RU2828020C2 - Methods of treating atopic dermatitis by administering il-4r antagonist - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to biochemistry, particularly to a method of treating atopic dermatitis (AD) in an individual suffering moderate to severe or severe AD.

EFFECT: invention makes it possible to effectively treat atopic dermatitis (AD) in an individual having moderate to severe or severe AD, where the individual's age ranges from ≥ 6 years before < 12 years old.

25 cl, 5 dwg, 13 tbl, 2 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application was filed on August 5, 2020, as a PCT international patent application, and claims priority to U.S. Provisional Patent Application Nos. 62/882,946, filed August 5, 2019; 62/940,108, filed November 25, 2019; 62/985,715, filed March 5, 2020; 63/024,467, filed May 13, 2020; and 63/032,408, filed May 29, 2020; the contents of each of which are incorporated herein by reference.

STATEMENT CONCERNING SEQUENCES

[002] This application contains a sequence listing that is provided in electronic form in ASCII format and is incorporated herein by reference in its entirety. Said ASCII copy, created on August 4, 2020, is named 40848-0098USU1-SEQLIST.TXT and is 11 kilobytes in size.

FIELD OF INVENTION

[003] The present invention relates to the use of interleukin-4 receptor (IL-4R) antagonists for the treatment of atopic dermatitis.

LEVEL OF TECHNOLOGY

[004] Atopic dermatitis (AD) is a chronic/recurrent inflammatory skin disease characterized by severe pruritus (i.e., itching), xerosis (dry skin), and eczematous lesions whose features include erythema, infiltrates/papules, oozing with crusting, excoriation, and lichenification. It 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 impairment, and decreased quality of life (QOL), which lead to high socioeconomic costs. It is estimated that 2% to 10% of adults suffer from AD (Bieber 2008, N. Engl. J. Med. 358:1483-94).

[005] AD is the most common inflammatory skin disease of childhood (Illi et al, 2004, J. Allergy Clin. Immunol. 113: 925-31). The disease usually begins in early infancy and childhood, but can also persist and begin in adulthood (Kay et al, 1994, J. Am. Acad. Dermatol. 30: 35-9). The disease affects 15 to 30% of children and 2 to 10% of adults in industrialized countries (Bieber 2008, N. Engl. J. Med. 358: 1483-94). A phase 1 international trial of asthma and allergy in children demonstrated a prevalence of up to 20% at 1 year of life in Australia, the UK and Scandinavia (Williams et al, 1999, J. Allergy Clin. Immunol. 103: 125–38). AD often represents the first stage of the atopic march (progression from one atopic disease to another). Up to 60% of patients with AD have concomitant asthma, allergic rhinitis or food allergy (Hong et al, 2012, Envt. Health Toxicol. 27: e2012006).

[006] The clinical pattern of AD varies with age. In infants, it typically presents with erythematous papules and vesicles on the cheeks, forehead, or scalp that are exudative and intensely pruritic. The childhood phase typically occurs from age 2 years to puberty. Children are less likely to have the exudative lesions of infancy and instead have more crusted papules and plaques reflecting a more chronic disease involving the hands, feet, wrists, ankles, and areas anterior to the elbows and popliteal fossa. The adult phase of AD begins at puberty and often continues into adulthood. Predominant areas of involvement include the flexor folds, face and neck, upper forearms and back, and the dorsal areas of the hands, feet, fingers, and toes. The rash is characterized by dry, scaly, erythematous papules and plaques and the formation of large, crusted plaques as a result of the chronic nature of the lesions.

[007] The disease has been shown to have a marked impact on quality of life (QOL), exceeding that seen in other common skin disorders such as psoriasis and acne (Lewis-Jones et al, 1995, Brit. J. Dermatol. 132: 942-9). Often severe, pruritus is a universal feature of AD and frequently leads to sleep disturbance, irritability, and generalized stress in both affected patients and family members (Kim et al, 2012, J. Kor. Med. Sci. 27: 1327-32). In addition to causing discomfort, sleep loss, and psychosocial problems, AD can impose significant financial burden on families due to direct medical care, home adjustments, and missed work (Su et al, 1997, Arch. Dis. Child. 76: 159–62; Verboom et al, 2002, Brit. J. Dermatol. 147: 716–24; Williams 2005, New Engl. J. Med. 352: 2314–24).

[008] Of particular interest in children is the phenomenon of the "atopic march", which is characterized by a typical sequence of progression of clinical features of atopic disease. Typically, clinical features of AD and food allergy precede the development of asthma and allergic rhinitis, indicating that AD is the "starting point" for subsequent allergic disease (Spergel 2003, J Allergy Clin Immunol. 112(6 Suppl):S118-27). The severity of AD correlates with the development of asthma and allergic rhinitis (Zheng 2011, Allergy Asthma Immunol Res . 3(2):67-73). The prevalence of asthma in children aged 6 years and older who developed eczema during the first 4 years of life is estimated to be approximately 35% (Van der Hulst 2007, J Allergy Clin Immunol. 120(3):565-9). In a prospective "atopic march" study of children with eczema in infancy, 47% of patients had allergic rhinoconjunctivitis and 29% had asthma (Ekback 2014, PLoS One . 9(6):e99609) by age 10 years. More severe skin disease is positively correlated with a higher risk of developing comorbidities (asthma, allergic rhinitis, food allergy, and mental health disorders) and is associated with more severe comorbidities (Silverberg 2013, Pediatr Allergy Immunol. 24(5):476–86). The incidence of mental health disorders such as anxiety, depression, and attention deficit hyperactivity disorder (ADHD) is also higher in children with AD (Yaghmaie 2013, J Allergy Clin Immunol. 131(2):428–33). The disease course in school-going children may be complicated by potentially life-threatening complications such as eczema herpeticum (Luca 2012, Pediatr . 161(4):671–5).

[009] Non-pharmacologic management of AD, which includes measures to control environmental factors (e.g., avoidance of antigens and skin irritants) and skin care measures (e.g., maintaining skin hydration with emollients), plays a supportive role, especially in children with moderate to severe disease. Pharmacologic control of AD in children is mainly limited to local 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 disorders, acneiform rash, and risks associated with systemic absorption (e.g., growth retardation, hypothalamic-pituitary axis effects, etc.). Topical calcineurin inhibitors such as tacrolimus and pimecrolimus are also used in AD as an alternative or in combination with TCS. More potent 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, a possible increased risk of malignancies (lymphoma and skin cancer) has been noted for TCI.

[010] In children aged 6 to 11 years, systemic agents (cyclosporine, systemic steroids, methotrexate, azathioprine, and mycophenolate mofetil) are used off-label. A recent European survey, the European TREatment of Severe Atopic Eczema in Children Taskforce (TREAT), found that approximately 70% of respondents initiated systemic therapy in children with severe AD (Proudfoot 2013, Br J Dermatol. 169(4):901-9). 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 disturbances and leukopenia (azathioprine). Furthermore, a high proportion of patients whose disease is initially controlled with systemic agents suffer relapse shortly after stopping therapy (Schmitt 2009, Brit J Dermatol; journal compilation:1-8).

[011] Thus, there is currently a high unmet medical need for safe and effective therapy for AD in children.

ESSENCE

[012] In one aspect, methods are provided for treating atopic dermatitis (AD) or improving an AD-associated parameter in an individual. In some embodiments, the method comprises administering to a pediatric individual having moderate to severe or severe AD, wherein the individual is ≥6 years old to <12 years old, one or more doses of an interleukin-4 receptor (IL-4R) antagonist. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof.

[013] In some embodiments, the method includes:

(a) selection of an individual with severe AD, where the individual's age is ≥6 years to <12 years; and

(b) administering to the individual one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that comprises 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.

[014] In some embodiments, the individual is an individual with severe AD that is inadequately controlled with topical anti-AD medications or for whom topical treatment is not medically recommended. In some embodiments, the individual is inadequately responsive to treatment with a topical corticosteroid (TCS). In some embodiments, the individual is an individual with severe AD who is a candidate for systemic therapy.

[015] In some embodiments, the individual:

(i) has a baseline Investigator Global Assessment (IGA) score ≥ 4;

(ii) has a baseline Eczema Area and Severity Index (EASI) score ≥ 21;

(iii) has a baseline body surface area (BSA) affected by AD ≥ 15%; and/or

(iv) has chronic AD diagnosed at least one year before starting treatment.

[016] In some embodiments, the individual:

(i) has a baseline Investigator Global Assessment (IGA) score of 4;

(ii) has a baseline Eczema Area and Severity Index (EASI) score ≥ 21;

(iii) has a baseline body surface area (BSA) affected by AD ≥ 15%; and/or

(iv) has chronic AD diagnosed at least one year before starting treatment.

[017] In some embodiments, the individual has at least one concomitant allergic condition. In some embodiments, the individual has a concomitant allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergy, allergic conjunctivitis, urticaria, chronic rhinosinusitis, nasal polyps, and eosinophilic esophagitis.

[018] In some embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose followed by one or more secondary doses, wherein the secondary dose is administered 1-4 weeks after the immediately preceding dose. In some embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose followed by one or more secondary doses, wherein each secondary dose is administered 1-4 weeks after the immediately preceding dose, wherein:

(i) for an individual with a body weight <30 kg, the initial dose of IL-4R antagonist is 200 mg and each booster dose is 100 mg; or

(ii) for an individual weighing ≥30 kg, the initial dose of IL-4R antagonist is 400 mg and each booster dose is 200 mg; or

(iii) the initial dose of IL-4R antagonist is 600 mg and each secondary dose is 300 mg.

[019] In some embodiments, the individual has a body weight <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 individual has a body weight ≥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).

[020] In some embodiments, the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more secondary doses, wherein:

(i) for an individual weighing <30 kg, the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q4W; or

(ii) for an individual weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered as an initial dose of 400 mg followed by one or more booster doses of 200 mg Q2W; or

(iii) for an individual weighing ≥60 kg, the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q2W.

[021] In some embodiments, the individual has a body weight <30 kg and the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more secondary doses of 300 mg Q4W. In some embodiments, the individual has a body weight between ≥15 kg and <30 kg and the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more secondary doses of 300 mg Q4W. In some embodiments, the individual has a body weight between ≥30 kg and <60 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 Q2W. In some embodiments, the individual has a body weight of ≥60 kg and the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q2W.

[022] 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 or loading dose. In some embodiments, the IL-4R antagonist is administered to an individual (e.g., an individual having a body weight <30 kg, or an individual having a body weight of ≥15 kg to <30 kg) at a dose of 100 mg Q2W, with or without an initial or loading dose. In some embodiments, the IL-4R antagonist is administered to an individual (e.g., an individual having a body weight of ≥30 kg, or an individual having a body weight of ≥30 kg to <60 kg) at a dose of 200 mg Q2W, with or without an initial or loading dose. In some embodiments, the IL-4R antagonist is administered to an individual (e.g., an individual having a body weight <30 kg or an individual having a body weight of ≥15 kg to <30 kg) at a dose of 300 mg Q4W, with or without an initial or loading dose. In some embodiments, the IL-4R antagonist is administered to an individual (e.g., an individual having a body weight ≥60 kg) at a dose of 300 mg Q2W, with or without an initial or loading dose.

[023] In some embodiments, the IL-4R antagonist is administered subcutaneously at a dose of about 50 mg to about 600 mg, with an initial or loading dose being administered as a "split dose," such as on two or more different days. In some embodiments, the initial or loading dose is administered as a split dose over about one week, about two weeks, about three weeks, or about four weeks. In some embodiments, the IL-4R antagonist is administered to the individual at an initial dose of 600 mg, wherein the initial dose is divided into two or more doses (e.g., a first dose of 300 mg and a second dose of 300 mg), followed by one or more secondary doses of 300 mg Q4W. In some embodiments, the IL-4R antagonist is administered to the individual at an initial dose of 400 mg, wherein the initial dose is divided into two or more doses (e.g., a first dose of 200 mg and a second dose of 200 mg), followed by one or more secondary doses of 200 mg Q2W. In some embodiments, the IL-4R antagonist is administered to the individual at an initial dose of 600 mg, wherein the initial dose is divided into two or more doses (e.g., a first dose of 300 mg and a second dose of 300 mg), followed by one or more secondary doses of 300 mg Q2W. In some embodiments, a portion of the initial dose is administered on day 1, then the remainder of the initial dose is administered one week, two weeks, three weeks, or four weeks later, and then one or more secondary doses are administered after the remainder of the initial dose has been administered. 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 (one week later), on day 15 (two weeks later), or on day 22 (three weeks later), followed by one or more booster doses after the remainder of the initial dose has been administered.

[024] In some embodiments, the IL-4R antagonist is administered to the individual at an initial dose of 300 mg on day 1, then 300 mg on day 15 (week 2), then subsequent doses of 300 mg Q4W are administered after day 15. In some embodiments, the IL-4R antagonist is administered to an individual having a body weight <30 kg, or an individual having a body weight ≥15 kg to <30 kg, at an initial dose of 300 mg on day 1, then 300 mg two weeks later, then subsequent doses of 300 mg Q4W are administered. In some embodiments, the IL-4R antagonist is administered to an individual having a body weight <30 kg, or an individual having a body weight ≥15 kg to <30 kg, at an initial dose of 300 mg on day 1, then 300 mg on day 15 (week 2), then after day 15, 300 mg Q4W is administered.

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

[026] In some embodiments, the IL-4R antagonist is administered to the individual at an initial dose of 300 mg, then, beginning 2 weeks after the initial dose, it is administered at a dose of 300 mg Q4W. In some embodiments, the IL-4R antagonist is administered to an individual having a body weight <30 kg, or an individual having a body weight ≥15 kg to <30 kg, at an initial dose of 300 mg, then, beginning 2 weeks after the initial dose, it is administered at a dose of 300 mg Q4W.

[027] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered to an individual (e.g., an individual ≥6 years to <12 years of age with moderate to 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 the IL-4R antagonist of about 400 mg or about 600 mg is administered. In some embodiments, no initial or loading dose is administered. In some embodiments, a divided loading dose is administered.

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

[029] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered to an individual (e.g., an individual ≥6 years to <12 years of age who has moderate to severe or severe AD and who is a candidate for systemic therapy) at a dose of 200 mg QW or 300 mg QW if the individual has a body weight of ≥60 kg.

[030] In some embodiments, the individual is administered an IL-4R antagonist in combination with a topical drug (e.g., a topical corticosteroid (TCS) or a topical non-steroidal drug). In some embodiments, the individual is administered an IL-4R antagonist in combination with a TCS. In some embodiments, the TCS is a moderate 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 that is administered to the individual relative to baseline.

[031] In some embodiments, treatment with an IL-4R antagonist results in an improvement in an AD-associated parameter that is selected from:

(i) a reduction from baseline IGA to an IGA of 0 or 1 by week 16 after the first dose of IL-4R antagonist; and

(ii) a reduction of at least 75% from baseline in EASI (EASI-75) score by 16 weeks after the first dose of the IL-4R antagonist.

[032] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that specifically binds IL-4R. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises 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. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and comprises a 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 bioequivalent thereof.

[033] In some embodiments, a method of treating AD or improving an AD-associated parameter in an individual comprises administering an IL-4R antagonist to an individual with moderate to severe or severe AD, wherein the individual is ≥6 years of age to <12 years of age, wherein the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that specifically binds IL-4R and that 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; wherein the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more booster doses, wherein:

(i) for an individual weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered as an initial dose of 600 mg followed by one or more booster doses of 300 mg Q4W; or

(ii) for an individual weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered as an initial dose of 400 mg followed by one or more booster doses of 200 mg Q2W; or

(iii) for an individual weighing ≥60 kg, the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q2W.

[034] In some embodiments, the subject is concomitantly administered with a topical drug (e.g., a topical corticosteroid (TCS) or a topical nonsteroidal drug such as a calcineurin inhibitor or crisaborole). In some embodiments, the subject is concomitantly administered with a TCS. In some embodiments, the TCS is a mid-potency TCS. In some embodiments, the TCS is a low-potency TCS.

[035] In some embodiments, methods are provided for treating AD or improving an AD-associated parameter in an individual, wherein the individual is ≥6 years of age to <18 years of age and has moderate to severe or severe AD, wherein the method comprises administering to the individual an anti-IL-4R antibody or antigen-binding fragment thereof that comprises 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; wherein:

(i) for an individual 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 booster doses of 300 mg Q4W; or

(ii) for an individual 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 booster doses of 200 mg Q2W; or

(iii) for an individual 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 booster doses of 300 mg Q2W.

[036] In some embodiments, the individual is ≥6 years old to <12 years old. In some embodiments, the individual has severe AD. In some embodiments, the individual is a candidate for systemic therapy.

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

[038] In another aspect, therapeutic dosage forms of a pharmaceutical composition comprising an IL-4R antagonist are provided. In some embodiments, the therapeutic dose of the IL-4R antagonist is 2 mg/kg, and weekly administration of the dosage form for four weeks to an individual 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 weekly administration of the dosage form for at least 24 weeks to an individual provides a mean serum concentration of the IL-4R antagonist of from 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 weekly administration of the dosage form to the individual for four 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 weekly administration of the dosage form to the individual for at least 24 weeks 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 weekly.

[039] In some embodiments, a therapeutic dosage form of the pharmaceutical composition comprises an IL-4R antagonist, and administration of the dosage form for 16 weeks to an individual 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.

[040] In some embodiments, the therapeutic dosage form is administered to an individual ≥6 years of age to <18 years of age. In some embodiments, the individual is ≥6 years of age to <12 years of age. In some embodiments, the individual is ≥12 years of age to <18 years of age.

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

[042] Other embodiments will become apparent from consideration of the detailed description below.

BRIEF DESCRIPTION OF DRAWINGS

[043] Fig. 1A-1I. Proportion of patients achieving specific endpoints over time in the overall population and in the subgroups with baseline body weight <30 kg and ≥30 kg. (AC) Proportion of patients achieving the co-primary endpoint IGA 0/1 over time in the overall population (A), in the subgroup with baseline body weight <30 kg (B), and in the subgroup ≥30 kg (C). (DF) Percentage of patients achieving the co-primary endpoint EASI-75 over time in the overall population (D), in the subgroup with baseline body weight <30 kg (E), and in the subgroup ≥30 kg (F). (GI) Standard deviation (LS) percentage change in EASI over time in the overall population (G), in the subgroup with baseline body weight <30 kg (H), and in the subgroup ≥30 kg (I). EASI=Eczema Area and Severity Index; EASI-75=≥75% improvement from baseline in EASI scores; IGA=Investigator Global Assessment; LS=Least Squares; Q2W=every 2 weeks; Q4W=every 4 weeks.

[044] Figs. 2A-2F. Proportions of patients with ≥3 point improvement (AC) and ≥4 point improvement (DF) in weekly mean maximum pruritus numeric rating scale score over time in the overall population (A, D), in the subgroup with baseline body weight <30 kg (B, E), and in the subgroup ≥30 kg (C, F). Q2W=every 2 weeks; Q4W=every 4 weeks.

[045] Figure 3 graphically depicts the overall SCORAD score over time for individuals who received 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.

[046] Figures 4A and 4B are graphs of mean log serum dupilumab concentrations over nominal time. Figure 4A: Phase 2a trial. Vertical arrows represent time points at which dupilumab 2 mg/kg or 4 mg/kg was administered. Figure 4B: Phase 3 OLE. Patients in the OLE were administered dupilumab 2 mg/kg once weekly or 4 mg/kg once weekly. C _max , maximum concentration; LLOQ, lower limit of quantification; SD, standard deviation; t _max , time to maximum concentration.

