Methods for treating atopic dermatitis by administering IL-4R inhibitor

Abstract

The present invention provides methods for treating moderate to severe or severe atopic dermatitis (AD). The methods of the 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.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980032103.7 (PCT / US2019 / 031801), titled "Methods for Treating Atopic Dermatitis by Administering IL-4R Inhibitors", with a filing date of May 10, 2019.

[0002] This application was filed as a PCT international patent application on May 10, 2019, and claims the priority benefit of U.S. Provisional Application No. 62 / 670,824, filed on May 13, 2018; and U.S. Provisional Application No. 62 / 840,493, filed on April 30, 2019, the entire disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to methods for treating atopic dermatitis. More specifically, the present invention relates to administering an interleukin-4 receptor (IL-4R) inhibitor to a subject in need thereof. Background Art

[0004] Atopic dermatitis (AD) is a chronic / recurrent inflammatory skin disease characterized by intense pruritus (i.e., itching), xerosis (dry skin), and eczematous lesions, which include erythema, infiltration / papule formation, crusted exudate, epidermal exfoliation, and lichenification. It is often associated with other atopic conditions such as allergic rhinitis and asthma. Severe disease can be extremely disabling due to several factors: significant psychological problems, severe insomnia, and impaired quality of life (QOL), resulting in high socioeconomic costs. It is estimated that 2% to 10% of adults are affected by AD (Bieber 2008, N. Engl. J. Med. 358:1483-94).

[0005] The pathophysiology of AD is influenced by the complex interplay between inflammation, environmental factors, genetics, and skin barrier dysfunction.

[0006] AD is the most common inflammatory skin disease in children (Illi et al 2004, J. Allergy Clin. Immunol. 113:925 - 31). The disease typically appears in early childhood and childhood, but it can persist into adulthood or start in adulthood (Kay et al 1994, J. Am. Acad. Dermatol. 30:35 - 9). The disease affects 15 to 30% of children and 2 to 10% of adults in industrialized countries (Bieber 2008, N. Engl. J. Med. 358:1483 - 94). The International Study of Asthma and Allergies in Childhood Phase 1 showed a prevalence of up to 20% in Australia, England, and Scandinavia over a 1 - year period (Williams et al 1999, J. Allergy Clin. Immunol. 103:125 - 38). AD often constitutes the first step in the atopic march (progression from one atopic disease to another). Approximately up to 60% of AD patients have concomitant asthma or allergic rhinitis or food allergy (Hong et al 2012, Envt. Health Toxicol. 27:e2012006).

[0007] The clinical pattern of AD varies with age. Infants typically present with erythematous papules and vesicles on the cheeks, forehead, or scalp, which are exudative and very itchy. The childhood phase usually occurs from 2 years of age to puberty. Children are less likely to have the exudative lesions of infants and instead present with more lichenified papules and plaques, which are a more chronic disease involving the hands, feet, wrists, ankles, and the antecubital and popliteal areas. The adult phase of AD begins at puberty and often persists into adulthood. The main areas involved include the flexural folds, face and neck, upper arms and back, and the dorsum of the hands, feet, fingers, and toes. The rash is characterized by dry, scaling erythematous papules and plaques, and large lichenified plaques formed from chronic lesions.

[0008] The disease has been shown to have a significant impact on the quality of life (QOL) of patients, greater than that seen in other common skin diseases such as psoriasis and acne (Lewis-Jones et al 1995, Brit. J. Dermatol. 132:942-9). Usually severe pruritus is a common finding in AD and often results in sleep disruption, irritability, and general stress in affected patients as well as family members (Kim et al 2012, J. Kor. Med. Sci. 27:1327-32). In addition to causing discomfort, sleep loss, and psychosocial challenges, AD can impose a major economic burden on families due to direct medical care, home accommodation, and lost work (Su et al 1997, Arch. Dis. Child. 76:159-62; Verboom et al 2002, Brit. J. Dermatol. 147:716-24; Williams 2005, New Engl. J. Med. 352:2314-24).

[0009] Current treatment options for pediatric patients such as topical steroid creams can cause skin abrasions and ruptures. Non-pharmacological control of AD, including environmental control measures (e.g., avoidance of antigens and skin irritants) and skin care measures (e.g., maintaining skin hydration by using emollients), plays a supportive role especially in children with moderate to severe disease. Pharmacological control of AD in children is mainly limited to topical treatment with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Topical corticosteroids reduce inflammation and pruritus and can be used to control acute flares. However, due to the risks of irreversible skin atrophy, abnormal pigmentation, acneiform eruptions, and risks associated with systemic absorption (e.g., growth retardation, hypothalamic-pituitary axis effects, etc.), long-term use of TCS is not recommended in children. Topical calcineurin inhibitors, such as tacrolimus and pimecrolimus, are also used in AD many times as an alternative to TCS or in combination with TCS. However, the use of TCI is often associated with skin irritation. In addition, it has been noted that TCI may increase the risk of malignancies (lymphoma and skin cancer) (see US prescribing information for the product).

[0010] To date, the only systemic medications approved for the treatment of pediatric AD are systemic corticosteroids. Other systemic medications are off label (cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil), and lack strong evidence for their use. Oral steroids and non-steroidal immunosuppressants may compromise the patient's health in later life. All of these systemic medications have significant side effects, including stunted growth, diabetes, hypertension, osteoporosis (corticosteroids), myelosuppression and hepatotoxicity (methotrexate), nephrotoxicity and hypertension (cyclosporine), and gastrointestinal disturbances and leukopenia (azathioprine). In addition, a high proportion of patients in whom the disease was initially controlled with systemic medications relapse soon after treatment is discontinued (Granlund et al 1995, Br. J. Dermatol. 132:106-112; Schmitt et al 2009, Br. J. Dermatol. 162:661-8).

[0011] Accordingly, there is a high unmet medical need for safe and effective therapies for AD in children. Summary of the Invention

[0013] According to certain aspects of the present invention, there are provided methods for treating, preventing atopic dermatitis (AD) and / or reducing the severity of its symptoms in patients who are ≥12 years old and <18 years old, wherein the atopic dermatitis (AD) includes moderate to severe AD or severe AD, and wherein the patient has a disease that cannot be adequately controlled by topical medications or for whom topical treatment is not advisable (e.g., due to intolerance, adverse side effects, or safety risks). In one embodiment, the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies (e.g., cyclosporine A, methotrexate, azathioprine, oral corticosteroids). In some embodiments, the present invention includes a method of treating a patient who is ≥12 years old and <18 years old and has severe AD, wherein the severe AD is uncontrolled despite treatment with a systemic therapeutic agent. In some embodiments, the present invention includes a method of treating a patient who is ≥12 years old and <18 years old and has severe AD, for whom 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 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 monotherapy. In other embodiments, the IL-4R inhibitor is administered in combination with topical treatment (such as topical corticosteroids or topical calcineurin inhibitors). In one embodiment, the IL-4R inhibitor is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R. In one embodiment, the method includes administering a starting dose comprising 400 mg of the IL-4R inhibitor when the patient weighs <60 kg, followed by one or more doses comprising 200 mg of the IL-4R inhibitor. In one embodiment, the method includes administering a starting dose comprising 600 mg of the IL-4R inhibitor when the patient weighs ≥60 kg, followed by one or more doses comprising 300 mg of the IL-4R inhibitor.

[0014] According to certain aspects of the present invention, there are provided methods for treating, preventing atopic dermatitis (AD) and / or reducing the severity of its symptoms in patients aged ≥6 years and <12 years, wherein the atopic dermatitis (AD) includes moderate to severe AD or severe AD, and wherein the patient has a disease that cannot be adequately controlled by topical medications or for which topical treatment is not advisable (e.g., due to intolerance, adverse side effects, or safety risks). In one embodiment, the patient has a history of moderate to severe AD and inadequate response, intolerance, or contraindications to systemic therapies (such as cyclosporine A, methotrexate, azathioprine, etc.). In some embodiments, the present invention includes methods for treating patients aged ≥6 years and <12 years with severe AD that remains uncontrolled despite treatment with systemic therapeutic agents. In some embodiments, the present invention includes methods for treating patients aged ≥6 years and <12 years with severe AD for whom treatment with systemic therapeutic agents (such as systemic immunosuppressants) is medically inadvisable. The methods of the present invention include administering to a subject or 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 a topical therapy (such as a topical corticosteroid or a topical calcineurin inhibitor). In one embodiment, the IL-4R inhibitor is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

[0015] In certain embodiments, the present invention includes methods for treating moderate to severe AD or improving at least one AD-related parameter in patients aged 6 to 18 years, the methods comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that binds to IL-4R, and determining an improvement in the AD-related parameter. In one embodiment, the patient has a history of moderate to severe AD and inadequate response, intolerance, or contraindications to systemic treatment (such as cyclosporine A, methotrexate, azathioprine, etc.). In certain embodiments, administration of the IL-4R inhibitor results in an improvement in one or more AD-related parameters selected from: Investigator's Global Assessment (IGA); body surface area (BSA) involved in atopic dermatitis; Eczema Area and Severity Index (EASI); SCORing Atopic Dermatitis (SCORAD); 5-D Pruritus Scale; and Numerical Rating Scale for Pruritus (NRS), as described elsewhere herein. In certain embodiments, administration of the IL-4R inhibitor results in an improvement in at least one patient-related outcome selected from Global Individual Signs Score (GISS), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS) as evaluated by the patient, and Dermatology Life Quality Index (DLQI) reported by the patient, as described elsewhere herein.

[0016] According to certain aspects, the present invention provides a method for treating a patient with moderate to severe AD, for reducing pruritus, or for improving at least one AD-related parameter in a patient with moderate to severe AD, wherein the patient has a disease that cannot be adequately controlled by topical medications or for which topical treatment is not advisable (e.g., due to intolerance, adverse side effects, or safety risks). In one embodiment, the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies (such as cyclosporine A, methotrexate, azathioprine, oral corticosteroids). In one embodiment, the patient has an attribute selected from the following or is selected based on an attribute selected from the following: (i) the patient has a baseline IGA score = 4; (ii) the patient has a baseline IGA score ≥ 3; (iii) the patient is ≥ 12 years old and < 18 years old; (iv) the patient weighs < 60 kg; (v) the patient weighs ≥ 60 kg; (vi) the patient is a candidate for systemic therapy; (vii) the patient has a disease that cannot be controlled by topical AD treatment; (viii) the patient has a documented history of inadequate response to topical AD treatment, or topical treatment is not advisable for the patient due to adverse side effects or safety risks; (ix) the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic treatment; (x) the patient has been previously treated with a drug or method selected from topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, skin therapeutic agents, systemic glucocorticoids, non-steroidal systemic immunosuppressants, cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil, ultraviolet (UV) light therapy, and phototherapy; and (xi) the patient has a comorbid disease or disorder selected from food allergy, asthma, seasonal allergy, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, house dust allergy, urticaria, and eosinophilic esophagitis. The method according to this aspect comprises administering to a patient in need thereof one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R inhibitor. In certain embodiments, the administration results in one or more of the following effects: (a) the EASI score is reduced by more than 60% from baseline; (b) the pruritus NRS is reduced by more than 35% from baseline from the time of administration of the first dose to week 4; (c) the pruritus NRS is reduced by ≥ 4 points from baseline as early as week 3 after administration of the first dose; (d) the patient achieves an IGA of 0 or 1 ("clearance" or "almost clearance"), with a reduction of ≥ 2 points from baseline on the IGA scale of 0 to 4; (e) the patient's quality of life is improved. In certain embodiments, the IL-4R inhibitor is administered as monotherapy. In other embodiments, the IL-4R inhibitor is administered in combination with a topical therapy (such as a topical corticosteroid or a topical calcineurin inhibitor).In one embodiment, the method includes administering a starting dose of an IL-4R inhibitor comprising 400 mg when the patient weighs <60 kg, followed by administering one or more doses of an IL-4R inhibitor comprising 200 mg. In one embodiment, the method includes administering a starting dose of an IL-4R inhibitor comprising 600 mg when the patient weighs ≥60 kg, followed by administering one or more doses of an IL-4R inhibitor comprising 300 mg.

[0017] In certain embodiments, the present invention includes a method of reducing dependence on topical corticosteroids (TCS) in a patient with moderate to severe AD, wherein the patient is 6 to 18 years old, and wherein the patient has a disease that cannot be adequately controlled by topical medications or for which topical treatment is not advisable (e.g., due to intolerance, adverse side effects, or safety risks), or the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies (e.g., cyclosporine A, methotrexate, azathioprine, etc.), the method including administering to a subject in need thereof one or more doses of an IL-4R inhibitor. In certain further embodiments, a moderately potent or highly potent TCS is administered in parallel with the IL-4R inhibitor. In another embodiment, after administering the first dose of the IL-4R inhibitor, the amount of TCS is gradually reduced by at least 20%, at least 30%, at least 40%, or at least 50%. In one embodiment, the method includes administering a starting dose of an IL-4R inhibitor comprising 400 mg when the patient weighs <60 kg, followed by administering one or more doses of an IL-4R inhibitor comprising 200 mg. In one embodiment, the method includes administering a starting dose of an IL-4R inhibitor comprising 600 mg when the patient weighs ≥60 kg, followed by administering one or more doses of an IL-4R inhibitor comprising 300 mg.

[0018] According to certain aspects, the present invention includes a method of reducing flares or AD exacerbations, the method including selecting a patient with moderate to severe or severe AD, wherein the patient is 6 to 18 years old, and wherein the patient has a disease that cannot be adequately controlled by topical medications or for which topical treatment is not advisable (e.g., due to intolerance, adverse side effects, or safety risks), or the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies (e.g., cyclosporine A, methotrexate, azathioprine, etc.); and administering to a patient in need thereof one or more doses of an IL-4R inhibitor. In certain embodiments, the patient has refractory AD or has relapsed after treatment with a systemic therapeutic agent (e.g., a systemic immunosuppressant).

[0019] According to certain aspects, the present invention includes methods of treating AD or reducing pruritus or improving AD-related parameters, the methods comprising: selecting a patient with moderate to severe or severe AD, wherein the patient is 6 to 18 years old and has previously been treated with an IL-4R inhibitor (such as an anti-IL-4R antibody, such as Dupilumab) more than 5 weeks ago, more than 8 weeks ago, more than 13 weeks ago, or more than 20 weeks ago; and re-treating the patient in need thereof with one or more doses of an IL-4R inhibitor, wherein the re-treatment results in a reduction in the EASI score of more than 70% from baseline, a reduction in the pruritus NRS of more than 50% from baseline, a reduction in the pruritus NRS of ≥4 points from baseline, and / or a reduction in the NRS on the IGA scale of ≥2 points from baseline. 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.

[0020] According to certain embodiments, the methods of the present invention comprise administering to a subject in need thereof one or more doses of an IL-4R inhibitor. In certain embodiments, the methods of the present invention comprise administering as a starting dose from about 10 mg to about 600 mg of an IL-4R inhibitor, followed by one or more second doses, each second dose comprising 25 to 400 mg of an IL-4R inhibitor. In certain embodiments, the starting dose and the one or more second doses each comprise from about 10 mg to about 600 mg of an IL-4R inhibitor. In certain embodiments, the IL-4R inhibitor is administered as a starting dose of 600 mg, followed by one or more second doses, wherein each second dose comprises 300 mg. According to this aspect of the present invention, the IL-4R inhibitor can be administered to the subject at a dosing frequency of, for example, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In one embodiment, each second dose is administered 1 week after the immediately preceding dose. In one embodiment, each second dose is administered 2 weeks after the preceding dose. In one embodiment, each second dose is administered 4 weeks after the preceding dose. In certain embodiments, the methods of the present invention comprise administering to a subject in need thereof an IL-4R inhibitor, wherein the IL-4R inhibitor comprises about 1 - 10 mg / kg of the subject's body weight. In certain embodiments, one or more doses of an IL-4R inhibitor are administered to a subject in need thereof, wherein each dose comprises 1, 2, 4, 5, or 10 mg / kg of the subject's body weight, and wherein each dose is administered 1 - 4 weeks after the immediately preceding dose.

[0021] In certain embodiments, the present invention includes a method for treating moderate to severe atopic dermatitis (AD) or improving AD-related parameters, the method comprising: (a) selecting a patient with moderate to severe AD, wherein the patient has a disease that cannot be adequately controlled with topical AD medications or for whom topical treatment is medically inadvisable, and wherein the patient is ≥12 years old and <18 years old, and / or the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies (such as cyclosporine A, methotrexate, azathioprine, etc.); and (b) administering to the patient in need thereof a starting dose, followed by one or more second doses of a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor; wherein if the patient weighs <60 kg, the starting dose comprises 400 mg, and each second dose comprises 200 mg of the IL-4R inhibitor.

