JP6898421B2 - Method of treating nasal polyps by administration of IL-4R antagonist - Google Patents

Description

Related Applications This application claims the interests of US Provisional Application Nos. 61 / 837,912 filed on June 21, 2013 and European Application No. 14305670.3 filed on May 7, 2014, which they claim. Each of them is incorporated herein by reference in their entirety.

The present invention relates to the field of therapeutic treatment of inflammatory conditions. More specifically, the present invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists for treating nasal polyps.

Nasal polyps (NPs) are clinical conditions characterized by the presence of multiple polyps in the upper nasal cavity that arise from the natural mouth route of the middle nasal meatus. NP is an inflammatory process driven by T helper cells-2 (Th-2) that affects the nasal mucosa and sinuses. High levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cation protein (ECP) and eotaxin (favorable), factors that attract and activate eosinophils Since eosinophils) are typically found in nasal polyps, eosinophils and their products are considered to be characteristic 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. NPs are characterized by long-term symptoms of nasal obstruction and blockage, 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.

In one aspect, the invention is a method of treating nasal polyps, the pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof. Provided is a method comprising the step of administering it to a subject in need thereof. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

Subjects suitable for treatment with IL-4R antagonists may have one or more of venous sinitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. , Or may have previously undergone surgery to treat nasal polyps. In some embodiments, the subject has chronic venous sinusitis or chronic nasal sinusitis. For example, the subject may have nasal polyps with severe symptoms of venous sinusitis.

In some embodiments, the IL-4R antagonist is administered at a dose of 0.1 mg to 600 mg (eg, 100 mg to 400 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg). In certain embodiments, the pharmaceutical composition is administered to the subject systemically or topically. For example, the pharmaceutical composition is administered subcutaneously, intravenously, or intranasally.

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

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist, such as an IL-4R antibody or antigen-binding fragment thereof. For example, in one embodiment, one or more additional agents, such as a second therapeutic agent, are TNF inhibitors, IL-1 inhibitors, IL-5 inhibitors, IL-8 inhibitors, IgE inhibitors, NSAIDs (nonsteroidal anti-inflammatory drugs), antibiotics, antifungal agents, intranasal corticosteroids, inhaled corticosteroids, systemic corticosteroids, long-acting beta ₂ agonists, decongestants or any of them It may be a combination. In one embodiment, the second therapeutic agent is an inhaled corticosteroid such as fluticasone or budesonide, or an intranasal corticosteroid such as an intranasal spray of mometasone furoate (MFNS). In another embodiment, the second therapeutic agent further comprises _{a long-acting beta 2 agonist such as salmeterol or formoterol.}

In certain embodiments, after administration of the IL-4R antagonist, one or more symptoms of nasal polyps improve. For example, after administration of an antagonist, 22 items of sinus evaluation test (SNOT-22) score; nasal symptom score; number of night awakenings; visual analog score (VAS) such as severity of nasal sinus inflammation; 5 items One or more, such as the Asthma Management Questionnaire (ACQ5) score; Maximum Nasal Inspiratory Flow (NPIF); University of Pennsylvania Smell Discrimination Test (UPSIT); Lund-McKay Score; Parameters related to nasal polyps may improve. In certain embodiments, after administration of the antibody or antigen-binding fragment thereof, an increase in one or both of NPIF and UPSIT, as well as a SNOT-22 score, nasal symptom score, VAS, Lund-McKay score and 3D-volume score. One or more of the reductions of one or more of them occur. In some embodiments, after administration of the IL-4R antagonist, a decrease in nasal polyp score occurs in the patient.

In one aspect, the invention is a single initial dose of an interleukin-4 receptor (IL-4R) antagonist, such as an IL-4R antibody or antigen-binding fragment thereof, followed by one or more IL-4R antagonists. Provided is a method of treating a nasal mushroom by continuously administering a secondary dose of the above to a subject in need thereof. In some embodiments, each secondary dose is administered 1 to 15 weeks after the previous dosing. In other embodiments, at least three secondary doses of the IL-4R antagonist are administered to the subject, with each secondary dose taking days or weeks (eg, one or two weeks or more) of the previous dosing. ) Will be administered later. In another embodiment, each of the initial dose and one or more secondary doses is a 50 mg to 500 mg IL-4R antagonist, eg, 100 mg to 400 mg IL-4R antagonist, eg, 150 mg, 200 mg, 250 mg, respectively. Contains 300 mg or 350 mg of IL-4R antagonist. In some embodiments, each of the initial dose and one or more secondary doses contains the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of IL-4R antagonist and each of the one or more secondary doses comprises a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times or 5 times or 5 times the second amount of IL-4R antagonist. It may be more than that.

In one embodiment, the subject (eg, patient) has or has one or more of venous sinitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, or nasal polyps. I have surgery for polyps. In some embodiments, the subject has chronic venous sinusitis or chronic nasal sinusitis. For example, the subject may have nasal polyps with severe symptoms of venous sinusitis.

Initial and secondary doses of IL-4R antagonists are administered by the same or different routes of administration. For example, the initial and secondary doses are administered subcutaneously, intravenously, or intranasally.

In certain embodiments, after administration of the initial dose and one or more secondary doses, a 22-item sinus evaluation test (SNOT-22) score; nasal symptom score; number of night awakenings; nasal sinus inflammation Visual analog score (VAS) such as severity of the disease; 5 item asthma management questionnaire (ACQ5) score; nasal maximum inspiratory flow rate (NPIF); Improvements in one or more nasal polyp-related parameters occur, such as improved three-dimensional volumetric measurements. In certain embodiments, after administration of the antibody or antigen-binding fragment thereof, an increase in one or both of NPIF and UPSIT, as well as a SNOT-22 score, nasal symptom score, VAS, Lund-McKay score; and 3D volume score. One or more of the reductions of one or more of them occur. In some embodiments, after administration of the IL-4R antagonist, a decrease in nasal polyp score occurs in the patient.

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist, such as an IL-4R antibody or antigen-binding fragment thereof. For example, in one embodiment, one or more additional agents, such as a second therapeutic agent, are TNF inhibitors, IL-1 inhibitors, IL-5 inhibitors, IL-8 inhibitors, IgE inhibitors, It may be an NSAID, antibiotic, antifungal agent, intranasal corticosteroid, inhaled corticosteroid, systemic corticosteroid, long-acting beta ₂ agonist, decongestant or any combination thereof. In one embodiment, the second therapeutic agent is an inhaled corticosteroid such as fluticasone or budesonide, or an intranasal corticosteroid such as an intranasal spray of mometasone furoate (MFNS). In another embodiment, the second therapeutic agent further comprises _{a long-acting beta 2 agonist such as salmeterol or formoterol.}

In one aspect, the invention is a method of treating nasal polyps with a minimum bilateral nasal polyp score of 5, or nasal block / blockage / blockage, anterior or posterior nasal leaks, facial pain or tightness, and sensation of smell. The step of selecting a patient with at least two or more of the chronic symptoms of venous sinitis selected from the group consisting of decreased or lost; as well as the patient's nasal polyp score is reduced or 2 of venous sinitis. Interleukin-4 receptors (IL-4R), such as antibodies that specifically bind to the interleukin-4 receptor (IL-4R) or antigen-binding fragments thereof, so as to improve one or more chronic symptoms. Provided is a method by the step of administering a pharmaceutical composition containing an antagonist to a selected patient. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention is a method of treating nasal polyps with a minimum bilateral nasal polyp score of 5, or nasal block / blockage / blockage, anterior or posterior nasal leaks, facial pain or tightness, and sensation of smell. The step of selecting a patient with at least two or more of the chronic symptoms of venous sinitis selected from the group consisting of decreased or lost; as well as the patient's nasal polyp score is reduced or 2 of venous sinitis. Interleukin-4 receptors (IL-4R), such as antibodies that specifically bind to the interleukin-4 receptor (IL-4R) or antigen-binding fragments thereof, so as to improve one or more chronic symptoms. A method is provided by the step of continuously administering to a patient a single initial dose of a pharmaceutical composition comprising an antagonist followed by a single or higher secondary dose of an antibody or antigen-binding fragment thereof. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention is a method of treating nasal mushrooms in a group consisting of thoracic gland and activation regulatory chemokine (TARC), eotaxin-3, periostin, cancer fetal antigen (CEA) and YKL-40. The step of determining the expression level of one or more genes selected from; specific to the interleukin-4 receptor (IL-4R) if the subject has an improved expression level of one or more genes. The step of selecting a subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody that binds specifically or an antigen-binding fragment thereof; as well as the level of one or more genes. Provided is a method by the step of administering to a selected subject a pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof so as to be reduced. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention is a method of treating nasal mushrooms in a group consisting of thoracic gland and activation regulatory chemokine (TARC), eotaxin-3, periostin, cancer fetal antigen (CEA) and YKL-40. The step of determining the expression level of one or more genes selected from; specific to the interleukin-4 receptor (IL-4R) if the subject has an improved expression level of one or more genes. The step of selecting a subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody that binds specifically or an antigen-binding fragment thereof; as well as the level of one or more genes. A single pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof so as to decrease. The method is provided by a step of serially administering a single initial dose followed by one or more secondary doses of the antibody or antigen-binding fragment thereof to selected subjects. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention is a method of treating nasal mushrooms, the step of determining the level of blood eosinophils or sputum eosinophils in a subject; the subject is blood eosinophils or sputum eosinophils. For treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof, if it has an improved level of The step of selecting a subject as a candidate for interleukin-4 receptor (IL-4R) or an antibody thereof so as to reduce the level of blood eosinophils or sputum eosinophils. Provided is a method by the step of administering to a selected subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an antigen binding fragment. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention is a method of treating nasal mushrooms, the step of determining the level of blood eosinophils or sputum eosinophils in a subject; the subject is blood eosinophils or sputum eosinophils. For treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof, if it has an improved level of The step of selecting a subject as a candidate for interleukin-4 receptor (IL-4R) or an antibody thereof so that the level of blood eosinophils or sputum eosinophils is reduced. Select a single initial dose of the pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an antigen-binding fragment, followed by a single or higher secondary dose of the antibody or antigen-binding fragment thereof. Provided is a method by a step of continuous administration to a subject. In one embodiment, the IL-4R antagonist is an antibody or antigen binding fragment comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2. An antibody that specifically binds to IL-4Rα or an antigen-binding fragment thereof. 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 an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

Other embodiments will become apparent from the drawings and detailed description below.

It is a figure which shows the schematic diagram of the example of the background treatment withdrawal period in the treatment of an asthma patient.

Prior to writing the invention, it is understood that the invention is not limited to the particular methods and experimental conditions described, and thus the methods and conditions may vary. It is also understood that the terms used herein are for the sole purpose of describing a particular embodiment and are not intended to be limiting.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. As used herein, the term "about" used with respect to a particular stated value means that the number can vary by no more than 1% from the stated value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

All publications referred to herein are incorporated herein by reference in their entirety.

Methods for Treating Nasal Polyps The present invention provides methods for treating nasal polyps. As used herein, a "nasal polyp" is an overgrowth of tissue in one or more nasal cavities. The condition of nasal polyps is called "nasal polyps". About 80% of nasal polyps are highly edematous and are filled with eosinophils. Nasal polyps may also be present as fibrous, glandular or cystic.

Nasal polyps (NPs) are clinical conditions characterized by the presence of multiple polyps in the upper nasal cavity that arise from the natural mouth route of the middle nasal meatus. NP is an inflammatory process driven by T helper cells-2 (Th-2) that affects the nasal mucosa and sinuses. High levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cation protein (ECP) and eotaxin (favorable), factors that attract and activate eosinophils Since eosinophils) are typically found in nasal polyps, eosinophils and their products are considered to be characteristic 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.

NPs are characterized by long-term symptoms of nasal obstruction and blockage, 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 coronary computed tomography (CT) scans.

IL-4R antagonists are used to treat nasal polyps associated with various conditions. For example, nasal polyps include venous sinusitis, rhinitis (eg, allergic and non-allergic rhinitis), asthma (eg, moderate to severe asthma), NSAID hypersensitivity (eg, aspirin hypersensitivity) and bacterial and fungal infections. Related to infection. Bacterial infections include, for example, staphylococcal infections. Subjects with nasal polyps may have a chronic bacterial infection, such as a chronic Staphylococcus aureus infection. In some embodiments, the subject has recurrent nasal polyps, such as those that may be associated with recurrent venous sinusitis. In other embodiments, the subject has cystic fibrosis or NARES (non-allergic rhinitis with eosinophilia syndrome). In another embodiment, the subject has relapsed nasal polyps after undergoing surgery to treat the polyp. Risk factors for nasal polyps include genetic susceptibility, anatomical abnormalities, mucosal ciliary dysfunction, infection and local immune imbalance.

IL-4R antagonists are also used to treat nasal polyps in patients who have not previously undergone treatment or surgery for NP. IL-4R antagonists are also used to treat nasal polyps in patients who have previously undergone surgery, such as for the treatment of nasal polyps. In certain embodiments, the IL-4R antagonist is administered to a subject with recurrent nasal polyps after the subject has undergone previous treatment for polyps such as previous rhinoplasty.

