure; and decreased or lost sense of smell.

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

In a related embodiment, a "subject in need thereof" is a subject who has been prescribed or is currently receiving an IL-4R antagonist prior to receiving an IL-4R antagonist, or a "background therapy" that is another medication. There may be. Background therapy may be, for example, an intranasal corticosteroid (INCS or ICS), such as mometasone furoate nasal spray (MFNS; Nasonex®). In some embodiments, the "subject in need thereof" has been prescribed INCS prior to receiving an IL-4R antagonist or in combination with a long-acting beta2 _- adrenergic antagonist (LABA). have or currently have asthma. Examples of INCS/LABA therapies include fluticasone/salmeterol combination therapy and budesonide/formoterol combination therapy. In some embodiments, background treatments include nasal saline, topical decongestants, local anesthetics, leukotriene antagonists or systemic antihistamines. In some embodiments, a "subject in need thereof" continues background therapy after the subject has received an IL-4R antagonist; - Stop receiving background therapy (eg, once or gradually) before receiving the 4R antagonist.

The following examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this invention, and are intended to assist the inventors in understanding the invention. It is not intended to limit the scope of what is considered. Efforts have been made to ensure accuracy with respect to numbers used (eg amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Example 1: Anti-IL-4R Antibody (mAb1) Administered Subcutaneously in Patients With Persistent Moderate to Severe Eosinophilic Asthma, Including Asthma Patients With Chronic Hypertrophic Eosinophilic Sinusitis A clinical trial of A. Study Objectives and Overview: A randomized, placebo-controlled, double-blind, parallel-group study was partially controlled/controlled with inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) treatment. Patients with persistent moderate-to-severe eosinophilic asthma who did not receive either 300 mg dupilumab (“mAb1”) or placebo subcutaneously once weekly for 12 weeks. Dupilumab is an anti-IL-4R antibody having a heavy chain variable region of SEQ ID NO:1 and a light chain variable region of SEQ ID NO:2. In certain exemplary embodiments, dupilumab comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10. Dupilumab is described in US Pat. No. 7,608,693.

The primary objective of the study was the reduction in the incidence of asthma exacerbations in patients with persistent moderate-to-severe eosinophilic asthma of mAb1 administered subcutaneously once weekly for 12 weeks compared to placebo. The purpose was to investigate the effect. The secondary objectives of this study were to assess the safety and tolerability of mAb1 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate-to-severe eosinophilic asthma and was to evaluate mAb1 serum concentrations after weekly subcutaneous dosing for 12 weeks in patients with moderate-to-severe eosinophilic asthma.

Prior to Screening, patients were required to have been on a stable dose of any of the following doses and regimens of ICS/LABA combination therapy (also referred to as "background therapy") for at least 1 month:
Fluticasone/Salmeterol combination therapy - Advair® Diskus - dry powder inhaler (DPI): 250/50 μg BID or 500/50 μg BID; or - Advair® HFA - metered dose inhaler (MDI): 230/42 μg BID or 460/42 μg BID; or budesonide/formoterol combination therapy (Symbicort® 160/9 μg BID or 320/9 μg BID); or mometasone/formoterol combination therapy (Dulera® 200/10 μg BID or 400/10 μg BID) BID).

Patients on budesonide/formoterol or mometasone/formoterol were switched to equivalent doses of fluticasone/salmeterol at randomization (Day 1) and patients on fluticasone/salmeterol were on background treatment remained the same.

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

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

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

Upon completion of 12 weeks of treatment with study drug (or after early discontinuation), patients were placed on fluticasone/salmeterol to control symptoms for an additional 8 weeks of off-study medication prior to final safety assessment. , budesonide/formoterol or mometasone/formoterol (dose at study entry) and the original dose of albuterol or levalbuterol as appropriate.

A schematic of the study protocol is given in FIG.

Adult patients were included in the study based on the following criteria: (1) Physician's diagnosis of persistent asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2009 guidelines; the airway inflammation may be eosinophilic; and (2) the asthma is partially controlled with inhaled corticosteroid/long-acting beta-agonist combination therapy according to the following criteria, or Not controlled: (i) Fluticasone/salmeterol combination therapy (DPI formulation: 250/50 μg BID or 500/50 μg BID or MDI formulation: 230/42 μg BID or 460/42 μg BID for at least 1 month prior to screening)
BID), or a stable dose of either budesonide/formoterol combination therapy (160/9 μg BID or 320/9 μg BID), or mometasone/formoterol combination therapy (200/10 μg BID or 400/10 μg BID); (ii) Screening Phase (iii) ≥1.5 and ≤3.0 Juniper Asthma Control Questionnaire (5-question version, ACQ) at Screening; Score; (iv) predicted normal with FEV1 50% or greater during the screening phase (up to 3 trials) and at randomization the day before the first dose (up to 3 trials); Within the previous 2 years, either treatment with one or more systemic (oral and/or parenteral) steroid bursts for asthma exacerbation, or hospitalization or emergency care visit for asthma exacerbation; and ( vi) Within 12 months of screening, documented reversibility meeting at least 12% and 200 mL (up to 3 trials) in FEV1 after 200 μg-400 μg albuterol (2-4 inhalations) during the criteria-screening phase or documented history of positive methacholine load (PD20 ≤8 mg methacholine) within 12 months prior to screening. Partially managed or managed with moderate to high dose combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT® or DULERA®) moderate to severe with blood eosinophils equal to or greater than 300 cells per microliter or sputum eosinophils equal to or greater than 3% during the screening phase of patients with asthma were included in the study.

Patients meeting all inclusion criteria were screened for the following exclusion criteria: (1) patients <18 years or >65 years; (2) clinically suggestive of unknown disease and requiring further evaluation; (3) chronic obstructive pulmonary disease (COPD) and/or other pulmonary diseases that impair pulmonary function testing; (4) requiring beta-adrenergic receptor blockers for any reason; (5) Current smoker or quit within 6 months prior to Screening; (6) History of smoking >10 packs per year; (7) Hospitalization or emergency care due to asthma exacerbation within 2 months prior to Screening. (8) Plan to initiate allergen immunotherapy within the study period; (9) Pre-screening period with less than 5 antibody half-lives but ≥30 days or unknown antibody half-life (10) previous enrollment in the current study; (11) if the patient is an investigator, a family member of the patient, (12) known or suspected non-compliance, alcohol or substance abuse; (13) inability to follow test procedures (e.g., due to language problems or psychological (14) reversal of sleep patterns (e.g., night workers); (15) treatment with drugs known to prolong the QTc interval; (16) ICS (e.g., active or inactive pulmonary tuberculosis); ) or concomitant serious illness contraindicating the use of LABA (e.g., diabetes, cardiovascular disease, hypertension, hyperthyroidism, thyrotoxicosis, etc.); (17) within 2 months prior to screening, or 6 prior to screening Use of more than 3 courses of injectable glucocorticosteroids or oral systemic glucocorticosteroids within a month; (18) alone or in combination with a non-steroidal controller (fluticasone/salmeterol combination therapy, (19) patients receiving prohibited concomitant medications (listed below); (20) doxycycline or related (21) unwillingness to become pregnant, breastfeed, or use effective methods of contraception during pregnancy or the study; and (22) recent history of parasitic infection or 6 months prior to screening. After Travel to parasite-endemic areas within.