[0022] In certain embodiments, the present invention includes a method for treating moderate to severe atopic dermatitis (AD) or improving AD-related parameters, the method comprising: (a) selecting a patient with moderate to severe AD, wherein the patient has a disease that cannot be adequately controlled with topical AD medications or for whom topical treatment is medically inadvisable, and wherein the patient is ≥12 years old and <18 years old, and / or the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindications to systemic therapies; and (b) administering to the patient in need thereof a starting dose, followed by one or more second doses of a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor; wherein if the patient weighs ≥60 kg, the starting dose comprises 600 mg, and each second dose comprises 300 mg of the IL-4R inhibitor.

[0023] Exemplary IL-4R inhibitors useful in the methods of the present invention include, for example, small molecule 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 (such as an antibody or an antigen-binding fragment thereof) that binds to the IL-4R α-chain and blocks the signaling of 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 the complementarity determining regions (CDRs) 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 SEQ ID NO: 3, an HCDR2 having the amino acid sequence SEQ ID NO: 4, an HCDR3 having the amino acid sequence SEQ ID NO: 5, a light chain CDR (LCDR1) having the amino acid sequence SEQ ID NO: 6, an LCDR2 having the amino acid sequence SEQ ID NO: 7, and an LCDR3 having the amino acid sequence SEQ ID NO: 8. One such antigen-binding protein useful in the methods of the present invention is an anti-IL-4Rα antibody, such as dupilumab.

[0024] In some embodiments, the IL-4R inhibitor is administered subcutaneously, intravenously, or intraperitoneally to a subject. In one embodiment, the IL-4R inhibitor is contained in a container selected from vials, syringes, prefilled syringes, autoinjectors, and microinfusers. In one embodiment, the IL-4R inhibitor is contained in a prefilled syringe. In one embodiment, the prefilled syringe is a single-dose prefilled syringe. In one embodiment, the IL-4R inhibitor is contained in an autoinjector. In one example, the autoinjector includes a prefilled syringe. In one embodiment, the volume of the IL-4R inhibitor is 1.15 mL. In one embodiment, the volume of the IL-4R inhibitor is 2.25 mL.

[0025] In certain embodiments, the present invention provides the use of an IL-4R inhibitor of the present invention in the preparation of a medicament for treating moderate to severe or severe AD or reducing pruritus in patients aged 6 to 18 years, wherein the patient has a disease that cannot be controlled by topical therapy or for whom topical therapy is medically inadvisable (e.g., due to intolerance, other significant side effects or safety risks). In certain embodiments, the patient is resistant or intolerant to systemic therapy, or for whom systemic therapy is inadvisable due to safety and health risks associated with suboptimal efficacy. In certain embodiments, the present invention provides the use of an IL-4R inhibitor of the present invention in the preparation of a medicament for reducing dependence on topical corticosteroids in patients with moderate to severe AD. In certain embodiments, the present invention provides the use of an IL-4R inhibitor in a method for treating moderate to severe AD or reducing pruritus in patients with moderate to severe AD, wherein the IL-4R inhibitor is administered to a subject in need thereof, and wherein the patient has a disease that cannot be controlled by topical therapy or for whom topical therapy is medically inadvisable (e.g., due to intolerance, other significant side effects or safety risks), and / or the patient has moderate to severe AD and an inadequate response, intolerance or contraindication history to systemic therapy (e.g., cyclosporine A, methotrexate, azathioprine, etc.). In certain embodiments, the present invention provides the use of an IL-4R inhibitor in a method for reducing dependence on topical corticosteroids in a subject with moderate to severe AD, wherein the IL-4R inhibitor is administered to a subject in need thereof. In one embodiment, the patient is ≥12 years to <18 years of age and weighs <60 kg. In one embodiment, the patient is ≥12 to <18 years of age and weighs ≥60 kg. In one embodiment, one or more doses of an IL-4R inhibitor are administered to the patient, wherein each dose comprises 50 - 600 mg of the IL-4R inhibitor. In one embodiment, the method comprises administering a starting dose of 400 mg of the IL-4R inhibitor to a patient who is ≥12 years to <18 years of age and weighs <160 kg, followed by one or more doses comprising 200 mg of the IL-4R inhibitor. In one embodiment, the IL-4R inhibitor is an antibody that binds to IL-4R or an antigen-binding fragment thereof. In one embodiment, the anti-IL-4R antibody comprises the HCVR / LCVR of SEQ ID NO: 1 / 2.

[0026] Other embodiments of the present invention will become apparent by reading the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0028] Before describing the present invention, it is to be understood that the invention is not limited to the specific 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, since the scope of the invention is limited only by the appended claims.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. When referring to a specifically recited numerical value, as used herein, the term "about" means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.). As used herein, the term "treat" and the like refer to alleviating symptoms, temporarily or permanently eliminating the cause of the symptoms, or preventing or slowing the onset of the symptoms of the disorder or condition described.

[0030] Although any methods and materials similar or equivalent to those described herein can be used to practice the present invention, the preferred methods and materials are now described. The entire contents of all publications mentioned herein are incorporated herein by reference.

[0031] Methods for treating moderate to severe atopic dermatitis in adolescents and children

[0032] The present invention includes methods that comprise administering to a subject in need thereof a therapeutic composition comprising an IL-4R inhibitor. As used herein, the expression "subject in need thereof" refers to a human or non-human animal that displays one or more symptoms or indicia of atopic dermatitis and / or has been diagnosed with atopic dermatitis.

[0033] As used herein, "atopic dermatitis" (AD) refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly and dry eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergy (e.g., allergy to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. The present invention encompasses methods for treating patients with moderate to severe or severe AD. As used herein, "moderate to severe AD" is characterized by widespread skin lesions with intense pruritus, which are typically complicated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. In many cases, chronic lesions include plaques with thickened skin, lichenification, and fibrotic papules. Patients with moderate to severe AD also typically have more than 20% of their body skin affected, or 10% of their skin area affected in addition to involvement of the eyes, hands, and body folds. Moderate to severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids. A patient may also be considered to have moderate to severe AD when the patient is resistant or refractory to treatment with topical corticosteroids or calcineurin inhibitors.

[0034] In certain preferred embodiments, the term "subject in need thereof" refers to a patient having moderate to severe AD, wherein the patient is ≥12 years old and <18 years old (adolescent). In other preferred embodiments, the term "subject in need thereof" refers to a patient having moderate to severe AD, wherein the patient is ≥6 years old and <12 years old (child). As used herein, "moderate to severe AD" refers to chronic relapsing AD that is refractory / intractable to treatment with mid- and high-potency TCS and / or immunosuppressive therapies. Moderate to severe AD is also characterized by chronic, intense pruritic lesions affecting more than 20% of the body surface area. In certain embodiments, the term refers to chronic AD according to the Eichenfield criteria (Eichenfield et al 2014, J. Am. Acad. Dermatol. 70:338-351) for which potent topical corticosteroid (TCS) treatment is indicated. In certain embodiments, the term includes chronic AD patients who are treated frequently with topical corticosteroids and / or have had prior treatment with systemic therapeutic agents and / or may be resistant to systemic corticosteroid and / or non-steroidal immunosuppressive therapies. Patients with moderate to severe AD may also exhibit frequent exacerbations or flares of the disease. In certain embodiments, the term "moderate to severe AD" refers to patients with an Investigator's Global Assessment (IGA) score ≥3. In certain embodiments, the term "subject in need thereof" includes patients 6 to 18 years old who do not show improvement in one or more AD-related parameters after treatment with topical therapies including topical corticosteroids or topical calcineurin inhibitors. Examples of AD-related parameters are described elsewhere herein. For example, treatment with topical therapies may result in no reduction in pruritus or Eczema Area and Severity Index (EASI) score or Body Surface Area (BSA) score. In some embodiments, the term refers to moderate to severe AD patients who have been treated with topical and / or systemic therapeutic agents but have relapsed and / or show increased AD exacerbations or flares. In certain embodiments, the term refers to moderate to severe or severe AD patients 6 to 18 years old for whom topical therapy is undesirable due to safety and health risks to the patient and suboptimal efficacy. In some embodiments, the present invention includes methods of treating moderate to severe AD or severe AD in patients who have been previously treated with systemic therapeutic agents for ≥1 month and do not show a reduction in one or more AD-related parameters. For example, the methods of the present invention can be used to treat patients with chronic relapsing AD who have been treated with systemic therapeutic agents and have a Body Surface Area (BSA) score ≥10% or an Investigator's Global Assessment (IGA) score ≥3.

[0035] As used herein, "flare" (also referred to as "exacerbation") refers to an increase in signs and / or symptoms that leads to an escalation of treatment, which can be an increase in the dose of an immunosuppressive agent (e.g., cyclosporine A), a switch to a more potent class of TCS, or the initiation of another oral immunosuppressive drug. In certain embodiments, the present invention includes methods of reducing the number of flares or exacerbations in patients with severe AD, the methods comprising administering to a patient in need thereof a therapeutically effective amount of an IL-4R inhibitor.

[0036] In certain embodiments, the term "subject in need thereof" includes patients 6 to 18 years of age who have received prior treatment with a systemic therapeutic agent and who have moderate to severe or severe AD. As used herein, the term "systemic treatment" refers to a therapeutic agent administered systemically (e.g., a corticosteroid administered orally). The term includes systemic immunosuppressive agents or immunomodulators. In the context of the present invention, the term "systemic immunosuppressive agent" includes, but is not limited to, cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, and interferon-γ. In certain embodiments, the term also includes immunobiologics, such as tumor necrosis factor α (TNFα) inhibitors (e.g., anti-TNFα antibodies, such as infliximab), CD11a inhibitors (e.g., anti-CD11a antibodies, such as efalizumab), IgE inhibitors (e.g., omalizumab), CD20 inhibitors (e.g., rituximab). Systemic therapies that include systemic immunosuppressive agents can be used for short-term treatment of flares or as a temporary measure to control the disease, but their 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 immunosuppressive agents also carries the risk of a rebound phenomenon, in which the symptoms of the disease may significantly worsen after treatment is discontinued. In certain embodiments, the terms "systemic treatment", "systemic therapeutic agent", and "systemic immunosuppressive agent" are used interchangeably in this disclosure.

[0037] In certain embodiments, the term "subject in need thereof" includes patients (adolescents or children) with moderate to severe or severe AD who have been administered one or more TCS for more than 6 months, more than 1 year, more than 2 years, more than 5 years, more than 7 years, or more than about 10 years, optionally with regular immunosuppressant therapy. In certain embodiments, the term "subject in need thereof" includes patients with moderate to severe or severe AD who have previously been treated with therapeutic agents selected from cyclosporin A, IgE inhibitors, TNFα inhibitors, CD11a inhibitors, CD20 inhibitors, IL-4R inhibitors (e.g., anti-IL-4R antibodies such as dupilumab), antibiotics, systemic immunosuppressants, topical corticosteroids, oral corticosteroids, calcineurin inhibitors, and phototherapy. The patient may wish to minimize or avoid the adverse side effects of TCS and / or immunosuppressants. The present invention includes methods of treating moderate to severe or severe AD in a patient, the method comprising co-administering an IL-4R inhibitor in parallel with TCS, wherein the doses are adjusted to minimize or prevent the adverse side effects of TCS. In certain embodiments, the present invention includes methods of reducing the dependence of a patient with moderate to severe or severe AD on TCS; the method comprising co-administering a therapeutically effective amount of an IL-4R inhibitor in parallel with a potent TCS, wherein the amount of TCS used by the patient is reduced by about 50% compared to a patient not administered the IL-4R inhibitor. In certain embodiments, the present invention includes methods of reducing the dependence of a patient with moderate to severe or severe AD on TCS; the method comprising co-administering a therapeutically effective amount of an IL-4R inhibitor in parallel with a potent TCS, wherein 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 the IL-4R inhibitor. In certain embodiments, the co-administration of an IL-4R inhibitor and TCS produces additive or synergistic activity in the treatment of AD compared to monotherapy.

[0038] As used herein, the term "TCS" includes Class I, II, III, and IV topical corticosteroids. Corticosteroids are classified as weak (Class I), intermediate (Class II), potent (Class III), and very potent (Class IV) based on their activity compared to hydrocortisone according to the World Health Organization's Anatomical Therapeutic Chemical Classification System. Class IV TCS (very potent) are up to 600 times as potent as hydrocortisone and include clobetasol propionate and halcinonide. Class III TCS (potent) are 50 to 100 times as potent as hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Class II TCS (intermediate) are 2 to 25 times as potent as hydrocortisone and include, but are not limited to, clobetasone butyrate and Triamcinolone acetonide. Class I TCS (mild) includes hydrocortisone.

[0039] Patients with moderate to severe AD or severe AD are often prescribed intermediate- or high-potency TCS for the treatment of AD. Such treatment can, for example, last for more than 2 months, more than 3 months, more than 4 months, more than 5 months or more than 6 months. It is known in the prior art that TCS treatment causes adverse side effects. In some aspects, the present invention includes methods for reducing the use of or dependence on TCS and / or reducing the adverse side effects of TCS in patients with severe AD, the methods comprising administering to a patient in need thereof one or more doses of an IL-4R inhibitor. In certain embodiments, the IL-4R inhibitor is administered in combination with an intermediate- or high-potency TCS, wherein the amount of TCS administered is gradually reduced such that the patient's severe AD is treated and / or one or more AD-related parameters are significantly improved, and the side effects and toxicity caused by TCS are minimized or prevented. In certain embodiments, the present invention includes methods for reducing or eliminating the rebound risk upon reduction or discontinuation of TCS or immunosuppressants, the methods comprising selecting patients with severe AD that cannot be controlled by background therapy and administering to a patient in need thereof one or more doses of an IL-4R inhibitor. In certain other embodiments, the patient initially receives one or more doses of an IL-4R inhibitor administered in combination with background therapy administered in parallel; then, the background therapy is gradually reduced. In certain embodiments, the background therapy includes therapeutic agents selected from TCS, calcineurin inhibitors, systemic immunosuppressants, and emollients. In one embodiment, the patient with severe AD has been previously treated with a systemic immunosuppressant, wherein the systemic immunosuppressant is cyclosporin 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 patients not administered an IL-4R inhibitor.

[0040] The present invention includes methods for treating moderate to severe AD by improving one or more atopic dermatitis (AD)-related parameters in a subject in need thereof, wherein the methods comprise selecting a patient with moderate to severe AD, wherein the patient is 6 to 18 years old, and wherein the patient has a disease that cannot be adequately controlled by topical therapy or for whom topical therapy is not advisable; and administering to the subject one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R inhibitor. In one embodiment, the pharmaceutical composition comprising the IL-4R inhibitor is administered in combination with a high-potency TCS.

[0041] Examples of "AD-related parameters" include: (a) Investigator's Global Assessment (IGA); (b) Body Surface Area (BSA) involved in atopic dermatitis; (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D itch scale; and (f) Numerical Rating Scale for Itch (NRS). "Improvement of AD-related parameters" means a decrease in one or more of IGA, BSA, EASI, SCORAD, 5-D itch scale, or NRS from baseline. As used herein, the term "baseline" with respect to an AD-related parameter refers to the value of the AD-related parameter of a subject before or at the time of administration of the pharmaceutical composition of the present invention.

[0042] To determine whether an AD-related parameter has "improved", the parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present invention. For example, it can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85 after the start of treatment with the pharmaceutical composition of the present invention; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer. The difference between the parameter value at a specific time point after the start of treatment and the baseline parameter value is used to determine whether the AD-related parameter has "improved" (e.g., decreased). AD-related parameters are described in U.S. Patent Publication No. US20140072583, which is hereby incorporated by reference in its entirety. In the context of the present invention, "subjects in need thereof" can include, for example, subjects who show (or have shown) one or more AD-related parameters, such as elevated IGA, BSA, EASI, SCORAD, 5D-itch, and / or NRS scores, before treatment. For example, the methods of the present invention include administering an IL-4R inhibitor to a patient having an IGA ≥ 3 or ≥ 4; or a BSA exceeding 10%.