As used herein, the term "venous sinusitis" is any of those characterized by sinus inflammation, including inflammation of the maxilla, frontal bone, ethmoid and / or sphenoid sinuses. Refers to an inflammatory condition. IL-4R antagonists are suitable for the treatment of nasal polyps associated with acute venous sinitis, subacute venous sinitis, chronic venous sinitis and recurrent venous sinitis. Acute venous sinusitis is characterized by the sudden onset of cold-like symptoms such as runny nose, stuffy nose and facial pain that do not heal after 10 to 14 days. Acute venous sinitis typically lasts less than 4 weeks. Subacute venous sinitis lasts 4-8 weeks. Chronic venous sinitis lasts for 8 weeks or longer, and recurrent venous sinitis is characterized by the development of venous sinus inflammation that occurs three or more times a year. More than 80% of patients with chronic venous sinitis with nasal polyps have eosinophilic upper respiratory tract inflammation.

Many patients with chronic venous sinitis have "chronic hyperplastic eosinophil sinusitis" characterized by marked inflammation of the sinuses, increased eosinophils and mixed mononuclear cells, and relatively small amounts of neutrophils. Has. Some of these patients have one or more of the associated nasal polyps, asthma and aspirin or NSAID susceptibility. In certain embodiments, IL-4R antagonists are used to treat nasal polyps in subjects with chronic hyperplastic eosinophil sinusitis.

The term "rhinitis" refers to an allergic reaction to common allergens ("allergic rhinitis", eg, perennial allergic rhinitis) or environmental stimulants (non-allergic rhinitis). Symptoms of allergic rhinitis include sneezing; stuffy nose or runny nose; tightness and pain in the sinuses or beating of the cheeks or nose; and itching of the nose, throat, eyes and ears.

Symptoms of non-allergic rhinitis include narrowing or inflammation of the nasal passages that lead to many of the same symptoms of allergic rhinitis. Non-allergic rhinitis is caused, for example, by strong chemical or smoking environments, or by long-term use of certain medications or dependence on nasal spray.

As used herein, the term "nasal sinusitis" refers to a condition that has symptoms of both rhinitis and venous sinusitis. Nasal sinusitis includes acute sinusitis and chronic sinusitis. Acute sinusitis is caused by infections such as bacterial, viral or fungal infections, or by chemical stimuli. Acute nasal sinusitis induced by cigarette smoke and chronic nasal sinusitis induced by chlorine gas are examples of acute nasal sinusitis. NP is most commonly associated with chronic nasal sinusitis (CRS), which is characterized by mucosal inflammation of the nasal and sinuses, with symptoms lasting longer than 8 weeks. Chronic eosinophilic nasal sinusitis with nasal polyps persists for more than 8 weeks.

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

A further subcategory of chronic venous sinusitis (and chronic nasal sinusitis) is produced by bacteria such as, for example, superantigen-induced eosinophilic chronic venous sinusitis (eg, Aspergillus aureus). Sinusitis induced by external toxins and internal toxins); allergic fungal sinusitis (eg, sinusitis induced by fungi such as Aspergillus or Alternaria); Includes non-allergic fungal eosinophil chronic sinusitis; and eosinophilic chronic sinusitis exacerbated by aspirin.

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

Methods of Improving Parameters Related to Nasal Polyps The present invention is a method of improving one or more parameters associated with nasal polyps in a subject in need thereof, the interleukin-4 receptor (IL-). 4R) Includes a method comprising administering to a subject a pharmaceutical composition comprising an antagonist. For example, IL-4R receptor antagonists can reduce endoscopic nasal polyp scores in patients. A nasal polyp score of 0 indicates the absence of polyps. A nasal polyp score of 1 indicates the presence of small polyps in the middle nasal meatus that do not reach below the lower edge of the middle turbinate. A nasal polyp score of 3 indicates a large polyp reaching the lower edge of the inferior turbinate or an intermediate polyp to the middle turbinate. A nasal polyp score of 4 indicates a large polyp that causes complete obstruction of the lower nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nasal cavity). Treatment with IL-4R antagonists can reduce nasal polyp scores by about 1 to about 8 points. For example, treatment with an IL-4R antagonist can reduce the nasal polyp score 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 results in a nasal polyp score of about 1 point or a percentage thereof; 2 points or a percentage thereof; 3 points or a percentage thereof; 4 points or a percentage thereof; 5 points or a percentage thereof; 6 points or a percentage thereof; 7 points or a percentage thereof; or 8 points or a percentage thereof can be reduced. A decrease in nasal polyp score can correlate with an improvement in one or more other nasal polyp-related parameters. However, such correlations are not always observed in all cases.

Other examples of "parameters associated with nasal polyps" include: (a) 22-item sinus evaluation test (SNOT-22) score; (b) nasal congestion / obstruction, anterior rhinorrhea (nasal drip) assessed by the subject. ), Post-nasal drip (post-nasal drip) and loss of smell; (c) Number of night awakenings; (d) Visual analog score (VAS) to assess the severity of nasal sinusitis associated with the patient (E) Five-item asthma management questionnaire (ACQ5) score in patients with asthma; (f) Maximum nasal inspiratory flow (NPIF); (g) Smell test (University of Pennsylvania Smell Identification Test (UPSIT)); (h) ) Physiological parameters measured by nasal endoscopy and CT scans; (i) Lund-Muckay score; and (j) three-dimensional volume measurement of the maxillary sinus.

22 items sinus evaluation test (SNOT-22) score. According to certain embodiments, administration of the IL-4R antagonist to the patient results in a reduction from baseline in the 22 item sinus evaluation study (SNOT-22). SNOT-22 is a questionnaire for assessing the effects of chronic nasal sinusitis (CRS) on quality of life. The questionnaire measures items related to sinus condition and surgical procedures. Scores range from 0 to 110, with higher scores indicating a greater effect of CRS on health-related quality of life (HRQoL) (Hopkins et al. 2009, Clin. Otollaryngol. 34: 447-454). ).

The present invention includes a therapeutic method that results in a decrease in SNOT-22 score from baseline by at least 1 point between 4 and 16 weeks after administration of the IL-4R antagonist. For example, administration of an IL-4R antagonist results in a decrease in the SNOT-22 score at 4, 6, 8, 12 or 16 weeks after the start of treatment. In some embodiments, administration of the IL-4R antagonist to subjects in need of it at about 1, 2, 3, 4, 5, 6, 7, at 4 weeks, 6 weeks, 8 weeks or 12 weeks, Causes a decrease in the SNOT-22 score from a baseline of 8, 9, 10, 11, 12, 13 points or more.

Individual and total nasal symptom scores. Symptoms assessed by the subject use a 0-3 classification scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), clogging / obstruction, It is assayed by answering individual nasal sinusitis symptom questions in the morning and evening, including symptoms of anterior rhinorrhea, posterior rhinorrhea and loss of olfactory sensation. Measurements of nocturnal arousal are also tracked. For example, measurements of nocturnal arousal are assessed according to the following scores based on the subject's self-assessment: 0 = no symptoms, slept all night; 1 = slept well, but had some medical condition in the morning; 2 = Woke up once due to symptoms of nasal sinusitis (including early awakening); 3 = Woke up several times due to symptoms (including early awakening); 4 = Could not sleep well, due to symptoms Awaken almost all night. Administration of the IL-4R antagonist is performed, for example, at least about 0.10 overnight awakenings from baseline overnight at 4 to 16 weeks after the start of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. May cause a decrease in the average number of. For example, a decrease in the frequency of overnight night awakenings from baseline at least about 0.10 times per night can be seen at 4, 6, 8, 12, or 16 weeks after the start of treatment. .. Administration of the IL-4R antagonist to subjects in need of it is, for example, about 0.10 times overnight, 0.15 times overnight, overnight at 4, 8, 12, or 16 weeks. 0.20 times, 0.25 times a night, 0.30 times a night, 0.35 times a night, 0.40 times a night, 0.45 times a night, 0 times a night .50 times, 0.55 times a night, 0.60 times a night, 0.65 times a night, 0.70 times a night, 0.75 times a night, 0.80 times a 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, one from baseline It can cause a decrease in the average number of night awakenings in the evening.

Visual analog score (VAS). The VAS is a scale for assessing the severity of patient-related nasal sinusitis symptoms on a scale of 1 to 10. Mild symptoms are indicated by a VAS 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 the IL-4R antagonist to subjects in need of it was approximately 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4 weeks, 6 weeks or 12 weeks. Causes a decrease in VAS score from baseline, 3.5 points, 4 points or more. A decrease in the VAS score can be seen as early as 4 weeks and at the latest 12 weeks or later after administration of the IL-4R antagonist.

Five-item asthma management questionnaire (ACQ) score. ACQ5 measures both the adequacy of asthma management and changes in asthma management that occur spontaneously or as a result of treatment. The five ACQ5 questions represent the top five asthma symptoms: symptoms awakened at night, symptoms awakened in the morning, restricted daily activities, shortness of breath and wheezing. Patients answered symptomatological questions on a 7-point scale (0 = no dysfunction, fully managed; 6 = maximum dysfunction, fairly unmanaged).

The present invention includes a therapeutic method that results in a decrease in ACQ5 score from baseline at least 0.10 points 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 at about 0.10 points, 0.15 points, 0.20 points at 4, 6 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, Causes a decrease in ACQ score from the baseline of 0.75 points, 0.80 points, 0.85 points or higher. A decrease in ACQ score can be seen as early as 4 weeks and at the latest 12 weeks or later after administration of the IL-4R antagonist.

Maximum nasal inspiratory flow rate (NPIF). Nasal maximal inspiratory flow (NPIF) represents the physiological measure of airflow through both nasal passages during forced inspiration and / or expiration, expressed in liters / minute. Nasal inspiration is mostly used to monitor rhinorrhea, correlating with the subjective sensation of obstruction. Administration of IL-4R antagonists to subjects in need of it was approximately 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0. 25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 Increase NPIF from baseline at liters / minute, 0.65 liters / minute, 0.70 liters / minute, 0.75 liters / minute, 0.80 liters / minute, 0.85 liters / minute or more cause. An increase in NPIF score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

University of Pennsylvania Smell Identification Test (UPSIT). UPSIT is a method for quantitatively evaluating human olfactory function. The test consists of a sample of odorous substances and the subject must describe the odor. The score is based on the number of correct answers. This test examines patients with a normal sense of smell (“normal sense of smell”) and patients with different levels of decline (“mild, moderate and severe microsmia”) or loss (“non-smell”). Can be identified. Administration of the IL-4R antagonist to subjects in need of it was approximately 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4 weeks, 6 weeks or 12 weeks. Causes an increase in UPSIT score from baseline, 3.5 points or higher. An increase in the UPSIT score can be seen as early as 4 weeks and at the latest 12 weeks or later after administration of the IL-4R antagonist.

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

Lund-Mackay score. The Lund-Mackay scoring system is based on localization by points given for opacity: 0 = normal, 1 = partial opacity, 2 = complete opacity. These points are then applied to the maxilla, anterior ethmois, posterior ethmois, sphenoid and frontal sinus on each side. The natural mouth route of the middle nasal meatus is graded as 0 = no obstruction or 2 = with obstruction, and a maximum score of 12 per one is derived. For patients lacking the Middle Nasal Mouth Route (OC) (due to previous surgery), the location of the previous OC is considered and scored as if the OC was there. Administration of IL-4R antagonists to subjects in need of it was approximately 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 at 4 weeks, 6 weeks 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 Causes a decrease in the Lund-Mackay score from the baseline of points, 0.85 points or higher. A decrease in the Lund-Muckay score can be seen as early as 4 weeks and at the latest 12 weeks or later after administration of the IL-4R antagonist.

Three-dimensional volume measurement of the maxillary sinus. This value is used to calculate the air volume (mL); mucosal volume (mL); the percentage of sinus occupied by the disease; and the wall thickness in the maxillary sinus. Administration of IL-4R antagonists to subjects in need of it causes an increase in 3D volumetric measurements.

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

SF-36 is a 36-item questionnaire that measures the degree of eight multi-items of health: physical function (10 items), social function (2 items), role restriction due to physical problems (4 items), Role restrictions due to emotional problems (3 items), mental health (5 items), energy / vitality (4 items), pain (2 items) and overall health (5 items). For each degree, item scores were coded, summed, and converted to a scale from 0 (the worst health condition measured by the questionnaire) to 100 (the best possible health condition). Two standardized summary scores can also be calculated from SF-36; Physical Component Summary (PCS) and Mental Health Component (MCS).

EQ-5D is a standardized health-related quality of life developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic assessment and inter-disease comparisons. It is a questionnaire of. Designed for patient self-administration, the EQ-5D consists of two parts, the EQ-5D description system and the EQ VAS. The EQ-5D description system includes 5 degrees: movement, personal care, routine activities, pain / discomfort and anxiety / blockage; each degree has 3 levels: no problem, some problem, quite problem Yes. The EQ Visual Analog Scale (VAS) records the respondent's self-related health relative to the vertical visual analog scale. The EQ VAS "Thermometer" has a maximum of 100 (best possible health condition) and a minimum of 0 (worst possible health condition) endpoints.

A questionnaire that uses materials related to nasal polyps is a questionnaire that uses health management materials for nasal polyps, including specialist visits, emergency medical visits, sick leave, and holidays.

Improvements in parameters related to nasal polyps, such as the parameters related to nasal polyps described above, can be expressed as percentages. For example, the score can be improved by 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more.

