Methods for treating atopic dermatitis by administering il-4r antagonist

Abstract

To provide a safe and effective therapy for atopic dermatitis (AD) in pediatric subjects.SOLUTION: Provided are methods for treating moderate-to-severe or severe atopic dermatitis in a pediatric subject. In one aspect, the methods comprise administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or an antigen-binding fragment thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed as a PCT International Patent Application on August 5, 2020, and claims priority to U.S. Provisional Patent Application No. 62 / 882,946, filed August 5, 2019; U.S. Provisional Patent Application No. 62 / 940,108, filed November 25, 2019; U.S. Provisional Patent Application No. 62 / 985,715, filed March 5, 2020; U.S. Provisional Patent Application No. 63 / 024,467, filed May 13, 2020; and U.S. Provisional Patent Application No. 63 / 032,408, filed May 29, 2020, the contents of each of which are incorporated herein by reference.

[0002] Array declarations This application has been submitted electronically in ASCII format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. This ASCII copy was created on August 4, 2020, is named 40848-0098USU1-SEQLIST.TXT, and is 11 kilobytes in size.

[0003] The present disclosure relates to the use of interleukin-4 receptor (IL-4R) antagonists to treat atopic dermatitis. [Background technology]

[0004] Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease characterized by intense pruritus (i.e., itching), xerosis (dry skin), and eczematous lesions (characterized by erythema, infiltrates / papules, exudation with crusting, epidermal peeling, and lichenification). Atopic dermatitis is often associated with other atopic disorders, such as allergic rhinitis and asthma. Severe disease can be extremely disabling due to several factors: significant psychological problems, significant sleep deprivation, and impaired quality of life (QOL) associated with high socioeconomic costs. An estimated 2% to 10% of adults are affected by AD (Non-Patent Document 1).

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

[0006] The clinical pattern of AD varies with age. Infants typically present with weeping, highly pruritic, erythematous papules and blisters on the cheeks, forehead, or scalp. Childhood plaques typically occur from age 2 years until puberty. Children are less likely to have infantile weeping lesions and instead present with more lichenified papules and plaques representing a more chronic disease involving the hands, feet, wrists, ankles, and anterior forearms and popliteal areas. Adult plaques of AD begin at puberty and often continue into adulthood. Primary areas of involvement include the flexural folds, face and neck, upper arms and back, and hands. It includes the feet, fingers, and dorsum of the toes. The rash is characterized by dry, scaly, erythematous papules and plaques, and the formation of large lichenified plaques as the lesions become chronic.

[0007] This disease has been shown to significantly impact patients' quality of life (QOL), greater than that seen in other common skin disorders such as psoriasis and acne (Non-Patent Document 6). Itching, often severe, is a common symptom of AD and often leads to sleep disturbances, irritability, and generalized stress in both affected patients and family members (Non-Patent Document 7). In addition to causing discomfort, sleep deprivation, and psychosocial problems, AD can impose a significant economic burden on families, including direct medical care, home care, and job loss (Non-Patent Document 8; Non-Patent Document 9; Non-Patent Document 10).

[0008] Of particular interest in children is the "atopic march" phenomenon, characterized by a typical progression of clinical signs of atopic disease. Clinical signs of AD and food allergies generally precede the onset of asthma and allergic rhinitis, suggesting that AD is a "gateway" for subsequent allergic diseases (Non-Patent Document 11). The severity of AD correlates with the onset of asthma and allergic rhinitis (Non-Patent Document 12). The prevalence of asthma among children aged 6 years or older who developed eczema in the first four years of life is estimated to be approximately 35% (Non-Patent Document 13). In a prospective study of the "atopic march" that followed children with eczema in infancy, 47% of patients had allergic rhinoconjunctivitis and 29% had asthma by the age of 10 (Non-Patent Document 14). More severe skin disease is directly correlated with a higher risk of developing comorbid conditions (asthma, allergic rhinitis, food allergies, and mental health disorders) and is associated with more severe comorbidities (Non-Patent Document 15). Also, the incidence of mental health disorders such as anxiety, depression, and attention-deficit hyperactivity disorder (ADHD) is higher in children with AD (Non-Patent Document 16). The course of the disease in school-age children can be complicated by potentially life-threatening complications such as herpetic eczema (Non-Patent Document 17).

[0009] Non-pharmacological management of AD, including environmental control measures (e.g., avoidance of allergens and skin irritants) and skin care measures (e.g., maintaining skin hydration through the use of emollients), plays a supportive role, especially in children with moderate to severe disease. Pharmacological management of AD in children is primarily limited to topical therapy with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs). However, long-term use of TCS in children is not recommended due to the risk of irreversible skin atrophy, pigmentation abnormalities, and acneiform rash, as well as risks associated with systemic absorption (e.g., growth retardation, hypothalamic-pituitary axis effects). Additionally, topical calcineurin inhibitors, such as tacrolimus and pimecrolimus, are used in AD as an alternative to or in combination with TCS. More effective TCI products (e.g., tacrolimus 0.1%) are not approved for use in children aged 6 to 11 years. Furthermore, TCI use is often associated with skin irritation. Furthermore, TCIs have been linked to a possible increased risk of malignancies (lymphoma and skin cancer).

[0010] Systemic agents are not indicated for use in children aged 6 to 11 years (cyclosporine, systemic steroids, methotrexate, azathioprine, and mycophenolate mofetil). A recent European study, the European Treatement of Severe Atopic Eczema in Children Taskforce (TREAT), found that approximately 70% of responders initiated systemic therapy for children with severe AD (18). All of these systemic agents have significant side effects in children, including growth retardation, diabetes, skin atrophy, hypertension, osteoporosis, and rebound exacerbation after discontinuation (corticosteroids), myelosuppression and hepatotoxicity (methotrexate), nephrotoxicity and hypertension (cyclosporine), increased risk of malignancies (cyclosporine, azathioprine), and gastrointestinal disorders and leukopenia (azathioprine). Furthermore, the risk of disease progression is high. The majority of patients whose disease is initially controlled with systemic agents suffer a relapse shortly after therapy is discontinued (19). [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Bieber 2008, N. Engl. J. Med. 358:1483-94 [Non-patent document 2] Illi et al., 2004, J. Allergy Clin. Immunol. 113:925-31 [Non-patent document 3] Kay et al., 1994, J. Am. Acad. Dermatol. 30:35-9 [Non-patent document 4] Williams et al., 1999, J. Allergy Clin. Immunol. 103:125-38 [Non-patent document 5] Hong et al., 2012, Envt. Health Toxicol. Vol. 27: e2012006 [Non-patent document 6] Lewis-Jones et al., 1995, Brit. J. Dermatol. 132:942-9 [Non-Patent Document 7] Kim et al., 2012, J. Kor. Med. Sci. 27:1327-32 [Non-patent document 8] Su et al., 1997, Arch. Dis. Child. 76:159-62 [Non-Patent Document 9] Verboom et al., 2002, Brit. J. Dermatol. 147:716-24 [Non-Patent Document 10] Williams 2005, New Engl. J. Med. 352:2314-24 [Non-Patent Document 11] Spergel 2003, J Allergy Clin Immunol. 112 (Suppl. 6): S118-27 [Non-Patent Document 12] Zheng 2011, Allergy Asthma Immunol Res. Volume 3 (No. 2): pp. 67-73. [Non-Patent Document 13] Van der Hulst 2007, J Allergy Clin Immunol. 120(3):565-9 [Non-Patent Document 14] Ekback 2014, PLoSOne. Volume 9 (No. 6): e99609 [Non-Patent Document 15] Silverberg 2013, Pediatr Allergy Immunol. 24(5):476-86 [Non-Patent Document 16] Yaghmaie 2013, J Allergy Clin Immunol. Volume 131 (No. 2): pp. 428-33. [Non-Patent Document 17] Luca 2012, Pediatr. 161(4):671-5 [Non-Patent Document 18] Proudfoot 2013, Br J Dermatol. Volume 169 (No. 4): pp. 901-9. [Non-Patent Document 19] Schmitt 2009, Brit J Dermatol;journal compilation: pp. 1-8 Summary of the Invention [Problem to be solved by the invention]

[0012] Thus, there is currently a large unmet medical need for safe and effective therapies for AD in children. [Means for solving the problem]

[0013] In one aspect, methods are provided for treating atopic dermatitis (AD) or improving AD-related parameters in a subject. In some embodiments, the methods include administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a pediatric subject with moderate-to-severe or severe AD, wherein the subject is ≥ 6 years old and < 12 years old. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof.

[0014] In some embodiments, the method comprises: (a) selecting a subject with severe AD, wherein the subject is ≥6 years old to <12 years old; and (b) administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. Includes:

[0015] In some embodiments, the subject is a subject with severe AD that cannot be adequately controlled by topical AD medication or topical treatment is not medically recommended.In some embodiments, the subject is an inadequate responder to topical corticosteroid (TCS) treatment.In some embodiments, the subject is a subject with severe AD that is a candidate for systemic therapy.

[0016] In some embodiments, the subject: (i) Baseline Investigator's Global Assessment (IGA) score ≥ 4; (ii) Baseline Eczema Area and Severity Index (EASI) and Severity Index) score ≥ 21; (iii) baseline body surface area (BSA) affected by AD ≥ 15%; and / or (iv) have chronic AD diagnosed at least 1 year before treatment initiation;

[0017] In some embodiments, the subject: (i) Baseline Investigator Global Assessment (IGA) score = 4; (ii) baseline Eczema Area and Severity Index (EASI) score ≥ 21; (iii) baseline body surface area (BSA) affected by AD ≥ 15%; and / or (iv) have chronic AD diagnosed at least 1 year before treatment initiation;

[0018] In some embodiments, the subject has at least one concomitant allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergies, allergic conjunctivitis, hives, chronic rhinosinusitis, nasal polyps, and eosinophilic esophagitis.

[0019] In some embodiments, the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more secondary doses, each secondary dose being administered 1-4 weeks after the immediately preceding dose. In some embodiments, the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more secondary doses, each secondary dose being administered 1-4 weeks after the immediately preceding dose. (i) for subjects weighing <30 kg, the initial dose of the IL-4R antagonist is 200 mg and each subsequent dose is 100 mg; or (ii) for subjects weighing ≥ 30 kg, the initial dose of the IL-4R antagonist is 400 mg and each secondary dose is 200 mg; or (iii) The initial dose of the IL-4R antagonist is 600 mg, and each secondary dose is 300 mg.

[0020] In some embodiments, the subject weighs <30 kg and the IL-4R antagonist is administered at an initial dose of 200 mg, followed by one or more secondary doses of 100 mg every two weeks (Q2W). In some embodiments, the subject weighs ≥30 kg and the IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more secondary doses of 200 mg every two weeks (Q2W). In some embodiments, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg every four weeks (Q4W).

[0021] In some embodiments, the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more secondary doses; (i) for subjects weighing <30 kg, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q4W; or (ii) for subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more secondary doses of 200 mg Q2W; or (iii) For subjects weighing ≥ 60 kg, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q2W.

[0022] In some embodiments, the subject weighs <30 kg and is administered an initial dose of 600 mg of the IL-4R antagonist, followed by one or more secondary doses of 300 mg Q4W. In some embodiments, the subject weighs ≥15 kg to <30 kg and is administered an initial dose of 600 mg of the IL-4R antagonist, followed by one or more secondary doses of 300 mg Q4W. In some embodiments, the subject weighs ≥30 kg to <60 kg and is administered an initial dose of 400 mg of the IL-4R antagonist, followed by one or more secondary doses of 200 mg Q2W. In some embodiments, the subject weighs ≥60 kg and is administered an initial dose of 600 mg of the IL-4R antagonist, followed by one or more secondary doses of 300 mg Q2W.

[0023] In some embodiments, the IL-4R antagonist is administered subcutaneously at a dose of about 50 mg to about 600 mg, with or without an initial dose or loading dose. In some embodiments, the IL-4R antagonist is administered to a subject (e.g., a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg) at a dose of 100 mg Q2W, with or without an initial dose or loading dose. In some embodiments, the IL-4R antagonist is administered to a subject (e.g., a subject weighing ≥30 kg or a subject weighing ≥30 kg to <60 kg) at a dose of 200 mg Q2W, with or without an initial dose or loading dose. In some embodiments, the IL-4R antagonist is administered to a subject (e.g., a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg) at a dose of 300 mg Q4W, with or without an initial dose or loading dose. In some embodiments, the IL-4R antagonist is administered to a subject (eg, a subject weighing ≧60 kg) at a dose of 300 mg Q2W, with or without an initial or loading dose.

[0024] In some embodiments, the IL-4R antagonist is administered subcutaneously in a dose of about 50 mg to about 600 mg as a "split dose," e.g., with an initial or loading dose administered two or more days apart. is administered as divided doses over the course of about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the IL-4R antagonist is administered to a subject at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q4W, where the initial dose is split into two or more doses (e.g., a first 300 mg dose and a second 300 mg dose). In some embodiments, the IL-4R antagonist is administered to a subject at an initial dose of 400 mg, followed by one or more secondary doses of 200 mg Q2W, where the initial dose is split into two or more doses (e.g., a first 200 mg dose and a second 200 mg dose). In some embodiments, the IL-4R antagonist is administered to a subject at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q2W, where the initial dose is divided into two or more doses (e.g., a first 300 mg dose and a second 300 mg dose). In some embodiments, a portion of the initial dose is administered on day 1, then the remainder of the initial dose is administered 1 week later, 2 weeks later, 3 weeks later, or 4 weeks later, followed by one or more secondary doses after the remainder of the initial dose. In some embodiments, a portion of the initial dose is administered on day 1, then the remainder of the initial dose is administered on day 8 (1 week later), day 15 (2 weeks later), or day 22 (3 weeks later), followed by one or more secondary doses after the remainder of the initial dose.

[0025] In some embodiments, the IL-4R antagonist is administered to a subject at an initial dose of 300 mg on day 1, then 300 mg on day 15 (week 2), with subsequent doses administered at 300 mg Q4W from day 15 onwards. In some embodiments, the IL-4R antagonist is administered to a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg at an initial dose of 300 mg on day 1, then 300 mg two weeks later, with subsequent doses administered at 300 mg Q4W. In some embodiments, the IL-4R antagonist is administered to a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg at an initial dose of 300 mg on day 1, then 300 mg on day 15 (week 2), with subsequent doses administered at 300 mg Q4W from day 15 onwards.

[0026] In some embodiments, the IL-4R antagonist is administered to a subject at a dose of 300 mg Q4W, with an additional dose administered on week 2 (e.g., day 15). In some embodiments, the IL-4R antagonist is administered to a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg at a dose of 300 mg Q4W, with an additional dose administered on week 2 (e.g., day 15).

[0027] In some embodiments, the IL-4R antagonist is administered to a subject at an initial dose of 300 mg, followed by 300 mg Q4W starting two weeks after the initial dose. In some embodiments, the IL-4R antagonist is administered to a subject weighing <30 kg or a subject weighing ≥15 kg to <30 kg at an initial dose of 300 mg, followed by 300 mg Q4W starting two weeks after the initial dose.

[0028] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered to a subject (e.g., a subject ≥ 6 years old to < 12 years old with moderate-severe or severe AD who is a candidate for systemic therapy) at a dose of 300 mg Q4W. In some embodiments, an initial or loading dose of about 400 mg or about 600 mg of the IL-4R antagonist is administered. In some embodiments, no initial or loading dose is administered. In some embodiments, a split loading dose is administered.