[047] Figures 5A and 5B are graphical representations of mean log serum dupilumab concentrations versus nominal time. Figure 5A: concentration-time profile for the phase 2a trial. The vertical arrows represent the time points when dupilumab 2 mg/kg or 4 mg/kg was administered. Figure 5B: concentration-time profile for the phase 3 OLE trial. For both (A) and (B), concentrations below the lower limit of quantification were defined as LLOQ/2 (represented by the dotted line).

DETAILED DESCRIPTION

[048] Before describing the present invention, it should be understood that the invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It should also be understood that the terminology used in this description is intended to describe particular embodiments only and is not intended to be limiting, since the scope of the present invention is limited only by the appended claims.

[049] Unless defined otherwise, 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.

[050] The terms "fig.", "FIG.", "figure" and "figures" are used interchangeably in this description.

[051] As used herein, the term "about," when used with respect to a particular stated numerical value, means that the value may deviate 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 in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[052] As used herein, the terms "treat,""treatment," etc., mean alleviating symptoms, eliminating the cause of symptoms either temporarily or permanently, or preventing or slowing the onset of symptoms of the disorder or condition in question.

[053] "Atopic dermatitis" or "AD," as used herein, refers to an inflammatory skin disorder characterized by itchy lesions (e.g., severe scratching) and scaly or dry eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollens, molds, house dust mites, animals, etc.), radiation exposure, and/or asthma. The present invention encompasses methods of treating patients with moderate to severe or severe AD. As used herein, "moderate to severe AD" is characterized by intensely pruritic, widespread lesions on the skin that are often complicated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. In many cases, chronic lesions include thickened plaques on the skin, lichenification, and fibrous papules. Patients suffering from moderate to severe AD also typically have involvement of more than 20% of the body skin or 10% of the skin area in addition to involvement of the eyes, hands, and body folds. Moderate to severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids. A patient may also be considered to have moderate to severe AD when the patient is resistant or refractory to treatment with either a topical corticosteroid or a calcineurin inhibitor. As used herein, "severe AD" is characterized by the presence of widespread lesions on the skin, persistent pruritus, or a physically or emotionally disabling disease that significantly impairs the patient's quality of life. In some cases, patients with severe AD also have one or more symptoms such as excoriation, marked thickening of the skin, bleeding, oozing 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 corticosteroid, calcineurin inhibitor, crisaborole, or phototherapy).

[054] As used herein, the term "individual in need thereof" refers to a human or non-human animal having AD (e.g., moderate to severe AD or severe AD). In some embodiments, the term "individual in need thereof" refers to patients with moderate to severe or severe AD, wherein the patient is ≥12 to <18 years of age (adolescents). In other embodiments, the term "individual in need thereof" refers to patients with moderate to severe or severe AD, wherein the patient is ≥6 to <12 years of age (children). The terms "individual" and "patient" are used interchangeably herein.

[055] In some embodiments, the term "individual in need thereof" includes patients with moderate to severe or severe AD who are between 6 and 18 years of age (e.g., adolescent patients ≥12 to <18 years of age or pediatric patients ≥6 to <12 years of age) and who are candidates for systemic therapy. In some embodiments, the individual is a candidate for systemic therapy if the individual'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 "individual in need thereof" includes patients with moderate to severe or severe AD who are between 6 and 18 years of age (e.g., adolescent patients ≥12 to <18 years of age or pediatric patients ≥6 to <12 years of age) and who have received prior treatment with systemic therapy. As used herein, the term "systemic therapy" refers to systemically administered therapeutic agents (e.g., orally administered corticosteroids). The term includes systemic immunosuppressants or immunomodulatory agents. In the context of the present invention, the term "systemic immunosuppressant" includes, but is not limited to, cyclosporin A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, and interferon-gamma. In certain embodiments, the term also includes immunobiological agents such as tumor necrosis factor alpha (TNFα) inhibitors (e.g., an anti-TNFα antibody such as infliximab), CD11a inhibitors (e.g., an anti-CD11a antibody such as efalizumab), IgE inhibitors (e.g., omalizumab), CD20 inhibitors (e.g., rituximab). Systemic therapy, including systemic immunosuppressants, can be used for short-term treatment of exacerbations or as a temporary measure to control the disease, but their use is limited by significant side effects, such as growth retardation in children, Cushing's syndrome, hypertension, impaired glucose tolerance, myopathy, osteonecrosis, glaucoma, and cataracts. The use of systemic immunosuppressants also carries the risk of a rebound phenomenon, where disease symptoms may significantly worsen after treatment is discontinued. In certain embodiments, the terms "systemic therapy,""systemic therapeutic agent," and "systemic immunosuppressant" are used interchangeably throughout this disclosure.

[056] 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 as weak (Group I), moderately potent (Group II), potent (Group III), and highly potent (Group IV), based on their potency relative to hydrocortisone. Group IV TCS (highly potent) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50-100 times more potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent; also interchangeably referred to herein as "moderately potent") are 2-25 times more potent than hydrocortisone and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (weak; also interchangeably referred to herein as "low potent") includes hydrocortisone.

[057] Although any methods and materials similar or equivalent to those described herein can be used in practicing the invention, representative methods and materials are described below. All publications mentioned in this specification are herein incorporated by reference in their entirety.

Methods of therapy

[058] In one aspect, methods are provided for treating atopic dermatitis (AD) or improving an AD-associated parameter in an individual. In some embodiments, the methods comprise administering to an individual having severe AD, wherein the individual is ≥6 years old to <12 years old, one or more doses of an interleukin-4 receptor (IL-4R) antagonist. In some embodiments, the IL-4R antagonist is administered concurrently with a topical AD therapy, such as a topical corticosteroid (TCS) or a topical nonsteroidal drug (e.g., a calcineurin inhibitor or crisaborole).

[059] In some embodiments, an individual treated according to the methods described herein is an individual ≥6 years to <12 years of age who has severe AD that has not responded adequately to topical therapy (e.g., TCS with or without topical calcineurin inhibitors (TCIs)) or for whom topical therapy is not recommended (e.g., due to adverse side effects or safety risks). In some embodiments, the individual has a history of documented inadequate response to a sufficient course of outpatient treatment with topical AD drug(s). As used herein, "inadequate response" refers to a failure to achieve and maintain remission or a state of low disease activity (comparable to an Investigator Global Assessment [IGA] of 0=none to 2=mild) despite treatment for at least 28 days with topical therapy (e.g., a moderate to high potency TCS regimen, ±TCI as appropriate). In some embodiments, an individual has an "insufficient response" if the patient has received documented systemic treatment for AD.

[060] In some embodiments, treatment with an IL-4R antagonist improves, alleviates, or reduces one or more symptoms of AD in an individual, including, but not limited to, pruritus (i.e., scratching), xerosis (dry skin), eczematous lesions, erythema, papule formation, edema, oozing/crusting, excoriation, lichenification, sleep disturbance, anxiety, and depression.

[061] In some embodiments, treatment with an IL-4R antagonist improves one or more AD-associated parameters in an individual. Examples of "AD-associated parameters" include, but are not limited to: (a) Investigator Global Assessment (IGA); (b) Body Surface Area Involvement in Atopic Dermatitis (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Numerical Pruritus Rating Scale (NRS). "Improvement in an AD-associated parameter" means a decrease from baseline in one or more of the IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, NRS/Worst Itch Scale, Patient Global Assessment of Disease, Patient Global Assessment of Change, Childhood Dermatology Life Quality Index (CDLQI), Patient Eczema Evaluation Severity (POEM), Dermatitis Family Impact Index (DFI) score, or Patient Reported Outcomes Information System (PROMIS) score for anxiety and/or depression. The term "baseline" as used in relation to an AD-associated parameter means the numerical value of the AD-associated parameter for an individual prior to or at the time of administration of the pharmaceutical composition as described herein.

[062] To determine whether an "improvement" in an AD-associated parameter has occurred, the parameter is quantified at baseline and at one or more time points following administration of the pharmaceutical composition of the present invention. For example, an AD-associated parameter can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or at the end of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks or more, after initial treatment with the pharmaceutical composition of the present invention. 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 determine whether an "improvement" (e.g., decrease) in an AD-associated parameter has occurred. AD-associated parameters are described in U.S. Patent Publication No. US 2014/0072583, incorporated herein by reference in its entirety.

[063] In some embodiments, treatment with an IL-4R antagonist in accordance with the methods of the invention results in an improvement in the IGA score of the individual relative to baseline. Methods for determining the IGA score of an individual are described in the Examples section below. In some embodiments, the individual being treated has a baseline IGA score ≥ 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 decrease in the baseline IGA score (e.g., from a baseline IGA score ≥ 4) by at least 1 point by week 16 after the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a decrease from baseline (e.g., from an IGA score ≥ 4) to an IGA score of 0 or 1 by week 16 after the first dose of the IL-4R antagonist.

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

[065] In some embodiments, treatment with an IL-4R antagonist in accordance with the methods of the present invention results in an improvement in the EASI score of the individual relative to baseline. Methods for determining the EASI score of an individual are described in the Examples section below. In some embodiments, the individual being treated has a baseline EASI score ≥ 21 (e.g., an EASI score ≥ 30). In some embodiments, treatment with an IL-4R antagonist results in a reduction 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% from baseline in the EASI score 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 the individual achieving an EASI-75 response (i.e., ≥ 75% improvement from baseline) by week 16 after the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in the individual achieving an EASI-50 response (i.e., ≥ 50% improvement from baseline) by week 16 after the first dose of the IL-4R antagonist.

[066] In some embodiments, treatment with an IL-4R antagonist in accordance with the methods of the present invention results in an improvement in the BSA score of the individual relative to baseline. Methods for determining the BSA score of an individual are described in the Examples section below. In some embodiments, the individual being treated has a baseline BSA score of ≥ 15% (e.g., ≥ 20%, ≥ 30%, ≥ 40%, ≥ 50%, ≥ 75%, or ≥ 90%). In some embodiments, the individual being treated has a baseline BSA score of ≥ 50%. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or more from baseline in the percentage of BSA affected by AD by week 16 after administration of the first dose of the IL-4R antagonist.

[067] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present invention results in an improvement in an itch score, such as a "worst itch scale" score, also referred to herein as an itching numeric rating scale (NRS) score, for the individual relative to baseline. Methods for determining an itch score are described in the Examples section below. In some embodiments, the treated individual has a weekly average worst itch score for maximum itch intensity that is ≥ 4 (such as ≥ 7). In some embodiments, treatment with an IL-4R antagonist results in a decrease of ≥ 3 points (such as ≥ 4 points) in the weekly average daily itch score (e.g., worst itch score) from baseline to week 16 after administration of the first dose of the IL-4R antagonist.

[068] In some embodiments, treatment with an IL-4R antagonist in accordance with the methods of the present invention results in an improvement in the SCORAD score of the individual relative to baseline. Methods for determining the SCORAD score of an individual are described in the Examples section below. In some embodiments, the individual being treated has a baseline SCORAD score of ≥ 40 (e.g., a SCORAD score of ≥ 50, ≥ 60, or ≥ 70). In some embodiments, treatment with an IL-4R antagonist results in a reduction in SCORAD by 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% from baseline by week 16 after the first dose of the IL-4R antagonist.

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

Interleukin-4 receptor antagonists

[070] In some embodiments, the methods of the present invention comprise administering to an individual in need thereof (e.g., a pediatric individual having severe 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-4Rblocker," 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 the IL-4 receptor type 1 and/or type 2. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. IL-4 receptor type 1 is a dimeric receptor comprising an IL-4Rα chain and a γc chain. IL-4 receptor type 2 is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. IL-4 receptors type 1 interact with and are stimulated by IL-4, while IL-4 receptors type 2 interact with and are stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that may be used in the methods of the present invention may function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. Thus, the IL-4R antagonists of the present invention can interfere with the interaction of IL-4 and/or IL-13 with the type 1 or type 2 receptor.

[071] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, IL-4R aptamers, peptide IL-4R inhibitors (e.g., "peptide antibody" molecules), "receptor antibodies" (e.g., engineered molecules comprising a ligand binding domain as a component of IL-4R), 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 IL-4 and/or IL-13.

Anti-IL-4Rα antibodies and their antigen-binding fragments

[072] In certain exemplary embodiments of the present invention, an IL-4R antagonist is an anti-IL-4Rα antibody or 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, linked together by disulfide bonds, as well as multimers thereof (e.g., IgM). In an exemplary antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V _H ) and a heavy chain constant region. The heavy chain constant region comprises three domains: _CH 1, _CH 2, and _CH 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V _L ) and a light chain constant region. The light chain constant region comprises one domain ( _CL 1). The V _H and V _L regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), separated by regions that are more conserved, called framework regions (FRs). Each V _H and V _L contains three CDRs and four FRs, arranged in the following order from T-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of the anti-IL-4R antibody (or antigen-binding fragment thereof) are naturally occurring or artificially modified.

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

[074] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition elements consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR), such as a CDR3 peptide), or a restricted FR3-CDR3-FR4 peptide. Also, the term "antigen-binding fragment" as used herein encompasses other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tribodies, tetrabodies, minibodies, nanoantibodies (e.g., monovalent nanoantibodies, divalent nanoantibodies, etc.), small modular immunopharmaceutical proteins (SMIPs), and shark IgNAR variable domains.

[075] An antigen-binding fragment of an antibody typically comprises at least one variable domain. The variable domain may be of any size or amino acid composition, and typically comprises at least one CDR that is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V _H domain linked to a V _L domain, the V _H and V _L domains may be arranged relative to one another in any suitable manner. For example, the variable region may be dimeric and may comprise V _H -V _H , V _H -V _L , or V _L -V _L dimers. Alternatively, the antigen-binding fragment of an antibody may comprise a monomeric V _H or V _L domain.

[076] 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 in an antigen-binding fragment of an antibody of the present invention include: (i) V _H -C _H 1; (ii) V _H -C _H 2; (iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) 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 -CH1} - _CH2 - _CH3 ; (xiii) V _{L -CH2} - _CH3 ; and (xiv) V _{L -CH} . In any configuration of the variable and constant domains, including any of the exemplary configurations given above, the variable and constant domains may either be directly linked to each other or may be linked through a full or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations described above, non-covalently linked to each other and/or to one or more monomeric V _H or V _L domains (e.g., via disulfide bond(s)).

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

[078] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody typically comprises at least two different variable domains, wherein each variable domain is capable of specifically binding to a distinct antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of an antibody or antigen-binding fragment of an antibody of the present invention using standard techniques available in the art. For example, in some embodiments, the methods of the present invention involve the use of bispecific antibodies, wherein one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Illustrative bispecific formats that can be used in the context of the present invention include, but are not limited to, e.g., scFv or diabody-based bispecific formats, IgG-scFv fusions, dual variable domain (DVD) Igs, quadroma, knob-in-hole constructs, common light chain (e.g., common light chain with knobs-in-holes, etc.), CrossMab, CrossFab, antibody-(primer), leucine zipper, duobody, IgG1/IgG2, Fab (DAF)-IgG dual-acting, and Mab ² bispecific formats (see, e.g., Klein et al , 2012, mAbs 4:6, 1-11, and references cited therein, for a review of the aforementioned formats). Bispecific antibodies can also be constructed using peptide/nucleic acid conjugation, for example, where unnatural amino acids with independently distinct reactivities are used to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valence, and geometry (see, e.g., Kazane et al , J. Am. Chem. Soc . [ Epub : Dec. 4, 2012 ]).

[079] In some embodiments, the antibodies used in the methods of the present invention are human antibodies. The term "human antibody," as used herein, includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the human antibodies of the invention may include amino acid residues not encoded by the human germline immunoglobulin sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or somatic mutation in vivo ), such as in the CDRs, and in particular CDR3. However, the term "human antibody," as used herein, does not include antibodies in which CDR sequences derived from a germline sequence of another mammalian species, such as a mouse, are grafted into human framework sequences.

[080] The antibodies used in the methods of the present invention can be recombinant human antibodies. The term "recombinant human antibody," as used herein, includes all human antibodies that are produced, expressed, created, or isolated by recombinant methods, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in detail below), antibodies isolated from a recombinant combinatorial library of human antibodies (described in detail below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al . (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, created, or isolated by any other methods that involve linking human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V _H and V _L regions of the recombinant antibodies are sequences that, although derived from and related to human germline V _H and V _L sequences, may not naturally exist in the human germline antibody repertoire in vivo .

[081] An "isolated antibody" refers to an antibody that is identified and removed and/or separated from at least one component of its natural environment. For example, an antibody that is removed or separated from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ in a recombinant cell. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody can be substantially free of other cellular material and/or chemicals.

[082] According to certain embodiments, antibodies used in the methods of the present invention specifically bind IL-4Rα. The term "specifically binds," as used herein, means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. In some embodiments, an antibody that "specifically binds" IL-4Rα binds IL-4Rα or a portion thereof with an equilibrium dissociation constant (K _D ) 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 in a surface plasmon resonance assay (e.g., BIAcore™, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, such as an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα exhibits cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[083] In some exemplary embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof that comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the IL-4R antibodies as taught in U.S. Patent No. 7,608,693. In some embodiments, the IL-4Rα antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof that comprises heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antagonist IL-4Rα is an anti-IL-4Rα antibody or antigen-binding fragment thereof that 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.

[084] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 3, 4, 5, 6, 7, and 8, respectively, and further comprises an HCVR having at least 85% sequence identity (such as 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 (such as 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.

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

[086] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present invention comprise using dupilumab or a bioequivalent thereof. The term "bioequivalent" as used herein with respect to dupilumab refers to anti-IL-4R antibodies or IL-4R binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and/or extent of absorption does not exhibit a significant difference from dupilumab when administered at the same molar dose under similar experimental conditions, either as a single dose or in multiple doses. In some embodiments, the term refers to antigen-binding proteins that bind to IL-4R that do not have clinically significant differences from dupilumab with respect to safety, purity, and/or efficacy.

[087] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, an antibody referred to and known in the art as AMG317 (Corren et al , 2010, Am J Respir Crit Care Med., 181 (8): 788-796), or MEDI 9314, or any of the anti-IL-4Rα antibodies mentioned in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, or U.S. Patent No. 8,877,189.

[088] In some embodiments, an anti-IL-4Rα antibody used in the methods of the present invention may have pH-dependent binding characteristics. For example, an anti-IL-4Rα antibody for use as described herein may exhibit reduced binding to IL-4Rα at acidic pH conditions compared to neutral pH. Alternatively, an anti-IL-4Rα antibody of the invention may exhibit enhanced binding to its antigen under acidic pH conditions compared to neutral pH. The term "acidic pH" includes pH values of less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. As used herein, the term "neutral pH" means a pH of from about 7.0 to about 7.4. The term "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.

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

[090] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for decreased (or increased) binding to a particular antigen at acidic pH values compared to neutral pH values. In addition, modifications of the antigen-binding domain at the amino acid level can provide antibodies with pH-dependent characteristics. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDRs) with a histidine residue, an antibody with decreased antigen binding at acidic pH values relative to neutral pH values can be obtained.