[0043] According to one aspect, the present invention provides a method for treating moderate to severe or severe AD or reducing itching or improving AD-related parameters, the method comprising: (1) selecting a patient with moderate to severe or severe AD, wherein the patient has an attribute selected from the following: (a) the patient has a documented history of inadequate response or intolerance to topical treatment including topical corticosteroids or topical calcineurin inhibitors; (b) the patient has a baseline peak itching NRS ≥ 4; (c) the patient has a baseline IGA score ≥ 3; (d) the patient has a baseline IGA score = 4; and (e) the patient has a comorbid disease or disorder selected from asthma, allergic rhinitis, food allergy, allergic conjunctivitis, urticaria, allergy to environmental allergens; and (2) administering to the patient in need thereof one or more doses of a therapeutically effective amount of an IL-4R inhibitor. In certain embodiments, the administration of the IL-4R inhibitor results in an effect selected from the following: (i) a reduction in EASI of more than 60% from baseline; (ii) a reduction in EASI of approximately 75% from baseline by week 2 after administration of the first dose of the IL-4R inhibitor; (iii) a reduction in itching NRS of more than 45% from baseline by week 16 after administration of the first dose of the IL-4R inhibitor; (iv) an improvement in peak itching NRS of ≥ 4 points by week 2 after administration of the first dose of the IL-4R inhibitor; (v) an improvement in the score of IGA by 2 points by week 16 after administration of the first dose of the IL-4R inhibitor; (vi) a reduction in IGA from baseline to an IGA score of 0 or 1 by week 16 after administration of the first dose of the IL-4R inhibitor; (vii) a decrease in the number of flares or exacerbations; (viii) a reduction in the incidence of skin infections; and (vii) an improvement in quality of life as determined by, for example, 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 (such as 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 topical corticosteroids and topical calcineurin inhibitors. In certain embodiments, each dose of the IL-4R inhibitor comprises 50 - 600 mg, and each dose is administered one week or two weeks after the immediately preceding dose. In one embodiment, each dose of the anti-IL-4R antibody comprises 300 mg, wherein each dose is administered once a week or once every two weeks. In certain specific embodiments, the one or more doses comprise a first dose containing 600 mg, followed by one or more second doses, wherein each second dose comprises 300 mg, and wherein each second dose is administered one week or two weeks after the immediately preceding dose.In certain specific embodiments, the one or more doses comprise a first dose containing 400 mg, followed by one or more second doses, wherein each second dose contains 200 mg, and wherein each second dose is administered 1 or 2 weeks after the previous dose. In certain specific embodiments, the one or more doses comprise a first dose containing 600 mg, followed by one or more second doses, wherein each second dose contains 300 mg, and wherein each second dose is administered 4 weeks after the previous dose.

[0044] According to one aspect, the present invention includes a method for treating AD or reducing itching or improving AD-related parameters in patients with moderate to severe or severe AD, wherein the patient has been previously treated with an IL-4R inhibitor (e.g., an anti-IL-4R antibody, such as dupilumab). In certain embodiments, more than 4 weeks ago, more than 8 weeks ago, more than 12 weeks ago, or more than 20 weeks ago, the patient has been previously treated with dupilumab. In certain embodiments, the present invention includes a method for treating moderate to severe or severe AD in a patient, wherein the prior treatment with an IL-4R inhibitor in the patient was discontinued more than 4 weeks ago, more than 8 weeks ago, or more than 12 weeks ago. The method according to this aspect includes retreatment of a patient in need thereof with an IL-4R inhibitor, wherein the retreatment comprises administering one or more doses of an IL-4R inhibitor such that the patient's disease is treated or at least one AD-related parameter is improved. In certain embodiments, the retreatment of the patient results in a reduction of more than 70% in the EASI score from baseline and / or a reduction of more than 50% in the itching NRS score from baseline after administration of the IL-4R inhibitor.

[0045] In certain embodiments, the method of the present invention can be used to treat patients showing an increase in the level of one or more AD-related biomarkers (e.g., IgE). AD-related biomarkers are described in U.S. Patent Publication No. US20140072583, the entire content of which is incorporated herein by reference. For example, the method of the present invention includes administering an IL-4R inhibitor to a patient with an increased level 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 shows (or has shown) an increase in the level of one or more AD-related biomarkers (e.g., IgE and / or TARC) before treatment. In certain embodiments, a "patient in need thereof" can include a subgroup that is more susceptible to AD or can show an increase in the level of AD-related biomarkers.

[0046] According to certain aspects, the present invention includes methods for treating moderate to severe or severe atopic dermatitis (AD) or improving AD-related parameters, the methods comprising: (a) selecting a patient with moderate to severe or severe AD, wherein the patient has an attribute selected from the following: (i) the patient has a baseline IGA score = 4; (ii) the patient has a baseline IGA score ≥ 3; (iii) the patient is between 6 and 18 years of age; (iv) the patient has a disease that cannot be controlled by topical AD treatment; (v) the patient has a documented history of inadequate response to topical AD treatment or for whom topical treatment is not advisable due to adverse side effects or safety risks; (vi) the patient has previously been treated with a drug or method selected from topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, skin therapeutic agents, systemic glucocorticoids, non-steroidal systemic immunosuppressants, cyclosporine A, azathioprine, UV (ultraviolet) phototherapy, and photopheresis; and (vii) the patient has a comorbid disease or disorder selected from food allergy, asthma, seasonal allergy, allergic rhinitis, house dust allergy, and allergic conjunctivitis; and (b) administering to the patient in need thereof one or more doses of a therapeutically effective amount of an IL-4R inhibitor. In one embodiment, the patient has moderate to severe AD and a history of inadequate response, intolerance, or contraindication to systemic therapies (e.g., cyclosporine A, methotrexate, azathioprine, etc.). In certain embodiments, administration of the IL-4R inhibitor results in a therapeutic effect selected from the following: (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 to an IGA score of 0 or 1 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 topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, antibacterial therapeutic agents, and therapeutic agents for obstructive airway diseases, lung diseases, and / or allergies.

[0047] Interleukin-4 receptor inhibitor

[0048] The method of the present invention comprises 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 active 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 SEQ ID NO:11. The type 1 IL-4 receptor is a dimer receptor comprising an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimer receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. The type 1 IL-4 receptor interacts with IL-4 and is stimulated by IL-4, while the type 2 IL-4 receptor interacts with both IL-4 and IL-13 and is stimulated by both IL-4 and IL-13. Thus, an IL-4R inhibitor that can be used in the method of the present invention can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or signaling mediated by both IL-4 and IL-13. Accordingly, the IL-4R inhibitor of the present invention can prevent the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0049] Non-limiting examples of classes of IL-4R inhibitors include IL-4 mutant proteins (e.g., pitrakinra), small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-body" (e.g., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4Rα. As used herein, an IL-4R inhibitor also includes an antigen-binding protein that specifically binds IL-4 and / or IL-13.

[0050] Other non-limiting examples of suitable IL-4R inhibitors that can be used in the context of the present disclosure include, for example, pitrakinra (AER-001; BAY-16-9996), Aeroderm (AER-003), and antibodies known and referred to in the art as dupilumab, AMG-317, CBP-201, MEDI9314, and MEDI2045.

[0051] Anti-IL-4Rα antibodies and antigen-binding fragments thereof

[0052] 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. As used herein, the term "antibody" includes an immunoglobulin molecule comprising four polypeptide chains (two heavy (H) chains and two light (L) chains interconnected by disulfide bonds) and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains C H 1, C H 2, and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region. The light chain constant region comprises one domain (C L 1). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged in the following order from the amino-terminus to the carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present invention, the FRs of the anti-IL-4R antibody (or its antigen-binding portion) can be the same as the human germline sequence, or can be naturally or artificially modified. A consensus amino acid sequence can be determined based on the juxtaposition analysis of two or more CDRs.

[0053] As used herein, the term "antibody" also includes antigen-binding fragments of whole antibody molecules. As used herein, terms such as "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc. include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be derived, for example, from whole antibody molecules using any suitable standard techniques (such as proteolytic digestion or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding the variable domains and optionally the constant domains of the antibody). Such DNA is known and / or readily obtainable from, for example, commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and chemically manipulated, or manipulated using molecular biology techniques, for example, to arrange one or more variable and / or constant domains in a suitable configuration, or to introduce codons, generate cysteine residues, modify, add or delete amino acids, etc.

[0054] 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 composed of amino acid residues that mimic antibody hypervariable regions (e.g., isolated complementarity-determining regions (CDRs), such as 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, tetra-bodies, 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.

[0055] An antigen-binding fragment of an antibody will generally comprise at least one variable domain. The variable domain can have any size or amino acid composition and will generally comprise at least one CDR adjacent to or in-frame with one or more framework sequences. In an antigen-binding fragment having a V L domain that binds to a V H domain, the V H and V L domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and comprise V H -V H 、V H -V L or V L -V L dimers. Alternatively, an antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0056] In certain embodiments, an antigen-binding fragment of an antibody can comprise at least one variable domain covalently linked to at least one constant domain. Exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies of the present 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) VH -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 L . In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or can be connected by all or part of a hinge or linker region. The hinge region can contain at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragment of the antibody of the present invention can comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above, wherein the variable and constant domain configurations are non-covalently bound to each other and / or to one or more monomeric VH or VL domains (e.g., via disulfide bonds).

[0057] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies generally will comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a different antigen or a different epitope on the same antigen. Any form of multispecific antibody can be modified using conventional techniques available in the art to be suitable for the antibodies or antigen-binding fragments of the invention. For example, the invention includes methods that comprise using bispecific antibodies, wherein 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 conjugated to a therapeutic moiety. Exemplary bispecific forms that can be used in the context of the invention include, but are not limited to, for example, scFv- or diabody-based bispecific forms, IgG-scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain containing knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual action Fab (DAF)-IgG, and Mab 2 Bispecific forms (for a review of the foregoing forms, see, e.g., Klein et al. 2012, mAbs 4:6, 1-11 and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugations, e.g., where non-natural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0058] The antibodies used in the methods of the invention can be human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the human antibodies of the invention can, for example, in the CDRs and particularly in CDR3, contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0059] The antibodies used in the methods of the present invention can be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced 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 transgenic animals (e.g., mice) of the human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295), or antibodies prepared, expressed, produced or isolated by any other means involving splicing human immunoglobulin gene sequences to 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 the case of using transgenic animals with human Ig sequences, in vivo somatic mutagenesis), and thus, the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that, although derived from and related to human germline VH and VL sequences, may not naturally occur within the antibody germline repertoire of humans in vivo.

[0060] According to certain embodiments, the antibodies used in the methods of the present invention specifically bind to IL-4Rα. The term "specifically binds" and the like refer to an antibody or an antigen-binding fragment thereof forming a relatively stable complex with an antigen under physiological conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. For example, an antibody that "specifically binds" IL-4Rα as used in the context of the present invention includes an antibody having a K D for binding to IL-4Rα or a portion thereof that is 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 in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-4Rα can be cross-reactive with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0061] 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, which comprises a heavy-chain variable region (HCVR), a light-chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing the amino acid sequence of any anti-IL-4R antibody listed in U.S. Patent No. 7,608,693. In certain exemplary embodiments, the anti-IL-4Rα antibody or an antigen-binding fragment thereof that can be used in the methods of the present invention includes: a heavy-chain complementarity-determining region (HCDR) containing a heavy-chain variable region (HCVR) with the amino acid sequence of SEQ ID NO:1 and a light-chain complementarity-determining region (LCDR) containing a light-chain variable region (LCVR) with the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or an 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. In some embodiments, the anti-IL-4R antibody or an antigen-binding fragment thereof includes: a HCVR containing SEQ ID NO:1 and a LCVR containing SEQ ID NO:2. According to certain exemplary embodiments, the methods of the present invention include using an anti-IL-4R antibody or a bioequivalent thereof comprising the amino acid sequence of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 of SEQ ID NO:3-4-5-6-7-8. In certain embodiments, the methods of the present invention include using an anti-IL-4R antibody, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises a light chain containing the amino acid sequence of SEQ ID NO:10. An exemplary antibody comprising 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 is a fully human anti-IL-4R antibody known in the art as "dupilumab". According to certain exemplary embodiments, the methods of the present invention include using dupilumab or a bioequivalent thereof. As used herein, the term "bioequivalent" refers to an anti-IL-4R antibody or an IL-4R-binding protein or a fragment thereof, which is a pharmaceutical equivalent or a pharmaceutical alternative and does not show a significant difference in the absorption rate and / or extent compared to the absorption rate and / or extent of dupilumab when administered in a single dose or multiple doses at the same molar dose under similar experimental conditions.In the context of the present invention, the term refers to an antigen-binding protein that binds to IL-4R and has no clinically significant difference from dupilumab in terms of its safety, purity, and / or efficacy.

[0062] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, antibodies known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI9314, CBP-201, or any anti-IL-4Rα antibody listed in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, or U.S. Patent No. 8,877,189, or WO2017 / 211319.

[0063] The anti-IL-4Rα antibodies used in the context of the methods of the present invention can have pH-dependent binding characteristics. For example, compared to neutral pH, the anti-IL-4Rα antibodies used in the methods of the present invention can show reduced binding to IL-4Rα at acidic pH. Alternatively, compared to neutral pH, the anti-IL-4Rα antibodies of the present invention can show enhanced binding to their antigen at acidic pH. The expression "acidic pH" includes pH values less than about 6.2, such as 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" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0064] In certain cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" can be expressed in terms of the ratio of the K D value of the antibody binding to IL-4Rα at acidic pH to the K D value of the antibody binding to IL-4Rα at neutral pH (or vice versa). For example, for the purposes of the present invention, if an antibody or its antigen-binding fragment shows an acidic / neutral K D ratio of about 3.0 or greater, then the antibody or its antigen-binding fragment can be considered to show "reduced binding to IL-4Rα at acidic pH compared to neutral pH". In certain exemplary embodiments, the acidic / neutral K DThe ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

[0065] For example, antibodies with pH-dependent binding characteristics can be obtained by screening an antibody population for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modifying the antigen-binding domain at the amino acid level can produce antibodies with pH-dependent characteristics. For example, antibodies with reduced antigen binding at acidic pH compared to neutral pH can be obtained by replacing one or more amino acids in the antigen-binding domain (e.g., within a CDR) with histidine residues. As used herein, the term "acidic pH" refers to a pH of 6.0 or less.

[0066] Drug Compositions and Administration

[0067] The invention includes methods of administering an IL-4R inhibitor to a patient, wherein the IL-4R inhibitor is contained within a pharmaceutical composition. The pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other materials that provide for appropriate transfer, delivery, tolerance, etc. A wide variety of suitable formulations are found in the pharmacopoeias known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing (cationic or anionic) microcapsules (such as LIPOFECTIN TM )), DNA conjugates, anhydrous absorbent pastes, water-in-oil and oil-in-water emulsions, carbowax (polyethylene glycols of various molecular weights) emulsions, semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0068] The dosage of the antibody administered to a patient according to the method of the present invention can vary depending on the patient's age and body size, symptoms, disease conditions, route of administration, etc. Generally, the dosage is calculated based on body weight or body surface area. Depending on the severity of the disease condition, the frequency and duration of treatment can be adjusted. The effective dosage and regimen for administering a pharmaceutical composition comprising an anti-IL-4R antibody can be determined empirically; for example, the patient's progress can be monitored by regular evaluations and the dosage adjusted accordingly. In addition, interspecies scaling of the dosage can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary dosages of anti-IL-4R antibodies that can be used in the context of the present invention and the administration regimens involving them are disclosed elsewhere herein.

[0069] A variety of delivery systems are known and can be used to administer a pharmaceutical composition comprising an IL-4R inhibitor, such as syringes, prefilled syringes, autoinjectors, microinfusers, glass vials, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.), and can be administered in combination with other bioactive agents.

[0070] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using standard needles and syringes. In one embodiment, the syringe is a prefilled syringe. Such a prefilled syringe can be single-dose. In one embodiment, the pharmaceutical composition of the present invention is delivered subcutaneously or intravenously using an autoinjector, wherein the autoinjector can comprise a prefilled syringe. Additionally, for subcutaneous delivery, a pen delivery device can be readily used to deliver the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device typically utilizes a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition within 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 used again. In a disposable pen delivery device, the cartridge is not replaceable. Instead, the disposable pen delivery device is prefilled with the pharmaceutical composition housed in a reservoir within the device. Once the pharmaceutical composition in the container is emptied, the entire device is discarded.

[0071] A number of reusable syringes, pens, and autoinjector delivery devices can be used for subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include, but are not limited to, AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (NovoNordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM , OPTIPEN PRO TM , OPTIPEN STARLET TM and OPTICLIK TM (Sanofi - Aventis, Frankfurt, Germany), to name just a few. Examples of disposable pen delivery devices that can be used for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR TM pen (Sanofi - Aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA TM Pen (Abbott Labs, Abbott Park IL), to name just a few.