During the first four weeks of the study, patients remain on a constant dose of background asthma therapy, after which the dose of background therapy is gradually reduced. First, the long-acting beta-agonist component of background therapy was withdrawn at week 4, then the inhaled corticosteroid dose was halved every 2 weeks for up to 12 weeks. Patients remained on study treatment until the end of the study or until withdrawal due to asthma exacerbation or any other reason.

B. Study Treatment Investigational Product: dupilumab or matching placebo. Formulation: Sterile dupilumab 150 mg/mL solution for SC injection was provided in 5 mL glass vials. Each vial contained 2 mL of drawable volume. Sterile placebos were provided in perfectly matched glass 5 mL vials. Route of administration: subcutaneous (SC) injection. Dose regimen: dupilumab 600 mg SC (loading dose) on D1, followed by weekly 300 mg SC injections for 15 weeks. Placebo SC loading dose on D1, followed by weekly SC injections for 15 weeks.

Non-Investigational Product (if applicable): Formulation: Mometasone furoate (NASONEX®) 50 micrograms/nasal spray actuation contained in bottle, which contained 18 g of formulation (140 actuations) . Route of administration: nasal spray. Dose Regimen: After Screening Visit (V1), all patients received mometasone furoate (NASONEX®) 50 μg/two actuations of nasal spray actuation (50 μg/actuation) in each nostril for 1 day. Received twice (total daily dose of 400 μg) or once daily (total daily dose of 200 μg) until the end of the post-treatment observation period.

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

C. Efficacy of Treatment The primary endpoint of this study was the development of asthma exacerbations defined by either: (1) 30% from baseline in morning peak expiratory flow (PEF) on 2 consecutive days; or (2) 6 or more additional seizure medication puffs of albuterol or levalbuterol (compared to baseline) in 24 hours on 2 consecutive days; or (3) (a ) systemic (oral and/or parenteral) steroid treatment, or (b) a 4-fold or greater increase in the last dose of ICS received prior to discontinuation from the study, or (c) hospitalization. Physician-determined exacerbation of asthma.

Study secondary endpoints included the mean change from baseline in the following parameters: assessed at baseline and treatment endpoint (week 12) to assess upper respiratory symptoms, (1 (2) morning and evening peak expiratory flow (AM PEF and PM PEF) in liters/min measured daily; (3) (4) five-item Asthma Control Questionnaire (ACQ5) score by visit; and (5) nocturnal awakenings measured daily (number of awakenings per night) ), and (6) the 22-Item Sinus Assessment Test (SNO
T-22). Secondary endpoints also included 6 or more additional seizure medication puffs of albuterol or levalbuterol (compared to baseline) in 24 hours on 2 consecutive days, and baseline in PEF in the morning on 2 consecutive days. The proportion of patients with combined asthma events defined by a 30% or greater drop from line was included. PEF, ACQ5, Asthma Symptom Score, Nocturnal Arousal, and Seizure Medication Treatment Use were obtained by electronic diary. Mean daily nocturnal awakenings ranging from 0 to 10 were averaged from the previous 7 days. Morning and evening asthma symptom scores consisted of unvalidated patient-reported outcomes rated on a 5-point Likert scale, with higher scores indicating worse outcomes (Table 2). Patients recorded global symptom scores twice daily before measuring PEF. Data are presented as averages for the 7 days preceding the specified time points.

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

An adverse event (AE) is any adverse medical occurrence in a subject who has received a drug or in a clinical study. Therefore, an AE is any unfavorable unintended symptom (including abnormal laboratory findings) temporally associated with the use of a medicinal product, whether or not it is considered to be associated with the medicinal product (investigational) product; It can be a symptom or disease. AEs may also be: Worsening of any pre-existing condition (i.e., any clinically significant change in frequency and/or intensity) temporally related to study drug use; and any adverse medical event.

Serious Adverse Events (SAEs) at any dose result in death; are life-threatening; require hospitalization or extension of current hospitalization; any adverse medical event that is a congenital anomaly/defect; or is a serious medical event.

E. Statistical Methods For the primary analysis of the proportion of patients experiencing asthma exacerbations, logistic regression models were used to compare the SAR group to placebo. The model included terms for treatment and stratification factors (preceding ICS/LABA combination therapeutic dose). The primary analysis was based on the modified intent-to-treat (mITT) population, which included all randomized patients who received at least one dose of mAb1. A stratified chi-square test was also used to confirm the primary analysis.

For secondary efficacy endpoints, with the exception of SNOT-22, changes from baseline were analyzed using a mixed effects model with a repeated measures (MMRM) approach. The model included change from baseline through week 12 as response variables, and factors for treatment (parameter effect), stratification factors, visits, interactions between visits and treatments, baseline values and visits. and baseline interactions. Statistical estimates for treatment comparisons for change from baseline at Week 12 were derived from a mixed effects model. Changes from baseline in SNOT-22 were analyzed using analysis using analysis of covariance (ANCOVA), with end-of-treatment measurements to impute missing data. Pharmacodynamic effects were assessed using the MMRM model in a post-hoc manner. No adjustment for multiplicity was made as there was only one primary endpoint and analysis. Safety variables including AEs, laboratory parameters, vital signs, ECG, clinical laboratory findings and physical examination were summarized using descriptive statistics.

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

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

(i) Primary Efficacy Endpoint The incidence of asthma exacerbations in the placebo and mAb1 treated groups is shown in Table 4.

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

The present study, as demonstrated by the need for immediate intervention in the form of treatment with either systemic corticosteroids or inhaled corticosteroids at doses four times or greater than the dose taken prior to the event. Of the 26 asthma exacerbations experienced during the period, 9 were considered severe. A summary of the incidence of severe asthma exacerbations is shown in Table 5.

As shown in Table 5, 8 severe asthma exacerbations were observed in the placebo group and only 1 severe asthma exacerbation was observed in the mAb1 treated group. The remaining 15 asthma exacerbations in the placebo group and 2 in the mAb1 group meet the protocol definition of an exacerbation based on decreased morning PEF and/or increased albuterol/lev-albuterol use. Within the active treatment group, sustained improvement over baseline was observed during the course of the study for all parameters despite steroid withdrawal.

mAb1 had a longer time to exacerbation and reduced risk of exacerbation compared to placebo (hazard ratio 0.10; 95% CI 0.03, 0.34; P<0.001). Analysis of time to asthma exacerbation by Kaplan-Meier plot showed that the effects of treatment with mAb1 persisted for longer periods, including after 8 weeks, when patients were at higher risk of developing exacerbations due to steroid withdrawal. made it clear that

Only one patient from the placebo group had a combined asthma event. A composite asthma event was defined as a reduction from baseline in the morning PEF on 2 consecutive days with 6 or more additional seizure medication puffs of albuterol or levalbuterol over a 24-hour period (compared to baseline) on 2 consecutive days. Defined as a decrease of 30% or greater.

(ii) Other Efficacy Endpoints Pulmonary function parameters (FEV1, AM PEF and PM PEF), asthma symptom-based endpoints (ACQ score, nocturnal awakening), and albuterol use were assessed for each patient at each visit. In addition, SNOT-22 scores were assessed at baseline and end of treatment. For all parameters, baseline and Week 12 (LOCF) mean values are summarized in Table 7, along with mean differences between treatment groups (ANOVA model for SNOT-22). In Table 7, the column labeled "Difference vs. Placebo" is the placebo correction from baseline to account for the observed change in the value of the parameter compared to the observed change for that parameter in the placebo-treated group. indicate a value.