[0029] In some embodiments, the IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered to a subject (e.g., a subject ≥ 6 years old and < 12 years old with moderate to severe or severe AD who is a candidate for systemic therapy) when the subject weighs ≥ 15 kg and < 30 kg. is administered at a dose of 300 mg Q4W, or if the subject weighs ≥ 30 kg to < 60 kg, at a dose of 200 mg Q2W, or if the subject weighs ≥ 60 kg, at a dose of 300 mg Q2W. In some embodiments, an initial or loading dose of about 400 mg or about 600 mg of IL-4R antagonist is administered. In some embodiments, no initial or loading dose is administered. In some embodiments, a split loading dose is administered.

[0030] In some embodiments, the IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered to a subject (e.g., a subject ≥ 6 years old to < 12 years old with moderate-severe or severe AD who is a candidate for systemic therapy) at a dose of 200 mg if the subject weighs ≥ 60 kg. It is administered at a dose of 100 mg QW or 300 mg QW.

[0031] In some embodiments, the subject is administered an IL-4R antagonist in combination with a topical agent (e.g., a topical corticosteroid (TCS) or a topical non-steroidal agent). In some embodiments, the subject is administered an IL-4R antagonist in combination with a TCS. In some embodiments, the TCS is a medium-potency TCS. In some embodiments, the TCS is a low-potency TCS. In some embodiments, treatment with an IL-4R antagonist reduces the amount of TCS administered to the subject compared to baseline.

[0032] In some embodiments, treatment with an IL-4R antagonist comprises: (i) a reduction in IGA score from baseline to achieve an IGA score of 0 or 1 by week 16 after administration of the first dose of the IL-4R antagonist; and (ii) At least a 75% reduction from baseline in the EASI score (EASI-75) by week 16 after the first dose of the IL-4R antagonist. and (c) improving an AD-related parameter selected from the group consisting of:

[0033] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab or a biological equivalent thereof.

[0034] In some embodiments, a method for treating AD in a subject or improving an AD-related parameter comprises administering an IL-4R antagonist to a subject with moderate-to-severe or severe AD, wherein the subject is ≧6 years old and <12 years old, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that specifically binds to IL-4R and 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; the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more secondary doses, (i) for subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q4W; or (ii) for subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more secondary doses of 200 mg Q2W; or (iii) For subjects weighing ≥ 60 kg, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q2W.

[0035] In some embodiments, the subject is concurrently administered a topical agent (e.g., a topical corticosteroid (TCS), or a topical non-steroidal agent such as a calcineurin inhibitor or crisaborole). In some embodiments, the subject is concurrently administered a TCS. In some embodiments, the TCS is a medium-potency TCS. In some embodiments, the TCS is a low-potency TCS.

[0036] In some embodiments, there is provided a method for treating AD or ameliorating an AD-related parameter in a subject, wherein the subject is ≧6 years of age and <18 years of age and has moderate-to-severe or severe AD, the method comprising administering to the subject an anti-IL-4R antibody or antigen-binding fragment thereof comprising an HCDR of an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCDR of an LCVR comprising the amino acid sequence of SEQ ID NO: 2; (i) for subjects weighing ≥15 kg to <30 kg, the anti-IL-4R antibody or antigen-binding fragment thereof is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q4W; or (ii) for subjects weighing ≥30 kg to <60 kg, the anti-IL-4R antibody or antigen-binding fragment thereof is administered at an initial dose of 400 mg, followed by one or more secondary doses of 200 mg Q2W; or (iii) for subjects weighing ≥ 60 kg, the anti-IL-4R antibody or antigen-binding fragment thereof is administered at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg Q2W; A method is provided.

[0037] In some embodiments, the subject is >= 6 years old to < 12 years old. In some embodiments, the subject has severe AD. In some embodiments, the subject is a candidate for systemic therapy.

[0038] In some embodiments, the IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof as disclosed herein) is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pen delivery device (e.g., a pre-filled pen).

[0039] In another aspect, therapeutic dosage forms of pharmaceutical compositions comprising an IL-4R antagonist are provided. In some embodiments, the therapeutic dose of the IL-4R antagonist is 2 mg / kg, and once-weekly administration of the dosage form to a subject for 4 weeks provides a mean serum concentration of the IL-4R antagonist of 74 (± 20) mg / L. In some embodiments, the therapeutic dose of the IL-4R antagonist is 2 mg / kg, and once-weekly administration of the dosage form to a subject for at least 24 weeks provides a mean serum concentration of the IL-4R antagonist of about 61 mg / L to about 77 mg / L. In some embodiments, the therapeutic dose of the IL-4R antagonist is 4 mg / kg, and once-weekly administration of the dosage form to a subject for 4 weeks provides a mean serum concentration of the IL-4R antagonist of 161 (± 60) mg / L. In some embodiments, the therapeutic dose of the IL-4R antagonist is 4 mg / kg, and once-weekly administration of the dosage form to a subject for at least 24 weeks provides a mean serum concentration of the IL-4R antagonist of 161 (± 60) mg / L. Once-weekly administration provides a mean serum concentration of the IL-4R antagonist of about 143 mg / L to about 181 mg / L, in some embodiments, the mean serum concentration of the IL-4R antagonist is maintained for at least 48 weeks when the therapeutic dosage form is administered once weekly.

[0040] In some embodiments, a therapeutic dosage form of the pharmaceutical composition comprises an IL-4R antagonist, and administration of the dosage form to a subject over a 16-week period provides a mean serum concentration of the IL-4R antagonist of 80-100 mg / L. In some embodiments, the therapeutic dose of the IL-4R antagonist is 200 mg administered every two weeks. In some embodiments, the therapeutic dose of the IL-4R antagonist is 300 mg administered every four weeks.

[0041] In some embodiments, the therapeutic dosage form is administered to a subject ≥ 6 years old and < 18 years old. In some embodiments, the subject is ≥ 6 years old and < 12 years old. In some embodiments, the subject is ≥ 12 years old and < 18 years old.

[0042] In some embodiments, the therapeutic dosage form comprises an IL-4R antagonist that is an anti-IL-4R antibody or antigen-binding fragment thereof, comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:3, an HCDR2 comprising the amino acid sequence of SEQ ID NO:4, an HCDR3 comprising the amino acid sequence of SEQ ID NO:5, an LCDR1 comprising the amino acid sequence of SEQ ID NO:6, an LCDR2 comprising the amino acid sequence of SEQ ID NO:7, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:8.

[0043] Other embodiments will become apparent from consideration of the following detailed description. [Brief explanation of the drawings]

[0044] [Figure 1-1] Figures 1A-1I show the proportion of patients achieving designated endpoints over time in the overall population and in the baseline weight <30 kg and ≥30 kg subgroups. (A-C) Percentage of patients achieving the co-primary endpoint of IGA 0 / 1 over time in the overall population (A), in the baseline weight <30 kg subgroup (B), and in the ≥30 kg subgroup (C). (D-F) Percentage of patients achieving the co-primary endpoint of EASI-75 over time in the overall population (D), in the baseline weight <30 kg subgroup (E), and in the ≥30 kg subgroup (F). (G-I) Percent least squares (LS) change in EASI over time in the baseline weight <30 kg subgroup (H) and in the ≥30 kg subgroup (I) in the overall population (G). EASI = Eczema Area and Severity Index; EASI-75 = ≥ 75% improvement in EASI score from baseline; IGA = Investigator Global Assessment; LS = Least Squares; Q2W = every 2 weeks; Q4W = every 4 weeks. [Figure 1-2] Continued from Figure 1-1. [Figure 1-3] Continued from Figure 1-2. [Figure 1-4] Continued from Figure 1-3. [Figure 1-5] Continued from Figure 1-4. [Figure 2-1]Figures 2A-2F show the proportion of patients who demonstrated a ≥3 (A-C) and ≥4-point (D-F) improvement in the peak pruritus numerical rating scale weekly mean over time in the total population (A, D), in the baseline weight <30 kg subgroup (B, E), and in the ≥30 kg subgroup (C, F). Q2W = every 2 weeks; Q4W = every 4 weeks. [Figure 2-2] Continued from Figure 2-1. [Figure 2-3] Continued from Figure 2-2. [Figure 3] Graph illustrating total SCORAD over time for subjects receiving placebo + topical corticosteroids (TCS), dupilumab 300 mg Q4W + TCS, or dupilumab 100 / 200 mg Q2W + TCS. **P<0.01; ***P<0.001 vs. placebo + TCS. [Figure 4A] 4A-4C are graphs illustrating the mean log-scale concentrations of dupilumab in serum over time. Figure 4A: Phase 2a study. Vertical arrows represent time points at which dupilumab 2 mg / kg or 4 mg / kg was administered. [Figure 4B] 4B is a graph illustrating the mean log-scale concentration of dupilumab in serum over time. Figure 4B: Phase 3 OLE. Patients in OLE received dupilumab at 2 mg / kg weekly or 4 mg / kg weekly. Cmax, maximum concentration; LLOQ, lower limit of quantification; SD, standard deviation; tmax, time to achieve maximum concentration. [Figure 5A] 5A-5C are graphs illustrating the mean log-scale concentrations of dupilumab in serum over time. Figure 5A: Concentration-time profiles from a Phase 2a study. Vertical arrows represent time points when dupilumab was administered at 2 mg / kg or 4 mg / kg. [Figure 5B] 5A and 5B are graphs illustrating the mean log-scale concentrations of dupilumab in serum over time. (A) and (B) are graphs illustrating the mean log-scale concentrations of dupilumab in serum over time. (B) Concentration-time profiles of the Phase 3 OLE study. In both (A) and (B), concentrations below the limit of quantitation were set as LLOQ / 2 (shown by the dotted line). DETAILED DESCRIPTION OF THE INVENTION

[0045] Before describing the present invention, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, since 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 present invention will be limited only by the appended claims.

[0046] 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.

[0047] The terms "figure", "figures", "drawing" and "figures" are used interchangeably herein.

[0048] As used herein, the term "about," when used in reference to a particular stated value, means that the value may vary from the stated value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0049] As used herein, the terms "treat" or "treating" and the like mean to relieve symptoms, eliminate the cause of symptoms either temporarily or permanently, or prevent or delay the onset of symptoms of the specified disorder or condition.

[0050] "Atopic dermatitis" or "AD," as used herein, refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly, dry, eczema-like lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. The present disclosure encompasses methods for treating patients with moderate-to-severe or severe AD. As used herein, "moderate-to-severe AD" is characterized by intensely pruritic, widespread skin lesions that are often complicated by persistent bacterial, viral, or fungal infections. Moderate-to-severe AD also includes patients with chronic AD. Chronic lesions often include thickened patches of skin, lichenification, and fibrous papules. Patients with moderate-to-severe AD generally have more than 20% of the body's skin or 10% of the 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. Patients may also develop a more severe form of AD if they are resistant or refractory to treatment with either topical corticosteroids or calcineurin inhibitors. A patient may be said to have moderate to severe AD. As used herein, "severe AD" is characterized by widespread skin lesions, constant itching, or the presence of physically or emotionally disabling illness that significantly impairs the patient's quality of life. In some cases, patients with severe AD also exhibit one or more symptoms, such as peeling, widespread skin thickening, bleeding, weeping, and / or cracking of the skin, and changes in pigmentation. In some embodiments, severe AD is refractory to treatment with topical therapy (e.g., topical corticosteroids, calcineurin inhibitors, crisaborole, or phototherapy).

[0051] As used herein, the term "subject in need thereof" refers to a human or non-human animal with AD (e.g., moderate to severe AD or severe AD). In some embodiments, the term "subject in need thereof" refers to a patient with moderate to severe or severe AD who is ≧12 and <18 years of age (adolescent). In other embodiments, the term "subject in need thereof" refers to a patient with moderate to severe or severe AD who is ≧6 and <12 years of age (child). The terms "subject" and "patient" are used interchangeably herein.

[0052] In some embodiments, the term "subject in need thereof" includes patients aged 6-18 years (e.g., adolescent patients ≥12 and <18 years or pediatric patients ≥6 and <12 years), with moderate to severe or severe AD, and who are candidates for systemic therapy. In some embodiments, a subject is a candidate for systemic therapy if the subject's disease is not adequately controlled with local therapy and / or if local therapy is not recommended (e.g., due to safety concerns). In some embodiments, the term "subject in need thereof" includes patients aged 6-18 years (e.g., adolescent patients ≥12 and <18 years or pediatric patients ≥6 and <12 years), with moderate to severe or severe AD, and who have previously been treated with systemic therapy. As used herein, the term "systemic therapy" refers to a systemically administered therapeutic agent (e.g., an orally administered corticosteroid). This term includes systemic immunosuppressants or immunomodulators. In the context of the present disclosure, the term "systemic immunosuppressants" includes, but is not limited to, cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, and interferon-gamma. In certain embodiments, the term also includes tumor necrosis factor alpha (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), and CD20 inhibitors (e.g., rituximab). Systemic therapies, including systemic immunosuppressants, can be used as short-term treatments for flares or as a temporary measure to control disease, but their use is limited by significant side effects, such as childhood growth retardation, Cushing's syndrome, hypertension, glucose intolerance, myopathy, osteonecrosis, glaucoma, and cataracts. Additionally, the use of systemic immunosuppressants carries the risk of rebound, which can result in significant worsening of disease symptoms after treatment is discontinued. In certain embodiments, the terms "systemic therapy," "systemic therapeutic agent," and "systemic immunosuppressant" are used interchangeably throughout this disclosure.

[0053] The term "TCS," as used herein, includes Group I, Group II, Group III, and Group IV topical corticosteroids. According to the Anatomical Therapeutic Classification System of the World Health Organization, corticosteroids are classified based on their activity as weak (Group I), moderately potent (Group II), potent (Group III), and very potent (Group IV) compared to hydrocortisone. Group IV TCS (very potent) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50 to 100 times more potent than hydrocortisone and include betamethasone valerate, dipropionate, and thiazolinone. These include, but are not limited to, betamethasone pionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent; also synonymously referred to herein as "mid-potency") are 2 to 25 times more potent than hydrocortisone, and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild; also synonymously referred to herein as "low-potency") include hydrocortisone.

[0054] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0055] treatment method In one aspect, methods are provided for treating atopic dermatitis (AD) or improving AD-related parameters in a subject. In some embodiments, the methods include administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject with severe AD, wherein the subject is ≥6 years old and <12 years old. In some embodiments, the IL-4R antagonist is administered simultaneously with a topical corticosteroid (TCS) or a topical non-steroidal agent (e.g., a calcineurin inhibitor or crisaborole).

[0056] In some embodiments, subjects treated according to the methods disclosed herein are subjects ≥ 6 years old to < 12 years old who have severe AD that has responded inadequately to topical therapy (e.g., TCS with or without a topical calcineurin inhibitor (TCI)) or for whom topical therapy is not recommended (e.g., due to adverse side effects or safety risks). In some embodiments, the subject has a documented history of inadequate response to a sufficient course of outpatient treatment with a topical AD medication. As used herein, "inadequate response" refers to the failure to achieve and maintain remission or a state of low disease activity (compared to an Investigator Global Assessment [IGA] of 0 = clear to 2 = mild) despite treatment with topical therapy (e.g., a regimen of medium- to high-potency TCS, ± TCI as needed) for at least 28 days. In some embodiments, a subject has an "inadequate response" if the patient has been documented to have received systemic treatment for AD.