[0072] In certain instances, 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, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In still another embodiment, the controlled release system can be placed near the target of the composition, such that only a fraction of the systemic dose is required (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0073] Injectable formulations can include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, etc. These injectable formulations can be prepared by known methods. For example, an injectable formulation can be prepared, for example, by dissolving, suspending, or emulsifying the above-described antibody or its salt in a sterile aqueous medium or an oily medium conventionally used for injection. As the aqueous medium for injection, there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc., which can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, for example, sesame oil, soybean oil, etc. can be utilized, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injection solution thus prepared can be filled in suitable ampoules.

[0074] Advantageously, the above-described pharmaceutical compositions for oral or parenteral use can be formulated into dosage forms suitable for a unit dose of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0075] Exemplary pharmaceutical compositions comprising an anti-IL-4R antibody that can be used in the context of the present invention are disclosed, for example, in U.S. Patent 8,945,559.

[0076] Administration Regimen

[0077] The present invention includes methods of administering an IL-4R inhibitor to a subject at the following dosing frequencies: about four times per week, twice per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or a lower frequency, so long as a therapeutic response is achieved. In certain embodiments involving the administration of an anti-IL-4R antibody, once-weekly dosing is utilized at an amount of about 25 mg, 50 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments involving the administration of an anti-IL-4R antibody, twice-weekly dosing is utilized at an amount of about 25 mg, 50 mg, 150 mg, 200 mg, or 300 mg. In certain embodiments, a loading dose is administered prior to once-weekly or once-every-two-weeks dosing, wherein the loading dose comprises twice (2X) the amount of antibody administered in subsequent doses.

[0078] In certain embodiments according to the present invention, multiple doses of an IL-4R inhibitor can be administered to a subject over a determined time course. The methods according to this aspect of the present invention include sequentially administering multiple doses of an IL-4R inhibitor to a subject. As used herein, "sequentially administering" refers to administering each dose of an IL-4R inhibitor 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 includes methods comprising sequentially administering a single starting dose of an IL-4R inhibitor to a patient, followed by administering one or more second doses of an IL-4R inhibitor, and optionally then administering one or more third doses of an IL-4R inhibitor.

[0079] The terms "starting dose", "second dose", and "third dose" refer to the chronological order of administration of the IL-4R inhibitor. Thus, the "starting dose" is the dose administered at the start of the treatment regimen (also referred to as the "baseline dose"); the "second dose" is the dose administered after the starting dose; and the "third dose" is the dose administered after the second dose. The starting, second, and third doses may all contain the same amount of the IL-4R inhibitor, but may generally differ from each other in the frequency of administration. However, in certain embodiments, the amounts of the IL-4R inhibitor contained in the starting, second, and / or third doses differ from each other during the course of the treatment (e.g., upregulated or downregulated as needed). In certain embodiments, the starting dose contains a first amount of an antibody or an antigen-binding fragment thereof, and each of one or more second doses contains a second amount of the antibody or an antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or an antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the start of the treatment regimen, followed by subsequent doses at a lower frequency (e.g., a "maintenance dose"). For example, the IL-4R inhibitor may be administered to a patient in need thereof at a loading dose of about 400 mg or about 600 mg, followed by one or more maintenance doses of about 25 mg to about 400 mg. In one embodiment, the starting dose and each of one or more second doses contain from 10 mg to 600 mg of the IL-4R inhibitor, such as from 100 mg to 400 mg of the IL-4R inhibitor, such as 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg of the IL-4R inhibitor.

[0080] In one exemplary embodiment of the invention, each second and / or third dose is administered 1 to 14 (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1Administered in 1 / 2 or more) weekly doses. As used herein, the phrase "immediately preceding dose" refers to the dose of the IL-4R inhibitor administered to a patient prior to the administration of the immediately succeeding dose in the order of multiple administrations, with no dose intervening between the two administrations.

[0081] The method according to this aspect of the invention may comprise administering to a patient any number of second and / or third doses of the IL-4R inhibitor. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0082] In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 6 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Optionally, the frequency of administering the second and / or third doses to the patient may be changed during the course of the regimen.

[0083] According to certain embodiments, the method of the invention comprises administering to a subject a combination of a topical corticosteroid (TCS) and an IL-4R inhibitor (e.g., an IL-4R antibody). As used herein, the expression "in combination with" means that the TCS is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or parallel administration of the IL-4R inhibitor and the TCS.

[0084] For example, when administered "before" the IL-4R inhibitor, TCS 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 the administration of the IL-4R inhibitor. When administered "after" the IL-4R inhibitor, TCS can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the IL-4R inhibitor. Administration "simultaneously" with the IL-4R inhibitor means that TCS is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or simultaneously) of the administration of the IL-4R inhibitor, or as a single combined dose formulation comprising both TCS and the IL-4R inhibitor to the subject.

[0085] Dosage

[0086] The amount of the IL-4R inhibitor (e.g., anti-IL-4R antibody) administered to the 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 the amount of the IL-4R inhibitor that results in one or more of the following: (a) an improvement in one or more AD-related parameters (as mentioned elsewhere herein); and / or (b) a detectable improvement in one or more symptoms or markers of atopic dermatitis. In the context of the present invention, "therapeutically effective amount" includes the amount of the IL-4R inhibitor that results in one or more of the following: (a) a reduction in EASI of at least 60% from baseline; (b) a reduction in pruritus of at least 30%; (c) a reduction in IGA of ≥2 points from baseline; (d) a reduction in NRS of ≥4 points from baseline; (e) a reduction in skin colonization with Staphylococcus aureus; (f) a reduction in the levels of AD-related biomarkers such as IgE or TARC; (g) a reduction in the use of TCS of at least 20%; and / or (h) a reduction in the number of flares or AD exacerbations.

[0087] In the case of an anti-IL-4R antibody, an immunologically effective amount can be from about 0.05 mg to about 600 mg, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg of an 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 a subject.

[0088] The amount of IL-4R inhibitor included within a single dose can be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R inhibitor can be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of subject body weight. Examples

[0089] The following examples are presented in order to provide a complete disclosure and description to those of ordinary skill in the art of how to make and use the methods and compositions of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure the accuracy of the data used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0090] Example 1: Pharmacokinetics, Safety and Efficacy of Dupilumab in the Pediatric Population with Moderate-to-Severe or Severe AD: Results from a Phase 2a Clinical Trial

[0091] This example describes a Phase 2a, multicenter, open-label, escalating-dose, sequential-cohort study (NCT02407756) that included adolescents (12 - 17 years old) with moderate to severe AD and children (6 - 11 years old) with severe AD who could not be controlled by topical medications. Patients received a single subcutaneous dose of dupilumab at 2 mg / kg or 4 mg / kg, were followed up for 8 weeks, and then received a dose of 2 mg / kg or 4 mg / kg four times a week.

[0092] Research Objectives

[0093] The primary objective of this study was to characterize the safety and PK of dupilumab in pediatric patients with moderate to severe AD (for adolescents aged ≥12 years to <18 years) or severe AD (for children aged ≥6 years to <12 years). The secondary objectives of this study were to explore the immunogenicity and efficacy of dupilumab in pediatric patients with moderate to severe AD (for adolescents aged ≥12 years to <18 years) or severe AD (for children aged ≥6 years to <12 years).

[0094] Study Design

[0095] This was conducted as a Phase 2a, multicenter, open-label, escalating-dose, sequential-cohort study to investigate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and efficacy of single and repeated subcutaneous (SC) doses of dupilumab in pediatric patients with moderate to severe AD (for adolescents aged ≥12 years to <18 years) or severe AD (for children aged ≥6 years to <12 years) whose AD was not adequately controlled by topical therapy.

[0096] Two consecutive escalating SC dose cohorts were designed: Dose Cohort 1 (2 mg / kg) and Dose Cohort 2 (4 mg / kg) up to a maximum dose of 300 mg. Within each dose cohort, approximately 36 to 40 patients were planned to be enrolled in two age subgroups: Subgroup A (adolescents aged ≥12 years to <18 years) and Subgroup B (children aged ≥6 years to <12 years). Recruitment and study drug administration started with Cohort 1A (2 mg / kg, adolescent age subgroup) and proceeded sequentially to Cohort 1B (2 mg / kg, children in the age subgroup ≥6 years to <12 years), Cohort 2A (4 mg / kg, adolescent age subgroup), and Cohort 2B (4 mg / kg, children in the age subgroup ≥6 years to <12 years); a safety review of data from the previous cohort was conducted before proceeding to the next cohort.

[0097] The study includes a screening period (days -35 to -1), a baseline visit, Part A (including a single-dose treatment followed by an 8-week semi-intensive PK sampling period), and Part B (including a 4-week repeated-dose treatment period [4 doses per week] followed by an 8-week follow-up period).

[0098] Patients receive concomitant medications (except prohibited medications) as needed while continuing study treatment. The frequency and type of use are recorded. Rescue treatment is provided to study patients if medically necessary. Rescue treatment includes more intensive topical treatment (medication and / or surgery), and then escalates to systemic medications (if medically appropriate). Patients who receive rescue treatment with systemic corticosteroids or systemic non-steroidal immunosuppressive medications (e.g., cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) during Part A (single-dose treatment and 8-week semi-intensive PK sampling period) need to discontinue such rescue treatment at least 2 weeks before the start of Part B (i.e., before starting the administration of repeated-dose study treatment); patients who receive any of these rescue treatments during the repeated-dose treatment period discontinue the study drug.

[0099] Dose Escalation: Drug administration starts with cohort 1A. Once the first 8 patients recruited in cohort 1A have all been observed for at least 2 weeks, completed the safety assessment at week 2 (day 15), and had the data reviewed, the next cohort (1B) is initiated. Once the first 20 patients recruited in cohort 1A and / or 1B have all been observed for at least 2 weeks, completed the safety assessment at week 2 (day 15), and had the data reviewed, drug administration is escalated to cohort 2A. Once the first 8 patients recruited in cohort 2A have all been observed for at least 2 weeks, completed the safety assessment at week 2 (day 15), and had the data reviewed, the next cohort (2B) is initiated.

[0100] Study Population

[0101] The study population includes pediatric patients with moderate to severe AD (for adolescents aged ≥12 years to <18 years at baseline) or severe AD (for children aged ≥6 years to <12 years at baseline) that is not adequately controlled with topical medications.

[0102] Inclusion Criteria:Patients must meet the following criteria to be eligible for inclusion in the study: (1) At baseline, male or female, aged ≥6 years to <18 years; (2) Diagnosis of AD confirmed according to the American Academy of Dermatology criteria (Eichenfield et al 2014, J. Am. Acad. Dermatol. 70:338-51) for at least 1 year prior to screening; (3) The patient has a documented recent medical history (within 6 months prior to the screening visit) as follows: inadequate response to outpatient treatment with adequate topical AD medications, or otherwise topical AD treatment is not advisable for the patient (e.g., due to side effects or safety risks). Note: For the purposes of this disclosure, an inadequate response means failure to achieve and maintain remission or low disease activity (equivalent to Investigator's Global Assessment [IGA] 0 = clear to 2 = mild) despite treatment with a regimen of medium to high potency TCS (±TCI as needed) for at least 28 days. Side effects or safety risks that may outweigh potential treatment benefits include intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and side effects related to systemic absorption. Acceptable documentation includes contemporaneous chart notes documenting TCS prescriptions with or without TCI and treatment outcomes, or investigator records based on communication with the patient's attending physician. If documentation is insufficient, potential patients may be rescreened after the patient has demonstrated failure of medium to high potency TCS (±TCI) for the above-specified treatment duration. (4) Baseline IGA: a. IGA = 3 or 4 in adolescents aged ≥12 years to <18 years; b. IGA = 4 in children aged ≥6 years to <12 years; (5) At baseline, AD lesions affect at least 10% of the body surface area (BSA). Note: This inclusion criterion has been modified from the original criterion to clarify that the BSA affected by AD should be based on the assessment conducted at baseline. (6) Willing and able to comply with clinical visits and study-related procedures; (7) Have a parent / caregiver or legal guardian who can understand the study requirements; (8) The parent or legal guardian must provide a signed informed consent form. Patients aged ≥7 years (or above the age determined by the IRB / IEC and in compliance with local regulations and requirements) must also provide informed consent to participate in the study and must sign and date a separate IAF or ICF; and (9) The parent or legal guardian / patient (as applicable) must be able to understand and complete study-related questionnaires.

[0103] Exclusion Criteria:Patients meeting any of the following criteria were excluded from the study: (1) Treatment with the study drug within 8 weeks prior to the baseline visit or within 5 half-lives (if known), whichever is longer; (2) The following treatments within 2 weeks prior to the baseline visit: a. Systemic corticosteroids, b. Immunosuppressive / immunomodulatory drugs (e.g., cyclosporine, mycophenolate mofetil, interferon-γ, Janus kinase inhibitors, azathioprine, or methotrexate), c. Phototherapy for AD; (3) The following biologic treatments: a. Any cell-depleting agents, including but not limited to rituximab, within 6 months prior to the baseline visit or until lymphocyte return to normal, whichever is longer, b. Other biologic agents within 5 half-lives (if known) or 4 months prior to the baseline visit, whichever is longer; (4) Planned or anticipated use of any prohibited drugs and surgeries during the study treatment; (5) Treatment with live (attenuated) vaccines within 3 months prior to the baseline visit; (6) Active chronic or acute infections requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 4 weeks prior to the baseline visit, or superficial skin infections within 1 week prior to the baseline visit; (7) Known or suspected immunodeficiency, including a history of invasive opportunistic infections despite infection resolution (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), or recurrent infections with an abnormal frequency or prolonged duration otherwise suggestive of an immunocompromised state; (8) A known history of human immunodeficiency virus infection; (9) Active hepatitis B or C infection at screening, or a history of prior active hepatitis B or C infection reported at screening; (10) Persistent (confirmed by repeated testing at intervals ≥2 weeks) elevation of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) above 3 times the upper limit of normal (ULN) during the screening period; (11) At baseline, the presence of any condition listed as a study treatment discontinuation criterion; (12) The presence of skin comorbidities that may interfere with study assessment; (13) A history of malignancy within 5 years prior to the baseline visit, excluding completely treated carcinoma in situ of the cervix and completely treated and resolved non-metastatic cutaneous squamous or basal cell carcinoma; (14) A history of clinical endoparasitosis (i.e., worm infection) within 12 months prior to the baseline visit, or high-risk worm infections, such as residence in or recent travel to an endemic area for endoparasites (within 12 months prior to the baseline visit), where circumstances are consistent with parasite exposure (e.g., long stay, rural or slum area, lack of running water, consumption of uncooked, undercooked, or otherwise contaminated food, close contact with carriers and vectors, etc.), unless subsequent medical evaluation (e.g., fecal examination, blood test, etc.) excludes the possibility of parasite infection / infestation; (15) A history of alcohol or drug abuse within 2 years prior to the screening visit.(16) Serious co-existing diseases that will have an adverse impact on the patient's participation in the study. Examples include, but are not limited to, patients with a short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c ≥ 9%), cardiovascular conditions (e.g., stage III or IV heart failure according to the New York Heart Association classification), severe kidney 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 patients with other severe endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic diseases; (17) Any other medical or psychological condition, including relevant laboratory abnormalities at the time of screening, that suggests a new and / or poorly understood disease and may pose an unreasonable risk to him / her due to the patient's participation in this clinical trial, may render the patient's participation unreliable, or may interfere with the study assessment; (18) Planned major surgery during the patient's participation in this study; (19) The patient is a member of the research team or his / her immediate family; and (20) Female patients who are pregnant, breastfeeding, planning to become pregnant or breastfeed during the study, or female patients of childbearing potential who are unwilling to use appropriate contraception for the entire duration of the study and for 120 days after the last dose of the study drug.

[0104] Study Treatments

[0105] Provide a sterile dupilumab drug product at 150 mg / mL in an aqueous buffer, pH 5.0. It is provided in 5 mL vials containing 2.5 mL (150 mg / mL), and the withdrawable volume is 2.0 mL or 300 mg of dupilumab. The study drug is administered SC by the investigator or other qualified research personnel according to the following dose and dosing schedule:

[0106] ● For dose cohort 1: 2 mg / kg, administered as a single dose on Day 1 in Part A, then as a repeated dose weekly from Day 1 to Week 3 in Part B

[0107] ● For dose cohort 2: 4 mg / kg, administered as a single dose on Day 1 in Part A, then as a repeated dose weekly from Day 1 to Week 3 in Part B

[0108] The subcutaneous injection sites of the study drug are alternated among different areas of the abdomen (avoiding the navel and lumbar regions), the upper thighs, and the upper arms, such that the same site is not injected for two consecutive weeks. To allow for adequate assessment of possible injection site reactions, the study drug is only administered into areas of the skin that appear normal.