Treatment with mAb1 resulted in a significant change from baseline in FEV1 at week 1, which was maintained through week 12 despite LABA and ICS withdrawal, and FEV1 at week 5 simultaneously with LABA withdrawal. decreased slightly. A similar improvement was observed in the morning PEF, but less so in the evening PEF. The least squares (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 scores improved in both treatment groups at week 1. However, although ACQ5 improved further with mAb1 between weeks 1 and 4, the placebo effect stabilized and maintained a difference up to 12 weeks.

Morning symptom scores increased from baseline to week 12 with placebo. With mAb1, there was an initial decline that remained below baseline by 12 weeks. A similar pattern (greater variability) was observed for nighttime asthma symptom scores.

Nocturnal awakening was stable from the placebo group until week 6, then increased from week 6 to week 12. In contrast, nocturnal awakening decreased in the mAb1 group by week 1 and remained improved relative to baseline by week 12.

Changes in albuterol/lev-albuterol use were similar to other secondary endpoints: return to baseline after initial decline with placebo. For mAb1, the initial decline was maintained over time.

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

For all secondary endpoints, week 12 measurements were significant in favor of mAb1 treatment (Tables 7 and 8), with the exception of nocturnal PEF and nocturnal awakening. A significant improvement with mAb1 was also observed for three SNOT-22 items associated with upper respiratory tract disease (Table 9).

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

No deaths were reported during the study period. Four treatment-emergent serious adverse events (SAEs) reported: 1 mAb1 patient experienced bipolar disorder, 3 placebo patients experienced asthma with pneumonia, gunshot wound with left pneumothorax and He experienced an SAE of a right ankle fracture. None of these SAEs were considered mAb1 related, and all but new ankle fractures resolved by the end of the study. There were no deaths.

A total of 6 patients discontinued the study due to TEAEs: 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). Angioedema TEAE occurred in a 42-year-old African American woman after the ninth dose of study treatment as a pruritic general rash observed at and away from the injection site. This persisted for 1 week and resolved after study treatment discontinuation and prednisone and diphenhydramine treatment. This was considered treatment related. This AE was after a milder rash at the injection site after the first and sixth doses of study treatment.

Among the most common AEs occurring in 3 or more patients in either treatment group (Table 10), injection site reactions, nasopharyngitis, nausea and headache occurred more frequently with mAb1 than with placebo. No clinically significant changes in vital signs, physical examination, laboratory tests or ECG findings were reported in either group.

G. CONCLUSIONS Significant improvements in lung function and other asthma management parameters were observed. Early and sustained efficacy was observed despite background treatment withdrawal. An approximately 87% relative reduction (p<0.0001) in the primary endpoint of the incidence of asthma exacerbations in patients with persistent moderate-to-severe asthma with eosinophilia compared with placebo (44.2%) ) after 12 weeks of treatment with 300 mg mAb1 once weekly (5.8%). As shown in Table 7, clinically meaningful and statistically significant (no multiplicity adjustment) improvements with treatment compared to placebo were observed in pulmonary function parameters (FEV1, PEF AM), asthma symptom score (ACQ ) and albuterol use. A beneficial trend was observed for PEF PM (p=0.0567) and nocturnal awakening (p=0.0518). A statistically significant (unmultiplicity-adjusted) improvement was also observed for SNOT-22 scores. Within the active treatment group, sustained improvement over baseline was observed during the course of the study for all parameters despite withdrawal of LABA and ICS. mAb1 was generally safe and well tolerated.

Example 2: Biomarker Studies Biomarker analyzes were performed on samples obtained from subjects who participated in clinical trials of mAb1 (see Example 1 above). Specifically associated with TH2 inflammation such as thymic and activating chemokines (TARC; CCL17), immunoglobulin E (IgE), eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils Serum/plasma biomarkers were measured in patient-derived samples at baseline and at different time points after initiation of study treatment. Baseline levels of these biomarkers were evaluated for their potential predictive value for treatment response. In addition, exhaled NO concentration (FeNO) and induced sputum eosinophils and neutrophils were measured as biomarkers of bronchial inflammation. Exhaled nitric oxide assessment was performed using a NIOX instrument (Aerocrine AB, Solna, Sweden) prior to spirometry and after at least 1 hour of fasting. Biomarkers were analyzed using mixed models and the least squares means derived from the models are reported below.

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

TARC, eotaxin-3 and IgE remained unchanged in response to placebo. In contrast, TARC (-22.7% vs. mean % change +0.3%; p=0.0003) and eotaxin-3 (-39.62% vs. mean % change 12.69%; p <0.0001) rapid decline was observed within 1 week in patients treated with mAb1 and persisted up to 12 weeks: TARC: +7.6% -26.0% vs. placebo (p=0) eotaxin-3: +5.13% -45.67% vs. placebo (p<0.0001).

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

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

Changes from baseline and placebo at week 12 for FeNO, TARC, eotaxin-3, and IgE all favored mAb1 (all P<0.001) (Table 11). No difference from baseline or between treatments was observed with YKL-40 or CEA.

There was a transient decrease in periostin levels followed by an increase with LABA/ICS withdrawal. Administration of mAb1 slowed the increase but did not prevent the increase over baseline. No consistent treatment effect was observed with CEA and YKL-40. The number of blood eosinophils remained unchanged until 6 weeks, but then increased at 8 and 12 weeks. Peripheral blood eosinophil counts did not change with placebo throughout treatment. Differences between treatments were not significant, and borderline increases were facilitated by greater blood eosinophilia in only a few patients treated with mAb1. Little or no increase was observed in most of the patients.

No conclusions could be drawn regarding the association between baseline biomarker levels and asthma exacerbations, as only 3 mAb1 patients experienced asthma exacerbations during the study.

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

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

Scatter plot analysis of change from baseline in baseline eosinophils vs. FEV1 at week 12 shows baseline eosinophils versus treatment effect, as measured by change from baseline in FEV1 at week 12 in the study population. (baseline eosinophils > 0.3 giga/L). Baseline eosinophils correlated with decreased ACQ and decreased albuterol/levalbuterol use. Periostin and YKL-40 at baseline correlated with decreased ACQ.

FEV1 change from baseline at Week 12 was exacerbated by ICS withdrawal (beginning at Week 4). A similar analysis suggested no association between baseline TARC or IgE and change from baseline in FEV1 at week 12 in the study population (baseline eosinophils > 0.3 giga/L). rice field.

Summary These results show that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, eotaxin-3 and IgE) and bronchial inflammation (FeNO) in adult asthmatics. The correlation between FeNO reduction and FEV ₁ improvement suggests a relationship between IL-4/IL-13 mediated anti-inflammatory activity and improved lung function in moderate to severe uncontrolled asthma.

Example 3. Clinical Trial of Subcutaneously Administered Anti-IL-4R Antibody (mAb1) in Patients With Bilateral Nasal Polyps and Chronic Symptoms of SinusitisA. Study Objectives and Summary The positive effect of mAb1 on the SNOT-22 test described in Example 1 suggests that anti-IL-4R antibodies may also be effective in treating chronic sinusitis associated with nasal polyps. bottom. Furthermore, nasal polyps are most commonly eosinophilic/TH2 driven and mAb1 significantly reduced biomarkers associated with Th2 inflammation (see Example 2). Therefore, a clinical trial was designed to test the therapeutic effect of mAb1 on chronic sinusitis associated with nasal polyps.

