ES2747630T3 - Methods of treatment of nasal polyposis by administering an IL-4R antagonist - Google Patents

Abstract

A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for use in a method of treating nasal polyposis in a subject in need thereof, wherein the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8, and wherein nasal polyposis is optionally bilateral nasal polyposis.

Description

DESCRIPTION

Methods of treatment of nasal polyposis by administering an IL-4R antagonist

Field of the Invention

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

Background

Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nostril, originating from the osteomeatal complex. PN is an inflammatory process caused by auxiliary T lymphocytes 2 (Th-2) that affects the mucosa of the nose and paranasal sinuses. Eosinophils and their products are believed to be a hallmark of inflammation associated with nasal polyps, since elevated levels of interleukin 5 (IL-5; promoting the survival and differentiation of eosinophils), eosinophilic cationic protein (ECP) are normally found in nasal polyps. ) and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils. Eosinophils are the predominant inflammatory cells found in the sinuses and nasal polyps, and nasal polyps are also associated with elevated levels of IgE. PN is characterized by long-term symptoms of nasal obstruction and congestion, reduced or lost sense of smell, anterior and posterior rhinorrhea, and facial pain. Current treatment options range from local or systemic corticosteroids to functional endoscopic breast surgery. N. A. Molfino et al: "Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor", Clinical & Experimental Allergy, vol. 42, No. 5, May 1, 2012, pages 712-737, discloses the use of any antibody against IL-5R (benralizumab) or against IL-5 (mepolizumab and reslizumab) to treat eosinophilic polyposis nasal.

Brief summary of the invention

In one aspect, the invention provides a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for use in a method of treating nasal polyposis in a subject in need thereof, wherein the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8, and wherein the nasal polyposis is optionally bilateral nasal polyposis. 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. N27,605,237 and 7,608,693.

A subject suitable for treatment with the antibody or antigen-binding fragment thereof may have one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), or have previously undergone surgery to treat nasal polyposis. In some embodiments, the subject has chronic sinusitis or chronic rhinosinusitis. For example, the subject may have nasal polyposis with severe symptoms of sinusitis.

In some embodiments, the antibody or antigen-binding fragment thereof 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 either systemically or locally. For example, the pharmaceutical composition can be administered subcutaneously, intravenously, or intranasally.

In one embodiment, the pharmaceutical composition is administered to the subject subcutaneously at a dose of 300 mg. In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after, or simultaneously with the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof. For example, in one embodiment, the one or more additional agents, such as a second therapeutic agent, may be a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, a IgE inhibitor, an NSAID (non-steroidal anti-inflammatory drug), an antibiotic, an antifungal agent, an intranasal corticosteroid, an inhaled corticosteroid, a systemic corticosteroid, a long-acting beta- ^2- agonist, a contraceptive, or any combination thereof. In one embodiment, the second therapeutic agent is an inhaled corticosteroid, such as fluticasone or budesonide, or an intranasal corticosteroid, such as mometasone furoate nasal spray (MFNS). In another embodiment, the second therapeutic agent further includes a long acting beta ² agonist, such as salmeterol or formoterol.

In certain embodiments, administration of the antibody or antigen-binding fragment thereof is followed by an improvement in one or more symptoms of nasal polyposis. For example, administration of the antibody or antigen-binding fragment thereof may be followed by an improvement in one or more parameters associated with nasal polyposis, such as an improvement in a 22-point nasal sinus outcome test score (SNOT -22); a nasal symptom score; number of night awakenings; a visual analog score (VAS), such as for the severity of rhinosinusitis symptoms; a five-point asthma control questionnaire score (ACQ5); peak nasal inspiratory flow (NPIF); the University of Pennsylvania Odor Identification Test (UPSIT); Lund-McKay score; and the three-dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen-binding fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of the SNOT-22 score, score of nasal symptoms, VAS, Lund-McKay score, and 3D volumetric score. In some embodiments, administration of the antibody or antigen-binding fragment thereof is followed by a decrease in the nasal polyps score in the patient.

In one aspect, use of the antibody or antigen-binding fragment thereof to treat nasal polyposis comprises sequentially administering to a subject in need thereof a single initial dose of the antibody or an antigen-binding fragment thereof, followed by one or plus secondary doses of the antibody or antigen-binding fragment thereof. In some embodiments, each secondary dose is administered 1 to 15 weeks after the immediately preceding dose. In other embodiments, the subject is administered at least three secondary doses of the antibody or antigen-binding fragment thereof, and each secondary dose is administered days or weeks (eg, 1 week or 2 weeks or more) after the dose immediately preceding. In another embodiment, the initial dose and the one or more secondary doses each include 50 mg to 500 mg of the IL-4R antagonist, eg, 100 mg to 400 mg of the antibody or antigen-binding fragment thereof, eg , 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg of the IL-4R antagonist. In some embodiments, the initial dose and the one or more secondary doses each contain the same amount of the antibody or antigen-binding fragment thereof. In other embodiments, the initial dose comprises a first amount of the antibody or antigen-binding fragment thereof, and the one or more secondary doses each comprise a second amount of the antibody or antigen-binding fragment thereof. For example, the first amount of the antibody or antigen-binding fragment thereof may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or greater than the second amount of the antibody or antigen-binding fragment. antigen thereof.

In one embodiment, the subject (eg, a patient) has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), or has undergone surgery for nasal polyps. In some embodiments, the subject has chronic sinusitis or chronic rhinosinusitis. For example, the subject may have nasal polyposis with severe symptoms of sinusitis.

The initial dose and secondary doses of the antibody or antigen-binding fragment thereof can be administered by the same routes of administration or different routes of administration. For example, the initial dose and secondary doses can be administered subcutaneously, intravenously, or intranasally.

In certain embodiments, administration of the initial dose and the one or more secondary doses is followed by an improvement in one or more parameters associated with nasal polyposis, such as an improvement in a 22-point nasal sinus outcome test score ( SNOT-22); a nasal symptom score; number of night awakenings; a visual analog score (VAS), such as for the severity of rhinosinusitis symptoms; a five-point asthma control questionnaire score (ACQ5); peak nasal inspiratory flow (NPIF); the University of Pennsylvania Odor Identification Test (UPSIT); Lund-McKay score; and the three-dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen-binding fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of the SNOT-22 score, score of nasal symptoms, VAS, Lund-McKay score, and 3D volumetric score. In some embodiments, administration of the antibody or antigen-binding fragment thereof is followed by a decrease in the nasal polyps score in the patient.

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

In one aspect, use in the nasal polyposis treatment method comprises selecting a patient with a minimum bilateral nasal polyps score of 5, or at least two or more of the chronic symptoms of sinusitis are selected from the group consisting of: nasal blockage / obstruction / congestion, anterior or posterior runny nose, facial pain or pressure, and reduction or loss of smell; and administering to the selected patient a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, so as to reduce the patient's nasal polyps score or improve the two or more chronic symptoms of sinusitis.

In one aspect, use in the method of treating nasal polyposis comprises selecting a patient with a minimum bilateral nasal polyp score of 5, or at least two or more of the chronic symptoms of sinusitis are selected from the group consisting of: nasal blockage / obstruction / congestion, anterior or posterior nasal drip, facial pain or pressure, and reduction or loss of smell; and sequentially administering to the patient a single initial dose of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, so as to reduce the The patient's nasal polyps score or improve the two or more chronic symptoms of sinusitis.

In one aspect, use in the method of treating nasal polyposis comprises determining in a subject the level of expression of one or more genes selected from the group consisting of activation-regulated thymic chemokine (TARC), eotaxin-3, periostin, antigen carcinoembryonic (CEA) and YKL-40; selecting the subject as a candidate for treatment with the antibody or antigen-binding fragment thereof, if the subject has a high level of expression of the one or more genes; and administering to the selected subject the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, so as to reduce the level of the one or more genes.

In one aspect, use in the method of treating nasal polyposis comprises determining in a subject the level of expression of one or more genes selected from the group consisting of activation-regulated thymic chemokine (TARC), eotaxin-3, periostin, antigen carcinoembryonic (CEA) and YKL-40; selecting the subject as a candidate for treatment with the antibody or antigen-binding fragment thereof, if the subject has a high level of expression of the one or more genes; and sequentially administering to the selected subject a single initial dose of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, so as to reduce the level of the one or more genes.

In one aspect, use in the method of treating nasal polyposis comprises determining in a subject the level of blood eosinophils or sputum eosinophils; selecting the subject as a candidate for treatment with the antibody or antigen-binding fragment thereof, if the subject has a high level of blood eosinophils or sputum eosinophils; and administering to the selected subject the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, so as to reduce the level of blood eosinophils or sputum eosinophils.

In one aspect, use in the method of treating nasal polyposis comprises determining in a subject the level of blood eosinophils or sputum eosinophils; selecting the subject as a candidate for treatment with the antibody or antigen-binding fragment thereof, if the subject has a high level of blood eosinophils or sputum eosinophils; and sequentially administering to the selected subject a single initial dose of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, so as to reduce the level of blood eosinophils or sputum eosinophils.

Other embodiments will be apparent from the figure below and the detailed description.

Brief description of the figures

FIG. 1 shows the schematic representation of an example of time period of withdrawal of the base therapy in the treatment of a patient with asthma.

Detailed description

Before describing the present invention, it should be understood that the present invention is not limited to the particular experimental methods and conditions described, since said methods and conditions may vary, but the invention is explained in the attached set of claims. Embodiments and / or examples in the following description that are not covered by the claims should not be considered as part of the present invention.

It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning that is commonly understood by one of ordinary skill in the art to which the present invention pertains. As used herein, the term "approximately", when used in reference to a particular quoted numerical value, means that the value may vary from the quoted value by not more than 1%. For example, as used herein, the term "approximately 100" includes 99 and 101 and all intermediate values (eg, 99,1,99,2, 99,3, 99,4, etc.).

Nasal polyposis treatment methods

The present invention provides a pharmaceutical composition for use in methods of treating nasal polyposis. As used herein, a "nasal polyp" is an overgrowth of tissue in one or more of the nostrils. The condition of nasal polyps is called "nasal polyposis." Approximately 80% of nasal polyps are highly edematous and full of eosinophils. Nasal polyps can also present as fibrous, glandular, or cystic.

Nasal polyposis (NP) is a clinical state characterized by the presence of multiple polyps in the upper nostril, originating from the osteomeatal complex. PN is an inflammatory process caused by auxiliary T lymphocytes 2 (Th-2) that affects the mucosa of the nose and paranasal sinuses. Eosinophils and their products are believed to be a hallmark of inflammation associated with nasal polyps, since elevated levels of interleukin-5 (IL-5; promoting the survival and differentiation of eosinophils), eosinophilic cationic protein (normally) are found in nasal polyps. ECP) and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils. Eosinophils are the predominant inflammatory cells found in the sinuses and nasal polyps, and nasal polyps are also associated with elevated levels of IgE.

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

The antibody or antigen-binding fragment thereof can be used to treat nasal polyposis associated with a variety of conditions. For example, nasal polyposis is associated with sinusitis, rhinitis (for example, allergic and non-allergic rhinitis), asthma (for example, moderate to severe asthma), sensitivity to NSAIDs (for example, sensitivity to aspirin), and infection, such as bacterial and fungal infection. Bacterial infections include, for example, staph infections. A subject with nasal polyposis may have a chronic infection, such as a chronic bacterial infection, eg, a chronic Staphylococcus aureus infection . In some embodiments, the subject has recurrent nasal polyposis, such as may be associated with recurrent sinusitis. In other embodiments, the subject has cystic fibrosis or NARES (non-allergic rhinitis with eosinophilia syndrome). In other embodiments, the subject has a relapse of nasal polyposis after receiving surgery to treat the polyps. Risk factors for nasal polyposis include genetic susceptibility, anatomic abnormality, mucociliary deficiency, infection, and local immune imbalance.

The antibody or antigen-binding fragment thereof may also be used to treat nasal polyposis in patients who have never previously received NP treatment or surgery. The antibody or antigen-binding fragment thereof can also be used to treat nasal polyposis in patients who have previously undergone surgery, such as nasal surgery, such as for treatment of nasal polyps. In certain embodiments, the antibody or antigen-binding fragment thereof is administered to a subject whose nasal polyposis has relapsed after the subject received prior treatment for the polyps, such as prior nasal surgery.

As used herein, the term "sinusitis" refers to any inflammatory condition characterized by inflammation of the paranasal sinuses, including inflammation of the maxillary, frontal, ethmoid, and / or sphenoid paranasal sinuses. The antibody or antigen-binding fragment thereof is suitable for the treatment of nasal polyposis associated with acute sinusitis, subacute sinusitis, chronic sinusitis, and recurrent sinusitis. Acute sinusitis is characterized by a sudden onset of cold-like symptoms such as runny nose, stuffy nose, and facial pain that does not subside after 10 to 14 days. Acute sinusitis normally lasts less than four weeks. Subacute sinusitis lasts from four to eight weeks. Chronic sinusitis lasts for eight weeks or more, and recurrent sinusitis is characterized by episodes of sinusitis that occur three or more times in a year. More than 80% of patients with chronic sinusitis with nasal polyps have eosinophilic inflammation of the upper respiratory tract.

Many patients with chronic sinusitis have "chronic hyperplastic eosinophilic sinusitis," characterized by marked sinus inflammation, elevated eosinophils and mixed mononuclear cells, and a relative shortage of neutrophils. Some of these patients have one or more associated nasal polyps, asthma, and sensitivity to aspirin or NSAIDs. In certain embodiments, the antibody or antigen-binding fragment thereof can be used to treat nasal polyposis in a subject having chronic hyperplastic eosinophilic sinusitis.

