Methods for treating severe atopic dermatitis by administering il-4r inhibitor

Abstract

To provide methods for treating moderate-to-severe or severe atopic dermatitis (AD).SOLUTION: The methods of the present invention comprise administering to a subject in need thereof one or more doses of an interleukin-4 receptor (IL-4R) inhibitor such as an anti-IL-4R antibody. In certain embodiments, the methods of the present invention are used to treat severe AD in a patient whose disease is not controlled with systemic therapy (e.g., cyclosporine A) or when such therapy is inadvisable.SELECTED DRAWING: None

Description

[Technical field]

[0001] Describing Arrays This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on September 11, 2017, is named SequenceList_29.TXT, and has a size of 10.9 kilobytes.

[0002] The present invention relates to methods for treating atopic dermatitis. More specifically, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) inhibitor in a subject in need thereof. [Background technology]

[0003] Atopic dermatitis (AD) is a chronic / recurrent inflammatory skin disease characterized by intense pruritus (i.e. itching), xerosis (dry skin), and eczematous lesions, including erythema, infiltration / papulation, oozing with crusting, excoriation, and lichenification. It is often associated with other atopic disorders, such as allergic rhinitis and asthma. Severe disease can be exacerbated by a number of factors: major psychological problems leading to high socio-economic costs, significant sleep loss, and impaired quality of life. An estimated 2% to 10% of adults suffer from AD (Non-Patent Document 1).

[0004] The pathophysiology of AD is influenced by a complex interplay between inflammation, environmental factors, genetics and skin barrier dysfunction.

[0005] AD is the most common inflammatory skin disease of early childhood (Non-Patent Document 2). The disease is usually present during early infancy and childhood, but may persist into or begin in adulthood (Non-Patent Document 3). In industrialized countries, the disease affects 15 to 30% of children and 2 to 10% of adults (Non-Patent Document 1). Phase 1 of the International Study of Asthma and Allergies in Childhood showed a 1-year prevalence rate of as much as 20% in Australia, the UK, and Northern Europe (Non-Patent Document 4). AD often constitutes the first stage of the atopic march (the progression from one atopic disease to another). Approximately 60% of AD patients also have asthma or allergic rhinitis or food allergies (Non-Patent Document 5).

[0006] Topical corticosteroids (TCS) are by far the most frequently prescribed drug class for AD patients. However, long-term application of TCS is not recommended due to the risk of skin atrophy, pigmentation disorders, acneiform rash, and risks associated with systemic absorption (e.g., hypothalamic-pituitary axis effects, Cushing's disease, etc.). Topical calcineurin inhibitors (TCIs) are generally effective and safe as short-term treatments, but concerns of increased risk of cutaneous malignancies and lymphomas have prompted regulatory agencies to require warnings regarding the long-term safety of topical tacrolimus and pimecrolimus in their prescribing information. Repeated application of either topical therapy over extended periods or to large surface areas also leads to poor patient compliance. First-generation antihistamines are widely prescribed for acute symptomatic treatment of pruritus, but their efficacy is limited, in large part due to their analgesic effects. Oral immunosuppressants (6) and glucocorticoids are effective, but are sometimes associated with severe toxicity and side effects, limiting their use to short-term and / or intermittent therapy. No systemic agents are approved for the treatment of AD in children. All systemic agents are off-label (cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, systemic corticosteroids) and have no evidential basis for use. All of these agents have broad immunosuppressive effects that predispose patients to serious infections when used long term, and have a high risk of malignancy. Other reported notable side effects of these agents include gastritis, stunting, diabetes, weight gain, hypertension, osteoporosis, and adrenal suppression (corticosteroids), nephrotoxicity, hypertension, tremor, hirsutism, headache, gingival hyperplasia (cyclosporine), gastrointestinal disorders, ulcerative stomatitis, bone marrow suppression, hepatotoxicity, and pulmonary fibrosis (methotrexate), hypersensitivity reactions, elevated liver enzymes, and leukopenia (azathioprine). Furthermore, the majority of patients whose disease is initially controlled with systemic agents will relapse once therapy is discontinued (7; 8).

[0007] Cyclosporine A (CSA) is a potent immunosuppressant that affects both humoral and cellular immune responses and is the latest therapy for severe AD in some areas. It increases susceptibility to infection and reduces immune surveillance of cancer. Other commonly recognized toxicities include hypertension and renal and hepatic dysfunction. In addition, CSA may interact with other commonly used drugs, affecting their metabolism and action. Patients' disease often relapses when treatment is discontinued, especially after administration of systemic glucocorticoids (Non-Patent Document 9, Non-Patent Document 10, Non-Patent Document 11). Biologic agents such as tumor necrosis factor alpha (TNF) inhibitors (e.g., infliximab, etanercept), IgE inhibitors (e.g., omalizumab), IL-5 inhibitors (e.g., mepolizumab), and CD11a inhibitors (e.g., efalizumab) have been generally ineffective in clinical trials. Therefore, there is a significant unmet medical need for alternative treatments for AD, particularly for alternative treatments for severe AD in patients who are candidates for systemic therapy. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Bieber 2008, N.Engl.J.Med.358:1483~94 [Non-Patent Document 2] Illi et al., 2004, J. Allergy Clin. Immunol. 113:925~31 [Non-Patent Document 3] Kay et al., 1994, J. Am. Acad. Dermatol. 30:35-9 [Non-Patent Document 4] Williams et al., 1999, J. Allergy Clin. Immunol. 103:125~38 [Non-Patent Document 5] Hong et al., 2012, Envt. Health Toxicol. 27:e2012006 [Non-Patent Document 6] Schmitt et al., 2007, JEADV21:606-619 [Non-Patent Document 7] Granlund et al., 1995, Br.J.Dermatol.132:106~112 [Non-Patent Document 8] Schmitt et al., 2009, Br.J.Dermatol.162:661~8 [Non-Patent Document 9] Schmitt et al., 2009, Brit J Dermatol journal compilation:1~8 [Non-Patent Document 10] Schram 2012, Allergy 67:99~106 [Non-Patent Document 11] Akhavan 2008, Semin Cutan Med Surg 2008;27:151~155 Summary of the Invention [Means for solving the problem]

[0009] According to certain aspects of the present invention, methods are provided for treating, preventing and / or reducing the severity of symptoms of atopic dermatitis (AD), including moderate to severe AD and severe AD. Certain embodiments of the present invention relate to methods for treating patients with severe AD that are resistant to or not adequately controlled by systemic therapy (including systemic immunosuppressants). In some embodiments, the present invention encompasses methods for treating patients with severe AD that is uncontrolled despite treatment with a systemic therapeutic agent. In some embodiments, the present invention encompasses methods for treating patients with severe AD for which treatment with a systemic therapeutic agent (e.g., a systemic immunosuppressant) is medically inadvisable. The methods of the present invention include administering to a subject or a patient in need thereof one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor. In certain embodiments, the IL-4R inhibitor is administered as a monotherapy. In other embodiments, the IL-4R inhibitor is administered in combination with an external therapy (e.g., an external corticosteroid or an external calcineurin inhibitor).

[0010] In certain embodiments, the systemic therapeutic agent is an immunosuppressant selected from the group consisting of cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, oral corticosteroids, and interferon-gamma.

[0011] In certain embodiments, the present invention encompasses a method for treating severe AD or improving at least one AD-related parameter in a patient, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds to IL-4R, and determining an improvement in the AD-related parameter. In certain embodiments, administration of an IL-4R inhibitor is performed according to the following criteria: Investigators Global Assessment (IGA); Body Surface Area Involvement of Atopic Dermatitis (BSA); Eczema Area and Severity Index (EASI); Scoring atopic dermatitis (SCORAD); 5-D pruritus scale; and Pruritus Numeric Rating Scale (PNU). In certain embodiments, administration of an IL-4R inhibitor results in an improvement in one or more AD-related parameters selected from the group consisting of Global Individual Signs Score (GISS), Patient Oriented Eczema Measure (POEM), Patient-Rated Hospital Anxiety and Depression Scale (HADS) and Patient-Reported Dermatology Life Quality Index (DLQI).

[0012] According to certain embodiments, the present invention provides a method for treating a patient with severe AD or improving at least one AD-related parameter in a patient with AD, wherein the patient is: (i) the patient has a baseline IGA score of 4; (ii) the patient has a baseline IGA score of 3 or greater; (iii) the patient is a candidate for systemic therapy; (iv) the patient has disease uncontrolled with topical AD therapy; (v) the patient has a documented history of inadequate response to topical AD therapy or topical therapy is not advisable for the patient due to adverse side effects or safety risks; (vi) the patient has previously received topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological treatments, systemic glucocorticoids, nonsteroidal systemic immunosuppressants, cyclosporine A, azathioprine, ultraviolet light, or other suitable anti-inflammatory drugs. and (vii) the patient has or is selected on the basis of a trait selected from the group consisting of: (i) having been treated with a medication or procedure selected from the group consisting of UV (ultraviolet) light therapy, and phototherapy; and (ii) the patient has a co-morbid disease or disorder selected from the group consisting of food allergy, asthma, seasonal allergy, allergic rhinitis, house dust allergy, and allergic conjunctivitis. The method, according to this embodiment, comprises administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R inhibitor. In certain embodiments, administration results in one or more of the following effects: (a) EASI score reduction of more than 70% from baseline; (b) pruritus NRS reduction of more than 50% from baseline from the second week after administration of the first dose; (c) pruritus NRS reduction of 4 points or more from baseline as early as the second week after administration of the first dose; (d) patient achieves an IGA of 0 or 1 ("cleared" or "almost cleared") and reduces 2 points or more from baseline on an IGA scale of 0 to 4; (e) improvement in patient quality of life.In certain embodiments, IL-4R inhibitor is administered as monotherapy.In other embodiments, IL-4R inhibitor is administered in combination with topical therapy (e.g. topical corticosteroid or topical calcineurin inhibitor).

[0013] According to certain embodiments, the present invention provides a method for treating or reducing pruritus in patients with severe AD, the patient being a candidate for systemic therapy. The method, according to these embodiments, comprises the steps of selecting a patient diagnosed with severe AD, the patient being resistant, insufficiently responsive, or intolerant to systemic immunosuppressants; and administering one or more doses of an IL-4R inhibitor to the patient in need thereof. In certain embodiments, the IL-4R inhibitor is administered as a monotherapy. In other embodiments, the IL-4R inhibitor is administered in combination with topical therapy (e.g., topical corticosteroids or topical calcineurin inhibitors). In certain embodiments, administration of the IL-4R inhibitor results in a reduction of more than 70% from baseline in EASI score, a reduction of more than 50% from baseline in pruritus NRS, a reduction of 4 or more points from baseline in pruritus NRS, and / or a reduction of 2 or more points from baseline on the IGA scale from 0 to 4.

[0014] According to certain embodiments, the present invention encompasses a method of treating a patient with severe AD, which, according to these embodiments, comprises the steps of selecting a patient with severe AD, the patient having been previously treated with a therapy selected from the group consisting of cyclosporine A, an IgE inhibitor, a TNF alpha inhibitor, a CD11a inhibitor, a CD20 inhibitor, an antibiotic, an IL-4R inhibitor (e.g., an anti-IL-4R antibody, e.g., dupilumab), a systemic immunosuppressant, a topical corticosteroid, an oral corticosteroid, a calcineurin inhibitor, and phototherapy; and administering one or more doses of an IL-4R inhibitor to the patient in need thereof.

[0015] In certain embodiments, the present invention encompasses a method for reducing dependency on topical corticosteroids (TCS) in patients with severe AD, comprising administering to a subject in need thereof one or more doses of an IL-4R inhibitor. In certain further embodiments, a medium-potency or high-potency TCS is administered simultaneously with an IL-4R inhibitor. In one further embodiment, the amount of TCS is gradually reduced by at least 20%, at least 30%, at least 40%, or at least 50% upon administration of the first dose of the IL-4R inhibitor.

[0016] According to certain embodiments, the present invention encompasses a method for reducing relapse or exacerbation of AD, comprising selecting a patient with severe AD and administering one or more doses of an IL-4R inhibitor to the patient in need thereof. In embodiments, the patient has refractory AD or is experiencing a relapse following therapy with a systemic therapeutic agent (eg, a systemic immunosuppressant).

[0017] According to certain embodiments, the present invention encompasses a method of treating AD or reducing pruritus or improving an AD-related parameter, comprising the steps of selecting a patient with moderate to severe or severe AD, where the patient has previously been treated with an IL-4R inhibitor (e.g., an anti-IL-4R antibody, e.g., dupilumab) more than 5 weeks prior, more than 8 weeks prior, more than 13 weeks prior, or more than 20 weeks prior, and re-treating the patient in need thereof with one or more doses of the IL-4R inhibitor, where the re-treatment results in a greater than 70% reduction from baseline in EASI score, a greater than 50% reduction from baseline in pruritus NRS, a 4 or more point reduction from baseline in pruritus NRS, and / or a 2 or more point reduction from baseline on an IGA scale of 0 to 4. In certain embodiments, each dose of the IL-4R inhibitor comprises about 50-600 mg and is administered 1, 2, 3, or 4 weeks after the immediately preceding dose.

[0018] According to certain embodiments, the present invention provides a method of treating AD or improving at least one AD-related parameter in a patient having AD, comprising the steps of: (a) selecting a patient having AD, wherein the patient is selected based on: (i) the patient has a baseline IGA score of 4; (ii) the patient has a baseline IGA score of 3 or greater; (iii) the patient is between 6 and 18 years of age; (iv) the patient has disease uncontrolled with topical AD therapy; (v) the patient has a confirmed history of inadequate response to topical AD therapy or topical therapy is not advisable for the patient due to adverse side effects or safety risks; (vi) the patient has previously received topical corticosteroids; (vii) the patient has been treated with a medication or procedure selected from the group consisting of steroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological treatments, systemic glucocorticoids, nonsteroidal systemic immunosuppressants, cyclosporine A, azathioprine, ultraviolet light therapy, and phototherapy; and (vii) the patient has a characteristic selected from the group consisting of food allergy, asthma, seasonal allergy, allergic rhinitis, house dust allergy, and allergic conjunctivitis; and (b) administering to a patient in need thereof a therapeutically effective amount of one or more doses of an IL-4R inhibitor. In certain embodiments, each dose of the IL-4R inhibitor comprises 1, 2, 3, 4, or 5 mg per kg of the patient's body weight, and each dose is administered 1 to 4 weeks after the previous dose.

[0019] According to certain embodiments, the method of the present invention comprises administering one or more doses of an IL-4R inhibitor to a subject in need thereof. In certain embodiments, the method of the present invention comprises administering about 10 mg to about 600 mg of an IL-4R inhibitor as an initial dose, followed by one or more secondary doses, each secondary dose comprising 25 to 400 mg of the IL-4R inhibitor. In certain embodiments, the initial dose and the one or more secondary doses each comprise about 10 mg to about 600 mg of the IL-4R inhibitor. In certain embodiments, the IL-4R inhibitor is administered in an initial dose of 600 mg, followed by one or more secondary doses, each secondary dose comprising 300 mg. According to this aspect of the present invention, the IL-4R inhibitor may be administered to a subject at an administration frequency of, for example, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, each secondary dose is administered one week after the immediately preceding dose. In one embodiment, each secondary dose is administered two weeks after the immediately preceding dose. In certain embodiments, the methods of the invention include administering an IL-4R inhibitor to a subject in need thereof, wherein the IL-4R inhibitor comprises about 1-10 mg per kg of the subject's body weight. In certain embodiments, the subject in need thereof is administered one or more doses of the IL-4R inhibitor, each dose being administered at least about 10 mg per kg of the subject's body weight. It contains 1, 2, 4, 5 or 10 mg per kg of body weight, with each dose being administered 1 to 4 weeks after the previous dose.

[0020] Exemplary IL-4R inhibitors that can be used in connection with the methods of the present invention include, for example, low molecular weight chemical inhibitors of IL-4R or its ligands (IL-4 and / or IL-13), or biological agents that target IL-4R or its ligands. According to certain embodiments, the IL-4R inhibitor is an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to the α chain of IL-4R and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13. In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises a complementarity determining region (CDR) in the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair of SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR (HCDR1) having the amino acid sequence of SEQ ID NO: 3, an HCDR2 having the amino acid sequence of SEQ ID NO: 4, an HCDR3 having the amino acid sequence of SEQ ID NO: 5, a light chain CDR (LCDR1) having the amino acid sequence of SEQ ID NO: 6, an LCDR2 having the amino acid sequence of SEQ ID NO: 7, and an LCDR3 having the amino acid sequence of SEQ ID NO: 8. One such type of antigen-binding protein that can be used in connection with the methods of the invention is an anti-IL-4Rα antibody, such as dupilumab.