[0109] Primary and Secondary Endpoints

[0110] The primary objective was to characterize the PK profile of dupilumab in pediatric AD patients aged ≥6 to <18 years. The secondary endpoints were:

[0111] ● The incidence of TEAE;

[0112] ● The percentage change from baseline in the Eczema Area and Severity Index (EASI);

[0113] ● The percentage change from baseline in the Scoring Atopic Dermatitis (SCORAD) score;

[0114] ● The percentage change from baseline in the Itch Numerical Rating Scale (NRS);

[0115] ● The percentage of patients with an IGA score of 0 or 1;

[0116] ● The change from baseline in the % BSA affected by AD.

[0117] Study Variables and Procedures

[0118] Safety and tolerability were evaluated by vital signs, physical examinations, clinical laboratory tests, and clinical evaluations. Patients were required to monitor all adverse events (AEs) experienced from informed consent until their last study visit. Serum samples were collected for dupilumab level determination, and PK parameters were calculated using dupilumab concentration data. Serum samples were collected for ADA determination and exploratory analysis. During the study, at designated clinical visits, efficacy was evaluated using the Itch NRS, SCORAD, and EASI, which measure the extent and severity of AD, and the IGA, which grades the overall severity of AD.

[0119] Results

[0120] (A) Baseline Disease Characteristics

[0121] This study enrolled adolescent patients aged ≥12 to <18 years with moderate to severe AD (baseline IGA score of 3 or 4) and pediatric patients aged ≥6 to <12 years with severe AD (baseline IGA score of 4; see the inclusion criteria for each age group). Thus, the disease characteristics at baseline were different between the two age groups.

[0122] Adolescent patients aged ≥ 12 years to < 18 years:The proportion of adolescent patients diagnosed with AD within the specified age range was generally similar between dose cohorts, and most patients in each dose cohort were diagnosed before the age of 5 (Table 1). The mean duration of AD was also similar between dose cohorts. As expected, the duration of AD was longer in older age subgroups within each dose cohort compared to younger patients. The mean baseline values for all AD assessments were consistent with moderate to severe AD. The mean EASI score, mean pruritus NRS score, mean BSA, and SCORAD score at baseline were minimally different, consistent with what was expected in the non-randomized group (Table 1). In summary, baseline disease characteristics were comparable between the two dose cohorts.

[0123] Table 1: Overview of baseline disease characteristics in adolescent patients aged ≥12 to <18 years

[0124]

[0125] BSA, body surface area; EASI, eczema area severity index; IGA, investigator global assessment; NRS, numerical rating scale; SAF, safety analysis group; SC, subcutaneous; SCORAD, atopic dermatitis score; SD, standard deviation

[0126] Patients aged ≥ 6 years to < 12 years: The proportion of patients aged ≥6 to <12 years diagnosed with AD within the specified age range was generally similar between dose cohorts, and most patients in each dose cohort were diagnosed before the age of 5 (Table 2). The mean duration of AD was also similar between dose cohorts. As expected, the duration of AD was longer in older age subgroups within each dose cohort compared to younger patients. The mean baseline values for all AD assessments were consistent with severe / moderate AD. The mean EASI score, mean pruritus NRS score, mean BSA, and SCORAD score at baseline were minimally different, consistent with what was expected in the non-randomized group (Table 2). In summary, baseline disease characteristics were comparable between the two dose cohorts.

[0127] Table 2: Overview of baseline disease characteristics in children aged ≥6 to <12 years

[0128]

[0129] BSA, body surface area; EASI, eczema area severity index; IGA, investigator global assessment; NRS, numerical rating scale; SAF, safety analysis group; SC, subcutaneous; SCORAD, atopic dermatitis score; SD, standard deviation (B) Medical History

[0130] The medical history was evaluated using a general questionnaire, and the specific atopic disease history was collected using a targeted questionnaire that elicited a broad atopic history.

[0131] Adolescent patients aged ≥ 12 years to < 18 years:Using a general questionnaire, all adolescent patients (100%) had a history finding of at least 1 year. Overall, the most common non-AD MedDRA PTs reported in ≥30% of 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%). A history of allergic conjunctivitis was present in 11 (27.5%) patients.

[0132] According to the specific atopic disease questionnaire, the proportion of patients with a family history of atopic / allergic disorders was similar between the two dose cohorts. The most common atopic / allergic disorder in the patients' family history was AD (37.5% overall). In the 2 mg / kg dose cohort, the most common atopic / allergic disorder in the patients' family history was AD (50.0%), while in the 4 mg / kg dose cohort, it was other allergy (30.0%). The most common current atopic / allergic disorder other than AD was other allergy (60.0% overall; 55.0% in the 2 mg / kg dose cohort and 65.0% in the 4 mg / kg dose cohort). Overall, 30.0% of all patients showed a current history of allergic conjunctivitis, 37.5% had a current history of asthma, and both were reported in a higher proportion of patients in the 4 mg / kg dose cohort. 5% of all patients had a current resolved atopic / allergic disorder. The most common current resolved atopic / allergic disorder was asthma, which was reported at a similar frequency in both dose cohorts.

[0133] Patients aged ≥ 6 years to < 12 years: Using a general questionnaire, all patients aged ≥6 years to <12 years (100%) had a history finding of at least 1 year. Overall, the most common non-AD MedDRA PTs reported in ≥30% of patients were food allergy (67.6%), allergic rhinitis (51.4%), house dust allergy (48.6%), asthma (43.2%), and seasonal allergy (35.1%). A history of allergic conjunctivitis was present in 9 (24.3%) patients. Generally, the history was similar between the two dose cohorts. Differences between the dose cohorts included that the incidences of food allergy (73.7%, 61.1%), milk allergy (15.8%, 5.6%), and allergic conjunctivitis (31.6%, 16.7%) were higher in the 4 mg / kg dose cohort than in the 2 mg / kg dose cohort, respectively. The incidences of allergy to animals (38.9%, 5.3%), mold allergy (16.7%, 5.3%), and allergic rhinitis (61.1%, 42.1%) were higher in the 2 mg / kg dose cohort than in the 4 mg / kg dose cohort, respectively.

[0134] Based on the specific atopic disease questionnaire, the proportion of patients with a family history of atopic / allergic disorders was higher in the 4 mg / kg dose cohort than in the 2 mg / kg dose cohort. The most common atopic / allergic disorder in the patients' family history was AD (32.4% overall). In the 2 mg / kg dose cohort, the most common atopic / allergic disorder in the patients' family history was allergic rhinitis (33.3%), while in the 4 mg / kg dose cohort, it was AD (36.8%). The most common current atopic / allergic disorders other than AD were other allergies and food allergies (64.9% each overall). The incidence of current food allergy was higher in the 4 mg / kg dose cohort (73.7%) than in the 2 mg / kg dose cohort (55.6%). Overall, 21.6% of all patients showed a history of current allergic conjunctivitis and 43.2% had a history of current asthma, both reported in a higher proportion of patients in the 4 mg / kg dose cohort.

[0135] (C) Previous Medications / Treatments

[0136] Previous medications / treatments were defined as medications taken or treatments performed before the first administration of the study drug.

[0137] Adolescent patients aged ≥ 12 years to < 18 years: All adolescent patients had received at least 1 previous medication. By type of therapeutic agent, the most commonly used (≥50% of all patients) previous medications were corticosteroid dermatological preparations (97.5%), systemic antihistamines (67.5%), and other dermatological preparations (67.5%). Between the 2 dose cohorts, previous medication use was generally similar. Corticosteroid dermatological preparations included potent (class III; 87.5% of patients overall), weak (class I; 35.0% of patients overall), intermediate (class II; 27.5% of patients overall), and very potent (class IV; 12.5% of patients overall). A total of 7 (17.5%) adolescent patients had a history of systemic glucocorticoid use. 13 patients reported previous use of non-steroidal systemic immunosuppressants including cyclosporine and azathioprine. 9 (22.5%) adolescent patients reported at least 1 previous treatment. The most commonly reported previous treatments in >1 patient were ultraviolet (UV) light therapy (7.5% of patients overall) and phototherapy (5.0% of patients overall).

[0138] Patients aged ≥ 6 years to < 12 years:All patients aged ≥6 years to <12 years received at least 1 prior medication. The most commonly used (≥50% of all patients) prior medications by therapeutic class were corticosteroid dermatologic preparations (97.3%), systemic antihistamines (91.9%), emollients and protectants (70.3%), and other dermatologic preparations (70.3%). Prior medication use was generally similar between the 2 dose cohorts. Corticosteroid dermatologic preparations included potent (class III; 83.8% of patients overall), moderately potent (class II; 43.2% of patients overall), weak (class I; 29.7% of patients overall), and very potent (class IV; 10.8%) agents. Eleven (29.7%) patients reported prior systemic glucocorticoid use. Ten patients reported prior use of nonsteroidal systemic immunosuppressants including cyclosporine and azathioprine. Seven (18.9%) patients reported at least 1 prior treatment procedure. Prior treatment procedures reported by >1 patient overall included UV light therapy (10.8% of patients overall) and phototherapy (5.4% of patients overall).

[0139] (D) Concurrent Medications and Treatments

[0140] Adolescent patients aged ≥ 12 years to < 18 years: During the entire study period, most adolescent patients (97.5%) received at least 1 concomitant medication. By therapeutic class, the most commonly used (≥25% of patients overall) concomitant medications during the entire study period were corticosteroid dermatologic preparations (75.0%), systemic antihistamines (67.5%), emollients and protectants (45.0%), other dermatologic preparations (42.5%), and medications for obstructive airway disease (27.5%). Overall, 77.5% of patients used concomitant therapy for AD during the study period, 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 (class III) TCS. Use of TCI 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 using any concomitant AD medication was higher during part A (31 [77.5%]) than during part B (11 [27.5%]). Use of TCS and TCI in adolescents was higher during part A than during part B for both dose cohorts. Systemic corticosteroid use was low and comparable between part A and part B.

[0141] Patients aged ≥ 6 years to < 12 years:During the entire study period, most patients aged ≥6 to <12 years (97.3%) received at least 1 concomitant medication. By type of therapeutic agent, the most commonly used (in ≥25% of patients overall) concomitant medications during the entire study period were systemic antihistamines (89.2%), corticosteroid dermatologic preparations (89.2%), emollients and protectants (75.7%), other dermatologic preparations (48.6%), medications for obstructive airway diseases (which may overlap with asthma as a comorbidity) (40.5%), and systemic antibacterial agents (27.0%). Overall, 91.9% of patients aged ≥6 to <12 years used concomitant AD therapy during the study period, including 88.9% of patients in the 2 mg / kg dose cohort and 94.7% of patients in the 4 mg / kg dose cohort. The use of any TCS was similar between the two dose cohorts, and the most commonly used TCS in both dose cohorts was a potent (class III) TCS. The 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 to <12 years who required any concomitant AD medication was higher during part A (33 [89.2%]) than during part B (10 [27%]). The use of TCS and TCI was higher during part A than during part B for both dose cohorts. In the age group of ≥6 to <12 years, systemic immunosuppressants were not required during either part A or part B.

[0142] (E) Efficacy

[0143] Forty adolescents / 38 children were enrolled (mean eczema area and severity index [EASI] ± SD = 31.7 ± 16.00 / 35.9 ± 17.22); 22.5% of adolescents / 16.2% of children did not respond to ≥1 previous systemic treatment. The pharmacokinetic profile of dupilumab was similar to that in adults (target-mediated drug disposition). No new safety signals were detected compared with adults.

[0144] In the adolescent patient group, dupilumab administered as a single dose of 2 mg / kg or 4 mg / kg induced a significant and rapid reduction in disease activity in patients at week 2 (for the 2 mg / kg and 4 mg / kg doses, the EASI scores decreased by 34% and 51% from baseline, respectively). In both dose cohorts, repeated weekly doses of dupilumab led to further improvement in disease severity in patients. At week 12, in the adolescent 2 mg / 4 mg cohorts, the baseline EASI improved significantly by 66.4% / 69.7%, and the peak pruritus numerical rating scale (NRS) improved by 30.8% / 37.6%; 10% / 35% achieved an investigator global assessment (IGA) of 0 - 1.

[0145] Dupilumab administered as a single dose of 2 mg / kg or 4 mg / kg induced a significant and rapid reduction in disease activity in patients at week 2 (for the 2 mg / kg and 4 mg / kg doses, the EASI scores decreased by 37% and 33% from baseline, respectively). In both dose cohorts, repeated weekly doses of dupilumab led to further improvement in disease severity in patients. At week 12, in the pediatric 2 mg / 4 mg cohort, the baseline EASI improved significantly by 76.2% / 63.4%, the peak pruritus NRS improved by 41.6% / 39.6%; 16.7% / 21.1% achieved an IGA of 0 - 1.

[0146] In summary, both of the investigated dose regimens showed significant clinical benefits in two pediatric age groups. Single-dose administration of 2 mg / kg and 4 mg / kg dupilumab led to a rapid reduction in AD signs and symptoms in both age groups. Repeated weekly doses provided improvement and a more durable response than single doses in both age groups. This clinical response was observed in patients with high disease activity at baseline in whom all approved therapies for their disease had failed.

[0147] Conclusions

[0148] In the two pediatric age groups included in this study, dupilumab administered as a single dose of 2 mg / kg and 4 mg / kg and repeated weekly for 4 weeks was generally safe and well tolerated. In pediatric patients with AD, the pharmacokinetic profile of dupilumab was consistent with that in adults; dupilumab provided clinical benefits (including improvement in pruritus) faster than the rates observed in adult clinical trials and had a similar safety profile.

[0149] Example 2: A clinical study to investigate the safety and efficacy of dupilumab monotherapy in patients aged ≥12 years to <18 years with moderate to severe atopic dermatitis (AD)

[0150] Research Objectives

[0151] The primary objective of this study was to elucidate the efficacy of dupilumab as monotherapy in patients aged ≥12 years to <18 years with moderate to severe AD. The secondary objective of this study was to evaluate the safety of dupilumab as monotherapy in patients aged ≥12 years to <18 years with moderate to severe AD.

[0152] Study Design

[0153] This is a randomized, double-blind, placebo-controlled, parallel-group study to investigate the efficacy and safety of dupilumab monotherapy in pediatric patients with moderate to severe AD. The study population included patients aged ≥12 years to <18 years with moderate to severe AD whose disease could not be adequately controlled with topical medications or for whom topical treatment was medically inadvisable (e.g., intolerance, other significant side effects or safety risks). Patients were randomized into one of the following treatment groups:

[0154] · Dupilumab every 2 weeks (Q2W) treatment group: 200 mg Q2W (patients <60 kg) or 300 mg Q2W (patients ≥60 kg)

[0155] · Dupilumab every 4 weeks (Q4W) treatment group: 300 mg Q4W, regardless of body weight

[0156] · Placebo group

[0157] This study consisted of the following 3 phases: up to 5 weeks of screening, 16 weeks of treatment, and 12 weeks of follow-up.

[0158] After the parent or legal guardian / patient provided informed consent (informed consent or informed assent, as appropriate), the patient's eligibility for the study was evaluated at the screening visit. During screening, systemic and topical treatments for AD were washed out as needed according to eligibility requirements. If patients failed the screening assessment due to reasons related to an incidental transient condition, they were rescreened once, unless the reason for screening failure was related to non-compliance with the disease severity inclusion criteria. Before randomization, patients were required to apply a moisturizer twice daily for at least 7 days and continue to apply it throughout the study.

[0159] Patients who meet the eligibility criteria at baseline undergo Day 1 / baseline assessments and are randomized in a 1:1:1 ratio as follows by baseline weight group (<60 kg and ≥60 kg) and baseline disease severity (moderate [Investigator's Global Assessment (IGA = 3)] vs. severe [IGA = 4] AD): □ Dupilumab Q2W treatment group: Patients with a baseline weight <60 kg receive a subcutaneous (SC) injection of 200 mg of dupilumab Q2W after a 400 mg loading dose on Day 1. Patients with a baseline weight ≥60 kg receive a Q2W SC injection of 300 mg of dupilumab after a 600 mg loading dose on Day 1. □ Dupilumab Q4W treatment group: Patients receive a Q4W SC injection of 300 mg of dupilumab after a 600 mg loading dose on Day 1. □ Placebo treatment group: Patients receive a placebo matching dupilumab Q2W (including doubling the placebo amount on Day 1 to match the loading dose). To maintain blinding of the study, patients in the <60 kg weight stratum receive, in a 1:1 ratio, a placebo matching 200 mg of dupilumab (including doubling the placebo amount on Day 1 to match the said loading dose) or a placebo matching 300 mg of dupilumab (including doubling the placebo amount on Day 1 to match the said loading dose). In the ≥60 kg weight stratum, patients randomized to the placebo group receive a placebo matching 300 mg of dupilumab (including doubling the placebo amount on Day 1 to match the said loading dose).