Obtaining human antibodies

[091] Methods for producing human antibodies in transgenic mice are known in the art. In the context of the present invention, any of such known methods can be used to produce human antibodies that specifically bind to human IL-4R.

[092] Using VELOCIMMUNE™ technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, high-affinity chimeric antibodies to IL-4R having a human variable region and a mouse constant region are initially isolated. VELOCIMMUNE® technology involves generating a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigen stimulation. DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[093] Typically, a VELOCIMMUNE® mouse is infected with an antigen of interest and lymphocytes (such as B cells) are obtained from mice that express the antibodies. The lymphocytes can be fused with a myeloma cell line to produce immortalized hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain can be isolated and linked to the desired isotypic constant regions of the heavy chain and light chain. Such an antibody protein can be produced in a cell, such as a CHO cell. Alternatively, DNA encoding antigen-specific chimeric antibodies or the variable domains of the light and heavy chains can be isolated directly from the antigen-specific lymphocytes.

[094] Initially, high-affinity chimeric antibodies having a human variable region and a mouse constant region are isolated. The antibodies are characterized and selected for desired characteristics, including affinity, selectivity, epitope, etc., using standard techniques known to those skilled in the art. The mouse constant regions are replaced with the desired human constant region to produce a fully human antibody of the invention, e.g., a wild-type or modified IgG1 or IgG4 IgG1 or IgG4. While the constant region selected may vary depending on the particular application, the characteristics of high-affinity antigen binding and target specificity are inherent in the variable region.

[095] In general, antibodies that may be used in the methods of the present invention have high affinity, as described above, as determined by binding to an antigen either immobilized on a solid phase or in solution phase. The mouse constant regions are replaced with the desired human constant regions to produce the fully human antibodies of the invention. While the constant region selected may vary depending on the particular application, the characteristics of high affinity antigen binding and target specificity are inherent in the variable region.

[096] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds IL-4R and that can be used in the methods described 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 in HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs in certain HCVR and/or LCVR amino acid sequences described herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of structural loop regions, and the AbM definition is based on 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 in an antibody.

Pharmaceutical compositions

[097] In one aspect, the present invention provides methods that comprise administering an IL-4R antagonist to an individual, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is in a pharmaceutical composition that comprises one or more pharmaceutically acceptable vehicles, carriers, and/or excipients. Various 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, and subcutaneous administration.

[098] Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucous membranes (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents. In some embodiments, the pharmaceutical composition as described herein is administered intravenously. In some embodiments, the pharmaceutical composition as described herein is administered subcutaneously.

[099] In some embodiments, the pharmaceutical composition comprises an injectable preparation, such as a dosage form for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be prepared by known methods. For example, the injectable preparations can be prepared, for example, by dissolving, suspending or emulsifying the antibody or salt thereof described above in a sterile aqueous medium or oil medium commonly used for injections. As an aqueous medium for injection, there are used, for example, physiological saline solution, isotonic solution containing glucose and other auxiliary substances, etc., which can be used in combination with a suitable solubilizing agent such as alcohol (e.g. ethanol), polyhydric alcohol (e.g. propylene glycol, polyethylene glycol), nonionic surfactant [e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As an oil medium, there are used, for example, sesame oil, soybean oil, etc., which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection prepared in this way can be filled into an appropriate ampoule.

[0100] The dose of antibody administered to an individual in accordance with the methods of the present invention may vary depending on the patient's age and size, symptoms, conditions, route of administration, and the like. The dose is typically calculated based on body weight and body surface area. The frequency and duration of treatment may be adjusted depending on the severity of the condition. Effective dosages and administration regimens for pharmaceutical compositions comprising anti-IL-4R antibodies may be determined empirically; for example, the individual's progress may be monitored through periodic assessment and the dose adjusted accordingly. Moreover, interspecies dosage scaling may be performed using methods well known in the art (e.g., Mordenti et al , 1991, Pharmaceut. Res. 8 :1351). Specific exemplary doses of anti-IL4R antibodies and administration regimens involving them that may be used in the context of the present invention are described herein.

[0101] In some embodiments, a pharmaceutical composition of the present invention is contained in a container. Thus, in another aspect, containers are provided that contain a pharmaceutical composition as described herein (e.g., a pharmaceutical composition comprising an IL-4R antagonist, such as an anti-IL-4R antibody, as described herein). For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an autoinjector.

[0102] In some embodiments, the pharmaceutical composition of the present invention is delivered, for example, subcutaneously or intravenously using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen delivery device or an autoinjector is used to deliver the pharmaceutical composition of the present invention (e.g., for subcutaneous delivery). The pen delivery device may be reusable or disposable. Typically, a reusable pen delivery device typically uses a replaceable cartridge that contains the pharmaceutical composition. After the pharmaceutical composition has been administered from the cartridge and the cartridge has been emptied, the empty cartridge can be easily discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. A disposable pen device does not have a replaceable cartridge. Instead, the disposable pen device is released pre-filled with the pharmaceutical composition contained in a reservoir of the device. After the reservoir of the pharmaceutical composition is emptied, the entire device is discarded.

[0103] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen-type delivery devices useful for subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), the SURECLICK ^™ self-injecting syringe (Amgen, Thousand Oaks, CA), PENLET ^™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA ^™ pen (Abbott Labs, Abbott Park, IL).

[0104] In some embodiments, the pharmaceutical composition is delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In another embodiment, the controlled release system can be placed near the target of the composition and thus only a portion of the systemic dose is required (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are reviewed in Langer, 1990, Science 249:1527-1533. Other delivery systems are known and can be used for administering the pharmaceutical composition, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al, 1987, J. Biol. Chem. 262:4429-4432).

[0105] In some embodiments, pharmaceutical compositions for use as described herein are prepared as unit dosage forms suitable for containing a dose of the active ingredients. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0106] Illustrative pharmaceutical compositions comprising an anti-IL-4R antibody that can be used in the context of the present invention are described, for example, in U.S. Patent No. 8,945,559.

Dosage and administration

[0107] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to an individual in accordance with the methods of the present invention in a therapeutically effective amount. As used herein in relation to an IL-4R antagonist, the term "therapeutically effective amount" means an amount of the IL-4R antagonist that results in one or more of: (a) an improvement in one or more AD-associated parameters (as referred to herein); and/or (b) a measurable improvement in one or more symptoms or signs of atopic dermatitis.

[0108] In the case of an anti-IL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of an anti- IL-4R. In some embodiments, the therapeutically effective amount is from about 75 mg to about 600 mg, or from about 100 mg to about 600 mg, or from about 200 mg to about 600 mg. In certain embodiments, the individual is administered 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of an anti-IL-4R antibody.

[0109] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in individual doses can be expressed in terms of milligrams of antibody per kilogram of individual body weight (i.e., mg/kg). For example, the IL-4R antagonist can be administered to an individual at a dose of from about 0.0001 to about 10 mg/kg of the individual's body weight, such as at a dose of from about 1 mg/kg to about 10 mg/kg, at a dose of from about 2 mg/kg to about 9 mg/kg, or at a dose of from about 3 mg/kg to about 8 mg/kg. In some embodiments, the IL-4R antagonist may be administered to the individual 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.

[0110] In some embodiments, the methods described herein comprise administering an IL-4R antagonist to an individual at a dosing frequency of about four times per week, twice per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently, provided that a therapeutic response is achieved.

[0111] In some embodiments, the individual is administered multiple doses of an IL-4R antagonist over a period of time. In some embodiments, the methods of the invention comprise sequentially administering multiple doses of an IL-4R antagonist to the individual. As used herein, "sequential administration" means that the doses of an IL-4R antagonist are administered to the individual at different time points, such as on different days, separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the invention comprise sequentially administering to the patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of an IL-4R antagonist, and optionally one or more tertiary doses of an IL-4R antagonist.

[0112] The terms "initial dose,""secondarydoses," and "tertiary doses" refer to the temporal sequence of administration of the IL-4R antagonist. Thus, an "initial dose" is a dose that is administered at the beginning of a treatment regimen (also referred to herein as a "loading dose");"secondarydoses" are doses that are administered after the initial dose; and "tertiary doses" are doses that are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but may generally differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, secondary, and/or tertiary doses varies (e.g., adjusted upward or downward, as appropriate) over the course of treatment. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered less frequently (e.g., "maintenance doses").

[0113] In some embodiments, the loading dose is a "split dose" that is administered as two or more doses (e.g., 2, 3, 4, or 5 doses) that are administered on different days. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered at least about one week apart. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered about 1 week, 2 weeks, 3 weeks, or 4 weeks apart. In some embodiments, the loading dose is divided 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 unevenly distributed across the 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 a divided dose, wherein a first portion of the loading dose (e.g., the first half) is administered on day 1 and a second portion of the loading dose (e.g., the second half) is administered 1 week later (e.g., on day 8), 2 weeks later (e.g., on day 15), 3 weeks later (e.g., on day 22), or 4 weeks later (e.g., on day 29), followed by one or more booster or maintenance doses.

[0114] For example, an IL-4R antagonist can be administered to an individual in 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, each of the initial dose and one or more secondary doses comprises 50 mg to 600 mg of the IL-4R antagonist, such as 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, each of the initial dose and one or more secondary doses comprises the same amount of the IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the IL-4R antagonist, and each of the one or more secondary doses comprises a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more times the second amount of the IL-4R antagonist. In one exemplary embodiment, the IL-4R antagonist is administered to the individual 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 an individual having a body weight <30 kg (e.g., ≥15 kg to <30 kg), the IL-4R antagonist is administered to the individual 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 an individual who has a body weight ≥30 kg (e.g., ≥30 kg to <60 kg), the IL-4R antagonist can be administered to the individual 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 another exemplary embodiment, for an individual having a body weight ≥ 60 kg, the IL-4R antagonist may be administered to the individual in a loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg. In some embodiments, the IL-4R antagonist is administered to the individual (e.g., one or more doses of about 50 mg to about 600 mg, such as 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 a loading dose.

[0115] In some embodiments, each secondary and/or tertiary dose is administered 1-14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ or more) weeks after the immediately preceding dose. The term "immediately preceding dose," as used herein, means, in the case of sequential multiple administrations, the dose of IL-4R antagonist that is administered to the patient prior to the administration of the next dose sequentially without intermediate doses.

[0116] The methods of the invention may include administering to the patient any number of secondary and/or tertiary doses of an IL-4R antagonist. For example, in certain embodiments, the patient is administered only one secondary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses. Similarly, in certain embodiments, the patient is administered only one tertiary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses.

[0117] In some embodiments involving 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 involving 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 secondary and/or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration may also be adjusted over the course of treatment by the physician based on the needs of the particular patient following clinical evaluation.

[0118] In some embodiments, for an individual having severe AD who is ≥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, wherein 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) if the individual's weight is <30 kg.

[0119] In some embodiments, for an individual having severe AD who is ≥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, wherein 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) if the individual's body weight is ≥30 kg.

[0120] In some embodiments, for an individual having severe AD ≥6 years to <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 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).

[0121] In some embodiments, for an individual having severe AD who is ≥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, wherein 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) if the individual's weight is <30 kg.

[0122] In some embodiments, for an individual having severe AD between the ages of ≥6 years and <12 years, 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., 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) if the individual's body weight is between ≥15 kg and <30 kg. In some embodiments, the initial dose is administered as a split dose, wherein 300 mg is administered on day 1 and 300 mg is administered two weeks later.

[0123] In some embodiments, for an individual having severe AD who is between ≥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 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) if the individual's body weight is between ≥30 kg and <60 kg.

[0124] In some embodiments, for an individual having severe AD who is ≥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, wherein 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) if the individual's body weight is ≥60 kg.

[0125] In some embodiments, the IL-4R antagonist is administered without an initial or loading dose. For example, in some embodiments, for an individual with severe AD ≥6 years to <12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of an IL-4R antagonist (e.g., an anti-IL-4R antibody) containing 100 mg administered every two weeks (Q2W) if the individual's weight is <30 kg.

[0126] In some embodiments, for an individual having severe AD who is ≥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 an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered every two weeks (Q2W) if the individual's body weight is ≥30 kg.

[0127] In some embodiments, for an individual having severe AD ≥6 years to <12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W).

[0128] In some embodiments, for an individual having severe AD ≥6 years to <12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W) if the individual's weight is <30 kg.

[0129] In some embodiments, for an individual having severe AD who is ≥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 an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every four weeks (Q4W) if the individual's body weight is ≥15 kg to <30 kg.

[0130] In some embodiments, for an individual having severe AD who is between ≥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 an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered every two weeks (Q2W) if the individual's body weight is between ≥30 kg and <60 kg.

[0131] In some embodiments, for an individual having severe AD who is ≥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 an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every two weeks (Q2W) if the individual's body weight is ≥60 kg.

[0132] In some embodiments, for an individual with severe AD ≥6 years to <12 years of age, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a dose of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 200 mg administered every week (QW) if the individual's body weight is ≥60 kg.

[0133] In some embodiments, for an individual having severe AD who is ≥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 an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprising 300 mg administered every week (QW) if the individual's body weight is ≥60 kg.

Therapeutic dosage forms

[0134] In another aspect, the present invention relates to therapeutic dosage forms of an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof), wherein administration of the dosage form to an individual over a period of time (e.g., over 4 weeks, 8 weeks, 12 weeks, 16 weeks, or more) results in prolonged maintenance of serum concentrations of the IL-4R antagonist.

[0135] In another aspect, the present invention relates to a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein the therapeutic dose is 2 mg/kg, wherein weekly administration of the dosage form for four weeks to an individual provides a mean serum concentration of 74 (± 20) mg/L. In one embodiment of a therapeutic dosage form of the invention, the mean serum concentration of the IL-4R antagonist is maintained for at least 48 weeks when the therapeutic dosage form is administered once per week.

[0136] In another aspect, the present invention relates to a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein the therapeutic dose is 4 mg/kg, wherein weekly administration of the dosage form for four weeks to an individual provides a mean serum concentration of 161 (± 60) mg/L. In one embodiment of a therapeutic dosage form of the invention, the mean serum concentration of the IL-4R antagonist is maintained for at least 48 weeks when the therapeutic dosage form is administered once per week.

[0137] In another aspect, the present invention relates to a therapeutic dosage form of a pharmaceutical composition comprising an IL-4R antagonist, wherein administration of the dosage form for 16 weeks to an individual provides a mean serum concentration of 80-100 mg/L. In one embodiment of a therapeutic dosage form of the invention, the therapeutic dose is 200 mg administered every two weeks. In another embodiment of a therapeutic dosage form of the invention, the therapeutic dose is 300 mg administered every four weeks.

[0138] In particular embodiments of a therapeutic dosage form of the invention, the subject is ≥6 years of age to <18 years of age. In further embodiments of a therapeutic dosage form of the invention, the IL-4R antagonist is an IL-4R antibody or antigen-binding fragment thereof that comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 3, HCDR2 comprising the amino acid sequence of SEQ ID NO: 4, HCDR3 comprising the amino acid sequence of SEQ ID NO: 5, LCDR1 comprising the amino acid sequence of SEQ ID NO: 6, LCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 8.

Gradually increase the dose

[0139] In another aspect, the present invention provides methods of treating AD (e.g., moderate to severe AD or severe AD) in an individual aged ≥6 to <18 years, wherein the dose of an IL-4R antagonist is gradually increased if the individual does not respond adequately to an initial dosing regimen. In some embodiments, the method comprises:

(a) administering a first dosing regimen of an IL-4R antagonist as described herein (e.g., an anti-IL-4R antibody) to an individual having moderate to severe AD or severe AD, wherein the individual is ≥6 years of age to <18 years of age;

(b) determining whether the individual's clinical response to the first dosing regimen is inadequate; and

(c) for an individual who has an inadequate clinical response, administering a second dosing regimen of an IL-4R antagonist to the individual, wherein the second dosing regimen comprises administering the IL-4R antagonist at (i) a dose of 200 mg Q2W if the individual has a body weight <60 kg; or (ii) a dose of 300 mg Q2W if the individual has a body weight ≥60 kg.

[0140] In some embodiments, the subject is a pediatric subject (≥6 to <12 years of age) with severe AD. In some embodiments, the initial dosing regimen for the pediatric subject comprises administering the IL-4R antagonist at an initial dose of 600 mg, followed by one or more booster doses of 300 mg every four weeks (Q4W). In some embodiments, the initial dosing regimen is at least 16 weeks in duration.

[0141] In some embodiments, the subject is an adolescent subject (≥12 to <18 years of age) 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 booster doses of 300 mg every four weeks (Q4W). In some embodiments, the initial dosing regimen is at least 16 weeks in duration.

[0142] In some embodiments, an "insufficient clinical response" is determined by assessing one or more AD-associated parameters as described herein (e.g., IGA or EASI scores). In some embodiments, an individual has an "insufficient clinical response" when the individual has an IGA score ≥ 2 after at least 16 weeks of treatment with the first dosing regimen. In some embodiments, an individual has an "insufficient clinical response" when the individual has an EASI score that does not decrease by at least 50% (e.g., at least 75%) from baseline after treatment for at least 16 weeks with the first dosing regimen. For an individual who is identified as having an inadequate clinical response to the first dosing regimen, the method comprises gradually increasing the dose of the IL-4R antagonist to one of the following regimens based on body weight: for patients with a body weight <60 kg, the dose of the IL-4R antagonist is gradually increased to a dose of 200 mg Q2W; for patients with a body weight ≥60 kg, the dose of the IL-4R antagonist is increased to a dose of 300 mg Q2W.

Combination therapies

[0143] In some embodiments, the methods of the present invention comprise administering to the individual 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 a topical non-steroidal drug such as TCI or crisaborole. As used herein, the term "in combination with" means that the topical therapeutic agent (e.g., TCS) is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or concomitant administration of the IL-4R inhibitor and the topical therapeutic agent (e.g., TCS).

[0144] For example, when administered "before" the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent can 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 administration of the pharmaceutical composition comprising the IL-4R antagonist. When administered "after" the pharmaceutical composition containing the IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition containing the IL-4R antagonist. Administering "concurrently" or with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the individual in a separate dosage form within less than 5 minutes (before, after, or simultaneously) from the administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the individual in a single combination dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0145] In some embodiments, the additional therapeutic agent is TCS. In some embodiments, the TCS is a moderate potency TCS. In some embodiments, the TCS is a low potency TCS. In some embodiments, the additional therapeutic agent is TCI. In some embodiments, the additional therapeutic agent is crisaborole.

EXAMPLES

[0146] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors believe to be their invention. Efforts have been made to ensure that the numbers used (e.g., amounts, temperatures, etc.) are accurate, but some experimental errors and variations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

Example 1: Clinical trial investigating the efficacy of dupilumab in pediatric patients with severe atopic dermatitis

Research design and objectives

[0147] This trial was a multicenter, randomized, double-blind, parallel-group trial to investigate the efficacy and safety of dupilumab, co-administered with topical corticosteroids (TCS), in pediatric patients with severe AD. The study population included patients aged ≥6 years to <12 years with severe AD whose disease was not adequately controlled with topical therapeutics. Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10; an HCVR/LCVR amino acid sequence pair comprising SEQ ID NO: 1/2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[0148] Eligible patients who successfully completed screening procedures were randomly assigned to one of the following treatment groups:

(1) dupilumab every 2 weeks (Q2W) group: 100 mg for patients <30 kg or 200 mg for patients ≥30 kg,

(2) dupilumab every 4 weeks (Q4W) group: 300 mg,

(3) placebo.