"Improvement of parameters associated with nasal polyps" is 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 rhinorrhea (post-nasal drip) and loss of smell; number of night awakenings; VAS score; Lund-Muckay score; and 3D volume score; and one of the ACQ5 scores in patients with asthma Or it means a further decrease from the 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 before or during administration of the pharmaceutical composition of the invention. means.

To determine if the parameters associated with nasal polyps have been "improved", the parameters are quantified at baseline and after administration of the pharmaceutical composition of the invention. For example, parameters related to nasal polyps are 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days after the start of treatment with the pharmaceutical composition of the present invention. Sun, 11th, 12th, 14th or 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week, 9th week, 10th week, 11th week, 12th week, 13th week, 14th week, 15th week, It is measured at 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks or longer. In some embodiments, the parameters are measured daily (eg, once or twice a day), weekly, biweekly or monthly. In other embodiments, the parameters are measured daily and the average value determined over the course of one month is compared to the baseline.

The difference between the value of the parameter at a particular point in time after the start of the procedure and the value of the parameter at baseline is that the parameters associated with the nose are "improved" (eg, in some cases to the particular parameter being measured). Used to demonstrate if it can increase or decrease depending on).

Interleukin-4 Receptor Antagonist In one embodiment, a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist is administered to a subject in need thereof. As used herein, "IL-4R antagonist" is when it binds to or interacts with IL-4R and IL-4R is expressed in vitro or in vivo on cells. It is any drug that inhibits the normal biological signaling function of IL-4R. Non-limiting examples of the IL-4R antagonist category include small molecule IL-4R antagonists, peptide-based IL-4R antagonists (eg, "peptibody" molecules), and human IL-4R specifically. Includes an antibody that binds or an antigen-binding fragment of the antibody.

The term "human IL-4R" (hIL-4R), as used herein, is a component of the IL-4 receptor types I and II, as well as the IL-13 receptor system, IL-4Rα. Intended to refer to a subunit. 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, is an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains. Also intended to refer to its multimer (eg, IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V _H) and a heavy chain constant region. The heavy chain constant region contains three domains, _CH 1, _CH 2 and _CH 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 ( _CL 1). The V _H and _VL regions are further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are incorporated into more conservative regions called framework regions (FRs). Each _VN and _VL is composed of 3 CDRs and 4 FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FR of the anti-Ang-2 antibody (or antigen-binding portion thereof) is identical to the human germline sequence or is naturally or artificially modified. The amino acid consensus sequence is a control analysis of two or more CDRs (side-by-side anal)
It is defined based on ysis).

The term "antibody" also, as used herein, also includes an antigen-binding fragment of a complete antibody molecule. As used herein, terms such as the "antigen-binding portion" of an antibody and the "antigen-binding fragment" of an antibody are any naturally occurring that specifically binds to an antigen to form a complex. , Containing polypeptides or glycoproteins available by enzymes or synthesized or genetically engineered. Antigen-binding fragments of an antibody can be prepared using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques involving manipulation and expression of DNA that encodes variable and optionally constant domains of the antibody, eg. , Derived from the complete antibody molecule. Such DNA is known and / or is readily available or synthesized, for example, from commercial sources, DNA libraries, such as phage-antibody libraries. DNA, for example, to place one or more variable and / or constant domains in an appropriate configuration, or to introduce codons, make cysteine residues, or modify, add, or delete amino acids. For example, it is sequenced and manipulated chemically or by using molecular biology techniques.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragment; (ii) F (ab') 2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single chain Fv (scFv). Minimal recognition units consisting of molecules; (vi) dAb fragments; and amino acid residues that mimic the hypervariable regions of (vi) antibodies (eg, isolated complementarity determining regions (CDRs) such as CDR3 peptides), or limitations. The FR3-CDR3-FR4 peptide produced is included. Domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, quadruspecific antibodies, minibodies, nanobodies (eg, eg Other engineered molecules such as monovalent nanobodies, divalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, as used herein, are also referred to as "antigens." It is included in the expression "bonded fragment".

Antigen-binding fragments of an antibody typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and is generally adjacent to one or more framework sequences, or at least one CDR of one or more framework sequences and in-frames. including. In antigen-binding fragment with a V _H domain in association with the V _L domain, V _H and V _L domains are positioned relative to each other in any suitable arrangement. For example, the variable region may be a dimer and may contain a V _H- V _H , V _H - _VL or V _L - _VL dimer. Alternatively, the antigen-binding fragment of the antibody may contain a _{monomeric V H} or _{VL domain.}

In certain embodiments, the 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 the antigen-binding fragment of an antibody include: (i) V _H- C _H 1; (ii) V _H- C _H 2; (iii) V _H. -C _H 3; (iv) V _H- C _H 1-C _H 2; (v) V _H- C _H 1-C _H 2-C _H 3; (vi) V _H- C _H 2-C _H 3 (Vii) V _H- C _L ; (vii) V _L- C _H 1; (ix) V _L- C _H 2; (x) V _L- C _H 3; (xi) V _L- C _H 1- includes and _{(xiv) V L -C L;} C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3. In any of the variable and constant domain configurations, including any of the exemplary configurations listed above, the variable and constant domains are either directly linked to each other or are linked by a full or partial hinge or linker region. To. The hinge regions are at least two (eg, 5, 10, 15, 20, 40, which result in flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Consists of 60 or more amino acids). In addition, the antigen-binding fragments of the antibody are non-covalently attached (eg, by disulfide bonds) to _{each other and / or to one or more monomeric VH} or _{VL domains, the variable and constant listed above.} It may contain any of the homodimers or heterodimers (or other multimers) of the configuration of the domain.

Like the fully antibody molecule, the antigen binding fragment may be monospecific or multispecific (eg, bispecific). A multispecific antigen-binding fragment of an antibody typically comprises at least two different variable domains, where each variable domain can specifically bind to a different antigen or a different epitope on the same antigen. Any multispecific antibody form, including the exemplary bispecific antibody form disclosed herein, is an antigen-binding fragment of an anti-IL-4R antibody using conventional techniques available in the art. Suitable for use in the context of.

The constant region of the antibody is important in the ability of the antibody to immobilize complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes are 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 with variable and constant regions derived from human germline immunoglobulin sequences. Nonetheless, the human antibodies characterized in the present invention are amino acid residues not encoded by the human germline immunoglobulin sequence, eg, in CDR and especially CDR3, at random or site-directed mutagenesis in vitro or in vivo. Mutations introduced by somatic mutations in However, the term "human antibody" as used herein includes an antibody in which a CDR sequence derived from the germline of another mammalian species, such as a mouse, is grafted onto a human framework sequence. Intended not.

The term "recombinant human antibody" as used herein means any human antibody produced, expressed, prepared or isolated by recombinant means, eg, recombinant expression transfected into a host cell. Antibodies expressed using the vector (described further below), antibodies isolated from the recombinant combinatorial human antibody library (described further below), and animals transgenic for the human immunoglobulin gene (described further below). For example, it comprises splicing an antibody isolated from a mouse) (see, eg, Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295), or another DNA sequence of a human immunoglobulin gene sequence. It is intended to include antibodies produced, expressed, prepared 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 undergo in vitro mutagenesis (or, if transgenic animals with respect to human Ig sequences are used, in vivo somatic mutagenesis). amino acid sequences of the _{V H} and _{V L} regions of the recombinant antibodies are derived from human germline _{V H} and _{V L} sequences, is related to human germline _{V H} and _{V L} sequences, the human antibody germline repertoire in vivo, It is a sequence that does not have to exist naturally in the inside.

Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150-160 kDa, where the dimer is held together by interchain heavy chain disulfide bonds. In the second form, the dimer is not linked via an interchain disulfide bond and contains a molecule of approximately 75-80 kDa composed of a covalently coupled light chain and heavy chain (half antibody). 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 the hinge region isotype of the antibody. Single amino acid substitutions in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to the levels typically observed using the human IgG1 hinge (Angal et al. (1993) Molecular. Immunology 30: 105). The present invention includes _{antibodies having one or more mutations in the hinge, CH} 2 or _CH 3 regions, which is desirable, for example, to improve the yield of the desired antibody form during production.

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

Terms such as "specifically bind" mean that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance and the like. For example, an antibody that "specifically binds" to IL-4R, as used herein, on IL-4R or a portion thereof, as measured by a surface plasmon resonance assay, <about 1000 nM, less than about 500 nM, Less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, about 5 nM comprising less than about 4 nM, less than about 3 nM, less than about 2 nM, antibodies that bind at about 1nM or less than about 0.5nM less _{K D.} However, isolated antibodies that specifically bind to human IL-4R may be cross-reactive with other antigens, such as IL-4R molecules from other (non-human) species.

Anti-IL-4R antibodies useful in the methods characterized herein are in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibody is derived. It may contain one or more amino acid substitutions, insertions, and / or deletions. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with, for example, germline sequences available from public antibody sequence databases. The present invention is a method comprising the use of an antibody and an antigen-binding fragment thereof derived from any of the amino acid sequences disclosed herein, wherein one or more frameworks and / or CDR regions. One or more of the amino acids are conservative amino acid substitutions of the corresponding residues of the germline sequence from which the antibody was derived, or the corresponding residues of another human germline sequence, or the corresponding germline residues. Includes methods that are mutated into (such sequence changes are collectively referred to herein as "germline mutations"). One of ordinary skill in the art will readily produce a large number of antibody and antigen binding fragments containing one or more individual germline mutations or combinations thereof, starting with the heavy and light chain variable region sequences disclosed herein. can do. In certain embodiments, _{all framework and / or CDR residues within the VH} and / or _VL domain are reverse mutated to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only specific residues are found, eg, only mutated residues found in the first eight amino acids of FR1 or in the last eight amino acids of FR4, or in CDR1, CDR2 or CDR3. Only mutated residues are reverse mutated to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues is the corresponding germline sequence of a different germline sequence (ie, a germline sequence different from the germline sequence from which the antibody was originally derived). Is mutated to. In addition, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR region, eg, where a particular individual residue is of a particular germline sequence. Mutated to the corresponding residue, but certain other residues that differ from the original germline sequence are retained or mutated to the corresponding residues of the 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 antagonist or agonist biology. One or more desired properties, such as properties (possibly), reduced immunogenicity, etc., can be easily tested. The use of antibodies and antigen binding fragments obtained in this general fashion is included within the invention.

The present invention also comprises the use of an anti-IL-4R antibody comprising any variant 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 compares, for example, 10 or less, 8 or less, 6 or less, 4 or less, as compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein. Includes the use of anti-IL-4R antibodies having HCVR, LCVR and / or CDR amino acid sequences that include conservative amino acid substitutions such as.

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

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

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. 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. The epitope may be either three-dimensional or linear. The conformational epitope is generated by spatially adjacent amino acids from different segments of the linear polypeptide chain. Linear epitopes result from adjacent amino acid residues in the polypeptide chain. In certain circumstances, the epitope may contain a portion of a saccharide, phosphoryl group or sulfonyl group on the antigen.

According to certain exemplary embodiments of the invention, the IL-4R antagonists are the amino acids of the anti-IL-4R antibodies 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) containing 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 is heavy chain complementarity of heavy chain variable regions (HCVRs) comprising the amino acid sequence of SEQ ID NO: 1. Includes the light chain complementarity determining regions (LCDRs) of the light chain variable regions (LCVR) containing the sex determining regions (HCDRs) and 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 of SEQ ID NO: 3. Contains amino acid sequence; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; LCDR3 Contains the amino acid sequence of SEQ ID NO: 8. In yet another embodiment, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. According to certain exemplary embodiments, the methods of the invention are referred to as dupilumab or bioequivalents thereof and include the use of anti-IL-4Rα antibodies known in the art.

The term "bioequivalent", as used herein, is administered at the same molecular dose such that the effect is considered to be essentially the same as the comparative molecule, both in terms of efficacy and safety. Molecules with similar bioavailability (percentage and degree of availability) later and under similar conditions (eg, the same route of administration). The two pharmaceutical compositions containing the IL-4R antagonist are bioequivalents if they are pharmaceutically equivalent, and they are the same amount of active ingredient (eg, for example) in the same dosage form for the same route of administration. , IL-4R antagonist), which meets the same or equivalent criteria. Bioequivalence can be determined, for example, by in vivo studies comparing pharmacokinetic parameters for two compositions. _{Parameters commonly used in bioequivalence} studies include peak plasma concentration (C max) and area under the plasma drug concentration time curve (AUC).

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

The anti-IL-4Rα antibody used in the context of the methods of the invention may have pH-dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the invention can exhibit reduced binding to IL-4Rα at acidic pH as compared to neutral pH. Alternatively, the anti-IL-4Rα antibody of the present invention can exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH. The expression "acidic pH" is less than about 6.2, for example about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5 .6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 Includes 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, "it reduced binding to IL-4R [alpha] at acidic pH as compared to neutral pH" of the IL-4R [alpha] in _{the K D} value pairs neutral pH of the antibody binding to IL-4R [alpha] at acidic pH It is expressed as a ratio of _KD values of antibody binding (or vice versa). For example, an antibody or antigen binding fragment thereof, where the antibody or antigen-binding fragment thereof exhibits an approximately 3.0 or more acidic / neutral K _D ratio, as compared to the "neutral pH for the purposes of the present invention the acidic It is considered to show "reduced binding to IL-4Rα" at pH. In certain exemplary embodiments, the acidic / neutral _{K D} ratio for the antibody or antigen-binding fragment of the present 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. 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 as compared to neutral pH. In addition, modification of the antigen binding domain at the amino acid level can yield antibodies with pH-dependent properties. For example, by substituting one or more amino acids in the antigen binding domain (eg, in the CDR) with a histidine residue, an antibody having reduced antigen binding at acidic pH relative to neutral pH can be obtained. it can. As used herein, the expression "acidic pH" means a pH of 6.0 or less.