A randomized, double-blind, phase 2, placebo-controlled, two-treatment arm study was conducted in patients with chronic sinusitis with nasal polyps (bilateral nasal polyps and chronic symptoms of sinusitis) for 16 weeks. A study was conducted to evaluate mAb1 administered subcutaneously (SC) once a week (QW) over the course of the day.

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

mAb1 was administered concurrently with mometasone furoate nasal spray (MFNS) (NASONEX® 50 micrograms/actuation twice daily, twice per nostril). Because of the high comorbidity of NP with asthma, aspirin/nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity and previous surgery, patients were not enrolled in the study unless they presented one of the following exclusion criteria: was allowed. Sixty patients were randomized into two treatment groups with 30 patients per group. Recruitment of NP patients without comorbid asthma when randomizing approximately 30 patients without asthma to ensure that at least 30 patients with comorbid asthma are included in this study stopped. Ultimately, there were 35 patients with asthma who entered the study and 25 patients without asthma who entered. Both patients and investigators were blinded to their assigned treatment groups.

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

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

A number of secondary efficacy endpoints were measured to more comprehensively assess the efficacy of mAb1. The study included SNOT-22 score, loss of sense of smell (daily AM/PM daily assessment), olfactory test (UPSIT), subject-assessed rhinitis symptoms (daily AM/PM assessment), Lund-Ma
ckay sinus CT scan score (central reading), nasal peak inspiratory flow (daily AM/PM assessment) and responder analysis (defined as 1 or 2 point improvement in total NPS at week 16 compared to baseline) checked for improvement.

Together with exploratory subgroup analyzes and biomarkers, these endpoints informed the therapeutic value of mAb1 in reducing nasal polyp scores and improving symptoms in NP and its subsets. The durability of the effect was also examined throughout the 4-month post-treatment evaluation period.

The 300 mg QW dose regimen met the apparent target-mediated clearance level (10-15 mg/L). This regimen has been tested and provided statistically significant and clinically relevant responses in two previous evidence of concept studies conducted with mAb1 in asthma and atopic dermatitis (e.g. (see Example 1, USSN 61/805797 and USSN 61/816191). The first dose utilized a loading dose of 600 mg to achieve steady state concentrations more quickly. This loading dose range was supported by the acceptable safety profile of the highest loading dose (600 mg) demonstrated in previous studies conducted in healthy Japanese subjects.

Furthermore, the Cmax after a loading dose of 600 mg was about 70 mg/L, the steady state Ctrough of 300 mg QW was about 150 mg/L, and the proposed dosing regimen (i.e., 600 mg ) after Cmax of 12 mg/kg
Given that the IV dose (421 mg/L) is below the mean Cmax, the highest single dose tested in well-tolerated healthy subjects, this dose regimen has an acceptable safety profile provided additional confidence that it should.

Patient inclusion criteria included (i) physician endoscopic diagnosis of bilateral nasal polyps for at least 8 weeks prior to screening (i.e., despite completion of previous intranasal corticosteroid (INCS) treatment; (ii) the following symptoms prior to screening: nasal blockage/obstruction/congestion or nasal rhinorrhea); facial pain/pressure; and decreased or lost sense of smell.

Patients meeting these criteria were screened for the following exclusion criteria: age <18 years or >65 years; any technical/administrative reason that patients could not be randomized in the study; SNOT22 score less than 7; any other investigational drug or prohibited for this study within 2 months prior to screening or 5 half-lives, whichever is longer Receiving oral corticosteroids (OCS) or intranasal corticosteroid drops within 2 months or 1 month prior to Screening, or taking OCS for another condition during the study period. treatment with mAB or immunosuppressive therapy; treatment with anti-immunoglobulin E (IgE) therapy (e.g., omalizumab) within 130 days of Visit 1; for ≥30 days prior to Visit 1 Treatment with a leukotriene antagonist/modifier for patients who did not continue continuous treatment; initiation of allergen immunotherapy within 3 months prior to Visit 1 or planning to initiate treatment during the Screening or Randomization Treatment Period; Any nasal surgery within 6 months prior to screening or more than 5 sinus surgeries in the past, up to 2 of which were surgeries that altered nasal wall structure; or patient was unable to assess the primary efficacy endpoint. Clearing conditions/comorbidities (e.g., posterior nostril nasal polyps; nasal septal deviation obstructing at least one nostril; acute sinusitis, nasal infection or upper respiratory tract infection at screening or 2 weeks prior to screening; ongoing medications Churg-Strauss syndrome, Young's syndrome, Kartagener's syndrome or ciliary dyskinesia syndrome, cystic fibrosis; signs of allergic fungal rhinosinusitis or suggested by CT scan). Patients with comorbid asthma were excluded if: the patient had a forced expiratory volume (FEV1) less than 60%; systemic (oral and/or parenteral) steroid treatment or hospitalization (24 an exacerbation requiring a >1000 μg dose of fluticasone or an equivalent dose of inhaled corticosteroids occurred within 3 months prior to screening; Other exclusion criteria included patients with a predicted short lifespan (less than 6 months); patients taking concomitant treatments prohibited in the study; women who are pregnant or intend to become pregnant during the study. or including lactating women. Other exclusion criteria include concurrent severe illness (e.g., active and inactive pulmonary tuberculosis, diabetes mellitus, etc.); diagnosed active parasitic infection; suspected or high risk of parasitic infection; human immunodeficiency History of viral (HIV) infection or positive HIC screening at visit 1; evidence of acute or chronic infection; Known or suspected immunosuppression, including history of pneumocystis, pneumocystis, aspergillosis); live vaccination within 12 weeks prior to Visit 1 or planning vaccination during study; active autoimmune disease or autoimmune disease (e.g., Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis) patients with positive or indeterminate hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibody at Visit 1; and liver injury-related criteria (e.g., Patients with underlying hepatobiliary disease or ALT>3 ULN) are included.

B. Study Treatments Study Drug: Various concentrations of sterile mAb1 were provided in 5 mL glass vials. Each vial contained 2 mL drawable volume: 150 mg/mL solution (300 mg dose/2 mL). Sterile placebos were provided in identically matched glass 5 mL vials, each vial containing a deliverable volume of 2 mL.

mAb1 was administered every 7±2 days (QW). Dosing of mAb1 was spaced at least 5 days to avoid overdosing. Two injections were given at Visit 2 (V2). After V2, a single injection of mAb1 was given once weekly at the study site throughout the randomized treatment period. mAb1 was administered after clinical treatment and blood collection. After each dose, patients were monitored for at least 1 hour for any signs or symptoms of local site injection or hypersensitivity reaction. Subcutaneous injection sites were alternated between the abdominal quadrant (avoiding the navel and hips) or the upper thigh so that the same site was not injected consecutively twice/week.

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

Screening Period: Prior to Screening, subjects continued on stable dose intranasal corticosteroids (INCS) at least 2 months prior to Visit 1 (V1). Patients were switched to MFNS if they had used an alternative INCS formulation other than MFNS prior to the screening visit at V1. After V1, all patients entered a 4-week run-in period, unless they could not tolerate BID INCS, in which case they remained on the low-dose (QD) regimen, MFNS: twice daily (BID) Each nostril received two actuations (50 μg/actuation) (400 μg total daily dose). To be accepted into this study, patients must have the following symptoms prior to Screening: Nasal blockage/obstruction/congestion or nasal discharge (pre/postnasal drip); +/- facial pain/pressure or +/- decreased sense of smell. Or at least two of the losses were present.