[0149] To account for differences in body size in the pediatric population and given the large therapeutic indices of dupilumab, a tiered fixed dosing regimen was chosen. This approach reduces the risk of dosing errors that may occur with weight-based dosing while also providing convenience of dosing by simplifying administration using a prefilled syringe/device. Dupilumab was dosed as follows: for the dupilumab Q2W arm, patients with baseline body weight <30 kg received 100 mg dupilumab (0.7 mL of a 150 mg/mL solution) Q2W subcutaneous injections from week 2 through week 14 following a 200 mg loading dose on day 1. Patients with baseline body weight ≥30 kg received subcutaneous injections of 200 mg dupilumab (1.14 mL of a 175 mg/mL solution) Q2W from week 2 to week 14, followed by a 400 mg loading dose on day 1. For the dupilumab Q4W group, all patients, regardless of body weight, received subcutaneous injections of 300 mg dupilumab Q4W (2 mL of a 150 mg/mL solution) from week 4 to week 12, followed by a 600 mg loading dose on day 1. For the placebo group, patients received matching placebo (including doubling the amount of placebo on day 1 to match the loading dose).

[0150] The study consisted of the following periods: (1) a screening period of up to 9 weeks; (2) a TCS standardization period of 2 weeks; (3) a treatment period of 16 weeks; and (4) a 12-week observation period (for patients who did not enter the OLE). During the screening period, washout of systemic AD therapies occurred, if applicable. The use of TCS (±TCI) during the screening period was permitted at the discretion of the investigator until Day -14. Beginning on Day -14, all patients began the standardized TCS treatment regimen.

[0151] During the treatment period, patients had weekly clinic visits until Week 4 and then Q4W clinic visits until Week 16, with weekly telephone calls between clinic visits. Parents/caregivers were trained to inject study drug at Clinic Visit 3 (day 1), Visit 5 (week 2), and Visit 7 (week 4) (patients who were treated with Q2W during the study). In weeks when there were no scheduled clinic visits, the parent/caregiver administered study drug to the patient. Parents/caregivers who did not wish to administer drug to the patient were given the option of having clinic staff perform all drug injections in the clinic. Safety, laboratory, and clinical assessments were performed during scheduled clinic visits. The end-of-treatment visit occurred at week 16, two weeks after the last dose of study drug for patients randomized to the Q2W treatment group or the Q2W placebo group, and 4 weeks after the last dose of study drug for patients randomized to the Q4W treatment group or the Q4W placebo group. The co-primary endpoints were assessed at this visit.

[0152] Patients who participated in the study were offered the opportunity to be screened for inclusion in the OLE study at the end of the treatment period (week 16). Patients who declined to participate in the OLE study or who did not meet the inclusion criteria for the OLE study had a 12-week observation period. For these patients, follow-up visits occurred every 4 weeks after week 16 from week 20 through week 28. During the observation period, patients were monitored for safety and tolerability and were assessed with laboratory and clinical assessments.

Study sample

[0153] This study included pediatric patients (aged ≥6 to <12 years at screening) who had severe AD that was not adequately controlled with topical anti-AD medications.

[0154] Inclusion Criteria: The patient had to meet the following criteria to be eligible for inclusion in the study: (1) male or female gender, ≥6 to <12 years of age at the screening visit; (2) diagnosis of AD according to the uniform criteria of the American Academy of Dermatology (Eichenfield 2003) at the screening visit; (3) chronic AD diagnosed 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) weekly mean worst pruritus maximal itch score at baseline ≥4 (note: mean worst pruritus maximal itch score is determined based on daily worst pruritus maximal itch scores (daily score ranges 0 to 10) during the 7 days immediately preceding randomization. A minimum of 4 daily scores over 7 days are required to calculate the mean score at baseline. A complete daily score consists of responses to both the questions “What was the worst pruritus today?” and “What was the worst pruritus last night?” For patients who did not have at least 4 daily scores reported during the 7 days immediately preceding the planned randomization date, randomization was deferred until this requirement was met, but not to exceed the maximum screening duration plus TCS standardization of 77 days). (8) Documented recent (within 6 months prior to the Baseline visit) inadequate response to a history of topical anti-AD medication(s) (note: inadequate response is defined as failure to achieve and maintain remission and low disease activity (comparable to IGA of 0=none to 2=mild) despite treatment with a daily TCS regimen with moderate to high efficacy (±TCI as appropriate) administered for at least 28 days. Patients with documented systemic treatment for AD within the past 6 months are also considered inadequate responders to topical treatment and are potentially eligible for treatment with dupilumab after appropriate washout. (9) At least 11 (out of 14 total) twice daily stable dose applications of topical emollient for 7 consecutive days immediately prior to the Baseline visit; (10) willingness and ability to comply with clinic visits and related research procedures; (11) the patient, either alone or with the assistance of a parent/legal guardian, as appropriate, must be able to understand and complete study-related questionnaires; (12) the parent or legal guardian must provide signed informed consent. Patients must also provide separate informed consent for inclusion in studies, and sign and date either a separate informed consent form (IAF) or an informed consent form (ICF) signed by the parent/legal guardian (as appropriate based on local regulations and requirements).

[0155] Exclusion Criteria: The study exclusion criteria were: (1) participation in a prior clinical trial of dupilumab; (2) treatment with a systemic investigational medicinal product prior to the baseline visit; (note: treatment with a systemic investigational medicinal product refers to treatment given in a clinical trial of a medicinal product that is not yet available on the market); (3) treatment with a topical investigational medicinal product within 2 weeks prior to the baseline visit; (4) treatment with crisaborole within 2 weeks prior to the baseline visit; (5) history of significant adverse events from moderate-potency topical corticosteroids (e.g., treatment intolerance, hypersensitivity reactions, severe skin atrophy, systemic effects) as assessed by the investigator or the patient's treating physician; (6) treatment with TCI within 2 weeks prior to the baseline visit; (7) Use of any of the following treatments within 4 weeks prior to the baseline visit, or any condition that, in the opinion of the investigator, is likely to require such treatment(s) within the first 4 weeks of study treatment: (a) Immunosuppressive/immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, etc.); (b) Phototherapy for AD; (8) Treatment with biologic agents such as the following: (a) Any cell-depleting agents, including but not limited to rituximab: within 6 months prior to the baseline visit or until lymphocyte and CD 19+ lymphocyte counts return to normal, whichever occurs later; (b) other biological agents: within 5 times the half-life (if known) or 16 weeks before the baseline visit, whichever is later; (9) treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit. (Note: for patients scheduled to receive live attenuated vaccines during the study (based on national vaccination schedule/local regulations), it had to be determined, in consultation with the pediatrician, whether the vaccine administration could be deferred until after the end of the trial, or brought forward to before the start of the trial, without adversely affecting the health of the patient. Patients for whom the live (attenuated) vaccine administration could be safely deferred were eligible for inclusion in the trial. Patients whose vaccination was brought forward could only be included in the trial after an interval of 4 weeks after vaccine administration.) (10) Planned or anticipated use of any prohibited drugs or procedures during study treatment; (11) body weight <15 kg at baseline; (12) initiation of AD treatment with moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (patients may continue to use such moisturizers at constant doses if intake of such moisturizers is initiated before the screening visit); (13) regular use (>2 visits per week) of vertical solarium/tanning salons within 8 weeks of the baseline visit; (14) active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the baseline visit. (Note: patients could be rescreened after infection resolution). (15) a known 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 or current tuberculosis or other mycobacterial infections; (17) a known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at a screening visit; (18) established diagnosis of hepatitis B virus infection at the time of screening or a positive result for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at the time of screening (note: patients who acquired immunity to hepatitis B virus infection after vaccination (patients who were HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and HBcAb negative) were eligible for inclusion in the study); (19) established diagnosis of hepatitis C virus infection at the time of screening or a positive result for hepatitis C antibody at 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 as indicated by persistent (confirmed by repeated tests at intervals ≥2 weeks) elevations in transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) greater than 3 times the upper limit of normal (ULN) during the screening period; (21) The presence of any 1 or more of the following laboratory test results at 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 was detected at screening, a repeat test was performed to confirm the abnormality); (22) the presence of cutaneous comorbidities that may interfere with trial evaluability, including but not limited to conditions such as scabies, seborrheic dermatitis, cutaneous T-cell lymphoma, psoriasis, etc.; (23) a history of malignancy before the baseline visit; (24) diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection, unless clinical and (if necessary) laboratory assessment excluded active infection before randomization; (25) severe comorbidity(ies) that, in the opinion of the investigator, may adversely affect the patient's participation in the study. Examples include, but are not limited to, patients with short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c ≥9%), patients with cardiovascular conditions (eg, New York Heart Association class III or IV heart failure), severe renal conditions (eg, patients on dialysis), hepatobiliary conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active significant autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. Specific circumstances for exclusion of patients according to these criteria were noted in the trial documents (chart entries, case report forms [CRFs], etc.); (26) any other medical or psychological condition, including significant laboratory abnormalities on screening, that in the opinion of the investigator indicate a new and/or poorly understood disease that may pose an unreasonable risk to the study patient as a result of his/her participation in this clinical trial, may render the patient's participation unreliable, or may interfere with evaluation in the study; (27) a major surgical procedure is planned during the patient's participation in this study; (28) the patient or his/her immediate family members are participants in the study team in the dupilumab trial; (29) the patient is a pregnant woman, is breastfeeding, or plans to become pregnant or breastfeed during the course of the study; (30) patients who are referred to the institutions as a result of an order issued by either a judicial or administrative authority; (31) The subject is a sexually active woman of childbearing potential* who is unwilling to use effective contraception before the initial dose, during the study, and for at least 12 weeks after the last dose of study medication. Highly effective contraception includes consistent use of combined (estrogen-progestogen) hormonal contraception (oral, vaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with ovulation inhibition initiated 2 or more menstrual cycles before screening; an intrauterine device (IUD); a hormone-releasing intrauterine system (IUS); bilateral tubal ligation; a partner who has had a vasectomy; and/or sexual abstinence**. [*For the purpose of this trial, any woman who had her first menstrual period (menarche) and was sexually active was considered to be of childbearing potential. Women who were not of childbearing potential at the start of the study but who began menstruating during the study and were sexually active were also required to have adequate fertility control to remain in the study. **Abstinence is 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 abstinence should be assessed in the context of the duration of the clinical trial and the individual's preferred and usual lifestyle.]

Treatment under investigation

[0156] Study and reference treatment :

Dupilumab 175 mg/mL: Each 1.14 mL single-use prefilled glass syringe with snap-off cap delivers 200 mg of study drug (1.14 mL of 175 mg/mL solution).

Dupilumab 150 mg/mL: Each 2.25 mL single-use prefilled glass syringe with snap-off cap delivers 300 mg of study drug (2.0 mL of 150 mg/mL solution).

Dupilumab 150 mg/mL: Each single-use 0.7 mL pre-filled glass syringe with snap-off cap delivers 100 mg of study drug (0.7 mL of 150 mg/mL solution).

Placebo matching dupilumab was given in the same formulation without added protein (i.e., the active substance, the 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).

[0157]Regions Subcutaneous injection sites of study drug were alternated between different quadrants of the abdomen (avoiding the umbilicus and waist area), upper thighs, and upper forearms so as not to inject the same area twice in a row. To ensure adequate assessment of potential injection site reactions, study drug was injected only into areas of normal-appearing skin (for patients with 100% BSA involvement, patients were instructed to inject into an area of apparently normal-appearing skin whenever possible).

[0158] Background Treatment : Patients were instructed to apply moisturizers (emollients) at least twice daily for at least 7 consecutive days immediately prior to randomization. Following randomization, patients were required to stop using moisturizers until the end of the study (all 28 weeks where applicable). However, to ensure adequate assessment of skin dryness, moisturizers were not to be used for at least 8 hours prior to each clinic visit. All types of moisturizers were acceptable, however, patients were not to initiate treatment with prescription moisturizers (e.g., ceramide-containing products such as EpiCeram®) or moisturizers containing additives (ceramide, hyaluronic acid, urea, flaggreen degradation products) during the screening period or during the trial. The patient could continue to use stable doses of such moisturizers if their use was initiated prior to the screening visit.

[0159] It was required that, starting on day -14, all patients were to initiate TCS treatment using a standardized regimen according to the following recommendations:

- Apply TCS of medium potency once daily to areas with active lesions. Based on the opinion of the investigator, TCS of low potency may be used once daily to areas of thin skin (face, neck, intertriginous and genital areas, areas of skin atrophy, etc.) or to areas where continued treatment with TCS of medium potency is considered unsafe.

- Once the patient achieves an IGA of 2 or less, reduce the frequency of application of the moderately effective TCS to 3 times per week and then stop once lesions resolve (IGA 0). Patients should be instructed to apply the TCS only to active lesions and to stop using the TCS if lesions resolve completely between clinic visits.

- If lesions recur, restart treatment with moderate-strength TCS with the same tapering approach described above as the lesion resolves.

- In case of signs of local (e.g. threat of skin atrophy) or systemic toxicity of TCS when using steroids of medium potency, patients should switch to steroids of low potency.

- For lesions that persist or worsen with daily use of a moderate potency TCS, patients may be treated (emergency) with a high potency TCS (super-potent/very high potency steroids are not allowed even for emergency use) unless the higher potency TCS is deemed unsafe (effective TCS should generally be limited to delicate skin areas [excluding face, flexures, groin] and should not be used for long periods of time to prevent development of cutaneous atrophy and suppression of the adrenal system. During these exacerbations, low potency steroids may generally be used for delicate skin areas (face, flexures, groin).

[0160] A list of acceptable steroids for use was provided by the investigators. It was recommended that patients use triamcinolone acetonide cream 0.1%, fluocinolone acetonide cream 0.025%, or clobetasone butyrate 0.05% for intermediate potency, and cortisone hydroacetate cream 1% for low potency. If rescue treatment with TCS was needed, it was recommended that patients use mometasone furoate ointment 0.1% as a high-potency steroid. Patients who had problems tolerating any of these steroids or if steroids were commercially unavailable could substitute them with products of the same potency from the list provided in the trial manual. The use of very high-potency or super-potent TCS was prohibited during the study because their use is not recommended for patients under 12 years of age.

[0161] Rescue care : Rescue care for AD was available to patients during the study according to the following guidelines: investigators were required to assess IGA before initiating rescue care and to initiate rescue care only in patients who either had an IGA score of 4 or had intolerable symptoms. If possible, investigators were encouraged to consider rescue care initially with topical treatment (eg, high-potency TCS) and to proceed to systemic therapy only in patients who had not responded adequately to topical treatment for at least 7 days. Patients could continue study treatment if rescue care consisted of topical treatment. Use of very high-potency or super-potent TCS is prohibited. Very high-potency topical corticosteroids include:

betamethasone dipropionate ointment enhanced 0.05%,

solution, foam, cream or ointment of clobetasol propionate 0.05%,

diflorasone diacetate ointment 0.05%,

halobetasol propionate cream or ointment 0.05%.

[0162] Patients who were administered systemic corticosteroids or systemic nonsteroidal immunosuppressive drugs (e.g., cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc.) as rescue medication during the study had the study drug discontinued permanently.

Procedures and evaluation

[0163] During the study, various parameters were determined to evaluate the efficacy and safety of dupilumab treatment. Efficacy parameters included patient-reported assessments including worst pruritus score, patient global assessment of disease, patient global assessment of change, CDLQI, POEM, DFI, patient-reported outcome information system (PROMIS) anxiety and/or depression score, facial pain scale, and investigator assessments (including BSA, AD affected, SCORAD, global individual symptom score [GISS], and EASI, which measures the extent and severity of AD, and IGA, which assesses the overall severity of AD). Safety parameters included vital signs, physical examination, clinical laboratory tests, 12-lead electrocardiograms (ECGs), and clinical assessment. Patients were asked to monitor all adverse events (AEs) experienced from the time of informed consent/approval until their last study visit.

Evaluation of effectiveness

[0164] Patient assessment of itching using the worst itching scale: The worst itching scale is a simple rating tool that patients use to report the intensity of their itching (scratching). It is an 11-point scale (0 to 10) in which 0 indicates no itching while 10 indicates the worst possible itching. Patients were asked the following two questions 2:

"What was the worst itch you've had today?"

"What was the worst itch last night?"

[0165] Patients were asked to answer these 2 questions every day throughout the study. Both questions were answered in the evening, and the daily worst itch score was calculated as the worst score of the 2 questions.

[0166] Patient Global Assessment of Disease : Patients rated their disease on a 5-level scale as follows: "Overall, how much itching have you had over the past 7 days?" • no itching at all • some itching • moderate itching • quite a lot of itching • very much itching. Patients were assessed at screening, baseline, and days 15, 29, 57, 85, and 113 (end of study) or early termination.

[0167] Patient Global Assessment of Change : Patients rated their disease on a 5-level scale as follows: "Since you started taking your study medication, how much has your itching changed?" • much better • a little better • the same • a little worse • much worse. Patients were assessed at Screening and at Days 15, 29, 57, 85, and 113 (end of study) or early termination.

[0168] Childhood Dermatologic Disease Quality of Life Index: The CDLQI is a validated questionnaire designed to determine the impact of skin disease on QOL in children (Lewis-Jones et al, 1995, Brit. J. Dermatol . 132: 942-9). The purpose of this questionnaire was to determine the extent to which the patient's skin problems had affected the patient during the assessment period over the past week. To complete the questionnaire, patients were required to answer 10 questions (questions focus on areas such as symptoms, feelings associated with the disease, impact of the disease on leisure time, school or weekends, personal relationships, sleep, and side effects of treatment for the skin disease). This instrument has an assessment period of 7 days. Nine of the 10 questions are scored as follows: • very much=3 • quite a lot=2 • only a little=1 • not at all=0 • no answer to question=0. Question 7 has an additional possible answer (barrier to school attendance) which was assigned a score of 3. The CDLQI for a patient is the sum of the scores for each question with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on QOL. The CDLQI can also be expressed as a percentage of a maximum possible score of 30. Patients were assessed at screening, baseline, and at 15, 29, 57, 85, and 113 (end of trial) or early termination.

[0169] Patient Eczema Severity Assessment: The POEM is a validated 7-item questionnaire used in clinical practice and in clinical trials to assess disease symptoms in children and adults (Charman et al, 2004, Arch. Dermatol. 140: 1513-9). The format is a rating of 7 items (dryness, itching, scaling, cracking, sleep loss, bleeding, and oozing) based on the frequency of these disease symptoms over the past week (i.e. 0=none of the days, 1=1 to 2 days, 2=3 to 4 days, 3=5 to 6 days, and 4=all days) with a scoring system from 0 to 28; the total score reflects disease-related disease severity. The survey was conducted at screening, baseline, and days 15, 29, 57, 85, and 113 (end of trial) or at early termination.

[0170] Dermatitis Family Impact Index : The DFI assesses the impact of a child with AD on family QOL (Lawson 1998). A 10-item disease-specific questionnaire was developed following ethnographic interviews and focus groups to identify areas of family QOL impacted by AD. The self-administered instrument is completed by an adult family member of the child with AD. Questions cover housework, meal preparation, sleep, family leisure activities, shopping, expenses, fatigue, emotional distress, relationships, and the impact of treatment assistance on the life of the primary caregiver. DFI questions are rated on a 4-point Likert scale from 0 to 3, so that the overall DFI score ranges from 0 to 30. The study frame is the past week. A higher DFI score indicates greater impairment in QOL as a result of AD. The survey was conducted at screening, at baseline, and at days 15, 29, 57, 85, and 113 (end of study) or at early termination.