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

Symptoms of non-allergic rhinitis include constriction or inflammation in the nostrils that lead to many of the same symptoms of allergic rhinitis. Non-allergic rhinitis can be caused, for example, by strong chemical or smoke-laden environments, or from long-term use of certain medications or dependence on nasal sprays.

As used herein, the term "rhinosinusitis '' refers to a condition that has symptoms of both rhinitis and sinusitis. Rhinosinusitis includes acute rhinosinusitis and chronic rhinosinusitis. Acute rhinosinusitis can be caused by an infection, such as a bacterial, viral or fungal infection, or a chemical irritation. Acute rhinosinusitis induced by tobacco smoke and chronic rhinosinusitis induced by chlorine fumes are examples of acute rhinosinusitis. PN is most commonly associated with chronic rhinosinusitis (CRS ), characterized by inflammation of the mucosa of the nostril and sinuses with symptoms lasting more than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps is a condition lasting more than 8 weeks. Chronic sinusitis (SC) and chronic rhinosinusitis (RSC) are conditions lasting more than eight weeks.The underlying causes of acute sinusitis and rhinosinusitis Acute infections can lead to chronic sinusitis or chronic rhinosinusitis if the resulting inflammation persists for more than 8 weeks. Chronic rhinosinusitis includes, for example, eosinophilic chronic hyperplastic rhinosinusitis.

Additional subcategories of chronic sinusitis (and chronic rhinosinusitis) include, for example, superantigen-induced chronic eosinophilic sinusitis (eg, exotoxin-induced sinusitis and endotoxins produced by bacteria such as Staphylococcus aureus ); allergic fungal sinusitis (eg, fungal-induced sinusitis such as Aspergillus or Alternaria); non-allergic fungal eosinophilic chronic sinusitis; and chronic eosinophilic sinusitis aggravated by aspirin.

The antibody or antigen-binding fragment thereof can be used to treat nasal polyposis in subjects having any of the disorders described above.

Methods of improving the parameters associated with nasal polyps

The use of the pharmaceutical composition of the present invention includes methods of improving one or more parameters associated with nasal polyps in a subject in need thereof, wherein the methods include administering the pharmaceutical composition comprising the antibody or binding fragment. to the antigen of the same to the subject. For example, the antibody or antigen-binding fragment thereof can reduce the endoscopic score of nasal polyps in a patient. A nasal polyps score of 0 indicates the absence of polyps. A nasal polyps score of 1 indicates the presence of small polyps in the middle meatus that do not extend below the inferior edge of the middle turbinate. A nasal polyps score of 3 indicates large polyps that reach the lower edge of the lower turbinate or polyps in the middle of the middle turbinate. A nasal polyps score of 4 indicates large polyps that cause complete obstruction of the lower nostril (see Table 15 below). The maximum score is 8 (4 points per nostril). Treatment with the antibody or antigen-binding fragment thereof can decrease the nasal polyps score by about 1 to about 8 points. For example, treatment with the antibody or antigen-binding fragment thereof can decrease the nasal polyps score by about 1 point or more, by about 2 points or more, or by about 3 points or more. In some embodiments, treatment with the antibody or antigen-binding fragment thereof can decrease the nasal polyps score by approximately 1 point, or a fraction thereof; at 2 points, or a fraction thereof; at 3 points, or a fraction thereof; at 4 points, or a fraction thereof; at 5 points, or a fraction thereof; at 6 points, or a fraction thereof; at 7 points, or a fraction thereof; or at 8 points or a fraction thereof. A reduction in nasal polyps score can be correlated with an improvement in one or more of other parameters associated with nasal polyps. However, this correlation is not necessarily observed in all cases.

Other examples of "parameters associated with nasal polyps" include: (a) 22-point nasal sinus outcome test score (SNOT-22); (b) subject-assessed nasal congestion / obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip), and loss of sense of smell; (c) number of night awakenings; (d) visual analog score (VAS) to assess the severity of rhinosinusitis symptoms evaluated by the patient; (e) five-point asthma control questionnaire score (ACQ5), such as in asthma patients; (f) peak nasal inspiratory flow (NPIF); (g) odor test (University of Pennsylvania Odor Identification Test (UPSIT)); (h) physiological parameters, as measured by nasal endoscopy and CT scan; (i) Lund-Mackay score; and (j) three-dimensional volumetric measurement of the maxillary sinus.

Score of the 22-point nasal sinus results test (SNOT-22). According to certain embodiments, the administration of an IL-4R antagonist to a patient results in a decrease from the baseline of the 22-point nasosinusal results test (SNOT-22). SNOT-22 is a questionnaire to assess the impact of chronic rhinosinusitis (RSC) on quality of life. The questionnaire measures points related to sinonasal conditions and surgical treatments. The score ranges from 0 to 110, and higher scores imply greater impact of CSR on health-related quality of life (HRQoL) (Hopkins et al 2009, Clin. Otolaryngol. 34: 447-454).

The use of the pharmaceutical composition of the present invention includes therapeutic methods that result in a decrease in the SNOT-22 score from baseline of at least 1 point at week 4 to week 16 after administration of the antibody or antigen-binding fragment thereof. For example, administration of the antibody or antigen-binding fragment thereof will result in a decrease in the SNOT-22 score at week 4, week 6, week 8, week 12, or week 16 after initiation of treatment. In some embodiments, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in SNOT-22 score from baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13 points, or more in week 4, week 6, week 8 or week 12.

Individual and total nasal symptoms score. Symptom-assessed symptoms are tested by answering questions about individual morning and evening rhinosinusitis symptoms using a 0-3 category scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms), and which includes the symptoms of congestion and / or obstruction, anterior rhinorrhea, posterior rhinorrhea and loss of the sense of smell. A measure of nighttime awakenings can also be followed. For example, a measure of nighttime awakenings can be assessed based on the following scores based on the subject's self-assessment: 0 = no symptoms, slept through the night; 1 = slept well, but with some discomfort in the morning; 2 = woke up once due to symptoms of rhinosinusitis (including waking up early); 3 = woke up several times due to symptoms (including waking up early); 4 = bad night, I wake up most of the night due to symptoms. Administration of the antibody or antigen-binding fragment thereof may result, for example, in a decrease in the average number of nighttime awakenings per night from baseline by at least about 0.10 times per night in week 4 to week 16 after the start of treatment with the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof. For example, a decrease in the frequency of nighttime awakenings per night from baseline of at least about 0.10 times per night can be detected in week 4, week 6, week 8, week 12, or week 16 after onset of treatment. Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof can cause a decrease in the average number of nighttime awakenings per night from baseline by approximately 0.10 times per night, 0.15 times per night, 0.20 times per night, 0.25 times per night, 0.30 times per night, 0.35 times per night, 0.40 times per night, 0.45 times per night, 0.50 times per night 0.55 times 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 0.85 times a night 0.90 times per night, 0.95 times per night, 1.0 time per night, 2.0 times per night, or more in week 4, week 8, week 12, or week 16, for example.

Visual analog score (VAS). VAS is a measure to assess the severity of patient-related rhinosinusitis symptoms on a scale of 1 to 10. Mild symptoms are indicated by a score of 0 to 3, moderate symptoms are indicated by a VAS score. > 3 to 7, and severe symptoms are indicated by a VAS score of> 7 to 10. Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes a decrease in the VAS score. from baseline of approximately 0.5 point, 1 point, 1.5 point, 2 point, 2.5 point, 3 point, 3.5 point, 4 point, or more in Week 4, Week 6, or Week 12 The decrease in VAS score can be detected as early as week 4, and as late as week 12 or later after administration of the IL-4R antagonist.

Asthma control questionnaire score of 5 points (ACQ). The ACQ5 measures both the adequacy of asthma control and the change in asthma control, which occurs either spontaneously or as a result of treatment. The five questions in the ACQ5 reflect the five highest-scoring asthma symptoms: awake at night for symptoms, awake in the morning with symptoms, limitation of daily activities, shortness of breath, and wheezing. Patients answer symptom questions on a 7-point scale (0 = no dysfunction, fully controlled; 6 = maximum dysfunction, severely uncontrolled).

The use of the pharmaceutical composition of the present invention includes therapeutic methods that result in a decrease in ACQ5 score from baseline of at least 0.10 points at week 12 after initiation of treatment with the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof. For example, according to the present invention, administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes a decrease in ACQ score from baseline of approximately 0.10 points, 0.15 points. , 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points , 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more in week 4, week 6, or week 12. The decrease in ACQ score can be detected as early as week 4, and as late as or after week 12 after administration of the antibody or antigen-binding fragment thereof.

Maximum nasal inspiratory flow (NPIF). Peak Nasal Inspiratory Flow (NPIF) represents a physiological measure of air flow through both nostrils during inspiration and / or forced expiration expressed in liters per minute. Nasal inspiration correlates for the most part with the subjective sensation of obstruction and is used to monitor nasal flow. Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes an increase in NPIF from baseline by approximately 0.10 liters per minute, 0.15 liters per minute, 0.20 liters per minute. 0.25 liters per minute, 0.30 liters per minute, 0.35 liters per minute, 0.40 liters per minute, 0.45 liters per minute, 0.50 liters per minute, 0.55 liters per minute, 0.60 liters per minute, 0.65 liters per minute, 0.70 liters per minute, 0.75 liters per minute, 0.80 liters per minute, 0.85 liters per minute, or more in week 4, week Week 6 or 12. Increase in NPIF score can be detected as early as week 4, and as late as week 12 or later after administration of the antibody or antigen-binding fragment thereof.

University of Pennsylvania Odor Identification Test (UPSIT). UPSIT is a method of quantitatively evaluating human olfactory function. The test consists of samples of odorants, and the subject has to describe the odor. The score is based on the number of correct answers. This test can distinguish patients with a normal sense of smell ("normosmia") from those with different levels of reduction ("mild, moderate and severe microsmia") or loss ("anosmia"). Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes an increase in the UPSIT score from baseline by approximately 0.5 point, 1 point, 1.5 point, 2 point, 2 , 5 points, 3 points, 3.5 points or more in week 4, week 6 or week 12. The increase in the UPSIT score can be detected as early as week 4, and as late as week 12 or later after administration of the antibody or antigen-binding fragment thereof.

Physiological parameters. The efficacy of the antibody or antigen-binding fragment thereof can be tested by measuring the effect of physiological parameters, such as within the nostrils, such as by nasal endoscopy or computed tomography (CT).

Lund-Mackay score. The Lund-Mackay scoring system is based on localization with points given the degree of opacification: 0 = normal, 1 = partial opacification, 2 = total opacification. These points then apply to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses on each side. The osteomeatal complex is classified as 0 = not occluded or 2 = occluded, deriving a maximum score of 12 per side. For patients lacking osteomeatal complex (CO) (due to previous surgery), the location of the old CO is considered and a score is provided as if the CO were there. Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes a decrease in the Lund-Mackay score from baseline by approximately 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more in week 4, week 6, or week 12. The decrease in the Lund-Mackay score can be detected as early as week 4, and as late as at or after week 12 after administration of the antibody or antigen-binding fragment thereof.

Three-dimensional volumetric measurement of the maxillary sinus. This value is used to calculate the volume of air (mL); mucosa volume (mL); the percentage of sinus occupied by the disease and the thickness of the lateral wall of the maxillary sinus. Administration of the antibody or antigen-binding fragment thereof to a subject in need thereof causes an increase in three-dimensional volumetric measurement.

Quality of life questionnaires (QoL). Various QoL questionnaires can be used to monitor the efficacy of an IL-4R antagonist, including the Short Form Questionnaire 36 (SF-36), the Euroqol-5D (EQ-5D), the Resource Use Questionnaire related to nasal polyps and the qualitative self-evaluation of the patient. The SF-36 is a 36-point questionnaire that measures eight dimensions of multiple points of health: physical functioning (10 points), social functioning (2 points), functional limitations due to physical problems (4 points), functional limitations due to emotional problems (3 points), mental health (5 points), energy / vitality (4 points), pain (2 points) and perception of general health (5 points). For each dimension, the point scores are coded, added, and transformed on a scale from 0 (worst possible health status measured by the questionnaire) to 100 (best possible health status). Two normalized summary scores can also be calculated from SF-36; the Physical Component Summary (PCS) and the Mental Health Component Summary (MCS).

The EQ-5D is a standardized health-related quality of life questionnaire developed by EuroQol Group to provide a simple and generic measure of health for clinical and economic insights and comparisons between diseases. The EQ-5D, designed to be self-completed by patients, consists of two parts, the EQ-5D descriptive system and the EQ VAS. The EQ-5D descriptive system comprises 5 dimensions: mobility, personal care, habitual activities, pain / discomfort and anxiety / depression; And each dimension has 3 levels: no problems, some problems, serious problems. The Visual Analog EQ Scale (VAS) records the self-rated health by the respondent on a vertical visual analog scale. The EQ VAS 'thermometer' has extremes of 100 (best imaginable health status) above and 0 (worst imaginable health status) below.

The questionnaire for the use of resources related to nasal polyps is a questionnaire for the use of health care resources for nasal polyposis, which includes consultations with the specialist, emergency consultations, sick leave, days off, etc.

The improvement of a parameter associated with nasal polyps, such as a parameter associated with nasal polyps described above, can be expressed as a percentage. For example, a score may improve by 30% or more, by 40% or more, by 50% or more, by 60% or more, by 70% or more, or by 80% or more.