[0021] In some embodiments, the IL-4R inhibitor is administered to the subject subcutaneously, intravenously, or intraperitoneally.

[0022] In certain embodiments, the present invention provides the use of the IL-4R inhibitor of the present invention in the manufacture of a medicament for treating moderate to severe or severe AD or reducing pruritus in a patient, the patient being a candidate for systemic therapy (e.g., systemic immunosuppressant) in certain embodiments, the patient being resistant or intolerant to systemic therapy, or systemic therapy is not advisable due to suboptimal efficacy as well as safety and health risks for the patient.In certain embodiments, the present invention provides the use of the IL-4R inhibitor of the present invention in the manufacture of a medicament for reducing dependency on topical corticosteroids in a patient with severe AD.In certain embodiments, the present invention provides the use of the IL-4R inhibitor in the method for treating severe AD or reducing pruritus in a patient with severe AD, the IL-4R inhibitor being administered to a subject in need thereof.In certain embodiments, the present invention provides the use of the IL-4R inhibitor in the method for reducing dependency on topical corticosteroids in a subject with severe AD, the IL-4R inhibitor being administered to a subject in need thereof.

[0023] Other embodiments of the present invention will become apparent from review of the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0025] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about," when used in reference to a specific recited numerical value, means that the value may vary by 1% or less from the recited value. For example, In this case, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.). As used herein, the terms "treat," "treating," and the like, mean to alleviate symptoms, either temporarily or permanently, eliminate the cause of symptoms, or prevent or delay the onset of symptoms of the specified disorder or condition.

[0026] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference and are herein set forth in their entirety.

[0027] Methods for treating severe atopic dermatitis The present invention encompasses a method comprising administering a therapeutic composition comprising an IL-4R inhibitor to a subject in need thereof. As used herein, the phrase "subject in need thereof" refers to a human or non-human animal exhibiting one or more symptoms or signs of atopic dermatitis and / or diagnosed with atopic dermatitis.

[0028] "Atopic dermatitis" (AD), as used herein, refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly, dry, eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), exposure to radiation, and / or asthma. The present invention encompasses methods of treating patients with moderate to severe or severe AD. "Moderate to severe AD," as used herein, is characterized by widespread skin lesions that cause intense pruritus, which are often complicated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also encompasses chronic AD in patients. In many cases, chronic lesions include thickened plaques, lichenification, and fibrous papules of the skin. Patients with moderate to severe AD generally have more than 20% of the body skin affected, or 10% of the skin area, including eyes, hands, and body folds. Moderate to severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids. Patients may also be referred to as having moderate to severe AD if they are resistant or refractory to treatment with either topical corticosteroids or calcineurin inhibitors.

[0029] In certain preferred embodiments, the term "subject in need thereof" refers to patients with severe AD. "Severe AD" as used herein refers to chronic relapsing AD that is refractory to treatment with moderate and high potency TCS and / or immunosuppressant therapy. Severe AD is also characterized by more than 20% of the body surface area being affected by chronic, intensely pruritic lesions. In certain embodiments, the term refers to chronic AD according to Eichenfield's criteria (Eichenfield et al., 2014, J. Am. Acad. Dermatol. 70:338-351), which supports treatment with potent topical corticosteroids (TCS). In certain embodiments, the term encompasses patients with chronic AD that are resistant to treatment with systemic corticosteroids and / or nonsteroidal immunosuppressants. Patients with severe AD may also exhibit frequent exacerbations or flare-ups of the disease. In certain embodiments, the term "severe AD" refers to patients with an Investigator's Global Assessment (IGA) score of 4.

[0030] As used herein, "flare-up" is also referred to as "exacerbation," which refers to an increase in signs and / or symptoms that leads to an escalation of therapy, where escalation of therapy is associated with an increase in immunosuppressant therapy. The treatment may be an increase in the dose of a therapeutic agent (e.g., cyclosporine A), a switch to a more potent TCS class, or the initiation of another oral immunosuppressant. In certain embodiments, the present invention encompasses a method of reducing the number of relapses or exacerbations in a patient with severe AD, comprising administering a therapeutically effective amount of an IL-4R inhibitor to a patient in need thereof.

[0031] In certain embodiments, the term "subject in need thereof" includes subjects who are resistant, non-responsive, or insufficiently responsive to treatment with a systemic immunosuppressant. The present invention includes a method of treating AD in a subject or patient who is resistant, non-responsive, or insufficiently responsive to treatment with a systemic immunosuppressant. The term "resistant, non-responsive, or insufficiently responsive to a systemic immunosuppressant" as used herein refers to a subject or patient with AD who is treated with a systemic immunosuppressant, but the immunosuppressant has no therapeutic effect. In some embodiments, the term refers to poor patient compliance, and / or toxic effects and side effects, and / or the administered immunosuppressant has no effect of reducing, alleviating, or diminishing symptoms of AD. In some embodiments, the term refers to patients with moderate to severe AD or severe AD that is refractory to treatment with a systemic immunosuppressant. In some embodiments, the term refers to patients with uncontrolled AD despite treatment with an immunosuppressant. In some embodiments, a patient who is "resistant, non-responsive, or inadequately responsive to systemic immunosuppressants" may not show improvement in one or more AD-related parameters. Examples of AD-related parameters are described elsewhere herein. For example, treatment with a systemic immunosuppressant may not result in a decrease in pruritus or eczema area and severity index (EASI) score or body surface area (BSA) score. In some embodiments, the term refers to a patient with severe AD who has been treated with a systemic immunosuppressant but has since relapsed and / or shows an increase in exacerbation or relapse of AD. In certain embodiments, the term refers to a patient with severe AD for whom immunosuppressant therapy is not advisable due to suboptimal efficacy as well as safety and health risks to the patient. In some embodiments, the present invention encompasses a method of treating moderate to severe AD or severe AD in a patient who has been initially treated with a systemic immunosuppressant for one month or more but does not show a decrease in one or more AD-related parameters.For example, the methods of the invention can be used to treat patients with chronic relapsing AD who are being treated with systemic immunosuppressants and who have a body surface area (BSA) score of 10% or greater or an Physician's Global Assessment (IGA) score of 3 or greater.

[0032] In certain embodiments, the term "subject in need thereof" includes patients with severe AD whose disease is not adequately controlled with TCS, whose disease is not adequately controlled with or who are intolerant to oral immunosuppressants, or whose treatment with immunosuppressants is deemed medically undesirable by a physician at the time according to the following: (A) Have not been previously exposed to immunosuppressive drugs (such patients are not candidates for such treatment at this time for the following reasons): Medical contraindications; Hypersensitivity to the active substances or excipients of immunosuppressants; Concurrent use of medications that interfere with immunosuppressants; or Increased susceptibility to immunosuppressant-induced kidney damage and increased risk of serious infections. or (B) Patients have been previously exposed to immunosuppressants and should not continue or restart immunosuppressants for the following reasons: Previous intolerance and / or intolerable toxicity Inadequate response, defined as relapse of AD on immunosuppressants tapered to a maintenance dose (2 to 3 mg / kg / day) after up to 6 weeks of high dose (5 mg / kg / day) or relapse after a minimum of 3 months on a maintenance dose. Relapse is defined as an increase in signs and / or symptoms that triggers an escalation of therapy, which may be an increase in the immunosuppressant dose, a switch to a higher potency TCS class, or initiation of another oral immunosuppressant; or Requiring immunosuppressants in doses or for durations greater than those specified in the prescribing information.

[0033] In certain embodiments, the term "subject in need thereof" includes patients with moderate to severe or severe AD who are candidates for systemic therapy. The term "systemic therapy" as used herein refers to the systemic administration of therapeutic agents (e.g., orally administered corticosteroids) and other immunosuppressants or immunomodulators. In the context of the present invention, the term "systemic immunosuppressants" includes, but is not limited to, cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, and interferon-gamma. In certain embodiments, the term also includes immunobiological agents, such as tumor necrosis factor alpha (TNFα) inhibitors (e.g., anti-TNFα antibodies, e.g., infliximab), CD11a inhibitors (e.g., anti-CD11a antibodies, e.g., efalizumab), IgE inhibitors (e.g., omalizumab), CD20 inhibitors (e.g., rituximab). Systemic therapy such as systemic immunosuppressants can be used for short-term treatment of relapse or as a temporary measure to control the disease, but its use is limited by significant side effects, such as growth retardation in children, Cushing's syndrome, hypertension, glucose intolerance, myopathy, osteonecrosis, glaucoma and cataracts.The use of systemic immunosuppressants also carries the risk of relapse phenomenon, in which the symptoms of the disease may significantly worsen after the interruption of treatment.In certain embodiments, the terms "systemic therapy", "systemic therapeutic agent" and "systemic immunosuppressant" are used interchangeably throughout this disclosure.

[0034] In certain embodiments, the term "subject in need thereof" includes patients with moderate to severe or severe AD who have been administered one or more TCSs for more than 6 months, more than 1 year, more than 2 years, more than about 5 years, more than about 7 years, or more than about 10 years in addition to regular immunosuppressant treatment.In certain embodiments, the term "subject in need thereof" includes patients with moderate to severe or severe AD who have been previously treated with a therapy selected from the group consisting of cyclosporine A, IgE inhibitors, TNF alpha inhibitors, CD11a inhibitors, CD20 inhibitors, IL-4R inhibitors (e.g., anti-IL-4R antibodies, e.g., dupilumab), antibiotics, systemic immunosuppressants, topical corticosteroids, oral corticosteroids, calcineurin inhibitors, and phototherapy.Patients may wish to minimize or avoid the adverse side effects of TCS and / or immunosuppressants. The present invention encompasses a method of treating moderate to severe or severe AD in a patient, comprising administering an IL-4R inhibitor simultaneously with a TCS, where the dosage is adjusted to minimize or prevent adverse side effects of the TCS. In certain embodiments, the present invention encompasses a method of reducing dependency on TCS in a patient with moderate to severe or severe AD, comprising administering a therapeutically effective amount of an IL-4R inhibitor simultaneously with an effective TCS, where the amount of TCS used by the patient is reduced by about 50% compared to a patient not administered an IL-4R inhibitor. In certain embodiments, the present invention encompasses a method of reducing dependency on TCS in a patient with moderate to severe or severe AD, comprising administering a therapeutically effective amount of an IL-4R inhibitor simultaneously with an effective TCS, where the amount of TCS used by the patient is reduced by at least 20%, at least 30%, at least 40%, or at least 50% compared to the amount used by the patient prior to treatment with an IL-4R inhibitor. In certain embodiments, administration of an IL-4R inhibitor and a TCS enhances the treatment of AD compared to monotherapy. These compounds provide additive or synergistic activity in the

[0035] The term "TCS" as used herein encompasses Group I, Group II, Group III and Group IV topical corticosteroids. According to the World Health Organization Anatomical Therapeutic Classification, corticosteroids are classified as weak (Group I), moderately potent (Group II) and potent (Group III) and highly potent (Group IV) based on their activity compared to hydrocortisone. Group IV TCS (highly potent) are up to 600 times more potent than hydrocortisone, examples of which include clobetasol propionate and halcinonide. Group III TCS (potent) are 50 to 100 times more potent than hydrocortisone, examples of which include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately effective) are 2 to 25 times more potent than hydrocortisone and examples include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild) include hydrocortisone.

[0036] Patients with severe AD are often prescribed moderate or high potency TCS to treat AD. Such treatment may be, for example, longer than 2 months, longer than 3 months, longer than 4 months, longer than 5 months, or longer than 6 months. It is known in the prior art that treatment with TCS causes adverse side effects. In certain embodiments, the present invention encompasses a method for reducing the use of or dependency on TCS and / or reducing the adverse side effects of TCS in patients with severe AD, comprising administering one or more doses of an IL-4R inhibitor to a patient in need thereof. In certain embodiments, an IL-4R inhibitor is administered in combination with moderate or high potency TCS, wherein the amount of TCS administered is gradually reduced so that the patient's severe AD is treated and / or one or more AD-related parameters are significantly improved, as well as the side effects and toxicity of TCS are minimized or prevented. In certain embodiments, the present invention encompasses a method for reducing or eliminating the risk of relapse upon reduction or discontinuation of TCS or immunosuppressants, comprising selecting a patient with severe AD uncontrolled by background therapy, and administering one or more doses of an IL-4R inhibitor to the patient in need thereof. In certain further embodiments, the patient is initially administered one or more doses of an IL-4R inhibitor in combination with background therapy administered simultaneously; followed by gradually reducing the background therapy. In certain embodiments, the background therapy comprises a therapeutic agent selected from the group consisting of TCS, a calcineurin inhibitor, a systemic immunosuppressant, and an emollient. In one embodiment, the patient with severe AD is initially treated with a systemic immunosuppressant, where the systemic immunosuppressant is cyclosporine A. In certain embodiments, the amount of background therapy is reduced by at least 20%, at least 30%, at least 40%, or at least 50% compared to a patient not administered an IL-4R inhibitor.

[0037] The present invention encompasses a method for treating severe atopic dermatitis (AD) by improving one or more AD-related parameters in a subject in need thereof, comprising the steps of selecting a patient with severe AD, the patient being resistant, insufficiently responsive or intolerant to systemic immunosuppressant therapy, and administering to the subject a pharmaceutical composition comprising an IL-4R inhibitor.In one embodiment, the pharmaceutical composition comprising an IL-4R inhibitor is administered in combination with an effective TCS.

[0038] Examples of "AD-related parameters" include: (a) Physician's Global Assessment (IGA); (b) Atopic Dermatitis Body Surface Area (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Pruritus Numeric Rating Scale (NRS). "Improvement in AD-related parameters" refers to a reduction from baseline in one or more of IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, or NRS. As used herein, the term "baseline" refers to the numerical value of the AD-related parameter for a subject before or at the time of administration of the pharmaceutical composition of the present invention, with respect to the AD-related parameter.

[0039] To determine whether an AD-related parameter has been "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present invention. For example, AD-related parameters can be measured on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th day; or at the end of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, or longer period following an initial treatment with a pharmaceutical composition of the present invention. The difference between the value of a parameter at a particular time point after the start of treatment and the value of the parameter at baseline can be used to determine whether the AD-related parameter has been "improved" (e.g., decreased). AD-related parameters are described in US Patent Publication No. 20140072583, which is incorporated herein in its entirety. In the context of the present invention, a "subject in need thereof" may include, for example, a subject who exhibits (or has exhibited) an elevation in one or more AD-related parameters, such as, for example, IGA, BSA, EASI, SCORAD, 5D-pruritus, and / or NRS score, prior to treatment. For example, the method of the present invention includes administering an IL-4R inhibitor to a patient with an IGA of 3 or more or 4 or more; or a BSA of more than 10%.

[0040] According to one aspect, the present invention provides a method of treating moderate-to-severe or severe AD, or reducing pruritus, or improving AD-related parameters, comprising: (1) selecting a patient with moderate-to-severe or severe AD, the patient having characteristics selected from the group consisting of: (a) the patient has a confirmed history of inadequate response or intolerance to cyclosporine A (CsA); (b) the patient has a peak pruritus NRS at baseline of 4 or greater; (c) the patient has an IGA score at baseline of 3 or greater; (d) the patient has an IGA score at baseline of 4; and (e) the patient has a concomitant disease or disorder selected from the group consisting of asthma, allergic rhinitis, food allergy, allergic conjunctivitis, wheal, allergy, and environmental allergen; and (2) administering one or more doses of a therapeutically effective amount of an IL-4R inhibitor to the patient in need thereof. In certain embodiments, administration of the IL-4R inhibitor results in: (i) a greater than 70% reduction from baseline in EASI; (ii) about a 75% reduction from baseline in EASI by week 2 after administration of the first dose of the IL-4R inhibitor; (iii) a greater than 50% reduction from baseline in pruritus NRS by week 16 after administration of the first dose of the IL-4R inhibitor; (iv) a 4 or greater improvement in peak pruritus NRS by week 2 after administration of the first dose of the IL-4R inhibitor; (v) a 2 point improvement in IGA score by week 16 after administration of the first dose of the IL-4R inhibitor; (vi) a reduction from baseline in IGA such that an IGA score of 0 or 1 is achieved by week 16 after administration of the first dose of the IL-4R inhibitor; (vii) a reduction in the number of flare-ups or exacerbations; and (viii) a reduction in the incidence of skin infections; and i) improve quality of life, e.g., as determined by the Dermatology Life Quality Index (DLQI) or any other patient-reported outcome disclosed herein. In certain embodiments, the IL-4R inhibitor is an anti-IL-4R antibody or an antigen-binding fragment thereof (e.g., dupilumab). In certain embodiments, the IL-4R inhibitor is administered in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is selected from the group consisting of a topical corticosteroid and a topical calcineurin inhibitor. In certain embodiments, each dose of the IL-4R inhibitor comprises 50-600 mg, and each dose is administered one or two weeks after the immediately preceding dose. In one embodiment, each dose of the anti-IL-4R antibody comprises 300 mg, and each dose is administered once a week or once every two weeks. In certain specific embodiments, the one or more doses include a first dose comprising 600 mg, followed by one or more secondary doses, where each secondary dose comprises 300 mg, and where each secondary dose is administered one or two weeks after the immediately preceding dose.