[0171] Facial Pain Scale-Revised : The Facial Pain Scale-Revised (FPS-R) is a self-reported measure of pain intensity developed for children (Hicks 2001). It was adapted from the Facial Pain Scale to allow pain perception to be rated on a widely accepted scale from 0 to 10. The scale shows a nearly linear relationship with visual analogue pain scales over the age range of 4 to 16 years. It is easy to administer and requires no equipment other than photocopied faces. The instrument has well-established psychometric properties and has been validated in school-going children. Interviews were administered at baseline and at 15, 29, 57, and 85 days or at early termination.

[0172] PROMIS Anxiety and Depression Scale : The PROMIS instrument assesses self-reported fear (fearfulness, panic), anxious distress (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms associated with arousal (racing heartbeat, dizziness). The PROMIS depression instrument assesses self-reported negative mood (sadness, guilt), self-esteem (self-criticism, feelings of worthlessness), and social cognition (loneliness, interpersonal withdrawal), as well as decreased positive affect and engagement (loss of interest, meaning, and purpose). Assessments using this instrument were conducted at screening, baseline, and days 15, 29, 57, 85, and 113 (end of study) or early termination.

[0173] Investigator Global Assessment : The IGA is an assessment tool used in clinical trials to globally assess the severity of AD based on a 5-point scale ranging from 0 (none) to 4 (severe). The IGA was assessed at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early termination.

[0174] Eczema Area and Severity Index : EASI is a validated score used in clinical practice and in clinical trials to assess the severity and extent of AD (Hanifin et al, 2001, Exp. Dermatol. 10: 11-18). EASI is a composite score with scores ranging from 0 to 72. Each of the four AD disease characteristics (erythema, thickness [induration, papulation, edema], excoriation, and lichenification) was rated for severity by the investigator or proxy measure on a scale from "0" (none) to "3" (severe). In addition, the area of AD involvement was estimated as a percentage of the area of the body region: head, trunk, upper limbs, and lower limbs, and converted to a score from 0 to 6. For each body region, this area was expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). EASI was obtained at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of trial) or early termination.

[0175] Global Individual Characteristic Score : Individual AD lesion components (erythema, infiltration/papulation, excoriation, and lichenification) are scored globally (i.e., each is scored for the entire body, not by anatomical region) on a 4-point scale (0=none to 3=severe) using the EASI severity assessment criteria. The Global Individual Characteristic Score (GISS) was assessed at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early termination.

[0176] Atopic dermatitis assessment : The Scoring of Atopic Dermatitis (SCORAD) is a validated instrument used in clinical trials and in clinical practice that was developed to standardize the assessment of the extent and severity of AD (European Task Force on Atopic dermatitis 1993, Dermatol. 186: 23-31). There are 3 components to the score: A=extent or BSA involved, B=severity, and C=subjective symptoms. The extent of AD is assessed as a percentage of each defined body surface area and is reported as the sum of all areas with a maximum score of 100% (which is referred to as "A" when calculating the overall SCORAD). The severity of 6 specific AD symptoms (erythema, swelling, oozing/cracking, excoriation, skin thickening/lichenification, and dryness) is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, which are assigned a "B" when calculating the overall SCORAD). Subjective assessment and sleep loss are recorded for each symptom by the patient or relative on a visual analogue scale, where 0 represents no itching (or insomnia) and 10 represents the worst imaginable itching (or insomnia), with a maximum possible score of 20. This parameter is assigned a "C" when calculating the overall SCORAD. SCORAD is calculated as: A/5+7B/2+C, where the maximum is 103. Patients were assessed at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or early termination.

[0177] Body surface area involvement in atopic dermatitis : The body surface area affected by AD is estimated for each body region using the rule of nine (the highest possible estimate for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and reported as a percentage of all major body regions combined. Patients receive this assessment at screening, baseline, and days 8, 15, 22, 29, 57, 85, and 113 (end of study) or at early termination.

[0178] Assessment of missed days of school : Patients who attend school are asked to report the number of days of school missed since the last study assessment. Patients were assessed at baseline and at days 29, 57, 85, and 113 (end of study) or at early termination.

[0179] Caregiver assessment of missed work days : This questionnaire asks the caregiver to report the impact of having a child with AD on their work days. Employed caregivers were asked to report the number of sick days since the last study assessment. Caregivers were assessed at baseline and at days 29, 57, 85, and 113 (end of study) or at early termination.

[0180] Topical Corticosteroid Recording : At each clinic visit, after the TCS standardization visit, staff recorded the type, amount, frequency, and potency of TCS used. The amount of TCS used was determined by weighing the tube at each visit until the end of the study.

Safety assessment

[0181] Safety was assessed by monitoring vital signs, physical examination, clinical laboratory tests, 12-lead electrocardiograms (ECG), clinical assessment, and by monitoring adverse events (AEs) and serious adverse events.

[0182] An adverse event (AE) is any undesirable medical occurrence in an individual or in an individual participating in a clinical trial who is administered a pharmaceutical product. Thus, an AE may be any unfavorable or unexpected sign (including abnormal laboratory findings), symptom, or disease associated over time with the use of a medical product, regardless of whether they are considered related to the medical (experimental) product. AEs also include: any worsening (i.e., any clinically significant change in the frequency and/or intensity) of a pre-existing condition that is associated over time with the use of an investigational medicinal product; abnormal laboratory findings considered clinically significant by the investigator; and any undesirable medical occurrence.

[0183] A serious adverse event (SAE) is any undesirable medical occurrence that, at any dose, causes death; is life-threatening; requires hospitalization or prolongs ongoing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/malformation; or is a major medical event.

Statistical analysis

[0184] For the primary analysis of efficacy, the Cochran-Mantel-Haenszel test, adjusted for randomization stratum (baseline weight group and region), was used to analyze the percentage of patients with IGA 0 or 1 at week 16 or the percentage of patients with EASI-75 at week 16. The Mantel-Fleiss (MF) test was tested and, if not met, a sensitivity analysis was performed including each stratification factor separately in the CMH test.

[0185] To account for the impact of rescue care on the efficacy effect: for the primary efficacy endpoints (which are binary efficacy endpoints), if rescue care was used, the patient was classified as a non-responder from the time that rescue care was started. If a patient refused to participate in the trial, that patient was counted as a non-responder for the endpoints after refusal.

[0186] A sensitivity analysis using the last observation carried forward (LOCF) approach to determine patient status at week 16 was performed to assess the robustness of the primary efficacy analysis with respect to handling missing data. Efficacy data were considered missing after the administration of rescue treatment, and the LOCF method was then used to determine patient status at week 16. In addition, the Cochran-Mantel-Haenszel test adjusted for randomization stratum was used for all observed data, regardless of whether rescue treatment was administered. A patient with missing data was considered a non-responder.

Results

Initial characteristics

[0187] Baseline demographics and disease characteristics are summarized in Tables 1A-1B, 2, and 3A-B.

Table 1A: Baseline demographic characteristics (general)

Pbo+TCS Q4W+TCS Q2W+TCS Total N
(Full Analysis Sample (FAS)) 123 122 122 367 Age (years), mean (SD) 8.3 (1.76) 8.5 (1.74) 8.5 (1.68) 8.5 (1.72) ≥ 6 - < 9 57 (46.3%) 60 (49.2%) 58 (47.5%) 175 (47.7%) ≥ 9 - < 12 66 (53.7%) 62 (50.8%) 64 (52.5%) 192 (52.3%) Gender (male), n (%) 61 (49.6%) 57 (46.7%) 65 (53.3%) 183 (49.9%) Race, n (%) Whites 77 (62.6%) 89 (73.0%) 88 (72.1%) 254 (69.2%) Black or African American 23 (18.7%) 19 (15.6%) 20 (16.4%) 62 (16.9%) Asians 13 (10.6%) 5 (4.1%) 10 (8.2%) 28 (7.6%) Body weight (kg), mean (SD) 31.5 (10.82) 31.0 (9.40) 32.1 (10.79) 31.5 (10.34) < 30 kg 61 (49.6%) 61 (50.0%) 63 (51.6%) 185 (50.4%) > 30 kg 62 (50.4%) 61 (50.0%) 59 (48.4%) 182 (49.6%) BMI (kg/ ^m2 ), mean (SD) 17.9 (3.90) 17.6 (2.93) 18.0 (3.68) 17.8 (3.53)

Table 1B: Baseline demographics (by weight at baseline)

Weight at baseline <30 kg Weight at baseline ≥30 kg Placebo+TCS (n=61) 300 mg q4w+TCS (n=61) 100 mg q2w+TCS (n=63) Placebo+TCS (n=62) 300 mg q4w+TCS (n=61) 200 mg q2w+TCS (n=59) Age, mean (SD), years 7.1 (1.3) 7.5 (1.4) 7.6 (1.4) 9.5 (1.3) 9.5 (1.5) 9.5 (1.4) Race, n (%) Whites 40 (65.6) 45 (73.8) 43 (68.3) 37 (59.7) 44 (72.1) 45 (76.3) Black/African American 9 (14.8) 9 (14.8) 12 (19.0) 14 (22.6) 10 (16.4) 8 (13.6) Asians 7 (11.5) 4 (6.6) 6 (9.5) 6 (9.7) 1 (1.6) 4 (6.8) Others 4 (6.6) 3 (4.9) 1 (1.6) 5 (8.1) 5 (8.2) 1 (1.7) Not reported/missing 1 (1.6) 0 1 (1.6) 0 1 (1.6) 1 (1.7) Gender (male), n (%) 30 (49.2) 27 (44.3) 32 (50.8) 31 (50.0) 30 (49.2) 33 (55.9) Body weight (kg), mean (SD) 23.3 (3.4) 23.8 (3.0) 24.5 (3.5) 39.5 (9.5) 38.1 (8.0) 40.2 (10.0) Body weight group, n (%) < 30 kg 61 (100) 61 (100) 63 (100) 0 0 0 > 30 kg 0 0 0 62 (100) 61 (100) 59 (100) BMI (kg/ ^m2 ), mean (SD) 16.0 (2.5) 15.7 (1.3) 16.1 (1.7) 19.8 (4.1) 19.5 (2.9) 20.2 (4.0)

Table 2: Comorbid conditions and previous drug treatment

Pbo+TCS Q4W+TCS Q2W+TCS Total N(SAF) N=120 N=120 N=122 N=362 # of patients with ≥ 1 concomitant allergic condition excluding AD 111 (92.5%) 107 (89.2%) 114 (93.4%) 332 (91.7%) ALLERGIC RHINITIS 72 (60.0%) 73 (60.8%) 73 (59.8%) 218 (60.2%) ASTHMA 54 (45.0%) 55 (45.8%) 60 (49.2%) 169 (46.7%) FOOD ALLERGY 83 (69.2%) 75 (62.5%) 75 (61.5%) 233 (64.4%) ALLERGIC CONJUNCTIVITIS 16 (13.3%) 14 (11.7%) 14 (11.5%) 44 (12.2%) HIVES 8 (6.7%) 14 (11.7%) 14 (11.5%) 36 (9.9%) CHRONIC RHINOSINUSITIS 4 (3.3%) 5 (4.2%) 2 (1.6%) 11 (3.0%) NASAL POLYPS 0 0 2 (1.6%) 2 (0.6%) EOSINOPHILIC ESOPHAGITIS 0 1 (0.8%) 1 (0.8%) 2 (0.6%) OTHER ALLERGY 81 (67.5%) 67 (55.8%) 79 (64.8%) 227 (62.7%) History of systemic drug treatment for AD, n/N1 (%) 36/120 (30.0) 42/120 (35.0) 40/122 (32.8) Patients who have previously received corticosteroids 17/120 (14.2) 25/120 (20.8) 30/122 (24.6) Patients previously treated with systemic nonsteroidal immunosuppressants 22/120 (18.3) 23/120 (19.2) 16/122 (13.1) Azathioprine 0 2/120 (1.7) 2/122 (1.6) Cyclosporine 12/120 (10.0) 17/120 (14.2) 11/122 (9.0) Methotrexate 11/120 (9.2) 7/120 (5.8) 3/122 (2.5) Mycophenolate 2/120 (1.7) 2/120 (1.7) 1/122 (0.8) Eosinophils, median value (Q1-Q3), ×10 ⁹ /l 0.7 (0.4-1.1) 0.8 (0.4-1.1) 0.6 (0.4-1.2)

Table 3A: Disease characteristics at baseline (overall)

Pbo+TCS Q4W+TCS Q2W+TCS Total N(FAS) 123 122 122 367 Duration of AD (years), mean (SD) 7.2 (2.15) 7.4 (2.44) 7.2 (2.31) 7.3 (2.30) EASI score (0-72), mean (SD) 39.0 (12.01) 37.4 (12.45) 37.3 (10.86) 37.9 (11.79) IGA (0-4), n (%) 3 0 1 (0.8%) 0 1 (0.3%) 4 123 (100%) 121 (99.2%) 122 (100%) 366 (99.7%) NRS Maximum Pruritus [0-10], mean (SD) 7.7 (1.54) 7.8 (1.58) 7.8 (1.52) 7.8 (1.54) POEM (0-30), mean (SD) 20.7 (5.48) 21.3 (5.51) 20.5 (5.50) 20.9 (5.49) CDLQI (0-30), mean (SD) 14.6 (7.41) 16.2 (7.85) 14.5 (6.78) 15.1 (7.38) SCORAD (0-103), mean (SD) 72.9 (12.01) 75.6 (11.71) 72.3 (10.83) 73.6 (11.59) BSA involvement (%), mean (SD) 60.2 (21.46) 54.8 (21.58) 57.8 (20.04) 57.6 (21.10) DFI, mean (SD) 15.0 (7.5) 16.9 (8.7) 14.9 (7.1) PROMIS Anxiety, Mean (SD) 57.3 (11.6) 59.8 (13.7) 58.6 (11.3) PROMIS Depression, Mean (SD) 55.0 (12.1) 58.1 (12.8) 56.3 (11.2)

Table 3B: Baseline disease characteristics (by baseline body weight)

Body weight <30 kg at baseline Body weight ≥30 kg at baseline Placebo+TCS (n=61) 300 mg q4w+TCS (n=61) 100 mg q2w+TCS (n=63) Placebo+TCS (n=62) 300 mg q4w+TCS
(n=61) 200 mg q2w+TCS
(n=59) Duration of AD (years), mean (SD) 6.3 (1.7) 6.8 (1.7) 6.4 (2.1) 8.0 (2.2) 8.0 (2.9) 8.1 (2.3) EASI score (0-72), mean (SD) 38.9 (12.6) 36.9 (12.4) 37.5 (10.0) 39.0 (11.5) 37.8 (12.6) 37.1 (11.8) Weekly mean daily NRS, mean (SD) 7.6 (1.6) 7.9 (1.5) 7.9 (1.5) 7.8 (1.5) 7.7 (1.7) 7.6 (1.5) BSA, mean (SD) 62.0 (20.9) 54.6 (21.9) 61.5 (19.4) 58.4 (22.1) 54.9 (21.4) 53.9 (20.2) SCORAD, mean (SD) 73.0 (12.6) 75.5 (12.6) 73.3 (10.4) 72.8 (11.5) 75.8 (10.9) 71.2 (11.3) CDLQI, mean (SD) 16.1 (6.9) 16.9 (8.1) 16.0 (7.0) 13.2 (7.7) 15.5 (7.7) 13.0 (6.3) POEM, mean (SD) 21.1 (4.9) 21.5 (6.0) 21.1 (5.6) 20.4 (6.0) 21.1 (5.1) 19.9 (5.3) DFI, mean (SD) 16.1 (7.6) 17.7 (8.9) 16.2 (6.8) 14.0 (7.4) 16.1 (8.4) 13.5 (7.1) PROMIS Anxiety, Mean (SD) 58.9 (11.8) 60.3 (13.6) 60.6 (10.5) 55.8 (11.4) 59.3 (13.8) 56.5 (11.8) PROMIS Depression, Mean (SD) 54.4 (12.3) 58.8 (13.1) 57.8 (10.6) 55.6 (11.9) 57.4 (12.5) 54.7 (11.7)

[0188] Baseline demographic characteristics were comparable among the three treatment groups. Patients in this study had a mean age of 8.5 years and had a longer duration of AD (mean 7.3 years). A high prevalence of atopic comorbidity was observed among all treatment groups. Overall, 91.7% of patients had at least one comorbid allergic condition. 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 NRS for maximum pruritus was 7.8. The mean POEM score was 20.9/30. On average, patients reported a very large effect on quality of life (mean CDLQI score 15.1/30). The mean SCORAD score was 73.6/103.

[0189] For patients who were randomly assigned to groups and treated, high patient compliance was observed for all treatment groups (Table 4).

Table 4: Allocation of patients for treatment

Pbo+TCS Q4W+TCS Q2W+TCS Combined Total Patients randomly assigned to groups 123 122 122 244 N=367 Patients randomly assigned to treatment groups 121 (98.4%) 120 (98.4%) 121 (99.2%) 241 (98.8%) 362 (98.6%) Completed treatment in the study, n (%) 114 (92.7%) 118 (96.7%) 119 (97.5%) 237 (97.1%) 351 (95.6%) Discontinued treatment in study, n (%) 9 (7.3%) 4 (3.3%) 3 (2.5%) 7 (2.9%) 16 (4.4%) Adverse event 1 (0.8%) 0 1 (0.8%) 1 (0.4%) 2 (0.5%) Lack of efficiency 2 (1.6%) 0 0 0 2 (0.5%) Incorrect stratification of patients 0 0 1 (0.8%) 1 (0.4%) 1 (0.3%) Patient randomized by mistake 1 (0.8%) 1 (0.8%) 1 (0.8%) 2 (0.8%) 3 (0.8%) Use of a prohibited drug 1 (0.8%) 1 (0.8%) 0 1 (0.4%) 2 (0.5%) Withdrawal of consent 4 (3.3%) 2 (1.6%) 0 2 (0.8%) 6 (1.6%)

Efficiency

[0190] Both dupilumab + TCS regimens (weight-stratified 100/200 mg Q2W + TCS and non-weight-stratified 300 mg Q4W + TCS) versus placebo + TCS significantly improved all prespecified efficacy endpoints. Tables 5A–5B and 6A–6B summarize improvements in various AD-associated parameters in patients treated with dupilumab.