An "improvement in a parameter associated with nasal polyps" means an increase from the baseline of one or more NPIF, UPSIT, and / or a decrease from the baseline of one or more of the SNOT-22 score, nasal congestion / obstruction evaluated by the subject, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip) and loss of sense of smell; number of night awakenings; VAS score; Lund-Mackay score; and 3D volumetric scores; and ACQ5 score in asthma patients. As used herein, the term "baseline", with respect to a parameter associated with nasal polyps, means the numerical value of the parameter associated with nasal polyps for a patient before or at the time of administration of a pharmaceutical composition of the present invention.

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

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

Interleukin-4 receptor antagonists

In one embodiment, a subject in need thereof is administered with a therapeutic composition comprising the antibody or antigen-binding fragment thereof, which is an interleukin-4 receptor antagonist (IL-4R). As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on a cell in in vitro or in vivo. Examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, peptide-based IL-4R antagonists (eg, "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R.

The term "human IL-4R" (hIL-4R), as used herein, is intended to refer to the IL-4Ra subunit, which is a component of type I and type II IL-4 receptors as well like the IL-13 receptor system. An IL-4R antagonist, such as an anti-IL-4Ra antibody or antigen-binding fragment thereof, blocks the signal transduction function of both IL-4 and IL-13.

The term "antibody" as used herein is intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains, and two light (L) chains interconnected by disulfide bonds, as well as multimers of the themselves (eg IgM). Each heavy chain comprises a variable region of the heavy chain (abbreviated herein as HCVR or Vh) and a constant region of the heavy chain. The heavy chain constant region comprises three domains, C ^h 1, C ^h 2 and CH3. Each light chain comprises a variable region of the light chain (abbreviated herein LCVR or VL) and a constant region of the light chain. The constant region of the light chain comprises a domain (CL1). The VH and VL regions can be further subdivided into hypervariability regions, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Structural Regions (FR). Each V ^h and V ^l is composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, c DR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-Ang-2 antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or they may be naturally or artificially modified. A consensus amino acid sequence can be defined based on a side-by-side analysis of two or more CDRs.

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

Non-limiting examples of antigen binding fragments include: (i) Fab fragments; (ii) F (ab ') 2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv molecules (scFv); (vi) fragments dAb; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (eg, an isolated Complementarity Determining Region (CDR) such as a CDR3 peptide), or a FR3-CDR3 peptide -FR4 limited. Also included within the term "antigen binding fragment", as used herein, are other manipulated molecules, such as domain specific antibodies, single domain antibodies, deleted domain antibodies, chimeric antibodies, grafted antibodies with CDRs, diabodies, triabodies, tetrabodies, minibodies, nanobodies (eg, monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and variable IgNAR domains from shark.

An antigen-binding fragment of an antibody will normally comprise at least one variable domain. The variable domain can be of any amino acid size or composition and will generally comprise at least one CDR that is adjacent to or in-frame with one or more framework region sequences. In antigen binding fragments having a Vh domain associated with a Vl domain, the Vh and Vl domains can be located in any suitable arrangement relative to each other. For example, the variable region may be dimeric and contain VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

In certain embodiments, an antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within an 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) Vh-Cl; (viii) Vl-Ch1; (ix) Vl-Ch2; (x) Vl-Ch3; (xi) Vl-Ch1-Ch2; (xii) Vl-Ch1-Ch2-Ch3; (xiii) Vl-Ch2-Ch3; and (xiv) Vl-CL. In any variable and constant domain configuration, which includes any of the exemplary configurations listed above, the variable and constant domains can be either directly linked to each other or can be linked by a hinge or full or partial connector region. . A hinge region can consist of at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids that result in a flexible or semi-flexible bond between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, an antigen-binding fragment of an antibody may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with each other and / or with one or plus monomeric Vh or Vl domains (eg, by disulfide bond (s)).

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

The constant region of an antibody is important in the ability of an antibody to bind to complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody can be selected based on whether the antibody is desired to mediate cytotoxicity.

The term "human antibody", as used herein, is intended to include antibodies that have variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies characterized in the invention may, however, include amino acid residues not encoded by human germ line immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of other mammalian species, such as germline sequences, have been grafted onto sequences in the human framework region, such like a mouse.

The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described below), antibodies isolated from a recombinant human antibody combinatorial library (described below), antibodies isolated from an animal (eg, mouse) that is transgenic for human immunoglobulin genes (see, eg, Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, created or isolated by any other means involving the splicing of human immunoglobulin gene sequences with other DNA sequences . Such recombinant human antibodies have variable and constant regions derived from immunoglobulin sequences of the line human germline. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using a transgenic animal for human Ig sequences, to in vivo somatic mutagenesis ) and thus the amino acid sequences of the Vh and Vl regions. of the recombinant antibodies are sequences that, although derived from and related to the human germline Vh and Vl sequences, cannot naturally exist within the germline repertoire of human antibody in vivo.

Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via interchain disulfide bonds and a molecule of approximately 75-80 kDa is formed composed of a covalently coupled light and heavy chain (semi-antibody). These forms have been extremely 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 antibody hinge region isotype. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30: 105) to levels normally observed using an IgG 1 hinge human. The present invention encompasses antibodies that have one or more hinge region mutations, CH2 or CH3 that may be desirable, for example, in production, to enhance the performance of the desired form of antibody.

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

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

Anti-IL-4R antibodies useful for the methods characterized herein may include one or more amino acid substitutions, insertions and / or deletions in the framework region and / or CDR regions of the heavy and light chain variable domains in comparison with the corresponding germline sequences from which the antibodies were derived. Such mutations can be easily established by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. The use of the pharmaceutical composition of the present invention includes methods involving the use of antibodies, and antigen binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions they are mutated to the corresponding residue (s) of the germline sequence from which the antibody was derived, or to the corresponding residue (s) of another human germline sequence , or to a conservative amino acid substitution of the corresponding germline residue (s) (such sequence changes are referred to herein together as "germline mutations"). One of ordinary skill in the art, based on the heavy and light chain variable region sequences disclosed herein, can readily produce numerous antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations of the same. In certain embodiments, all residues in the framework region within the Vh and / or Vl domains are back-mutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are transmuted back to the original germline sequence, for example, only mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4. In other embodiments, one or more of the framework region residues are mutated to the corresponding residue (s) of a different sequence from the germline (that is, a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies may contain any combination of two or more germline mutations within framework regions, for example, where certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that they differ from the original germline sequence, they are maintained or mutated to the corresponding residue of a different germline sequence. Once obtained, the antibodies and antigen binding fragments containing one or more germline mutations can be easily tested for one or more desired properties such as improved binding specificity, increased binding affinity, antagonistic biological properties or improved agonists or enhanced (as the case requires), reduced immunogenicity, etc. The use of the antibodies and antigen binding fragments obtained in this general manner is encompassed within the present invention.

The use of the pharmaceutical composition of the present invention also includes methods involving the use of anti-IL-4R antibodies comprising variants of any of the HCVR and / or LCVR amino acid sequences disclosed herein that have one or more conservative substitutions. For example, the present invention includes the use of anti-IL-4R antibodies having amino acid sequences of HCVR and / or LCVR with, for example, 10 or less, 8 or less, 6 or less, 4 or less, etc. , conservative amino acid substitutions with respect to any of the HCVR and / or LCVR amino acid sequences disclosed herein.

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

The term "Kd", as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-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 can have more than one epitope. Thus, different antibodies can bind to different areas on an antigen and can have different biological effects. Epitopes can be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is that produced by adjacent amino acid residues in a polypeptide chain. Under certain circumstances, an epitope can include saccharide residues, phosphoryl groups, or sulfonyl groups on the antigen.

The term "bioequivalent", as used herein, refers to a molecule that has similar bioavailability (rate and degree of availability) after administration at the same molar dose and under similar conditions (eg, the same route of administration), so that the effect, with respect to both efficacy and safety, can be expected to be essentially the same as in the comparative molecule. Two pharmaceutical compositions comprising an IL-4R antagonist are bioequivalent if they are pharmaceutically equivalent, which means that they contain the same amount of active ingredient (for example, IL-4R antagonist), in the same pharmaceutical form, for the same route of administration and that they meet the same or comparable standards. Bioequivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Commonly used parameters in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration curve over time (AUC).

Other anti-IL-4Ra antibodies that can be used in the context of the present disclosure include, for example, the antibody designated and known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181 (8): 788-796), or any of the anti-IL-4Ra antibodies as set forth in US Pat. N27,186,809, or U.S. Patent No. N28.092.804.

The anti-IL-4Ra antibodies used in the context of the present disclosure may have pH dependent binding characteristics. For example, an anti-IL-4Ra antibody for use in the methods of the present disclosure may exhibit reduced binding to IL-4Ra at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Ra antibody of the disclosure may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values 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, or less. As used herein, the term "neutral pH" means a pH of from about 7.0 to about 7.4. The term "neutral pH" includes pH values of approximately 7.0, 7.05, 7.1,7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

In certain cases, "reduced binding to IL-4Ra at acidic pH compared to neutral pH" is expressed in terms of a relationship between the Kd value of antibody binding to IL-4Ra at acidic pH and the Kd value of the Antibody binding to IL-4Ra at neutral pH (or vice versa). For example, an antibody or fragment binding to the antigen thereof exhibits "reduced binding to IL-4Ra at acidic pH compared to neutral pH" for the purposes of the present disclosure if the antibody or antigen binding fragment thereof has an acid / neutral K ^d ratio of approximately 3, 0 or greater. The acid / neutral Kd ratio for an antibody or antigen binding fragment of the present disclosure may be approximately 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12, 5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0. 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

Antibodies with pH dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at pH acid compared to neutral pH. Furthermore, modifications of the antigen binding domain at the amino acid level can give antibodies with pH dependent characteristics. For example, by replacing one or more amino acids of an antigen binding domain (eg, within a CDR) with a histidine residue, an antibody with reduced antigen binding can be obtained at acidic pH relative to neutral pH. As used herein, the term "acidic pH" means at pH 6.0 or less.

Pharmaceutical compositions

The use of the pharmaceutical composition of the present invention includes administering the antibody or antigen-binding fragment thereof to a patient, where the antibody or antigen-binding fragment thereof is contained within the pharmaceutical composition. The pharmaceutical compositions characterized in the invention are formulated with suitable vehicles, excipients, and other agents that provide adequate transfer, administration, tolerance, and the like. A multitude of appropriate formulations can be found in the form known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid-containing vesicles (cationic or anionic) (such as LIPOFECTIN ™), DNA conjugates, anhydrous absorption pastes, oil emulsions in water and water in oil, Carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing Carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52: 238-311.

The dose of antibody administered to a patient can vary depending on the age and size of the patient, symptoms, conditions, route of administration, and the like. The preferred dose is normally calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and schedules for administering pharmaceutical compositions comprising anti-IL-4R antibodies can be empirically determined; for example, the patient's progress can be monitored by periodic evaluation, and the dose adjusted accordingly. Furthermore, inter-species scaling of the dosages can be performed using methods well known in the art (eg, Mordenti et al., 1991, Pharmaceut. Res. 8: 1351).

Various delivery systems are known and can be used to administer a pharmaceutical composition containing an IL-4R antagonist, including encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, 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 can be administered by any convenient route, for example by infusion or bolus injection, by absorption through the epithelial or mucocutaneous linings (for example, oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with other biologically active agents.

A pharmaceutical composition can be administered subcutaneously or intravenously with a standard needle and syringe. Furthermore, with respect to subcutaneous administration, a pen delivery device easily has applications in administering a pharmaceutical composition. Said pen administration device, which includes a pen administration device for self-injection, can be reusable or disposable. A reusable pen delivery device generally uses a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition has been delivered into the cartridge and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Instead, the disposable pen delivery device is pre-filled with the pharmaceutical composition contained in a reservoir within the device. Once the reservoir of the pharmaceutical composition is emptied, the entire device is discarded.

Numerous reusable pen and auto-injector delivery devices have applications in the subcutaneous administration of a pharmaceutical composition. Examples include, but are not limited to AUTOPEN ™ (Owen Mumford, Inc., Woodstock, UK), DISETRONiC ™ Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 ™ Pen, HUMALOG ™ Pen, HUMALIN Pen 70/30 ™ (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 STARLET ™ and OPTICLIK ™ (Sanofi-aventis, Frankfurt, Germany), to name but a few. Examples of disposable pen delivery devices that have applications in the subcutaneous administration of a pharmaceutical composition include, but are not limited to, the SOLOSTAR ™ pen (Sanofiaventis), FLEXPEN ™ (Novo Nordisk), and KWIKPEN ™ (Eli Lilly), the SURECLICK ™ autoinjector (Amgen, Thousand Oaks, C ^a ), PENLET ™ (Haselmeier, Stuttgart, Germany), EPÍPEN (Dey, LP) and the HUM ⁱ R ^a ™ pen (Abbott Labs, Abbott Park IL), to name only a few.

For direct administration to the breasts, pharmaceutical compositions containing IL-4R antagonists can be administered using, for example, a microcatheter (for example, an endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. .

In certain situations, the pharmaceutical composition can be administered in a controlled release system. In one embodiment, a pump can be used (see Langer, above; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.

14: 201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, eg, Goodson, 1984, in Medical Applications of Controlled Release, supra). , vol. 2, pp. 115-138). Other controlled release systems are covered in the review by Langer, 1990, Science 249: 1527-1533.