[0041] According to one embodiment, the present invention encompasses a method for treating AD or reducing pruritus or improving AD-related parameters in a patient with moderate to severe or severe AD, where the patient has previously been treated with an IL-4R inhibitor (e.g., an anti-IL-4R antibody, e.g., dupilumab). In certain embodiments, the patient has previously been treated with dupilumab more than 4 weeks, more than 8 weeks, more than 12 weeks, or more than 20 weeks ago. In certain embodiments, the present invention encompasses a method for treating moderate to severe or severe AD in a patient who has discontinued a prior treatment with an IL-4R inhibitor more than 4 weeks, more than 8 weeks, or more than 12 weeks ago. The method, according to this embodiment, includes re-treating a patient in need thereof with an IL-4R inhibitor, where re-treating includes administering one or more doses of the IL-4R inhibitor such that the patient's disease is treated or at least one AD-related parameter is improved. In certain embodiments, retreatment of the patient results in a greater than 70% reduction from baseline in the EASI score and / or a greater than 50% reduction from baseline in the Pruritus NRS score upon administration of the IL-4R inhibitor.

[0042] In certain embodiments, the methods of the present invention can be used to treat patients who exhibit elevated levels of one or more AD-associated biomarkers (e.g., IgE). AD-associated biomarkers are described in US Patent Publication No. 20140072583, which is incorporated herein in its entirety. For example, the methods of the present invention include administering an IL-4R inhibitor to a patient who has elevated levels of IgE or TARC or periostin. In the context of the present invention, a "patient in need thereof" can include, for example, a subject who exhibits (or has exhibited) elevated levels of one or more AD-associated biomarkers, such as IgE and / or TARC, prior to treatment. In certain embodiments, a "subject in need thereof" can include a subset of a population that may be more susceptible to AD or exhibit elevated levels of AD-associated biomarkers.

[0043] In some embodiments, the methods described herein can be used to treat severe AD in children under 1 year old.For example, the methods of the present invention can be used to treat infants under 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or under 12 months.In other embodiments, the present invention encompasses methods of treating children and / or adolescents under 18 years old.For example, the methods of the present invention can be used to treat children or adolescents under 17 years old, 16 years old, 15 years old, 14 years old, 13 years old, 12 years old, 11 years old, 10 years old, 9 years old, 8 years old, 7 years old, 6 years old, 5 years old, 4 years old, 3 years old or under 2 years old.

[0044] According to certain embodiments, the present invention provides a method for treating moderate-to-severe or severe atopic dermatitis (AD) or improving AD-related parameters, comprising the steps of: (a) selecting a patient with moderate-to-severe or severe AD, wherein the patient: (i) has a baseline IGA score of 4; (ii) has a baseline IGA score of 3 or greater; (iii) is between 6 and 18 years of age; (iv) has disease uncontrolled with topical AD therapy; (v) has a confirmed history of inadequate response to topical AD therapy or topical therapy is not advisable for the patient due to adverse side effects or safety risks; (vi) has previously (vii) the patient has been treated with a medication or procedure selected from the group consisting of topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological treatments, systemic glucocorticoids, nonsteroidal systemic immunosuppressants, cyclosporine A, azathioprine, ultraviolet light therapy, and phototherapy; and (vii) the patient has a characteristic selected from the group consisting of having a co-morbid disease or disorder selected from the group consisting of food allergies, asthma, seasonal allergies, allergic rhinitis, house dust allergy, and allergic conjunctivitis; and (b) administering to a patient in need thereof one or more doses of a therapeutically effective amount of an IL-4R inhibitor. In certain embodiments, administration of the IL-4R inhibitor results in a therapeutic effect selected from the group consisting of: (i) a greater than 30% reduction from baseline in EASI score by week 2 after administration of the first dose of the IL-4R inhibitor; (ii) a greater than 50% reduction from baseline in Pruritus NRS; and (iii) a reduction from baseline in IGA score such that an IGA score of 0 or 1 is achieved by week 12 after administration of the first dose of the IL-4R inhibitor.In certain embodiments, the IL-4R inhibitor is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, an emollient, an antibacterial therapeutic agent, and a therapeutic agent for obstructive airways disease, pulmonary disorders and / or allergic reactions.

[0045] Interleukin-4 receptor inhibitors The method of the present invention includes administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) inhibitor. As used herein, an "IL-4R inhibitor" (also referred to herein as an "IL-4R inhibitor", "IL-4Rα antagonist", "IL-4R blocker", "IL-4Rα blocker", etc.) is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising the α chain and the γc chain of IL-4R. Type 2 IL-4 receptor is a dimeric receptor comprising the α chain of IL-4R and the α1 chain of IL-13R. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, whereas type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, IL-4R inhibitors that can be used in the methods of the invention may function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, IL-4R inhibitors of the invention can prevent the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0046] Non-limiting examples of categories of IL-4R inhibitors include small molecular weight IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptorbodies" (e.g., engineered molecules that contain the ligand-binding domain of an IL-4R element), and antibodies or antibody-antibody aptamers that specifically bind to human IL-4Rα. As used herein, IL-4R inhibitors also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0047] Anti-IL-4Rα antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the IL-4R inhibitor is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody" as used herein includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or VVR). H The heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (herein, LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more highly conserved regions called framework regions (FRs). H and V Lis composed of three CDRs and four FRs, which are arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present invention, the FRs of the anti-IL-4R antibodies (or their antigen-binding sites) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0048] The term "antibody", as used herein, also encompasses antigen-binding fragments of a complete antibody molecule. The terms "antigen-binding site" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, encompass any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, for example, from complete antibody molecules using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (e.g., phage-antibody libraries, etc.), or can be synthesized. The DNA can be sequenced, chemically, or manipulated by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable position, or to introduce codons, to insert cysteine ​​residues, to modify, add or delete amino acids, etc.

[0049] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity determining regions (CDRs), e.g., CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment" as used herein.

[0050] An antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame with one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, H and V L The domains may be present relative to one another in any suitable arrangement. For example, the variable region may be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomeric V H or V L It may contain domains.

[0051] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C LIn any arrangement of variable and constant domains, including any of the exemplary arrangements listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be linked to each other and / or to one or more monomeric V H or V L The variable and constant domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above, non-covalently associated (e.g., by disulfide bonds) with the domains.

[0052] The term "antibody" as used herein also includes antibodies with multiple specificities (e.g., bispecific). A multispecific antibody or antigen-binding fragment of an antibody is typically expected to contain at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use with the antibody or antigen-binding fragment of an antibody of the present invention using routine techniques available in the art. For example, the present invention includes methods that include the use of bispecific antibodies, where one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in connection with the present invention include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knob-into-hole, common light chains (such as common light chains containing knob-into-holes), CrossMab, CrossFab, (SEED) bodies, leucine zippers, duobodies, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include (see, e.g., Klein et al., 2012, mAbs 4:6, 1-11, and references cited therein, for a review of such formats). Bispecific antibodies can also be constructed, for example, using peptide / nucleic acid conjugation, where unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that are then self-assembled into multimeric complexes with defined composition, valency and geometry (see, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: 2012 Dec 12, 2012). [see April 4th].

[0053] The antibody used in the method of the present invention may be a human antibody. The term "human antibody" as used herein is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. The human antibody of the present invention may nevertheless include amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), e.g., in the CDRs, particularly in CDR3, that are not encoded by human germline immunoglobulin sequences. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, e.g., mouse, are grafted onto human framework sequences.

[0054] The antibody used in the method of the present invention may be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to encompass all human antibodies that are produced, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, created or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when transgenic animals for human Ig sequences are used), thereby improving the V H and V L The amino acid sequence of the region is human germline V H and V LThese are sequences that are derived from and related to the sequence, but may not naturally occur in the germline repertoire of human antibodies in vivo.

[0055] In a particular embodiment, the antibody used in the method of the present invention specifically binds to IL-4Rα. The term "specifically binds" and the like means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and examples thereof include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, as used in the context of the present invention, an antibody that "specifically binds" to IL-4Rα has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM as measured by a surface plasmon resonance assay. D The term "antibody" includes antibodies that specifically bind to IL-4Rα or a portion thereof. However, an isolated antibody that specifically binds to human IL-4Rα may have cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0056] According to certain exemplary embodiments of the present invention, the IL-4R inhibitor is an anti-IL-4Rα antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies described in U.S. Pat. No. 7,608,693. In certain exemplary embodiments, the anti-IL-4Rα antibody or an antigen-binding fragment thereof that can be used in accordance with the methods of the present invention comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1. The light chain variable region (LCVR) comprises a light chain complementarity determining region (LCDR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2. According to certain exemplary embodiments, the methods of the invention include the use of an anti-IL-4R antibody comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence of SEQ ID NO:3-SEQ ID NO:4-SEQ ID NO:5-SEQ ID NO:6-SEQ ID NO:7-SEQ ID NO:8, or a biological equivalent thereof. In certain embodiments, the methods of the invention include the use of an anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:10. An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10 is a fully human anti-IL-4R antibody referred to as "dupilumab" and known as such in the art. According to certain exemplary embodiments, the methods of the invention include the use of dupilumab or a biological equivalent thereof. The term "bioequivalent," as used herein, refers to an anti-IL-4R antibody or IL-4R binding protein, or fragment thereof, that is a pharmacologic equivalent or pharmaceutical substitute that exhibits a rate and / or extent of absorption that is not significantly different from that of dupilumab when administered at the same molar dose, either in single or multiple doses, under similar experimental conditions.In the context of the present invention, the term refers to antigen-binding proteins that bind to IL-4R that have no clinically meaningful differences from dupilumab in their safety, purity and / or potency.

[0057] Other anti-IL-4Rα antibodies that can be used in accordance with the methods of the invention include, for example, the antibody designated AMG317 and known in the art as such (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI9314, or any of the anti-IL-4Rα antibodies described in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or 8,877,189.

[0058] The anti-IL-4Rα antibody used in the method of the present invention may have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibody for use in the method of the present invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibody of the present invention may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" encompasses pH values ​​less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 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 expression "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" encompasses pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0059] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K D K value of antibody binding to IL-4Rα at acidic pH DExpressed as a ratio of values ​​(or vice versa), e.g. For purposes of the present invention, an antibody or antigen-binding fragment thereof has an acidic / neutral K of about 3.0 or greater. D When a ratio is presented, it can be considered to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K D The ratio may be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or greater.

[0060] 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 acidic pH compared to neutral pH. In addition, antibodies with pH-dependent characteristics can be obtained by modifying the antigen-binding domain at the amino acid level. For example, an antibody with reduced antigen binding at acidic pH compared to neutral pH can be obtained by replacing one or more amino acids of the antigen-binding domain (e.g., in the CDR) with histidine residues. As used herein, the expression "acidic pH" refers to a pH of 6.0 or lower.

[0061] Pharmaceutical Compositions The present invention encompasses methods comprising administering an IL-4R inhibitor to a patient, the IL-4R inhibitor being contained in a pharmaceutical composition. The pharmaceutical compositions of the present invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, etc. A large number of suitable formulations can be found in the formulary known to every pharmacist: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions, carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Powell et al., "Compendium of See also "Excipients for Parenteral Formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0062] The dose of the antibody administered to a patient according to the method of the present invention may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be empirically determined; for example, the progress of the patient can be monitored by periodic evaluation and the dose adjusted accordingly. Furthermore, approximation of dosages between species can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses of anti-IL4R antibodies that can be used in connection with the present invention and administration regimes including the same are disclosed elsewhere herein.

[0063] Various delivery systems are known that can be used to administer pharmaceutical compositions containing IL-4R inhibitors, including, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), or may be administered together with other bioactive agents.

[0064] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. In addition, for subcutaneous delivery, the application of a pen delivery device is easy in delivering the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge 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 filled with the pharmaceutical composition held in a reservoir in the device. Once the pharmaceutical composition in the reservoir is empty, the entire device is discarded.

[0065] Numerous reusable pen and autoinjector delivery devices are adapted for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX75 / 25™ pen, HUMALOG™ pen, HUMALIN70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN ... STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen-type delivery devices applied to subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name a few.

[0066] In certain circumstances, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed proximal to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems can be used. The release system is discussed in a review by Langer, 1990, Science 249:1527-1533.

[0067] The injection preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, and the like. These injection preparations can be manufactured by known methods. For example, the injection preparations can be manufactured by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous medium or oily medium that is conventionally used for injections. Examples of aqueous media for injections include physiological saline, isotonic solutions containing glucose and other auxiliary agents, and the like, which can be used in combination with appropriate solubilizers, such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. Examples of oily media include sesame oil, soybean oil, and the like, which can be used in combination with solubilizers, such as benzyl benzoate, benzyl alcohol, and the like. The injections manufactured in this manner can be filled into appropriate ampoules.

[0068] Advantageously, the above-mentioned pharmaceutical compositions for oral or parenteral use are prepared in a dosage form with a unit dose adapted to the dose of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0069] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in accordance with the present invention are disclosed, for example, in US Pat. No. 8,945,559.

[0070] Dosing regimen The present invention encompasses a method comprising administering an IL-4R inhibitor to a subject at a dosage frequency of about 4 times per week, 2 times per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently as long as a therapeutic response is achieved.In certain embodiments involving the administration of anti-IL-4R antibodies, weekly administration is employed in an amount of about 25mg, 50mg, 150mg, 200mg, or 300mg.In certain embodiments involving the administration of anti-IL-4R antibodies, weekly administration is employed in an amount of about 25mg, 50mg, 150mg, 200mg, or 300mg.

[0071] According to certain embodiments of the present invention, multiple doses of an IL-4R inhibitor may be administered to a subject over a period of time. The method according to this aspect of the present invention includes sequentially administering multiple doses of an IL-4R inhibitor to a subject. As used herein, "sequentially administering" means that each dose of an IL-4R inhibitor is administered to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention encompasses methods that include sequentially administering to a patient a single initial dose of an IL-4R inhibitor, followed by one or more secondary doses of the IL-4R inhibitor, optionally followed by one or more tertiary doses of the IL-4R inhibitor.

[0072] The terms "initial dose", "secondary dose", and "tertiary dose" refer to the time sequence of administration of an IL-4R inhibitor. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R inhibitor, but generally may differ from each other depending on the frequency of administration. However, in certain embodiments, the amount of IL-4R inhibitor contained in the initial, secondary, and / or tertiary doses may vary over the course of treatment. In certain embodiments, the first dose comprises a first amount of the antibody or antigen-binding fragment thereof, and each of the one or more secondary doses comprises a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or antigen-binding fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the second amount of the antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as a "loading dose", followed by subsequent doses (e.g., "maintenance doses") administered less frequently. For example, the IL-4R inhibitor may be administered to a patient in need thereof at a loading dose of about 300 mg or about 600 mg, followed by one or more maintenance doses of about 25 mg to about 400 mg. In one embodiment, the initial dose and the one or more secondary doses each comprise between 10 mg and 600 mg of an IL-4R inhibitor, e.g., between 100 mg and 400 mg of an IL-4R inhibitor, e.g., 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg of an IL-4R inhibitor.

[0073] In one exemplary embodiment of the invention, each secondary and / or tertiary dose is administered 1 to 14 weeks (e.g., 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5 weeks, 6 weeks, 6.5 weeks, 7 weeks, 7.5 weeks, 8 weeks, 8.5 weeks, 9 weeks, 9.5 weeks, 10 weeks, 10.5 weeks, 11 weeks, 11.5 weeks, 12 weeks, 12.5 weeks, 13 weeks, 13.5 weeks, 14 weeks, 14.5 weeks, or more) after the immediately preceding dose. The phrase "immediately preceding dose" as used herein means a dose of an IL-4R inhibitor administered to a patient prior to administration of the next dose in a series of multiple doses, with no intervening doses therebetween.