Table 5A: Efficacy results for co-primary and secondary endpoints (overall)

The final result AD-1652 FAS Pbo+TCS 300 mg Q4W +TCS 100/200 mg Q2W+TCS N(FAS) 123 122 122 Co-primary IGA 0/1, n (%) 14 (11.4%) 40 (32.8%) ^¶ 36 (29.5%)* EASI-75, n (%) 33 (26.8%) 85 (69.7%) ^¶ 82 (67.2%) ^¶ Key secondary % change EASI, LS mean (SE) -48.6 (2.46) -82.1 (2.37) ^¶ -78.4 (2.35) ^¶ % change in NRS pruritus, LS mean (SE) -25.9 (2.90) -54.6 (2.89) ^¶ -57.0 (2.77) ^¶ Other secondary Reduction of ≥4 points in PNRS, n/N1 ¹ (%) 15/122 (12.3%) 61/120 (50.8%) ^¶ 70/120 (58.3%) ^¶ Decrease of ≥3 points in PNRS, n/N1 ¹ (%) 26/123 (21.1%) 73/121 (60.3%) ^¶ 81/120 (67.5%) ^¶ EASI-50, n (%) 53 (43.1%) 111 (91.0%) ^¶ 101 (82.8%) ^¶ EASI-90 (n (%) 9 (7.3%) 51 (41.8%) ^¶ 37 (30.3%) ^¶ Change in POEM, LS mean value (SE) -5.3 (0.69) -13.6 (0.65) -13.4 (0.65) ^¶ CDLQI change, LS mean (SE) -6.4 (0.51) -10.6 (0.47) -10.7 (0.46) ^¶ % change in SCORAD, LS mean (SE) -29.8 (2.26) -62.4 (2.13) -60.2 (2.11) ^¶

* P <0.001; ^† P <0.05; ^¶ P <0.0001; ^‡ P <0.01; ^§ nominal P value. [1] N1 represents the number of patients with baseline pruritus NRS ≥4 (3); * p value=0.0004. LS, root mean square; SE, standard error.

Table 5B: Efficacy results for co-primary and secondary endpoints (by baseline body weight)

Body weight <30 kg at baseline Body weight ≥30 kg at baseline Placebo+TCS (n=61) 300 mg Q4W+TCS (n=61) 100 mg Q2W+TCS (n=63) Placebo+TCS (n=62) 300 mg Q4W+TCS (n=61) 200 mg Q2W+TCS (n=59) Co-primary endpoints For patients with IGA 0/1, n (%) 8 (13.1) 18 (29.5) ^§† 13 (20.6) 6 (9.7) 22 (36.1) ^† * 23 (39.0) ^§ * Proportion of patients with EASI-75, n (%) 17 (27.9) 46 (75.4) ^§¶ 38 (60.3) ^§ * 16 (25.8) 39 (63.9) ^§¶ 44 (74.6) ^§¶ Secondary endpoints % change EASI, LS mean ±SE -49.1 (3.3) -84.3 (3.0) ^§¶ -76.7 (3.0) ^§¶ -48.3 (3.6) -79.9 (3.6) ^§¶ -80.4 (3.6) ^§¶ Proportion of patients with EASI-50, n (%) 26 (42.6) 58 (95.1) ^§¶ 50 (79.4) ^§¶ 27 (43.5) 53 (86.9) ^§¶ 51 (86.4) ^§¶ % change in weekly mean daily NRS maximum pruritus, LS mean ±SE -27.0 (4.2) -55.1 (3.9) ^§¶ -56.1 (3.9) ^§¶ -25.0 (4.0) -54.3 (4.2) ^§¶ -58.2 (4.0) ^§¶ Proportion of patients with a ≥4-point reduction in weekly mean daily NRS for maximum pruritus, n/N1 (%) 7/60 (11.7) 33/61 (54.1) ^§¶ 35/63 (55.6) ^§¶ 8/62 (12.9) 28/59 (47.5) ^§¶ 35/57 (61.4) ^§¶ Proportion of patients with a ≥3-point reduction in weekly mean NRS for maximum pruritus, n/N2 (%) 11/61 (18.0) 38/61 (62.3) ^§¶ 43/63 (68.3) ^§¶ 15/62 (24.2) 35/60 (58.3) ^§ * 38/57 (66.7) ^§¶ Proportion of patients with EASI-90, n (%) 4 (6.6) 28 (45.9) ^§¶ 16 (25.4) ^§‡ 5 (8.1) 23 (37.7) ^§¶ 21 (35.6) ^§* Change in POEM, LS mean ±SE -5.9 (1.0) -14.0 (1.0) ^§¶ -13.3 (0.9) ^§¶ -4.7 (0.9) -13.2 (0.9) ^§¶ -13.6 (0.9) ^§¶ CDLQI change, LS mean ±SE -7.2 (0.8) -11.5 (0.7) ^§¶ -11.6 (0.7) ^§¶ -5.6 (0.7) -9.7 (0.6) ^§¶ -9.8 (0.6) ^§¶ % change in SCORAD, LS mean ±SE -28.9 (3.1) -65.3 (2.9) ^§¶ -58.1 (2.8) ^§¶ -30.7 (3.3) -59.3 (3.1) ^§¶ -62.7 (3.1) ^§¶

* P <0.001; ^† P <0.05; ^¶ P <0.0001; ^‡ P <0.01; ^§ nominal P value. N1, number of patients with baseline NRS score ≥4 and no missing values at each visit; N2, number of patients with baseline NRS score ≥3 and no missing values at each visit; LS, mean square; SE, standard error.

Table 6A: Efficacy results for other secondary outcomes (overall)

The final result AD-1652 FAS Pbo+TCS 300 mg Q4W+TCS 100/200 mg Q2W+TCS N(FAS) 123 122 122 Change in NRS from baseline week to week 16, LS mean (SE)/Diff -2.05 (0.215) -4.22 (0.207)/
-2.18 -4.45 (0.206)/
-2.41 Change in BSA from baseline to week 16, LS mean (SE)/Diff -21.65 (1.72) -40.53 (1.648)/
-18.88 -39.37 (1.629)/
-17.72 Time to onset of effect on pruritus (≥4 point reduction in NRS from baseline), median/HR NC 10 (7.13)/
2,921 10.0 (8.12)/
3,114 Time to effect on pruritus (≥3 point reduction in NRS from baseline), median/HR NC 6 (5.9)/
2,075 5 (5.7)/
2,278 Change from baseline in Dermatitis Family Impact Score (DFI), LS mean (SE)/Diff -6.77 (0.497) -10.75 (0.476)/
-3.98 -10.89 (0.469)/
-4.11 Change from Baseline in Pediatric Patient-Reported Outcomes Information System (PROMIS) Anxiety Score, LS Mean (SE)/Diff -9.48 (0.855) -12.30 (0.807)/
-2.82* -12.62 (0.806)/
-3.14** Change from Baseline in PROMIS Pediatric Depressive Symptom Score, LS Mean (SE)/Diff -7.42 (0.848) -12.84 (0.793)/
-5.42 -11.92 (0.790)/
-4.50 Proportion of days free from drug therapy by TCS, mean (SD) 0.11 (0.184) 0.20 (0.232)** 0.19 (0.207)** Mean weekly TCS dose for low/medium efficacy TCS, LS mean (SE)/Diff 20.1 (1.37) 15.0 (1.36)/
-5.1** 14.4 (1.38)/
-5.7** Mean weekly dose of TCS for high-efficacy TCS, LS mean (SE)/Diff 4.2 (1.18) 6.9 (1.70)/
2.7 ^# 5.8 (0.83)/
1.6 ^# Incidence of TEAE with skin infection (excluding herpes infections) at week 16, n(%)/Diff 16 (13.0%) 7 (5.7%)/
-7.3% ^# 10 (8.2%)/
-4.8% ^# SAE occurrence, n(%)/Diff 2 (1.6%) 2 (1.6%)/
0% ^# 0/
-1.6% ^# Change in VAS sleep component in SCORAD, LS mean±SE ^a -2.0 (0.3) -4.3 (0.2) ^¶ -4.5 (0.2) ^¶ Change in POEM sleep question responses, LS mean ±SE ^b -1.0 (0.1) -2.1 (0.1) ^¶ -2.1 (0.1) ^¶ Change in CDLQI Sleep Question Responses, LS Mean ±SE ^c -0.6 (0.1) -1.4 (0.1) ^¶ -1.4 (0.1) ^¶

Nominal P values are given for end points not according to hierarchy. No asterisk indicates P value < 0.001, ^# indicates P value ≥0.05, * indicates P value < 0.05, ^¶ indicates P value < 0.0001, ** indicates P value < 0.01. Sleep debt was assessed using the sleep component ^{of a} SCORAD, a visual analogue scale with a maximum score of 10 indicating the worst imaginable sleep debt; ^b the response to the POEM sleep question (“Over the past week, on how many nights has your sleep been disturbed by your eczema?”); ^c the response to the CDLQI sleep question (“Over the past week, how often has your sleep been disturbed by your skin problem?”). LS, root mean square; SE, standard error.

Table 6B: Efficacy results for other secondary endpoints (by baseline body weight)

Body weight <30 kg at baseline Body weight ≥30 kg at baseline Placebo+TCS (n=61) 300 mg Q4W+TCS (n=61) 100 mg Q2W+TCS (n=63) Placebo+TCS (n=62) 300 mg Q4W+TCS (n=61) 200 mg Q2W+TCS (n=59) Change in weekly mean daily NRS maximum pruritus, LS mean ±SE NA Change in BSA, LS mean ±SE -23.9 (2.3) -43.2 (2.2) ^§¶ -40.6 (2.1) ^§¶ -19.8 (2.5) -38.2 (2.5) ^§¶ 38.4 (2.5) ^§¶ Change in DFI, LS mean ±SE NA Change in PROMIS anxiety, LS mean ±SE NA Change in PROMIS depression, LS mean ±SE NA Mean proportion of TCS-free days (SD) NA Average weekly use of low or moderate efficacy TCS, LS mean ±SE, g NA Change in sleep component in SCORAD VAS, LS mean ±SE ^a -2.0 (0.4) -4.6 (0.3) ^§¶ -4.5 (0.3) ^§¶ -2.1 (0.4) -3.9 (0.3) ^§* -4.5 (0.3) ^§¶ Change in POEM sleep question responses, LS mean ±SE ^b -1.0 (0.2) -2.2 (0.2) ^§¶ -1.9 (0.2) ^§* -0.9 (0.2) -2.0 (0.2) ^§¶ -2.3 (0.2) ^§¶ Change in CDLQI Sleep Question Responses, LS Mean ±SE ^c -0.7 (0.1) -1.5 (0.1) ^§¶ -1.4 (0.1) ^§¶ -0.6 (0.1) -1.2 (0.1) ^§¶ -1.3 (0.1) ^§¶

* P <0.001; ^† P <0.05; ^¶ P <0.0001; ^‡ P <0.01; ^§ nominal P value. Sleep debt was assessed using the sleep component ^{of a} SCORAD, a visual analogue scale with a maximum score of 10 indicating the worst imaginable sleep debt; ^b the response to the POEM sleep question (“Over the past week, on how many nights was your sleep disturbed by your eczema?”); ^c the response to the CDLQI sleep question (“Over the past week, how often was your sleep disturbed by your skin problem?”). LS, mean square; SE, standard error.

[0191] Statistical significance was achieved for the primary endpoint (IGA 0/1) and co-primary endpoint (EASI-75) at week 16 for both dupilumab treatment groups (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 the key secondary efficacy endpoints for both dupilumab groups (mean % change in EASI: placebo: -48.6%; 300 mg Q4W: -82.1%; 100/200 mg Q2W: -78.4%; mean % change in NRS pruritus: placebo: -25.9%; 300 mg Q4W: -54.6%; 100/200 mg Q2W: -57.0%). See Table 5A and Fig. 1G. Statistical significance was also achieved for all other endpoints in the hierarchy for both dupilumab treatment groups (Table 5A) and the additional endpoints (Table 6A); also see Figs. 2A and 2D.

[0192] Efficacy results in this study were comparable to the severe AD subgroup of the Phase 3 adult co-administered TCS (CHRONOS) trial: for the primary endpoint of IGA 0/1, responders were 32.8% for 300 mg Q4W and 29.5% for 100 mg Q2W, compared with 28.3% of adults in the severe AD subgroup. EASI-75% responder rates were 69.7% for 300 mg Q4W, 67.2% for 100/200 mg Q2W, and 67.9% for adults in the severe AD group. Results were also comparable for the secondary endpoints: % change in EASI, % change in NRS pruritus, PNRS reduction ≥ 4 points, PNRS reduction ≥ 3 points, EASI-50, EASI-90, POEM change, and % change in SCORAD.

[0193] The overall efficacy results by dose group and body weight are presented in Tables 5B and 6B, and are summarized in Table 7. For patients in the <30 kg subgroup, a higher percentage of patients in the 300 mg Q4W treatment group met the IGA 0/1 endpoint compared to the 100 mg Q2W treatment group (29.5% vs. 20.6%). A higher percentage of patients in the 300 mg Q4W treatment group also met the co-primary EASI-75 endpoint compared to the 100 mg q2w treatment group (75.4% vs. 60.3%). For several secondary endpoints, the results were numerically greater for the 300 mg Q4W treatment group compared to the 100 mg Q2W treatment group: a higher percentage change in EASI was observed for the 300 mg Q4W treatment group (-84.3% vs. -76.7%); more patients achieved EASI-50 in the 300 mg Q4W treatment group (95.1% vs. 79.4%); and more patients achieved EASI-90 in the 300 mg Q4W treatment group (45.9% vs. 25.4%). See Figs. 1B, 1E, and 1H. However, for the other secondary endpoints, such as percentage change in pruritus NRS, ≥4-point reduction in NRS, ≥3-point reduction in NRS, change in POEM score, and change in CDLQI score, comparable efficacy was shown for the 300 mg Q4W and 100 mg Q2W treatment groups. See Figs. 2B and 2E.

[0194] For patients in the ≥30 kg subgroup, results were numerically superior for the 200 mg Q2W treatment group compared with the 300 mg Q4W treatment group for the categorical pruritus endpoints: 61.4% of patients in the 200 mg Q2W treatment group demonstrated a reduction in NRS of ≥4 points compared with 47.5% of patients in the 300 mg Q4W treatment group; 66.7% of patients in the 200 mg Q2W treatment group demonstrated a reduction in NRS of ≥3 points compared with 58.3% of patients in the 300 mg q4w treatment group. See Figs. 2C and 2F. For the co-primary EASI-75 endpoint, 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 Fig. 1F. Other primary and secondary endpoints were generally comparable between the 300 mg Q4W and 200 mg Q2W treatment groups (Table 7 and Figs. 1C and 1I).

Table 7: Overall efficacy by dose group and body weight

[1] N1 represents the number of patients with a baseline pruritus NRS score ≥4 (3).

The final result Pbo+TCS 300 mg Q4W+TCS Q2W+TCS <30 kg ≥30 kg <30 kg ≥30 kg <30 kg
(100 mg) ≥30 kg
(200 mg) N=61 N=62 N=61 N=61 N=63 N=59 IGA 0/1, n (%) 8 (13.1%) 6 (9.7%) 18 (29.5%) 22 (36.1%) 13 (20.6%) 23 (39.0%) EASI-75, n (%) 17 (27.9%) 16 (25.8%) 46 (75.4%) 39 (63.9%) 38 (60.3%) 44 (74.6%) % change EASI, LS mean (SE) -49.1 (3.30) -48.3 (3.63) -84.3 (3.08) -79.9 (3.57) -76.7 (3.04) -80.4 (3.61) % change in NRS pruritus, LS mean (SE) -27.0 (4.24) -25.0 (3.95) -55.1 (3.94) -54.3 (4.19) -56.1 (3.86) -58.2 (4.01) NRS decrease ≥4 points, n/N1 ¹ (%) 7/60 (11.7%) 8/62 (12.9%) 33/61 (54.1%) 28/59 (47.5%) 35/63 (55.6%) 35/57 (61.4%) NRS decrease ≥3 points, n/N1 ¹ (%) 11/61 (18.0%) 15/62 (24.2%) 38/61 (62.3%) 35/60 (58.3%) 43/63 (68.3%) 38/57 (66.7%) EASI-50, n (%) 26 (42.6%) 27 (43.5%) 58 (95.1%) 53 (86.9%) 50 (79.4%) 51 (86.4%) EASI-90, n (%) 4 (6.6%) 5 (8.1%) 28 (45.9%) 23 (37.7%) 16 (25.4%) 21 (35.6%) Change in POEM, LS mean value (SE) -5.9 (1.04) -4.7 (0.91) -14.0 (0.95) -13.2 (0.89) -13.3 (0.94) -13.6 (0.90) CDLQI change, LS mean (SE) -7.2 (0.76) -5.6 (0.66) -11.5 (0.69) -9.7 (0.63) -11.6 (0.67) -9.8 (0.63) % change in SCORAD, LS mean (SE) -28.9 (3.05) -30.7 (3.28) -65.3 (2.87) -59.3 (3.12) -58.1 (2.83) -62.7 (3.14)

[0195] For the primary endpoint of IGA 0/1 at week 16, comparative efficacy was observed between the 300 mg Q4W and 100/200 mg Q2W groups. At week 16, 32.8% of patients in the 300 mg Q4W group and 29.5% of patients in the 100/200 mg Q2W group achieved IGA 0 or 1, compared with only 11.4% of patients in the placebo+TCS group. The increase in the proportion of patients achieving IGA 0 or 1 was evident as early as week 2 of treatment for the 300 mg Q4W treatment group (5.7% of responders vs. 1.6% of patients in the placebo group), and by week 8, 24.6% of patients in the 300 mg Q4W treatment group achieved IGA 0 or 1 (vs. 7.3% for placebo). For the 100/200 mg Q2W treatment group, at week 6, 6.6% of patients achieved IGA 0 or 1 (vs 3.3% for placebo), and by week 8, 23% of patients in the 100/200 mg Q2W treatment group achieved IGA 0 or 1 (vs 7.3% for placebo).

[0196] For the co-primary endpoint EASI-75, comparable efficacy was observed between the 300 mg Q4W and 100/200 mg Q2W treatment groups 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 between the Q4W and Q2W treatment groups for each of the EASI-50/75/90 response thresholds (Table 5), although a small decrease in the proportion of responders was observed at weeks 12–16 for the Q2W treatment group (for EASI-50, a decrease from 86.1% at week 12 to 82.8% at week 16; for EASI-90, a decrease from 31.1% at week 12 to 30.3% at week 16). Comparable efficacy in terms of percentage change in EASI from baseline to week 16 was observed between the dupilumab treatment groups (-82.1% for the 300 mg Q4W treatment group and -78.4% for the 100/200 mg Q2W treatment group vs -48.6% for the placebo+TCS group). For both dupilumab treatment groups, efficacy according to EASI-75 response rate and EASI percentage change was comparable to that observed with dupilumab with concomitant TCS for adults in the severe AD subgroup.

[0197] The pruritus NRS response rates were numerically greater for 100/200 mg Q2W across the pruritus categorical endpoints. For the NRS response endpoint ≥ 3 at week 16, 67.5% of patients in the 100/200 mg Q2W treatment group were responders, while 60.3% of patients in the 300 mg Q4W treatment group were responders. Both treatment groups were significantly better than placebo (21.1%). For each NRS response endpoint ≥ 4 at week 16, 58.3% of patients in the 100/200 mg Q2W treatment group were responders, while 50.8% of patients in the 300 mg Q4W treatment group were responders. Both treatment groups were significantly better than placebo (12.3%). The effect on pruritus was evident at week 2 in both dupilumab treatment groups: at week 2, 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 terms of percentage change from baseline in pruritus NRS (-54.6% for the 300 mg Q4W treatment group and -57% for the 100/200 mg Q2W treatment group, versus -25.9% for placebo).