Treatment Period: The treatment period proceeded as indicated in the study flow chart in Table 14.

During the treatment period, patients remained on stable dosing of mometasone furoate: two actuations of MFNS in each nostril BID or QD (if patients cannot tolerate high doses). At Visit 2, patients completed the SNOT-22 test in patients with asthma, VAS and QoL questionnaires (SF-36, EQ-5D, questionnaire using materials related to nasal polyps), olfactory test and ACQ- Received 5.

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

Temporary treatment discontinuation was considered by the investigator due to a suspected adverse event (AE). Resumption of treatment with mAb1 if study inclusion criteria are still met at the time the investigator considers mAb1 to be unlikely to cause the related event according to his/her best medical judgment were performed under close and appropriate clinical/and/or laboratory monitoring.

An AE was any adverse medical event in a patient or clinical trial patient to whom the drug was administered and which did not necessarily have a causal relationship to this treatment.

Serious adverse events (SAEs) were fatal or life-threatening at any dose (the term "life-threatening" in the definition of "serious" means that the patient was at risk of death at the time of the event) refers to an event; not an event hypothesized to be potentially fatal if more severe); permanent, requiring hospitalization for treatment or an extended period of hospitalization or any adverse medical event resulting in significant disability/disability or congenital/birth defect or was a medically significant event. Medical and scientific judgments are not immediately life threatening, do not result in death or hospitalization, but may endanger the patient or have other consequences as described in the definition above. determine whether expedited reporting is appropriate in other circumstances, such as a significant medical event that may require intervention (i.e., specific measures or corrective action) to prevent one of (The following list of medically significant events is intended to serve as a guideline for determining which conditions should be considered medically significant events). The list was not intended to be comprehensive: Intensive care in the emergency room or at home: allergic bronchospasm, anaphylaxis, blood disorders (i.e., agranulocytosis, aplastic anemia, myelodysplasia, bone marrow) dysplasia, pancytopenia, etc.), convulsions (seizures, epilepsy, epileptic seizures, absence, etc.), development of drug dependence or abuse; Suggestion of any event of suicidal attempt or suicidality; syncope, loss of consciousness (unless documented as a result of blood sampling); bullous skin rash; diagnosed during or on study chronic neurodegenerative disease (newly diagnosed) or worsened during study (particularly judged abnormal/serious by the investigator in studies evaluating the effects of study drugs in these diseases) only if you have

Post-Treatment Period: Upon completion of the randomized treatment period (or after premature discontinuation of mAb1), patients continued treatment with a stable dose of MFNS maintained over the randomized treatment period or Treatment was modified based on human judgment.

The following concomitant treatments were not allowed during the Screening and Randomized Treatment Periods: Intranasal medications that interfere with symptoms of disease except nasal saline (antihistamines, nasal atropine, ipratropium bromide, nasal systemic corticosteroids; decongestants (topical or systemic) excluding previous endoscopies; long-term use of systemic antibiotics (2 weeks or longer); lipoxygenase inhibitors; any immunosuppressive treatment including but not limited to methotrexate, cyclosporine, mycophenolic acid, tacrilomus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (IgE) therapy (omalizumab); and aspirin or NSAIDs in patients with hypersensitivity to aspirin.

The following concomitant treatments were allowed: MFNS during screening and throughout the study; nasal saline; ), and local anesthetics (e.g., lidocaine allowed prior to endoscopy); short-term (less than 2 weeks) use of antibiotics; and SABA, LABA and methylxanthines (e.g., theophylline) for patients with asthma. , aminophylline). The following inhaled corticosteroids have been tolerated in patients continuing on a stable dose of ≤1000 μg fluticasone (or an equivalent dose of another inhaled CS; see Table 16) for 30 days prior to Visit 1: Only patients who continued stable doses for ≥ 30 days were allowed: leukotriene antagonists/modifiers were allowed only for patients who were on continuous treatment for ≥ 30 days prior to Visit 1 during the study; histamine; and initiation of allergen immunotherapy (nominal allergen immunotherapy allowed for >3 months prior to Visit 1).

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

Nasal endoscopy was performed at the end of the scheduled visit and preceded topical administration of an anesthetic combined with a decongestant. A standard video sequence was downloaded or sent to a centralized reader. Centralized image data evaluation and scoring by an independent physician reviewer of the image data was performed for all endoscopies. Only the V1 central read was made available to the site to confirm eligibility in V2. Final results of center readings were made available after the study.

For the analysis of the primary endpoint, the central V2 reading was used for comparison with the end-of-treatment (EOT) reading. The site removed subject-identifying information from the image data headers prior to sending the image data to the central reader.

Secondary endpoints of the study were patient-reported symptoms (including SNOT-22); subject-assessed nasal congestion/blockage, anterior nasal drip (runny nose), posterior nasal drip (postnasal drip), and sense of smell. (daily AM and PM electronic diary) monthly mean; number of nocturnal awakenings; severity of patient-related rhinosinus symptoms using a visual analogue scale (VAS); 5 items in the asthma subgroup Nasal peak inspiratory flow (NPIF); Olfactory test (UPSIT); NPS in patients with comorbid asthma; CT scan assessment; Spirometry (overall and subgroups with asthma); time to first response (≥1 point improvement) in ; time to study treatment discontinuation; and change from baseline at 16 weeks in incidence of treatment discontinuation due to OCS or need for nasal surgery .

Quality of life (QoL) endpoints were based on a 36-item short-form health survey (SF36); the European Quality of Life Scale (EQ-5D); and a questionnaire using materials related to nasal polyps at 16 weeks. Including variations from the line.

Disease-specific efficacy measurements include: computed tomography (CT). Sinus CT was performed at EOT prior to V2. For both maxillary sinus Lund-Mackay scores and 3D volumetric measurements, the same acquisition (sequence) was used for centralized image data evaluation, and the image data was scored by an independent physician reviewer. Center readings of V2 were used for comparison with EOT. Final results of central readings were made available after the study.

For three-dimensional volumetric measurements of the maxillary sinuses, pre-V2 central readings were used for comparison with EOT readings. The site removed subject-identifying information from the image data headers before sending the image data to the central reader. The % change in EOT turbidity was calculated from the BL.

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

Three NPIF attempts were performed by the patient; all three values were recorded by the patient in an electronic diary and the highest value was used for evaluation. Baseline AM NPIF was the mean AM measurement recorded during the 28 days prior to the first dose of study drug, and baseline PM NPIF was recorded during the 28 days prior to the first dose of study drug. It was an average PM measurement.

To rate disease-specific daily symptoms, patients scored on: a categorized scale from 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms. ) to question individual rhinosinus symptoms morning and night, including symptoms of congestion and/or obstruction, anterior nasal drip (runny nose), posterior nasal drip (postnasal drip), and loss of sense of smell. used an electronic diary to answer The number of nocturnal awakenings was also recorded.

The same safety assessment was applied across all treatment groups. Adverse events, including SAEs and adverse events of special interest (AESIs), were collected at each visit.

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

Optional sampling for DNA and RNA preliminary analysis that required separate pharmacogenetic informed consent.