[0074] The method according to this aspect of the present invention may include administering any number of secondary and / or tertiary doses of IL-4R inhibitor to the patient.For example, in certain embodiments, only one single secondary dose is administered to the patient.In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.Similarly, in certain embodiments, only one single tertiary dose is administered to the patient.In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0075] In embodiments that include multiple secondary doses, each secondary dose may be administered with the same frequency as other secondary doses. For example, each secondary dose may be administered to a patient 1 to 6 weeks after the immediately preceding dose. Similarly, in embodiments that include multiple tertiary doses, each tertiary dose may be administered with the same frequency as other tertiary doses. For example, each tertiary dose may be administered to a 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 change during the course of the regimen.

[0076] The method of the present invention, according to certain embodiments, comprises administering a topical corticosteroid (TCS) to a subject in combination with an IL-4R inhibitor (e.g., an anti-IL-4R antibody). As used herein, the phrase "in combination with" means that the TCS is administered before, after, or concurrently with the IL-4R inhibitor. The term "in combination with" also encompasses sequential or simultaneous administration of the IL-4R inhibitor and the TCS.

[0077] For example, when TCS is administered "before" an IL-4R inhibitor, it can be administered more than 72 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4R inhibitor. When TCS is administered "after" an IL-4R inhibitor, it can be administered about 10 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4R inhibitor. The TCS may be administered within about 5 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the IL-4R inhibitor. Administration "concurrently" with an IL-4R inhibitor means that the TCS is administered to the subject in a separate dosage form within less than 5 minutes of administration of the IL-4R inhibitor (either before, after, or simultaneously with administration of the IL-4R inhibitor), or is administered to the subject as a single combined dosage formulation including both the TCS and the IL-4R inhibitor.

[0078] dosage The amount of IL-4R inhibitor (e.g., anti-IL-4R antibody) administered to a subject according to the method of the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of IL-4R inhibitor that results in one or more of: (a) an improvement in one or more AD-related parameters (as described elsewhere herein); and / or (b) a detectable improvement in one or more symptoms or signs of atopic dermatitis. In the context of the present invention, a "therapeutically effective amount" encompasses an amount of an IL-4R inhibitor that results in one or more of the following: (a) at least a 70% reduction from baseline in EASI; (b) at least a 30% reduction in pruritus; (c) a 2 or more point reduction from baseline in IGA; (d) a 4 or more point reduction from baseline in NRS; (e) a reduction in Staphylococcus aureus skin colonization; (f) a reduction in the levels of AD-related biomarkers, such as IgE or TARC; (g) at least a 20% reduction in TCS use; and / or (h) a reduction in the number of flare-ups or exacerbations of AD.

[0079] In the case of an anti-IL-4R antibody, an immunologically effective amount is 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, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg. , about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of the anti-IL-4R antibody. In certain embodiments, 10 mg, 25 mg, 50 mg, 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody is administered to the subject.

[0080] The amount of IL-4R inhibitor contained in each dose can be expressed in units of milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, the IL-4R inhibitor may be administered to a subject at a dose of about 0.0001 to about 100 mg per kg of the subject's body weight.

[0081] Selected implementations In embodiment 1, the present invention provides a method of treating severe atopic dermatitis (AD), comprising the steps of: (a) selecting a patient with severe AD, wherein the patient is resistant, inadequately responsive, or intolerant to systemic immunosuppressant therapy, and / or wherein said therapy is inadvisable; and (b) administering to the patient in need thereof one or more doses of an interleukin-4 receptor (IL-4R) inhibitor. The present invention encompasses a method comprising the steps of:

[0082] In embodiment 2, the invention encompasses the method of embodiment 1, where therapy is inadvisable due to suboptimal efficacy in addition to safety and health risks to the patient.

[0083] In embodiment 3, the invention encompasses the method of embodiment 1 or 2, wherein the systemic immunosuppressant is selected from the group consisting of cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic corticosteroids, and interferon-gamma.

[0084] In embodiment 4, the invention encompasses the method of embodiment 3, wherein the systemic immunosuppressant is cyclosporine A (CSA).

[0085] In embodiment 5, the invention encompasses the method of embodiment 4, wherein the patient has not been previously exposed to CSA and CSA therapy is not advisable due to a condition selected from the group consisting of medical contraindications, hypersensitivity to CSA or excipients, use of concomitant medications prohibited for use with CSA, increased susceptibility to CSA-induced kidney damage, increased susceptibility to CSA-induced liver injury, and increased risk of serious infection.

[0086] In embodiment 6, the invention encompasses the method of embodiment 4, wherein the patient has previously been exposed to CSA and CSA therapy is not advisable due to a condition selected from the group consisting of intolerance, unacceptable toxicity, inadequate response, need for CSA at a dose greater than 5 mg / kg of patient body weight per day, and need for CSA administration for a duration of more than one year.

[0087] In embodiment 7, the invention encompasses the method of any one of embodiments 1-3, wherein the patient has previously been treated with a therapeutic agent selected from the group consisting of cyclosporine A, an IgE inhibitor, a TNF alpha inhibitor, a CD11a inhibitor, a CD20 inhibitor, an antibiotic, a topical corticosteroid, an oral corticosteroid, a calcineurin inhibitor, and phototherapy.

[0088] In embodiment 8, the present invention encompasses a method of treating or reducing pruritus, comprising: (a) selecting a patient with severe AD, wherein the patient is resistant, inadequately responsive, or intolerant to systemic immunosuppressant therapy; and (b) administering one or more doses of an IL-4R inhibitor to a patient in need thereof.

[0089] In embodiment 9, the invention encompasses the method of embodiment 8, wherein the systemic immunosuppressant is selected from the group consisting of cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic corticosteroids, and interferon-gamma.

[0090] In embodiment 10, the invention encompasses the method of embodiment 8 or 9, wherein the systemic immunosuppressant is cyclosporine A (CSA).

[0091] In embodiment 11, the invention encompasses the method of any one of embodiments 8 to 10, wherein the patient has severe AD.

[0092] In embodiment 12, the present invention relates to a method for treating pruritus in a patient, comprising administering an IL-4R inhibitor to said patient. The method of any one of embodiments 8-11, which results in at least a 30% reduction from baseline.

[0093] In embodiment 13, the present invention encompasses a method of treating severe AD, comprising: (a) selecting a patient having severe AD, wherein the patient has previously been treated with a therapy selected from the group consisting of cyclosporine A, an IgE inhibitor, a TNF alpha inhibitor, a CD11a inhibitor, a CD20 inhibitor, an antibiotic, an IL-4R inhibitor, dupilumab, a systemic immunosuppressant, a topical corticosteroid, an oral corticosteroid, a calcineurin inhibitor, and phototherapy; and (b) administering one or more doses of an IL-4R inhibitor to a patient in need thereof.

[0094] In embodiment 14, the invention encompasses the method of embodiment 13, wherein the patient is resistant, inadequately responsive or intolerant to the treatment.

[0095] In embodiment 15, the invention encompasses the method of embodiment 13 or 14, where therapy is not advisable due to suboptimal efficacy in addition to safety and health risks to the patient.

[0096] In embodiment 16, the invention encompasses the method of any one of embodiments 1 to 15, wherein one or more doses comprise 50 to 600 mg of an IL-4R inhibitor.

[0097] In embodiment 17, the invention encompasses the method of any one of embodiments 1 to 15, wherein one or more doses comprises 300 mg of an IL-4R inhibitor.

[0098] In embodiment 18, the invention encompasses the method of embodiment 16 or 17, wherein the one or more doses of the IL-4R inhibitor are administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0099] In embodiment 19, the invention encompasses the method of any one of embodiments 1 to 15, wherein the IL-4R inhibitor is administered in an initial dose followed by one or more secondary doses.

[0100] In embodiment 20, the invention encompasses the method of embodiment 19, wherein the first dose comprises 50-600 mg of the IL-4R inhibitor and each secondary dose comprises 25-400 mg of the IL-4R inhibitor.

[0101] In embodiment 21, the invention encompasses the method of embodiment 20, wherein the first dose comprises 600 mg of the IL-4R inhibitor and each secondary dose comprises 300 mg of the IL-4R inhibitor.

[0102] In embodiment 22, the invention encompasses the method of embodiment 19 or 20, wherein each secondary dose is administered one week after the immediately preceding dose.

[0103] In embodiment 23, the invention encompasses the method of embodiment 19 or 20, wherein each secondary dose is administered two weeks after the immediately preceding dose.

[0104] In embodiment 24, the present invention relates to a method for treating atopic dermatitis, comprising administering an IL-4R inhibitor to a patient with atopic dermatitis, the method comprising administering an IL-4R inhibitor to a patient with atopic dermatitis, the patient being treated with an IL-4R inhibitor, and ... (d) a reduction of at least 2 points from baseline in Physician's Global Assessment (IGA) score; and (e) a reduction of at least 3 points from baseline in NRS score.

[0105] In embodiment 25, the invention encompasses the method of any one of embodiments 1 to 24, wherein administration of an IL-4R inhibitor results in an improvement in at least one patient-related outcome selected from the group consisting of Global Individual Symptom Score (GISS), Patient Oriented Eczema Scale (POEM), Patient-Rated Hospital Anxiety and Depression Scale (HADS) and Patient-Reported Dermatology Life Quality Index (DLQI).

[0106] In embodiment 26, the invention encompasses the method of any one of embodiments 1 to 25, wherein administration of an IL-4R inhibitor reduces the number of exacerbations or exacerbations in the patient.

[0107] In embodiment 27, the invention encompasses the method of any one of embodiments 1 to 26, wherein the IL-4R inhibitor is administered subcutaneously.

[0108] In embodiment 28, the invention encompasses the method of any one of embodiments 1 to 27, wherein the IL-4R inhibitor is administered simultaneously with the second therapeutic agent.

[0109] In embodiment 29, the invention encompasses the method of embodiment 28, wherein the second therapeutic agent is selected from the group consisting of topical corticosteroids, calcineurin inhibitors, and emollients.

[0110] In embodiment 30, the invention encompasses the method of embodiment 29, wherein the topical corticosteroid is selected from the group consisting of low potency TCS, medium potency TCS, and high potency TCS.

[0111] In embodiment 31, the invention encompasses the method of embodiment 30, wherein the amount of topical corticosteroid used by the patient is gradually reduced after administration of the first dose of the IL-4R inhibitor.

[0112] In embodiment 32, the invention encompasses the method of embodiment 31, wherein the amount of topical corticosteroid used by the patient is reduced by at least about 20% four weeks after administration of the first dose of the IL-4R inhibitor.

[0113] In embodiment 33, the invention encompasses the method of embodiment 31 or 32, wherein the amount of topical corticosteroid used by the patient is reduced by about 50% four weeks after administration of the first dose of the IL-4R inhibitor.

[0114] In embodiment 34, the present invention encompasses the method according to any one of embodiments 1 to 33, wherein the IL-4R inhibitor is an antibody or an antigen-binding fragment thereof that binds to IL-4Rα and prevents the interaction of IL-4 and / or IL-13 with the type 1 or type 2 IL-4 receptor.

[0115] In embodiment 35, the invention encompasses the method of embodiment 34, wherein the antibody or antigen-binding fragment thereof prevents interaction of IL-4 and IL-13 with both type 1 and type 2 IL-4 receptors.

[0116] In embodiment 36, the invention encompasses the method of embodiment 34 or 35, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2.

[0117] In embodiment 37, the present invention encompasses the method of embodiment 34 or 35, 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.

[0118] In embodiment 38, the present invention encompasses the method of embodiment 37, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:1 and the LCVR comprises the amino acid sequence of SEQ ID NO:2.

[0119] In embodiment 39, the invention encompasses the method of embodiment 36 or 37, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0120] In embodiment 40, the invention encompasses the method of any one of embodiments 1 to 38, wherein the IL-4R inhibitor is dupilumab or a biological equivalent thereof.

[0121] In embodiment 41, the invention encompasses the method of embodiment 34, wherein the antibody or antigen-binding fragment thereof is MEDI9314 or AMG317.

[0122] In embodiment 42, the present invention provides a method for treating moderate-to-severe or severe atopic dermatitis (AD) or improving AD-related parameters, comprising the steps of: (a) selecting a patient with moderate-to-severe or severe AD, wherein the patient is: (i) the patient has a baseline IGA score of 4; (ii) the patient has a baseline IGA score of 3 or greater; (iii) the patient is between 6 and 18 years of age; (iv) the patient has disease uncontrolled with topical AD therapy; (v) the patient has a confirmed history of inadequate response to topical AD therapy or topical therapy is not advisable for the patient due to adverse side effects or safety risks; (vi) the patient has previously (vii) the patient has been treated with a medication or procedure selected from the group consisting of topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological treatments, systemic glucocorticoids, nonsteroidal systemic immunosuppressants, cyclosporine A, azathioprine, ultraviolet light therapy, and phototherapy; and (vii) the patient has a characteristic selected from the group consisting of having a co-morbid disease or disorder selected from the group consisting of food allergies, asthma, seasonal allergies, allergic rhinitis, house dust allergy, and allergic conjunctivitis; and (b) administering to a patient in need thereof one or more doses of a therapeutically effective amount of an IL-4R inhibitor.

[0123] In embodiment 43, the invention encompasses the method of embodiment 42, wherein the patient has severe AD, is between 6 and 11 years of age, has an IGA score at baseline of 4, and has disease uncontrolled with topical therapy.

[0124] In embodiment 44, the present invention encompasses the method according to embodiment 42 or 43, wherein the IL-4R inhibitor is an anti-IL-4R antibody according to any one of embodiments 34 to 41. do.

[0125] In embodiment 45, the invention encompasses the method of any one of embodiments 42 to 44, wherein each dose of the IL-4R inhibitor comprises 1, 2, 3, 4 or 5 mg / kg of patient body weight, and each dose is administered 1 to 4 weeks after the immediately preceding dose.

[0126] In embodiment 46, the invention encompasses the method of any one of embodiments 42 to 44, wherein each dose comprises 20 to 600 mg of the IL-4R inhibitor, and each dose is administered 1 to 4 weeks after the immediately preceding dose.

[0127] In embodiment 47, the present invention encompasses the method of any one of embodiments 42 to 46, wherein administration of the IL-4R inhibitor results in an effect selected from the group consisting of: (i) a reduction in EASI score of more than 30% from baseline by week 2 after administration of the first dose of the IL-4R inhibitor; (ii) a reduction in pruritus NRS of more than 50% from baseline; and (iii) a reduction in IGA score from baseline such that an IGA score of 0 or 1 is achieved by week 12 after administration of the first dose of the IL-4R inhibitor.

[0128] In embodiment 48, the invention encompasses the method of any one of embodiments 42 to 47, wherein the IL-4R inhibitor is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, an emollient, an antibacterial therapeutic agent, and a therapeutic agent for obstructive airways disease. EXAMPLES

[0129] The following examples are provided 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 of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. EXAMPLES

[0130] A clinical trial of an anti-IL-4R antibody in adult patients with severe atopic dermatitis (AD) that is not adequately controlled with or intolerant to cyclosporine A, or where this treatment is medically undesirable. This is a 32-week, double-blind, randomized, placebo-controlled, parallel-group study to determine the efficacy, safety, and tolerability of dupilumab administered to adults with severe AD where cyclosporine A (CSA) has either not demonstrated sufficient efficacy, has unacceptable side effects, or initiation of CSA is medically undesirable.

[0131] Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; a HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs:3-8.

[0132] The study will include a 2-week screening period, a 2-week medium-potency TCS standardization period, a 16-week treatment period, and a 12-week safety follow-up period. The study will be conducted to evaluate dupilumab treatment in these patients who have also previously demonstrated an inadequate response to TCS. All patients will receive 100 mg of dupilumab to reflect standard of care treatment in this severely ill population. , received concurrent medium-potency TCS as background concomitant therapy.

[0133] Research Objective The primary objective of the study is to evaluate the efficacy of a two-dose regimen of dupilumab compared with placebo administered with concurrent topical corticosteroids (TCS) in adult patients with severe AD who are not adequately controlled with or intolerant to oral CSA, or where this treatment is currently medically undesirable.