[0160] To maintain blinding, all patients receive injections Q2W from Day 1 through Week 14. During weeks when dupilumab is not administered, patients receive placebo injections.

[0161] For each patient, the duration of the study is approximately 28 weeks, excluding the screening period. During treatment, patients have in-clinic visits weekly until Week 4, then every 4 weeks until Week 16, with weekly phone visits between in-clinic visits. During the second in-clinic visit (Day 1) through the sixth visit (Week 4), patients and / or parents / caregivers (as appropriate based on patient age) are trained to inject the study drug. During weeks without scheduled in-clinic visits, patients either self-inject the study drug or parents / caregivers administer the study drug to the patient. In cases where the patient does not want to self-inject and the parent / caregiver does not want to administer the study drug to the patient, the patient has all study drug injections administered by clinical staff in the clinic. Safety, laboratory, and clinical assessments are performed at the designated clinical visits. The end of the treatment period visit occurs at Week 16, two weeks after the last dose of the study drug. The co-primary endpoints are evaluated at this visit.

[0162] Study Population

[0163] The study population included pediatric patients (aged ≥ 12 years to < 18 years at baseline) with moderate to severe AD that was not adequately controlled with topical AD medications or for whom topical treatment was medically inadvisable (e.g., intolerance, other significant side effects, or safety risks).

[0164] Inclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in this study:

[0165] 1) Males or females aged ≥ 12 years to < 18 years at screening visit;

[0166] 2) AD diagnosed at screening visit according to the American Academy of Dermatology Consensus Criteria (Eichenfield et al 2014, J. Am. Acad. Dermatol. 70:338 - 51);

[0167] 3) Diagnosed with chronic AD for at least 1 year prior to screening visit;

[0168] 4) IGA ≥ 3 at screening and baseline visits

[0169] 5) EASI ≥ 16 at screening and baseline visits

[0170] 6) Mean score of the baseline Itch Numerical Rating Scale (NRS) for maximum itch intensity ≥ 4

[0171] Note: The mean baseline itch NRS for maximum itch intensity was determined based on the mean of the daily NRS scores for maximum itch intensity during the 7 - day period immediately prior to randomization (daily scores ranged from 0 to 10). A minimum of 4 daily scores over 7 days were required to calculate the baseline mean. For patients who did not report at least 4 daily scores during the 7 - day period immediately prior to the planned randomization date, randomization should be delayed until this requirement is met, but not exceeding a maximum screening duration of 35 days.

[0172] 7) Body surface area (BSA) affected by AD ≥ 10% at screening and baseline visits

[0173] 8) A recent history of documented inadequate response to topical AD medications (within 6 months prior to screening visit) or topical treatment being medically inadvisable for them (e.g., intolerance due to significant side effects or safety risks).

[0174] Note:

[0175] ● Inadequate response is defined as failure to achieve and maintain remission or low disease activity (equivalent to IGA 0 = clear to 2 = mild), despite treatment with a daily regimen of medium- to stronger-potency TCS (± TCI, as appropriate) for at least 28 days or the maximum duration recommended in the product prescribing information (e.g., 14 days for ultra-high-potency TCS), whichever is shorter.

[0176] ● Patients with a documented history of systemic treatment for AD (systemic immunosuppressive drugs such as cyclosporine, methotrexate, corticosteroids, etc.) in the past 6 months are also considered inadequate responders to topical treatment and potentially eligible for dupilumab treatment after an appropriate washout.

[0177] ● Serious side effects or safety risks are those that outweigh the potential therapeutic benefits, including intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic effects, as evaluated by the investigator or the patient's treating physician.

[0178] ● Acceptable documentation includes contemporaneous chart notes recording topical medication prescriptions and treatment outcomes, or investigator records based on communication with the patient's attending physician. If documentation is insufficient, a treatment course with a daily regimen of medium- or higher-potency TCS (± TCI, as appropriate) can be provided to potential patients, administered for at least 28 days during the screening period or for the maximum duration recommended by the product prescribing information, whichever is shorter. As defined above, patients who demonstrate inadequate response during this period will be eligible for inclusion in the study after an appropriate washout.

[0179] 9) Administer a stable dose of a topical lubricant (moisturizer) twice daily for at least 7 consecutive days immediately prior to the baseline visit

[0180] 10) Willing and able to comply with all clinical visits and study-related procedures

[0181] 11) Able to understand and complete study-related questionnaires

[0182] 12) A parent or legal guardian must provide a signed informed consent form. The patient must also provide a separate informed consent form to participate in the study and sign and date it on a separate informed consent form (IAF) or on the informed consent form (ICF) signed by the parent / legal guardian (depending on local regulations and requirements).

[0183] Exclusion Criteria:Patients meeting any of the following criteria were excluded from the study: 1. Participation in a previous dupilumab clinical study. 2. Treatment with a systemic investigational drug prior to the baseline visit. 3. Treatment with a topical investigational drug within 4 weeks or 5 half-lives (if known), whichever is longer, prior to the baseline visit. 4. Treatment with TCS or TCI within 2 weeks prior to the baseline visit (patients may be rescreened). 5. Use of any of the following treatments within 4 weeks prior to the baseline visit, or having any condition that in the investigator's opinion may require such treatment during the first 4 weeks of study treatment: a. Immunosuppressive / immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon γ, Janus kinase inhibitors, azathioprine, methotrexate, etc.), b. Phototherapy for AD. 6. Treatment with the following biologics: a. Any cell depleting agent, including but not limited to rituximab: within 6 months prior to the baseline visit, or until lymphocyte and CD19+ lymphocyte counts return to normal, whichever is longer; b. Other biologics: within 5 half-lives (if known) or 16 weeks prior to the baseline visit, whichever is longer; 7. Treatment with live (attenuated) vaccines within 4 weeks prior to the baseline visit. Note: For patients who are planned to receive live attenuated vaccine inoculation during the study (based on national vaccination programs / local guidelines), after consultation with a pediatrician, it will be determined whether the administration of the vaccine can be postponed until after the study is completed, or advanced to before the study starts, without compromising the patient's health: □ Patients who can safely postpone the administration of live (attenuated) vaccines will be eligible for the study. □ Patients who have been vaccinated in advance can be included in the study only after a 4-week interval after the vaccine is given. 8. Planning or anticipating the use of any prohibited drugs and procedures during the study treatment. 9. Treatment with crisaborole within 2 weeks prior to the baseline visit. 10. Body weight < 30 kg at baseline. 11. Initiation of AD treatment with a prescribed moisturizer or a moisturizer containing additives such as ceramides, hyaluronic acid, urea, or filaggrin degradation products during the screening period (if initiated prior to the screening visit, the patient may continue to use a stable dose of such moisturizer). 12. Regular use (more than 2 visits per week) of an artificial solarium / room within 4 weeks of the baseline visit. 13. Active chronic or acute infections requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit. Note: Patients may be rescreened after the infection has resolved. 14. Known or suspected immunodeficiency, including: a history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite resolution of the infection; or otherwise, recurrent infections with an abnormal frequency or prolonged duration suggestive of an immunocompromised state as judged by the investigator. 15. Known human immunodeficiency virus infection or a history of HIV seropositivity at the time of screening.16. Diagnosed as hepatitis B virus infection at screening, or positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at screening. Note: Patients who have acquired immunity to hepatitis B virus infection after vaccination (patients negative for HBsAg, positive for hepatitis B surface antibody [HBsAb], and negative for HBcAb) are eligible to participate in this study. These patients will be allowed to participate in the study but will be followed up using routine clinical and liver function tests. 17. Diagnosed as hepatitis C virus infection at screening, or positive for hepatitis C antibody at the screening visit. 18. Current liver disease treatment, including but not limited to acute or chronic hepatitis, cirrhosis, or liver failure, or evidence of liver disease indicated by a persistent (confirmed by tests taken ≥ 2 weeks apart) elevation of transaminases (alanine transaminase [ALT] and / or aspartate aminotransferase [AST]) above the upper limit of normal (ULN) by 3-fold during the screening period. 19. Presence of any one or more of the following abnormalities in laboratory test results at screening: ● Platelets ≤ 100 × 10. 3 / μL ● Neutrophils < 1.5 × 10 3 / μL ● Creatine phosphokinase (CPK) > 5 × ULN ● Serum creatinine > 1.5 × ULN. Note: If an abnormal value is detected during screening, a repeat test should be performed to confirm the abnormality. Only if the repeat test confirms the abnormality is the patient classified as a screening failure. 20. Presence of skin comorbidities that may interfere with study evaluation. 21. History of malignancy prior to the baseline visit. 22. Diagnosed active endoparasitic infection; suspected or high-risk endoparasitic infection, unless active infection has been excluded by clinical and (if necessary) laboratory evaluation prior to randomization. 23. History of alcohol or drug abuse within 2 years prior to the screening visit, or signs of such abuse documented by positive results in alcohol and / or drug panel laboratory tests performed at the screening visit. Note: If a patient has a positive drug test for a prescription drug used for medical reasons, the patient remains eligible. In such cases, the site needs to confirm the medical reason used by the treating physician. 24. Severe concomitant illness that, in the investigator's judgment, will adversely affect the patient's participation in the study. 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., New York Heart Association class III or IV heart failure), severe kidney 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 endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. The specific reasons for excluding patients under this criterion will be noted in the study documents (chart notes, case report forms [CRF], etc.). 25. Any other medical or psychological condition at screening, including relevant laboratory abnormalities, that, in the investigator's opinion, suggests a new and / or poorly understood disease, a risk that may be unreasonable for the patient due to their participation in this clinical trial, may make the patient's participation unreliable, or may interfere with study evaluation. The specific reasons for excluding patients under this criterion will be noted in the study documents (chart notes, CRF, etc.). 26. Exclude patients who are under institutional control by order of a judicial or administrative agency from this study. 27. Major surgery is planned during the patient's participation in this study. 28. The patient is a member of the dupilumab study team or his / her immediate family member. 29. Female patients who are pregnant, breastfeeding, planning to become pregnant, or breastfeeding during the study. 30. Patients who are fertile and sexually active and are unwilling to use adequate contraception for the duration of the entire study and for 120 days after the last dose of the study drug ** and fertile * and sexually active women.

[0184] Study Treatments

[0185] Study Drugs: Dupilumab is administered every other week or every 4 weeks:

[0186] · Dupilumab Q2W treatment:

[0187] Dupilumab is injected subcutaneously, a loading dose of 400 mg on day 1, then 200 mg Q2W from week 2 to week 14, or

[0188] Dupilumab is injected subcutaneously, a loading dose of 600 mg on day 1, then 300 mg Q2W from week 2 to week 14.

[0189] ● Dupilumab Q4W treatment: Dupilumab is injected subcutaneously, a loading dose of 600 mg on day 1, then 300 mg Q4W from week 4 to week 12; to maintain blinding, during the dosing period from week 2 to week 14, placebo is injected subcutaneously between Dupilumab doses so that the injection frequency matches that of the other 2 groups.

[0190] Placebo: Matched placebo

[0191] Placebo is injected subcutaneously to match Dupilumab Q2W (including doubling the amount of placebo on day 1 to match the loading dose). To maintain blinding of the study, patients randomized to the placebo group in the <60 kg body weight stratum receive, in a 1:1 ratio, placebo matching 200 mg of Dupilumab (including doubling the amount of placebo on day 1 to match the said loading dose) or placebo matching 300 mg of Dupilumab (including doubling the amount of placebo on day 1 to match the said loading dose).

[0192] Background Treatments: All patients are required to apply a moisturizer (emollient) at least twice daily for at least 7 consecutive days immediately prior to randomization. After randomization, patients are required to continue applying the moisturizer throughout the study period (all 28 weeks if applicable). However, to adequately evaluate skin dryness, moisturizer application is not permitted to the non-lesional skin area designated for this evaluation for at least 8 hours prior to each clinical visit. All types of moisturizers are permitted, but patients cannot start treatment with a prescription moisturizer or a moisturizer containing additives during the screening period or during the study. If started prior to the screening visit, patients may continue using a stable dose of such moisturizers.

[0193] Salvage Treatments:If medically necessary (i.e., to control intolerable AD symptoms), rescue treatment for AD is provided to the study patients. If possible, investigators are encouraged to consider starting rescue initially with topical treatment (e.g., mid / high-potency TCS), and escalating to systemic treatment only for patients who do not respond adequately after at least 7 days of topical treatment. Topical calcineurin inhibitors can be used alone or in combination with TCS for rescue, but the use of TCI is reserved for problem areas (e.g., face, neck, intertriginous areas, genital areas, etc.). Investigators may also consider using crisaborole for rescue. The rescue treatment for these topical treatments is used in accordance with the prescription information and local guidelines. If the rescue consists of topical medications, the patient can continue the study treatment. Patients who receive systemic corticosteroids or systemic non-steroidal immunosuppressive drugs (e.g., cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) as rescue medications during the study permanently discontinue the study drug.

[0194] Study Endpoints

[0195] The primary endpoint is the proportion of patients with an IGA of 0 to 1 (on a 5-point scale) at Week 16. The co-primary endpoints are the proportion of patients with an Eczema Area and Severity Index (EASI)-75 (≥ 75% improvement from baseline) at Week 16, and the proportion of patients with an IGA of 0 to 1 (on a 5-point scale) at Week 16.

[0196] Key secondary endpoints include: ● Percentage change in EASI score from baseline to Week 16 ● Percentage change in the weekly mean of the daily peak pruritus NRS from baseline to Week 16 ● Proportion of patients with an improvement (decrease) of ≥ 3 in the weekly mean of the daily peak pruritus NRS from baseline to Week 16 ● Proportion of patients with an improvement (decrease) of ≥ 4 in the weekly mean of the daily peak pruritus NRS from baseline to Week 16

[0197] Other secondary endpoints included: ● The proportion of patients with EASI-50 at Week 16 ● The proportion of patients with EASI-90 at Week 16 ● The time to onset of action on pruritus during 16-week treatment (the weekly mean of peak pruritus NRS decreased by ≥3 points from baseline) ● The time to onset of action on pruritus during 16-week treatment (the weekly mean of peak pruritus NRS decreased by ≥4 points from baseline) ● The change in the percentage of body surface area (BSA) affected by AD from baseline to Week 16 ● The percentage change in the Scoring Atopic Dermatitis (SCORAD) from baseline to Week 16, the change in the Children's Dermatology Life Quality Index (CDLQI) from baseline to Week 16 ● The change in the Patient-Oriented Eczema Measure (POEM) from baseline to Week 16 ● The change in the weekly mean of daily peak pruritus NRS from baseline to Week 16 ● The percentage change in the weekly mean of daily peak pruritus NRS from baseline to Week 4 ● The change in the Hospital Anxiety and Depression Scale (HADS) from baseline to Week 16 ● The proportion of patients with an improvement (decrease) in the weekly mean of daily peak pruritus NRS of ≥4 from baseline to Week 4. The incidence of skin-infection treatment-emergent adverse events (TEAEs) (excluding herpes infections) by Week 16. ● The incidence of severe TEAEs by Week 16

[0198] Methods and Assessments

[0199] During the study period, at the scheduled clinical visits, efficacy was evaluated using investigator-reported assessments (including the IGA for evaluating the overall severity of AD, the EASI, SCORAD, BSA affected by AD, and GISS for measuring the extent and severity of AD). Additionally, patient-reported assessments (including the pruritus NRS, pruritus PCS, patient global disease assessment, patient global treatment assessment, CDLQI, POEM, HADS, 5-question version of the Asthma Control Questionnaire (ACQ-5), total nasal symptom score [TNSS], patient assessment of injection pain using a visual analog scale [VAS], and assessment of the number of school days missed by patients (for enrolled patients)) were used to evaluate the relevant endpoints. Safety was evaluated by vital signs, physical examination, clinical laboratory tests, 12-lead electrocardiogram (ECG), and clinical evaluation. Patients were required to monitor all adverse events (AEs) experienced from the time of informed consent until their last study visit.