Pharmacokinetics. Functional mAb1 and anti-mAb1 antibodies in serum were assayed by ELISA. Concentrations of Predose Functional mAb1 in Serum at Visit 2 (Day 1), mAb1 Trough Concentrations at Weeks 2, 4, 8, 12, 16 and Weeks 20, 24, 28 and 32 A follow-up serum mAb1 was provided. Anti-mAb1 antibody status (negative or titer value) at Visits 2 (day 1), Weeks 2, 4, 8, 12, 16 and 32 was also provided. Patients with ADA titers greater than or equal to 1000 at the end of the study visit were scheduled to return approximately 6 months later for further evaluation of ADA titers. Further follow-up was considered based on antibody titers and gross evaluation of clinical findings.

pharmacodynamics. Since secretion of specific proteins is at least partially Th2 cytokine-dependent and associated with chronic inflammation of airway mucosa, including sinus tissue, the expression of specific biomarkers was assayed to monitor the therapeutic efficacy of mAb1. These biomarkers were also evaluated for their value in predicting toxicity and/or recording the time course of drug response. Values used as baseline were collected on Day 1 (pre-dose assessment).

Nasal discharge was obtained by inserting nasal swabs into the bilateral nostrils for 5 minutes. Nasal secretions were saved for possible analysis of additional biomarkers associated with nasal polyps and response to mAb1 treatment.

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

Biopsied nasal polyp tissue was evaluated for various biomarkers of inflammation and disease processes or responses. For example, RNA was extracted and used for expression profiling (eg, microarrays, transcriptome sequencing or quantitative RT-PCR, etc.).

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

Analysis of the proportion of patients with binary events. The proportion of patients with a binary event was assessed: ≥1 point improvement (decrease) in NPS at Week 16 (central reading); 10% or greater improvement in CT opacification from baseline at Week 16; Oral CS or surgery-induced decline; or increase in INCS after 8 weeks as response variable and treatment group, pooled country/region and pre-study stratification factor as covariate, respectively, logistic model with above response. was analyzed using

Analysis of time-event changes. Time-event (e.g., first response with ≥1 point improvement (decline) in NPS, study treatment discontinuation, etc.) as dependent variables, time-event and treatment, pooled country/region, pre-study as covariate were analyzed using the Cox regression model with asthma comorbidity. The Kaplan-Meier method was used to derive the proportion of patients with events unique to each treatment group at weeks 4, 8, 12 and 16. For analysis during the treatment period, if a patient had no events prior to treatment interruption/completion, the patient was considered event free until the end of the treatment period (day of last dose + 7 days).

Analysis of change from baseline for continuous variables. Lund Mackay score for patients with comorbid asthma; SNOT-22; subject-assessed obstruction and/or obstruction score; NPIF; ACQ-5 in patients with comorbid asthma; 5D) and changes from baseline at week 16 in VAS were analyzed using the same MMRM as the primary endpoint. Descriptive statistics including number of patients, mean, standard error and LS mean were provided. In addition, LS means, corresponding 95% Cl and p-value differences were provided for comparison of each dose to placebo.

Analysis of efficacy at baseline biomarkers of a defined subset. To examine baseline biomarkers for their potential value for predicting treatment response, analysis of change in NPS was also performed on the total ITT population and selected pooled doses by the following subsets and each dose group: It was performed on groups.

Subgroup analysis. To assess the consistency of treatment effects across subgroup levels and examine baseline biomarkers for their potential value for predicting treatment response, preliminary subgroup analyzes were conducted for age group, gender, region, race, INCS dose level,
Baseline NPS, baseline CT scan score, asthma comorbidity and change from baseline in NPS for selected biomarkers before the study were performed.

Anti-mAb1 antibody result (negative or antibody titer) terms were presented by patient, time point and treatment group. ADA titer levels were categorized: low, medium and high. A low ADA titer was defined as a titer less than 1000; a moderate ADA titer was defined as a titer between 1000 and 10,000; a high ADA titer was defined as a titer greater than 10,000. defined as value.

Anti-mAb1 antibody assay results are listed by category. The following summaries are provided for patients who had any positive ADA assay response during the TEAE period; and patients who had a treatment-induced positive ADA assay response during the TEAE period. Patients with treatment-induced positive ADA assay responses during the TEAE period were further described as patients with transient positive responses and patients with persistent positive responses. Patients with any positive ADA assay response during the TEAE period were defined as having at least one sample positive in the ADA assay.

Treatment-induced positive ADA assay response: Patients without a positive assay response at baseline but with a positive assay response during the TEAE period or patients with a positive ADA assay response at baseline and also during the TEAE period defined as patients with at least a 4-fold increase in titer during .

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

Statistical Analysis A pre-specified primary analysis was performed at the end of the 16-week treatment period. Efficacy analyzes were performed using an intention-to-treat (ITT) population, pre-defined as all randomized patients, regardless of whether they received study treatment. Safety analyzes were performed using a pre-defined safety population of all randomized patients exposed to the study drug, regardless of the amount of treatment administered.

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

CT scan data were collected at both baseline and 16 weeks. Changes from baseline to week 16 in Lund-Mackay total score (left sinus plus right sinus sum) were analyzed using the ANCOVA model. Factors in this model included treatment, stratification factor, and baseline value as covariates. To further evaluate the effect of dupilumab treatment on nasal polyp disease, responder analyzes were performed using logistic regression analysis with terms for treatment and stratification variables. Two categories of response were predefined; a decrease in NPS of ≥1.0 units or ≥2.0 units from baseline at 16 weeks.

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

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

Primary endpoint. The primary analysis compared the dupilumab-treated group with the placebo group. The primary efficacy assessment was the change from baseline at 16 weeks in bilateral endoscopic NPS in the ITT population using mixed effects model (MMRM) analysis with repeated measures.

The least squares (LS) mean (SE) change from baseline at Week 16 was −0.30 (0.34) in the placebo group and −1.85 (0.30) in the dupilumab group, resulting in The LS mean difference was −1.55 (95% CI, −2.43 to −0.67, p=0.0009) in favor of dupilumab (Table 17, Table 52 and FIG. 2A). A pre-specified responder analysis showed that a change in NPS of 1 point (NPS1 score) or greater was observed in 70% of patients receiving dupilumab versus 20% of patients receiving placebo, with an odds ratio (OR) of was 9.5 (95% CI, 2.8-31.8, p=0.0003). A change of ≥2 points (NPS2 score) was observed in 10% of patients receiving placebo and 53.3% of patients receiving dupilumab, OR=10.6 (2.6-43.6, p=0 .001) was obtained (Table 19). Changes in NPS persisted at the end of the 16-week follow-up period in which patients received MFNS alone (Table 53).

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

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

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

Baseline weight less than 90 kg but ≥90 kg did not affect the benefit of dupilumab treatment (Table 18).

A responder analysis was performed to further evaluate the treatment effect of dupilumab on nasal polyp disease. Two categories of response were predefined; an NPS drop from baseline of ≥1.0 (NPS1 response) at 16 weeks and an NPS drop from baseline of ≥2.0 (NPS2 response) at 16 weeks.

For patients with comorbid asthma, the responder analysis results showed a statistically significant NPS1 response (75%) at week 16 in the dupilumab-treated group compared to placebo (10.5%), p=0. 0009, was demonstrated. NPS2 responses were also numerically favorable for dupilumab (56.3%) compared to placebo (0) (Table 20).