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

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

Dosage

The amount of the 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 term "therapeutically effective amount" means a dose of the antibody or antigen-binding fragment thereof resulting in a detectable improvement in one or more symptoms associated with nasal polyps, or a dose of the antibody or antigen-binding fragment thereof that inhibits, prevents, decreases, or slows the progression of nasal polyps or a condition associated with nasal polyps. The therapeutically effective amount may be from about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg , approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, a approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg approximately 580 mg, about 590 mg, or about 600 mg, of the antibody or antigen-binding fragment thereof.

The amount of the antibody or antigen-binding fragment thereof contained within the individual doses can be expressed in terms of milligrams of antibody per kilogram of the patient's body weight (is say, mg / kg). For example, the antibody or antigen-binding fragment thereof can be administered to a patient at a dose of from about 0.0001 to about 10 mg / kg of the patient's body weight.

Combination therapies

Methods, in accordance with certain embodiments, include administering to the subject one or more additional therapeutic agents in combination with the antibody or antigen-binding fragment thereof. As used herein, the term "in combination with" means that additional therapeutic agents are administered before, after, or simultaneously with the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof. For example, when the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof is administered "before," the additional therapeutic agent may be administered approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours, approximately 24 hours. hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 15 minutes or approximately 10 minutes before the administration of the pharmaceutical composition which it comprises the antibody or antigen-binding fragment thereof. When the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof is administered "after", the additional therapeutic agent can be administered approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 10 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours or approximately 72 hours after administration of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof. "Concurrent" administration with the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof means that the additional therapeutic agent is administered to the subject in a separate pharmaceutical form within less than 5 minutes (before, after or at the same time) of administration of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the antibody or antigen-binding fragment of the same.

The additional therapeutic agent may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, an IL-1 antagonist as disclosed in US Patent No. 6,927. 044), an IL-6 antagonist, an IL-6R antagonist (including, for example, an anti-IL-6R antibody as disclosed in US Patent No. 7,582,298), an antagonist of IL-13, a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, an antibiotic ( for example, doxycycline), an antifungal agent, a leukotriene, an antihistamine, an a-adrenergic decongestant, a mucolytic, an NSAID, a long-acting beta ² agonist (eg, salmeterol or formoterol), a short-acting beta2 agonist , a steroid (for example, an oral steroid), a corticosteroid, such as an intranasal corticosteroid (for example, mometasone furoate (MFNS; for example, Nasonex®)), or an inhaled corticosteroid (eg, fluticasone or budesonide), an allergen immunotherapy, or combinations thereof. For example, in certain embodiments, the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof is administered in combination with a combination comprising a long-acting beta2-agonist and an inhaled corticosteroid (eg, fluticasone salmeterol [eg , Advair® (GlaxoSmithKline)]; or budesonide formoterol [eg, Symbicort® (Astra Zeneca)]).

In some embodiments, the antibody or antigen-binding fragment thereof is administered after a subject undergoes surgery to treat nasal polyposis.

Administration guidelines

According to certain embodiments, multiple doses of the antibody or antigen-binding fragment thereof can be administered to a subject over a defined period of time. Methods include, for example, sequentially administering to a subject multiple doses of the antibody or antigen-binding fragment thereof. As used herein, "administer sequentially" means that each dose of the antibody or antigen-binding fragment thereof is administered to the subject at a different point in time, eg, on different days separated by a predetermined interval ( for example, hours, days, weeks, or months). The present invention includes methods comprising sequentially administering to the patient a single initial dose of the antibody or antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, and optionally followed by one or plus tertiary doses of the antibody or antigen-binding fragment thereof.

The terms "starting dose", "secondary dose" and "tertiary dose" refer to the sequence of temporary administration of the antibody or antigen-binding fragment thereof. Thus, the "starting dose" is the dose given at the beginning of the treatment regimen (also called the "starting level dose");"secondarydoses" are the doses that are administered after the initial dose; and "tertiary doses" are the doses that are administered after the secondary doses. Initial, secondary and tertiary doses may all contain the same amount of the antibody or antigen-binding fragment thereof, but will generally differ from each other in terms of frequency of administration. In certain embodiments, however, the amount of the antibody or antigen-binding fragment of the same content in the initial, secondary, and / or tertiary doses will vary from one to the other (eg, adjusted up or down as appropriate) during the course of treatment.

In an exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 (eg, 1, 1 /, 2, 2 /, 3, 3 /, 4, 4 /, 5, 5 /, 6 , 6 /, 7, 7 /, 8, 8 /, 9, 9 /, 10, 10 /, 11, 11 /, 12, 12 /, 13, 13 /, 14, 14 / or more) weeks after the immediately preceding dose. The term "immediately preceding dose", as used herein, means, in a sequence of multiple administrations, the dose of the antibody or antigen-binding fragment thereof that is administered to a patient prior to administration of the next dose in sequence with no intermediate doses.

These methods may include administering to a patient any number of secondary and / or tertiary doses of the antibody or antigen-binding fragment thereof. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Also, 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 involving multiple secondary doses, each secondary dose can be administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose can be administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which secondary and / or tertiary doses are administered to a patient may vary during the course of the treatment regimen. The frequency of administration can also be adjusted during the course of treatment by a physician depending on the needs of the individual patient after the clinical examination.

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

Treatment populations

The use of the pharmaceutical composition of the present invention includes administering to a subject in need thereof a therapeutic composition comprising the antibody or antigen-binding fragment thereof. As used herein, the term "a subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or indication of nasal polyposis, or that has been diagnosed with nasal polyposis, or chronic symptoms of sinusitis. For example, a subject in need thereof has bilateral nasal polyps, and a nasal polyps score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each nostril. In certain embodiments, the polyps are at the middle meatus. In certain embodiments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has bilateral mucosal disease, which is confirmed by a method such as CT. As used herein, "bilateral mucosal disease" is an infection of the mucous lining of the sinus cavities, eg, the maxillary sinus cavities. In some embodiments, nasal polyposis (for example, a nasal polyps score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each nostril) persists even after a treatment regimen inhaled corticosteroids (INCS), such as where INCS was administered for at least 6 weeks, at least 7 weeks, at least 8 weeks, or longer.

In certain embodiments, a subject in need thereof has anterior and / or posterior mucopurulent drainage, nasal obstruction, and a reduced sense of smell. In certain embodiments, a subject in need thereof has had symptoms of nasal polyposis for 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In still other embodiments, the subject has received prior treatment, such as with an intranasal corticosteroid (eg, MFNS), for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks or more, before receiving treatment with the antibody or antigen-binding fragment thereof. In some embodiments, the subject will continue to receive INCS while receiving treatment with the antibody or antigen-binding fragment thereof. In other embodiments, the subject stops receiving INCS before receiving treatment with the antibody or antigen-binding fragment thereof, or the subject stops receiving INCS treatment if administration with the antibody or antigen-binding fragment. Antigen thereof is effective in treating nasal polyposis. In some embodiments, the subject lowers the INCS dose before completely stopping treatment.

A subject in need thereof may have been additionally diagnosed with nasal polyposis based on one or more of the following: (a) 22-point nasal sinus outcome test score (SNOT-22); (b) nasal congestion / obstruction assessed by the subject, anterior rhinorrhea, posterior rhinorrhea and loss of sense of smell; (c) number of night awakenings; (d) visual analog score (VAS) to assess the severity of rhinosinusitis symptoms evaluated by the patient; (e) score of the five-point asthma control questionnaire (ACQ5) in patients with asthma; (f) peak nasal inspiratory flow (NPIF); (g) odor test (University of Pennsylvania Odor Identification Test (UPSIT); (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) Lund-Mackay score and (k) measurement three-dimensional volumetric of the maxillary sinus.

For example, in certain embodiments, a "subject in need thereof" is a human patient with chronic symptoms of sinusitis, which are the presence of at least two of the following symptoms: blockage / obstruction / nasal congestion or nasal discharge (runny nose) before, after); facial pain / pressure; and reduction or loss of smell.

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

In a related embodiment, a "subject in need thereof" may be a subject who, prior to receiving the antibody or antigen-binding fragment thereof, has been prescribed or is currently taking another medication, "base therapy" . Base therapy may be, for example, an intranasal corticosteroid (INCS, or ICS), such as mometasone furoate nasal spray (MFNS; Nasonex®). In some embodiments, a "subject in need thereof" is an asthma patient who, prior to receiving the antibody or antigen-binding fragment thereof, has been prescribed or is currently taking an INCS in combination with a beta- ² antagonist - long-acting adrenoceptor (LABA). Examples of INCS / LABA therapies include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. In some embodiments, the base therapy is a nasal saline solution, a topical decongestant, a topical anesthetic, a leukotriene antagonist, or a systemic antihistamine. In some embodiments, the "subject in need thereof" follows the base therapy after the subject receives the antibody or antigen-binding fragment thereof, and in other embodiments, the subject in need thereof stops receiving therapy base (eg, all at once or gradually) before receiving the antibody or antigen-binding fragment thereof.

EXAMPLES

The following examples are presented so as to provide those of ordinary skill in the art with a full disclosure and description of how to make and use the methods and compositions characterized in the invention, and are not intended to limit the scope of what the inventors consider to be their invention. . Efforts have been made to ensure accuracy with respect to the numbers used (eg quantities, temperature, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise noted, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade, and pressure is at or near atmospheric.

Example 1: Clinical trial of anti-IL-4R (m Abl) antibody administered subcutaneously to patients with persistent moderate to severe eosinophilic asthma, including patients with asthma with chronic hyperplastic eosinophilic sinusitis

A. Objectives and overview of the study

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

The primary objective of the study was to investigate the effects of mAb1 administered subcutaneously once weekly for 12 weeks compared with placebo on reducing the incidence of asthma exacerbations in patients with moderate to severe persistent eosinophilic asthma. Secondary objectives of the study were to assess the safety and tolerability of mAb1 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma and to assess serum concentrations of mAb1 after subcutaneous dosing once per week for 12 weeks in patients with persistent eosinophilic asthma of moderate to severe.

Prior to screening, patients were required to be on a stable dose of any of the following doses and ICS / LABA combination therapy formulations (also called “base therapy”) for at least 1 month:

Fluticasone / salmeterol combination therapy

- Advair® Diskus - dry powder inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or

- Advair® HFA - metered dose inhaler (MDI): 230/42 ug BID or 460/42 ug BID; or

Budesonide / formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or

Mometasone / formoterol combination therapy (Dulera® 200/10 ug BID or 400/10 ug BID)

Patients who were on budesonide / formoterol or mometasone / formoterol were switched to an equivalent dose of fluticasone / salmeterol on randomization (day 1), and patients who had been on fluticasone / salmeterol remained the same as base therapy.

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

The study comprised a 2-week selection period, a 12-week treatment period comprising a stable phase of 4-week baseline therapy, and a withdrawal phase of baseline therapy 8-weeks after randomization, followed by a follow-up period of 8 weeks after treatment.

Algorithm for withdrawal of basic therapy (ICS / LABA):

Patients remained on fluticasone / salmeterol BID base therapy for 4 weeks after starting additional therapy or treatment with 300 mg mAb1 (or placebo). 4 weeks after randomization, patients were switched from fluticasone / salmeterol BID combination therapy to an equivalent ICS dose of fluticasone monotherapy (comprising either the DPI formulation Flovent® Diskus 250 ug or 500 ug BID; or the 220 ug or 440 ug BID MDI Flovent® HFA formulation). The LABA component (i.e. salmeterol) was discontinued. On subsequent visits, starting with week 6, the dose of fluticasone was reduced by approximately 50%, provided that the patient did not meet any of the criteria for an exacerbation of asthma (as defined below). If no asthma exacerbations occurred, ICS withdrawal proceeded according to the following dosing schedule:

After completing 12 weeks of treatment with the investigational product (or after early discontinuation), patients were placed on their original dose of fluticasone / salmeterol, budesonide / formoterol, or mometasone / formoterol (study entry dose) ) and albuterol or levalbuterol as needed to control your symptoms for an additional 8 weeks of off-study medication before a final safety assessment.

An outline of the study protocol is provided in Figure 1.

Adult patients were included in the study based on the following criteria: (1) physician's diagnosis of persistent asthma for at least> 12 months based on 2009 Global Initiative for Asthma (GINA) guidelines, whose inflammation of the airways it is likely to be eosinophilic; and (2) whose asthma is partially controlled or uncontrolled with long-acting inhaled corticosteroid / beta-agonist combination therapy according to the following criteria: (i) stable dose of either fluticasone / salmeterol combination therapy (DPI formulation: 250/50 pg BID or 500 / 50 pg BID or MDI formulation: 230/42 pg BID or 460/42 pg BID), or budesonide / formoterol combination therapy (160/9 pg BID or 320/9 pg BID), or mometasone combination therapy / formoterol (200/10 pg BID or 400/10 pg BID) for at least 1 month before selection; (ii) blood eosinophils> 300 cells / pL or sputum eosinophils> 3% during the selection phase; (iii) Juniper asthma control questionnaire score (5-question version, ACQ) of> 1.5 and <3.0 in the selection; (iv) FEV1> 50% of the predicted normal during the selection phase (3 attempts maximum) and on the day of randomization before the first dose (3 attempts maximum); (v) has had within 2 years prior to selection or treatment with one or more systemic steroid shocks (oral and / or parenteral) due to worsening asthma or hospitalization of the patient or emergency room consultation for worsening asthma; and (vi) documented history of reversibility within 12 months of selection meeting the criteria - at least 12% and 200 mL in FEV1 after 200 pg to 400 pg (2 to 4 inhalations) of albuterol during the phase of screening (3 attempts maximum), or documented history of positive methacholine exposure (PD20 methacholine <8 mg) within 12 months prior to screening. Patients with moderate to severe asthma that is partially controlled or uncontrolled with moderate to high doses of combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT® or DULERA®) and with eosinophils were included in the study. in blood greater than or equal to 300 cells per microliter, or eosinophils in sputum greater than or equal to 3% during the selection phase.