Pharmaceutical Composition The present invention comprises a step of administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained within the pharmaceutical composition, comprising a step. The pharmaceutical compositions characterized in the present invention are formulated with suitable carriers, excipients and other agents that provide suitable transfer, delivery, resistance and the like. Multiple suitable formulations can be found in a collection of formulations known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) -containing vesicles (such as LIPOFECTIN ™), DNA conjugates, anhydrous absorption pastes, etc. Includes 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. Powerell et al. "Compendium
See also "of excipients for partial formulas" PDA (1998) J Pharm Sci Technology 52: 238-311.

The dose of antibody administered to the patient may vary depending on 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. The frequency and duration of treatment is adjusted depending on the severity of the condition. The schedule for administering the effective dosage and the pharmaceutical composition containing the anti-IL-4R antibody is empirically determined; for example, the patient's progression is monitored by regular evaluation and the dose is adjusted accordingly. In addition, interspecific scaling of dosages is performed using methods well known in the art (eg, Mordent 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 composition is administered by any conventional route, eg, by infusion or bolus injection, by absorption through the epithelial or mucosal lining of the skin (eg, oral mucosa, rectum and intestinal mucosa) and is otherwise biologically active. Administered with the drug.

The pharmaceutical composition is delivered subcutaneously or intravenously using standard needles and syringes. Moreover, with respect to subcutaneous delivery, pen-type delivery devices are readily useful in the delivery of pharmaceutical compositions. Such pen-type delivery devices, including automatic injection pen-type delivery devices, may be reusable or disposable. Reusable pen-type delivery devices typically utilize replaceable cartridges containing pharmaceutical compositions. When 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-type delivery device is then reused. There are no replaceable cartridges for disposable pen delivery devices. Rather, the disposable pen-type delivery device is pre-filled with a pharmaceutical composition held in a reservoir within the device. When the pharmaceutical composition is emptied from the reservoir, the entire device is discarded.

Numerous reusable pen-type and automated infusion delivery devices have utility in subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, AUTOPEN ™ (Offen Mumford, Inc., Woodstock, UK), DISETRONIC ™ Pen (Disteronic Medical Systems, Bergdorf, Switzerland), HUMA. 25 ™ Pen, HUMALOG ™ Pen, HUMALIN 70/30 ™ Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN ™ I, II and III (Novo Nordisk, Copenhagen, Denmark) NOVOPEN JUNIOR ™ (Novo Nordisk, Copenhagen, Denmark), BD ™ Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ™, OPTIPEN PRO ™, OPTIPEN (Trademark) (Sanofi-aventis, Frankfurt, Trademark) are included. Examples of disposable pen-type delivery devices that have utility in subcutaneous delivery of pharmaceutical compositions are, but are not limited to, SOLOSTAR ™ pen (sanofi-aventis), FLEXPEN ™ (Novo Nordisk). ) And KWIKPEN ™ (Eli Lilly), SURECLICK ™ Automatic Injector (Amen, Thousand Oaks, CA), PENLET ™ (Haselmeier, Stuttgart, Germany), EPIPEN (Day, L.P. ™ pens (Abbott Labs, Abbott Park IL) are included.

For direct administration to the sinuses, pharmaceutical compositions containing IL-4R antagonists use, for example, microcatheter (eg, endoscopes and microcatheter), aerosolizers, powder dispensers, nebulizers or inhalers. Is administered.

In certain circumstances, the pharmaceutical composition is delivered in a controlled release system. In one embodiment, a pump is used (see Ranger, supra; Lefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201). In another embodiment, a polymeric material is used; Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press. , Boca Raton, Florida. In yet another embodiment, the controlled release system is placed in close proximity to the target of the composition and therefore requires only a portion of the systemic dose (eg, Goodson, 1984, in Medical Applications of Controlled Release, supra, 2). Volume, pp. 115-138). Other controlled release systems are described in the overview by Ranger, 1990, Science 249: 1527-1533.

The pharmaceutical product for injection may include a dosage form for intravenous, subcutaneous, intradermal and intramuscular injection, infusion and the like. These injectable formulations are produced by known methods. For example, an injectable preparation is produced, for example, by dissolving, suspending or emulsifying the above antibody or salt thereof in a sterile aqueous medium or oily medium conventionally used for injection. Aqueous media for injection include, for example, isotonic solutions containing saline, glucose and other auxiliaries, which are alcohols (eg ethanol), polyalcohols (eg propylene glycol, polyethylene glycol). ), Nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hardened castor oil)] and the like used in combination with suitable solubilizers. As the oil-based medium, for example, sesame oil, soybean oil and the like are used, and these are used in combination with a solubilizer such as benzyl benzoate and benzyl alcohol. The injection thus produced is preferably filled in a suitable ampoule.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are made into dosage forms in unit doses suitable to match the dose of the active ingredient. Dosage forms at such unit doses 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 characterized herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to the dose of IL-4R antagonist that produces a detectable improvement in one or more symptoms associated with nasal polyps, or nasal polyps or nasal polyps. Means the dose of IL-4R antagonist that inhibits, prevents, reduces or delays the progression of conditions associated with. For anti-IL-4R antibodies, therapeutically effective amounts are 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, about 340 mg, About 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg , About 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg of anti-IL-4R antibody or antigen binding fragment.

The amount of IL-4R antagonist contained within an individual dose is expressed as milligrams of antibody per kilogram of patient body 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 of patient body weight.

Combination Therapeutic The method according to a particular embodiment comprises administering to the subject one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the expression "in combination with" means that an 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 "before" the pharmaceutical composition containing the IL-4R antagonist, additional therapeutic agents may be administered at about 72 hours, about 60 hours, about 48 hours, after administration of the pharmaceutical composition containing the IL-4R antagonist. Administered 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 Will be done. When administered "after" the pharmaceutical composition containing the IL-4R antagonist, additional therapeutic agents are about 10 minutes, about 15 minutes, about 30 minutes, about 1 of the administration of the pharmaceutical composition containing the IL-4R antagonist. It is administered after 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. Administration of the pharmaceutical composition containing the IL-4R antagonist "simultaneously" means that the additional therapeutic agent is a separate agent within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition containing the IL-4R antagonist. It is meant to be administered to the subject in the form, or to be administered to the subject as a single combination dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

Additional therapeutic agents include, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonist described in US Pat. No. 6,927,044), an IL-6 antagonist, an IL- 6R antagonists (including, for example, the anti-IL-6R antagonist described in US Pat. No. 7,582,298), IL-13 antagonists, TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists. , IL-5 antagonist, IgE antagonist, CD48 antagonist, antibiotic (eg, doxicycline), antifungal drug, leukotriene, antihistamine, α-adrenaline action decongestant, mucolytic drug, NSAID, long-acting beta ₂ agonist (Eg salmeterol or formoterol), short-acting β ₂ antagonists, steroids (eg oral steroids), intranasal corticosteroids (eg mometazone furoate (MFNS; eg Nasonex®)) or inhalation It may be a corticosteroid such as a corticosteroid (eg, fluticazone or budesonide), an allergen immunotherapy, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist combination comprising a long-acting _beta-2 agonist and inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair (R) (GlaxoSmithKline )]; Or administered in combination with budesonide + formoterol [eg, Symbicort® (AstraZeneca)]).

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

Dosage regimen According to certain embodiments, multiple doses of the IL-4R antagonist are administered to the subject over a defined time lapse. The method comprises, for example, the step of serially administering to the subject multiple doses of the IL-4R antagonist. As used herein, "continuously administered" means that each dose of IL-4R antagonist is separated by different time points, eg, predetermined intervals (eg, hours, days, weeks or months). Means to be administered to the subject. The present invention presents a single initial dose of an IL-4R antagonist followed by a single or higher secondary dose of the IL-4R antagonist, and optionally a single or higher tertiary dose of the IL-4R antagonist. Includes methods that include the step of continuous administration to.

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

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

These methods may include 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 secondary doses (eg, 2, 3, 4, 5, 6, 7, 8 or more) 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 that include multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose is administered to the patient 1-2 weeks after the previous dosing. Similarly, in embodiments that include multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient 2-4 weeks after the previous dosing. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient may vary throughout the course of the treatment regimen. The frequency of dosing is also adjusted during the course of treatment by the physician after clinical examination, depending on the needs of the individual patient.

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 times, 2 times, 2.5 times, 3 times or more of the secondary dose.

Treatment Population The method characterized in the present invention comprises the step of administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. As used herein, the expression "subject in need of it" indicates a person who presents with one or more symptoms or symptoms of nasal polyps or is diagnosed with chronic symptoms of nasal polyps or venous sinusitis. Or it means a non-human animal. For example, a subject in need of it has a bilateral nasal polyp, and a nasal polyp score of at least 5 to a maximum of 8 for both nostrils, with a score of at least 2 for each nostril. In certain embodiments, the polyp is in the middle nasal meatus. In certain embodiments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has a bilateral mucosal disease identified by methods such as CT scans. As used herein, "bilateral mucosal disease" is an infection of the mucosal lining of the nasal cavity, eg, the maxillary nasal cavity. In some embodiments, nasal polyps (eg, a score of at least 2 for each nostril and a nasal polyp score of at least 5 to a maximum of 8 for both nostrils) have an INCS of at least 6 weeks, at least 7 weeks, and at least 8 weeks. It persists even after a treatment regimen of inhaled corticosteroids (INCS), such as when administered for or longer.

In certain embodiments, the subject in need of it has anterior and / or posterior mucopurulent drainage, nasal obstruction and reduced sense of smell. In certain embodiments, subjects in need of it have symptoms of nasal polyps for 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In yet another embodiment, the subject is at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks or more before being treated with an IL-4R antagonist. During the above, he has previously been treated with intranasal corticosteroids (eg, MFNS). In some embodiments, the subject continues to receive INCS while being treated with an IL-4R antagonist. In other embodiments, the subject ceases to receive INCS prior to being treated with an IL-4R antagonist, or the subject is effective in treating nasal polyps when administration with an IL-4R antagonist. Stop receiving treatment by INCS. In some embodiments, the subject gradually reduces the dose of INCS before stopping treatment altogether.

Subjects in need of it are further diagnosed with nasal polyps based on one or more of the following: (a) 22-item sinus evaluation test (SNOT-22) score; (b) assessed by subject Rhinorrhea / obstruction, anterior rhinorrhea, posterior rhinorrhea and loss of smell; (c) number of night awakenings; (d) visual to assess the severity of nasal sinusitis associated with the patient Analog score (VAS); (e) Five-item asthma management questionnaire (ACQ5) score in patients with asthma; (f) Maximum nasal inspiratory flow (NPIF); (g) Smell test (University of Pennsylvania Smell Identification Test (UPSIT)) ); (H) Physiological parameters measured by nasal endoscopy, CT scan, etc .; (i) Lund-Muckay score; and (k) Three-dimensional volume measurement of the maxillary sinus.

For example, in certain embodiments, the "subject in need of it" is a human patient with chronic symptoms of venous sinusitis in which at least two of the following symptoms are present: rhinorrhea / obstruction / blockage. Or runny nose (anterior / posterior rhinorrhea); facial pain / tightness; and decreased or lost sensation.

In certain embodiments, the "objects in need of it" are more than about 7, more than about 10, more than about 15, more than about 20, more than about 25, more than about 30, more than about 35, more than about 40, about 45. A human patient with a SNOT-22 score of more than or greater than about 50. "Subjects in need of it" are also over 4, about 5, over 6, about 6, over 7, over 8, over 9, about 9, over 10, over 11, over 12, or over 13 It may be a human patient showing a Lund-Mackay score of.

In a related embodiment, the "subject in need of it" is a subject who has been or is currently receiving another drug, "background treatment", before receiving the IL-4R antagonist. There may be. Background treatment may be, for example, an intranasal corticosteroid (INCS or ICS) such as intranasal spray of mometasone furoate (MFNS; Nasonex®). In some embodiments, the "subject in need of it" is prescribed INCS before receiving an IL-4R antagonist or in combination with a long-acting beta ₂ -adrenergic antagonist (LABA). Or are currently suffering from asthma. Examples of INCS / LABA treatments include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. In some embodiments, background treatments include nasal saline, local decongestants, local anesthetics, leukotriene antagonists or systemic antihistamines. In some embodiments, the "subject in need of it" continues background treatment after the subject has received an IL-4R antagonist, and in other embodiments, the subject in need of it is IL. Stop receiving background treatment (eg, once or gradually) before receiving a -4R antagonist.

The following examples are presented to provide those skilled in the art with complete disclosure and description of the methods and methods of making and using the compositions characterized in the present invention. It is not intended to limit the scope of what is considered. Efforts have been made to ensure accuracy with respect to the numbers used (eg, quantity, temperature, etc.), but some experimental errors and deviations must be taken into account. Unless otherwise indicated, the number of copies is parts by weight, the molecular weight is the average molecular weight, the temperature is degrees Celsius, and the pressure is at or near atmospheric pressure.