[0057] In some embodiments, treatment with an IL-4R antagonist ameliorates, relieves, or reduces one or more symptoms of AD in a subject, including, but not limited to, pruritus (i.e., itching), xerosis (dry skin), eczematous lesions, erythema, papulation, edema, weeping / crusting, excoriation, lichenification, sleep disorders, anxiety, and depression.

[0058] In some embodiments, treatment with an IL-4R antagonist improves one or more AD-related parameters in a subject. Examples of "AD-related parameters" include, but are not limited to, (a) Investigator Global Assessment (IGA), (b) Atopic Dermatitis Body Surface Area Involvement (BSA), (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Pruritus Numerical Rating Scale (NRS). "Improvement of AD-related parameters" refers to improvements in IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, NRS / worst itch score, patient global impression of disease, patient global impression of change, Children's Skin Quality of Life Index, and the like. Dermatology Life Quality Index) (CDLQI), "Baseline" refers to a reduction from baseline in one or more of the Patient Oriented Eczema Measure (POEM), Dermatitis Family Index (DFI) score, or Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and / or depression scores. The term "baseline," when used in reference to an AD-related parameter, refers to the value of the AD-related parameter in a subject before or at the time of administration of a pharmaceutical composition as disclosed herein.

[0059] To determine whether an AD-related parameter is "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present disclosure. For example, AD-related parameters may 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; 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, following initial treatment with a pharmaceutical composition of the present disclosure. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the AD-related parameter. AD-related parameters are described in U.S. Patent Application Publication No. 2014 / 0072583, which is incorporated herein in its entirety.

[0060] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the subject's IGA score compared to baseline. Methods for determining a subject's IGA score are described in the Examples section below. In some embodiments, the subject to be treated has a baseline IGA score of ≧3 (e.g., an IGA score of 3 or an IGA score of 4). In some embodiments, treatment with an IL-4R antagonist results in a reduction in the IGA score of at least 1 point from baseline (e.g., from a baseline IGA score of ≧4) by 16 weeks after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the IGA score from baseline (e.g., from an IGA score of ≧4) to 0 or 1 by 16 weeks after administration of the first dose of the IL-4R antagonist.

[0061] In some embodiments, treatment with an IL-4R antagonist results in a reduction in the IGA score of at least 1 point from baseline (e.g., from a baseline IGA score of ≥ 3) by 16 weeks after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the IGA score from baseline (e.g., from an IGA score of ≥ 3) to 0 or 1 by 16 weeks after administration of the first dose of the IL-4R antagonist.

[0062] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the subject's EASI score compared to baseline. Methods for determining a subject's EASI score are described in the Examples section below. In some embodiments, the subject to be treated has a baseline EASI score of ≥ 21 (e.g., an EASI score of ≥ 30). In some embodiments, treatment with an IL-4R antagonist results in an improvement in the EASI score from baseline of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% by week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a subject achieving an EASI-75 response (i.e., a ≥ 75% improvement from baseline) by 16 weeks after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a subject achieving an EASI-50 response (i.e., a ≥ 50% improvement from baseline) by 16 weeks after administration of the first dose of the IL-4R antagonist.

[0063] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the subject's BSA score compared to baseline. Methods for determining a subject's BSA score are described in the Examples section below. In some embodiments, the subject to be treated has a baseline BSA score of ≥ 15% (e.g., ≥ 20%, ≥ 30%, ≥ 40%, ≥ 50%, ≥ 75%, or ≥ 90%). In some embodiments, the subject to be treated has a baseline BSA score of ≥ 50%. In some embodiments, treatment with an IL-4R antagonist results in a reduction from baseline in the percent BSA affected by AD of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more by 16 weeks after administration of the first dose of the IL-4R antagonist.

[0064] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the subject's itch score, such as a "worst itch scale" score, also referred to herein as a pruritus numerical rating scale (NRS) score, compared to baseline. Methods for determining the itch score are described in the Examples section below. In some embodiments, the subject to be treated has a baseline Worst Itch Score weekly average score with a maximum itch intensity of ≧4 (e.g., ≧7). In some embodiments, treatment with an IL-4R antagonist results in a reduction from baseline in the weekly average of daily itch score (e.g., worst itch score) by ≧3 points (e.g., ≧4 points) by week 16 after administration of the first dose of the IL-4R antagonist.

[0065] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the subject's SCORAD score compared to baseline. Methods for determining a subject's SCORAD score are described in the Examples section below. In some embodiments, the subject to be treated has a baseline SCORAD score of ≧40 (e.g., ≧50, ≧60, or ≧70). In some embodiments, treatment with an IL-4R antagonist results in a reduction in SCORAD score from baseline of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% by 16 weeks after administration of the first dose of the IL-4R antagonist.

[0066] In some embodiments, treatment with an IL-4R antagonist enhances the efficacy and / or safety of topical therapy for AD. As used herein, a topical therapy (e.g., TCS) regimen is "enhanced" if one or more of the following outcomes or phenomena are observed or achieved in a subject: (1) the amount of concurrently administered topical agent (e.g., TCS) is reduced; (2) the number of days that topical agent (e.g., TCS) is concurrently administered is reduced; (3) a lower-potency topical agent is administered to the patient (e.g., the patient is switched from a medium-potency TCS to a low-potency TCS); (4) one or more side effects of the topical agent (e.g., TCS) are reduced or eliminated; or (5) toxicity of the topical agent (e.g., TCS) is reduced. In some embodiments, the amount of a topical agent (e.g., TCS) concurrently administered to a subject increases by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more compared to the subject's baseline value or compared to a subject not administered an IL-4R inhibitor. In some embodiments, treatment with an IL-4R antagonist allows for tapering or cessation of concomitant treatment with a topical agent (e.g., TCS).

[0067] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure comprise administering to a subject in need thereof (e.g., a pediatric subject with severe AD or moderate-to-severe AD) an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor," "IL-4R blocker," or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, whereas type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that can be used in the methods of the present disclosure can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, the IL-4R antagonists of the present disclosure can prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptor.

[0068] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., genetically engineered molecules containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0069] Anti-IL-4Rα antibodies and their antigen-binding fragments In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody," as used herein, includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or VL). H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The region can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V Lis composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0070] The term "antibody" as used herein also refers to the antigen-binding activity of a full-length antibody molecule. The terms "antigen-binding portion" of an antibody and "antigen-binding fragment" of an antibody, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from full-length antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques to, for example, place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine ​​residues, or modify, add, or delete amino acids.

[0071] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other genetically engineered molecules such as shark variable IgNAR domains are also encompassed by the term "antigen-binding fragment" as used herein.

[0072] Antigen-binding fragments of antibodies will typically contain at least one variable domain, which may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. H Domain is V L In the antigen-binding fragment associated with the domain, V H and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer of the monomer V H or V L It may also include a domain.

[0073] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the present disclosure include the following: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C LIn any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, the antigen-binding properties of the antibodies of the present disclosure may be enhanced by the addition of a linker region. The sex fragments may be linked to each other and / or to one or more monomeric V H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above, with the domains non-covalently associated (e.g., by disulfide bonds).

[0074] The constant region of an antibody is important for the antibody's ability to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0075] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies will typically comprise at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope of the same antigen. Any multispecific antibody format can be constructed for use in the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure using routine techniques available in the art. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include (for a review of the aforementioned formats, see, e.g., Klein et al., 2012, mAbs 4:6, pp. 1-11, and the references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation. For example, unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates. The conjugates then self-assemble to form multimeric complexes with defined composition, valency, and shape. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0076] In some embodiments, the antibody used in the methods of the present disclosure is a human antibody. The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or in vivo somatic mutation), for example, in the CDRs, particularly CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0077] The antibodies used in the methods of the present disclosure may be recombinant human antibodies. The term "recombinant human antibody," as used herein, refers to antibodies expressed using recombinant expression vectors (described further below) transfected into host cells, antibodies isolated from recombinant combinatorial human antibody libraries (described further below), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies derived from human immunoglobulin gene sequences integrated into other DNA sequences. The term "human antibodies" is intended to include all human antibodies that are prepared, expressed, produced, or isolated by recombinant means, including antibodies prepared, expressed, created, or isolated by any other means, including splicing into a sequence. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or, if an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis), thus modifying the V and constant regions of the recombinant antibody. H Area and V LThe amino acid sequence of the region is human germline V H Array and V L These sequences are derived from and related to sequences, but may not naturally occur within the human germline repertoire in vivo.

[0078] An "isolated antibody" refers to an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from the tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0079] According to certain embodiments, the antibody used in the methods of the present disclosure specifically binds to IL-4Rα. As used herein, the term "specifically binds" means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and include, for example, equilibrium dialysis and surface plasmon resonance. In some embodiments, an antibody that "specifically binds" to IL-4Rα has an equilibrium dissociation constant (K) of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM, as measured by a surface plasmon resonance assay (e.g., BIAcore™, Biacore Life Sciences Division of GE Healthcare, Piscataway, NJ). D) binds to IL-4Rα or a portion thereof. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) can also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα exhibits cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0080] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies as described in U.S. Pat. No. 7,608,693. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LDCRs (LCDR1, LDCR2, and LDCR3), 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: Contains the amino acid sequence of No. 8.

[0081] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LDCR1, LDCR2, and LDCR3 of SEQ ID NOs: 3, 4, 5, 6, 7, and 8, respectively, and further comprises an HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1, and an LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2.

[0082] In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0083] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include the use of dupilumab or a biological equivalent thereof. The term "biological equivalent," as used herein with respect to dupilumab, refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute whose rate and / or extent of absorption does not significantly differ from that of dupilumab when administered at the same molar dose under similar experimental conditions, whether in a single dose or multiple doses. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R whose safety, purity, and / or potency do not exhibit clinically meaningful differences from dupilumab.

[0084] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present disclosure include, for example, the antibodies known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI9314, or any of the anti-IL-4Rα antibodies set forth in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or 8,877,189.

[0085] In some embodiments, the anti-IL-4Rα antibody used in the methods of the present disclosure may have pH-dependent binding characteristics. For example, an anti-IL-4Rα antibody for use as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use as disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​below about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or lower. As used herein, the term "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.

[0086] In certain cases, the binding to IL-4Rα at acidic pH compared to neutral pH "The K value of antibodies that bind to IL-4Rα at acidic pH is reduced" D K values ​​of antibodies binding to IL-4Rα at neutral pH DFor example, an antibody or antigen-binding fragment thereof may have an acidic / neutral K of about 3.0 or greater. D In certain exemplary embodiments, an antibody or antigen-binding fragment thereof exhibits a ratio of 0.01 to 0.10, and the ... D The ratio may be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0087] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, antibodies with pH-dependent characteristics can be produced by modifying the antigen-binding domain at the amino acid level. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody can be obtained that has reduced antigen-binding properties at acidic pH compared to neutral pH.

[0088] Preparation of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. In the context of the present disclosure, such known methods can be used to generate human antibodies that specifically bind to human IL-4R.

[0089] Using VELOCIMMUNE™ technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves generating transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the antibody heavy and light chain variable regions is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0090] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphocytes (such as B cells) expressing antibodies are collected from the mice. The lymphocytes are fused with a myeloma cell line to prepare immortal hybridoma cell lines, which are then screened and selected to identify hybridoma cell lines producing antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions may be isolated and linked to constant regions of the desired heavy and light chain isotypes. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibody or the light and heavy chain variable domains may be isolated directly from antigen-specific lymphocytes.

[0091] First, high-affinity chimeric antibodies having human variable regions and mouse constant regions are isolated. Using standard procedures known to those skilled in the art, the antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with the desired human constant regions to generate fully human antibodies of the present disclosure, e.g., wild-type or modified IgG1 or IgG4. The constant region selected may vary depending on the particular use, but the high affinity antigen binding and target specificity characteristics reside in the variable region.

[0092] Generally, the antibody that can be used in the method of the present disclosure has high affinity as described above, when measured by binding to either solid-phase immobilized or liquid-phase antigens.The mouse constant region is replaced with the desired human constant region to generate the fully human antibody of the present disclosure.The constant region selected can vary depending on the specific use, but the high affinity antigen binding characteristics and target specificity characteristics reside in the variable region.

[0093] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the methods disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within a given HCVR and / or LCVR amino acid sequence disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, MD (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0094] Pharmaceutical Composition In one aspect, the present disclosure provides a method comprising administering to a subject an IL-4R antagonist, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. A variety of pharmaceutically acceptable carriers and excipients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0095] Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents. In some embodiments, the pharmaceutical compositions disclosed herein are administered intravenously. In some embodiments, the pharmaceutical compositions disclosed herein are administered subcutaneously.

[0096] In some embodiments, the pharmaceutical composition includes an injectable preparation, such as a dosage form for intravenous, subcutaneous, intradermal, and intramuscular injection, drip infusion, etc. Such an injectable preparation can be prepared by a known method. For example, the injectable preparation can be prepared by dissolving, suspending, or administering the antibody or salt thereof described above in a sterile aqueous or oily medium conventionally used for injection. Or they can be prepared by emulsification. Aqueous vehicles for injection include, for example, isotonic solutions containing physiological saline, glucose, and other auxiliary agents, which can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Oily vehicles include, for example, sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injections prepared in this way can be filled into appropriate ampoules.

[0097] The dose of an antibody administered to a subject according to the methods of the present disclosure may vary depending on the subject's age and size, symptoms, condition, route of administration, and the like. Doses are typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be empirically determined. For example, subject progress can be monitored by periodic evaluation, and the dose can be adjusted accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses of anti-IL-4R antibodies and administration regimens including the same that can be used in the context of the present disclosure are disclosed elsewhere herein.

[0098] In some embodiments, the pharmaceutical composition of the present disclosure is contained within a container. Accordingly, in another aspect, a container is provided that contains a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising an IL-4R antagonist, such as an anti-IL-4R antibody, as disclosed herein). For example, in some embodiments, the pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an auto-injector.

[0099] In some embodiments, the pharmaceutical composition of the present disclosure is delivered subcutaneously or intravenously, for example, using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, the pharmaceutical composition of the present disclosure is delivered using a pen delivery device or an auto-injector (e.g., in the case of subcutaneous delivery). The pen delivery device may be reusable or disposable. Typically, a reusable pen delivery device uses a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge is administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. Disposable pen delivery devices do not have a replaceable cartridge. Rather, disposable pen delivery devices are provided pre-filled with the pharmaceutical composition, which is held in a reservoir within the device. Once the reservoir of pharmaceutical composition is emptied, the entire device is discarded.

[0100] Examples of suitable pen delivery devices and autoinjector delivery devices include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTI ... PEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices having application for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly & Co.), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, California), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park, Illinois).

[0101] In some embodiments, the pharmaceutical composition is delivered using a controlled release system. In one embodiment, a pump may be used (Langer, supra; Sefton, 1987, CRC (See Crit. Ref. Biomed. Eng. 14:201.) In another embodiment, polymeric materials may be used: Medical Applications of See, Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, FL. In yet another embodiment, a controlled-release system can be placed in proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533. Other delivery systems, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis, are known and can be used to deliver pharmaceutical compositions (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

[0102] In some embodiments, the pharmaceutical compositions for use as described herein are prepared in a dosage form suitable for dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0103] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in US Pat. No. 8,945,559.