[0134] The secondary objective of the study is to evaluate the safety and tolerability of a two-dose regimen of dupilumab compared with placebo administered simultaneously with TCS in adult patients with severe AD who are not adequately controlled with or intolerant to oral CSA, or when this treatment is currently medically undesirable.

[0135] research design The study will include a 2-week screening period, a 2-week standardization period with moderate-potency TCS, a 16-week treatment period, and a 12-week safety follow-up period. The study will evaluate dupilumab treatment in patients with severe AD who have also demonstrated poor response to TCS to date. All patients received concurrent moderate-potency TCS as background concomitant therapy to reflect the standard of care treatment for this severe population.

[0136] After providing informed consent, patients were assessed for study eligibility at a screening visit. Patients were screened between days -28 and -15 prior to randomization. During this 2-week screening period, TCS treatment was at the physician's discretion.

[0137] Beginning on day -14, all patients were initiated on a standardized TCS treatment regimen and continued the standardized medium potency regimen until the end of the treatment period (week 16). During the 12-week follow-up period, patients could continue to receive TCS at physician discretion due to intolerable AD disease activity.

[0138] Patients were also required to apply moisturizer at least twice daily for at least 7 consecutive days immediately prior to randomization (baseline / day 1) and continued at least twice daily throughout the study.

[0139] Patients who continued to meet the eligibility criteria at baseline (Day 1) were evaluated and randomized in a 1:1:1 ratio to receive subcutaneous (SC) injections of 300 mg dupilumab (followed by a 600 mg SC loading dose on Day 1) or matching injectable placebo, including a placebo for the loading dose, either weekly (qw) or once every 2 weeks (q2w). During weeks when dupilumab was not administered (in the q2w regimen), patients received an injectable placebo. To maintain blinding, all patients received an injection (active or placebo) each week from Day 1 through Week 16 (treatment period).

[0140] Patients were stratified by 1) baseline assessment of disease severity (physician global assessment [IGA] 3 vs. IGA 4) and 2) confirmed medical history of no prior CSA exposure versus prior CSA exposure that was not a candidate for CSA treatment at that time or that should not be continued or resumed.

[0141] At the end of the treatment period, patients were followed for safety for an additional 12 weeks.

[0142] Study population Adult, male and female patients with severe AD may be those whose disease is not adequately controlled with TCS, those whose disease is not adequately controlled with or is intolerant to oral CSA, or those whose CSA treatment is deemed medically inadvisable by a physician at the time according to the following: (A) Have not been previously exposed to CSA (such patients are not candidates for CSA treatment at this time for the following reasons): Medical contraindications; Hypersensitivity to the active substances or excipients of CSA; Concurrent use of medications that interfere with CSA; or Increased susceptibility to CSA-induced kidney damage, including increased risk of serious infections. or (B) Patients who have been previously exposed to CSA should not continue or restart CSA for the following reasons: Previous intolerance and / or intolerable toxicity Inadequate response, defined as relapse of AD on CSA tapered to a maintenance dose (2 to 3 mg / kg / day) after up to 6 weeks of high dose (5 mg / kg / day) or relapse after a minimum of 3 months on the maintenance dose. Relapse is defined as an increase in signs and / or symptoms that triggers an escalation of therapy, which may be an increase in the CSA dose, a switch to a higher potency TCS class, or initiation of another oral immunosuppressant; or The need for CSA at doses or for durations greater than those specified in the prescribing information.

[0143] Inclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) Males or females aged 18 years or older with severe chronic AD for which treatment with efficacious TCS was indicated (according to the American Academy of Dermatology consensus criteria [Eichenfield et al., 2014, J. Am. Acad. Dermatol. 70:338-351]); (2) Eczema Area Severity Index (EASI) score ≥ 20 at screening and baseline visits (Leshem et al., 2015, doi:10.1111 / bjd.13662 [epublished ahead of print]). If the EASI score at the first screening visit is either 18 or 19, a one-time reassessment of the EASI score is permitted within 48 hours of the first screening; (3) IGA score ≥3 (on an IGA scale of 0 to 4) at the screening and baseline visits; (4) ≥10% body surface area (BSA) with AD involvement at screening and baseline visits; (5) A physician-confirmed medical history of any of the following: (A) Have not been previously exposed to CSA and are not currently a candidate for CSA treatment for the following reasons: medical contraindications (e.g., uncontrolled hypertension during drug therapy), or Use of prohibited concomitant medications (e.g., statins, digoxin, macrolide antibiotics, barbiturates, anti-seizure medications, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, St. John's wort, etc.); or Increased susceptibility to CSA-induced kidney damage (elevated creatinine) and liver damage (elevated functional tests), or Increased risk of serious infections, or Hypersensitivity to the CSA active substance or excipients, or (B) You have been previously exposed to CSA and should not continue or resume CSA treatment because: intolerance and / or unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, uncontrolled hypertension, paresthesia, headache, nausea, hirsutism, etc.); or Inadequate response to CSA (defined as relapse of AD on CSA tapered to a maintenance dose [2 to 3 mg / kg / day] after up to 6 weeks of high dose [5 mg / kg / day] or relapse after a minimum of 3 months on the maintenance dose). Relapse is defined as an increase in signs and / or symptoms that triggers an escalation of therapy, which may be an increase in dose, a switch to a higher potency TCS class, or initiation of another systemic nonsteroidal immunosuppressant; or ·requiring CSA at doses or durations (>1 year) greater than 5 mg / kg / day greater than those specified in the prescribing information; (6) Recent (within 6 months prior to the screening visit) history of confirmed inadequate response to treatment with TCS. Note: Inadequate response is defined as failure to achieve and maintain remission or a state of low disease activity (equivalent to 0=resolved to 2=mild IGA) despite treatment with a once-daily regimen of a medium- to higher-potency TCS (± TCI as needed) applied for at least 28 days or the maximum duration recommended by the product's prescribing information (e.g., 14 days for very high-potency TCS), whichever is shorter; (7) a stable dose of topical emollient (moisturizer) applied twice daily for at least 7 consecutive days immediately prior to the baseline visit; (8) Willingness and ability to undergo clinical visits and study-related procedures; (9) Provide signed informed consent; and (10) Ability to understand and complete all study-related questionnaires.

[0144] Exclusion Criteria: Patients who met any of the following criteria were excluded from the study: (1) participation in a prior dupilumab clinical study; (2) treatment with the investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, prior to screening; (3) hypersensitivity and / or intolerance to corticosteroids or any other components contained in the TCS product used in the study; (4) systemic CSA, systemic corticosteroids, or phototherapy within 4 weeks prior to screening, and azathioprine ( (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or Janus kinase (JAK) inhibitors; (5) treatment with TCIs within 1 week prior to the screening visit; (6) treatment with biologics, including: (a) any cell depleting agent, such as, but not limited to, rituximab, within 6 months prior to the screening visit or until lymphocyte counts return to normal, whichever is longer; (b) other biologics within 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer; (7) base At the time of the screening visit, 30% or more of the total superficial lesions are in areas of thin skin that cannot be safely treated with medium-potency TCS (e.g., face, neck, intertriginous areas, genital areas, areas of skin atrophy);(8) initiation of AD treatment with a prescription moisturizer or a moisturizer containing additives such as ceramides, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients may continue using a stable dose of such a moisturizer if started prior to the screening visit);(9) initiation of AD treatment with a prescription moisturizer or a moisturizer containing additives such as ceramides, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients may continue using a stable dose of such a moisturizer if started prior to the screening visit); (10) Planned or anticipated use of any prohibited medications and procedures during study treatment; (11) Treatment with live (attenuated) vaccines within 12 weeks prior to the screening visit; (12) Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, anthelmintics, antiprotozoals, or antifungals within 2 weeks prior to the screening visit, or epidermal infection within 1 week prior to the screening visit.Note: Patients will be rescreened as soon as 2 weeks after recovery from infection, with permission from the sponsor's medical monitor. (13) known or suspected history of immunosuppression, such as a history of invasive opportunistic infections (e.g., tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, pneumocystiosis, aspergillosis), whether or not the infection has resolved, as determined by the physician; or unusually frequent, recurrent, or prolonged infection; (14) presence of any one of the following TB criteria: (a) a positive tuberculin skin test at the screening visit; (b) a positive blood QuantiFERON®-TB or T-spot test at the screening visit; or (c) a chest x-ray (posteroanterior and lateral views) at the time of screening or within 3 months prior to the screening visit with findings consistent with prior TB infection (e.g., but not limited to, periapical scarring, periapical fibrosis, or multiple calcifying granulomas) (radiology report must be available). This does not include noncaseating granulomas. Note: All three of these TB tests are performed country-specifically according to local guidelines only when required by regulatory authorities or ethical committees; (15) a history of human immunodeficiency virus (HIV) infection or positive HIV serology at screening; (16) positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCV) at the screening visit. Ab);(17) the presence at baseline of any of the conditions listed as criteria for discontinuation of study drug;(18) the presence of skin features that may interfere with study evaluations;(19) a history of malignancy within 5 years prior to the screening visit, except for fully treated intraepithelial neoplasia of the cervix or fully treated and resolved nonmetastatic squamous cell or basal cell carcinoma of the skin;(20) a diagnosis of active endoparasitic infection, unless active infection was excluded by clinical and (if appropriate) laboratory evaluation prior to randomization; suspected or high risk of endoparasitic infection;(21) a history of alcohol or drug abuse within 2 years prior to the screening visit;(22) any severe comorbid illness that, in the physician's judgment, would adversely affect the patient's participation in the study.Examples include, but are not limited to, patients with reduced life expectancy, patients with uncontrolled diabetes (hemoglobin A1c [HbA1c] ≧9%), patients with cardiovascular conditions (e.g., stage III or IV heart failure according to the New York Heart Association classification), severe renal conditions (e.g., dialysis patients), hepatobiliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating diseases), active primary autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), neuroinflammatory diseases, other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. Specific reasons for patients being excluded under this criterion will be documented in the study documentation (chart notes, case report form [CRF], etc.);(23) any other medical or psychiatric condition (including significant laboratory abnormalities at screening) that, in the physician's opinion, may suggest a new and / or poorly understood disease that may pose an undue risk to the study patient as a result of participation in this clinical trial, may make the patient's participation unreliable, or may interfere with the evaluation of the study.Specific reasons for patients being excluded under this criterion will be documented in the study documentation (chart notes, CRF, etc.);(24) planned or anticipated major surgical procedures during the patient's participation in the study;(25) the patient being a member of the investigational team or a close relative of the patient;(26) pregnant or breastfeeding women, or women who plan to become pregnant or breastfeed during the study; and(27) women of reproductive potential and sexually active who are unwilling to use adequate contraception.

[0145] Study Procedures Study Medication: Patients received either dupilumab 300 mg qw SC injections (after a 600 mg loading dose on day 1) or dupilumab 300 mg q2w SC injections (after a 600 mg loading dose on day 1) during the 16-week treatment period. During weeks when dupilumab was not administered (in the q2w regimen), patients received an injectable placebo.

[0146] Placebo: Patients received weekly injections of matching placebo (after a "loading dose" of placebo on day 1) during the 16-week treatment period.

[0147] Background Actions Topical corticosteroids: Starting on day -14, all patients were required to be treated with TCS using a standardized regimen according to the following guidelines: Apply medium potency TCS once daily to areas with active disease. Low potency TCS should be used once daily on areas with thin skin (e.g., face, neck, intertriginous, and genital areas, areas of skin atrophy) or in areas where continued treatment with medium potency TCS is deemed unsafe. Monitor patients for signs of local or systemic TCS toxicity and discontinue treatment if necessary.

[0148] Patients are advised to use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency and hydrocortisone 1% cream for low potency. If a patient has tolerance problems with any of these steroids or if they are not commercially available in some countries, they may be substituted with products of the same potency from the list provided in the Study Reference Manual. To areas treated with TCS, moisturizer should only be applied once a day when TCS is not being applied (i.e., do not use moisturizer and TCS simultaneously on the same area during the day). For example, if TCS is applied in the afternoon, moisturizer should not be used on the area treated with TCS in the afternoon, but applied to that area in the morning. Moisturizer should be applied twice a day, in the morning and afternoon, to areas not treated with TCS.

[0149] The type, amount, frequency, and potency of topical products used during the study will be recorded by patients in a medication diary at home. Patients will return TCS tubes at each clinic visit through week 16, and these tubes will be weighed by on-site staff to determine the actual amount of TCS used. During the 12-week safety follow-up period, weighing the tubes will no longer be required.

[0150] During the 16-week placebo-controlled study treatment period, the dosing frequency of the medium potency TCS will be adjusted symptom-based (IGA score) once every 4 weeks according to the following protocol-specified tapering algorithm:

[0151] On day 29 (week 4): * If a patient on once daily (qd) dosing achieves an IGA of 0, the patient is switched to every other day (qod) dosing until day 57 (week 8); * If patients on qd did not achieve an IGA of 0, they remained on qd until day 57 (week 8).

[0152] On Day 57 (Week 8): * If a patient on qd treatment achieves an IGA of 0, the patient is switched to qod treatment until day 85 (week 12); * If a patient on qd does not achieve an IGA of 0, they will remain on qd until day 85 (week 12); * If patients on qod maintain an IGA of 0, they are switched to twice weekly dosing until day 85 (week 12); * If patients on qod did not maintain an IGA of 0, they were switched to qd dosing until day 85 (week 12).

[0153] On Day 85 (Week 12): * If a patient on qd does not achieve an IGA of 0, they will remain on qd until day 113 (week 16); * If a patient on qd treatment achieves an IGA of 0, the patient is switched to qod treatment until day 113 (week 16); * If patients on qod maintain an IGA of 0, they are switched to twice weekly dosing until day 113 (week 16); * If patients on twice weekly dosing maintain an IGA of 0, patients will Maintain twice weekly dosing until (week 16); * If patients on twice weekly dosing did not maintain an IGA of 0, they were switched to qod dosing until day 113 (week 16).

[0154] Emollients: All patients were required to apply moisturizer (emollient) at least twice daily for at least 7 consecutive days immediately prior to randomization (baseline / day 1) and continue throughout the study (total 32 weeks). However, to allow adequate assessment of skin dryness, moisturizer should not be applied on areas of non-lesional skin indicated for such assessment for at least 8 hours prior to each clinic visit. All types of moisturizers are acceptable, but patients may not begin treatment with prescription moisturizers or moisturizers containing additives during the screening period or during the study. Patients may continue to use a stable dose of prescription moisturizer or moisturizer containing additives if started prior to the screening visit.

[0155] Remedies If medically necessary (i.e., to control intolerable AD symptoms), AD rescue treatment may be provided to study patients, beginning with high-potency TCS for patients who do not respond adequately after at least 7 days of topical treatment, and titrating to systemic drug therapy, if necessary.

[0156] Study Endpoints The primary endpoint in the study was the proportion of patients with an Eczema Area and Severity Index (EASI) of 75 (≥75% improvement from baseline) at 16 weeks.

[0157] Secondary endpoints were:

[0158] Efficacy:· For patients previously using CSA, the proportion of patients with an EASI of 75 (≥75% improvement from baseline) at week 16;· The proportion of patients with an IGA of 0 or 1 (on a 5-point scale) and a reduction of ≥2 points from baseline at week 16;· The percentage of change from baseline to week 16 in the Pruritus Numeric Rating Scale (NRS);· The proportion of patients with an improvement (reduction) of ≥3 in the Pruritus NRS at week 16;· The percentage of change from baseline to week 16 in the EASI score;· The change from baseline to week 16 in the percentage of body surface area (BSA);· The percentage of patients with an improvement (reduction) of ≥3 in the Atopic Dermatitis Assessment Score (SCORAD). · Percent change from baseline to week 16 in patients with a SCORAD of 50 (≥50% improvement from baseline) at week 16; · Percent change from baseline to week 16 in Global Individual Symptom Score (GISS) (erythema, infiltration / papulation, excoriation, lichenification); · Change from baseline to week 16 in Dermatology Life Quality Index (DLQI); · Change from baseline to week 16 in Patient Oriented Eczema Scale (POEM); · Change from baseline to week 16 in Hospital Anxiety and Depression Scale (HADS); · Percent change from baseline to week 2 in Pruritus NRS; · Mean weekly dose of TCS through week 16.

[0159] Safety and tolerability:· incidence of treatment-emergent adverse events (TEAEs) of skin infections requiring systemic treatment from baseline over the on-treatment period;· incidence of treatment-emergent serious adverse events (TESAEs) from baseline over the on-treatment period;· incidence of TEAEs leading to treatment discontinuation from baseline over the on-treatment period;· overall incidence of TEAEs from baseline over the on-treatment period.