Patients who fulfilled all the inclusion criteria were selected for the following exclusion criteria: (1) patients younger than 18 years or older than 65 years; (2) clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation; (3) chronic obstructive pulmonary disease (COPD) and / or other lung diseases that affect lung function tests; (4) patients requiring beta-adrenergic receptor blockers for any reason; (5) current or quit smoker within 6 months prior to selection; (6) previous smoking with a history of smoking of> 10 packets of cigarettes-year; (7) hospitalization of the patient or emergency room consultation due to exacerbation of asthma in the 2 months before selection; (8) plans to start allergen immunotherapy in the study period; (9) exposure to another investigational antibody in a period prior to selection that is less than 5 half-lives of the antibody but not less than 30 days, or if the half-life of the antibody is not known, then a period of time before the selection that is at least 6 months; (10) prior enrollment in the current study; (11) the patient was the investigator, a family member, or an employee of the research site; (12) known or suspected lack of compliance, alcohol or drug abuse; (13) inability to follow study procedures (for example, due to language problems or psychological disorders); (14) reversal of the sleep pattern (eg, night shift workers); (15) treatment with drugs known to prolong the QTc interval; (16) Simultaneous severe disease (s) for which the use of ICS (eg, active or inactive pulmonary tuberculosis) or LABA (eg, diabetes, cardiovascular disease, hypertension, hyperthyroidism, thyrotoxicosis) is contraindicated , etc.); (17) use of injectable glucocorticoids or oral systemic glucocorticosteroids within 2 months before selection or more than 3 cycles within 6 months before selection; (18) pretreatment with variable doses of ICS, both alone and in combination with a non-steroidal controller (other than combination therapy with fluticasone / salmeterol, combination therapy with budesonide / formoterol, or combination therapy with mometasone / formoterol); (19) patients receiving prohibited concurrent medications (listed below); (20) known allergy to doxycycline or related compounds; (21) pregnancy or intention to become pregnant during the course of the study, lactation or refusal to use an effective method of contraception, and (22) recent history of parasitic infection or travel to a parasitic endemic area within 6 months prior to selection.

The patients remained on a constant dose of the base asthma therapy for the first four weeks of the study, after which the base therapy dose was gradually reduced. First, the long-acting beta agonist component of the base therapy was withdrawn at week 4, and then the dose of inhaled corticosteroid was halved every 2 weeks until week 12. The patients continued with the study treatment. until the end of the study or until they were withdrawn due to an exacerbation of asthma or for any other reason.

B. Study Treatments

Investigational product: A 150 mg / mL sterile mAb1 solution was provided for SC injection in a 5 mL glass vial. Each vial contained a removable volume of 2 mL. A dose of 300 mg was administered subcutaneously at the study site once a week in the morning for 12 weeks. Placebo: Sterile placebo for SC injection was provided in an identically matched 5 mL glass vial. Each vial contained a removable volume of 2 mL. Placebo was administered subcutaneously at the study site once a week in the morning for 12 weeks.

The following concomitant medications were not allowed during the study period: any inhaled steroid other than the protocol-administered fluticasone / salmeterol or fluticasone combination therapy (or budesonide / formoterol or mometasone / formoterol during the selection period); systemic steroids or eyepieces; LABAs other than the salmeterol component of the protocol-administered fluticasone / salmeterol combination therapy; any other ICS / LABA combination product other than those given above; any inhaled anticholinergic agent (for example, ipratropium or tiotropium bromide); methylxanthines (theophylline, aminophyllines); cromonas; anti-lgE therapy; lipoxygenase inhibitors; and leukotriene receptor antagonists or leukotriene synthesis inhibitors.

C. Efficacy of treatment

The primary endpoint of this study was the occurrence of an asthma exacerbation as defined by any of the following: (1) a 30% or greater reduction from baseline maximum expiratory flow (PEF) within two days consecutive or (2) six or more additional palliative discharges of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days or (3) deterioration of asthma, as determined by the investigator, requiring : (a) systemic steroid treatment (oral and / or parenteral) or (b) an increase in ICS> 4 times the last dose received before the study was discontinued or (c) hospitalization. The secondary endpoints of the study included mean changes from baseline for the following parameters: (1) forced expiratory volume in 1 second (FEV1) in liters measured at each visit; (2) maximum morning and evening expiratory flow (AM PEF and PM PEF) in liters / minute measured daily; (3) daily use of albuterol / levalbuterol in inhalations / day; (4) five-point asthma control questionnaire score (ACQ5) at each visit and (5) nocturnal awakenings (No. of times per night) measured daily, and (6) 22-point nasosinusal results test (SNOT-22 ), evaluated at the initial level and at the end of the treatment (at week 12), to assess the symptoms of the upper respiratory tract. Secondary endpoints also included the proportion of patients with a compound asthma event defined by a 30% or greater reduction from baseline in morning PEF on two consecutive days along with> 6 additional palliative discharges of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days. PEF, ACQ5, asthma symptom scores, night awakenings, and use of palliative medication were collected in an electronic journal daily. Average daily nighttime awakenings, ranging from 0-10, were averaged over the previous 7 days. Morning and evening asthma symptom scores consisted of an unvalidated patient-reported outcome assessed on a 5-point Likert-type scale, indicating higher scores and worse outcomes (Table 2). Patients recorded global symptom scores twice daily before measuring PEF. Data were described as the average for the 7 days before the specified time point.

Table 2: Assessment of asthma symptom score

D. Monitoring of adverse events

Safety was assessed throughout the study by monitoring for adverse events and serious adverse events.

An adverse event (AE) is any inappropriate medical manifestation in a subject or subject under clinical investigation administered with a pharmaceutical product. An AE can therefore be any unfavorable and involuntary sign (including abnormal laboratory data), symptom or disease temporarily associated with the use of a pharmaceutical specialty, whether considered or not related to the pharmaceutical specialty (under investigation). AEs also include: any worsening (ie, any clinically significant change in frequency and / or intensity) of a pre-existing condition that is temporarily associated with the use of the study drug; abnormal laboratory data considered by the investigator to be clinically significant and any inappropriate medical manifestations.

A serious adverse event (SAE) is any inappropriate medical manifestation that results in death at any dose; it is life threatening; requires hospitalization of the patient or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; it is a congenital anomaly / birth defect; or is it a major medical event.

E. Statistical methods

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

For secondary endpoints, except SNOT-22, change from baseline was analyzed using a repeated measures mixed effects model (MMRM) approach. The model included the change from baseline values up to week 12 as response variables and the factors (fixed effects) for treatment, stratification factor, visit, treatment interaction per visit, initial level value and initial level interaction. per visit. Statistical inferences about treatment comparisons were derived for change from baseline at week 12 of the mixed effects model. Change from baseline in SNOT-22 was analyzed using an analysis of covariance (ANCOVA), using end-of-treatment measurements to attribute missing data. Pharmacodynamic effects were evaluated using MMRM models in an a posteriori mode. No adjustments were made for multiplicity since there was only one primary end point and analysis. Safety variables, including AEs, laboratory parameters, vital signs, ECG, clinical laboratory observations, and physical examinations, were summarized using descriptive statistics.

Demographic and clinical characteristics were summarized using descriptive characteristics. Graphs of the secondary and pharmacodynamic variables are presented as mean change from baseline over time with standard error. Comparison of treatment effects of MMRM analyzes are based on the change in the least squares mean (95% confidence intervals [CI]) from baseline at week 12.

F. Results

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

Table 3. Demographic and clinical characteristics of the initial level of the treatment groups. *

(i) Primary efficacy endpoint

The incidence of asthma exacerbations in the placebo and mAbl treatment groups is presented in Table 4.

Table 4. Incidence of asthma exacerbations in the mITT population.

There were a total of 26 asthma exacerbations during the treatment period, and no patient was hospitalized for asthma exacerbations. There were 23 patients (44.2%) who experienced an exacerbation of asthma in the placebo group, while only 3 patients (5.8%) experienced an exacerbation of asthma in the mAb1 treatment group. The odds ratio is 0.077 (p <0.0001) and the relative risk reduction is approximately 87%.

Of the 26 asthma exacerbations experienced during this study, 9 were considered severe as demonstrated by the need for immediate intervention in the form of treatment with systemic corticosteroids or with inhaled corticosteroids at a dose of 4 or more times the dose taken before the event. . A summary of the incidence of severe exacerbations of asthma is presented in Table 5.

Table 5. Incidence of severe exacerbations of asthma in the mITT population.

As shown in Table 5, eight severe asthma exacerbations were observed in the placebo group, and only 1 severe asthma exacerbation in the mAb1 treatment group. The remaining 15 asthma exacerbations in the placebo group and 2 in the mAb1 group met the protocol definition of exacerbation based on reduced morning PEF and / or increased albuterol / levalbuterol use. In the active treatment group, sustained improvement over baseline was observed over the course of the study for all parameters, despite withdrawal of steroids.

Table 6. Exacerbation Events

With mAb1, the time to exacerbation was longer, and the risk of exacerbation was reduced relative to placebo (risk ratio 0.10, 95% CI 0.03, 0.34, P <0.001). An analysis of the time to asthma exacerbation by the Kaplan-Meier graph revealed that the effect of treatment with mAb1 is sustained over time, including after 8 weeks when patients are at a higher risk of developing exacerbations due to steroid withdrawal.

Only 1 patient in the placebo group had a compound asthma event. A compound asthma event is defined as a 30% or greater reduction from baseline in morning PEF on 2 consecutive days along with> 6 additional palliative releases of albuterol or levalbuterol in a 24 hour period (compared to baseline) ) on 2 consecutive days.

(ii) Other efficacy assessment criteria

Pulmonary function parameters (FEV1, AM PEF, and PM PEF), endpoints based on asthma symptoms (ACQ score, night awakenings), and albuterol use for each patient at each visit were evaluated. In addition, the SNOT-22 score was evaluated at the initial level and at the end of the treatment. For all the parameters, mean values of baseline and week 12 (LOCF) are summarized in Table 7, together with the mean difference between treatment groups (ANOVA model for SNOT-22). In Table 7, the column marked “Difference vs. Placebo” reflects the placebo-corrected value from baseline, which takes into account the observed changes in the parameter value compared to the observed changes for that parameter in the placebo group.

Table 7. Secondary Parameters of Lung Function and Symptom Scores

MAbl treatment produced a significant change from baseline FEV1 at week 1, which was maintained through week 12 despite withdrawal of LABA and ICS, with a small decrease in FEV1 at week 5 coinciding with withdrawal from LABA. Similar improvements were seen in morning PEF, but less in evening PEF. The change in mean least squares (LS) from baseline to week 12 in FEV1 was - 0.22 L for placebo and 0.05 L for the mAb1 group (p = 0.0009).

The ACQ5 score improved in both treatment groups at week 1. However, although ACQ5 further improved with mAb1 between weeks 1 and 4, the placebo effect stabilized, maintaining the difference until week 12.

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

Night awakenings were stable in the placebo group until week 6, then increased from weeks 6 to 12. In contrast, nighttime awakenings decreased in the mAb1 group at week 1 and continued to improve from baseline until week 12.

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

There was a non-significant difference at baseline between SNOT-22 values with the mean placebo score at 26.24 and the mean mAb1 score at 39.02. At week 12, the change in mean LS 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 represents a magnitude of improvement of 8.49 points for the mAb1 group (p = 0.0027).

Table 8. Secondary Valuation Criteria

Table 9. Change from baseline at week 12 on SNOT-22 points relevant to upper respiratory tract disease.

For all secondary endpoints, measurements at week 12 favored mAb1 treatment and were significant, except for evening PEF and nighttime awakenings (Tables 7 and 8). Significant improvements with mAb1 were also observed for the three SNOT-22 sites relevant to upper respiratory tract disease (Table 9)

(iii) Security

mAbl was generally safe and well tolerated. Treatment emergent adverse events (TEAEs) were similarly reported by 40 (76.9%) of the placebo-treated patients and by 42 (80.8%) of the mAb1-treated patients (Table 10). The TEAEs were non-specific, generally of mild to moderate intensity, and most remitted at the end of the study. An increase in reports of the following TEAEs was observed for mAb1 compared to placebo: injection site reactions were reported by 15 (28.8%) mAb1 patients and by 5 (9.6%) placebo patients; Nasopharyngitis was reported by 7 (13.5%) mAb1 patients and 2 (3.8%) placebo patients; Headache was reported by 6 (11.5%) mAb1 patients and 3 (5.85) placebo patients and nausea was reported by 4 (7.7%) mAb1 patients and 1 (1.9%) placebo patient .

Table 10. Adverse events.

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

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

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

G. Conclusion

Significant improvements were observed for lung function and other parameters of asthma control. Early and sustained efficacy was observed despite withdrawal of base therapy. A relative reduction of approximately 87% (p <0.0001) was observed in the primary endpoint of incidence of asthma exacerbations in patients with persistent moderate to severe asthma with eosinophilia after 12-week treatment with 300 mg mAb1 once a week (5.8%) compared to placebo (44.2%). As shown in Table 7, clinically significant and statistically significant improvements (without multiplicity adjustment) were observed with treatment compared to placebo in lung function parameters (FEV1, PEF AM), asthma symptom scores (ACQ) and use of albuterol. Positive trends were observed for PEF PM (p = 0.0567) and night awakenings (p = 0.0518). A statistically significant improvement (without multiplicity adjustment) was also observed for the SNOT-22 score. In the active treatment group, sustained improvement from baseline was observed over the course of the study for all parameters, despite withdrawal of LABA and ICS. MAb1 was generally safe and well tolerated.