[0104] Dosage and Administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject according to the methods of the present disclosure in a therapeutically effective amount. As used herein with respect to an IL-4R antagonist, the phrase "therapeutically effective amount" refers to an amount of IL-4R antagonist that results in one or more of: (a) an improvement in one or more AD-related parameters (as referred to elsewhere herein); and / or (b) a detectable improvement in one or more symptoms or signs of atopic dermatitis.

[0105] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 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, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg 40mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250m g, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about The therapeutically effective amount may be 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 some embodiments, the therapeutically effective amount is about 75 mg to about 600 mg, about 100 mg to about 600 mg, or about 200 mg to about 600 mg. In certain embodiments, 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of an anti-IL-4R antibody is administered to a subject.

[0106] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in each dose can be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of subject body weight, e.g., about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 9 mg / kg, or about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist can be administered to a subject at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[0107] In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject at a dosing frequency of about 4 times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently as long as a therapeutic response is achieved.

[0108] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined time course. In some embodiments, the methods of the present disclosure include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequential administration" means that each dose of an IL-4R antagonist is administered to a subject at a different time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the present disclosure include sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL-4R antagonist, and optionally followed by one or more tertiary doses of the IL-4R antagonist.

[0109] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order of administration of an IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also called a "loading dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist but may generally differ from one another in terms of administration frequency. However, in certain embodiments, the amount of IL-4R antagonist included in the initial, secondary, and / or tertiary doses differ from one another over the course of treatment (e.g., adjusted upward or downward as needed). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) are administered at the beginning of a treatment regimen as a "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered less frequently.

[0110] In some embodiments, the loading dose is a "split dose" administered as two or more doses (e.g., 2, 3, 4, or 5 doses) administered on separate days. In some embodiments, the loading dose is administered as a split dose, with the two or more doses administered at least about one week apart. In some embodiments, the loading dose is administered as two or more split doses. The above doses are administered as split doses administered at intervals of about 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the loading dose is divided evenly into two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is divided unequally into two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion). In some embodiments, the loading dose is administered as split doses in which the first portion (e.g., the first half) of the loading dose is administered on day 1 and the second portion (e.g., the second half) of the loading dose is administered 1 week later (e.g., day 8), 2 weeks later (e.g., day 15), 3 weeks later (e.g., day 22), or 4 weeks later (e.g., day 29), followed by one or more secondary or maintenance doses.

[0111] For example, the IL-4R antagonist may be administered to a subject at a loading dose of about 200 mg, 400 mg, or about 600 mg, followed by one or more maintenance doses of about 75 mg to about 300 mg. In one embodiment, the initial dose and one or more secondary doses each contain 50 mg to 600 mg of the IL-4R antagonist, e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg of the IL-4R antagonist. In some embodiments, the initial dose and one or more secondary doses each contain the same amount of the IL-4R antagonist. In other embodiments, the initial dose contains a first amount of the IL-4R antagonist, and the one or more secondary doses each contain a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more greater than the second amount of the IL-4R antagonist. In one exemplary embodiment, the IL-4R antagonist is administered to a subject at a loading dose of about 400 mg or about 600 mg, followed by one or more maintenance doses of about 200 mg or 300 mg. In another exemplary embodiment, for a subject weighing <30 kg (e.g., ≥ 15 kg to < 30 kg), the IL-4R antagonist is administered to a subject at a loading dose of about 200 mg, followed by one or more maintenance doses of about 100 mg, or at a loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg. In another exemplary embodiment, for a subject weighing ≧30 kg (e.g., ≧30 kg to <60 kg), the IL-4R antagonist may be administered to the subject at a loading dose of about 400 mg, followed by one or more maintenance doses of about 200 mg, or at a loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg. In yet another exemplary embodiment, for a subject weighing ≧60 kg, the IL-4R antagonist may be administered to the subject at a loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg.In some embodiments, the subject is administered one or more doses of an IL-4R antagonist (e.g., about 50 mg to about 600 mg, e.g., about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg) without an initial dose.

[0112] In some embodiments, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or longer) weeks after the immediately preceding dose. The phrase "immediately preceding dose," as used herein, refers to a dose of an IL-4R antagonist administered to a patient without an intervening dose prior to administration of the immediately succeeding dose in a multiple administration sequence.

[0113] The methods of the disclosure may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist. The method may include administering to the patient a secondary dose. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0114] In some embodiments comprising multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in some embodiments comprising multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the individual patient's needs following clinical testing.

[0115] In some embodiments, for subjects with severe AD ≥ 6 years and < 12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, where if the subject weighs < 30 kg, the initial dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg and each secondary dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 100 mg administered every two weeks (Q2W).

[0116] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, where if the subject weighs ≥ 30 kg, the initial dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 400 mg and each secondary dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W).

[0117] In some embodiments, for subjects ≥ 6 years old to < 12 years old with severe AD, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, wherein the initial dose of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 600 mg and each secondary dose of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W).

[0118] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) for a subject with severe AD ≥ 6 years and < 12 years of age comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, where if the subject weighs < 30 kg, the initial dose of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 600 mg and each secondary dose of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W).

[0119] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, where if the subject weighs ≥ 15 kg to < 30 kg, the initial dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 600 mg and each secondary dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W). In some embodiments, the initial dose is administered as a split dose of 300 mg administered on day 1 and 300 mg administered two weeks later. can be.

[0120] In some embodiments, for subjects with severe AD ≥ 6 years and < 12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, wherein if the subject weighs ≥ 30 kg and < 60 kg, the initial dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 400 mg and each secondary dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W).

[0121] In some embodiments, for subjects ≥ 6 years old to < 12 years old with severe AD, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises an initial (loading) dose followed by one or more secondary (maintenance) doses, where if the subject weighs ≥ 60 kg, the initial dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 600 mg and each secondary dose of the IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W).

[0122] In some embodiments, the IL-4R antagonist is administered without an initial or loading dose. For example, in some embodiments, for subjects with severe AD aged ≥ 6 years to < 12 years, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 100 mg administered every two weeks (Q2W) if the subject weighs < 30 kg.

[0123] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered every two weeks (Q2W) when the subject weighs ≥ 30 kg.

[0124] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W).

[0125] In some embodiments, for subjects with severe AD ≥ 6 years and < 12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W) if the subject weighs < 30 kg.

[0126] In some embodiments, for subjects with severe AD ≥ 6 years and < 12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W) when the subject weighs ≥ 15 kg and < 30 kg.

[0127] In some embodiments, for subjects with severe AD ≥ 6 years and < 12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered every two weeks (Q2W) when the subject weighs ≥ 30 kg and < 60 kg.

[0128] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) is ≥ 600 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) administered every two weeks (Q2W) if the subject weighs ≥ 60 kg. For example, the dose of an anti-IL-4R antibody.

[0129] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered weekly (QW) when the subject weighs ≥ 60 kg.

[0130] In some embodiments, for subjects with severe AD ≥ 6 years old to < 12 years old, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered weekly (QW) when the subject weighs ≥ 60 kg.

[0131] Therapeutic Dosage Form In another aspect, the present disclosure provides a therapeutic dosage form of an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof), wherein administration of the dosage form to a subject for a period of time (e.g., 4 weeks, 8 weeks, 12 weeks, 16 weeks, or longer) results in sustained serum concentrations of the IL-4R antagonist.

[0132] In yet another aspect, the present disclosure provides a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein the therapeutic dose is 2 mg / kg, and wherein weekly administration of the dosage form to a subject for 4 weeks provides a mean serum concentration of 74 (±20) mg / L. In one embodiment of a therapeutic dosage form according to the present disclosure, the mean serum concentration of the IL-4R antagonist is maintained for at least 48 weeks when the therapeutic dosage form is administered weekly.

[0133] In yet another aspect, the present disclosure provides a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein the therapeutic dose is 4 mg / kg, and wherein weekly administration of the dosage form to a subject for four weeks provides a mean serum concentration of 161 (±60) mg / L. In one embodiment of a therapeutic dosage form according to the present disclosure, the mean serum concentration of the IL-4R antagonist is maintained for at least 48 weeks when the therapeutic dosage form is administered weekly.

[0134] In yet another aspect, the present disclosure provides a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein administration of the dosage form to a subject over a 16-week period provides a mean serum concentration of 80-100 mg / L. In one embodiment of a therapeutic dosage form according to the present disclosure, the therapeutic dose is 200 mg administered every two weeks. In another embodiment of a therapeutic dosage form according to the present disclosure, the therapeutic dose is 300 mg administered every four weeks.

[0135] In certain embodiments of the therapeutic dosage form according to the present disclosure, the subject is ≥ 6 years old and < 18 years old. In additional embodiments of the therapeutic dosage form according to the present disclosure, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 3, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 5, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 8.

[0136] Dose increase In another aspect, the disclosure provides methods for treating AD (e.g., moderate-to-severe AD or severe AD) in a subject ≥6 to <18 years of age, wherein the dose of an IL-4R antagonist is increased if the subject does not adequately respond to an initial dosing regimen. In some embodiments, the method comprises: (a) administering a first dosing regimen of an IL-4R antagonist (e.g., an IL-4R antibody) as disclosed herein to a subject with moderate to severe AD or severe AD. wherein the subject is ≥ 6 years old to < 18 years old; (b) determining whether the subject exhibits an inadequate clinical response to the first dosing regimen; and (c) if the subject exhibits an inadequate clinical response, administering to the subject a second dosing regimen of an IL-4R antagonist, the second dosing regimen comprising administering the IL-4R antagonist at a dose of (i) 200 mg Q2W if the subject weighs <60 kg, or (ii) 300 mg Q2W if the subject weighs ≥60 kg. Includes:

[0137] In some embodiments, the subject is a pediatric subject (≥ 6 to < 12 years old) with severe AD. In some embodiments, the initial dosing regimen for the pediatric subject comprises administering an IL-4R antagonist at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg every four weeks (Q4W). In some embodiments, the initial dosing regimen has a duration of at least 16 weeks.

[0138] In some embodiments, the subject is an adolescent subject (≥ 12 to < 18 years old) with moderate to severe AD. In some embodiments, the initial dosing regimen for the adolescent subject comprises administering an IL-4R antagonist at an initial dose of 600 mg, followed by one or more secondary doses of 300 mg every four weeks (Q4W). In some embodiments, the initial dosing regimen has a duration of at least 16 weeks.

[0139] In some embodiments, an "inadequate clinical response" is determined by assessing one or more AD-related parameters (e.g., IGA or EASI score) as disclosed herein. In some embodiments, a subject has an "inadequate clinical response" if the subject has an IGA score of ≧2 after at least 16 weeks of treatment with a first dosing regimen. In some embodiments, a subject has an "inadequate clinical response" if the subject has an EASI score that is not reduced by at least 50% (e.g., at least 75%) from baseline after at least 16 weeks of treatment with a first dosing regimen. For subjects identified as having an inadequate clinical response to the first dosing regimen, the method includes escalating the dose of the IL-4R antagonist to one of the following regimens based on body weight: for patients weighing <60 kg, the dose of the IL-4R antagonist is escalated to a dosage of 200 mg Q2W; for patients weighing ≥60 kg, the dose of the IL-4R antagonist is escalated to a dosage of 300 mg Q2W.

[0140] Combination therapy In some embodiments, the methods of the present disclosure include administering to a subject an IL-4R antagonist in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a topical therapeutic agent, such as TCS or TCI, or a topical nonsteroidal agent such as crisaborole. As used herein, the term "in combination with" means that the topical therapy (e.g., TCS) is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or simultaneous administration of the IL-4R inhibitor and the topical therapy (e.g., TCS).

[0141] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered 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 pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, or about 10 minutes after the administration of the pharmaceutical composition comprising an IL-4R antagonist. The additional therapeutic agent may be administered within 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently with" or together with an IL-4R antagonist-containing pharmaceutical composition means that the additional therapeutic agent is administered in a separate dosage form within less than 5 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising an IL-4R antagonist, or is administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0142] In some embodiments, the additional therapeutic agent is a TCS. In some embodiments, the TCS is a medium-potency TCS. In some embodiments, the TCS is a low-potency TCS. In some embodiments, the additional therapeutic agent is a TCI. In some embodiments, the additional therapeutic agent is crisaborole. [Example]

[0143] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the disclosed methods and compositions, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. [Example]

[0144] A clinical trial investigating the efficacy of dupilumab in pediatric patients with severe atopic dermatitis Study design and objectives This was a phase 3, multicenter, randomized, double-blind, parallel-group study to investigate the efficacy and safety of dupilumab administered concomitantly with topical corticosteroids (TCS) in pediatric patients with severe AD. The study population included patients aged ≥6 to <12 years with severe AD whose disease could not be adequately controlled with topical medications. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs:3-8.

[0145] Eligible patients who successfully completed the screening procedures were randomized to one of the following treatment groups: (1) Every 2 weeks (Q2W) dupilumab treatment group: 100 mg for patients <30 kg or 200 mg for patients ≥30 kg (2) Dupilumab treatment group: 300 mg every 4 weeks (Q4W) (3) Placebo.

[0146] Considering the body size differences in the pediatric population and the large therapeutic index observed with dupilumab, a stepped fixed dosing regimen was selected. This approach reduces the risk of dosing errors that can occur with weight-based dosing and allows for dosing convenience by simplifying administration using prefilled syringes / devices. Dupilumab was administered as follows: For the dupilumab Q2W treatment group, patients with a baseline weight <30 kg received 100 mg dupilumab (0.7 mL of a 150 mg / mL solution) Q2W SC injections from Weeks 2 through 14, following a 200 mg loading dose on Day 1. Patients with a baseline weight ≥30 kg received 200 mg dupilumab (1.14 mL of a 175 mg / mL solution) Q2W SC injections from Weeks 2 through 14, following a 400 mg loading dose on Day 1. For the dupilumab Q4W treatment group, all patients, regardless of weight, received 6 doses of dupilumab Q4W SC injections on Day 1. After the 00 mg loading dose, patients will receive 300 mg dupilumab (2 mL of a 150 mg / mL solution) Q4W SC injections from Week 4 through Week 12. For the placebo treatment group, patients will receive a matching placebo (including doubling the amount of placebo on Day 1 to match the loading dose).

[0147] The study consisted of the following periods: (1) a maximum 9-week screening period; (2) a 2-week TCS standardization period; (3) a 16-week treatment period; and (4) a 12-week follow-up period (for patients not participating in the OLE). During the screening period, patients were washed out of systemic AD treatment as needed. The use of TCS (±TCI) was permitted at the investigator's discretion during the screening period until day -14. Starting on day -14, all patients began the standardized TCS treatment regimen.

[0148] During the treatment period, patients visited the clinic weekly until Week 4, then Q4W until Week 16, with weekly telephone consultations between visits. Parents / caregivers were trained to administer study drug injections at Visit 3 (Day 1), Visit 5 (Week 2), and Visit 7 (Week 4) (for patients receiving Q2W treatment during the study). During weeks when no visits were scheduled, parents / caregivers administered the study drug to their patients. Parents / caregivers who did not wish to administer the study drug to their patients had the option of having all study drug injections administered by hospital staff at the clinic. Safety, laboratory, and clinical assessments were conducted at designated clinic visits. The end of treatment visit occurred at Week 16, 2 weeks after the final dose of study drug for patients randomized to the Q2W or placebo Q2W treatment group and 4 weeks after the final dose of study drug for patients randomized to the Q4W or placebo Q4W treatment group. The co-primary endpoint was assessed at this visit.