[0160] Procedures and Evaluation Overall safety will be assessed by monitoring / evaluation of TEAEs, vital signs, physical examination, electrocardiogram (ECG), and clinical safety laboratory tests.

[0161] Other measures will include pharmacokinetic (PK) assessment, potential emergence of anti-drug antibodies (ADA) to dupilumab, and investigational studies.

[0162] Efficacy Procedure Various parameters will be collected during the study to assess efficacy / effectiveness of dupilumab, including measures of AD severity, use of concomitant treatments for AD, and patient-reported measures of AD symptoms and quality of life. Efficacy will be assessed using the Pruritus NRS, Pruritus Classification Scale, POEM, HADS, DLQI, European Quality of Life-5 Dimensions (EQ-5D), Patient Global Assessment of Disease, Patient Global Assessment of Treatment, Asthma Control Questionnaire (ACQ-5), Sino-Nasal Outcome Test (SNOT-22), assessment of sick leave / school absence days, IGA, EASI, BSA of AD involvement, GISS, and SCORAD.

[0163] The Pruritus NRS, Pruritus Classification Scale, POEM, HADS, DLQI, European Quality of Life-5 item (EQ-5D), Patient Global Assessment of Disease, Patient Global Assessment of Treatment, IGA, EASI, BSA of AD involvement, GISS and SCORAD are described in U.S. Patent Publication No. 20140072583, which is incorporated herein in its entirety.

[0164] Juniper Asthma Control Questionnaire: Juniper's 5-item ACQ is a validated questionnaire for assessing asthma control. The questionnaire is only applicable to a subset of patients who have a history of asthma and who are fluent speakers of the language in which the questionnaire is presented (based on the availability of a licensed translation in the participating country).

[0165] The Sinus Outcomes Trial: SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on quality of life. The questionnaire is only applicable to a subset of patients who have a chronic inflammatory condition of the nasal mucosa and / or paranasal sinuses (e.g., chronic rhinitis / rhinosinusitis, nasal polyps, allergic rhinitis) and who speak fluently the language in which the questionnaire is presented.

[0166] Assessment of number of sick leave / school absence days: Patients recruited or enrolled in a school will be asked to report the number of sick leave / school absence days since the last study assessment.

[0167] Global individual symptom score: Individual components of AD lesions (erythema, infiltrates / papulation, epidermal peeling, and lichenification) are globally graded (i.e., each is assessed with respect to the whole body and not by anatomical region) on a 4-point scale (0=none to 3=severe) using the EASI severity grading criteria.

[0168] Exploratory Biomarker Studies The biomarkers analyzed in this study are TARC and serum total IgE. These are exploratory evaluations for further understanding of AD-related biomarkers and response to dupilumab treatment. Thymus and activation-regulated chemokines and total IgE are markers of Th2 activity and downstream of IL-4 / 13 signaling. These analytes will be evaluated as measures of Th2 activity and pharmacodynamic action of the drug. These results can also be used to model dupilumab activity at the drug level. Thymus and activation-regulated chemokine levels will also be evaluated as exploratory markers of efficacy, as they were also closely associated with AD disease activity and severity. These markers can also be evaluated for their potential value in predicting treatment response.

[0169] Safety assessment Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

[0170] An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal product or in a clinical investigational subject. Thus, an AE can be any untoward and unexpected sign (including abnormal laboratory findings), symptom or disease temporarily related to the use of a medicinal product, whether or not it is considered related to the medicinal (investigational) product. AE also encompasses any worsening of a pre-existing condition (i.e., any clinically significant change in frequency and / or intensity) temporarily related to the use of the investigational drug; an abnormal laboratory finding that is deemed clinically significant by a physician; and any untoward medical occurrence.

[0171] A serious adverse event (SAE) is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires hospitalization for treatment or prolonged hospitalization; results in permanent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a major medical event.

[0172] result At the end of the study period, dupilumab administration is expected to treat AD, including severe and / or refractory AD, in patients with severe AD that is not adequately controlled with or intolerant to oral cyclosporine A, or where this treatment is not medically advisable at the time. Patients treated with dupilumab show significant improvement in at least one AD-related parameter compared to placebo. Patients treated with dupilumab use up to 50% less TCS than placebo.

[0173] Baseline demographics and baseline disease characteristics were similar between treatment groups (Table 1 ).

[0174] [Table 1]

[0175] Compared with placebo, both dupilumab dose regimens (300 mg qw + TCS; 300 mg q2w + TCS) demonstrated robust efficacy across multiple clinical outcomes reflecting improvements in objective signs of AD, pruritus, quality of life, and mental health. The primary endpoint at week 16 was achieved for both dupilumab dose regimens. Compared with placebo plus TCS, dupilumab q2w plus TCS significantly improved patient-reported itch, sleep, skin symptoms, quality of life (QoL), and health status as measured by the Pruritus Numeric Rating Scale; the Atopic Dermatitis Assessment Score Visual Analog Scale for Sleep Deprivation; the Patient-Directed Eczema Scale; and the Dermatology Quality of Life Index. Table 2 shows the primary and secondary efficacy outcomes for endpoints in the hierarchy of endpoints identified in the SAP.

[0176] [Table 2]

[0177] The sequence of endpoints was tracked according to the prespecified hierarchical testing sequence in the SAP.All secondary endpoints, except for AE-related endpoints, were statistically significant at the 5% significance level.

[0178] Table 3 summarizes some of the patient-reported outcomes and improvements over baseline.

[0179] [Table 3]

[0180] [Table 4]

[0181] Safety: Dupilumab plus concurrent TCS treatment was well tolerated and demonstrated an acceptable safety profile during the 16-week treatment period. Table 4 summarizes selected AEs during the 16-week treatment period.

[0182] [Table 5]

[0183] No deaths occurred during the study. The percentage of patients with treatment-emergent adverse events (TEAEs) was similar across all treatment groups. Serious adverse events were evenly distributed across treatment groups (2 events in each group). There were fewer severe TEAEs in the combined dupilumab-treated group compared to placebo. Treatment with dupilumab did not increase infection rates, and infection and invasion adverse events occurred at similar rates in all treatment groups. There were also fewer skin infections in the combined dupilumab-treated group compared to placebo. There was a higher incidence of conjunctivitis in the dupilumab-treated group, with more events occurring in the 300 mg Q2W group than in the 300 mg QW group. Only events were severe in intensity, and no patients discontinued treatment due to conjunctivitis AEs. Injection site reactions were more common in the dupilumab groups and occurred at a higher rate in the 300 mg qw group than in the 300 mg q2w group; no severe ISRs were observed.

[0184] conclusion In this 16-week study of dupilumab + TCS versus placebo + TCS, the primary efficacy endpoint of EASI-75 at week 16 was satisfactory for both dupilumab dose regimens. EASI-75 response rates at week 16 were 29.6% in the placebo + TCS group, 62.6%, and 59.1% for dupilumab 300 mg q2w + TCS and dupilumab 300 mg qw + TCS, respectively. All prespecified primary and other secondary efficacy endpoints were satisfactory for the dupilumab 300 mg qw + TCS group, including the endpoint of incidence of skin infections.

[0185] Dupilumab with concurrent TCS was generally well tolerated with a tolerable safety profile.

[0186] In patients with a history of intolerance or inadequate response to CsA, or in whom treatment with CsA was otherwise not medically advisable, dupilumab and concurrent TCS significantly improved patient-reported itch, sleep, skin symptoms, and QoL compared with TCS alone, with a tolerable safety profile. EXAMPLES

[0187] Pharmacokinetics, safety, and efficacy of dupilumab in a pediatric population with moderate-to-severe or severe AD: Results from a phase 2a clinical trial This example describes a Phase 2a, multicenter, open-label, ascending dose sequential cohort study (NCT02407756) that encompassed adolescents (ages 12-17) with moderate to severe AD and children (ages 6-11) with severe AD uncontrolled by topical pharmacotherapy. Patients received a single dose of subcutaneous dupilumab at 2 mg / kg or 4 mg / kg and 8 weeks of observation, followed by four weekly doses of 2 mg / kg or 4 mg / kg.

[0188] Research Objective The primary objective of the study was to characterize the safety and PK of dupilumab in pediatric patients with moderate to severe AD (adolescents aged 12 years and older and younger than 18 years) or severe AD (children aged 6 years and older and younger than 12 years). The secondary objective of the study was to investigate the immunogenicity and efficacy of dupilumab in pediatric patients with moderate to severe AD (adolescents aged 12 years and older and younger than 18 years) or severe AD (children aged 6 years and older and younger than 12 years).

[0189] research design This was performed as a phase 2a, multicenter, open-label, ascending dose sequential cohort study investigating the safety, tolerability, pharmacokinetics (PK), immunogenicity, and efficacy of single and repeated doses of subcutaneously administered (SC) dupilumab in pediatric patients with moderate to severe AD (adolescents aged ≥12 years and <18 years) or severe AD (children aged ≥6 years and <12 years) not adequately controlled by topical treatments.

[0190] Two sequentially escalating SC dose cohorts were planned: Dose Cohort 1 (2 mg / kg) and Dose Cohort 2 (4 mg / kg) up to a maximum dose of 300 mg. In each dose cohort, approximately 36 to 40 patients were planned to be enrolled in two age subsets: Subset A (adolescents aged 12 years or older and <18 years) and Subset B (children aged 6 years or older and <12 years). Enrollment and study dosing began with Cohort 1A (2 mg / kg, adolescent age subset) and progressed sequentially to Cohort 1B (2 mg / kg, children aged 6 years or older and <12 years), Cohort 2A (4 mg / kg, adolescent age subset), and Cohort 2B (4 mg / kg, children aged 6 years or older and <12 years); A safety review of data from this cohort was performed before proceeding to the next cohort.

[0191] The study consisted of a screening period (days -35 to -1), a baseline visit, part A (encompassing single-dose treatment followed by an 8-week moderately dense PK sampling period), and part B (encompassing a 4-week repeat-dose treatment period [4 weekly doses] followed by an 8-week follow-up period).

[0192] Patients received concurrent medications (excluding prohibited medications) as needed while continuing study treatment. The frequency and type of treatment use were recorded. Study patients were offered rescue treatments when medically necessary. Rescue treatments encompassed more intensive topical treatments (medications and / or procedures) before escalating rescue to systemic medications, when medically appropriate. Patients who received rescue with systemic corticosteroids or systemic nonsteroidal immunosuppressants (e.g., cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) during Part A (single-dose treatment and the 8-week moderately dense PK sampling period) were required to discontinue such rescue treatments for at least 2 weeks prior to the initiation of Part B (i.e., before beginning administration of repeat doses of study treatment); patients who received any of these rescue treatments during the repeat-dose treatment period discontinued study drug.

[0193] Dose escalation: Dosing began with cohort 1A. Once all of the first 8 patients enrolled in cohort 1A had been observed for at least 2 weeks, the next cohort (1B) was entered, safety assessments at week 2 (day 15) were completed, and data were reviewed. Once all of the first 20 patients enrolled in cohorts 1A and / or 1B had been observed for at least 2 weeks, dose escalation occurred in cohort 2A, safety assessments at week 2 (day 15) were completed, and data were reviewed. Once all of the first 8 patients enrolled in cohort 2A had been observed for at least 2 weeks, the next cohort (2B) was entered, safety assessments at week 2 (day 15) were completed, and data were reviewed.

[0194] Study population The study population encompassed pediatric patients with moderate to severe AD (adolescents aged ≥12 years and <18 years at baseline) or severe AD (children aged ≥6 years and <12 years at baseline) that was not adequately controlled with topical pharmacotherapy.

[0195] Inclusion criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) male or female aged 6 years or older and younger than 18 years at baseline; (2) diagnosis of AD according to the American Academy of Dermatology criteria established at least 1 year prior to screening (Eichenfield et al., 2014, J. Am. Acad. Dermatol. 70:338-51); (3) patients with a confirmed recent history (within 6 months prior to the screening visit) of inadequate response to a sufficient course of outpatient treatment with topical AD medication or patients for whom topical AD therapy is otherwise inadvisable (e.g., due to side effects or safety risks). Note: For purposes of this disclosure, inadequate response indicates failure to achieve and maintain remission or a state of low disease activity (Physician's Global Assessment [IGA] equivalent to 0=clear to 2=mild) despite treatment for at least 28 days with a regimen of moderate-to-high potency TCS (±TCI as needed). Side effects or safety risks that may outweigh the potential treatment benefits included intolerance to the treatment, hypersensitivity reactions, significant skin atrophy, and side effects related to systemic absorption. Acceptable documentation included physician documentation based on contemporaneous chart notes recording TCS with or without prescription of TCI and treatment outcomes, or communication with the physician treating the patient. In cases where documentation was insufficient, it was also possible to rescreen potential patients after they had been shown to be ineffective with medium- to higher-potency TCS (±TCI) at the defined treatment lengths mentioned above. (4) Baseline IGA at line: a. IGA = 3 or 4 in adolescents aged 12 years and under 18 years; b. IGA = 4 in children aged 6 years and under 12 years; (5) at least 10% of body surface area (BSA) affected by AD lesions at baseline. Note: This inclusion criterion was modified from the original criteria to clarify that BSA affected by AD should be based on the assessment performed at baseline; (6) willing and able to undergo clinical site visits and study-related procedures; (7) parent / caregiver or legal guardian must be able to understand the requirements of the study; (8) parent or legal guardian must provide signed informed consent. Patients aged 7 years and over (or older as determined by the IRB / IEC according to local regulations and requirements) must also provide an informed consent to enroll in the study and must sign and date either a separate IAF or ICF; and (9) parent or legal guardian / patient must be able to understand and complete study-related questionnaires, as appropriate.

[0196] Exclusion Criteria: Patients who met any of the following criteria were excluded from the study: (1) treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, prior to the baseline visit; (2) treatment with the following within 2 weeks prior to the baseline visit: a. systemic corticosteroids, b. immunosuppressants / immunomodulators (e.g., cyclosporine, mycophenolate mofetil, interferon-gamma, Janus kinase inhibitors, azathioprine, or methotrexate), c. phototherapy for AD; (3) treatment with biologics, such as: a. (b) any cell depleting agents, such as rituximab, within 6 months prior to the baseline visit or until lymphocytes return to normal, whichever is longer; (c) any other biologic within 5 half-lives (if known) or within 4 months prior to the baseline visit, whichever is longer; (4) planned or anticipated use of any prohibited medications and procedures during study treatment; (5) treatment with live (attenuated) vaccines within 3 months prior to the baseline visit; (6) systemic antibiotics, antivirals, or other antivirals within 4 weeks prior to the baseline visit. (7) known or suspected immunodeficiency, such as a history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), regardless of whether the infection has resolved, or other recurrent infections of unusual frequency or duration suggestive of a state of compromised immune function; (8) known history of human immunodeficiency virus infection; (9) known history of infection with the human immunodeficiency virus; ) active hepatitis B or C infection at screening or prior history of active hepatitis B or C infection reported at screening; (10) prolonged (confirmed by repeat testing at least 2 weeks apart) elevation of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) greater than 3 times the upper limit of normal (ULN) during the screening period; (11) presence at baseline of any of the conditions listed as criteria for discontinuing study treatment;(12) Presence of cutaneous comorbidities that may interfere with study assessments; (13) History of malignancy within 5 years prior to the baseline visit, except for fully treated intraepithelial neoplasia of the cervix and fully treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin; (14) History of clinical endoparasitic condition (i.e., helminth infection) within 12 months prior to the baseline visit, or high risk of helminth infection, e.g., possible parasitic infection / infestation as determined by subsequent medical evaluation (e.g., stool test, blood test, etc.). residence in or recent travel (within 12 months prior to the baseline visit) to an area where endoinfestation is endemic, unless excluded, where such circumstances equate to exposure to the parasite (e.g., extended stays in rural or slum areas, lack of running water, consumption of uncooked, undercooked, or otherwise potentially contaminated foods, close contact with reservoirs and vectors, etc.); (15) history of alcohol or drug abuse within 2 years prior to the screening visit; (16) to a study; Severe comorbid illnesses that are expected to adversely affect patient participation. Examples include, but are not limited to, patients with a short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c ≥ 9%), patients with cardiovascular conditions (e.g., stage III or IV heart failure according to the New York Heart Association classification), severe renal conditions (e.g., dialysis patients), hepatobiliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), and other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases; (17) suggesting new and / or poorly understood diseases. Any other medical or psychiatric condition, including significant laboratory abnormalities at screening, that might pose undue risk to the study patient as a result of participation in this clinical trial, that might make the patient's participation unreliable, or that might interfere with the study evaluations; (18) major surgical procedures planned during the patient's participation in the study; (19) the patient was a member of the investigational team or a close relative of the patient; and (20) female patients who were pregnant, breastfeeding, or planned to become pregnant or breastfeed during the study, or female patients of childbearing potential who were not willing to use adequate contraception throughout the study period and until 120 days after the last dose of study drug.