Example 2: Biomarker studies

Biomarker analysis was performed on samples taken from subjects who participated in mAb1 clinical trials (see Example 1 above). In particular, serum / plasma biomarkers associated with TH2 inflammation such as thymic activation chemokine (TARC; CCL17), immunoglobulin E (IgE), eotaxin-3, periostin, carcinoembriogenic antigen (CEA), YKL-40, and YKL-40 were measured. Blood eosinophils in patient samples at baseline and at different time points after the start of the study treatment (s). Baseline levels of these biomarkers were assessed for possible predictive value for response to treatment. Furthermore, the fraction of exhaled NO (FeNO) and eosinophils and neutrophils in sputum induced as biomarkers of bronchial inflammation were measured. Assessment of exhaled nitric oxide was performed before spirometry and after a fast of at least 1 hour using a NIOX instrument (Aerocrine AB, Solna, Sweden). Biomarkers were analyzed using a mixed model and the least squares mean derived from the model is reported below.

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

TARC, eotaxin-3, and IgE remained unchanged in response to placebo. In contrast, a rapid reduction in TARC was observed (change in mean% -22.7% vs. 0.3%; p = 0.0003) and eotaxin-3 (change in mean% -39.62% vs. 12 , 69%; p <0.0001) within one week in patients treated with mAb1 and persisted until week 12: TARC: -26.0% vs. 7.6% of placebo (p = 0.0005) ; eotaxin-3: -45.67% vs. 5.13% placebo (p <0.0001).

TARC levels responded within one week after exposure to 300 mg mAb1 administered subcutaneously. TARC levels stabilize at approximately 50% of baseline level in subjects treated with mAb1, regardless of ICS withdrawal. The data suggests that TARC expression is more directly linked to IL-4R signaling than FEV1 changes (which decrease in parallel with ICS withdrawal [after week 4]) and that IL-4R blockade induces a shift towards a TH1 signature as observed, for example, with the administration of IFN-gamma. It might be possible to adjust the dose of mAb1 using TARC (and for example CXCL10), particularly in patients requiring long-term treatment and at risk of TH1-type immune diseases.

Total serum IgE also decreased after mAb1 treatment. The total serum IgE response was more heterogeneous and delayed compared to the TARC response. The mean IgE levels of the initial level (SD) were 694.68 Ul / L (1837.82) for the placebo group (n = 52) and 657.66 (1482.25) for the mAb1 group (n = 52), while the median was 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend towards a decrease in IgE was observed in patients exposed to mAb1 compared to placebo, however only from week 4. Serum IgE was significantly reduced in the mAb1 group compared to placebo. (change in mean%, -10.1% vs. 13.5%; p = 0.0325) from week 4 and continued to decrease until week 12 (change in mean%, -36.8% for mAb1 vs. -5.5% for placebo; p <0.0001).

All changes from baseline and placebo at week 12 for FeNO, TARC, eotaxin-3, and IgE favored mAb1 (all P <0.001) (Table 11). No differences were observed from baseline or between treatments on YKL-40 or CEA.

Table 11. Percentage change from baseline at week 12 in pharmacodynamic endpoints.

Change in percentage of least squares mean ± error Standard result Placebo p value (N = 52) mAb1 (N = 52)

FeNO 35.0 ± 10.8 28.7 ± 11.2 <0.001 TARC 7.6 ± 6.9 -26.0 ± 6.9 <0.001 Eotaxin-3 5.1 ± 4.7 -45.7 ± 4.7 <0.001 IgE 5.5 ± 3.6 -36.8 ± 3.6 <0.001 Eosinophils in blood 2.7 ± 15.8 41.6 ± 15.7 0.078

Administration of mAb1 delayed the increase, but did not prevent the increase above baseline with ICS / LABA. No consistent effect of CEA and YKL-40 treatment was observed. The number of blood eosinophils remained unchanged until week 6, but then increased at weeks 8 and 12. Peripheral blood eosinophil numbers did not change with placebo throughout treatment. The difference between treatments was not significant, with a marginal increase caused by higher elevations of blood eosinophils in only a few patients treated with mAb1. Few if any increases were observed in most patients.

Table 12. Proportions of patients reaching thresholds of change in blood eosinophil levels.

Change in eosinophils Number% of patients

Placebo (n = 52) mAb1 (n = 52)

> 15% decrease 13 (30.2) 21 (47.7)

15% decrease - 0% change 7 (16.3) 6 (13.6)

0% - 15% increase 8 (18.6) 4 (9.1)

15% - 100% increase 13 (30.2) 6 (13.6)

100% - 200% increase 2 (4.7) 3 (6.8)

> 200% increase 0 4 (9.1)

Since only 3 mAb1 patients experienced exacerbation of asthma during the study, no conclusions could be drawn regarding the association between baseline biomarker levels and asthma exacerbations.

MAb1 treatment was also associated with a significant decrease from baseline FeNO at week 4, and FeNo remained below baseline until week 12, regardless of ICS withdrawal (mean% change at week 12: -28.7 for mAb1 vs. 35.0 for placebo; p <0.0001). In contrast, placebo FeNO values remained stable until week 8, followed by an increase at week 12 coinciding with ICS withdrawal.

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

Table 13. Correlation between the FEVi and FD endpoints.

Result Correlation Value of p

FeNO -0.408 <0.009

TARC -0.248 0.10

Eotaxin-3 -0.146 0.34

IgE -0.279 0.06

Eosinophils in blood 0.165 0.28

Analysis of the baseline eosinophil scatter plot versus change from baseline in FEV1 at week 12 did not appear to suggest an association of baseline eosinophils and treatment effect, as measured by change from baseline at FEV1 at week 12 in the study population (baseline eosinophils> 0.3 Giga / L). Baseline eosinophils were correlated with decreased ACQ and decreased albuterol / levalbuterol use. Periostatin and YKL-40 at baseline were correlated with decreased ACQ.

The change in FEV1 from baseline worsened at week 12 by withdrawal of ICS (from week 4). Similar analyzes did not suggest an association between baseline TARC or IgE and change from baseline in FEV1 at week 12 in the study population (baseline eosinophils> 0.3 Giga / L).

H. Summary

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

Example 3. Clinical trial of anti-IL-4R antibody (mAb1) administered subcutaneously to patients with bilateral nasal polyposis and chronic symptoms of sinusitis

A. Objectives and overview of the study

The positive effect of mAb1 on the SNOT-22 test described in Example 1 suggested that the anti-IL-4R antibody could also be effective in treating nasal polyposis. Furthermore, nasal polyps are most commonly eosinophilic / TH2-elicited, and mAb1 significantly reduced biomarkers associated with Th2 inflammation (see Example 2). Therefore, a clinical trial was designed to test the therapeutic effect of mAb1 on nasal polyposis.

A randomized, double-blind, phase 2, placebo-controlled, 2-arm study will be performed to evaluate mAb1 administered once weekly (QW) subcutaneously (SC) for 16 weeks in patients with bilateral nasal polyposis and symptoms. chronic sinusitis. The primary objective of the study will be to evaluate the efficacy of mAb1 in the treatment of bilateral nasal polyposis (NP) by evaluating the endoscopic score of nasal polyps compared to placebo. Secondary objectives of the study include evaluation of mAb1 in patients with bilateral nasal polyps for sinus symptoms, changes in computed tomography (CT), nasal polyps score in the subgroup of patients with comorbid asthma, safety and tolerability, pharmacodynamic responses based on suppression of TH2 biomarkers, serum mAb1 concentrations, immune response to mAb1 (anti-drug antibodies (ADA)) and effect of mAb1 on patient-reported outcomes and quality of life scales (QoL).

MAb1 will be administered simultaneously with mometasone furoate nasal spray (MFNS). Therefore, there is a high comorbidity of PN with asthma, hypersensitivity to aspirin / non-steroidal anti-inflammatory drugs (NSAIDs) and previous surgeries and, therefore, patients will be allowed to enter the study unless they meet any of the criteria for exclusion described below. Approximately 56 patients will be randomized into 2 treatment groups of 28 patients per group. To ensure that at least 28 patients with comorbid asthma are included in the study, recruitment of PN patients without comorbid asthma will be stopped when approximately 28 patients without asthma are randomized. Both the patient and the investigator will be unaware of the assigned treatment group.

The study will consist of three periods: 1) a 4-week pre-inclusion selection period with MFNS (visit 1); (2) a 16-week randomized placebo or mAb1 treatment period (visits 2-18) and (3) a 16-week post-treatment period to test for pharmacokinetics, immunogenicity, safety and efficacy (visits 19-22). The total duration of the study is up to 36 weeks.

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

Numerous secondary efficacy endpoints will be measured to further assess the efficacy of mAb1. The study will explore the improvement of nasal polyposis and CT-associated sinus inflammation, improvement of the specific condition, and general medical questionnaires to gain a better understanding of the impact of severe nasal polyposis on the subject's quality of life (QoL). .

These endpoints, together with exploratory subgroup analysis and biomarkers, will provide information on the therapeutic value of mAb1 to reduce nasal polyps score and to improve symptoms in NP and its subsets. The sustainability of the effect will also be explored during the 4-month evaluation period after treatment.

The 300 mg QW dosage regimen is anticipated to saturate the apparent target-mediated elimination level (10 15 mg / L). This regimen has been tested and provided a statistically significant and clinically relevant response in two previous preliminary efficacy studies conducted with mAb1 in asthma and atopic dermatitis (see, for example, Example 1 above, USSN 61/805797 and USSN 61 / 816191). The first dose will use a 600 mg loading dose to achieve a faster steady state concentration. This loading dose range is supported by the acceptable safety profile of the highest loading dose (600 mg) demonstrated in a previous study conducted in healthy Japanese subjects.

In addition, since Cmax after the 600 mg loading dose is approximately 70 mg / L and C300 at steady state QW is approximately 150 mg / L, Cmax after the proposed dosage regimen (i.e., dose of 600 mg load followed by 300 mg QW) will be below the mean Cmax of 12 mg / kg IV dose (421 mg / L), the highest single dose tested in healthy subjects that was well tolerated, providing additional confidence of that this dosage regimen should have an acceptable safety profile.

Patient inclusion criteria include (i) a physician endoscopic diagnosis of bilateral nasal polyposis (i.e., a minimum bilateral nasal polyp score of 5 out of a maximum score of 8 for both nostrils, with at least a score of 2 for each nostril, despite the end of a previous treatment with INCS (intranasal corticosteroid) for at least 8 weeks before selection and (ii) chronic symptoms of sinusitis, which are the presence of at least two of the following symptoms before selection: blockage / obstruction / nasal congestion or runny nose (anterior / posterior nasal drip); facial pain / pressure; and reduction or loss of smell.

Patients who meet these criteria will be selected for the following exclusion criteria: age <18 or> 65 years; any technical / administrative reason that makes randomization of the patient in the study impossible; previous participation in any mAb1 clinical trial; a SNOT22 score of <7; receiving any other investigational drug or therapy prohibited for this study within 2 months prior to selection or 5 half-lives, whichever is longer; receiving oral corticosteroids (OCS) or intranasal corticosteroid drops within 2 months or 1 month before selection or scheduled to receive OCS during the study period for another condition; treatment with mAB or immunosuppressive therapy; treatment with anti-immunoglobulin E (IgE) therapy (eg omalizumab) within 130 days before the visit 1; treatment with a leukotriene antagonist / modifier for patients who were not on continuous treatment for> 30 days before the visit 1; initiation of allergen immunotherapy within 3 months before visit 1 or plan to start therapy during the selection period or the randomized treatment period; any nasal surgery within six months before screening or having had more than five nasosinusal surgeries in the past, of which at most two were surgeries that changed the structure of the lateral wall of the nose; or a simultaneous condition / disease that renders the patient assessable by the primary efficacy endpoint (eg, anthrochoanal polyps; deviation of the nasal septum that would plug at least one nostril; acute sinusitis, nasal infection, or upper respiratory infection in the selection or within 2 weeks prior to selection; ongoing rhinitis; Churg-Strauss syndrome, Young's syndrome, Kartagener syndrome, or dyskinetic ciliary syndromes, cystic fibrosis; signs or CT scans suggesting allergic fungal rhinosinusitis). Comorbid asthma patients are excluded if: the patient has a forced expiratory volume (FEV1) of 60% or less; an exacerbation requiring treatment with systemic steroids (oral and / or parenteral) or hospitalization (> 24 h) for the treatment of asthma that occurred within 3 months before selection; or the patient is receiving a dose greater than 1000 pg of fluticasone or the equivalent of inhaled corticosteroids. Other exclusion criteria include patients with low life expectancy (less than 6 months); patients receiving simultaneous treatment prohibited in the study; women who are pregnant or intend to become pregnant during the study, or lactating women. Other exclusion criteria include simultaneous serious illness (eg, active and inactive pulmonary tuberculosis, diabetes mellitus, etc.); diagnosed active parasitosis; suspected or high risk of parasitosis; history of human immunodeficiency virus (HIV) infection or HIV positive screening at visit 1; evidence of acute or chronic infection; known or suspected immunosuppression, including a history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite the disappearance of the infection; live vaccines within 12 weeks before visit 1 or planned vaccinations during the study; patients with active autoimmune disease or patients using therapy immunosuppressive for autoimmune disease (eg, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis); patients with positive or undetermined hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at visit 1; patients with criteria related to liver injury (eg, underlying hepatobiliary disease or ALT> 3 ULN).