[0200] Patient Itch Assessment Using a Numerical Rating Scale:The Itch NRS is a simple assessment tool for patients to report the intensity of their itching (pruritus) during a 24-hour recall period. Patients are asked the following question: For the maximum itching intensity: "On a scale of 0 to 10, where 0 is 'no itching' and 10 is 'the worst itching imaginable', how would you rate your itching at its worst during the previous 24-hour period?" Patients are instructed to record their Itch NRS scores at screening and baseline visits using a patient diary. Throughout the study (screening, treatment, and follow-up periods), patients complete the rating scale daily.

[0201] Patient Itch Assessment Using an Itch Categorical Scale: The Itch Classification Scale is a 4-point scale used to assess symptoms and has been used in previous AD clinical studies. Patients are less likely to give an "average" response compared to the tendency of patients using a 5-point scale (Kaufmann et al 2006, Allergy 61: 375-81). The scale is scored as follows: 0 = no itching; 1 = mild itching (occasional mild itching / scratching); 2 = moderate itching (persistent or intermittent itching / scratching, not interfering with sleep); and 3 = severe itching (troublesome itching / scratching, interfering with sleep). Patients are instructed to record their Itch Classification Scale scores at screening and baseline visits using a patient diary. Throughout the study (screening, treatment, and follow-up periods), patients complete the rating scale daily.

[0202] Overall Patient Disease Assessment: Patients rate their disease based on the following 5-point scale: Overall, how would you rate your eczema symptoms right now? ● No symptoms ● Mild symptoms ● Moderate symptoms ● Severe symptoms ● Very severe symptoms. Patients perform this assessment at screening, at baseline, and on days 15, 29, 57, 85, 113, 141, 169, and 197 (end of the study) or at early termination.

[0203] Overall Patient Treatment Assessment: Patients answer the following question based on the following 5-point scale: Compared to before you started this study, how would you rate your eczema symptoms right now? ● Much better ● Slightly better ● No difference ● Slightly worse ● Much worse. Patients perform this assessment on days 15, 29, 57, 85, 113, 141, 169, and 197 or at early termination.

[0204] Children's Dermatology Life Quality Index:The CDLQI is a validated questionnaire designed to measure the impact of skin disease on children's QOL (Lewis-Jones et al 1995, Brit J Dermarol. 132:942-9). The aim of the questionnaire is to measure how much the patient's skin problems have affected the patient during a recall period of the previous week. To complete the questionnaire, the patient needs to provide answers to 10 questions (the questions focus on aspects such as symptoms, disease-related feelings, the impact of the disease on leisure, school or holidays, personal relationships, sleep and side effects of skin disease treatment, etc.). The tool has a 7-day recall period. Nine of the 10 questions are scored as follows: ● A great deal = 3 ● Quite a lot = 2 ● Only a little = 1 ● None at all = 0 ● Question not answered = 0. Question 7 has another possible answer (truancy), which is assigned a score of 3. The patient's CDLQI is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on QOL. The CDLQI can also be expressed as a percentage of the maximum possible score of 30. The patient undergoes this assessment at screening, at baseline and on days 15, 29, 57, 85, 113, 141, 169 and 197 or at early termination.

[0205] Patient-Oriented Eczema Measure: The POEM is a 7-item validated questionnaire for use in clinical practice and clinical trials to assess disease symptoms in children and adults (Charman et al 2004, Arch. Dermatol. 140:1513-9). The format is 7 items (dryness, itch, scale, fissure, sleep loss, bleeding and exudation) based on the frequency of these disease symptoms during the previous week (i.e., 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days), using a scoring system of 0 to 28; the total score reflects disease-related morbidity. The questionnaire is applied at screening, at baseline and on days 15, 29, 57, 85, 113, 141, 169, 197 or at early termination.

[0206] Patient-Administered Hospital Anxiety and Depression Scale:The HADS is a tool for screening anxiety and depression in non-psychiatric populations; repeated administration can also provide information on changes in the patient's emotional state (Zigmond and Snaith 1983, Acta Psychiatr. Scand 67:361 - 70; Herrmann 1997, J. Psychosom. Res. 42:17 - 41). The HADS consists of 14 items, 7 for anxiety and 7 for depressive symptoms; for each subscale, the possible score range is 0 to 21. For both subscales, the following cut-off scores are recommended: 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. The questionnaire is administered only to the subgroup of patients who speak fluently the language in which the questionnaire is presented (based on the availability of a validated translation in the participating country) at screening, at baseline, and at days 15, 29, 57, 85, 113, 141, 169, 197 or at early termination.

[0207] Juniper Asthma Control Questionnaire-5: The 5-question version of the Asthma Control Questionnaire (ACQ) is a validated questionnaire for assessing asthma control. The questionnaire is administered only to the subgroup of patients who have ongoing asthma and who speak fluently the language in which the questionnaire is presented (based on the availability of a validated translation in the participating country) at screening, at baseline, and at days 113 and 197 or at early termination.

[0208] Total Nasal Symptom Score: The Total Nasal Symptom Score (TNSS) is used to evaluate the effect of the study drug on allergic rhinitis symptoms. The total score includes the following 5 symptoms: rhinorrhea, nasal congestion, nasal itching, sneezing, and sleep difficulty, each graded on a severity scale of 0 to 3. This tool has been widely used in previous trials of patients with allergic rhinitis (Berger et al 2015, Am. J. Rhinol. Allergy 29:273 - 82; Benninger et al 2010, Ann. Allergy Asthma Immunol. 104:13 - 29). The questionnaire is administered only to the subgroup of patients who have a history of allergic rhinitis and who speak fluently the language in which the questionnaire is presented (based on the availability of a validated translation in the participating country). Patients are instructed to use a patient diary to record their TNSS throughout the screening period (at least 7 days before baseline / day 1) and only for the 7 days before visits 6, 18, and 21.

[0209] Visual Analogue Scale for Injection Site Pain: Patients are required to provide an assessment of the pain experienced during the injection of the study drug using a Visual Analogue Scale (VAS). This assessment was performed at days 15, 29, 57, and 85 at certain clinic visits after the injection of the study drug.

[0210] Investigator's Global Assessment:IGA is an assessment tool for clinical research that provides an overall score for the severity of AD on a 5-point scale from 0 (clear) to 4 (severe). IGA scores are evaluated at screening, baseline, and on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0211] Eczema Area and Severity Index EASI is a validated instrument for use in clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al 2001, Exp. Dermatol. 10:11-18). EASI is a composite index with a score range from 0 to 72. Four AD disease features (erythema, thickness [induration, papulation, edema], excoriation [epidermal detachment], and lichenification) are each evaluated for severity by the investigator or examiner on a scale from "0" (absent) to "3" (severe). Additionally, the area involved by AD is evaluated as a percentage of the body surface area of the head, trunk, upper extremities, and lower extremities and converted to a score from 0 to 6. In each body region, the area is represented as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). EASI is collected at screening, baseline, and on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0212] Overall Individual Sign Score: Using the EASI severity grading criteria, an overall score is provided for each individual component of the AD lesion (erythema, infiltration / papulation, epidermal detachment, and lichenification) on a 4-point scale (from 0 = none to 3 = severe) (i.e., all are evaluated for the whole body rather than by anatomical region). This overall single-lesion score (GISS) is evaluated at screening, baseline, and on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0213] Atopic Dermatitis Score:The Scoring Atopic Dermatitis (SCORAD) is a validated tool used in clinical research and clinical practice, which was developed to standardize the assessment of the extent and severity of AD (European Task Force on Atopic Dermatitis 1993, Dermatol. 186:23 - 31). There are three components for assessment: A = extent of affected BSA, B = severity, C = subjective symptoms. The extent of AD is evaluated as the percentage of each defined body area and reported as the sum of all areas, with a maximum score of 100% (designated as "A" in the overall SCORAD calculation). The severity of six specific symptoms of AD (erythema, swelling, exudation / crusting, exfoliation, skin thickening / lichenification, and dryness) is evaluated using the following scale: none (0), mild (1), moderate (2), or severe (3) (maximum total score of 18 points, designated as "B" in the overall SCORAD calculation). The subjective evaluation of pruritus and insomnia is recorded by the patient or relative on a visual analogue scale for each symptom, where 0 is no itching (or insomnia) and 10 is the worst imaginable itching (or insomnia), with a maximum possible score of 20. In the overall SCORAD calculation, this parameter is designated as "C". The SCORAD is calculated as: A / 5 + 7B / 2 + C, with a maximum value of 103. This assessment is performed on patients at screening, baseline, and on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0214] Body Surface Area Affected by Atopic Dermatitis: Using nine rules (the possible maximum score for each area is: head and neck [9%], trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitalia [1%]), the body surface area affected by AD is evaluated for each part of the body and reported as the percentage of the combination of all major body parts. This assessment is performed on patients at screening, baseline, and on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0215] Assessment of School Absence Days: Patients enrolled are required to report the number of school days missed since the last study assessment. This assessment is performed on patients at baseline and on days 29, 57, 85, 113, 141, 169, 197 (end of study) or at early termination.

[0216] Safety Assessments

[0217] Throughout the study period, safety is evaluated by monitoring adverse events and serious adverse events.

[0218] An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product or in a subject in a clinical investigation. Thus, an AE can be any adverse and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the pharmaceutical product, whether or not considered related to the pharmaceutical (investigational) product. An AE also includes: any exacerbation of a pre-existing condition temporally associated with the use of the investigational drug (i.e., any clinically significant change in frequency and / or intensity); any abnormal laboratory finding considered clinically significant by the investigator; and any untoward medical occurrence.

[0219] A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is an important medical event.

[0220] Results

[0221] Baseline Characteristics:

[0222] Baseline demographics and disease characteristics are summarized in Table 3.

[0223] Table 3: Baseline demographics and disease characteristics

[0224]

[0225]

[0226] The baseline demographics of the three treatment groups were comparable. The baseline disease severity was slightly higher in adolescents compared to adults in earlier clinical studies.

[0227] Table 4: Disease burden at screening

[0228]

[0229]

[0230] The mean age of patients in this study was 14.5 years, and the disease duration was long (mean 12.2 years). Most (92%) had at least one allergic comorbidity, and 42.4% had used previous systemic medications. The mean BSA affected by AD was 22.1%; 45% had IGA 4 (severe disease), while the mean EASI and SCORAD scores were 31.9 and 65.9, respectively. The mean peak pruritus NRS and SCORAD VAS sleep loss scores were 7.2 / 10 and 4.9 / 10, respectively. The mean POEM score was 20.7 / 28; according to the POEM scoring bands, 18.3%, 52.2%, and 28.3% of patients reported moderate, severe, and very severe symptoms, respectively. Based on the PGADS classification, 32.3%, 42.2%, and 15.1% of patients experienced "moderate", "severe", and "very severe" symptoms, respectively. On average, patients reported a very large impact on quality of life (mean CDLQI, 13.3 / 30). As defined by HADS A / HADS-D scores ≥8, 50.6% and 17.5% of patients reported anxiety and depressive symptoms, respectively (Table 4).

[0231] Efficacy

[0232] Tables 5 - 7 summarize the improvements in various AD - related parameters in dupilumab - treated patients.

[0233] Table 5: Efficacy results for primary and key secondary endpoints

[0234]

[0235] Table 6: Efficacy results for other secondary endpoints

[0236]

[0237] Table 7: Proportion of patients requiring rescue medications

[0238]

[0239] For the dupilumab q2w / dupilumab q4w / placebo groups, at baseline, the mean (standard deviation) values of the weekly mean of the daily peak pruritus NRS were 7.5 (1.52) / 7.5 (1.84) / 7.7 (1.62), consistent with severe pruritus. A significant improvement in pruritus of dupilumab vs placebo was observed as early as Day 5 for dupilumab Q2w and as early as Day 6 for the dupilumab Q4w regimen. On Day 5, the least-squares mean percent change (standard error) from baseline in the daily peak pruritus NRS score for dupilumab q2w / q4w vs placebo was: -12.5 (2.43) / -8.8 (2.41) vs -4.9 (2.39); P<0.05 / not significant. The values on Day 6 were: -13.0 (2.28) / -12.9 (2.27) vs -4.5 (2.24); both P<0.01. The improvement in pruritus scores continued through Day 15: -25.3 (2.68) / -21.8 (2.69) vs -5.7 (2.64); both P<0.0001. In the dupilumab q2w group, a higher proportion of patients showed a clinically meaningful response (≥3-point improvement) in the daily peak pruritus NRS score compared with the placebo group as early as Week 13 (P<0.05). By Week 15, a significantly higher proportion of patients in both dupilumab groups had achieved a clinically meaningful improvement from baseline: 25.6% / 25.3% for dupilumab q2w / dupilumab q4w vs 9.4% for placebo; both P<0.01.

[0240] The placebo-adjusted responses were generally comparable to those seen in adult patients. For the Q2W and Q4W dosing regimens, the primary endpoint IGA (0,1) and the co-primary endpoint EASI-75 were met at Week 16. For both doses, all pre-specified key efficacy endpoints were met. Compared with placebo, both dupilumab treatment groups showed a percentage reduction in EASI as early as Week 1. For IGA, compared with placebo, for both dosing regimens, the effect of dupilumab was observed as early as Week 4. The Q2W and Q4W treatment groups showed similar efficacy for consecutive endpoints. However, the Q2W dosing group showed numerically superior effects for IGA (0,1), NRS>4, and EASI-50. Both treatment groups showed comparable effects until Week 8 of treatment (due to the effect of the loading dose), however, Q2W showed numerically superior effects at subsequent time points. In patients with severe disease, the Q2W group showed a higher response than Q4W (baseline IGA = 4); both treatment groups were superior to placebo.

[0241] In two body weight subgroups, the dupilumab treatment group was superior to the placebo. Among patients <60 kg, dupilumab 200 mg Q2W was numerically superior to dupilumab 300 mg Q4W. Among patients ≥60 kg, dupilumab 300 mg Q2W was comparable to dupilumab 300 mg Q4W.

[0242] In the q4w / q2w / placebo groups, at week 16, 69 out of 84 patients, 62 out of 82 patients, and 83 out of 85 patients did not achieve IGA 0 / 1, respectively. Among these patients, in terms of the Eczema Area and Severity Index (EASI), significantly greater improvements from baseline were observed in the q4w / q2w vs. placebo groups (least squares [LS] mean % change) (–58.4% / –55.0% vs –20.7%; for both comparisons, P<0.0001), the Numerical Rating Scale for Pruritus (NRS; –41.2% / –44.2% vs –17.4%; for both, P<0.0001), the Patient-Oriented Eczema Measure (POEM; –8.4% / –8.5% vs –3.5%; for both, P<0.0001), and the Children's Dermatology Life Quality Index score (LS mean change, –8.46 / –8.44 vs –5.61; for both, P = 0.002). Relative to placebo, a greater proportion of dupilumab-treated patients achieved an improvement in EASI of ≥50% from baseline (44.9% / 48.4% vs 10.8%; both P<0.0001), an improvement in pruritus NRS of ≥3 points (30.4% / 43.5% vs 7.2%; P = 0.0001 / P<0.0001), a reduction in POEM score of ≥6 points (39.1% / 53.2% vs 8.5%; both P<0.0001), and an improvement in the body surface area affected by AD (LS mean change, –31.32 / –24.53 vs –10.78; P<0.0001 / P = 0.0002).

[0243] Compared with the Q2W group, a higher proportion of patients in the Q4W group required rescue medications (Table 7). However, during the treatment, the effect of dupilumab was strong and excellent compared with placebo, regardless of the use of rescue medications. The impact of using rescue medications on improving the response rate was minimal. Overall, compared with adult patients, a higher proportion of adolescent patients required rescue medications, indicating the severity of the disease in adolescents. For the primary analysis, patients receiving rescue medications were considered non-responders and the data were examined.

[0244] Adolescent patients showed a high incidence of comorbid allergic diseases (Table 8).

[0245] Table 8: Comorbid allergic conditions in the patient population

[0246]

[0247]

[0248] Table 9 shows the previous systemic medications used by the patients. Table 9: Proportion of patients treated with previous systemic medications

[0249]

[0250] A high proportion of patients had used previous systemic medications. The systemic medications had been used off-label based on limited evidence of efficacy and were known to be associated with significant toxicity. The previous use of systemic medications and the resulting lack of efficacy were confirmed by the baseline severity of the disease in this study.

[0251] Table 10: Changes in sleep measures

[0252]

[0253]

[0254] a Week 2 was the earliest time point for post-baseline assessment. CDLQI, Children's Dermatology Life Quality Index; LS, least squares; POEM, Patient-Oriented Eczema Measure; SCORAD, Severity of Atopic Dermatitis; SE, standard error; VAS, Visual Analogue Scale.

[0255] As early as week 1, compared with placebo, dupilumab treatment showed significant improvement in sleep, which continued until week 16 (Table 10).