[0197] Study Procedures Sterile dupilumab drug product was provided at 150 mg / mL in an aqueous buffered vehicle, pH 5.0. It was supplied in 2.0 mL withdrawable volumes or 5 mL vials containing 2.5 mL containing 300 mg of dupilumab (150 mg / mL). Study drug was administered SC by a physician or other qualified investigator at the following doses and dosing schedules: For dose cohort 1: 2 mg / kg on day 1 as a single dose in Part A, then weekly on days 1 through weeks 3 as repeat doses in Part B. For dose cohort 2: 4 mg / kg on day 1 as a single dose in Part A, then weekly on days 1 through week 3 as repeat doses in Part B.

[0198] Subcutaneous injection sites of study drug were rotated between different abdominal quadrants (avoiding the navel and waist areas), upper thighs, and upper arms to avoid injections at the same site on two consecutive weeks. Only areas of normal appearing skin were administered study drug to allow adequate evaluation of possible injection site reactions.

[0199] Primary and secondary endpoints The primary objective was to characterize the PK profile of dupilumab in pediatric patients aged 6 years and older and less than 18 years with AD. Secondary endpoints were: Incidence of TEAEs Percentage change from baseline in Eczema Area and Severity Index (EASI) Percentage change from baseline in Scores for the Assessment of Atopic Dermatitis (SCORAD) scores Percentage change from baseline in pruritus numerical rating scale (NRS) Percentage of patients with an IGA score of 0 or 1 Change from baseline in % of BSA affected by AD.

[0200] Study variables and procedures Safety and tolerability were assessed by vital signs, physical examination, clinical laboratory tests, and clinical evaluations. Patients were questioned to monitor any adverse events (AEs) experienced from the time of informed consent / assent to their last study visit. Serum samples were collected for assay of dupilumab levels, and dupilumab concentration data were used to calculate PK parameters. Serum samples were collected for assay of ADA and for exploratory analyses. Efficacy was assessed during the study at specific clinic visits using the Pruritus NRS, SCORAD, and EASI, which measure the extent and severity of AD, and the IGA, which assesses the overall severity of AD.

[0201] result (A) Baseline disease characteristics The study enrolled young patients aged 12 to 18 years with moderate to severe AD (IGA score of 3 or 4 at baseline) and children aged 6 to 12 years with severe AD (IGA score of 4 at baseline; see inclusion criteria for each age group). Therefore, baseline disease characteristics differed between the two age groups.

[0202] Young patients aged 12 years or older and younger than 18 years: The proportion of young patients diagnosed with AD within the specified age range was generally similar between dose cohorts with the majority of patients in each dose cohort diagnosed before age 5 years (Table 1). The mean duration of AD was also similar between dose cohorts. As expected, patients in the older age subsets within each dose cohort had longer duration of AD than younger patients. The mean baseline values ​​of all AD assessments were consistent with moderate to severe AD. Differences in mean EASI score, mean pruritus NRS score, mean BSA, and SCORAD score at baseline were small and consistent with those expected in the nonrandomized group (Table 5). In summary, baseline disease characteristics were comparable between the two dose cohorts.

[0203] [Table 6]

[0204] Patients aged 6 years and older and younger than 12 years: The proportion of patients aged 6 years and older and younger than 12 years diagnosed with AD within the specified age ranges was generally similar between dose cohorts with the majority of patients in each dose cohort diagnosed before age 5 years (Table 2). The mean duration of AD was also similar between dose cohorts. As expected, patients in the older age subsets within each dose cohort had longer duration of AD than younger patients. The mean of all AD assessments was Mean baseline values ​​were consistent with severe / moderate AD. Differences in mean EASI scores, mean pruritus NRS scores, mean BSA, and SCORAD scores at baseline were small and consistent with those expected in the nonrandomized group (Table 6). In summary, baseline disease characteristics were comparable between the two dose cohorts.

[0205] [Table 7]

[0206] (B) Medical history Medical history was assessed using a general questionnaire, and history of specific atopic diseases was collected using a targeted questionnaire eliciting a broader atopic medical history.

[0207] Youth patients aged 12 years or older and younger than 18 years: All youth patients (100%) had at least one medical history found using the general questionnaire. The most common non-AD MedDRA PTs reported in 30% or more of all patients were food allergy (45.0%), asthma (45.0%), house dust allergy (35.0%), seasonal allergy (35.0%), allergic rhinitis (35.0%), and allergy to animals (30.0%). Eleven (27.5%) patients had a history of allergic conjunctivitis.

[0208] Based on specific atopic disease questionnaires, the proportion of patients with a family history of an atopic / allergic condition was similar between the two dose cohorts. The most common atopic / allergic condition in the patients' family history was AD (37.5% overall). The most common atopic / allergic condition in the patients' family history in the 2 mg / kg dose cohort was AD (50.0%) compared to other allergies in the 4 mg / kg dose cohort (30.0%). The most common current atopic / allergic condition other than AD was other allergies (60.0% overall; 55.0% in the 2 mg / kg dose cohort, and 65.0% in the 4 mg / kg dose cohort). In summary, 30.0% of all patients indicated a current medical history of allergic conjunctivitis, and 37.5% had a current medical history of asthma, both of which were reported in a higher proportion of patients in the 4 mg / kg dose cohort. Five percent of all patients had a currently resolved atopic / allergic condition. The most common currently resolved atopic / allergic condition was asthma. This was consistent across both dose cohorts. A similar frequency was reported in a study.

[0209] Patients aged 6 to 12 years: All patients aged 6 to 12 years (100%) had at least one medical history found using the general questionnaire. The most common non-AD MedDRA PTs reported in 30% or more of all patients were food allergy (67.6%), allergic rhinitis (51.4%), house dust allergy (48.6%), asthma (43.2%), and seasonal allergies (35.1%). Nine (24.3%) patients had a history of allergic conjunctivitis. Overall, medical histories were similar between dose cohorts. Differences between dose cohorts included a higher incidence of food allergy (73.7%, 61.1%), cow's milk allergy (15.8%, 5.6%), and allergic conjunctivitis (31.6%, 16.7%) in the 4 mg / kg dose cohort compared with the 2 mg / kg dose cohort, respectively. The incidence of allergy to animals (38.9%, 5.3%), fungal allergy (16.7%, 5.3%), and allergic rhinitis (61.1%, 42.1%) was higher in the 2 mg / kg dose cohort than in the 4 mg / kg dose cohort, respectively.

[0210] The proportion of patients with a family history of an atopic / allergic condition based on specific atopic disease questionnaires was higher in the 4 mg / kg dose cohort than in the 2 mg / kg dose cohort. The most common atopic / allergic condition in the patient's family history was AD (32.4% overall). The most common atopic / allergic condition in the patient's family history in the 2 mg / kg dose cohort was allergic rhinitis (33.3%) compared with AD in the 4 mg / kg dose cohort (36.8%). The most common current atopic / allergic conditions other than AD were other allergies and food allergies (64.9% overall, respectively). The incidence of current food allergies was higher in the 4 mg / kg dose cohort (73.7%) than in the 2 mg / kg dose cohort (55.6%). In summary, 21.6% of all patients demonstrated a current history of allergic conjunctivitis and 43.2% had a current history of asthma, both of which were reported in a higher proportion of patients in the 4 mg / kg dose cohort.

[0211] (C) Previous medications / procedures Prior medication / procedure was defined as a medication or procedure taken prior to the first administration of study drug.

[0212] Adolescent patients aged ≥12 years and <18 years: All adolescent patients had at least one prior medication. The most commonly used (≥50% of all patients) prior medications by therapeutic class were corticosteroid skin preparations (97.5%), antihistamines for systemic use (67.5%), and other skin preparations (67.5%). Use of prior medications was generally similar between the two dose cohorts. Skin preparations of corticosteroids included potent (group III; 87.5% of patients overall), weakly potent (group I; 35.0% of patients overall), moderately potent (group II; 27.5% of patients overall), and highly potent (group IV; 12.5%). A total of seven (17.5%) adolescent patients had a history of systemic glucocorticoid use. Thirteen patients reported prior use of nonsteroidal systemic immunosuppressants, including cyclosporine and azathioprine. Nine (22.5%) young patients reported at least one prior procedure. The most commonly reported prior procedures in more than one patient were ultraviolet (UV) phototherapy (7.5% of patients overall) and phototherapy (5.0% of patients overall).

[0213] Patients aged 6 to 12 years: All patients aged 6 to 12 years were required to have at least one prior Prior medications were received from 11 (29.7%) patients. The most commonly used (≥50% of all patients) prior medications by therapeutic class were corticosteroid skin preparations (97.3%), antihistamines for systemic use (91.9%), emollients and protectants (70.3%), and other skin preparations (70.3%). Use of prior medications was generally similar between the two dose cohorts. Corticosteroid skin preparations included potent (group III; 83.8% of patients overall), moderately potent (group II; 43.2% of patients overall), weakly potent (group I; 29.7% of patients overall), and highly potent (group IV; 10.8%). Prior systemic glucocorticoid use was reported in 11 (29.7%) patients. Ten patients reported prior use of nonsteroidal systemic immunosuppressants, including cyclosporine and azathioprine. Seven (18.9%) patients reported at least one prior procedure. Prior procedures reported by more than one patient overall included ultraviolet light therapy (10.8% of patients overall) and phototherapy (5.4% of patients overall).

[0214] (D) Concomitant medications and procedures Young patients aged 12 years or older and younger than 18 years: Most young patients (97.5%) received at least one concurrent medication during the entire study. The most commonly used concurrent medications by therapeutic class across the study (overall ≥25% of patients) were corticosteroid skin preparations (75.0%), antihistamines for systemic use (67.5%), emollients and protectants (45.0%), other skin preparations (42.5%), and medications for obstructive airway disease (27.5%). In summary, 77.5% of patients used concurrent treatments for AD during the study, including 85.0% of patients in the 2 mg / kg dose cohort and 70.0% of patients in the 4 mg / kg dose cohort. Use of any TCS was higher in the 2 mg / kg dose cohort than in the 4 mg / kg dose cohort. The most commonly used TCS in both dose cohorts was potent (group III) TCS. Use of TCIs was also higher in the 2 mg / kg dose cohort than in the 4 mg / kg dose cohort. Tacrolimus was the most commonly used TCI in both dose cohorts. The number of adolescent patients who used any concurrent AD medication was higher during Part A (31 [77.5%]) than during Part B (11 [27.5%]). Use of TCS and TCIs in adolescents was higher in both dose cohorts during Part A compared with Part B. Use of systemic corticosteroids was low and similar between Parts A and B.

[0215] Patients aged 6 to 12 years: Most patients aged 6 to 12 years (97.3%) received at least one concurrent medication during the entire study. The most commonly used concurrent medications by therapeutic class across studies (overall ≥25% of patients) were antihistamines for systemic use (89.2%), corticosteroid skin preparations (89.2%), emollients and protectants (75.7%), other skin preparations (48.6%), medications for obstructive airway disease that may represent an overlap with asthma as a comorbidity (40.5%), and antimicrobials for systemic use (27.0%). In summary, 91.9% of patients aged 6 to 12 years used a concurrent treatment for AD during the study, including 88.9% of patients in the 2 mg / kg dose cohort and 94.7% of patients in the 4 mg / kg dose cohort. Use of any TCS was similar between dose cohorts, with potent (group III) TCS being the most commonly used TCS in both dose cohorts. Use of TCI was higher in the 2 mg / kg dose cohort than in the 4 mg / kg dose cohort. Tacrolimus was the most commonly used TCI in both dose cohorts. The number of patients aged 6 years or older and younger than 12 years who required the use of any concurrent AD medication was higher during Part A (33 [89.2%]) than during Part B (10 [27%]). Use of TCS and TCI was also higher during Part A than during Part B in both dose cohorts. In the aged 6 years or older and younger than 12 years group, No systemic immunosuppressant use was required during either Part A or Part B.

[0216] (E) Efficacy Forty adolescents / 38 children (mean Eczema Area and Severity Index [EASI] ± SD = 31.7 ± 16.00 / 35.9 ± 17.22) were enrolled; 22.5% adolescents / 16.2% children had failed to respond to one or more prior systemic treatments. The pharmacokinetic profile of dupilumab was similar to that of adults (target-mediated drug properties). No new safety signals were detected compared to adults.

[0217] In the younger patient group, dupilumab administered as a single dose of either 2 mg / kg or 4 mg / kg induced a marked and rapid reduction in disease activity in patients at week 2 (34% and 51% reduction from baseline in EASI score for the 2 mg / kg and 4 mg / kg doses, respectively). Repeated weekly doses of dupilumab led to further improvements in disease severity in patients in both dose cohorts. At week 12, in the younger 2 mg / 4 mg cohort, EASI at baseline was markedly improved by 66.4% / 69.7%, peak pruritus numerical rating scale (NRS) by 30.8% / 37.6%; 10% / 35% achieved an Physician Global Assessment (IGA) of 0 to 1.

[0218] Dupilumab administered as a single dose of either 2 mg / kg or 4 mg / kg induced a marked and rapid reduction in disease activity in patients at week 2 (37% and 33% reduction from baseline in EASI score for the 2 mg / kg and 4 mg / kg doses, respectively). Repeated weekly doses of dupilumab led to further improvements in disease severity in patients of both dose cohorts. At week 12, in the 2 mg / 4 mg cohort of children, EASI at baseline was markedly improved by 76.2% / 63.4% and peak pruritus NRS by 41.6% / 39.6%; 16.7% / 21.1% achieved an IGA of 0 to 1.

[0219] In summary, both dose regimens studied demonstrated significant clinical benefit in both pediatric age groups. Single doses of 2 mg / kg and 4 mg / kg dupilumab resulted in rapid reductions in signs and symptoms of AD in both age groups. Repeated weekly doses provided improved and more durable responses than single doses in both age groups. This clinical response was seen in patients who had high disease activity at baseline and had failed all approved available therapies for their disease.

[0220] conclusion Dupilumab, administered as single and repeated weekly doses of 2 mg / kg and 4 mg / kg for 4 weeks, was generally safe and well tolerated in both pediatric age groups enrolled in the study. In pediatric patients with AD, the pharmacokinetic profile of dupilumab was consistent with adults; dupilumab provided clinical benefit (e.g., improvement in pruritus) at a faster rate than observed in adult clinical trials with a similar safety profile. EXAMPLES

[0221] Treatment interruption did not affect efficacy or long-term safety of dupilumab: a phase 3 open-label study Treatment interruptions may occur in clinical practice, and the objective of this study was to demonstrate the effect of treatment interruptions on the long-term safety and efficacy of dupilumab.

[0222] This example provides an interim analysis of an ongoing multicenter, open-label study (NCT01949311) of dupilumab treatment for up to 3 years. Adults with moderate to severe atopic dermatitis (AD) were enrolled following participation in a prior dupilumab study. Safety and efficacy at week 52 [Wk] were evaluated in dupilumab-naïve (previously unexposed) and retreated (interval between parent and open-label studies >13 weeks) patients.

[0223] Of the 1,491 treated patients, 116 naïve and 290 retreated patients were included in this analysis (including patients who finished or discontinued before week 52). Naïve and retreated patients had 432.5 and 371.0 adverse events / 100 patient years (AE / 100PY), 11.7 and 5.4 serious AEs / 100PY, and 2.6% and 2.8% treatment discontinuations due to AEs, respectively; there were no deaths. At week 52, 49.1% / 50.7% of naïve / retreated patients had a physician's global assessment score of 0 or 1, and 73.3% / 80.7% achieved EASI-75 (from parent study baseline); peak pruritus numerical rating scale scores at week 52 were reduced by 64.9% and 60.6% from parent study baseline in naïve and retreated patients. In summary, efficacy assessments at all time points prior to week 52 showed similar results between groups.