[0149] Patients enrolled in the study were offered the opportunity to screen for participation in the OLE study at the end of the treatment period (week 16). Patients who declined to enroll in the OLE study or did not meet the eligibility criteria for the OLE study underwent a 12-week follow-up period. After week 16, these patients had follow-up visits every 4 weeks from weeks 20 to 28. During the follow-up period, patients were monitored for safety and tolerability and underwent laboratory and clinical evaluations.

[0150] Study population The study enrolled pediatric patients (≥6 to <12 years at screening) with severe AD that could not be adequately controlled with topical AD medications.

[0151] Inclusion criteria: Patients had to meet the following criteria to be eligible for study participation: (1) male or female ≥6-12 years of age at the screening visit; (2) diagnosed with AD according to the American Academy of Dermatology consensus criteria (Eichenfield 2003) at the screening visit; (3) diagnosed with chronic AD at least 1 year prior to the screening visit; (4) IGA = 4 at the screening and baseline visits; (5) EASI ≥ 21 at the screening and baseline visits; (6) BSA ≥ 15% at the screening and baseline visits; (7) baseline worst itch score weekly mean score of maximum itch intensity ≥ 4 (Note: baseline worst itch score of maximum itch intensity is calculated by the daily worst score of maximum itch intensity for the 7 days immediately prior to randomization). It is determined based on the average of the itch scores (daily scores range from 0 to 10). A minimum of four daily scores over a seven-day period is required to calculate a baseline mean score. A complete daily score consists of answering both the questions, "What was your worst itch rating today?" and "What was your worst itch rating last night?" For patients who do not report at least four daily scores in the seven days immediately preceding the scheduled randomization date, randomization should be postponed until this requirement is met, but screening + TCS standardization should not exceed a maximum period of 77 days. .) (8) A recent documented history of inadequate response to topical AD medications (within 6 months prior to the baseline visit) (Note: Inadequate response is defined as the inability to achieve and maintain remission or low disease activity (equivalent to IGA 0 = clear to 2 = mild) despite treatment with a once-daily regimen of medium- to high-potency TCS (± TCI as needed), applied for at least 28 days. Patients with documented systemic treatment for AD in the past 6 months were also considered inadequate responders to topical treatment and were not eligible for Dupilumab after appropriate washout. (9) Patients must have applied a stable dose of topical emollient (moisturizer) twice daily for at least 11 consecutive days (14 total visits) immediately prior to the baseline visit; (10) be willing and able to comply with all visits and study-related procedures; (11) Patients must be able to understand and complete study-related questionnaires, either independently or with the assistance of a parent / legal guardian, as appropriate; (12) a parent or legal guardian must provide signed informed consent. Patients must also provide a separate informed consent form and sign and date either a separate informed consent form (IAF) or an informed consent form (ICF) signed by a parent / legal guardian (as appropriate based on local regulations and requirements) to be enrolled in the study.

[0152] Exclusion Criteria: The exclusion criteria for this study were: (1) previous participation in a dupilumab clinical study; (2) receipt of treatment with a systemic study drug before the baseline visit (Note: treatment with a systemic study drug refers to treatment received in a clinical study with a drug that is not yet commercially available); (3) receipt of treatment with a topical study drug within 2 weeks before the baseline visit; (4) receipt of treatment with crisaborole within 2 weeks before the baseline visit; (5) receipt of treatment with intermediate-potency topical corticosteroids as assessed by the investigator or the patient's treating physician. (5) history of significant side effects (e.g., intolerance to treatment, hypersensitivity reaction, significant skin atrophy, systemic effects); (6) having received treatment with a TCI within 2 weeks prior to the baseline visit; (7) having used any of the following treatments within 4 weeks prior to the baseline visit or having any condition that, in the opinion of the investigator, is likely to require such treatment during the first 4 weeks of study treatment: (a) immunosuppressive / immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon gamma, Januscitidine, cyclosporine ... (b) phototherapy for AD; (8) received treatment with any of the following biologics: (a) any cytodepleting 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 within 16 weeks prior to the baseline visit, whichever is longer; (9) received treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit. (Note: Patients who will receive a planned vaccination with a live attenuated vaccine during the course of the study (based on national vaccination schedules / local guidelines) will consult with their pediatrician to determine whether vaccination can be postponed until after the end of the study or whether it can be brought forward before the start of the study without compromising the patient's health. Patients who can safely defer administration of a live (attenuated) vaccine will be eligible for study enrollment. Patients who have received an accelerated vaccination may only participate in the study after a 4-week interval following vaccination.(10) planned or anticipated use of any prohibited medications and procedures during study treatment; (11) baseline weight <15 kg; (12) initiation of AD treatment with prescription moisturizers or moisturizers containing additives such as ceramides, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients could continue using a stable dose of such moisturizers if started before the screening visit); (13) regular use of tanning booths / parlors (more than two visits per week) within 8 weeks prior to the baseline visit; (14) having an active chronic or acute infection 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; (15) a confirmed diagnosis of a primary immunodeficiency disorder (e.g., severe combined immunodeficiency, Wiskott-Aldrich syndrome, DiGeorge syndrome, X-linked agammaglobulinemia, common variable immunodeficiency) or secondary immunodeficiency; (16) a history of past or current tuberculosis or other mycobacterial infection; (17) a known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at the time of the screening visit; (18) a confirmed diagnosis of hepatitis B virus infection at the time of screening or a positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) test at the time of screening (Note: Patients who have gained immunity to hepatitis B virus infection after vaccination (HBsAg-negative, hepatitis B surface antibody [HBsAb]-positive, and HBcAb-negative patients) were not eligible for the study. (19) a confirmed diagnosis of hepatitis C virus infection at the time of screening or a positive hepatitis C antibody test at the time of the screening visit; (20) current treatment for liver disease, including, but not limited to, acute or chronic hepatitis, cirrhosis, or liver failure, or evidence of liver disease during the screening period, as indicated by persistent (confirmed by repeat testing at ≥ 2-week intervals) elevations of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) greater than 3 times the upper limit of normal (ULN); (21) the presence of any one or more of the following laboratory abnormalities at the time of screening: (i) platelets ≤ 100 × 103 / μL; (ii) neutrophils < 1.5 × 103 / μL; (iii) creatine phosphokinase (CPK) > 5 × ULN; (iv) serum creatinine > 1.5 × ULN (Note: If an abnormal value is detected at screening, a repeat test should be performed to confirm the abnormality); (22) The presence of a skin comorbidity that may interfere with study evaluation, including, but not limited to, conditions such as scabies, seborrheic dermatitis, cutaneous T-cell lymphoma, and psoriasis; (23) A history of malignancy before the baseline visit; (24) An active endoparasitic infection diagnosed; suspected or high risk for endoparasitic infection unless active infection is ruled out by clinical and (if necessary) laboratory evaluation before randomization; (25) Having a severe intercurrent illness that, in the investigator's judgment, would 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%), cardiovascular disease (e.g., New York Heart Association class III or IV heart failure), severe renal conditions (e.g., diabetic patients), hepatobiliary disease (e.g., Child-Pugh syndrome), and (26) Patients with a medical condition that, in the opinion of the investigator, suggests a new and / or poorly understood disease or may represent an undue risk to the study patient as a result of participating in the study, or is unreliable for patient participation. (27) any other medical or psychological condition, including relevant test abnormalities at screening, that may interfere with or interfere with study evaluation; (28) a major surgical procedure is planned during the patient's participation in this study; (29) the patient or their immediate family members are members of the dupilumab clinical trial team; (30) the patient is a woman who is pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study; (31) the patient is institutionalized pursuant to an order issued by either a judicial or administrative authority; (32) the patient is of childbearing potential. *Women who are sexually active and unwilling to use highly effective contraception before the first dose, during the study, and for at least 12 weeks after the final dose of investigational drug; highly effective contraception includes stable use of combined (estrogen- and progestogen-containing) hormonal contraceptives (oral, vaginal, transdermal) or progestogen-only hormonal contraceptives (oral, injectable, implantable) associated with ovulation inhibition, started two or more menstrual cycles before screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomy partner and / or sexual abstinence ** Examples include: * For the purposes of this study, any female who has had her first menstrual period (menarche) and is sexually active will be considered of childbearing potential. Female patients who are not of childbearing potential at the start of the study but who begin menarche during the course of the study and become sexually active will also be required to follow an adequate method of contraception in order to continue participating in the study. ** Sexual abstinence is considered highly effective only if it is defined as abstinence from heterosexual intercourse for the entire risk period associated with the study treatment. The reliability of sexual abstinence must be evaluated in the context of the duration of the clinical trial and the subject's preferred usual lifestyle.

[0153] research treatment Investigational and reference treatments: Dupilumab 175 mg / mL: Disposable pre-filled 1.14 mL glass syringes with snap-off lids each deliver 200 mg of study drug (1.14 mL of 175 mg / mL solution). Dupilumab 150 mg / mL: Disposable pre-filled 2.25 mL glass syringes with snap-off lids each deliver 300 mg of study drug (2.0 mL of a 150 mg / mL solution). Dupilumab 150 mg / mL: Disposable pre-filled 0.7 mL glass syringes with snap-off lids each deliver 100 mg of study drug (0.7 mL of a 150 mg / mL solution). Dupilumab-matched placebos were prepared using the same formulation without the addition of protein (i.e., the active substance, anti-IL-4Rα monoclonal antibody). Three matching placebo formulations were used: 2 mL placebo matching the 300 mg dupilumab formulation, 1.14 mL placebo matching the 200 mg dupilumab formulation, and 0.7 mL placebo matching the 100 mg dupilumab formulation.

[0154] The subcutaneous injection site of the study drug was alternated between different quadrants of the abdomen (avoiding the navel and lumbar regions), upper thigh, and upper arm to ensure that the same site was not injected for two consecutive doses. The study drug was administered only to areas of normal-appearing skin to allow adequate assessment of possible injection site reactions (for patients with 100% BSA involvement, patients were instructed to administer the injection into skin that appeared as close to normal as possible).

[0155] Background Treatment: Patients were instructed to apply moisturizer (emollient) at least twice daily for at least 7 consecutive days immediately prior to randomization. After randomization, patients were required to continue applying moisturizer throughout the study (all 28 weeks, if applicable). However, to allow adequate assessment of skin dryness, moisturizer should not be applied for at least 8 hours before each visit. All types of moisturizer were permitted, but patients were not to begin treatment with prescription moisturizers (e.g., ceramide-containing products such as EpiCeram®) or moisturizers containing additives (ceramides, hyaluronic acid, urea, filaggrin degradation products) during the screening period or during the study. Patients were allowed to continue using a stable dose of such moisturizer if initiated before the screening visit.

[0156] Starting on day -14, all patients were required to begin treatment with TCS using a standardized regimen according to the following guidelines: Medium-potency TCS will be applied once daily to areas with active disease. At the investigator's discretion, low-potency TCS may be used once daily on areas with thin skin (e.g., face, neck, intertriginous and genital areas, areas of skin atrophy) or in areas where continued treatment with medium-potency TCS is deemed unsafe. Once patients achieve an IGA score of 2 or lower, the frequency of use of the medium-potency TCS is reduced to 3 times per week and discontinued once lesions have cleared (IGA 0). Patients should be monitored for active lesions. Patients should be instructed to use TCS only if the lesions disappear completely between visits and to discontinue TCS use. If the lesion recurs, resume treatment with intermediate-potency TCS using the same step-down technique described above for lesion resolution. If there are signs of local (e.g., impending skin atrophy) or systemic TCS toxicity with medium-potency steroids, patients should be switched to low-potency steroids. For lesions that persist or worsen with once-daily treatment with medium-potency TCS, patients may be treated (rescue) with higher-potency TCS (super-potent / very high-potency steroids are not permitted, even for rescue) unless higher-potency TCS is deemed unsafe (high-potency TCS should generally be restricted to non-delicate skin areas [except the face, flexors, and groin] and should not be used prolonged to prevent the development of skin atrophy and adrenal axis suppression). Low-potency steroids should generally be used on these flaring, delicate skin areas (face, flexors, and groin).

[0157] A list of acceptable steroids was provided to the investigators. Patients were encouraged to use triamcinolone acetonide 0.1% cream, fluocinolone acetonide 0.025% cream, or clobetasone butyrate 0.05% for medium potency and hydrocortisone acetate 1% cream for low potency. If rescue with TCS was required, patients were encouraged to use mometasone furoate 0.1% ointment as a high-potency steroid. Patients with tolerance issues to any of these steroids or if the steroid was not available commercially could substitute a product of the same potency from the list provided in the study reference manual. The use of very high-potency or extra-potent TCS is not recommended for patients under 12 years of age and was prohibited during the study.

[0158] Rescue Treatment: Patients had access to rescue treatment for AD during the study with the following guidelines: Investigators will be required to perform an IGA assessment before initiating rescue treatment and to initiate rescue treatment only in patients who either have an IGA score = 4 or intolerable symptoms. When possible, investigators are encouraged to consider rescue with topical treatments (e.g., high-potency TCS) initially, and transition to systemic agents only for patients who do not adequately respond after at least 7 days of topical treatment. If rescue consists of topical agents, patients may continue with study treatment. The use of very high-potency or ultra-potent TCS is prohibited. Very high-potency topical corticosteroids include: Betamethasone dipropionate fortified 0.05% ointment Clobetasol propionate 0.05% solution, foam, cream, or ointment Diflorasone diacetate 0.05% ointment Halobetasol propionate 0.05% cream or ointment.

[0159] Patients who received systemic corticosteroids or systemic nonsteroidal immunosuppressants (e.g., cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) as rescue medications during the study were permanently discontinued from the study drug.

[0160] Procedures and Evaluation Various parameters were collected during the study to assess the efficacy and safety of dupilumab therapy. Efficacy parameters included patient-reported assessments, including worst itch score, patient global impression of illness, patient global impression of change in state, CDLQI, POEM, DFI, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression score, Faces pain scale, and investigator-reported assessments (BSA, SCORAD, Global Individual Signs Score [GISS], and EISS, which measures the extent and severity of AD). Patients were monitored for all adverse events (AEs) experienced from the time of informed consent / ascent to the final study visit.

[0161] Efficacy evaluation Patient Assessment of Pruritus Using the Worst Itch Scale: The Worst Itch Scale is a simple assessment tool used by patients to report the intensity of their pruritus (itch). It is an 11-point scale (0-10), with 0 indicating no itch and 10 indicating the worst itch imaginable. Patients were asked the following two questions: "What was your worst itch score today?" "What was the worst itch rating last night?"

[0162] Patients were asked to provide answers to these two questions daily throughout the study. Both questions were answered in the evening, and the worst daily itch score was calculated as the worse of the two scores.