Example 1: Subcutaneously administered anti-IL-4R antibody (mAb1) in patients with persistent moderate to severe eosinophil asthma, including asthma patients with chronic hypertrophic eosinophil sinusitis. Clinical study A. Study Objectives and Overview Randomized, placebo-controlled, double-blind, parallel-group studies were partially managed / controlled by inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) treatment. Patients with non-persistent moderate to severe eosinophil asthma were given either 300 mg of dupilumab (“mAb1”) or placebo subcutaneously once a week 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. Dupilumab is described in US Pat. No. 7,608,693.

The main purpose of the study was to administer mAb1 subcutaneously once a week for 12 weeks compared to placebo for a reduced incidence of exacerbation of asthma in patients with persistent moderate to severe eosinophil asthma. It was to investigate the effect. The secondary objective of this study was to assess the safety and tolerability of mAb1 administered subcutaneously once a week for 12 weeks in patients with persistent moderate to severe eosinophil asthma, as well as persistence. It was to assess mAb1 serum levels after weekly subcutaneous dosing for 12 weeks in patients with moderate to severe eosinophil asthma.

Prior to screening, patients had to be on a stable dose of one of the following doses of ICS / LABA combination therapy (also referred to as "background therapy") and prescription for at least one month:
Fluticasone / Salmeterol Combination Treatment-Advir® Discus-Dry Powder Inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or-Advir® HFA-Quantitative Inhaler (MDI): 230/42 ug BID or 460/42 ug BID; or budesonide / formotelol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or mometasone / formosterol combination therapy (Dullera® 200/10 ug BID or 400/10 ug) BID).

Patients who were on budesonide / formoterol or mometasone / formoterol were switched to equivalent doses of fluticasone / salmeterol at randomization (day 1), and patients who were on fluticasone / salmeterol were treated in the background. Remained the same as.

Patients who met inclusion and exclusion criteria (see below) were randomly selected for one of the following treatments: mAb1 300 mg subcutaneously for 12 weeks; or placebo for 12 weeks, It was administered subcutaneously once a week.

The study included a 2-week screening period, a 12-week treatment period including a 4-week background treatment stabilization period after randomization and an 8-week background treatment withdrawal period, 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 additive treatment or treatment with 300 mg mAb1 (or placebo). After 4 weeks of randomization, patients were treated with BID fluticasone / salmeterol combination therapy to equivalent ICS dose of fluticasone monotherapy (250 ug or 500 ug BI).
It was switched to the Fluvent® Discus-DPI formulation of D; or including either the Fluvent® HFA-MDI formulation of 220 ug or 440 ug BID. The LABA component (ie, salmeterol) was discontinued. If the patient did not meet any of the criteria for exacerbation of asthma (as defined below) at subsequent visits, starting at week 6 the fluticasone dose was reduced by about 50%. If asthma exacerbation did not occur, ICS withdrawal proceeded according to the schedule below:

After 12 weeks of treatment with the investigational drug (or after early discontinuation), patients are treated with fluticasone / salmeterol for an additional 8 weeks of out-of-study drug therapy prior to final safety assessment. , Budesonide / formotelol or mometasone / formotelol (dose at study enrollment) and optionally the original dose of albuterol or levalbuterol.

A summary of the research protocol is given in Figure 1.

Adult patients were included in the study based on the following criteria: (1) Doctor's diagnosis of persistent asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2009 Guidelines, The airway inflammation can be eosinophil; and (2) the asthma is partially controlled or managed with inhaled corticosteroid / long-acting beta-agonist combination therapy according to the following criteria: Uncontrolled: (i) Fluticazone / 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), or budesonide / for at least 1 month prior to screening. A stable dose of either formoterol combination therapy (160/9 μg BID or 320/9 μg BID) or mometazone / formoterol combination therapy (200/10 μg BID or 400/10 μg BID); Acid spheres ≥ 300 cells / μl or sputum eosinophils ≥ 3%; (iii) Juniper asthma management questionnaire (5-question version, ACQ) score of 1.5 or more and 3.0 or less at the time of screening; (iv) screening Predicted to be normal at ≥50% FEV during the phase (up to 3 trials) and at randomization the day before the first dose (up to 3 trials); (v) within 2 years prior to screening. Either one or more systemic (oral and / or parenteral) steroid burst treatments for asthma exacerbations, or hospitalization or emergency treatment visits for asthma exacerbations; and (vi) 12 months of screening Within, a reversible documented history that meets at least 12% and 200 mL (up to 3 trials) in FEV1 after 200 μg-400 μg (2-4 inhalations) of albuterol during the reference-screening phase, or A documented history of positive metacholine loading (PD20 metacholine 8 mg or less) 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 of cells equal to or greater than 300 cells per microliter during the screening phase, or 3% or more of sputum eosinophils Patients with asthma were included in the study.

Patients who met all inclusion criteria were screened for the following exclusion criteria: (1) patients under 18 years of age or above 65 years of age; (2) clinically suggesting unknown disease and requiring further evaluation Related abnormal clinical test values; (3) Chronic obstructive pulmonary disease (COPD) and / or other pulmonary diseases that impair lung function testing; (4) Need beta-adrenaline receptor blocker for some reason Patients; (5) Current smoker or quit within 6 months prior to screening; (6) Past smoking history of more than 10 boxes per year; (7) Hospitalization or emergency treatment due to exacerbation of asthma during 2 months prior to screening Visit; (8) Allergen immunotherapy will be started within the study period; (9) Less than 5 half-life of the antibody but 30 days or more, pre-screening period, or unknown half-life of the antibody Exposure to another study antibody within the pre-screening period, if at least 6 months; (10) previous enrollment in the current study; (11) the patient is the investigator, the patient's family, Or was an employee at the laboratory; (12) known or suspected non-compliance, alcohol or drug abuse; (13) inability to follow test procedures (eg, due to language problems or psychological disorders) ); (14) Reversal of sleep patterns (eg, night workers); (15) Treatment with drugs known to prolong the QTc interval; (16) ICS (eg, active or inactive pulmonary tuberculosis) ) Or LABA (eg, diabetes, cardiovascular disease, hypertension, hyperthyroidism, thyroid intoxication, etc.) are contraindicated for concomitant serious illness; (17) within 2 months before screening or 6 before screening Use of injectable glycocorticosteroids or oral systemic glycocorticosteroids for more than 3 processes within months; (18) alone or in combination with non-steroidal controllers (fluticazone / salmeterol combination therapy, budesonide / formosterol combination therapy) Or pretreatment with variable doses of ICS, either (other than mometazone / formotelol combination therapy); (19) patients receiving banned concomitant medications (listed below); (20) doxicycline or related Known allergies to the compound; (21) willingness to become pregnant in the course of pregnancy or testing, refraining from using effective methods of breastfeeding, or contraception; and (22) recent history of parasite infection or 6 months prior to screening After that A trip to a parasite endemic area within.

During the first 4 weeks of the study, patients maintain a constant dose of background asthma treatment, after which the dose of background treatment is gradually reduced. First, the long-acting beta-agonist component of background treatment was withdrawn at week 4, and then the inhaled corticosteroid dose was reduced by half every two weeks until week 12. Patients continued study treatment until the end of the study, or until withdrawal due to exacerbation of asthma or any other reason.

B. Study Treatment Investigator: A sterile mAb1 150 mg / mL solution for SC injection was provided in 5 mL glass vials. Each vial contained a pullable volume of 2 mL. A 300 mg dose was subcutaneously administered to the study site once a week for 12 weeks in the morning. Placebo: Sterile placebo for SC injection was provided in exactly the same matching 5 mL glass vials. Each vial contained a pullable volume of 2 mL. Placebo was subcutaneously administered to the study site once a week for 12 weeks in the morning.

The following combination therapies were not allowed during the study period: either fluticasone / salmeterol combination therapy or fluticasone (or budesonide / salmeterol or mometazone / formotelol during the screening period) given according to the protocol. Inhaled steroids; systemic or ocular steroids; LABA other than the salmeterol component of fluticasone / salmeterol combination therapy administered according to the protocol; any other ICS / LABA combination product other than those listed above; any inhaled anticholinergic agent (Eg, ipratropium bromide or thiotropium); methylxanthine (theophylline, aminophyllin); chromone; anti-IgE therapy; lipoxygenase inhibitor; and leukotriene receptor antagonist or leukotriene synthesis inhibitor.

C. Treatment Efficacy The primary endpoint of this study was the occurrence of asthma exacerbations defined by any of the following: (1) 30 consecutive days from baseline in morning peak expiratory flow (PEF). % Or more reduction; or (2) 6 or more additional asthma treatment puffs of albuterol or levalbutamol (compared to baseline) in 24 hours for 2 consecutive days; or (3) (a) ) Systemic (oral and / or parenteral) steroid treatment, or (b) a four-fold or greater increase in the last dose of ICS received prior to discontinuation from the study, or (c) investigative responsibility requiring hospitalization Exacerbation of asthma as determined by the doctor.

Secondary endpoints of the study included mean changes from baseline in the following parameters: evaluated at baseline and at the end of treatment (week 12) to assess upper respiratory tract symptoms, (1). ) 1-second forced expiratory volume in liters measured at each visit (FEV1); (2) Maximum morning and evening expiratory flow at liters / minute measured daily (AM PEF and PM PEF); (3) ) Daily use of albuterol / levalbuterol by inhalation / day; (4) 5-item asthma management questionnaire (ACQ5) score per visit; and (5) daily measured night arousal (number of times per night) ), And (6) 22-item sinus evaluation test (SNOT-22). Secondary endpoints are also base in the morning PEF for 2 consecutive days, 24 hours (compared to baseline) with 6 or more additional seizure treatment puffs of albuterol or levalbuterol. Included was the proportion of patients with complex asthma events defined by a 30% or more reduction from the line. PEF, ACQ5, asthma symptom score, nocturnal arousal, and seizure medication therapeutic use were obtained in an electronic diary. Average daily night awakenings ranging from 0 to 10 were averaged from the previous 7 days. Morning and evening asthma symptom scores consist of results reported by unverified patients evaluated on a 5-point Likert scale, with higher scores showing worse results (Table 2). Patients recorded overall symptom scores twice daily before measuring PEF. Data are shown as an average of the 7 days prior to the time of identification.

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

An adverse event (AE) is an adverse medical event in either a drug-administered subject or a clinical review subject. Therefore, AE is any undesired unintended sign (including abnormal laboratory findings) that is temporally related to the use of the drug, whether or not it is considered to be associated with the drug (clinical trial) product. It can be a symptom or a disease. AEs are also: Deterioration of any of the existing conditions (ie, clinically significant changes in either frequency and / or intensity) that are temporally related to the use of the study drug; clinically by the investigator Abnormal laboratory findings considered significant; and include any adverse medical events.

Serious adverse events (SAEs) result in death at any dose; life-threatening; require hospitalization or extension of current hospitalization; persistent or significant disability / incapacity Any adverse medical event that is a congenital anomaly / congenital defect; or a serious medical event.

E. Statistical Methods For a primary analysis of the proportion of patients who experienced exacerbation of asthma, a logistic regression model was used to compare the SAR group to placebo. This model included a section on treatment and stratification factors (preceding ICS / LABA combination therapeutic doses). The primary analysis was based on a modified intention-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 support the primary analysis.

For secondary efficacy endpoints, with the exception of SNOT-22, changes from baseline were analyzed using a mixed-effects model using a iterative measurement (MMRM) approach. The model is based on changes from baseline values up to 12 weeks as response variables, and treatment factors (parameter effect), stratification factors, visits, visit-to-treatment interactions, baseline values and visits. Included baseline interactions. Statistical inferences for treatment comparisons for changes from baseline at week 12 were derived from a mixed-effects model. Changes from baseline in SNOT-22 were analyzed using analysis of covariance analysis (ANCOVA) and end-of-treatment measurements to complement missing data. The pharmacodynamic effect was evaluated using the MMRM model in a post-hoc manner. No adjustment was made for multiplicity as there was only one primary endpoint and analysis. Safety variables including AE, test parameters, vital signs, ECG, laboratory findings and physical examination were summarized using descriptive statistics.

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

F. Results The results observed in all 104 randomized patients (screened from 491) who completed or discontinued the treatment phase of the study are summarized below. All randomized patients were exposed to the study procedure and included in the mITT population. Baseline features were similar between groups. Demographics and clinical features were similar between the two groups (Table 3). As shown above, patients were treated with either 300 mg subcutaneous mAb1 or placebo once a week. The study procedure period was completed in 86.5% and 67.3% of patients with mAb1 and placebo, 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 Table 4 shows the incidence of exacerbation of asthma in the placebo and mAb1 treatment groups.

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%) in the placebo group experienced exacerbation of asthma, while only three patients (5.8%) in the mAb1 treatment group experienced exacerbation of asthma. The odds ratio was 0.077 (p <0.0001) and the relative risk reduction was about 87%.

This study demonstrates the need for immediate intervention in the form of treatment with either systemic corticosteroids or inhaled corticosteroids that are four or more doses taken prior to the event. Of the 26 exacerbations of asthma experienced during the period, 9 were considered severe. Table 5 summarizes the incidence of exacerbations of severe asthma.