[0224] In conclusion, interruption of dupilumab treatment for more than 3 months had no effect on safety or efficacy endpoints compared with untreated patients in adults with moderate to severe AD. EXAMPLES

[0225] Efficacy and safety of dupilumab in adult patients with atopic dermatitis who were candidates for systemic treatment with cyclosporine: Subgroup analyses from a 1-year study Atopic dermatitis (AD) is a chronic inflammatory skin disease that may last for decades requiring long-term systemic therapy. Cyclosporine (CsA) provides rapid and broad immunosuppressive effects, but its long-term use is limited due to safety concerns such as hypertension and renal and hepatic dysfunction. Dupilumab is a fully human monoclonal antibody directed against interleukin (IL)-4 receptor alpha and inhibits the type 2 cytokines IL-4 and IL-13. The long-term safety and efficacy of dupilumab were investigated in a phase 3 clinical trial (NCT02260986).

[0226] This example describes a 1-year double-blind, randomized, placebo-controlled, parallel-group study in adults with moderate to severe AD and a history of inadequate response to topical corticosteroids (TCS). Patients were randomized 3:1:3 (dupilumab 300 mg once weekly [qw], once every 2 weeks [q2w], or placebo). Patients received concurrent low- and / or medium-potency TCS, which could be tapered and discontinued based on clinical response. Topical calcineurin inhibitors could be used in areas where TCS was deemed inadvisable.

[0227] Here we compared the efficacy and safety of dupilumab versus placebo in two patient subsets of the population: those with a confirmed history of inadequate response or intolerance to CsA or who had been considered for CsA based on AD severity but did not receive CsA treatment as it was contraindicated or inappropriate (CsA-ineligible, n=126), and the remaining CsA-eligible subset of patients (n=497).

[0228] CsA-ineligible patients had, on average, more severe disease than CsA-eligible patients, as assessed by the Eczema Area and Severity Index (EASI) (mean baseline ± SD E ASI scores were 36.9 ± 13.09 vs. 31.5 ± 12.66; nominal p < 0.001 [post-hoc analysis]. At week 52 in both subsets, dupilumab treatment increased the proportion of patients who achieved a 75% improvement in EASI (CsA-ineligible: 18.6% with placebo, 52.4% / 50.0% with dupilumab q2w / qw; CsA-eligible: 22.4% with placebo, 69.1% / 67.0% with dupilumab q2w / qw). Dupilumab treatment also increased the proportion of patients who achieved a ≥4-point improvement on the peak pruritus numerical rating scale at week 52 (CsA-ineligible: 12.3% placebo, 42.9% / 35.6% dupilumab q2w / qw; CsA-eligible: 13.0% placebo, 53.8% / 39.7% dupilumab q2w / qw). Treatment groups had similar treatment-emergent adverse event (TEAE) rates (CSA-ineligible: 88.5%, 91.7% / 88.5%; CSA-eligible: 88.3%, 87.2% / 81.7%).

[0229] In further analyses, efficacy and safety of dupilumab versus placebo (PBO) at week 52 were compared in two patient (pt) subsets of the population: those initially treated with CsA but with an inadequate response or intolerance to CsA (subset A; n=114), and those in the remaining study population (subset B; n=509). Patients in subset A had, on average, more severe disease as assessed by the Eczema Area and Severity Index (EASI) than patients in subset B (mean baseline ± SD EASI score, 37.0 ± 12.70 vs. 31.6 ± 12.77; nominal p<0.0001 [post-hoc analysis]). At week 52 in both subsets, dupilumab treatment increased the proportion of patients who achieved a 75% improvement in EASI; and a 4-point or greater improvement in the peak pruritus numerical rating scale (Table 7). Treatment groups had similar treatment-emergent adverse events (TEAE) rates (subset A: 88.9%, 90.9% / 87.0%; subset B: 83.5%, 87.5% / 82.2%).

[0230] [Table 8]

[0231] The most common TEAEs were upper respiratory tract infection, nasopharyngitis, conjunctivitis, exacerbation of AD, and injection site reactions.

[0232] In conclusion, long-term treatment with dupilumab significantly improved signs and symptoms of AD, regardless of a documented history of inadequate response or intolerance to CsA, and even though these patients had significantly increased disease activity at baseline. Similarly, dupilumab also improved signs and symptoms of AD in CsA-eligible patients. EXAMPLES

[0233] Efficacy and safety of dupilumab in adult patients with atopic dermatitis who were candidates for treatment with cyclosporine: A pooled secondary subgroup analysis of two phase 3 randomized trials Introduction: Patients (pts) with atopic dermatitis (AD) refractory to topical treatments are candidates for systemic treatment. Cyclosporine (CsA) is approved for this indication; however, its clinical use is limited primarily due to safety concerns, such as hypertension and renal and hepatic dysfunction. Dupilumab is a fully human anti-interleukin (IL)-4 receptor alpha monoclonal antibody that potently inhibits both IL-4 and IL-13 signaling. Dupilumab has been reported to improve AD outcomes while having a tolerable safety profile in two similarly designed phase 3 trials (NCT02277743 and NCT02277769) with patients with moderate to severe AD.

[0234] Objectives and Methods: To evaluate the efficacy and safety of dupilumab versus placebo in two subsets of the pooled population: patients with a confirmed history of inadequate response or intolerance to CsA or who were considered for CsA based on AD severity but did not receive CsA treatment as it was contraindicated or inappropriate (CsA-ineligible, n=288), and the remaining CsA-eligible subset of patients (n=1091).Patients (N=1379) with moderate to severe AD whose disease was not adequately controlled by topical medical therapy or for whom topical treatment was medically inadvisable were randomized to receive placebo (PBO) or dupilumab 300 mg subcutaneous injections once every 2 weeks (q2w) or once weekly (qw) for 16 weeks.

[0235] Results: CsA-ineligible patients had, on average, more severe disease than CsA-eligible patients, as assessed by the Eczema Area and Severity Index (EASI; mean baseline ± SD EASI score was 36.1 ± 14.54 vs. 32.1 ± 13.35; nominal p < 0.0001). In both subsets, dupilumab treatment increased the proportion of patients who achieved a 75% improvement in EASI; achieved a physician's global assessment of 0 to 1; or reported a 4-point or greater improvement on the peak pruritus numeric rating scale (Table 8). The most common adverse events occurring during treatment in these studies were nasopharyngitis, exacerbation of AD, and injection site reactions. In both subsets, the rates of bacterial conjunctivitis (CsA ineligible 1.1%, PBO 3.8% / 4.2%; dupilumab q2w / qw; CsA eligible 0.3%, 0.6% / 1.1%) and conjunctivitis (CsA ineligible 2.3%, 1.9% / 4.2%; CsA eligible 0.3%, 5% / 3.3%) were numerically higher in the dupilumab group than in the PBO group.

[0236] [Table 9]

[0237] In further analyses, efficacy and safety of dupilumab versus placebo were compared in two subsets of the pooled population: patients who had a confirmed history of inadequate response or intolerance to CsA (subset A; n=255), and patients in the remaining study population (subset B; n=1124). Patients in subset A had, on average, more severe disease than patients in subset B, as assessed by the Eczema Area and Severity Index (EASI; mean baseline ± SD EASI score, 37.2 ± 14.69 vs. 32.0 ± 13.29; nominal p<0.0001). In both subsets, dupilumab treatment increased the proportion of patients who achieved a 75% improvement in EASI (Table 5); achieved a physician's global assessment of 0 to 1 (Table 9); or reported a 4-point or greater improvement on the peak pruritus numerical rating scale (Table 9).

[0238] [Table 10]

[0239] Conclusions: Sixteen weeks of dupilumab monotherapy significantly improves signs and symptoms of AD in both patients not eligible for CsA treatment, as well as in those eligible for CsA treatment, even though these patients had significantly increased disease activity at baseline. EXAMPLES

[0240] Pharmacokinetics of Dupilumab in a Long-Term Phase 3 Study in Adult Patients With Moderate-to-Severe Atopic Dermatitis This example provides pharmacokinetic (PK) data from two long-term Phase 3 studies conducted to evaluate the efficacy and safety of dupilumab in adults with moderate to severe atopic dermatitis.

[0241] Methods: The clinical trial was a 52-week randomized, multicenter, double-blind, placebo-controlled study (NCT02260986) of subcutaneous dupilumab and concurrent topical corticosteroids (TCS) in 740 adult patients randomized 3:1:3 to placebo, dupilumab 300 mg once every 2 weeks (q2w) and dupilumab 300 mg once weekly (qw); patients randomized to dupilumab received a loading dose of 600 mg. An open-label extension study (NCT01949311) of dupilumab 300 mg qw is ongoing in patients who participated in the prior study, and results from 1076 patients treated for up to 68 weeks will also be reported. This example describes functional dupilumab concentrations measured in serum from blood samples at various time points and analyzed using descriptive statistics.

[0242] Results: In the randomized study, mean functional concentrations of dupilumab in serum increased from week 2 to week 16, reaching 80 mg / L and 185 mg / L in the q2w and qw treatment groups, respectively. Concomitant use did not affect the PK of dupilumab, as the results were consistent with published data from patients not receiving TCS. Steady-state concentrations were maintained for the remainder of treatment. Concentrations in the qw group of the 52-week study were similar from weeks 20 to 68 in the open-label extension study.

[0243] Conclusions: Mean functional concentrations of dupilumab in serum were consistent in both studies, suggesting no time-dependent changes in PK during chronic treatment. EXAMPLES

[0244] Pharmacokinetics of Dupilumab in a Phase 3 Confirmatory Study in Adult Patients with Moderate-to-Severe Atopic Dermatitis This example describes pharmacokinetic (PK) data from two Phase 3 studies performed to evaluate the efficacy and safety of dupilumab monotherapy in adults with moderate to severe atopic dermatitis.

[0245] Methods: The study was a multicenter, randomized, double-blind, placebo-controlled study of subcutaneous dupilumab in 1379 adult patients; each duration was 16 weeks (NCT02277743 and NCT02277769). Patients were randomized 1:1:1 to placebo, dupilumab 300 mg once weekly (qw), and dupilumab 300 mg once every 2 weeks (q2w); patients randomized to dupilumab received a 600 mg loading dose. Here we provide functional dupilumab concentrations measured in serum from blood samples at various pharmacokinetic timepoints and analyzed using descriptive statistics.

[0246] Results: Mean functional concentrations of dupilumab in serum increased from week 2 to week 16, reaching approximately 75 mg / L and 180 mg / L in the dupilumab 300 q2w and dupilumab 300 qw treatment groups, respectively, with a ratio (qw:q2w) of 2.4 at week 16. Mean C trough From the values, the C of dupilumab trough C values ​​indicated steady state at weeks 12 to 16 for both dose regimens. The 600 mg loading dose allowed for a rapid approach to steady state with the q2w dose, and C values ​​at week 12 trough Approximately 80% of patients with qw dosing achieved C at week 12 by week 4. trough Approximately 67% of patients achieved this by the fourth week.

[0247] Conclusions: The pharmacokinetic profile of dupilumab in the phase 3 study was consistent with earlier phase clinical studies, with C trough The ratios were close to the equivalent doses for the q2w and qw regimens studied. EXAMPLES

[0248] Effect of dupilumab on the pharmacokinetics of cytochrome P450 substrates in adult patients with moderate to severe atopic dermatitis: An open-label phase I study This study evaluated the effect of dupilumab on the PK of five CYP isoform-specific substrates, as well as the safety and efficacy of dupilumab in an open-label Phase 1 trial (NCT02647086).

[0249] METHODS:Adults with moderate to severe AD received an oral cocktail consisting of midazolam, omeprazole, S-warfarin, caffeine, and metoprolol (metabolized by CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, respectively) on days 1 and 36. Dupilumab was administered subcutaneously on day 8 as a loading dose of 600 mg, followed by weekly doses of 300 mg on days 15 to 50. PK parameters included AUC measured on days 1 and 36. last (area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration) and C max The geometric mean ratio (GMR) of the maximum observed plasma concentration (maximum plasma concentration) was included, while the efficacy evaluation These included changes in Eczema Area and Severity Index (EASI) scores (scale 0-72).

[0250] RESULTS: A total of 14 patients were enrolled in the study (mean EASI score [SD] at baseline = 29.2 [14.2]), of whom 13 completed the study. AUC last and C max Both GMRs and 90% confidence intervals (Table 10) indicate no meaningful effect of dupilumab on the PK of midazolam, omeprazole, S-warfarin, or caffeine. Based on the small increase in metoprolol exposure, blockade of IL-4 / IL-13 signaling by dupilumab may have a small numerical effect on CYP2D6 activity that is deemed of little or no clinical relevance. A total of three patients had at least one adverse event (AE); there was one serious AE (systemic inflammatory response syndrome) that led to discontinuation of treatment. Mean EASI (SD) scores decreased by 59.3% (37.6) and 87.2% (13.4) at days 35 and 50, respectively.

[0251] [Table 11]

[0252] Conclusions: This study demonstrated that blockade of IL-4 / IL-13 signaling via IL-4Rα with dupilumab had no meaningful effect on CYP3A, CYP2C19, CYP2C9, CYP1A2, or CYP2D6 activity in adult patients with moderate-to-severe AD. Consistent with previous studies, dupilumab had a tolerable safety profile and provided substantial clinical benefit to patients with AD.

[0253] The present invention is not intended to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of anti-IL-4R antibody for use in a method of treating atopic dermatitis (AD) in subjects with moderate to severe or severe atopic dermatitis (AD), The anti-IL-4R antibody is a human antibody and comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (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. The subjects are those who (i) have a physician-reported comprehensive assessment (IGA) score of 3 or higher at baseline, and (ii) have a body surface area (BSA) affected by AD lesions of at least 10% at baseline. The aforementioned pharmaceutical composition.

2. A method for producing a pharmaceutical product containing an anti-IL-4R antibody for use in a method for treating subjects with moderate to severe or severe AD, A step of obtaining a pharmaceutical composition containing the anti-IL-4R antibody, and A process of filling a delivery device with the pharmaceutical composition to obtain a pharmaceutical product. Includes, The anti-IL-4R antibody is a human antibody and comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (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. The subjects are those who (i) have a physician-reported comprehensive assessment (IGA) score of 3 or higher at baseline, and (ii) have a body surface area (BSA) affected by AD lesions of at least 10% at baseline. The aforementioned method.

3. The use of anti-IL-4R antibodies in the manufacture of pharmaceuticals for treating atopic dermatitis (AD) in subjects with moderate to severe or severe atopic dermatitis (AD), The anti-IL-4R antibody is a human antibody and comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (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. The subjects are those who (i) have a physician-reported comprehensive assessment (IGA) score of 3 or higher at baseline, and (ii) have a body surface area (BSA) affected by AD lesions of at least 10% at baseline. The pharmaceutical product, (a) A single injection dose of 200 mg of the anti-IL-4R antibody or (b) A single injection dose of 300 mg of the anti-IL-4R antibody including, The aforementioned use.

4. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

5. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

6. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the anti-IL-4R antibody is dupilumab.

7. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the subject is resistant to, unresponsive to, insufficiently responsive to, or intolerant to systemic immunosuppressants.

8. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the subject has severe AD, is between 6 and 11 years of age, has a baseline IGA score of 4, and has a disease that is uncontrollable with topical AD therapy.

9. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the subject is 12 years of age or older but under 18 years of age.

10. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the subject is 6 years of age or older but under 12 years of age.

11. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the subject is 18 years of age or older and has severe chronic AD and an eczema area and severity index (EASI) score of 20 or more.

12. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the IL-4R antibody is administered in an initial dose and one or more subsequent secondary doses, the initial dose comprising about 400 mg of the IL-4R antibody and the secondary dose comprising about 200 mg of the IL-4R antibody.

13. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the IL-4R antibody is administered in an initial dose and one or more subsequent secondary doses, the initial dose comprising about 600 mg of the IL-4R antibody and the secondary dose comprising about 300 mg of the IL-4R antibody.

14. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the IL-4R antibody is administered in combination with a second therapeutic agent selected from the group consisting of topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, antibacterial therapeutic agents, and therapeutic agents for obstructive airway diseases.

15. The pharmaceutical composition according to claim 1, or the method according to claim 2, or the use according to claim 3, wherein the anti-IL-4R antibody is administered subcutaneously.

16. The pharmaceutical composition or pharmaceutical product is placed in a syringe, as described in claim 1, the method according to claim 2, or the use described in claim 3.

17. The pharmaceutical composition or pharmaceutical product is placed in a pen-type delivery device, as described in claim 1, or the method according to claim 2, or the use according to claim 3.

18. The pharmaceutical composition or pharmaceutical product described in claim 1, or the method according to claim 2, or the use described in claim 3, wherein the pharmaceutical composition or pharmaceutical product is placed in an auto-injector.