[0256] Safety

[0257] No new or unexpected side effects were observed in this trial compared to those observed in adult patient trials. For the 16-week treatment period, the overall incidence of adverse events was comparable between the dupilumab groups and placebo (72% for dupilumab every two weeks, 64% for dupilumab every four weeks, and 69% for placebo). There were no serious adverse events or events leading to treatment discontinuation in either dupilumab treatment group. As seen in adult patient trials, skin infections (determined, including herpes infections) were also numerically higher in the placebo group (11% for dupilumab every two weeks, 13.3% for dupilumab every four weeks, compared to 20% for placebo). Adverse events observed at higher rates with dupilumab included injection site reactions HLT (8.5% for dupilumab every two weeks, 6% for dupilumab every four weeks, compared to 3.5% for placebo) and conjunctivitis CMQ (9.8% for dupilumab every two weeks, 10.8% for dupilumab every four weeks, compared to 4.7% for placebo).

[0258] Clinical Pharmacology

[0259] Exposure in adolescents was slightly lower compared to that predicted by adult PK studies. Exposure measured by serum trough concentration was comparable between 200mg Q2W (<60kg) and 300mg Q2W (>60kg). Exposure was significantly lower with 300mg Q4W in both weight groups. Higher exposure was associated with numerically higher response rates on %EASI. No high-titer anti-drug antibodies (ADA) were observed. Low and persistent ADA rates were observed in all treatment groups and placebo, similar to adults.

[0260] At baseline, the treatment groups had similar clinical and laboratory characteristics. The mean eosinophil count (x10 9 / L) was within the normal range. Transient increases from baseline were observed in both dupilumab groups, with the highest mean increase at week 8 (q4w 0.177; q2w 0.189; placebo -0.086). These increases had no clinical consequences and returned to baseline by week 16. The mean changes from baseline to week 16 for other hematological parameters (although not significantly different between groups) were as follows: white blood cells (x10 9 / L, q4w 7.61; q2w 8.01; placebo 7.55); hemoglobin (g / L, q4w -0.8; q2w -1.2; placebo -0.8); platelets (x10 9( / L, q4w - 15.4; q2w - 17.6; placebo - 8.1). Mean changes in electrolyte and renal function parameters were also similar between the two groups, including potassium (mmol / L, q4w < 0.1; q2w - 0.01; placebo 0.04) and creatinine (μmol / L, q4w < 0.1; q2w - 1.3; placebo - 1.1). No meaningful differences were found for alkaline phosphatase (U / L, q4w 5.3; q2w 12.4; placebo - 5.7) and bilirubin (μmol / L, q4w - 0.149; q2w 0.432; placebo 0.212).

[0261] Conclusions

[0262] Adolescent patients with moderate to severe AD have a substantial multidimensional disease burden, as assessed by AD signs, patient-reported symptoms, and impact on quality of life.

[0263] Dupilumab demonstrated clinically meaningful and statistically significant improvements in different aspects of AD in adolescents, including signs, symptoms, and quality of life. For most endpoints, the Q2W and Q4W regimens were comparable; the Q2W regimen was numerically superior to Q4W in some categorical endpoints (e.g., NRS > 4, IGA(0,1), EASI-50). Compared with placebo, dupilumab treatment showed rapid improvement in pruritus in adolescents with moderate-to-severe AD as early as day 5 and clinically meaningful improvement by day 13. In the Q4W group, a higher proportion of patients required rescue medication treatment. Dupilumab was generally safe and well tolerated in adolescents with AD. The adverse event profile was similar to that seen in adults. No new adolescent-specific safety signals were seen in the study. Compared with adults, the incidence of SAE, AE, and common ADRs leading to permanent treatment discontinuation was slightly lower in adolescents. Both regimens were equally well tolerated. No dose-dependent toxicity was observed except for injection site reactions. PK exposure was lower in Q4W compared with the Q2W regimen. No clinically meaningful impact of ADA on efficacy or safety was observed. No clinically meaningful changes in laboratory parameters occurred with dupilumab treatment in adolescents with moderate to severe AD.

[0264] In adolescent patients who did not achieve IGA 0 / 1 at week 16, dupilumab led to statistically significant and clinically meaningful improvements in other AD signs, symptoms, and QoL compared with placebo.

[0265] In summary, treatment with dupilumab as monotherapy significantly improved measures of overall disease severity, skin clearing, pruritus, and quality of life.

[0266] Example 3: Dupilumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis and a History of Inadequate Response, Intolerance, or Contraindication to Cyclosporine A: Results from a 16-Week Trial

[0267] This example describes the results from a Phase 3 trial of dupilumab (DPL) (NCT03054428) in a subgroup of adolescents with inadequate response, intolerance, or contraindication to cyclosporine A (CsA).

[0268] Patients (≥12–17 years) were randomized to: subcutaneous dupilumab every 2 weeks (q2w; baseline [BL] weight <60 kg: 200 mg; BL weight ≥60 kg: 300 mg); every 4 weeks (q4w; 300 mg), or placebo (PBO) q2w for 16 weeks (wks). This analysis compared 16-week efficacy of DPL vs. PBO in patients with inadequate response, intolerance, or contraindication to CsA.

[0269] Fourty-one and a half (41 / 251) patients (PBO n = 14; DPL q4w n = 13; DPL q2w n = 14) met the inclusion criteria for analysis. DPL led to numerically higher proportions of patients with an Investigator's Global Assessment score of 0 / 1 (q2w / q4w vs PBO 14.3% / 7.7% vs. 0%; P = 0.1761 / 0.3173) and patients with an Eczema Area and Severity Index (EASI) score reduction of ≥ 75% (28.6% / 30.8% vs 7.1%; P = 0.1800 / 0.1495). DPL showed numerical improvements in EASI scores (% change: -51.5 / -58.2 vs -12.7; P = 0.0769 / 0.0521) and Peak Pruritus Numerical Rating Scale vs PBO ([PP-NRS]; 4.03 / -3.83 vs -2.67; P = 0.6437 / 0.5086). Relative to PBO, more DPL patients achieved improvements of ≥ 3 points and ≥ 4 points in the PP-NRS (57.1% / 33.3% vs 7.1%; P = 0.0036 / 0.1214 and 42.9% / 16.7% vs 0%; P = 0.0088 / 0.1343). DPL improved the AD score (SCORAD) Sleep Loss Visual Analogue Scale (VAS) score in patients with a SCORAD Sleep Loss VAS ≥ 2 at BL (q2w / q4w vs PBO: -5.01 / -6.37 vs -3.91; P = 0.3525 / 0.0417); the Patient-Oriented Eczema Measure (POEM) questionnaire #2 assessing sleep disruption frequency (q2w / q4w vs PBO: -1.26 / -2.57 vs -0.74; P = 0.4022 / 0.0032); and the Children's Dermatology Life Quality Index (CDLQI) questionnaire #9 assessing sleep impact (q2w / q4w vs PBO: -1.59 / -2.08 vs -1.12; P = 0.2100 / 0.0114). Relative to PBO, DPL improved the POEM score (q2w / q4w vs PBO: -7.17 / -11.51 vs -2.12; P = 0.1579 / 0.0128). Numerical improvements in CDLQI were observed for DPL vs PBO (q2w / q4w vs PBO: –9.34 / –12.25 vs –7.87; P = 0.4559 / 0.0590). More DPL vs PBO patients had changes in the POEM and CDLQI that were meaningful in individuals (improvement ≥ 6 points) (50.0% / 46.2% vs 14.3%; P = 0.0296 / P = 0.1037; and 64.3% / 45.5% vs 15.4%; P = 0.0221 / 0.1246). In the overall population, DPL was generally well tolerated.

[0270] Dupilumab monotherapy improved skin lesions, symptoms, and quality of life in this small subgroup of adolescents with moderate to severe AD and a history of inadequate response, intolerance, or contraindications to CsA.

[0271] The scope of the present invention is not limited to the specific embodiments described herein. Indeed, various modifications of the invention will become apparent to those skilled in the art in light of the foregoing specification and drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for treating moderate to severe atopic dermatitis (AD) or improving AD-related parameters, the method comprising: (a) selecting a patient ≥ 12 and < 18 years of age with moderate to severe AD that is not adequately controlled with topical AD medications or for whom topical treatment is medically inadvisable; and (b) administering to a patient in need thereof one or more doses of a therapeutically effective amount of an interleukin-4 (IL-4R) inhibitor.

2. The method of claim 1, wherein the patient is selected based on a characteristic selected from: (i) the patient has a baseline IGA score = 4; (ii) the patient has a baseline IGA score ≥ 3; (iii) the patient has a body weight < 60 kg; (iv) the patient has a body weight ≥ 60 kg; (v) the patient has a history of inadequate response to topical AD treatment or for whom topical treatment is inadvisable due to adverse side effects or safety risks; (vi) the patient has a history of inadequate response, intolerance, or contraindication to systemic treatment; (vii) the patient has been previously treated with a drug or method selected from topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological therapeutic agents, systemic glucocorticoids, non-steroidal systemic immunosuppressants, cyclosporin A, azathioprine, methotrexate, mycophenolate mofetil, ultraviolet therapy, and phototherapy; and (viii) the patient has a co-morbid disease or condition selected from food allergy, asthma, seasonal allergy, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, house dust allergy, urticaria, and eosinophilic esophagitis.

3. The method of claim 2, wherein the patient has a body weight < 60 kg.

4. The method of claim 2, wherein the patient has a body weight ≥ 60 kg.

5. The method of any one of claims 1-4, wherein the IL-4R inhibitor is an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof.

6. The method of any one of claims 1-5, wherein each dose comprises 20-600 mg of the IL-4R inhibitor.

7. The method of claim 2, wherein the IL-4R inhibitor is administered as an initial dose, followed by one or more second doses, wherein each second dose is administered 1 to 4 weeks after the immediately preceding dose.

8. The method of claim 7, wherein the initial dose comprises 50-600 mg of the IL-4R inhibitor.

9. The method of claim 8, wherein each second dose comprises 25-400 mg of the IL-4R inhibitor.

10. The method of claim 7, wherein the initial dose comprises 400 mg of the IL-4R inhibitor and each second dose comprises 200 mg of the IL-4R inhibitor.

11. The method of claim 7, wherein the initial dose comprises 600 mg of the IL-4R inhibitor and each second dose comprises 300 mg of the IL-4R inhibitor.

12. The method of claim 10 or 11, wherein each second dose is administered 1 week after the immediately preceding dose.

13. The method of claim 10 or 11, wherein each second dose is administered 2 weeks after the immediately preceding dose.

14. The method of claim 10 or 11, wherein each second dose is administered 4 weeks after the immediately preceding dose.

15. A method for treating moderate to severe atopic dermatitis (AD) or improving AD-related parameters, the method comprising: (a) selecting a patient with moderate to severe AD, wherein the patient has a disease that cannot be adequately controlled with topical AD medications or for whom topical treatment is medically inadvisable, wherein the patient is ≥ 12 and < 18 years old, and wherein the patient's weight < 60 kg; and (b) administering to a patient in need thereof a starting dose, followed by one or more second doses, of a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor; wherein the starting dose comprises 400 mg of the IL-4R inhibitor, and each second dose comprises 200 mg of the IL-4R inhibitor.

16. A method for treating moderate to severe atopic dermatitis (AD) or improving AD-related parameters, the method comprising: (a) selecting a patient with moderate to severe AD, wherein the patient has a disease that cannot be adequately controlled with topical AD medications or for whom topical treatment is medically inadvisable, wherein the patient is ≥ 12 and < 18 years old, and wherein the patient's weight ≥ 60 kg; and (b) administering to a patient in need thereof a starting dose, followed by one or more second doses, of a therapeutically effective amount of an interleukin-4 receptor (IL-4R) inhibitor; wherein the starting dose comprises 600 mg of the IL-4R inhibitor, and each second dose comprises 300 mg of the IL-4R inhibitor.

17. The method of claim 15 or 16, wherein the patient is selected based on characteristics selected from: (i) the patient has a baseline IGA score = 4; (ii) the patient has a baseline IGA score ≥ 3; (iii) the patient's weight < 60 kg; (iv) the patient's weight ≥ 60 kg; (v) the patient has a history of inadequate response to topical AD therapy or for whom topical therapy is inadvisable due to adverse side effects or safety risks; (vi) the patient has a history of inadequate response, intolerance, or contraindication to systemic treatment; (vii) the patient has previously been treated with a drug or method selected from topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, dermatological therapeutic agents, systemic glucocorticoids, non-steroidal systemic immunosuppressants, cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil, ultraviolet therapy, and phototherapy; and (viii) the patient has a comorbid disease or condition selected from food allergy, asthma, seasonal allergy, allergic conjunctivitis, allergic rhinitis, chronic sinusitis, nasal polyps, house dust allergy, urticaria, and eosinophilic esophagitis.

18. The method of any one of claims 15 - 17, wherein the IL-4R inhibitor is an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof.

19. The method of claims 15 - 18, wherein each second dose is administered 1 to 4 weeks after the immediately preceding dose.

20. The method of claim 19, wherein each second dose is administered 1 week after the immediately preceding dose.

21. The method of claim 19, wherein each second dose is administered 2 weeks after the immediately preceding dose.

22. The method of claim 19, wherein each second dose is administered 4 weeks after the immediately preceding dose.

23. The method of any one of claims 1 - 22, wherein administration of the IL - 4R inhibitor results in an effect selected from: (i) by week 2 after administration of the first dose of the IL - 4R inhibitor, the EASI score is reduced by more than 30% from baseline; (ii) the pruritus NRS is reduced by more than 45% from baseline; and (iii) by week 16 after administration of the first dose of the IL - 4R inhibitor, the IGA score is reduced from baseline to achieve an IGA score of 0 or 1.

24. The method of any one of claims 1 - 23, wherein the IL - 4R inhibitor is administered in combination with a second therapeutic agent selected from topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, antibacterial therapeutic agents, and therapeutic agents for obstructive airway diseases.

25. The method of any one of claims 1 - 24, wherein the IL - 4R inhibitor is an antibody or an antigen - binding fragment thereof that binds to IL - 4Rα and blocks the interaction of IL - 4 and / or IL - 13 with type 1 or type 2 IL - 4 receptors.

26. The method of claim 25, wherein the antibody or an antigen - binding fragment thereof blocks the interaction of IL - 4 with type 1 and type 2 IL - 4 receptors.

27. The method of claim 26, wherein the antibody or antigen-binding fragment thereof comprises: The heavy - chain complementarity - determining regions (HCDRs) of the heavy - chain variable region (HCVR) comprising the amino acid sequence SEQ ID NO: 1 and the light - chain complementarity - determining regions (LCDRs) of the light - chain variable region (LCVR) comprising the amino acid sequence SEQ ID NO:

2.

28. The method of claim 26, wherein the antibody or an 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 SEQ ID NO: 3; HCDR2 comprises the amino acid sequence SEQ ID NO: 4; HCDR3 comprises the amino acid sequence SEQ ID NO: 5; LCDR1 comprises the amino acid sequence SEQ ID NO: 6; LCDR2 comprises the amino acid sequence SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence SEQ ID NO:

8.

29. The method of claim 28, wherein the HCVR comprises the amino acid sequence SEQ ID NO: 1 and the LCVR comprises the amino acid sequence SEQ ID NO:

2.

30. The method of claim 29, wherein the antibody or an antigen - binding fragment thereof comprises a heavy chain comprising the amino acid sequence SEQ ID NO: 9 and a light chain comprising the amino acid sequence SEQ ID NO:

10.

31. The method of any one of claims 1-29, wherein the IL-4R inhibitor is dupilumab or a bioequivalent thereof.

32. The method of claim 25, wherein the IL-4R inhibitor is AMG 317 or MEDI9314.

33. The method of any one of claims 1-32, wherein the IL-4R inhibitor is administered subcutaneously.

34. The method of any one of claims 1-33, wherein the IL-4R inhibitor is contained in a container selected from vials, syringes, prefilled syringes, autoinjectors, and microinfusers.

35. The method of any one of claims 1-34, wherein the IL-4R inhibitor is contained in a prefilled syringe.

36. The method of claim 35, wherein the prefilled syringe is a single-dose prefilled syringe.

37. The method of any one of claims 1-34, wherein the IL-4R inhibitor is contained in an autoinjector.

38. The method of any one of claims 35-37, wherein the IL-4R inhibitor is contained in a volume of 1.15 mL.

39. The method of any one of claims 35-37, wherein the IL-4R inhibitor is contained in a volume of 2.25 mL.

40. The method of claim 37, wherein the autoinjector contains a prefilled syringe.

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