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

At mAb1, the time to exacerbation was longer and the risk of exacerbation was reduced compared to placebo (hazard ratio 0,10; 95% CI 0.03, 0.34; P <0.001). An analysis of the time to asthma exacerbation by Kaplan-Meier plot shows that the effect of treatment with mAb1 persists for a long period of time, including 8 weeks after the patient is at higher risk of developing exacerbations due to steroid withdrawal. It was made clear that it would be done.

Only one patient from the placebo group had a compound asthma event. Combined asthma events occur at 24 hours (compared to baseline) for 2 consecutive days, with 6 or more additional seizure treatment puffs of salbutamol or levalbutamol, for 2 consecutive days from baseline in the morning PEF. It is defined as a reduction of 30% or more.

(Ii) Other efficacy endpoints Pulmonary function parameters (FEV1, AM PEF and PM PEF), asthma symptom-based endpoints (ACQ score, nocturnal arousal), and albuterol use were evaluated for each patient at each visit. In addition, SNOT-22 scores were evaluated at baseline and at the end of treatment. For all parameters, baseline and 12-week (LOCF) mean values are summarized in Table 7 (ANOVA model for SNOT-22) with mean differences between treatment groups. In Table 7, the column labeled "Differences relative to placebo" is a placebo correction from baseline that takes into account the observed changes in the value of the parameter compared to the changes observed for that parameter in the placebo treatment group. Indicates a value.

Treatment with mAb1 produced a significant change from baseline in FEV1 at week 1, which was maintained until week 12 despite LABA and ICS withdrawal, and at the same time with LABA withdrawal at week 5 FEV1. Decreased slightly. Similar improvements were observed in the morning PEF, but less in the evening PEF. The least squares (LS) mean change from baseline in FEV1 up to week 12 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, ACQ5 improved further with mAb1 between the 1st and 4th weeks, but the placebo effect stabilized and maintained the difference until the 12th week.

Morning symptomatology scores increased with placebo from baseline to 12 weeks. At mAb1, there was an initial decrease that remained below baseline until 12 weeks. A similar pattern (larger variation) was observed in the nocturnal asthma symptom score.

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

Changes in salbutamol / levalbutamol use were similar to other secondary endpoints: returned to baseline after an initial reduction at placebo. At mAb1, the initial decrease was maintained over time.

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

For all secondary endpoints, except for night PEF and nocturnal arousal, 12-week measurements were favorable and significant with mAb1 treatment (Tables 7 and 8). Significant improvement in mAb1 was also observed for three SNOT-22 items associated with upper respiratory tract disease (Table 9).

(Iii) Safety mAb1 was generally safe and showed good tolerability. Treatment-induced adverse events (TEAEs) were similarly reported by 40 (76.9%) placebo-treated patients and 42 (80.8%) mAb1-treated patients (Table 10). .. TEAEs were non-specific, generally mild to moderate intensity, and most recovered by the end of the study. The following increased reports of TEAE 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; 6 (11.5%) mAb1 patients and 3 (11.5%) headaches 5.85) was reported by placebo patients, and nausea was reported by 4 (7.7%) mAb1 patients and 1 (1.9%) placebo patients.

No deaths were reported during the study period. Serious adverse events (SAE) that occurred under the four reported treatments: one mAb1 patient experienced bipolar disorder, and three placebo patients had asthma with pneumonia, gunshot wounds with left pneumothorax, and I experienced a SAE with a fracture of my right ankle. None of these SAEs were considered associated with mAb1 and all but new ankle fractures had recovered by the end of the study. There was no death.

A total of 6 patients discontinued the study due to TEAE: 3 patients in the mAb1 group (bipolar disorder, asthma with wheezing and vascular edema) 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 as a common pruritic rash observed at and away from the injection site after the ninth study treatment dosing. This lasted for 1 week and resolved after discontinuation of study treatment and treatment with prednisone and diphenhydramine. This was considered to be treatment related. This AE was after a milder rash at the injection site after the first and sixth study treatment dosing.

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

G. CONCLUSIONS: Significant improvements were observed in lung function and other asthma management parameters. Despite the background treatment withdrawal, efficacy was observed early and persistently. A relative reduction of approximately 87% (p <0.0001) in the primary endpoint of the incidence of exacerbation of asthma in patients with persistent moderate to severe asthma with eosinophilia was placebo (44.2%). ), Which was observed after 12 weeks of treatment with 300 mg mAb1 once weekly (5.8%). As shown in Table 7, clinically significant (no spirometry) improvement in treatment compared to placebo is associated with lung function parameters (FEV1, PEF AM), asthma symptom score (ACQ). ) And with albuterol use. Beneficial tendencies were observed for PEF PM (p = 0.0567) and nocturnal arousal (p = 0.0518). A statistically significant (no multiplicity adjustment) improvement was also observed for the SNOT-22 score. Within the active treatment group, sustained improvement over baseline was observed during the course of the study for all parameters, despite LABA and ICS withdrawal. mAb1 was generally safe and showed good tolerability.

Example 2: Biomarker study Biomarker analysis was performed on samples obtained from subjects who participated in a mAb1 clinical trial (see Example 1 above). In particular, it is associated with TH2 inflammation such as thymus and activated chemokines (TARC; CCL17), immunoglobulin E (IgE), eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and plasma eosinophils. Serum / plasma biomarkers were measured in samples from patients at baseline and at different time points after the start of the study procedure. Baseline levels of these biomarkers were evaluated for potential predictions for treatment response. In addition, exhaled NO concentration (FeNO) and induced sputum eosinophils and neutrophils were measured as biomarkers of bronchial inflammation. Expiratory nitric oxide assessments were performed using NIOX instruments (Aerocline AB, Solna, Sweden) prior to spirometry and after at least 1 hour of fasting. Biomarkers are analyzed using a mixed model and the least squares averages derived from the model are reported below.

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

TARC, eotaxin-3 and IgE remained unchanged in response to placebo. In contrast, TARC (mean% change + 0.3% vs. -22.7%; p = 0.0003) and eotaxin-3 (mean% change 12.69% vs. -39.62%; p A rapid decrease of <0.0001) was observed within 1 week in patients treated with mAb1 and persisted up to 12 weeks: TARC: + 7.6% -26.0% (p = 0) relative to placebo. 0005); Eotaxin-3: +5.13% -45.67% (p <0.0001) relative to placebo.

TARC levels responded within 1 week after exposure to mAb1 subcutaneously administered at 300 mg. TARC levels remained constant at approximately 50% of baseline levels in subjects treated with mAb1, regardless of ICS withdrawal. The data show that TARC expression is more directly associated with IL-4R signaling than FEV1 changes (which decreased in parallel with ICS withdrawal [4 weeks later]), and that IL-4R blockade. However, it induces a shift to TH1 features, as observed, for example, with IFN gamma administration. It may be possible to titrate mAb1 doses using TARC (and eg CXCL10), especially in patients who require long-term treatment and are at risk for TH1 type immune disease.

Total serum IgE was also reduced after mAb1 treatment. The total serum IgE response was more heterogeneous and was delayed compared to the TARC response. Mean (SD) baseline IgE levels were 694.68 IU / L (1837.82) for the placebo group (n = 52) and 657.66 (1482.25) for the mAb1 group (n = 52). On the other hand, the median was 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend of reduced IgE was observed in patients exposed to mAb1 compared to placebo, but 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), which began at week 4 and was 12 weeks. Continued to decrease (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 were all favorable for mAb1 (all P <0.001) (Table 11). No differences from baseline or between treatments were observed with YKL-40 or CEA.

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

Only three mAb1 patients experienced exacerbation of asthma during the study, so no conclusions were reached regarding the association between baseline biomarker levels and exacerbation of asthma.

mAb1 treatment was also associated with a significant reduction of FeNO from baseline at week 4, and despite ICS withdrawal, FeNo remained below baseline until week 12 (mean% at week 12). Changes: -28.7 for mAb1 vs. p <0.0001 for 35.0 for placebo. In contrast, placebo FeNo levels remained stable until week 8 and then increased at week 12, consistent with ICS withdrawal.

The improvement in forced expiratory volume (FEV ₁ ) for 1 second was significantly correlated with the decrease in FeNO (r = -0.408, p = 0.009) at 12 weeks. Similarly, improvements in AM-PEF and PM-PEF correlated with a decrease in FeNO. Other correlations with FeNO were not significant. See Table 13.

Spirometry of changes from baseline in baseline eosinophils vs. FEV1 at week 12 was measured by changes in FEV1 from baseline at week 12 in the study population and was measured with baseline eosinophils and therapeutic effects. It did not appear to be associated with (baseline eosinophils ≥ 0.3 giga / L). Baseline eosinophils were correlated with reduced ACQ and reduced salbutamol / salbutamol use. Periostin and YKL-40 at baseline were correlated with reduced ACQ.

The FEV1 change from baseline at week 12 was exacerbated by the withdrawal of ICS (starting at week 4). Similar analysis did not suggest an association between baseline TARC or IgE and changes in FEV1 from baseline at week 12 in the study population (baseline eosinophils ≥ 0.3 giga / L). It was.

H. Summary These results indicate that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, eotaxin-3 and IgE) and bronchial inflammation (FeNO) in adult asthma patients. The correlation between decreased FeNO and _{improved FEV 1} 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 trials of subcutaneously administered anti-IL-4R antibody (mAb1) in patients with chronic symptoms of bilateral nasal polyps and venous sinusitis A. Study Objectives and Summary The positive effect of mAb1 on the SNOT-22 study described in Example 1 suggested that anti-IL-4R antibodies could also be effective in treating nasal polyps. In addition, nasal polyps were most commonly driven by eosinophilia / TH2, with mAb1 significantly reducing biomarkers associated with Th2 inflammation (see Example 2). Therefore, a clinical trial was designed to test the therapeutic effect of mAb1 on nasal polyps.

A study of two treatment groups, randomized, double-blind, phase II, and placebo-controlled, was conducted once a week (QW) for 16 weeks in patients with chronic symptoms of bilateral nasal polyps and venous sinusitis. It was performed to evaluate mAb1 administered subcutaneously (SC). The main purpose of the study was to assess the efficacy of mAb1 in the treatment of bilateral nasal polyps (NP) by assessing endoscopic nasal polyp scores compared to placebo. Secondary objectives of the study were based on symptoms of venous sinitis, computed tomography (CT) scan changes, nasal polyp scores in a subgroup of patients with comorbid asthma, safety and tolerance, and suppression of TH2 biomarkers. Bilateral nasal polyps with respect to the medicinal response, the concentration of mAb1 in the serum, the immune response to mAb1 (anti-drug antibody (ADA)) and the effect of mAb1 on the results reported by the patient and the scale of quality of life (QoL). Included an assessment of mAb1 in patients with.

mAb1 was administered at the same time as the intranasal spray of mometasone furoate (MFNS). Patients are also subject to asthma, aspirin / non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, and high co-morbidity of NP with previous surgery, unless one of the exclusion criteria listed below is present. , Registration for research was allowed. Approximately 56 patients were randomized into two treatment groups of 28 patients per group. If approximately 28 patients without asthma were randomized to ensure that at least 28 patients with co-morbid asthma were included in this study, then NP patients without co-morbid asthma Stopped mobilization. We were blinded to the treatment group to which both the patient and the investigator were assigned.

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

The primary endpoint changed from baseline in the bilateral nasal polyp score (NPS) at 16 weeks.

Many secondary efficacy endpoints were measured to more comprehensively assess the efficacy of mAb1. The study was a condition-specific and overall medical questionnaire to gain a better understanding of the effects of severe nasal polyps on the subject's quality of life (QOL), improvement of nasal polyps and associated sinusitis on CT scans. I investigated the improvement.

Together with experimental subgroup analysis and biomarkers, these endpoints provided information on the therapeutic value of mAb1 to lower nasal polyp scores and improve symptoms in NP and its subsets. Persistence of effect was also examined throughout the 4-month post-treatment evaluation period.

A 300 mg QW dose regimen was predicted to saturate the apparent target-mediated clearance levels (10-15 mg / L). This regimen has been tested and has provided statistically significant and clinically relevant responses in two previous evidences of conceptual studies conducted with mAb1 in asthma and atopic dermatitis (eg, supra). Example 1, USSN61 / 805977 and USSN61 / 816191). The initial dose utilized a loading dose of 600 mg to achieve stable concentrations more quickly. This loading dose range was supported by the tolerable safety profile of the highest loading dose (600 mg) demonstrated in previous studies conducted in healthy Japanese subjects.

In addition, the Cmax after a loading dose of 600 mg was about 70 mg / L, the steady-state Ctrogh of 300 mg QW was about 150 mg / L, and the proposed dosing regimen (ie, a loading dose of 600 mg, followed by a QW of 300 mg). ) Later Cmax is 12 mg / kg
Given that the IV dose (421 mg / L) is below the average Cmax, the highest single dose tested in healthy subjects showing good tolerability has a safety profile to which this dose regimen is acceptable. It provided additional credibility that it should be.

Patient enrollment criteria include (i) despite the completion of bilateral nasal polyp physician endoscopic diagnosis (ie, previous INCS (nasal corticosteroid) treatment during at least 8 weeks prior to screening. With a score of at least 2 for each cavity, a minimum bilateral nasal polyp score of 5 to a maximum of 8) for both nasal passages, and (ii) before screening the following symptoms: rhinorrhea / obstruction / blockage or nasal polyps (before / after) Rhinorrhea); facial pain / tightness; and chronic symptoms of venous sinusitis in which at least two of the decreased or lost sense of smell are present.