[0163] Patient's overall illness impression: Patients rated their illness on a 5-point scale: "Overall, how itchy have you been over the past 7 days?" · Not itchy at all · A little itchy · Moderate itchy · Quite itchy · Extremely itchy. Patients completed this assessment at screening, baseline, and days 15, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0164] Patient's overall impression of change in condition: Patients rated their disease on a 5-point scale: "How has your itching changed since you started the study drug?" · Much better · A little better · Same · A little worse · Much worse. Patients completed this assessment at screening and on days 15, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0165] The Pediatric Dermatological Quality of Life Index (CDLQI) is a validated questionnaire designed to measure the impact of skin diseases on children's quality of life (Lewis-Jones et al., 1995, Brit. J. Dermatol. 132:942-9). The purpose of the questionnaire was to measure the extent to which the patient's skin problems affected them during a recall period of the past week. To complete the questionnaire, patients must provide responses to 10 questions (the questions focus on areas such as symptoms, illness-related feelings, the impact of the disease on leisure time, school, or holidays, personal relationships, sleep, and side effects of skin disease treatment). The recall period for this instrument is 7 days. Nine of the 10 questions are scored as follows: Very = 3, Quite a bit = 2, Only a little = 1, Not at all = 0, and Not answered = 0. Question 7 has an additional possible response (missed school), which was assigned a score of 3. A 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 quality of life. The CDLQI can also be expressed as a percentage of the maximum possible score of 30. Patients completed this assessment at screening, baseline, and days 15, 29, 57, 85, and 113 (at the end of the study) or upon early discontinuation.

[0166] The Patient Oriented Eczema Scale (POEM) is a seven-item validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults (Charman et al., 2004, Arch. Dermatol. 140:1513-9). This format assesses the frequency of these disease symptoms over the past week (i.e., 0 = 0 days, 1 = 1-2 days, 2 = 3-4 days, 3 = The scale was based on responses to seven items (dryness, itching, peeling, cracking, lack of sleep, bleeding, and oozing) on ​​a 0-28 scoring system (5 = 5-6 days, and 4 = all days), with the total score reflecting disease-related morbidity. Questionnaires were completed at screening, baseline, and on days 15, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0167] Dermatitis Family Index: The DFI assesses the impact of having a child with AD on family quality of life (Lawson 1998). A 10-item disease-specific questionnaire was developed after ethnographic interviews and focus groups identified areas of family quality of life affected by AD. This self-administered questionnaire is completed by adult family members of children affected by AD. Items address the impact of housework, meal preparation, sleep, family leisure activities, shopping, spending, fatigue, emotional distress, relationships, and treatment support on the primary caregiver's life. DFI questions are scored on a 4-point Likert scale ranging from 0 to 3, resulting in a total DFI score ranging from 0 to 30. The time frame of reference is the past week. Higher DFI scores indicate greater impairment of family quality of life affected by AD. Questionnaires were completed at screening, baseline, and days 15, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0168] Facial Pain Scale-Revised: The Facial Pain Scale-Revised (FPS-R) is a self-report measure of pain intensity developed for children (Hicks 2001). It is an adaptation of the Facial Pain Scale, allowing pain sensations to be scored on a widely accepted 0-10 scale. The scale shows a close linear relationship with visual analog pain scales in the age range of 4-16 years. It is easy to complete and requires no equipment other than a photocopied face drawing. The instrument has well-established psychometric properties and has been validated in school-age children. Questionnaires were completed at baseline and at days 15, 29, 57, 85, and 85, or at early discontinuation.

[0169] PROMIS Anxiety and Depression Scales: The PROMIS anxiety instrument measures self-reported fear (fear, panic), anxiety distress (worry, dread), hyperarousal (tension, nervousness, restlessness), and arousal-related physical symptoms (pounding heart, dizziness). The PROMIS depression instrument assesses self-reported negative mood (sadness, guilt), self-view (self-criticism, feelings of worthlessness), and social cognition (loneliness, interpersonal alienation), as well as decreased positive affect and engagement (loss of interest, meaning, and purpose). Questionnaires were completed at screening, baseline, and days 15, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0170] Investigator Global Assessment (IGA) is a rating tool used in clinical studies to globally assess the severity of AD based on a 5-point scale ranging from 0 (clear) to 4 (severe). IGA scores were assessed at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0171] Eczema Area and Severity Index (EASI) is a validated index used in clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al., 2001, Exp. Dermatol. 10:11-18). The EASI is a composite index with scores ranging from 0 to 72. Four AD disease features (erythema, thickening [induration, papulation, edema], excoriation [epidermal peeling], and lichenification) are each rated for severity by the investigator or designee on a scale of "0" (absent) to "3" (severe). Additionally, the area of ​​AD involvement is assessed as a percentage of the body area for the head, trunk, upper limbs, and lower limbs and converted to a score of 0 to 6. For each body region, the area was assigned as 0, 1 (1%-9%), 2 (10%-29%), 3 (30%-49%), 4 (50%-69%), 5 (70%-89%). %), or 6 (90%–100%). EASI scores were collected at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0172] Global Individual Sign Score: The individual components of AD lesions (erythema, infiltrates / papulation, excoriation, and lichenification) are assessed globally (i.e., each is assessed systemically, not by anatomical region) on a 4-point scale (0 = absent to 3 = severe) using the EASI severity rating scale. The Global Individual Sign Score (GISS) was assessed at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0173] Scoring Atopic Dermatitis: Scoring Atopic Dermatitis (SCORAD) is a validated tool used in clinical research and practice developed to standardize the assessment of the extent and severity of AD (European Task Force on Atopic Dermatitis 1993, Dermatol. 186:23-31). The assessment has three components: A = extent or affected BSA, B = severity, and C = subjective symptoms. The extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a maximum score of 100% (assigned an "A" in the total SCORAD calculation). The severity of six specific symptoms of AD (redness, swelling, oozing / crusting, peeling, thickened / lichenified skin, and dryness) is assessed using the following scale: absent (0), mild (1), moderate (2), or severe (3) (maximum total of 18 points, assigned a "B" in the total SCORAD calculation). Subjective assessments of itch and insomnia are recorded for each symptom by the patient or relative on a visual analog scale, where 0 is no itch (or insomnia) and 10 is the worst itch (or insomnia) imaginable, with a maximum possible score of 20. This parameter is assigned a "C" in the total SCORAD calculation. SCORAD is calculated as A / 5 + 7B / 2 + C, with a maximum value of 103. Patients underwent this assessment at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0174] Body Surface Area Involvement of Atopic Dermatitis: Body surface area affected by AD was assessed by body compartment using a rule of nine (maximum possible scores for each area: head and neck [9%], forearm [18%], back [18%], upper extremities [18%], lower extremities [36%], and genitals [1%]) and reported as a percentage of all major body compartment areas combined. Patients underwent this assessment at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early discontinuation.

[0175] Assessment of days of school absence: Patients enrolled in school were asked to report the number of days of school absence since the last study assessment. Patients completed this assessment at baseline and on days 29, 57, 85, and 113 (end of study) or early discontinuation.

[0176] Assessment of caregiver absenteeism: In this questionnaire, caregivers were asked to report the impact of having a child with AD on the number of days they worked. Employed caregivers were asked to report the number of sick days they had since the last study assessment. Caregivers completed this assessment at baseline and at days 29, 57, 85, and 113 (end of study) or early discontinuation.

[0177] Topical Corticosteroid Accountability: At all visits after the TCS standardization visit, the type, amount, frequency, and potency of TCS used were recorded by field personnel. The amount of TCS used was determined by weighing the tube at each visit until the end of the study.

[0178] Safety evaluation Safety was assessed by monitoring vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), clinical assessment, and by monitoring adverse events (AEs) and serious adverse events.

[0179] An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal product or in a clinical investigational subject. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not it is considered related to the medicinal (investigational) product. AEs also include: any worsening of a pre-existing condition (i.e., any clinically significant change in frequency and / or intensity) temporally associated with the use of an investigational drug; an abnormal laboratory finding deemed clinically important by the investigator; and any adverse medical occurrence.

[0180] A serious adverse event (SAE) is any untoward medical occurrence at any dose that results in death; is life-threatening; requires patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a significant medical event.

[0181] statistical analysis For the primary efficacy analysis, the Cochran-Mantel-Haenszel test adjusted by randomization strata (baseline weight group and region) was used to analyze the percentage of patients with an IGA of 0 or 1 at week 16 or the percentage of patients with EASI-75 at week 16. Mantel-Fries (MF) criteria were considered, and if not met, sensitivity analyses including each stratification factor were performed separately with the CMH test.

[0182] To account for the impact of rescue therapy on efficacy, if rescue therapy was used: for the primary efficacy endpoint (binary efficacy endpoint), patients were classified as non-responders from the time rescue therapy was used. If a patient withdrew from the study, they were counted as a non-responder for the endpoint after withdrawal.

[0183] A sensitivity analysis using the last observation carried forward (LOCF) method to determine patient status at week 16 was performed to assess the robustness of the primary efficacy analysis with respect to handling missing data. Because efficacy data were set as missing after rescue treatment was used, the LOCF method was used to determine patient status at week 16. In addition, a Cochran-Mantel-Haenszel method adjusted by randomization strata was performed on all observed data, regardless of whether rescue treatment was used. Patients with missing data were counted as non-responders.

[0184] result Baseline characteristics Baseline demographic and disease characteristics are summarized in Tables 1A-1B, 2, and 3A-B.

[0185] [Table 1]

[0186] [Table 2]

[0187] [Table 3]

[0188] [Table 4] [Table 5]

[0189] Baseline demographics were comparable across the three treatment groups. The mean age of patients in this study was 8.5 years, and the duration of AD was long (mean 7.3 years). A high incidence of atopic comorbidities was observed in all treatment groups. Overall, 91.7% of patients had at least one Patients had concomitant allergic conditions. The mean BSA affected by AD was 57.6%. Nearly all (99.7%) patients had IGA 4 (severe disease). The mean EASI score was 37.9. The mean peak pruritus NRS score was 7.8. The mean POEM score was 20.9 / 30. On average, patients reported a very significant impact on their quality of life (mean CDLQI score 15.1 / 30). The mean SCORAD score was 73.6 / 103.

[0190] For randomized and treated patients, high patient retention rates were observed in all treatment groups (Table 4).

[0191] [Table 6]

[0192] efficacy Both dupilumab + TCS regimens (weight-specific 100 / 200 mg Q2W + TCS and non-weight-specific 300 mg Q4W + TCS) significantly improved all predefined efficacy endpoints compared with placebo + TCS. Tables 5A-5B and 6A-6B summarize the improvements in various AD-related parameters in patients treated with dupilumab.

[0193] [Table 7]

[0194] [Table 8]

[0195] [Table 9]

[0196] [Table 10]

[0197] Both dupilumab treatment groups achieved statistical significance for the primary endpoint (IGA 0 / 1) and co-primary endpoint (EASI-75) at week 16 (300 mg Q4W and 100 / 200 mg Q2W) (IGA (0 / 1) responder rates: placebo: 11.4; 300 mg Q4W 32.8%; 100 / 200 mg Q2W: 29.5%; EASI-75 responder rates: placebo: 26.8%; 300 mg Q4W 69.7%; 100 / 200 mg Q2W: 67.2%). See Table 5A and Figures 1A and 1D. Statistical significance was achieved for key secondary efficacy endpoints in both dupilumab treatment groups (mean % change in EASI: placebo: -48.6%; 300 mg Q4W: -82.1%; 100 / 200 mg Q2W: -78.4%; mean % change in Pruritus NRS: placebo: -25.9%; 300 mg Q4W: -54.6%; 100 / 200 mg Q2W: -57.0%). See Table 5A and Figure 1G. Statistical significance was also achieved for all remaining endpoints within strata (Table 5A) and additional endpoints (Table 6A) in both dupilumab treatment groups. See also Figures 2A and 2D.

[0198] Efficacy results in this trial were comparable to those in the severe AD subgroup of the adult Phase 3 study with TCS (CHRONOS): For the primary endpoint of IGA 0 / 1, 32.8% of the 300 mg Q4W group and 29.5% of the 100 / 200 mg group were responders compared with 28.3% of adults in the severe AD subgroup. The EASI-75% responder rates were 69.7% for the 300 mg Q4W group, 67.2% for the 100 / 200 mg Q2W group, and 67.9% for adults in the severe AD subgroup. Results were also comparable for the secondary endpoints of EASI percent change, pruritus NRS percent change, PNRS ≥ 4-point reduction, PNRS ≥ 3-point reduction, EASI-50, EASI-90, POEM change, and SCORAD percent change.

[0199] Overall efficacy results by dose and weight group are shown in Tables 5B and 6B and are also summarized in Table 7. Among patients in the <30 kg subgroup, a higher percentage of patients in the 300 mg Q4W treatment group achieved the IGA 0 / 1 endpoint compared with the 100 mg Q2W treatment group (29.5% vs. 20.6%). A higher percentage of patients in the 300 mg Q4W treatment group achieved the EASI-75 coprimary endpoint compared with the 100 mg q2w treatment group (75.4% vs. 60.3%). For several secondary endpoints, the 300 mg Q4W treatment group was numerically greater compared to the 100 mg Q2W treatment group: a higher EASI percentage change was observed in the 300 mg Q4W treatment group (-84.3% vs. -76.7%); more patients in the 300 mg Q4W treatment group achieved EASI-50 (95.1% vs. 79.4%); and more patients in the 300 mg Q4W treatment group achieved EASI-90 (45.9% vs. 25.4%). See Figures 1B, 1E, and 1H. However, for other secondary endpoints, such as percentage change in pruritus NRS, ≥4-point NRS reduction, ≥3-point NRS reduction, change in POEM score, and change in CDLQI score, the 300 mg Q4W and 100 mg Q2W treatment groups demonstrated comparable efficacy. See Figures 2B and 2E.

[0200] For patients in the ≥30 kg subgroup, outcomes were numerically greater in the 200 mg Q2W treatment group compared with the 300 mg Q4W treatment group for the categorical itch endpoint: 61.4% of patients in the 200 mg Q2W treatment group experienced a ≥4-point NRS reduction compared with 47.5% of patients in the 300 mg Q4W treatment group; 66.7% of patients in the 200 mg Q2W treatment group experienced a ≥3-point NRS reduction compared with 58.3% of patients in the 300 mg Q4W treatment group. See Figures 2C and 2F. For the coprimary endpoint, EASI-75, a higher percentage of patients in the 200 mg Q2W treatment group were responders compared with the 300 mg Q4W treatment group (74.6% vs. 63.9%). See Figure 1F. Other primary and secondary endpoints were generally comparable between the 300 mg Q4W and 200 mg Q2W treatment groups (Table 7 and Figures 1C and 1I).

[0201] [Table 11]

[0202] For the primary endpoint of IGA 0 / 1 at week 16, comparable efficacy was observed between the 300 mg Q4W and 100 / 200 mg Q2W treatment groups. At week 16, 32.8% of patients in the 300 mg Q4W treatment group and 29.5% of patients in the 100 / 200 mg Q2W treatment group achieved an IGA of 0 or 1, compared with only 11.4% of patients in the placebo + TCS group. An increase in the proportion of patients achieving an IGA of 0 or 1 was evident as early as week 2 of treatment in the 300 mg Q4W treatment group (5.7% of patients were responders, compared with 1.6% of patients in the placebo group), and by week 8, 24.6% of patients in the 300 mg Q4W treatment group had achieved an IGA of 0 or 1 (compared to 7.3% for placebo). In the 100 / 200 mg Q2W treatment group, 6.6% of patients achieved an IGA of 0 or 1 at week 6 (compared to 3.3% on placebo), and by week 8, 23% of patients in the 100 / 200 mg Q2W treatment group achieved an IGA of 0 or 1 (compared to 7.3% on placebo).