For patients without comorbid asthma, responder analyzes were similarly numerically favorable for dupilumab for both NPS1 and NPS2 responses (64.3% and 50%, respectively), whereas the placebo group was , showed a responder rate of 36.4% and 27.3% (Table 21), therefore the difference in the numbers between the two treatment groups of NPS1 and NPS2 responders compared to patients with comorbid asthma was , was smaller in patients without comorbid asthma.

Sinus evaluation test (SNOT-22)
SNOT-22 was used by patients during the study to assess the impact of rhinosinusitis on quality of life. Higher scores indicated worse disease; the overall maximum score was 110. Results demonstrated a significant difference in favor of dupilumab at week 16; the LS mean (SE) change from baseline at week 16 was −9.17 (2.96) in the placebo group and −27.0 in the dupilumab group. 28 (2.71), resulting in a LS mean difference of −18.11 (95% CI, −25.62 to −10.60, p<0.0001) (Table 22). The effect of dupilumab on SNOT-22 scores was observed from weeks 4 to 16 (Figure 5).

Additional patient-reported results were the visual analogue scale (1-10 cm) that patients used to grade the severity of their rhinosinus symptoms, a daily (AM/PM) loss of smell score. (0-3 point scale), an olfactory test (UPSIT), and ratings of typical rhinitis symptoms (nasal obstruction/blockage, runny nose and post-nasal drip) (0-3 point scale).

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

The results of patient-reported assessments of loss of smell (daily AM/PM electronic diary entries and olfactory test scores using the University of Pennsylvania Olfactory Discrimination Test (UPSIT)) were statistically significant in favor of dupilumab at 16 weeks. (Tables 24-26). The dupilumab-treated treatment group demonstrated better olfactory abilities at the earliest time point of each of these patient-reported assessments in this study (FIGS. 7-9). Significant improvements were also observed for the secondary endpoints of morning anterior rhinorrhea, subjective sense of smell, nocturnal symptoms and nocturnal awakenings (Table 54). Changes in symptom-based endpoints persisted at the end of the 16-week follow-up period (Table 53).

Typical symptoms of rhinitis (nasal obstruction/blockage, runny nose and post-nasal drip) were assessed daily (AM/PM electronic recording) by the patient. Results demonstrated statistical significance in favor of dupilumab at week 16 across all these assessments (Tables 27-32). Improvement in rhinosinus symptoms was observed from weeks 4 to 16 for each of these patient-reported outcomes in the dupilumab-treated arm (FIGS. 10-15).

Nasal peak inspiratory flow (NPIF) was assessed with an NPIF meter to assess the effect of nasal polyp disease on forced AM/PM inspiration and expiration through the nasal cavity (L/min). Flow rates for normal NPIF were about 140 L/min or higher, but very limited flow rates ranged from 110 to 120 L/min. The AM/PM NPIF flux results demonstrated statistical significance (p=0.0073 and p=0.0064, respectively) in favor of dupilumab at Week 16 (Tables 33 and 34). The effect of dupilumab on AM/PM NPIF was observed from weeks 4 to 16 (Figures 16 and 17). Changes in AM NPIF persisted at the end of the 16-week follow-up period (Table 53).

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

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

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

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

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

Th2 biomarkers in nasal secretions (saline eluate) were significantly (or borderline significantly) lower after dupilumab (DPL) treatment versus placebo (PBO) treatment (baseline Mean % change from): Eotaxin- 3, ECP at weeks 12 (−2.5 DPL vs +102.6 PBO p=0.055) and 16 (+7.2 DPL vs +120.2 PBO p=0.072) and 8 weeks (−15. 7 DPL vs +60.1 PBO p=0.043) to 16 weeks (−15.9 DPL vs +43.8 PBO p=0.025) (Figures 24A, 24C and 24D, respectively). Mean serum ECP, unlike mean NS ECP, did not show a decrease during dupilumab treatment. There was a transient increase (mean percent change from baseline) in blood eosinophil count (Eos) after dupilumab (W4: +49 DPL vs +0.2 PBO) that resolved during treatment ( W16: -5.8 DPL vs. +3.8 PBO) (Fig. 23D). The mean absolute changes from baseline in nasal discharge biomarkers at Week 16 are shown in Table 56 below.

The study endpoints are summarized in Table 52.

Safety was assessed by evaluation of AE reports, physical examination findings, ECG and clinical test results.

Twenty-nine of the 30 patients in the dupilumab-treated group reported a treatment-emergent adverse event (TETA), compared with 25 of the 30 patients in the placebo group, with 2 dupilumab patients and the placebo patients Four individuals each reported a serious TEAE. No patient died during the treatment period. One patient in the dupilumab group and five patients in the placebo group discontinued treatment due to TEAEs (Table 36).

The most frequent system system (SOC) afflictions were: infections and parasitosis (56.7% for placebo and 70.0% for dupilumab); respiratory, thoracic and mediastinal disorders (33.3% with placebo and 43.3% with dupilumab); nervous system disorders (20.0% with placebo and 36% with dupilumab); gastrointestinal disorders (20.0% each for placebo and dupilumab); and musculoskeletal and connective tissue disorders (3.3% for placebo and 26.7% for dupilumab) (Table 37).

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

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

A total of 6 patients (5 in the placebo group and 1 in the dupilumab group) discontinued the study due to TEAEs. Except for asthma, which was reported by two placebo patients, all other terms were reported only once (Table 39).

Adverse events of particular interest (AESIs) were defined as: ALT increased; anaphylactic and acute allergic reactions requiring emergency treatment; severe injection site reactions lasting longer than 24 hours; including severe infections; pregnancy; and overmedication (Table 40).

Only a small number of laboratory values met the criteria for abnormalities that could be clinically significant. Although balanced between the two treatment groups, more patients documented elevated basophil and eosinophil counts (Tables 41-46).

There were no clinically meaningful differences between treatment groups for any of vital signs, ECG and physician's observations (Tables 47, 48 and Figure 20).

For patients with available anti-drug antibody (ADA) results at baseline, 7/28 and 7/30 in the placebo and dupilumab treatment groups, respectively, had pre-existing ADA titers. Pre-existing ADA titers were not increased during the treatment period, except for one patient in the dupilumab group (Table 49).

During the study treatment period, 3 patients with placebo and 2 patients with dupilumab each had a positive treatment-developed ADA titer. One patient treated with dupilumab was transiently ADA positive and had a negative ADA titer after 8 weeks. Placebo patients had low titers ranging from 30 to 60, whereas titers in patients treated with dupilumab ranged from 480 to 1920 (Table 50).

As this study was ongoing in the interim analysis period, no definite conclusions regarding ADA response could be drawn. A final assessment of ADA response will be made at the end of this study.

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

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

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

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

A low incidence of treatment-emergent anti-drug antibody responses was observed in both dupilumab and placebo treatment groups. Since this study was ongoing in the interim analysis period, no definite conclusions regarding ADA response could be made. A final assessment of ADA response will be made at the end of this study.