Patients who met these criteria were screened for the following exclusion criteria: ages <18 or>65; any technical / administrative reason for not being able to randomize patients in the study; either mAb1 Previous participation in clinical trials; SNOT22 score of less than 7; any other trial drug under study or treatment prohibited for this study within 2 months prior to screening or 5 half-life, whichever is longer Have received; received oral corticosteroid (OCS) or intranasal corticosteroid droplets within 2 or 1 months prior to screening, or received OCS for another condition during the study period Is planned; treatment with mAB or immunosuppressive therapy; treatment with antiimmunoglobulin E (IgE) treatment (eg, omalizumab) within 130 days of visit 1; continuous treatment for at least 30 days prior to visit 1. Treatment with leukotriene antagonist / modifier for patients who did not continue; plan to start allergen immunotherapy within 3 months prior to visit 1 or during screening or randomized treatment period; pre-screening Any nasal surgery within 6 months or more than 5 sinus surgery in the past, up to 2 of which have changed the lateral wall structure of the nose; or the patient is unable to evaluate the primary efficacy endpoint / Comorbidities (eg, posterior nasal mushrooms; nasal septal deviation that occludes at least one nasal hole; acute venous sinusitis, nasal infection or upper airway infection at or 2 weeks before screening; ongoing drug-induced rhinitis Charg-Strauss Syndrome, Young Syndrome, Cartagener Syndrome or Hairy Diskinezy Syndrome, Cystic Fibrosis; Signs of Allergic Fungal Nasal Syndrome or Suggested by CT Scan). Patients with co-morbid asthma were excluded if: Patients had less than 60% forced expiratory lung activity (FEV1); systemic (oral and / or parenteral) steroid treatment or hospitalization (24) for the treatment of asthma Exacerbations requiring (more than an hour) occurred within 3 months prior to screening; or the patient was receiving doses greater than 1000 μg of fluticasone or equal doses of inhaled corticosteroids. Other exclusion criteria include patients who are expected to have a short lifespan (less than 6 months); patients who are undergoing combination treatments prohibited in the study; women who are pregnant or willing to become pregnant during the study. Or include lactating women. Other exclusion criteria include concomitant severe illness (eg, active and inactive pulmonary tuberculosis, diabetes, etc.); diagnosed active parasite infection; suspected or high risk of parasite infection; human immunodeficiency History of viral (HIV) infection or positive HIC screening at 1 visit; evidence of acute or chronic infection; invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidiosis) regardless of whether the infection has healed , Pneumocystis disease, Aspergillosis), known or suspected immunosuppression; planning vaccination during live vaccination or study within 12 weeks prior to visit 1; active autoimmune disease Immunosuppressive therapy for patients with or autoimmune diseases (eg, Hashimoto thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis) Patients using; Patients with positive or uncertain hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibody at 1 visit; liver injury-related criteria (eg, endogenous) Includes patients with hepatitis bile disease or ALT> 3ULN).

B. Study Treatment Investigator: Various concentrations of sterile mAb1 were provided in 5 mL glass vials. Each vial contained a pullable volume of 2 mL: 150 mg / mL solution (300 mg dose / 2 mL). Sterile placebo was provided in exactly the same matching glass 5 mL vials, each vial containing a deliverable volume of 2 mL.

mAb1 was administered every 7 ± 2 days (QW). Dosing of mAb1 avoided overdosing at intervals of 5 days or more. Two injections were performed at visit 2 (V2). After V2, a single injection of mAb1 was given weekly at the study site throughout the randomized treatment period. MAb1 was administered after clinical treatment and blood sampling. 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 a quarter of the abdomen (avoiding the navel and lower back) or the upper thigh so that the same site was not injected twice / week in a row.

Every day during the study, subjects used an electronic diary to record their daily use of MFNS. Mometasone furoate (NASONEX®) 50 micrograms / intranasal spray actuation was included in the bottle, which bottle contained 18 g (140 actuation) of the formulation.

Screening Period: Prior to screening, subjects should continue to receive stable doses of intranasal corticosteroids (INCS) at least 2 months prior to visit 1. If the patient used an alternative INCS preparation other than MFNS before the screening visit at V1, the patient switched to MFNS. After V1, all patients were enrolled for a 4-week study period and unless the patient was intolerant of BID INCS (in which case the patient could remain in the low dose (QD) regimen), the patient was given MFNS: Twice a day (BID) Each of the nostrils was administered twice daily (50 μg / actuation) (400 μg total daily dose). To be accepted in this study, patients had the following symptoms before screening: nasal obstruction / obstruction / blockage or runny nose (anterior / postnasal drip); +/- facial pain / tightness or +/- decreased sense of smell. Or at least two of the losses must be present.

Treatment period: The treatment period proceeded as shown in the study flowchart in Table 14.

During the treatment period, the patient continued stable dosing of mometasone furoate: two activations of MFNS in each nostril BID or QD (if the patient cannot tolerate high doses). At visit 2, patients were asked to take the SNOT-22 study, VAS and QoL questionnaires (SF-36, EQ-5D, questionnaires using materials related to nasal polyps), olfactory tests and ACQ- in patients with asthma. Received 5.

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

Temporary discontinuation of treatment was considered by the investigator due to suspected AE. Careful resumption of treatment with mAb1 if the investigator considers that the role of mAb1 in the occurrence of related events is unlikely to occur and further meets the selection criteria for the study, according to optimal medical judgment. Performed under appropriate clinical / and / or laboratory monitoring.

An adverse event (AE) is any adverse medical event in a patient who is administered a drug and does not necessarily have a causal relationship with this procedure or in a clinical trial patient.

Serious adverse events (SAEs) are any adverse medical events at any time of medication: death-causing or life-threatening (“life-threatening” in the definition of “serious”). The term refers to an event in which the patient is at risk of death at the time of the event; if more severe, it does not refer to an event that could cause death by assumption); admission of an inpatient or extension of an existing hospitalization. Necessary, or persistent or serious disability / incapacity, or congenital / birth defect; reports processed are not immediately life-threatening, or death or hospitalization Although not resulting, it may endanger the patient or requires intervention (ie, specific means or corrective action) to prevent one of the other consequences described above. Medical and scientific judgments of medically important events that should be made in determining whether they are suitable in other situations, such as gaining significant medical events (below medically important events). The list is intended to serve as a guideline for determining that a condition should be considered a medically significant event). The list is not intended to be comprehensive: intensive treatment in the emergency room or at home: allergic bronchial spasm, anaphylaxis, blood disorders (ie, syncope, poor regenerative anemia, myelodystrophy, bone marrow) Diagnosis, panthroplasty, etc.), convulsions (seizures, epilepsy, seizures of epilepsy, absence, etc.), onset of drug dependence or drug abuse; 10 × ULN; Suggestions of any event of attempted suicide or suicide tendency; syncope, loss of consciousness (unless documented as a result of blood sampling); bullous skin rash; diagnosed or studied during the study Cancer exacerbated during; chronic neurodegenerative disorders (newly diagnosed) or exacerbated during studies (especially determined to be abnormal / serious by the investigator in studies assessing the efficacy of research agents in these disorders) Only if).

Post-Treatment Period: At the completion of the randomized treatment period (or after an early discontinuation of mAb1), the patient continued treatment with a stable dosing of MFNS maintained over the randomized treatment period, or medically. The treatment was modified based on the judgment.

The following combination treatments were not permitted during the screening and randomized treatment periods: intranasal medications (anti-histamines, nasal aspirin, ipratropium bromide, nasal) that interfere with the symptoms of the disease except nasal physiological saline. Use of chromolin); INCS drops; systemic corticosteroids; decongestant (local or systemic) except previous endoscopy; long-term use of systemic antibiotics (2 weeks or more); lipoxygenase Inhibitors; any immunosuppressive treatment including, but not limited to, methotrexate, cyclosporin, mycophenolic acid, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (IgE) Treatment (omalizumab); and aspirin or NSAIDs in patients with hypersensitivity to aspirin.

The following combination treatments were acceptable: MFNS during screening and throughout the study; nasal saline; topical congestive congestants (eg, oxymetazoline hydrochloride to reduce swelling and widen the passage for endoscopy) Zolin), and local anesthetics (eg lidocaine was tolerated prior to endoscopy); short-term use of antibiotics (less than 2 weeks); and for patients with asthma, SABA, LABA and methylxanthine (eg Lidocaine). , Theophylline, Aminophylline). The following inhaled corticosteroids are tolerated in patients who continue on stable doses of 1000 μg or less of fluticasone (or another inhaled CS of equal dose; see Table 16), 30 days prior to visit 1. Only patients who continued to have stable doses above were tolerated: leukotriene antagonists / modifiers were tolerated only to patients who continued continuous treatment for at least 30 days prior to visit 1 during the study; synthetic anti Histamine; and initiation of allergen immunotherapy (prescribed allergen immunotherapy was allowed for at least 3 months prior to visit 1).

C. Treatment Efficacy The primary endpoint of this study is the change from baseline in bilateral endoscopic nasal polyp scores at 16 weeks.

Nasal endoscopy was performed at the end of the planned visit and preceded topical administration of an anesthetic in combination with a decongestant. You downloaded a standard video sequence or sent it to a centralized reader. Centralized image data evaluation and scoring by an independent physician reviewer of the image data was performed for all endoscopy. Only V1-centric reads were made available to the site to confirm eligibility in V2. The final result of the central reading was made available after the study.

For the analysis of the primary endpoint, the V2 central reading was used for comparison with the EOT reading. The site removed the subject-identified information from the image data header before sending the image data to the central reader.

Secondary endpoints of the study were patient-reported symptoms (including 22-item sinus evaluation study (SNOT-22)); subject-assessed nasal congestion / obstruction, anterior rhinorrhea (runny nose), posterior nose. Leakage (post-nasal drip) and loss of smell, monthly average (daily AM and PM electronic diary); number of night awakenings; severe nasal sinusitis symptoms associated with patients using visual analog scale (VAS) Degree; 5 items in the asthma subgroup Asthma management questionnaire (ACQ-5); Maximum nasal inspiratory flow (NPIF); Smell test (UPSIT); NPS in patients with coexisting asthma; CT scan evaluation; Pulmonary activity measurement (overall and Subgroup with asthma); Time to first response in NPS (1 point or more improvement); Time to study treatment discontinuation; and at 16 weeks in the occurrence of treatment discontinuation due to the need for OCS or nasal surgery Included changes from baseline.

Quality of life (QoL) endpoints are 36-item informal health survey (SF36); European quality of life scale (EQ-5D); and 16-week basis on questionnaires using materials related to nasal polyps. Included changes from the line.

Disease-specific efficacy measurements include: Computed Tomography (CT). Cave CT should be performed during EOT before V2. For both the Lund-Muckay score and 3D volumetric measurements of the maxillary sinus, the same acquisition (sequence) was used for centralized image data evaluation and the image data was scored by an independent physician reviewer. The center reading of V2 was used for comparison with EOT. The final result of the central reading was made available after the study.

For three-dimensional volumetric measurements of the maxillary sinus, the pre-V2 center reading was used for comparison with the EOT reading. The site removed the subject-identified information from the image data header before sending the image data to the central reader. The% change in EOT turbidity was calculated from BL.

At screening (visit 1), patients issued NPIF measurements to record morning (AM) and evening (PM) NPIF. Patients were instructed to record the following changes in their daily electronic diary: NPIF of AM performed within 15 minutes after occurrence (between 6 am and 10 am) prior to receiving MFNS; and night 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 in the electronic diary by the patient and the highest value was used for evaluation. The baseline of AM NPIF was the mean AM measurement recorded during the 28 days prior to the first dose of study drug, and the baseline of PM NPIF was recorded during the 28 days prior to the first dose of study drug. It was an average PM measurement.

To assess the daily symptoms specific to the disease, patients: 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms. ), Individual nasal sinusitis questions in the morning and evening, including symptoms of blockage and / or obstruction, anterior rhinorrhea (nasal drip), posterior rhinorrhea (postnasal drip) and loss of olfactory sensation. I used an electronic diary to answer. The number of night awakenings was also recorded.

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

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

Optional sampling for preliminary analysis of DNA and RNA requiring separate pharmacogenetics informed consent.

Pharmacokinetics. Functional mAb1 and anti-mAb1 antibodies in serum were assayed by ELISA. Pre-dose functional mAb1 concentration in serum at visit 2 (1 day), mAb1 trough concentration at 2, 4, 8, 12, and 16 weeks, and 20, 24, 28, and 32 weeks. The follow-up serum mAb1 in. Anti-mAb1 antibody status (negative or potency value) at visit 2 (1 day), 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks and 32 weeks was also provided.
Patients with an ADA titer of 1000 or higher at the end of the study visit were planned to be returned after approximately 6 months for further assessment of the ADA titer. Further follow-up was considered based on an overall assessment of antibody titers and clinical findings.

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

Rhinorrhea was obtained by inserting a cotton swab for nasal passage into the nasal cavities on both sides for 5 minutes. Rhinorrhea was stored for further biomarkers associated with nasal polyps and possible analysis of response to mAb1 treatment.

Nasal polyp tissue was optionally obtained by biopsy at selected clinical sites using 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).

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

DNA and RNA samples could be used to determine possible relationships between genes and responses to treatment with mAb1 and possible side effects on mAb1.