[0203] Comparable efficacy was observed between the 300 mg Q4W and 100 / 200 mg Q2W treatment groups for the co-primary endpoint, EASI-75, at week 16. At week 16, 69.7% of patients in the 300 mg Q4W treatment group and 67.2% of patients in the 100 / 200 mg Q2W treatment group achieved EASI-75, compared with only 26.8% of patients in the placebo + TCS group. Comparable efficacy was observed for each of the EASI-50 / 75 / 90 response thresholds in the Q4W and Q2W treatment groups (Table 5), although a slight decrease in the proportion of responders was observed from weeks 12 to 16 in the Q2W treatment group (EASI-50 decreased from 86.1% at week 12 to 82.8% at week 16, and EASI-90 decreased from 31.1% at week 12 to 30.3% at week 16). Efficacy in percent change in EASI from baseline to week 16 was observed to be comparable between dupilumab treatment groups (-82.1% for the 300 mg Q4W treatment group and 30.3% for the 100 / 200 mg Q4W treatment group). -78.4% in the 2W treatment group vs. -48.6% in the placebo plus TCS group. In both dupilumab treatment groups, efficacy in terms of EASI-75 response rate and EASI percent change was similar to that observed with dupilumab plus TCS for adults with severe AD subgroups.

[0204] The pruritus NRS response rate for categorical pruritus endpoints was 100 / 200 mg. For the endpoint NRS ≥ 3 response at week 16, 67.5% of patients in the 100 / 200 mg Q2W treatment group were responders, compared with 300 mg 60.3% of patients in the Q4W treatment group were responders. This was significantly greater in both treatment groups than in placebo (21.1%). For the Week 16 endpoint NRS ≥ 4 response, 58.3% of patients in the 100 / 200 mg Q2W treatment group were responders, and 50.8% of patients in the 300 mg Q4W treatment group were responders. This was significantly greater in both treatment groups than in placebo (12.3%). At Week 2, a benefit for pruritus was evident in both dupilumab treatment groups: 17.4% of patients in the 300 mg Q4W treatment group and 12.5% ​​of patients in the 100 / 200 mg Q2W treatment group achieved an NRS ≥ 3, compared with only 6.5% of patients in the placebo group. Both dupilumab treatment groups demonstrated comparable efficacy in percent change from baseline in pruritus NRS (-54.6% for the 300 mg Q4W treatment group, -57% for the 100 / 200 mg Q2W treatment group, compared with -25.9% for placebo).

[0205] In children with moderate to severe AD, skin lesions often cover a large body surface area (BSA), resulting in pruritus and sleep deprivation, significantly impacting the quality of life of young patients and their caregivers. The Scoring for AD (SCORAD) is an AD-specific measurement tool recommended by the European AD Guidelines. It assesses investigator-assessed affected BSA and symptom severity, as well as patient-reported pruritus and sleep deprivation symptoms. The effect of dupilumab in combination with standardized topical treatment on the SCORAD and its components was assessed using least squares (LS) mean (standard error [SE]) scores for the total SCORAD (score range 0-103) and its components: AD-affected BSA (0-100%); objective SCORAD (o-SCORAD, 0-83); SCORAD pruritus visual analog scale (VAS, 0-10); and sleep deprivation VAS (0-10). Multiple imputation was used for censoring after rescue treatment use.

[0206] Baseline demographics and disease characteristics are shown in Table 8 below. Treatment with dupilumab + TCS resulted in significant improvements in total SCORAD scores by week 1 for Q4W + TCS and week 2 for Q2W + TCS, with further improvements observed through the end of treatment at week 16 (Figure 3, Table 8). By week 2, both dupilumab treatment regimens resulted in significant reductions in diseased BSA, with further reductions observed through week 16. o-SCORAD significantly improved as early as week 1 for dupilumab Q4W + TCS and week 2 for dupilumab Q2W + TCS compared to placebo + TCS, and these results continued to improve through week 16. Pruritus and sleep deprivation symptoms, as measured by the SCORAD pruritus VAS and sleep deprivation VAS, significantly improved by week 2 with both dupilumab treatment regimens compared with placebo plus TCS, and both continued to improve through the end of treatment at week 16 (Table 8).

[0207] [Table 12]

[0208] Thus, in children ≥6 to <12 years of age with severe AD, treatment with dupilumab and concomitant medium-potency TCS resulted in rapid and significant reductions in AD-affected BSA and improvements in AD symptoms, pruritus, and poor sleep, as assessed by total SCORAD and SCORAD components.

[0209] Based on the data in Table 8 at week 16, the percentage improvement in the total SCORAD and SCORAD component parameters was calculated. For subjects receiving placebo and TCS, the total SCORAD score of 51.3 at week 16 corresponded to approximately 70% of the initial (baseline) total SCORAD score of 72.9. In other words, the total SCORAD score of subjects receiving placebo and TCS showed only a reduction of approximately 30% (100%-70%) from baseline. In comparison, for subjects receiving dupilumab 300 mg Q4W and TCS, the total SCORAD score of 27.4 at week 16 corresponded to approximately 36% of the initial (baseline) total SCORAD score of 75.6. In other words, the total SCORAD score of subjects receiving dupilumab 300 mg Q4W and TCS showed a reduction of approximately 64% (100%-36%) from baseline. Furthermore, for subjects receiving dupilumab 100 / 200 mg For total SCORAD scores in subjects receiving Q2W and TCS, score 2 at week 16 The score of 9.5 represented approximately 40% of the initial (baseline) total SCORAD score of 72.3. In other words, subjects receiving dupilumab 100 / 200 mg Q2W and TCS experienced a reduction of approximately 60% (100% - 40%) in the total SCORAD score from baseline.

[0210] Similar rescue rates were observed between the 300 mg Q4W and 100 / 200 mg Q2W treatment groups; the dupilumab rescue rate was significantly lower than that in the placebo group (with placebo, 19.5% of patients required rescue therapy by week 16, compared with 2.5% of patients in the 300 mg Q4W and 4.1% of patients in the 100 / 200 mg Q2W treatment groups). Rescue rates in these pediatric dupilumab-treated patients were overall lower than those in adolescents and adults with severe AD (Table 9).

[0211] [Table 13]

[0212] safety No new or unexpected side effects were observed in this study compared with those seen in adult or adolescent patient trials. See Table 10 below. During the 16-week treatment period, the overall adverse event rate was lower in the dupilumab groups compared with placebo (65% for dupilumab 300 mg Q4W, 67.2% for dupilumab 100 / 200 mg Q2W, and 73.3% for placebo). All serious adverse events were unrelated to study drug. Treatment discontinuation due to AEs was rare (placebo + TCS, n=2; 100 / 200 mg Q2W + TCS, n=2). No fatal or treatment-related events of hypersensitivity or anaphylaxis occurred during the study. No new safety concerns were observed. Adverse events observed at higher rates with dupilumab included conjunctivitis (narrow CMQ) (narrow conjunctivitis was 6.7% with dupilumab every 4 weeks compared with 4.2% with placebo, and 14.8% with dupilumab every 2 weeks); conjunctivitis (broad CMQ) (8.3% with dupilumab every 4 weeks and 18.9% with dupilumab every 2 weeks compared with 7.5% with placebo); and injection site reactions (10% with dupilumab every 4 weeks and 10.7% with dupilumab every 2 weeks compared with 5.8% with placebo). Most conjunctivitis events resolved or were resolving with standard ophthalmic care during study drug treatment. The highest incidence of conjunctivitis (24%) occurred in the treatment group with the lowest exposure (100 mg Q2W + TCS). This is consistent with previous analyses suggesting that conjunctivitis associated with dupilumab treatment may be due to relative undertreatment within the ocular compartment (Akinlade et al., Br J Dermatol, 2019, 181(3):459-473). The incidence of conjunctivitis was observed to be lower in the Q4W treatment group compared with the Q2W treatment group. As seen in clinical trials of adult and adolescent patients, and consistent with long-term experience with dupilumab treatment, confirmed skin infections and herpes virus infections were significantly lower compared with the placebo group. Lower rates were observed in the dupilumab treatment groups (confirmed skin infections: 13.3% with placebo, 5.8% with dupilumab every 4 weeks, and 8.2% with dupilumab every 2 weeks; herpes virus infections: 5% with placebo, 1.7% with dupilumab every 4 weeks, and 3.3% with dupilumab every 2 weeks).

[0213] In this patient population with a high burden of comorbid type 2 inflammatory diseases, the incidence of type 2 inflammatory AEs was lower with higher dupilumab exposure, as expected given dupilumab's demonstrated efficacy for these conditions. In patients weighing <30 kg, AD exacerbations, asthma, and allergic rhinitis AEs were less common with the 300 mg Q4W + TCS group than with the 100 mg Q2W + TCS group (Table 10). A similar trend was observed in patients weighing ≥30 kg, with lower incidence with the 200 mg Q2W + TCS group than with the 300 mg Q4W + TCS group.

[0214] The long-term safety of dupilumab and TCS treatment in pediatric subjects from the 16-week clinical trial described above was evaluated in an open-label extension study. Of the patients enrolled in this study, 110 (30%) had moderate and 72 (20%) had severe atopic dermatitis at enrollment in the open-label extension study. The safety profile of dupilumab plus TCS in subjects followed through week 52 of the open-label extension was similar to that observed at week 16 of the 16-week trial. The long-term safety profile of dupilumab plus TCS observed in pediatric patients was consistent with that seen in adults and adolescents with atopic dermatitis.

[0215] [Table 14-1] [Table 14-2]

[0216] Clinical Pharmacology and Pharmacokinetics The 300 mg Q4W and 200 mg Q2W regimens produced lower trough concentrations The 300 mg Q4W + TCS regimen achieved similar steady-state (Week 16) trough concentrations (80 mg / L) compared with the 100 mg Q2W regimen, which achieved similar steady-state (Week 16) trough concentrations (50 mg / L). Week 16 functional dupilumab trough concentrations by weight category and treatment group showed lower concentrations in the 100 mg Q2W < 30 kg and 300 mg Q4W ≥ 30 kg groups. Consistent with efficacy analyses, the 300 mg Q4W + TCS regimen maintained substantially higher trough blood levels than the 100 mg Q2W + TCS regimen in the < 30 kg stratum (mean C at Week 16). トラフ In the ≥30 kg group, the 200 mg Q2W + TCS regimen maintained significantly higher trough blood levels than the 300 mg Q4W + TCS regimen (86 mg / L vs. 54 mg / L). Exposure / response relationships over time, assessed by quartile exposure analysis of percent change from baseline in EASI and percentage of patients achieving IGA 0 / 1, and logistic regression of binary endpoints (EASI-50, EASI-75, EASI-90, and IGA 0 / 1), demonstrated significant correlations with C トラフ The drug effect tended to increase with increasing dose (data not shown).

[0217] conclusion In pediatric patients aged 6 to 11 years with severe AD not adequately controlled with topical agents, 16 weeks of treatment with dupilumab resulted in rapid, clinically meaningful, and statistically significant improvements in AD-related parameters, including itch, anxiety, and depression, as well as sleep and quality of life. Most efficacy measures continued to show improvement at 16 weeks, suggesting further benefit with longer-term treatment.

[0218] Monthly (300 mg Q4W) and weight-based (100 mg Q2W for patients weighing <30 kg and 200 mg Q2W for patients weighing ≥30 kg) dosing regimens were comparable for most endpoints. In the subgroup of patients weighing <30 kg, the Q4W regimen was numerically superior to the Q2W regimen for some endpoints (IGA 0 / 1 at the end of 16 weeks; EASI-50 / 75 / 90 at the end of 16 weeks; and percentage change in EASI). However, for certain other endpoints (pruritus NRS, ≥4-point NRS reduction, ≥3-point NRS reduction, change in POEM score, and change in CDLQI score), the efficacy of the Q4W and Q2W regimens was comparable. In the subgroup of patients weighing ≥30 kg, the Q2W regimen was numerically superior to the Q4W regimen for some endpoints (≥4-point NRS reduction, ≥3-point NRS reduction, and EASI-75), but the Q2W and Q4W regimens exhibited comparable efficacy for other primary and secondary endpoints.

[0219] No new safety concerns were observed. Similar to previous studies of dupilumab in AD, only injection site reactions and conjunctivitis were significantly increased with dupilumab compared with placebo; most cases were mild to moderate and resolved over the course of the study. The overall incidence of TEAEs was lower with dupilumab treatment. This observation may be related to dupilumab's effect on comorbid type 2 inflammatory conditions and skin infections. Notably, this pediatric study population with severe AD suffered from a significantly higher burden of comorbid type 2 or allergic conditions; nearly half of these children had asthma; approximately 60% had allergic rhinitis; and approximately 65% ​​reported food allergies. In addition, children with severe AD were at significantly higher risk for skin infections. Consistent with the notion that patients with severe AD have a systemic disruption of the immune axis due to Th-2 polarization, which can be addressed by dupilumab, dupilumab treatment not only improved all measures of AD in these patients but also resulted in a reduction in type 2 AEs. Additionally, infections in these patients result from a breakdown in skin integrity, and dupilumab treatment, by its ability to restore skin integrity, was associated with a reduced incidence of skin and herpesvirus infections. Dupilumab-associated reductions in type 2 comorbidities and infections correlated with pharmacokinetic exposure. The benefit of dupilumab on infections was due to the highly immunosuppressive nature of the treatment. This contrasts with the experience with most other immunomodulatory therapies, such as Janus kinase inhibitors, tumor necrosis factor inhibitors, interleukin-23 inhibitors, corticosteroids, cyclosporine, and FK506 inhibitors, which tend to be toxic. Clearly, an AD treatment that avoids immunosuppression while also addressing associated comorbid atopic conditions would be beneficial in this pediatric population. In summary, this study demonstrates the efficacy and safety of dupilumab coadministered with TCS in pediatric patients ≥6 to <12 years of age with severe AD. [Example]

[0220] Pharmacokinetic analysis of dupilumab in children and adolescents with uncontrolled moderate-to-severe atopic dermatitis To characterize the pharmacokinetic profile of dupilumab in children (≥6 to <12 years) and adolescents (≥12 to <18 years) with moderate-to-severe AD, we followed 37 children and 40 adolescents enrolled in the Phase 2a study NCT02407756, incorporated herein in its entirety, and 33 children and 36 adolescents enrolled in the Phase 3 OLE study NCT02612454, incorporated herein in its entirety. Patients selected for enrollment in the Phase 2a and Phase 3 OLE studies included pediatric patients (≥6 to <18 years) with AD who were not adequately controlled with topical medications or for whom topical therapy was not recommended. Eligible patients had AD for >1 year prior to screening, based on American Academy of Dermatology criteria; a baseline IGA score of 3 or 4; and a BSA affected by AD of ≥10%.

[0221] The Phase 2a study consisted of a screening period of up to 35 days, a baseline visit, and two treatment phases. In Part A, patients received a single dose of dupilumab (2 mg / kg or 4 mg / kg), followed by an 8-week systemic drug concentration sampling period. In Part B, patients received the same dose weekly for 4 weeks, followed by an 8-week safety follow-up observation period. The primary outcome of the Phase 2a study was to characterize the pharmacokinetics of dupilumab.

[0222] The Phase 3 OLE study enrolled pediatric patients who had participated in previous dupilumab AD trials (the Phase 2a study described here and other studies). Patients enrolled in the OLE study continued to receive dupilumab at 2 mg / kg or 4 mg / kg weekly; the study consisted of a screening period (days -28 to -1), a treatment period lasting until regulatory approval of the product for that patient age group in that geographic region, and a 12-week follow-up observation period. Data from the baseline visit of the OLE study through week 52 are reported herein.