[0198] In children with moderate to severe AD, skin lesions often involve a large body surface area (BSA), resulting in pruritus and sleep loss, which have a significant impact on the quality of life of young patients and their caregivers. The Scoring of AD (SCORAD) is an AD-specific measurement tool recommended by the European AD guidelines that assesses investigator-assessed lesional BSA and symptom severity, as well as patient-reported symptoms of pruritus and sleep loss. The effect of dupilumab in combination with a standardized topical treatment on SCORAD and its components was assessed using the root mean square (LS) scores (standard error [SE]) for the overall SCORAD (score range 0-103) and its components, namely AD lesional BSA (0-100%); objective SCORAD (o-SCORAD, 0-83); visual analogue scale of itching SCORAD (VAS, 0-10); and VAS of sleep loss (0-10). The method of multiple imputation was used with censoring after the use of emergency care.

[0199] Baseline demographic and disease characteristics are presented in Table 8 below. Treatment with dupilumab+TCS resulted in significant improvements in overall SCORAD at 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, significant reductions in lesional BSA were observed for both dupilumab regimens, with further reductions observed through week 16. o-SCORAD was significantly improved as early as week 1 with dupilumab Q4W+TCS and week 2 with dupilumab Q2W+TCS, both versus placebo+TCS, and these results continued to improve through week 16. By week 2, pruritus and sleep loss symptoms were significantly improved with both dupilumab versus placebo+TCS treatment regimens as measured by the SCORAD Pruritus VAS and Sleep Loss VAS, and both continued to improve until the end of treatment at week 16 (Table 8).

Table 8. Baseline characteristics and efficacy results at week 1, week 2, and week 16 for total SCORAD and SCORAD components

LS index of mean value (± SE) Range of the indicator Placebo+TCS
(n=123) Dupilumab
300 mg Q4W+TCS
(n=122) Dupilumab
100/200 mg Q2W+TCS
(n=122) Overall SCORAD, baseline 0-103 72.9 (1.1) 75.6 (1.1) 72.3 (1.0) Week 1 63.4 (1.2) 58.9 (1.2)** 61.2 (1.2) Week 2 60.0 (1.3) 49.4 (1.3)*** 52.5 (1.3)*** Week 16 51.3 (1.6) 27.4 (1.5)*** 29.5 (1.5)*** BSA, AD affected (%), baseline 0-100 58.9 (2.0) 54.7 (2.0) 56.5 (1.9) Week 1 48.0 (1.4) 46.9 (1.4) 47.8 (1.4) Week 2 46.7 (1.6) 38.9 (1.6)*** 38.6 (1.6)*** Week 16 36.0 (1.8) 16.5 (1.7)*** 18.5 (1.7)*** o-SCORAD, baseline 0-83 59.6 (0.9) 61.1 (0.9) 58.7 (0.8) Week 1 51.7 (1.0) 48.3 (1.0)* 50.3 (1.0) Week 2 48.4 (1.1) 40.3 (1.1)*** 43.0 (1.1)*** Week 16 41.7 (1.4) 23.0 (1.3)*** 25.1 (1.3)*** VAS pruritus in SCORAD, baseline 0-10 7.4 (0.2) 7.8 (0.2) 7.6 (0.2) Week 1 6.5 (0.2) 6.0 (0.2) 6.0 (0.2) Week 2 6.3 (0.2) 5.1 (0.2)*** 5.3 (0.2)** Week 16 5.1 (0.2) 2.6 (0.2)*** 2.5 (0.2)*** VAS sleep loss in SCORAD, baseline 0-10 6.0 (0.3) 6.8 (0.3) 6.0 (0.3) Week 1 5.1 (0.2) 4.8 (0.2) 4.9 (0.2) Week 2 5.2 (0.3) 4.1 (0.3)** 4.1 (0.3)** Week 16 4.2 (0.3) 2.0 (0.3)*** 1.8 (0.3)***

*P < 0.05; **P < 0.01; ***P < 0.001 versus placebo +TCS.

[0200] Thus, in children aged ≥ 6 to < 12 years with severe AD, treatment with dupilumab and concomitant moderate-strength TCS resulted in rapid, significant reductions in AD-affected BSA and improvements in AD features, pruritus, and sleep loss as assessed by total SCORAD and SCORAD components.

[0201] Based on the data in Table 8, the percentage improvement in overall SCORAD and SCORAD component parameters were calculated at week 16. For the overall SCORAD score in subjects who received placebo and TCS, the score at week 16 of 51.3 was approximately 70% of the initial (baseline) overall SCORAD score of 72.9. That is, subjects who received placebo and TCS demonstrated only approximately a 30% reduction (100%-70%) in overall SCORAD score from baseline. In comparison, for the overall SCORAD score in subjects who received dupilumab 300 mg Q4W and TCS, the score at week 16 of 27.4 was approximately 36% of the initial (baseline) overall SCORAD score of 75.6. In other words, individuals who received dupilumab 300 mg Q4W and TCS demonstrated a reduction of approximately 64% (100%-36%) from baseline in total SCORAD. Moreover, for total SCORAD, individuals who received dupilumab 100/200 mg Q2W and TCS had a reduction of approximately 40% (100%-36%) from baseline in total SCORAD. Furthermore, for total SCORAD, individuals who received dupilumab 100/200 mg Q2W and TCS had a reduction of approximately 60% (100%-40%) from baseline in total SCORAD.

[0202] Comparable rates of EDs were observed between the 300 mg Q4W and 100/200 mg Q2W treatment groups; the ED rate for the dupilumab treatment group was significantly lower than for the placebo group (for placebo, 19.5% of patients required EDs at week 16, while 2.5% of patients in the 300 mg Q4W group and 4.1% of patients in the 100/200 Q2W group required EDs). The ED rate for these pediatric patients treated with dupilumab was generally lower than the ED rate in adolescents and adults with severe AD (Table 9).

Table 9: Emergency care

6 - ≤ 12 years (with TCS) 12 - ≤ 18 years (without TCS)
Subgroup IGA4 Adults by 16 weeks
(with TCS)
IGA Subgroup 4 Pbo+TCS 300 mg Q4W+TCS 100/200 mg Q2W+TCS Pbo 300 mg Q4W 100/200 mg Q2W Pbo 300 mg Q2W+TCS 123 122 122 46 46 43 147 53 % of patients who received emergency care by week 16 19.5% 2.5% 4.1% 67.4% 32.6% 18.6% 48.3% 9.4%

Safety

[0203] No new or unexpected adverse events were observed in this trial compared with adverse events observed in trials in adult or adolescent patients. See Table 10 below. For the 16-week treatment period, the overall incidence of adverse events was lower for 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. Discontinuations due to AEs were uncommon (placebo + TCS, n = 2; 100/200 mg Q2W + TCS, n = 2). There were no deaths or treatment-related hypersensitivity or anaphylaxis events during the study. No new safety signals were observed. Adverse events that occurred at higher frequencies with dupilumab included conjunctivitis (narrow CMQ) (6.7% for narrow conjunctivitis with dupilumab Q4W and 14.8% for dupilumab Q2W, compared with 4.2% for placebo); conjunctivitis (broad CMQ) (8.3% for dupilumab Q4W and 18.9% for dupilumab Q2W, compared with 7.5% for placebo); and injection site reaction (10% for dupilumab Q4W and 10.7% for dupilumab Q2W, compared with 5.8% for placebo). Most conjunctivitis events resolved or were treated with standard ophthalmologic care during study drug treatment. The highest incidence of conjunctivitis (24%) occurred in the lowest-exposure treatment group (100 mg Q2W +TCS), consistent with previous analyses suggesting that conjunctivitis associated with dupilumab treatment may be a result of relatively undertreatment in the ocular compartment (Akinlade et al, Br J Dermatol , 2019, 181(3):459–473). A lower incidence of conjunctivitis was observed in the Q4W treatment group compared with the Q2W treatment group. As seen in the adult and adolescent trials and consistent with long-term experience with dupilumab, confirmed skin infections and herpes virus infections were observed at lower rates in the dupilumab treatment groups compared with the placebo group (confirmed skin infection: 13.3% for placebo, 5.8% for dupilumab every four weeks, and 8.2% for dupilumab every two weeks; herpes virus infections: 5% for placebo, 1.7% for dupilumab every four weeks, and 3.3% for dupilumab every two weeks).

[0204] In this patient population with a high burden of type 2 inflammatory disease comorbidities, and as would be expected given the demonstrated efficacy of dupilumab in these conditions, the incidence of type 2 inflammatory AEs was lower with higher dupilumab exposure. Among patients <30 kg, AEs of AD exacerbation, asthma, and allergic rhinitis were less common in the 300 mg Q4W +TCS group than in the 100 mg Q2W +TCS group (Table 10). A similar trend was observed for patients ≥30 kg, with a lower incidence for 200 mg Q2W +TCS than for 300 mg Q4W +TCS.

[0205] The long-term safety of treatment with dupilumab and TCS in pediatric subjects from the 16-week clinical trial described above was assessed in an open-label extension study. Of the patients enrolled in this trial, 110 (30%) had moderate and 72 (20%) had severe atopic dermatitis at the end of enrollment in the open-label extension study. The safety profile of dupilumab+TCS in subjects observed through week 52 of the open-label extension study was similar to the safety profile observed at week 16 in the 16-week trial. The long-term safety profile of dupilumab+TCS observed in pediatric subjects was consistent with that observed in adults and adolescents with atopic dermatitis.

Table 10: Safety Assessment

All Body weight <30 kg at baseline Body weight ≥ 30 kg at baseline Placebo+TCS (n=120) 300 mg Q4W+
TCS (n=120) 100/200 mg Q2W+
TCS (n=122) Placebo+TCS (n=60) 300 mg Q4W+
TCS (n=60) 100 mg Q2W+
TCS (n=63) Placebo+TCS (n=60) 300 mg Q4W+
TCS (n=60) 200 mg Q2W+
TCS (n=59) Patients with ≥1 TEAE, n (%) 88 (73.3) 78 (65.0) 82 (67.2) 43 (71.7) 39 (65.0) 46 (73.0) 45 (75.0) 39 (65.0) 36 (61.0) Patients with ≥1 serious TEAE, n (%) ^* 2 (1.7) 2 (1.7) 0 0 2 (3.3) 0 2 (3.3) 0 0 Patients with ≥1 TEAE leading to permanent treatment discontinuation ^** 2 (1.7) 0 2 (1.6) 2 (3.3) 0 1 (1.6) 0 0 1 (1.7) Deaths 0 0 0 0 0 0 0 0 0 TEAEs (PT) reported for ≥5% of patients, n (%) Atopic dermatitis, exacerbation 17 (14.2) 8 (6.7) 10 (8.2) 7 (11.7) 4 (6.7) 8 (12.7) 10 (16.7) 4 (6.7) 2 (3.4) Asthma 12 (10.0) 2 (1.7) 4 (3.3) 7 (11.7) 0 4 (6.3) 5 (8.3) 2 (3.3) 0 Allergic rhinitis 5 (4.2) 3 (2.5) 4 (3.3) 2 (3.3) 1 (1.7) 3 (4.8) 3 (5.0) 2 (3.3) 1 (1.7) Nasopharyngitis 8 (6.7) 15 (12.5) 8 (6.6) 2 (3.3) 6 (10.0) 6 (9.5) 6 (10.0) 9 (15.0) 2 (3.4) Upper respiratory tract infection 12 (10.0) 13 (10.8) 10 (8.2) 5 (8.3) 9 (15.0) 5 (7.9) 7 (11.7) 4 (6.7) 5 (8.5) Respiratory viral infection of the upper respiratory tract 6 (5.0) 2 (1.7) 1 (0.8) 5 (8.3) 1 (1.7) 1 (1.6) 1 (1.7) 1 (1.7) 0 Vomit 8 (6.7) 6 (5.0) 6 (4.9) 4 (6.7) 3 (5.0) 2 (3.2) 4 (6.7) 3 (5.0) 4 (6.8) Cough 9 (7.5) 3 (2.5) 5 (4.1) 5 (8.3) 0 2 (3.2) 4 (6.7) 3 (5.0) 3 (5.1) Headache 10 (8.3) 6 (5.0) 7 (5.7) 3 (5.0) 1 (1.7) 1 (1.6) 7 (11.7) 5 (8.3) 6 (10.2) Other adverse events, n (%) Infections and Contaminations (SOC) 61 (50.8) 52 (43.3) 49 (40.2) 30 (50) 26 (43.3) 28 (44.4) 31 (51.7) 26 (43.3) 21 (35.6) Cluster of conjunctivitis ^a 5 (4.2) 8 (6.7) 18 (14.8) 2 (3.3) 4 (6.7) 13 (20.6) 3 (5.0) 4 (6.7) 5 (8.5) Keratitis cluster ^b 0 0 1 (0.8) 0 0 1(1,6) 0 0 0 Skin infection (confirmed) ^c 16 (13.3) 7 (5.8) 10 (8.2) 8 (13.3) 4 (6.7) 5 (7.9) 8 (13.3) 3 (5.0) 5 (8.5) Injection site reactions (HLT) 7 (5.8) 12 (10.0) 13 (10.7) 4 (6.7) 6 (10.0) 5 (7.9) 3 (5.0) 6 (10.0) 8 (13.6) Herpes simplex virus infections (HLT) 6 (5.0) 2 (1.7) 4 (3.3) 3 (5.0) 0 3 (4.8) 3 (5.0) 2 (3.3) 1 (1.7)

^a The conjunctivitis cluster (narrow conjunctivitis) includes the PT conjunctivitis (MedDRA Preferred Terms): allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, and atopic keratoconjunctivitis.

^b The keratitis cluster includes PT keratitis: ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, and ophthalmic herpes simplex.

^c Skin infections were confirmed on a case-by-case basis and included bacterial, viral and fungal infections.

Clinical pharmacology and pharmacokinetics

[0206] The 300 mg Q4W and 200 mg Q2W regimens achieved similar steady-state (week 16) trough concentrations (80 mg/L) compared to the 100 mg Q2W regimen, which achieved a lower trough concentration (50 mg/L). Functional dupilumab trough concentrations at week 16 by body weight category and treatment group demonstrated lower concentrations in the 100 mg Q2W <30 kg and 300 mg Q4W ≥30 kg groups. In the efficacy analysis, the 300 mg Q4W +TCS regimen maintained substantially higher blood trough levels than the 100 mg Q2W +TCS regimen in the <30 kg stratum (mean C _trough at week 16 99 mg/L vs 63 mg/L). In the ≥30 kg group, the 200 mg Q2W +TCS regimen maintained consistently higher blood trough 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 for percentage change in EASI from baseline and percentage of patients achieving IGA 0/1, and logistic regression for binary endpoints (EASI-50, EASI-75, EASI-90, and IGA 0/1), showed a trend toward increased drug effect with increasing _Ctrough (data not shown).

Conclusion

[0207] In pediatric patients aged 6-11 years with severe AD inadequately controlled with topical medications, treatment with dupilumab for 16 weeks resulted in clinically meaningful, statistically significant, and rapid improvements in AD-associated parameters, including pruritus, anxiety and depression, and sleep and QoL. Because most efficacy measures continued to show improvement at week 16, it is possible that additional benefit accrues with longer treatment duration.

[0208] The once-monthly (300 mg Q4W) and weight-based (100 mg Q2W for patients <30 kg, 200 mg Q2W for patients ≥30 kg) dosing regimens were comparable for most endpoints. For the subgroup of patients weighing <30 kg, for some endpoints (IGA 0/1 at end of 16 weeks; EASI-50/75/90 at end of 16 weeks; percent change in EASI), the Q4W regimen was numerically superior to the Q2W regimen. However, for some other endpoints (pruritus NRS, NRS reduction ≥4 points, NRS reduction ≥3 points, change in POEM score, and change in CDLQI score), the Q4W and Q2W regimens were comparable in efficacy. For subgroups of patients weighing ≥30 kg, for some endpoints (NRS reduction ≥4 points, NRS reduction ≥3 points and EASI-75), the Q2W regimen was numerically superior to the Q4W regimen, although the Q2W and Q4W regimens demonstrated comparable efficacy in terms of other primary and secondary endpoints.

[0209] No safety signals were identified. As with prior trials of dupilumab in AD, only injection site reactions and conjunctivitis were significantly increased with dupilumab versus placebo; most events were mild to moderate and resolved during the trial. The overall incidence of TEAEs was lower with dupilumab. This observation is likely related to the effect of dupilumab on co-morbid type 2 inflammatory conditions as well as skin infections. Notably, this pediatric study population with severe AD had a very high burden of co-morbid type 2 or allergic conditions: nearly half of these children had asthma; approximately 60% had allergic rhinitis; and approximately 65% reported food allergy. In addition, children with severe AD have a significantly increased risk of skin infections. Consistent with the idea that patients suffering from severe AD have a systemic impairment of their immune axis – resulting from Th-2 polarization – that can be targeted by dupilumab, treatment with dupilumab not only improved all AD endpoints in these patients but resulted in a reduction in type 2 AEs. Furthermore, because infections in these patients are a result of compromised skin integrity and because dupilumab treatment can restore skin integrity, dupilumab treatment was associated with lower rates of skin infections and herpes virus infections. The dupilumab-associated reduction in type 2 comorbidities and infections correlated with pharmacokinetic exposure. The benefit of dupilumab against infections is in contrast to the experience with most other immunomodulatory therapies - eg, Janus kinase inhibitors, tumor necrosis factor inhibitors, interleukin 23 inhibitors, corticosteroids, cyclosporines, FK506 inhibitors, etc. - which tend to be more immunosuppressive. In this pediatric population, there is a clear benefit for the treatment of AD that may also address associated comorbid atopic conditions while avoiding immunosuppression. In essence, this study demonstrates the efficacy and safety of dupilumab co-administered with TCS in pediatric patients aged ≥6 years to <12 years with severe AD.

Example 2: Pharmacokinetic analysis of dupilumab in pediatric and adolescent patients with uncontrolled moderate to severe atopic dermatitis

[0210] To characterize the pharmacokinetic profile of dupilumab in children (≥6 to <12 years of age) and adolescents (≥12 to <18 years of age) with moderate to severe AD, a study was conducted in 37 children and 40 adolescents enrolled in the Phase 2a trial NCT02407756, which is included herein in full, and 33 children and 36 adolescents enrolled in the Phase 3 OLE trial NCT02612454, which is included herein in full. Patients eligible for inclusion in the Phase 2a and Phase 3 OLE trials included pediatric patients (≥6 to <18 years of age) with AD that was inadequately controlled with topical therapies 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; one baseline IGA score of 3 or 4, and ≥10% BSA affected by AD.

[0211] The Phase 2a trial consisted of a screening period of up to 35 days, a baseline visit, and 2 treatment phases: Part A, in which patients were administered a single dose of dupilumab (2 mg/kg or 4 mg/kg) followed by an 8-week sampling period to determine systemic drug exposure; and Part B, in which patients were administered the same dose weekly for 4 weeks followed by an 8-week safety observation period. In the Phase 2a trial, the primary outcome was characterization of the pharmacokinetics of dupilumab.

[0212] The Phase 3 OLE trial included pediatric patients who had participated in previous trials of dupilumab in AD (the currently described Phase 2a trial and other trials). Patients enrolled in the OLE trial continued to receive 2 mg/kg or 4 mg/kg dupilumab weekly; the study consisted of a screening period (day -28 through day -1), a treatment period that lasted until regulatory approval of the product for the patient age group in the geographic region, and an observation period of 12 weeks. Data from the OLE trial through week 52 from the baseline visit are described herein.