Analysis of the proportion of patients with two-component events. Percentage of patients with bicomponent events was assessed: 1 point or more improvement (decrease) in NPS at 16 weeks (read centrally); 10% or more improvement in CT opacity from baseline at 16 weeks; Logistic model with oral CS or surgical descent; or increased INCS after 8 weeks as pre-study stratification factors as response variables and treatment groups, pooled countries / regions and covariates, respectively. Was analyzed using.

Analysis of time-event changes. Time-events (eg, initial response with 1 or more points of improvement (decrease) in NPS, discontinuation of study treatment, etc.) as dependent variables: time-events and treatments, pooled countries / regions, covariates before study Was analyzed using a Cox regression model with comorbidities with asthma. The Kaplan-Meier method was used to derive the proportion of patients with events specific to each treatment group at 4, 8, 12 and 16 weeks. For analysis during the treatment period, if the patient had no events prior to treatment discontinuation / completion, the patient was considered event-free until the end of the treatment period (last dosing day + 7 days).

Analysis of changes from baseline for continuous variables. NPS for patients with co-morbid asthma; Lund Mackay score; 22-item sinus evaluation test (SNOT-22); clogging and / or obstruction score assessed by the subject; maximum nasal inspiratory flow (NPIF); co-morbid asthma ACQ-5; QoL measurements (SF36, EQ-5D) and changes from baseline in VAS at 16 weeks in patients with had were analyzed using the same MMRM as the primary endpoint. Descriptive statistics including patient number, mean, standard error and LS mean were provided. In addition, differences in LS mean, corresponding 95% Cl and p values were provided for comparison of each dose relative to placebo.

Analysis of efficacy in baseline biomarkers of a well-defined subset. To test baseline biomarkers for their potential values to predict treatment response, analysis of NPS changes was also performed with the following subset and the entire ITT population with each dosing group and selected pooled dosing. Performed on groups.

Subgroup analysis. Consistency across subgroup levels Preliminary subgroup analysis, age group, gender, region, to assess treatment efficacy and test baseline biomarkers for their potential values to predict treatment response , Race, INCS dose level, baseline NPS, baseline CT scan score, asthma comorbidities and changes from baseline in NPS for biomarkers selected prior to the study.

The items of anti-mAb1 antibody results (negative or antibody titer) were represented by patient, time point and treatment group. ADA titer levels are categorized: low, medium and high. A low level ADA titer is defined as a titer less than 1000; a medium level ADA titer is defined as a titer between 1000 and 10,000; a high level ADA titer is defined as a titer above 10,000. Defined as titer.

The results of the anti-mAb1 antibody assay are categorically described. The following abstracts were provided: Patients with any positive ADA assay response during the TEAE period; Patients with treatment-induced positive ADA assay response during the TEAE period; Treatment-induced during the TEAE period Patients with positive ADA assay reactions were further described as patients with transient positive reactions and patients with persistent positive reactions. Patients with any positive ADA assay response during the TEAE period were defined as having at least one sample that was positive in the ADA assay.

Treatment-induced positive ADA assay response: Patients who do not have a positive assay response at baseline but have a positive assay response during the TEAE period or who have a positive ADA assay response at baseline and also have a TEAE period. Defined as a patient whose titer increased at least 4-fold during the period.

Persistent positive reactions are treatment-induced positives in which at least two consecutive post-baseline samples from the patient are positive in the ADA assay or the last post-baseline sample taken is positive in the ADA assay. ADA assay reaction. A transient positive reaction is defined as a positive ADA assay reaction induced by any treatment that is not considered persistent.

The present invention is not limited in scope by the particular embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the above description and accompanying drawings. Such modifications are intended to be within the appended claims.

Claims (28)

A pharmaceutical composition comprising an antibody that specifically binds to an interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof for use in a method of treating nasal polyps, wherein the method is the pharmaceutical composition. The subject has been prescribed or is currently receiving background treatment for nasal polyps, the antibody or antigen-binding fragment thereof, comprising the step of administering to a subject in need thereof. It comprises a light chain CDR sequence of 8 and a heavy chain CDR sequence of SEQ ID NOs: 3, 4 and 5, where the method optionally treats bilateral nasal polyps and the background treatment comprises systemic corticosteroids. , The pharmaceutical composition. Subjects have one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, or have undergone surgery for nasal polyps. The pharmaceutical composition according to claim 1. The pharmaceutical composition according to claim 1, wherein the antibody or antigen-binding fragment thereof is administered at a dose of 0.1 mg to 600 mg, 100 mg to 400 mg, or 300 mg. The pharmaceutical composition according to claim 1, wherein the antibody or an 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. below:
(A) The pharmaceutical composition is systemically administered to the subject;
(B) The pharmaceutical composition is administered topically to the subject;
(C) The pharmaceutical composition is administered to the subject subcutaneously, intravenously, or intranasally; and (d) the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg;
The pharmaceutical composition according to claim 1, wherein one or more of the conditions of the above is satisfied. After administration of the antibody or its antigen-binding fragment, the following:
a) 22 items sinus evaluation test (SNOT-22) score;
b) Nasal symptom score;
c) Number of night awakenings;
d) Visual analog score (VAS) for the severity of nasal sinusitis symptoms;
e) 5 items asthma management questionnaire (ACQ5) score;
f) Maximum nasal inspiratory flow rate (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
h) Lund-McKay score; and i) One or more nasal polyp-related parameters selected from the group consisting of three-dimensional volumetric measurements of the maxillary sinus are improved; or
After administration of the antibody or antigen-binding fragment thereof, one or both of NPIF and UPSIT is increased; or after administration of the antibody or antigen-binding fragment thereof, SNOT-22 score, nasal symptom score, VAS, Lund- The pharmaceutical composition according to claim 1, wherein one or more of the McKay score and the 3D-volume score are reduced; or the nasal polyp score in the patient is reduced after administration of the antibody or antigen-binding fragment thereof. A pharmaceutical composition comprising an antibody that specifically binds to an interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof for use in a method of treating nasal mushrooms, wherein the method is the pharmaceutical composition. A single initial dose of, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, comprising the step of continuously administering to a subject in need thereof, the subject receiving background treatment for nasal mushrooms. The antibody or antigen-binding fragment thereof, which has been prescribed or is currently received, 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, wherein the antibody or antigen-binding fragment thereof contains. The pharmaceutical composition, wherein the method optionally treats bilateral nasal mushrooms and the background treatment comprises a systemic corticosteroid. The administration strategy is as follows:
(A) Each secondary dose is administered 1 to 15 weeks after the previous dose;
(B) At least three secondary doses of the antibody or antigen-binding fragment thereof are administered to the subject, each secondary dose being administered 2 weeks after the previous dose;
(C) Each of the initial dose and one or more secondary doses comprises 50 mg to 500 mg of antibody or antigen-binding fragment thereof; and (d) each of the initial dose and one or more secondary doses. Contains the same dose of antibody or antigen-binding fragment thereof;
The pharmaceutical composition according to claim 7 , wherein one or more of the criteria of the above is satisfied. Subjects have one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, or have undergone surgery for nasal polyps. The pharmaceutical composition according to claim 7. The initial and secondary doses are administered by the same or different routes of administration; or the initial and secondary doses are administered subcutaneously, intravenously, or intranasally.
The pharmaceutical composition according to claim 7. After administration of the initial dose and one or more secondary doses:
a) 22 items sinus evaluation test (SNOT-22) score;
b) Nasal symptom score;
c) Number of night awakenings;
d) Visual analog score (VAS) for the severity of nasal sinusitis symptoms;
e) 5 items asthma management questionnaire (ACQ5) score;
f) Maximum nasal inspiratory flow rate (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
h) Lund-McKay score; and i) One or more nasal polyp-related parameters selected from the group consisting of three-dimensional volumetric measurements of the maxillary sinus are improved; or
After administration of the antibody or antigen-binding fragment thereof, one or both of NPIF and UPSIT is increased; or after administration of the antibody or antigen-binding fragment thereof, SNOT-22 score, nasal symptom score, VAS, Lund- The pharmaceutical composition according to claim 7 , wherein one or more of the McKay score and the 3D-volume score are reduced; or the nasal polyp score in the patient is reduced after administration of the antibody or antigen-binding fragment thereof. A pharmaceutical composition comprising an antibody that specifically binds to an interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof for use in a method for treating nasal polyps, wherein the method is the pharmaceutical composition. The subject has undergone surgery for nasal polyps and has relapsed after undergoing surgery, and the antibody or antigen-binding fragment thereof is designated by SEQ ID NO: The pharmaceutical composition comprising light chain CDR sequences of 6, 7 and 8 as well as heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, wherein the method optionally treats bilateral nasal polyps. The pharmaceutical composition according to claim 12 , wherein the subject has one or more of sinusitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity. The pharmaceutical composition according to claim 12 , wherein the antibody or antigen-binding fragment thereof is administered at a dose of 0.1 mg to 600 mg, 100 mg to 400 mg, or 300 mg. The pharmaceutical composition according to claim 12 , 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. below:
(A) The pharmaceutical composition is systemically administered to the subject;
(B) The pharmaceutical composition is administered topically to the subject;
(C) The pharmaceutical composition is administered to the subject subcutaneously, intravenously, or intranasally; and (d) the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg;
12. The pharmaceutical composition according to claim 12, which satisfies one or more of the conditions of the above. After administration of the antibody or its antigen-binding fragment, the following:
a) 22 items sinus evaluation test (SNOT-22) score;
b) Nasal symptom score;
c) Number of night awakenings;
d) Visual analog score (VAS) for the severity of nasal sinusitis symptoms;
e) 5 items asthma management questionnaire (ACQ5) score;
f) Maximum nasal inspiratory flow rate (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
h) Lund-McKay score; and i) One or more nasal polyp-related parameters selected from the group consisting of three-dimensional volumetric measurements of the maxillary sinus are improved; or
After administration of the antibody or antigen-binding fragment thereof, one or both of NPIF and UPSIT is increased; or after administration of the antibody or antigen-binding fragment thereof, SNOT-22 score, nasal symptom score, VAS, Lund- The pharmaceutical composition according to claim 12 , wherein one or more of the McKay score and the 3D-volume score are reduced; or the nasal polyp score in the patient is reduced after administration of the antibody or antigen-binding fragment thereof. A pharmaceutical composition comprising an antibody that specifically binds to an interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof for use in a method for treating nasal polyps, wherein the method is the pharmaceutical composition. A single initial dose of, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, comprising the step of continuously administering to a subject in need thereof, the subject having surgery for nasal polyps. The antibody or antigen-binding fragment thereof has relapsed after undergoing surgery and undergoing surgery, and 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 are used. Included, wherein the method optionally treats bilateral nasal polyps, said pharmaceutical composition. The administration strategy is as follows:
(A) Each secondary dose is administered 1 to 15 weeks after the previous dose;
(B) At least three secondary doses of the antibody or antigen-binding fragment thereof are administered to the subject, each secondary dose being administered 2 weeks after the previous dose;
(C) Each of the initial dose and one or more secondary doses comprises 50 mg to 500 mg of antibody or antigen-binding fragment thereof; and (d) each of the initial dose and one or more secondary doses. Contains the same dose of antibody or antigen-binding fragment thereof;
The pharmaceutical composition according to claim 18 , wherein one or more of the criteria of the above is satisfied. The pharmaceutical composition according to claim 18 , wherein the subject has one or more of sinusitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity. The initial and secondary doses are administered by the same or different routes of administration; or the initial and secondary doses are administered subcutaneously, intravenously, or intranasally.
The pharmaceutical composition according to claim 18. After administration of the initial dose and one or more secondary doses:
a) 22 items sinus evaluation test (SNOT-22) score;
b) Nasal symptom score;
c) Number of night awakenings;
d) Visual analog score (VAS) for the severity of nasal sinusitis symptoms;
e) 5 items asthma management questionnaire (ACQ5) score;
f) Maximum nasal inspiratory flow rate (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
h) Lund-McKay score; and i) One or more nasal polyp-related parameters selected from the group consisting of three-dimensional volumetric measurements of the maxillary sinus are improved; or
After administration of the antibody or antigen-binding fragment thereof, one or both of NPIF and UPSIT is increased; or after administration of the antibody or antigen-binding fragment thereof, SNOT-22 score, nasal symptom score, VA.
S, 1 or more is reduced among the Lund-McKay score and 3D- volume score; after administration of or an antibody or antigen binding fragment thereof, reduces nasal polyps scores in patients, according to claim 18 Pharmaceutical composition. The pharmaceutical composition according to any one of claims 2, 9, 13 and 20 , wherein the subject has sinusitis, which is a serious symptom of sinusitis. The pharmaceutical composition according to any one of claims 5, 10, 16 and 21 , wherein the pharmaceutical composition is administered subcutaneously using an automatic infusion delivery device, a needle and syringe, or a pen-type delivery device. The pharmaceutical composition according to any one of claims 1 to 24 , wherein the antibody comprises dupilumab or an antigen-binding fragment thereof. Further comprising a second therapeutic agent, the antibody or antigen-binding fragment thereof is an additive treatment for the treatment of bilateral nasal polyps (NP) and the subject is persistent in nasal polyps despite existing treatments. The pharmaceutical composition according to any one of claims 1 to 25 , which has signs and symptoms. The pharmaceutical composition according to claim 12 or 13 , wherein the subject is improperly controlled with an intranasal corticosteroid (INCS). The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition reduces the need for surgery.

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