[0223] Outcome The primary endpoint of the phase 2a study was functional dupilumab serum concentrations and other PK parameters over time; key secondary outcomes included the incidence of treatment-emergent adverse events (TEAEs) and percentage changes from baseline in the Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis (SCORAD), and Peak Pruritus Numerical Rating Scale (NRS). The primary endpoint of the phase 3 OLE study was the incidence and rate of TEAEs (events / patient year [PY]). Key secondary endpoints included the incidence and rate of serious TEAEs and TEAEs of special interest (events / PY); the proportion of patients with an IGA score of 0 / 1; the proportion of patients achieving a ≥75% reduction in EASI from parent study baseline (EASI75); the percentage change from parent study baseline in EASI score; the percentage change from parent study baseline in SCORAD score; and the change from OLE baseline in the Pediatric Dermatological Quality of Life Index (CDQLI).

[0224] Pharmacokinetics PK samples were collected in a semi-dense fashion in Part A of the Phase 2a study and at sparse time points in Part B of the Phase 2a and OLE studies. To limit blood collection in this pediatric population, patients were randomized to a sampling schedule that included a subset of potential time points. Mean concentration-time profiles were generated from the pool of all collected samples, and the maximum mean concentration (t max ) and the area under the concentration-time curve from time zero to the time of the last measurable concentration in Part A (AUC last ) was used to determine the maximum dupilumab concentration in serum (C max ) to t max PK samples were collected at time points. トラフSamples were evaluated over a 24-48 week period. Dupilumab serum samples were analyzed using a validated enzyme-linked immunosorbent assay with a lower limit of quantitation of 0.078 mg / L. The PK analysis set included patients with ≥1 non-missing functional dupilumab result after the first dose of study drug.

[0225] statistical analysis No formal sample size or power calculations were performed. PK, safety, and efficacy variables were summarized descriptively. The statistical analysis plan did not prespecify inferential statistical tests to allow comparisons between treatment groups. Any differences observed in the descriptive summaries of PK, safety, and efficacy variables were based on numerical comparisons. The safety and efficacy analysis sets for all statistical analyses in both studies included all patients who received any study drug. Data were set to missing after rescue therapy use during Part B of the Phase 2a study. For continuous endpoints, missing values ​​during the 4-week repeat-dose treatment period in Part B were imputed using the last observation carried forward method. Missing data were not imputed after the end of treatment in Part B. For categorical variables, patients with missing values ​​were considered non-responders. Patients who withdrew from the study were counted as non-responders after withdrawal. Patients who received rescue therapy during Part B were considered non-responders from the time of rescue use. For the phase 3 OLE, an all-observed method was used, regardless of the use of rescue therapy or whether data were collected after withdrawal from treatment (missing values ​​were not imputed). All analyses were performed using Statistical Analysis Software (SAS) version 9.2 (SAS Institute, Inc.).

[0226] Results: Adolescents (≥12 to <18 years old) In adolescents with moderate to severe AD, the dupilumab pharmacokinetic profile was similar to that observed in adults. Dupilumab exhibited nonlinear target-mediated pharmacokinetics. After a single dose, C max(±SD) were 10 (±2) mg / L and 23 (±9) mg / L in the 2 mg / kg and 4 mg / kg dose groups, respectively; max The mean serum trough dupilumab concentrations (±SD) of 74 (±19) mg / L and 161 (±60) mg / L were observed in the 2 mg / kg and 4 mg / kg regimens, respectively, ranging from 4 to 8 days (Figure 4A).

[0227] Results - Children (≥6 to <12 years old) Thirty-eight children (≥6 to <12 years of age) were enrolled in the Phase 2 study. One patient (3%) in the 4 mg / kg dose group withdrew from the study during Part A (withdrawn consent due to fear of the study injection). Thirty-seven children (97%) completed Parts A and B. All 37 patients continued the pediatric OLE; four were 12 years of age at enrollment and are not included in this analysis. The mean time from the last dose in the Phase 2a study to the first dose of OLE was 118 days and 97 days for the 2 mg / kg and 4 mg / kg dose groups, respectively.

[0228] Baseline demographics and disease characteristics are shown in Table 11. The mean (±standard deviation [SD]) age for both dose groups was 8 (2) years, and the mean duration of AD was 7 (2) years. As shown in Table 11, disease characteristics at baseline in the Phase 2a study were consistent with severe AD. The mean (SD) EASI scores were 33 (16) and 39 (19) in the 2 mg / kg and 4 mg / kg groups, respectively; the peak pruritus NRS scores were 6 (2) and 7 (2), and the percentage of affected BSA was 59% (22) and 62% (30). Baseline disease severity was numerically higher in the 4 mg / kg group compared with the 2 mg / kg group in both the Phase 2a and OLE studies. Three patients (17%, 2 mg / kg) and seven patients (37%, 4 mg / kg) had received nonsteroidal immunosuppressants before baseline in the Phase 2a study, of which one (6%) and five (5%), respectively, did not respond to this treatment. Most patients (78%, 2 mg / kg and 90%, 4 mg / kg) had other concurrent atopic / allergic diseases, including asthma, allergic rhinitis, and food allergies.

[0229] [Table 15]

[0230] AUC calculated from the mean serum concentration-time profile after a single subcutaneous dose of dupilumab on Day 1 of a Phase 2a study last The t values ​​were 160 mg / L and 330 mg / L at 2 mg / kg and 4 mg / kg, respectively. max was observed, and C max In the 4 mg / kg group, the mean serum creatinine concentration (Tc) was 14.3 mg / L (5.9%) after 4 days of administration. max was observed, and C max The mean (±SD) of the steady-state dupilumab trough concentration was 32.4 mg / L (7.0) (Figure 5A). In the OLE, the mean steady-state dupilumab trough concentration from weeks 24 to 48 was 1.2 mg / L (7.0). Mean (±SD) concentrations ranged from 61.3 mg / L (35.0) to 76.8 mg / L (35.8) in the 2 mg / kg weekly group and from 143 mg / L (40.3) to 181 mg / L (65.9) in the 4 mg / kg weekly group ( Figure 5B ).

[0231] As shown in Table 12, the majority of TEAEs reported in Phase 2a were mild or moderate in severity (14% of patients reported severe TEAEs). The overall incidence of serious TEAEs was low, with two patients (11%) experiencing serious TEAEs in both 4 mg / kg dose groups in Part A of the study. Serious TEAEs included bacterial arthritis, infectious dermatitis, and AD exacerbation, which were considered unrelated to treatment. None of the events led to permanent treatment discontinuation. The most common TEAEs were nasopharyngitis and AD exacerbation. The proportion of patients with TEAEs was numerically higher in the 4 mg / kg dose cohort than in the 2 mg / kg dose cohort. This was due to a higher incidence of skin infection (high-level term), cough (preferred term [PT]), and infectious dermatitis (PT). Skin infections and AD exacerbations occurred most frequently in patients not receiving dupilumab treatment at the time of the TEAE (follow-up period in Part A or B). Injection site reactions were mild and occurred only in the 4 mg / kg dose group. Three patients reported conjunctivitis events. These were all in the 4 mg / kg dose group (both Parts A and B) and were not severe, serious, or led to treatment discontinuation; conjunctivitis resolved in two patients. One patient in each dose group reported a non-herpes virus infection in Part A of the study.

[0232] During the OLE, nearly all children reported ≥1 TEAE (Table 12). However, serious TEAEs were rare; two (12%) and three (19%) patients in the 2 mg / kg and 4 mg / kg dose groups, respectively, experienced ≥1 serious TEAE, none of which were treatment-related or led to study drug discontinuation. During the OLE, the most common TEAEs were nasopharyngitis and AD exacerbation. The proportion of patients with TEAEs, including skin infections, was similar between the 4 mg / kg and 2 mg / kg dose groups. However, when examining exposure-adjusted incidence rates (nP / 100PY), TEAEs tended to be numerically higher in the 4 mg / kg group compared with the 2 mg / kg group. Two (12%) and four (25%) patients reported herpes virus infections. Injection site reactions were mild and occurred in three patients across both dose groups. Seven patients: 2 (12%) and 5 (31%) in the 2 mg / kg and 4 mg / kg dose groups, respectively, reported conjunctivitis events, of which 1 patient (6.3%) in the 4 mg / kg group reported conjunctivitis as treatment-related. Conjunctivitis resolved in all patients. None of the events were severe or critical, nor did they lead to treatment discontinuation.

[0233] Efficacy outcomes for the Phase 2a and Phase 3 OLE studies are shown in Table 13. By week 2 of the Phase 2a study, EASI decreased after single doses of 2 mg / kg and 4 mg / kg dupilumab, with mean (±SD) percentage changes from baseline of -37 (34) and -33 (28), respectively; EASI improvement was maintained through week 52 of OLE (-92

[14] and -84

[17] in the 2 mg / kg and 4 mg / kg groups, respectively). The proportion of patients achieving EASI-75 or IGA 0 or 1 at week 12 of the Phase 2a study further increased through week 52 of OLE. By week 12 of the Phase 2a study, 56% and 47% of patients receiving dupilumab at 2 mg / kg and 4 mg / kg, respectively, achieved EASI-75, with the proportion increasing to 94% and 75%, respectively, at week 52 of OLE. Similarly, by week 12 of phase 2a, 17% and 21% achieved an IGA of 0 or 1, respectively, and the proportions further increased to 76% and 25% at week 52 of OLE. Peak pruritus NRS scores decreased from baseline by a mean (±SD) percentage change of -17% (46) and -20% (47), respectively, at week 2 of the phase 2a study after a single dose of dupilumab at 2 mg / kg and 4 mg / kg; improvements were maintained through week 52 of OLE (-70% at 2 mg / kg and 4 mg / kg, respectively). %

[32] and -58%

[33] ). Further improvements in other pruritus outcomes (patients with a ≥3-point or ≥4-point reduction from baseline in peak pruritus NRS) were seen through week 52 of the OLE. Sustained improvements were also seen in EASI-50, EASI-90, SCORAD, and percentage of BSA affected by AD in the phase 2a study and the OLE study through week 52. AD symptoms and QoL, as assessed by POEM and CDLQI, also improved from baseline through week 48 of the OLE.

[0234] Overall, 89% and 95% of patients in the 2 mg / kg and 4 mg / kg dupilumab arms of the phase 2a study, respectively, used topical treatments as concomitant medications. The most commonly used topical treatment in both treatment groups was potent TCS (Group III). In the OLE, 82% (2 mg / kg) and 94% (4 mg / kg) of children used concomitant topical medications, and the majority (65% and 69%) used potent (Group III) TCS.

[0235] [Table 16-1] [Table 16-2]

[0236] [Table 17-1] [Table 17-2]

[0237] Consideration In children aged ≥6 to <12 years with severe AD, dupilumab was well tolerated through week 52 with a favorable safety profile and no new safety concerns, consistent with studies in adolescents and adults with moderate-to-severe AD. No adverse events led to treatment discontinuation, and none of the reported serious TEAEs were considered related to dupilumab.

[0238] The incidence of TEAEs was higher in the 4 mg / kg dose group compared with the 2 mg / kg dose group in the phase 2a study, but the incidence of TEAEs was similar in the OLE. No substantial differences in SAEs or TEAEs leading to treatment discontinuation were observed between the two dose regimens. Furthermore, patients in this sequential cohort study were not randomized to dose regimens, leading to differences in OLE baseline disease severity, and the small number of patients in each dose regimen precluded rigorous comparisons between dose regimens. In the phase 2a study, a higher incidence of skin infections was observed with the 4 mg / kg dose compared with the 2 mg / kg dose, but the incidence was similar in the OLE. Most skin infections occurred in patients not receiving dupilumab treatment at the time of TEAE onset (patients were within the follow-up period in Parts A or B). Many patients with AD have skin colonization with Staphylococcus aureus, and patients with AD are prone to developing skin infections. Dupilumab, by treating AD, should be associated with a reduction in skin infections. A phase 3 trial in adults and adolescents with AD showed a numerically lower incidence of skin infections in patients treated with dupilumab compared with placebo. See Simpson et al., JAMA Dermatol 2020, 156:44-56.

[0239] Signs and symptoms of AD, including pruritus, showed rapid improvement with a single dose of dupilumab at both the 2 mg / kg and 4 mg / kg doses in a phase 2a study. Improvements in clinical scores (EASI, SCORAD) and peak pruritus NRS were observed as early as week 2 and further improved with continued treatment through week 52 in the OLE. QoL also improved with long-term treatment. The PK profile in children with severe AD was similar to that in adults and adolescents with moderate to severe AD and was characterized by nonlinear target-mediated kinetics. These safety and efficacy results support the use of dupilumab as continuous, long-term treatment for children ≥6 to <12 years of age with severe AD.

[0240] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in a method for treating atopic dermatitis (AD) or improving AD-related parameters in subjects with moderate to severe AD, The subjects are between 6 and 12 years old and have a weight between 15 kg and 30 kg; The IL-4R antagonist is an anti-IL-4R antibody comprising heavy chain complementarity-determining regions (HCDRs) of the heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and light chain complementarity-determining regions (LCDRs) of the light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2; and The IL-4R antagonist is administered subcutaneously at a dose of 300 mg every four weeks (Q4W) without using a loading dose, according to the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the target subject is a subject with severe AD that cannot be adequately controlled with topical AD drugs or for which topical treatment is not medically recommended.

3. The subject is the pharmaceutical composition according to claim 2, which has an insufficient response to treatment with topical corticosteroids (TCS).

4. The subject is a pharmaceutical composition according to any one of claims 1 to 3, which is a candidate for systemic therapy.

5. The target is, (i) Having a baseline Investigator Assessment (IGA) score of 4; (ii) Having a baseline eczema area and severity index (EASI) score of ≥ 21; (iii) Having a baseline body surface area (BSA) of ≥15% affected by AD; and / or (iv) Having chronic AD diagnosed at least one year prior to the start of treatment A pharmaceutical composition according to any one of claims 1 to 3.

6. IL-4R antagonists are administered as monotherapy. A pharmaceutical composition according to any one of claims 1 to 5.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the IL-4R antagonist is administered in combination with TCS.

8. The pharmaceutical composition according to claim 7, wherein the TCS is a medium-potency TCS.

9. The pharmaceutical composition according to claim 7, wherein the TCS is a low-potency TCS.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein treatment with an IL-4R antagonist reduces the amount of TCS administered to the subject compared to baseline.

11. Treatment with IL-4R antagonists is (i) By week 16 following the initial dose of the IL-4R antagonist, the IGA score is reduced from baseline to achieve an IGA score of 0 or 1; and (ii) The EASI score is reduced by at least 75% from baseline by week 16 after the initial dose of the IL-4R antagonist (EASI-75). A pharmaceutical composition according to any one of claims 1 to 10, which results in improvement of AD-related parameters selected from.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the anti-IL-4R antibody 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.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the anti-IL-4R antibody comprises HCVR containing the amino acid sequence of SEQ ID NO: 1 and LCVR containing the amino acid sequence of SEQ ID NO:

2.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the anti-IL-4R antibody is dupilumab.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector.

17. The pharmaceutical composition according to claim 16, wherein the IL-4R antagonist is contained in a pre-filled syringe.

18. The pharmaceutical composition according to claim 17, wherein the pre-filled syringe is a single-dose pre-filled syringe.

19. The pharmaceutical composition according to claim 16, wherein the IL-4R antagonist is contained in an autoinjector.

20. The pharmaceutical composition according to claim 16, wherein the IL-4R antagonist is contained in a pen-type delivery device.

Images