B. Study Treatments

Product under investigation: Sterile mAb1 of various concentrations will be provided in 5 mL glass vials. Each vial will contain a removable volume of 2 mL: 150 mg / mL solution (300 mg / 2 mL dose). Sterile placebo will be provided in identically matched 5 mL glass vials, where each vial contains a 2 mL administrable volume.

MAb1 will be administered every 7 ± 2 days (QW). MAb1 doses will be separated in> 5 days to avoid overdose. At visit 2 (V2), 2 injections will be made. After V2, an injection of mAb1 will be made weekly at the research site throughout the randomized treatment period. MAb1 will be administered after clinical procedures and blood collection. Patients will be monitored for at least 1 hour after each administration for any signs or symptoms of a local site injection or hypersensitivity reaction. Subcutaneous injection sites will alternate between the 4 quadrants of the abdomen (avoiding the navel and waist areas) or upper thighs, so that you do not inject at the same site for two consecutive weeks / weeks.

Daily throughout the study, the subject will use an electronic journal to record daily use of MFNS. Mometasone Furoate Nasal Spray (NASONEX ®) 50 micrograms / download is contained in a bottle containing 18 g (140 downloads) of product formulation.

Selection period: Before selection, subjects should be on a stable dose of intranasal corticosteroids (INCS) for> 2 months prior to visit 1. If the patient is using an alternative INCS product other than MFNS before the visit selection, in V1, the patient will be changed to MFNS. After V1, all patients will enter a 4-week run-in period where they will receive MFNS: 2 shocks (50 pg / shock) in each nostril twice daily (BID) (total daily dose of 400 pg), unless who are intolerant to INCS BID, in which case they can continue with the lower dose (QD) regimen. To be accepted into the study, patients must also have at least two of the following symptoms present before selection: nasal blockage / obstruction / congestion or rhinorrhea (anterior / posterior nasal drip); / - facial pain / pressure or / - reduction or loss of smell.

Treatment period: The treatment period will continue as indicated in the study flow chart in Table 14.

Table 14.

The selection period is 28 days in any patient with MFNS and to collect the initial level data. V2 will take place in a window of 28 days ± 2 days after V1

a No administration of mAb1 during this visit. Patients who discontinue treatment early as soon as possible will be evaluated using the procedures normally planned for the end-of-treatment visit and the 4 visits of the post-treatment period.

b Before screening, patients should have a stable dose of INCS for more than 8 weeks

c Spirometry: all patients should have FEV1 at any time during the selection period (before V2) and at the other scheduled visits during the randomized treatment period.

d Weekly administrations of mAb1 from V2 at the research site must be separated by at least 5 days.

e Electronic journal / NPIF meter is used for daily recording of MFNS use, night awakenings, morning and evening NPIF, and rhinosinusitis symptom scores 1) nasal congestion / obstruction, 2) anterior rhinorrhea (runny nose), 3) rhinorrhea posterior (postnasal drip) and 4) loss of sense of smell, scored using a 0-3 category scale where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms); This device is dispensed on visit 1 and the information on this device is downloaded on the other days indicated. The average of the last 7 days before V2 is necessary to determine the value of the initial level

f Nasal endoscopy: Endoscopy (including the use of decongestants prior to the procedure) will be performed after all other efficacy evaluations have been completed for each visit; Standard video sequences will be downloaded by the researcher to the secure centralized reader website. For eligibility, the centralized reading of V1 will be used. In V2, the investigator reviews the V1 results from the centralized reader to confirm entry criteria and reconfirm eligibility based on inclusion / exclusion criteria and local endoscopic reading in V2

9 CT should be performed at any time during the selection period before the first administration of mAb1 and in EOT. The centralized reading will be used for comparison of the initial level (BL) with EOT

h For patients with comorbid asthma only, ACQ-5 is completed in the patient's electronic journal during clinic visits.1

1 Hematology: hemoglobin, hematocrit, number of platelets, number of total leukocytes with differential count in five parts, differential count, and number of total red blood cells. Serum chemistry (fast on planned visits less in V2): creatinine, blood urea nitrogen, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate and creatine phosphokinase. Clinical laboratory tests at visit 1 include hepatitis screening (hepatitis B surface antigen (HBsAg), hepatitis B IgM core antibody (HBcAb-lgM), hepatitis C antibodies (Ac HC), HIV screening (anti-HIV-1 and HIV-2 antibodies), anti-nuclear antibody (ANA) .The clinical laboratory test at visit 2 is limited to hematology and a separate hematology sample obtained for local analysis. Note: the anti-dsDNA antibody if ANA is positive (title> 1: 160) Clinical laboratory test at visit 2 consists of hematology only 1 Serum pregnancy test at visit 1 and urine pregnancy tests at other visits. Negative result should be obtained at visits 1 and 2 before randomization visits

k Serum pharmacokinetic samples, immune response assessment (ADA) samples, and optional whole blood RNA samples will be collected prior to administration of the investigational product during the randomized treatment period. During the post-treatment period, FC samples will be collected at all visits and ADA samples will be collected at the EOS visit only. Patients with ADA titers> 1000 at the last visit can be followed up after the study. Blood samples will be collected for HR and ADA evaluation at any time in the event of SAE.

m Nasal discharge samples will be collected and stored for possible future discovery work to identify prognostic factors for response to treatment.

n Biopsies of optional polyps will be collected at selected clinical centers

0 Samples will be collected prior to administration of the investigational product during the randomized treatment period

During the treatment period, patients will continue with the stable dose of mometasone furoate: two shots of MFNS in each nostril BID or QD (in case the patient cannot tolerate the high dose). At visit 2, patients will be administered the SNOT-22 test, the VAS and QoL questionnaires (SF-36, EQ-5D, resource use questionnaire related to nasal polyps), the odor test and ACQ-5 in asthma patients.

The clinical laboratory trial at visit 2 is limited to hematology, pharmacokinetics, anti-drug antibodies, biomarkers in serum and plasma, panel sampling of allergen-specific IgE. Blood samples are taken before administration of mAb1. Nasal discharge sampling for biomarkers. For patients who have signed a specific informed consent statement, collect blood samples for DNA and RNA sampling (before administration of the investigational product during the randomized treatment period).

The investigator may consider a temporary interruption of treatment due to suspected AEs. Restarting the mAb1 treatment will be done under close and appropriate clinical and / or laboratory monitoring once the investigator has considered, in his best medical judgment, that the responsibility of the mAb1 in the appearance of the referred event was unlikely and if the criteria are still met. selection for the study.

An adverse event (AE) is any inappropriate medical manifestation in a patient or clinical research patient administered with a pharmaceutical product and that does not necessarily have to be causally related to this treatment.

A serious adverse event (SAE) is any inappropriate medical manifestation that at any dose: results in death, or is life-threatening (the term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of dying at the time of the event; does not refer to an event that hypothetically could have caused death if it were more serious); requires hospitalization of the patient or prolongation of existing hospitalization, or results in permanent disability / incapacity, or is a congenital abnormality / birth defect; it is a medically important event and a medical and scientific opinion should be practiced to decide whether a report issued in other situations is appropriate, such as major medical events that may not be immediately life-threatening or result in death or hospitalization, but may put endanger the patient or may require intervention (i.e. specific measures or corrective treatment) to prevent one of the other outcomes listed in the definition above (the following list of medically important events is intended to serve as a guideline in determining which condition is to be considered as a medically important event The list is not intended to be exhaustive: Intensive treatment in an emergency room or at home for: allergic bronchospasm, anaphylaxis, blood dyscrasias (ie agranulocytosis, bone marrow aplasia, myelodysplasia, pancytopenia , etc.), seizures (seizures, epilepsy, epileptic seizure, absence, etc.), development of drug dependence or abuse): ALT> 3 x ULN total bilirubin> 2 x ULN or asymptomatic increase in ALT> 10 x ULN; suicide attempt or any event that suggests suicide ideas; syncope, loss of consciousness (except if documented as a result of blood sampling); blistering skin rashes; cancers diagnosed during the study or aggravated during the study; chronic (newly diagnosed) or aggravated neurodegenerative diseases during the study (only if assessed as unusual / significant by researchers in studies that specifically assess the effect of a study drug on these diseases).

Post-treatment period: After the end of the randomized treatment period (or after early discontinuation of mAb1), patients will continue treatment with the stable dose of MFNS maintained during the period of randomized treatment, or modified treatment based on medical criteria.

The following simultaneous treatments are not allowed during the selection period and the randomized treatment period: use of intranasal medication that interferes with the symptoms of diseases (antihistamines, nasal atropine, ipratropium bromide, nasal chromolin), except nasal saline; INCS drops; systemic corticosteroid; decongestion (topical or systemic) except before endoscopy; long-term use of systemic antibiotics (for 2 weeks or more); lipoxygenase inhibitors; any immunosuppressive therapy including, but not limited to, methotrexate, cyclosporine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (IgE) therapy (omalizumab); and aspirin or NSAIDs in patients with hypersensitivity to aspirin.

The following simultaneous treatments are allowed: MFNS during selection and throughout the study; normal nasal saline; topical decongestants (eg oxymetazoline hydrochloride to reduce swelling and extend the path for the endoscope) as well as a topical anesthetic, eg lidocaine, are permitted before endoscopy; short-term use of antibiotics (<2 weeks); and, for asthma patients, SABA, LABA, and methylxanthines (eg, theophylline and aminophyllines). The following inhaled corticosteroids are allowed for patients with a stable dose of <1000 gg of fluticasone (or the equivalent dose of another inhaled CS; see Table 16) and only for patients with a stable dose> 30 days before visit 1: Leukotriene antagonists / modifiers are allowed during the study, only for patients who were on continuous treatment for> 30 days before the visit 1; systemic antihistamines; and initiation of allergen immunotherapy (ongoing allergen immunotherapy is allowed for> 3 months prior to visit 1).

C. Efficacy of treatment

The primary endpoint of this study is the change from baseline at week 16 in the score for endoscopic bilateral nasal polyps.

Table 15.

Nasal endoscopy will be performed at the end of scheduled visits and preceded by local administration of anesthetic drugs in combination with a decongestant. Standard video clips will either be downloaded or sent to a centralized reader. Centralized imaging data evaluations and scores will be performed for all endoscopies by an independent medical reviewer for the imaging data. To confirm eligibility in V2, only the centralized read from V1 will be provided to the site. Final results of centralized reading will be provided after the study.

For the analysis of the primary endpoint, the centralized V2 reading will be used for comparison with the EOT reading. Sites will remove subject identification information from the imaging header before submitting the imaging data to the centralized reader.

Secondary endpoints of the study will include change from baseline at week 16 in: patient-reported symptoms (including the 22-point clinical sinonasal sinus test (SNOT-22)); nasal congestion / obstruction evaluated by the subject, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip) and loss of sense of smell, monthly mean (daily morning and evening in the electronic journal); number of night awakenings; Symptom severity of rhinosinusitis assessed by the patient using a visual analog scale (VAS); 5-point asthma control questionnaire (ACQ-5) in the asthma subgroup); peak nasal inspiratory flow (NPIF); odor test (UPSIT); NPS in patients with comorbid asthma; TAC assessments; spirometry (global and in the asthma subgroup); time to first response (improvement> 1 point) in NPS; time: until discontinuation of study treatment; and incidence of treatment interruption due to the need for OCS or nasal surgery.

Quality of life (QoL) endpoints will include change from baseline at week 16 in: 36-point short form health survey (SF36); European quality of life scale (EQ-5D) and questionnaire on the use of resources related to nasal polyps.

Disease-specific measures of efficacy include: computed tomography (CT). A CAT scan of the breasts should be performed before V2 and on EOT. For both Lund-Mackay scores and 3D volumetric measurement of the maxillary sinus, the same acquisitions (sequences) will be used for centralized imaging evaluations and data scores by an independent medical reviewer for imaging data. The centralized reading of V2 will be used for comparison with EOT. Final results of centralized reading will be provided after the study.

For three-dimensional volumetric measurement of the maxillary sinus, the centralized reading before V2 will be used for comparison with the EOT reading. Sites will remove subject identification information from the imaging header before submitting the imaging data to the centralized reader. The% change in opacification from BL to EOT will be calculated.

At screening (visit 1), patients will be given an NPIF meter to record morning (AM) and evening (PM) NPIF. Patients will be instructed to record the following variables in the electronic journal daily: AM NPIF performed within 15 minutes after rising (between 06:00 and 10:00) before taking MFNS and PM NPIF performed in the afternoon (between 18:00 and 22:00) before taking ^m F ⁿ S.

Three NPIF attempts will be made by the patient; The 3 values will be recorded by the patient in the electronic journal and the highest value will be used for the evaluation. The initial level AM NPIF will be the average morning measurement recorded during the 28 days before the first dose of the product under investigation, and the initial level MP NPIF will be the average evening measurement recorded during the 28 days before the first dose. of product under investigation.

To assess disease-specific daily symptoms, the patient will use an electronic diary to: answer individual morning and evening rhinosinusitis symptom questions using a 0-3 category scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms) and that includes symptoms of congestion and / or obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (postnasal drip) and loss of sense of smell. The number of night awakenings will also be recorded.

The same safety evaluations will apply for all arms. Adverse events, including serious adverse events (SAEs) and adverse events of special interest (AESI), will be collected at each visit.

Pre-dose blood samples will be collected for determination of serum functional mAb1 and anti-mAb1 antibodies as designated in Table 14.