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

Endpoints in patients with and without comorbid asthma.
In a subset of patients with comorbid asthma, treatment with dupilumab was associated with improved pulmonary function (Figure 22A) and asthma control (Figure 22B), with an LS mean difference between treatment groups of 7 in FEV1 (%). .2% (95% CI, 0.4-13.9, p=0.04), with a reduction in ACQ-5 of 0.3 (0.3) units in the placebo group and 1.0 in the dupilumab group. 4 (0.4) units, resulting in an LS mean difference in ACQ scores of −1.1 units (95% CI, −1.5 to −0.6, p<0.0001). Additionally, in this subgroup, the mean change in bilateral endoscopic nasal polyp score from baseline to week 16 was 0.3 (0.9) in the placebo group and -2.4 (-2.4) in the dupilumab group. 2.0), resulting in a LS mean difference of −2.3 (95% CI, −3.4 to −1.2, p=0.0002) in favor of dupilumab. Patients with asthma also experienced improvements in UPSIT, SNOT-22, and blockage symptoms with dupilumab/MFNS (Table 55).

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

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

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

Six patients had serious adverse events: four in the placebo group (uterine cancer, transient ischemic attack, asthma and nasal polyps) and two in the dupilumab group (herpes zoster in one patient; and other patients' arrhythmias and upper extremity pain/numbness); there were no serious adverse events considered study drug-related by the investigator. One patient in the dupilumab group also experienced (constipation), whereas five patients in the placebo group had adverse events leading to study drug discontinuation (otitis media, bronchitis, hypersensitivity, headache, hypertension, asthma and abdominal pain). Experienced. No clinically significant changes in vital signs or physical examination, clinical laboratory tests or ECG findings were reported in either group.

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

Rapid and significant improvements in endoscopic, clinical, radiographic and pharmacodynamic endpoints were observed with administration of dupilumab to patients with chronic sinusitis with nasal polyps. This indicates an important role for IL-4 and IL-13 in the pathogenesis and clinical manifestations of this disease. A significant efficacy of dupilumab on outcomes for CSwNP was also observed in analyzes restricted to a subset of patients with comorbid asthma; these patients also experienced improved lung function and asthma control (an important asthma outcome). . These data indicate that attenuation of IL-4 and IL-13 mediated signaling pathways can have broad therapeutic efficacy in patients with multiple concurrent Th-2 mediated diseases.

Compared to other approaches, dupilumab treatment resulted in sustained clinical improvements over time that exceeded those observed with systemic glucocorticoids. Additionally, this study added dupilumab or placebo to the current standard of care for CSwNP and ^asthma3 . When added to the current standard of care, dupilumab treatment was associated with widespread and significant improvement in multiple clinically relevant CSwNP and asthma parameters.

Levels of biomarkers of Th2 inflammation, including serum IgE, eotaxin-3 and TARC, decreased with dupilumab, correlating with clinical improvement, confirming the drug's biological activity in many of these pathways. . In this study, patients with CSwNP who also reported a diagnosis of asthma generally exhibited impaired pulmonary function, suboptimal disease control, and had disease that was adult-onset. The clinical benefits observed in patients with both CSwNP and asthma illustrate that a common set of Th2-associated inflammatory pathways appears to be shared between asthma and CSwNP in at least one subset of patients; We have demonstrated that targeting these pathways can lead to clinical improvement in both diseases.

In summary, this example demonstrates that in patients with CSwNP who are refractory to intranasal corticosteroids, treatment with dupilumab was associated with improved endoscopy, radiographic and clinical measures of disease. do. The efficacy of dupilumab was increased in patients with comorbid asthma, who also experienced concomitant improvements in lung function and disease control. Further studies will be performed to fully elucidate the impact of targeting IL-4 and IL-13 in patients with multiple concurrent atopic diseases.

Claims (23)

1. A pharmaceutical composition for use in improving pulmonary function or asthma management and nasal polyp-related parameters in a subject in need thereof, comprising:
The pharmaceutical composition comprises an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R);
The antibody or antigen-binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5;
the subject has chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid asthma;
Said pharmaceutical composition. Nasal polyp-related parameters included endoscopic nasal polyp score (NPS), University of Pennsylvania Olfactory Discrimination Test (UPSIT), nasal congestion/obstruction (NC) severity, sinus computed tomography (CT) scan opacification, total 2. The method of claim 1 selected from the group consisting of Symptom Score (TSS), 22-item Sinus Assessment Test (SNOT-22) score, loss of sense of smell, runny nose, posterior rhinorrhea, and nasal peak inspiratory flow (NPIF). pharmaceutical composition of 3. The pharmaceutical composition of claim 2, wherein said nasal polyp-related parameter is endoscopic nasal polyp score (NPS). 4. The pharmaceutical composition of claim 3, wherein the improvement is at least 1 or 2 points in endoscopic nasal polyp score (NPS). 2. The pharmaceutical composition of claim 1, wherein the subject's forced expiratory volume in one second (FEV1) is improved. 6. The pharmaceutical composition of claim 5, wherein FEV1 is improved by at least 1%, 2%, 3%, 4%, 5%, 6%, or 7%. 2. The pharmaceutical composition of claim 1, wherein a 5-item Asthma Control Questionnaire (ACQ-5) score is improved in the subject. 8. The pharmaceutical composition of claim 7, wherein ACQ-5 is improved by at least 1 point. The pharmaceutical composition of any one of claims 1-8, wherein the subject has refractory CRSwNP. The pharmaceutical composition according to any one of claims 1-8, wherein said pharmaceutical composition reduces the need for treatment with systemic corticosteroids or nasal polyp surgery. The pharmaceutical composition according to any one of claims 1-8, wherein the subject is at least 18 years old. 9. The pharmaceutical composition of any one of claims 1-8, wherein one or more maintenance doses of intranasal corticosteroid (INCS) is administered to the subject. 13. The pharmaceutical composition of claim 12, wherein the INCS is mometasone furoate nasal spray (MFNS). The pharmaceutical composition according to any one of claims 1-8, wherein said pharmaceutical composition is administered in one or more doses of about 300 mg. The pharmaceutical composition according to any one of claims 1-8, wherein the subject has severe chronic rhinosinusitis with bilateral nasal polyps. 9. The pharmaceutical composition of any one of claims 1-8, wherein the antibody or antigen-binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO:1 and LCVR having the amino acid sequence of SEQ ID NO:2. 17. The pharmaceutical composition of claim 16, wherein the antibody is dupilumab. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition is administered subcutaneously. 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is administered using an auto-injector, needle and syringe, or pen delivery device. 1. A pharmaceutical composition for use in improving pulmonary function or asthma management and nasal polyp-related parameters in a subject in need thereof, comprising:
The pharmaceutical composition comprises an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises the light weight peptides of SEQ ID NOS:6, 7 and 8. comprising the chain CDR sequences and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5;
the subject has chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid asthma;
the pharmaceutical composition is administered in an initial dose of about 300 mg and in one or more subsequent doses of about 300 mg each;
Subsequent doses are administered once every 14 days,
the subject is at least 18 years old;
Said pharmaceutical composition. 1. A pharmaceutical composition for use in improving pulmonary function or asthma management and nasal polyp-related parameters in a subject in need thereof, comprising:
The pharmaceutical composition comprises an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises the light weight peptides of SEQ ID NOS:6, 7 and 8. comprising the chain CDR sequences and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5;
the subject has asthma and chronic rhinosinusitis with comorbid nasal polyps (CRSwNP);
Said pharmaceutical composition. 22. The pharmaceutical composition of claim 21, wherein the antibody or antigen-binding fragment thereof is administered in an initial dose of about 600 mg and one or more secondary doses of about 300 mg. 23. The pharmaceutical composition of Claim 22, wherein the secondary dose is administered once every 14 days.

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