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

Pharmacokinetics. Functional mAb1 and anti-mAb1 antibodies will be tested in serum by ELISA. The concentrations of functional mAb1 will be provided before the serum dose at visit 2 (day 1), the minimum concentrations of mAb1 at week 2, week 4, week 8, week 12, week 16 and the follow-up serum mAb1 in at week 20, week 24, week 28, and week 32. Anti-mAb1 antibody status (negative or titer) will also be provided at visit 2 (day 1), week 2, week 4, week 8, week 12 , week 16 and week 32. Patients with ADA titers> 1000 at the end of study visit will be scheduled to return approximately 6 months later for further evaluation of ADA titre. Additional follow-up will be considered based on global assessment of antibody titers and clinical presentation.

Pharmacodynamics. Since the secretion of certain proteins depends, at least in part, on Th2 cytokines and is associated with chronic inflammation of the airway mucosa, including breast tissue, the expression of certain biomarkers will be tested to monitor the therapeutic effect of mAb1. These biomarkers will also be evaluated for their value in predicting toxicity and / or in documenting the time course of the drug response. The values to be used as initial levels will be those collected on day 1 (evaluations before the dose).

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

At a selected clinical site (s), and with specific informed consent, nasal polyp tissue will optionally be obtained by biopsy. An initial level V2 biopsy will be obtained from the study. After randomization, another biopsy of nasal polyp tissue will be obtained at the end-of-treatment visit (week 16). Biopsied nasal polyp tissue will be evaluated for various biomarkers of inflammation and disease process or response. For example, RNA will be extracted and used to obtain expression profiles (for example, microarrays, transcriptome sequencing or quantitative RT-PCR).

DNA and RNA samples can be used to determine a possible relationship between genes and response to mAb1 treatment and possible side effects to mAb1.

Analysis of the proportion of patients with binary events. The proportion of patients with binary events will be evaluated for: improvement of> 1 point (reduction) in NPS at week 16 (read centrally); a 10% or more improvement in TAC opacification from baseline at week 16; abandonment due to oral CS or surgery; o The increase in INCS after 8 weeks will be analyzed using a logistic model with the previous answers, respectively, as the response variable and the treatment group, countries / regions combined and the stratification factor (s) before the study. as covariates.

Analysis of time variables until the event. Time to event (eg, first response with> 1 point improvement (reduction) in NPS, discontinuation of study treatment, etc.) will be analyzed using a Cox regression model with time to event as a variable dependent and treatment, countries / regions combined and asthma comorbidity before study as covariates. The Kaplan-Meier method will be used to derive the proportion of patients with an event at week 4, 8, 12, and 16 specific to each treatment group. For analysis during the treatment period, if a patient has no event prior to treatment interruption / termination, then the patient will be considered event-free until the end of the treatment period (date of last dose 7 days).

Analysis of change from baseline for continuous variables. The change from baseline at week 16 will be analyzed in: NPS for patients with comorbid asthma; Lund-Mackay score; 22-point nasal sinus test (SNOT-22); congestion and / or obstruction score evaluated by the subject; peak nasal inspiratory flow (NPIF); ACQ-5 in patients with comorbid asthma; QoL (SF36, EQ-5D) and VAS measurements using MMRM as well as the primary endpoints. Descriptive statistics will be provided, including number of patients, mean, standard error, and LS means. In addition, differences in LS means, corresponding 95% CI, and p-value will be provided for comparisons of each dose versus placebo. Analysis of the efficacy of initial level biomarkers of defined subsets of characteristics. To examine baseline biomarkers for their potential value in predicting response to treatment, analyzes of NPS changes will also be performed for the following subsets and the entire ITT population for each selected dose group and combined dose group.

Subgroup analysis. To assess consistency of treatment effects by subgroup levels and to examine baseline biomarkers for their potential potential value in predicting response to therapy, exploratory subgroup analyzes for change from baseline in NPS will be performed with regarding age group, gender, region, race, INCS dose level, baseline NPS, baseline TAC score, asthma comorbidity, and biomarkers selected prior to the study.

Lists of anti-mAb1 antibody results (negative or titer value) will be presented by patient, time point, and treatment groups. ADA title levels will be classified into categories: low, moderate, and high. Low ADA levels are defined as titles below 1000; Moderate ADA levels are defined as titers between 1,000 and 10,000; High levels of ADA titles are defined as titles> 10,000.

The results of the anti-mAb1 antibody assay will be described by categories. The following summary will be provided for: patients with any ADA positive test response during the TEAE period; patients with a positive test response of treatment-induced ADA during the period of TEAE; Patients with treatment-induced ADA positive test response during the TEAE period will be further described as patients with transient positive response and patients with persistent positive response. Patients with any positive ADA test response during the TEAE period are defined as those who have at least one positive sample in the ADA test.

Treatment-induced ADA positive test response is defined as: patients with no positive test response at baseline but with a positive test response during the TEAE period or patients with a positive test ADA response at baseline Initial and they also have an increase of at least 4 times in the title during the TEAE period.

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

Claims (22)

1. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for use in a method of treating nasal polyposis in a subject in need of the itself, wherein the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8, and wherein nasal polyposis is optionally bilateral nasal polyposis. 2. The pharmaceutical composition for use of claim 1, wherein the subject has one or more of sinusitis, rhinitis, asthma, hypersensitivity to aspirin, hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), has undergone surgery for polyps nasal, or have chronic rhinosinusitis. 3. The pharmaceutical composition for the use of claim 1, wherein the antibody or antigen-binding fragment thereof is administered in a dose of 0.1 mg to 600 mg, 100 mg to 400 mg, or 300 mg. 4. The pharmaceutical composition for the use of claim 1, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. 5. The pharmaceutical composition for the use of claim 1, wherein one or more of the following conditions are met: (a) the pharmaceutical composition is administered to the subject systemically; (b) the pharmaceutical composition is administered to the subject locally; (c) the pharmaceutical composition is administered to the subject subcutaneously, intravenously, or intranasally; Y (d) the antibody or antigen-binding fragment thereof is administered subcutaneously to the subject at a dose of 300 mg. 6. The pharmaceutical composition for the use of claim 1, wherein a second therapeutic agent meets one or more of the following criteria: (a) the second therapeutic agent is administered to the subject before, after or simultaneously with the pharmaceutical composition; (b) the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic agent, and an antifungal agent; (c) the second therapeutic agent comprises an intranasal corticosteroid, optionally wherein the intranasal corticosteroid is mometasone furoate nasal spray (MFNS); (d) the second therapeutic agent comprises an inhaled corticosteroid, optionally wherein the inhaled corticosteroid is fluticasone or budesonide; Y (e) the second therapeutic agent comprises a long-acting beta2 agonist, optionally wherein the long-acting beta2 agonist is salmeterol or formoterol. 7. The pharmaceutical composition for use of claim 1, wherein administration of the antibody or antigen-binding fragment thereof is followed by an improvement in one or more parameters associated with nasal polyposis selected from the group consisting of: a) score of the 22-point nasal sinus results test (SNOT-22); b) nasal symptoms score; c) number of night awakenings; d) visual analog score (VAS) for the severity of rhinosinusitis symptoms; e) five-point asthma control questionnaire score (ACQ5); f) maximum nasal inspiratory flow (NPIF); g) University of Pennsylvania Odor Identification Test (UPSIT); h) Lund-McKay score; Y i) Three-dimensional volumetric measurement of the maxillary sinus. 8. The pharmaceutical composition for use of claim 1, wherein administration of the antibody or antigen-binding fragment thereof is followed by a decrease in the nasal polyps score in the patient. 9. The pharmaceutical composition for the use of claim 1, wherein the subject is administered sequentially with a single initial dose of said pharmaceutical composition followed by one or more secondary doses of the antibody or antigen-binding fragment thereof. 10. The pharmaceutical composition for the use of claim 9, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2. 11. The pharmaceutical composition for use of claim 9, wherein the dosage strategy satisfies one of the following criteria: (a) each secondary dose is administered 1 to 15 weeks after the immediately preceding dose; or (b) at least 3 secondary doses of the antibody or antigen-binding fragment thereof are administered to the subject, wherein each secondary dose is administered 1 week, 2 weeks or 4 weeks after the immediately preceding dose. 12. The pharmaceutical composition for use of claim 9, wherein the dosage strategy satisfies one of the following criteria: (a) the initial dose and the one or more secondary doses each comprise 50 mg to 600 mg of the antibody or antigen-binding fragment thereof; (b) the initial dose and the one or more secondary doses each comprise 100 mg to 400 mg of the antibody or antigen-binding fragment thereof; (c) the initial dose and the one or more secondary doses each comprise 300 mg of the antibody or antigen-binding fragment thereof; or (d) the initial dose and the one or more secondary doses each comprise an equal amount of the antibody or antigen-binding fragment thereof. 13. The pharmaceutical composition for the use of claim 9, wherein the dosing strategy satisfies one of the following criteria: (a) the initial dose comprises a first quantity of the antibody or antigen-binding fragment thereof, and the one or more secondary doses each comprise a second quantity of the antibody or antigen-binding fragment thereof; or (b) the initial dose comprises a first quantity of the antibody or antigen-binding fragment thereof, and the one or more secondary doses each comprise a second quantity of the antibody or antigen-binding fragment thereof, wherein the first quantity of the antibody or antigen-binding fragment thereof is 1.5x, 2x, 2.5x, 3x, 3.5x or 5x the second amount of the antibody or antigen-binding fragment thereof. 14. The pharmaceutical composition for use of claim 9, wherein the subject has one or more of bilateral nasal polyposis, sinusitis, chronic rhinosinusitis, rhinitis, asthma, hypersensitivity to aspirin, hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), or have had surgery for nasal polyps. 15. The pharmaceutical composition for the use of claim 9, wherein the initial dose and secondary doses satisfy one or more of the following criteria: (a) the initial dose and the secondary doses are administered by the same routes of administration or different routes of administration; (b) the initial dose and secondary doses are administered subcutaneously, intravenously, or intranasally. 16. The pharmaceutical composition for the use of claim 9, wherein the administration of the initial dose and the one or more secondary doses is followed by an improvement in one or more parameters associated with nasal polyposis selected from the group consisting of: a) score of the 22-point nasal sinus results test (SNOT-22); b) nasal symptoms score; c) number of night awakenings; d) visual analog score (VAS) for the severity of rhinosinusitis symptoms; e) five-point asthma control questionnaire score (ACQ5); f) maximum nasal inspiratory flow (NPIF); g) University of Pennsylvania Odor Identification Test (UPSIT); h) Lund-McKay score; Y i) Three-dimensional volumetric measurement of the maxillary sinus. j) nasal congestion / obstruction evaluated by the subject. 17. The pharmaceutical composition for the use of claim 9, wherein the dosage strategy satisfies one or more of the following criteria: (a) administration of the antibody or antigen-binding fragment thereof is followed by a decrease in the nasal polyps score in the patient; (b) a second therapeutic agent is administered to the subject before, after, or simultaneously with the initial dose or the one or more secondary doses; (c) a second therapeutic agent is administered to the subject before, after, or simultaneously with the initial dose or the one or more secondary doses, wherein the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic agent, and an antifungal agent; (d) a second therapeutic agent is administered to the subject before, after, or simultaneously with the initial dose or the one or more secondary doses, wherein the second therapeutic agent comprises an intranasal corticosteroid, optionally where the intranasal corticosteroid is furoate nasal spray. mometasone (MFNS); (e) a second therapeutic agent is administered to the subject before, after, or simultaneously with the initial dose or the one or more secondary doses, wherein the second therapeutic agent comprises an inhaled corticosteroid, optionally where the inhaled corticosteroid is fluticasone or budesonide; Y (f) a second therapeutic agent is administered to the subject before, after, or simultaneously with the initial dose or the one or more secondary doses, wherein the second therapeutic agent further comprises a long acting beta2 agonist, optionally wherein the beta2 agonist of Long-acting is Salmeterol or Formoterol. 18. The pharmaceutical composition for the use of claim 1, wherein said use comprises selecting a patient based on one or more of the following standards: i) a minimum bilateral nasal polyp score of 5; ii) at least two or more of the chronic symptoms of sinusitis are selected from the group consisting of: nasal blockage / obstruction / congestion, anterior or posterior nasal drip, facial pain or pressure, and reduction or loss of smell; iii) an elevated level of one or more genes selected from the group consisting of activation-regulated thymic chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40; Y iv) an elevated level of blood eosinophils or sputum eosinophils; Y wherein the selected patient is administered with one or more doses of said pharmaceutical composition such that one or more of the following criteria are met: i) the patient's nasal polyp score is reduced; ii) improve the two or more symptoms of chronic sinusitis; iii) the level of one or more genes selected from the group consisting of activation-regulated thymic chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40; Y iv) the level of blood eosinophils or sputum eosinophils is reduced when compared to the level prior to administration. 19. The pharmaceutical composition for use of claim 1, 9 or 18, wherein the antibody comprises dupilumab or an antigen-binding fragment thereof. 20. The pharmaceutical composition for use of claim 1, 9 or 18, further comprising a second therapeutic agent, for use to treat chronic sinusitis (CS) with bilateral nasal polyposis (NP) in the subject or the patient. 21. The pharmaceutical composition for the use of claim 1, 9 or 18, wherein the subject or the patient is not less than 18 years old and not more than 65 years. 22. The pharmaceutical composition for use of claim 1, wherein nasal polyposis is inadequately controlled with intranasal corticosteroids (INCS), wherein said subject is administered sequentially with a single initial dose of said pharmaceutical composition followed by one or more doses secondary to the antibody or antigen-binding fragment thereof, and wherein one or more additional therapeutic agents are administered to the subject before, after, or simultaneously with the pharmaceutical composition.