Results

[0213] The primary endpoint of the Phase 2a trial was functional dupilumab serum concentrations over time and other PK parameters; key secondary outcomes included the incidence of treatment-emergent adverse events (TEAEs) and percent changes from baseline in Eczema Area Severity Index (EASI), Scoruditis Atopic Dermatitis Rating Scale (SCORAD), and Numerical Pruritus Rating Scale (NRS). The primary endpoints of the Phase 3 OLE were the presence and incidence (events/patient-years [PY]) of TEAEs. Key secondary endpoints included the presence and incidence (events/PY) of severe TEAEs and TEAEs of special interest; proportion of patients with an IGA score of 0/1; proportion of patients with a decrease in EASI ≥75% (EASI 75) from the original study baseline; percent change in EASI score from the original study baseline; percentage change in SCORAD score from baseline in the initial study and percentage change in the Childhood Dermatological Quality of Life Index (CDQLI) from baseline in the OLE.

Pharmacokinetics

[0214]Samples PKs were obtained at half-time density in Part A of the Phase 2a trial and at infrequent time points in Part B of the Phase 2a and OLE trials. To limit blood draws in this pediatric population, patients were randomized to a sampling schedule that included a number of potential time points. Mean concentration-time profiles were generated by pooling all samples obtained and were used to determine the time to maximum mean concentration (t_max) and the area under the concentration-time curve from time zero to the last measurable concentration in part A (AUC_last). The maximum serum concentration of dupilumab (C_max) were calculated for patients with PK samples obtained at time t_max. In OLE, samples for determining stationary C_troughwere assessed over 24-48 weeks. Serum samples for dupilumab were analyzed using a validated enzyme-linked immunosorbent assay with a lower limit of quantification of 0.078 mg/L. The PK analysis set included patients with ≥1 non-missing dupilumab functional endpoint after the first dose of study drug.

Statistical analysis

[0215] No formal sample size or power calculations were performed. PK, safety, and efficacy variables were summarized descriptively; no inferential statistical tests were pre-built into the statistical analysis plan 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 for both trials included all patients who received any study drug. Post-acute care data from Part B of trial 2a were assumed to be missing. For continuous endpoints, missing values during the 4-week Part B repeated-dose treatment period through the end-of-treatment visit were imputed using the last observation carried forward method. Missing data were not carried forward after the end of treatment in Part B. For categorical variables, patients with missing values were considered non-responders. Patients who withdrew from the trial were counted as non-responders after withdrawal. Patients who received rescue care during Part B were considered non-responders from the time of rescue care. For phase 3 OLE, the all observed values method was used regardless of rescue care use or data collection after treatment refusal (missing data were not carried forward). Statistical Analysis Software (SAS) version 9.2 (SAS Institute, Inc) was used for all analyses.

Results - adolescents (aged ≥12 to <18 years)

[0216] In adolescents with moderate to severe AD, the pharmacokinetic profile of dupilumab was similar to that observed in adults. Dupilumab exhibited nonlinear target-dependent pharmacokinetics. Following a single dose, C _max (±SD) was 10 (±2) mg/L and 23 (±9) mg/L for the 2 mg/kg and 4 mg/kg dose groups, respectively; t _max was 4-8 days (Figure 4A). In OLE, dupilumab concentrations increased in a slightly more than dose-proportional manner from baseline to week 48 between the 2 mg/kg and 4 mg/kg regimens, achieving mean (±SD) serum dupilumab trough concentrations of 74 (±19) mg/L and 161 (±60) mg/L, respectively (Fig. 4B).

Results - Children (aged ≥6 to <12 years)

[0217] Thirty-eight pediatric patients (≥6-<12 years of age) were enrolled in the Phase 2 trial. One patient (3%) in the 4 mg/kg dose group withdrew from the trial during Part A (withdrawal of consent due to fear of trial injections). Thirty-seven pediatric patients (97%) completed Part A and Part B. All 37 patients continued in the pediatric OLE; 4 were 12 years of age at enrollment and are not included in this analysis. The median interval between the last dose of the Phase 2a trial and the first dose of OLE was 118 and 97 days for the 2 mg/kg and 4 mg/kg dose groups, respectively.

[0218] Baseline demographic and disease characteristics are presented in Table 11. The mean (±standard deviation [SD]) age was 8 (2) years and the mean duration of AD was 7 (2) years across both dose groups. As shown in Table 11, disease characteristics at baseline in the Phase 2a trial were consistent with severe AD. Mean (SD) EASI scores were 33 (16) and 39 (19); NRS maximum pruritus scores were 6 (2) and 7 (2) and percentage of BSA involved were 59% (22) and 62% (30) in the 2 mg/kg and 4 mg/kg groups, respectively. Baseline disease severity was numerically higher in the 4 mg/kg group versus 2 mg/kg group in both the Phase 2a and OLE trials. Three (17%, 2 mg/kg) and seven (37%, 4 mg/kg) patients were treated with nonsteroidal immunosuppressants prior to phase 2a trial baseline, of whom one (6%) and five (26%), respectively, did not respond to this treatment. Most patients (78%, 2 mg/kg and 90%, 4 mg/kg) had other concomitant atopic/allergic diseases, including asthma, allergic rhinitis, and food allergy.

Table 11: Baseline demographic and disease characteristics

Phase 2a trial (N=37) OLE Phase 3 Trial (N=33) 2 mg/kg (n=18) 4 mg/kg (n=19) 2 mg/kg (n=17) 4 mg/kg (n=16) Mean age ± SD (years) 8 ± 2 8 ± 2 9 ± 2 8 ± 2 Race, n (%) Whites 17 (94) 18 (95) 16 (94) 15 (94) Black or African American 0 1 (5) 0 1 (6) Others 1 (6) 0 1 (6) 0 Gender, male, n (%) 9 (50) 11 (58) 8 (47) 9 (56) Mean body weight ± SD (kg) 30.8 ± 8.7 29.6 ± 9.8 30.9 ± 9.0 29.3 ± 8.6 Mean BMI ± SD (kg/ ^m2 ) 17.5 ± 2.8 16.8 ± 2.0 16.9 ± 3.0 17.0 ± 2.2 Mean duration of AD ± SD (years) 7 ± 2 7 ± 2 7 ± 3 8 ± 2 Mean EASI ± SD (scale 0-72) 33 ± 16 39 ± 19 21 ± 18 32 ± 20 IGA index, n (%) (scale 0-4) 0 or 1 N/A N/A 1 (6) 0 2 N/A N/A 3 (18) 1 (6) 3 1 (6) ^a 0 9 (53) 7 (44) 4 17 (94) 19 (100) 4 (24) 8 (50) Mean NRS of maximum pruritus ± SD (scale 0-10) 6 ± 2 7 ± 2 6 ± 3 6 ± 2 Mean BSA affected by AD, ± SD (%) 59 ± 22 62 ± 30 37 ± 27 50 ± 31 Mean SCORAD ± SD (scale 0-103) 66 ± 13 73 ± 13 52 ± 17 67 ± 18 Mean POEM ± SD (scale 0-28) N/A N/A 17 ± 8 20 ± 5 Mean ± CDLQI SD (scale 0-30) N/A N/A 12 ± 8 12 ± 4 Any previous nonsteroidal systemic immunosuppressants, n (%) 3 (17) 7 (37) N/A N/A Azathioprine, n (%) 0 2 (11) N/A N/A Cyclosporine A, n (%) 3 (17) 5 (26) N/A N/A Lack of response to previous nonsteroidal systemic immunosuppressants, n (%) 1 (6) 5 (26) N/A N/A Patients with a current history of atopic allergic conditions excluding AD, n (%) 14 (78) 17 (90) N/A N/A Allergic rhinitis 9 (50) 10 (53) N/A N/A Food allergy 10 (56) 14 (74) N/A N/A Asthma 7 (39) 9 (47) N/A N/A Allergic conjunctivitis 3 (17) 5 (26) N/A N/A Chronic rhinosinusitis 0 1 (5) N/A N/A Hives 1 (6) 0 N/A N/A Other allergies 12 (67) 12 (63) N/A N/A

AD, atopic dermatitis; BMI, body mass index; BSA, body surface area; CDLQI, Childhood Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; IGA, investigator global assessment; N/A, not applicable; NRS, numerical rating scale; POEM, patient assessment of eczema severity; SCORAD, score on atopic dermatitis; SD, standard deviation. ^a One patient in this age group included in the trial had a baseline IGA disease severity of 3 but was nevertheless included in the analysis set.

[0219] Following a single subcutaneous dose of dupilumab on day 1 of the Phase 2a study, AUC _last , calculated from the mean serum concentration-time profile, was 160 day*mg/L and 330 day*mg/L for the 2 mg/kg versus 4 mg/kg groups, respectively. In the 2 mg/kg group, t _max occurred 2 days after dosing with a C _max (±SD) of 14.3 mg/L (5.9). In the 4 mg/kg group, t _max occurred 4 days after dosing with a C _max (±SD) of 32.4 mg/L (7.0) (Figure 5A). In OLE, mean steady-state dupilumab trough concentrations (±SD) at weeks 24–48 ranged from 61.3 mg/L (35.0) to 76.8 mg/L (35.8) in the 2 mg/kg once weekly group and from 143 mg/L (40.3) to 181 mg/L (65.9) in the 4 mg/kg once weekly group (Fig. 5B).

[0220] As shown in Table 12, the majority of reported TEAEs in Phase 2a were mild or moderate in severity (14% of patients reported a severe TEAE). The overall incidence of serious TEAEs was low, with 2 patients (11%) experiencing serious TEAEs, both in the 4 mg/kg dose group of Part A of the trial. Serious TEAEs included bacterial arthritis, infective dermatitis, and AD exacerbation, which were considered unrelated to treatment. None of the events led to permanent discontinuation of treatment. The highest incidence of TEAEs were nasopharyngitis and AD exacerbation. The proportion of patients with TEAEs was numerically higher in the 4 mg/kg dose group than in the 2 mg/kg dose group, which was determined by the higher incidence of skin infections (high-level term), cough (preferred term [PT]), and infective dermatitis (PT). Skin infections and AD exacerbations occurred primarily in patients who were not receiving dupilumab treatment at the time of TEAE initiation (Part A or B observation periods). Injection site reactions were mild and occurred only in the 4 mg/kg dose group. Three patients reported conjunctivitis events, all in the 4 mg/kg dose group (in both Parts A and B), none of which were severe or serious or led to treatment discontinuation; conjunctivitis resolved in 2 patients. One patient per dose group reported nonherpesvirus infections in Part A of the trial.

[0221] In the OLE, virtually all children reported ≥1 TEAE (Table 12). However, serious TEAEs were rare, with 2 (12%) and 3 (19%) patients having ≥1 serious TEAE in the 2 mg/kg and 4 mg/kg dose groups, respectively, none of which were treatment-related or resulted in discontinuation of study drug. In the OLE, the most common TEAEs were nasopharyngitis and exacerbation of AD. The proportions of patients with TEAEs, including skin infections, were comparable between the 4 mg/kg and 2 mg/kg dose groups. However, there was a trend toward numerically higher TEAEs in the 4 mg/kg group versus the 2 mg/kg group when considering duration-adjusted incidence (nP/100PY). Two (12%) and 4 (25%) reported herpes virus infections. Injection site reactions were mild and occurred in 3 patients in both dose groups. Seven patients reported conjunctivitis events: 2 (12%) and 5 (31%) in the 2 mg/kg and 4 mg/kg dose groups, respectively, of which conjunctivitis was described as radiation-related in 1 patient (6.3%) in the 4 mg/kg group; conjunctivitis resolved in all patients. No events were severe or serious or led to discontinuation of treatment.

[0222] Efficacy results for the Phase 2a and Phase 3 OLE trials are presented in Table 13. By week 2 of the Phase 2a trial, EASI had decreased with a mean percentage change (±SD) from baseline of -37 (34) and -33 (28) following a single dose of 2 mg/kg and 4 mg/kg dupilumab, respectively; EASI improvements were maintained through week 52 in OLE (-92 [14] and -84 [17] in the 2 mg/kg and 4 mg/kg groups, respectively). The proportions of patients achieving EASI-75 or IGA 0 or 1 at week 12 in the Phase 2a trial subsequently increased through week 52 in OLE. By week 12 of the Phase 2a trial, 56% and 47% of patients administered 2 mg/kg and 4 mg/kg, respectively, of dupilumab achieved EASI-75, with these proportions increasing to 94% and 75%, respectively, at week 52 in OLE. Similarly, by week 12 in Phase 2a, 17% and 21% achieved IGA 0 or 1, respectively, with the proportions subsequently increasing to 76% and 25% at week 52 in OLE. NRS maximum pruritus scores decreased from baseline by a mean percentage (±SD) of -17% (46) and -20% (47) at week 2 of the phase 2a trial after a single dose of 2 mg/kg and 4 mg/kg dupilumab, respectively; improvements were maintained through week 52 in OLE (-70% [32] and -58% [33], 2 mg/kg and 4 mg/kg, respectively). Other improvements in other pruritus outcomes (patients with a decrease in NRS for maximum pruritus of ≥3 points or ≥4 points from baseline) were observed through week 52 in OLE. Sustained improvements in EASI-50, EASI-90, SCORAD, and percentage BSA affected by AD were also observed in the phase 2a trial and OLE through week 52. AD symptoms and QoL, as assessed by the POEM and CDLQI, also improved from baseline to week 48 in OLE.

[0223] Overall, 89% and 95% of patients in the 2 mg/kg and 4 mg/kg dupilumab groups of the Phase 2a trial, respectively, used concomitant topical treatment; the most commonly used topical treatment in both treatment groups was effective TCS (Group III). In OLE, 82% (2 mg/kg) and 94% (4 mg/kg) of pediatric patients used concomitant topical treatment, with the majority (65% and 69%) using effective (Group III) TCS.

Table 12: Safety Assessment

Phase 2a trial (N=37) OLE Phase 3 Trial (N=33) 2 mg/kg (n=18) 4 mg/kg (n=19) 2 mg/kg (n=17) 4 mg/kg (n=16) 2 mg/kg (n=17) 4 mg/kg (n=16) Part A Part B Part A Part B Number of TEAE n n nE/100 PY All TEAE 18 23 47 47 136 139 353 458 All serious TEAE ^a 0 0 3 0 2 5 5 16 All treatment-related TEAEs 0 1 4 4 14 2 36 7 All serious treatment-related TEAEs 0 0 0 0 0 0 0 0 All TEAEs that led to permanent discontinuation of study medicinal product 0 0 0 0 0 0 0 0 Patients with TEAE n (%) n (%) nP/100 PY Any TEAE 9 (50) 10 (56) 16 (84) 17 (89) 16 (94) 16 (100) 266 471 Any serious TEAE 0 0 2 (11) 0 2 (12) 3 (19) 6 11 Any treatment-related TEAEs 0 1 (6) 3 (16) 3 (16) 4 (24) 2 (13) 13 7 Any TEAE leading to treatment discontinuation 0 0 0 0 0 0 0 0 Patients with TEAEs resulting in death 0 0 0 0 0 0 0 0 Any infection (SOC) 6 (33) 8 (44) 10 (53) 12 (63) 12 (71) 15 (94) 98 209 Skin infection (HLT) 1 (6) 1 (6) 7 (37) 5 (26) 5 (29) 6 (38) 17 25 Non-herpetic skin infections (confirmed) 1 (6) 1 (6) 6 (32) 5 (26) 4 (24) 3 (19) 12 11 Herpes simplex virus infections (HLT) 1 (6) 0 1 (5) 0 2 (12) 4 (25) 6 15 Injection site reactions (HLT) 0 0 1 (5) 1 (5) 2 (12) 1 (6) 5 3 Conjunctivitis ^b 0 0 1 (5) 2 (11) 2 (12) 5 (31) 5 21 The most common TEAEs ^are: Nasopharyngitis 3 (17) 4 (22) 6 (32) 4 (21) 8 (47) 9 (56) 35 37 Atopic dermatitis 4 (22) 4 (22) 5 (26) 3 (16) 5 (29) 2 (13) 16 7 Cough 0 1 (6) 5 (26) 3 (16) 2 (12) 5 (31) 6 20 Infectious dermatitis 1 (6) 0 3 (16) 2 (11) 2 (12) 0 5 0 Headache 0 1 (6) 2 (11) 1 (5) 4 (24) 2 (13) 13 7 Upper respiratory tract infection 0 1 (6) 0 1 (5) 2 (12) 4 (25) 6 16 Herpes simplex 0 0 0 0 0 4 (25) 0 15

^a Serious TEAEs reported in the OLE included lymphadenopathy, anaphylactic reaction, pneumonia, allergy, arthralgia, complex regional pain syndrome, and postural dizziness. ^b Includes PT: allergic conjunctivitis, bacterial conjunctivitis, conjunctivitis, viral conjunctivitis, atopic keratoconjunctivitis. ^c Includes all MedDRA PTs reported in ≥15% or ≥20% of patients in any treatment arm of a phase 2a or phase 3 OLE trial, respectively. HLT, MedDRA high-level term; MedDRA, Medical Dictionary of Regulatory Terminology; nE, number of events; nP, number of patients; PT, MedDRA preferred term; PY, patient-years; SOC, MedDRA system organ class; TEAE, treatment-emergent adverse event.

Table 13: Performance Evaluation

Dupilumab 2 mg/kg Dupilumab 4 mg/kg Phase 2a trial (n=18) Phase 3 OLE (n=17) Phase 2a trial (n=19) Phase 3 OLE (n=16) Week 2 Week 12 Week 0 ^a Week 16 Week 52 Week 2 Week 12 Week 0 ^a Week 16 Week 52 Mean EASI ± SD (n) 23 ± 18 (18) 9 ± 13 (16) 21 ± 18 (17) 9 ± 14 (17) 2 ± 3 (17) 26 ± 16 (18) 16 ± 15 (19) 32 ± 20 (16) 7 ± 8 (15) 5 ± 5 (16) Mean % change in EASI from baseline in phase 2a trial ± SD (N1) -37 ± 34 (18) -76 ± 25 (16) -37 ± 37
17) -73 ± 42 (170) -92 ± 14 (17) -33 ± 28 (18) -63 ± 25 (19) -20 ± 32
(16) -84 ± 14 (15) -84 ± 17 (16) Patients achieving EASI-50 from baseline in phase 2a trial, n/N (%) 7/18 (39) 14/18
(78) 7/17 (41) 16/17
(94) 16/17
(94) 5/19 (26) 11/19
(58) 3/16 (19) 14/15
(93) 15/16
(94) Patients achieving EASI-75 from baseline in phase 2a trial, n/N (%) 3/18 (17) 10/18 (56) 4/17 (24) 10/17
(59) 16/17
(94) 2/19 (11) 9/19 (47) 1/16 (6) 11/15
(73) 12/16
(75) Patients with EASI-90 from baseline phase 2a, n/N (%) 1/18 (6) 6/18 (33) 0/17 (0) 7/17 (41) 12/17 (71) 0/19 (0) 5/19 (26) 0/16 (0) 5/15 (33) 7/16 (44) Patients achieving IGA 0 or 1, n/N (%) 1/18 (6) 3/18 (17) 1/17 (6) 6/17 (35) 13/17
(76) 0/19 (0) 4/19 (21) 0/16 (0) 6/15 (40) 4/16 (25) Mean NRS of maximum pruritus ± SD (N1) 5 ± 3 (17) 3 ± 2 (16) 6 ± 3 (17) 3 ± 2 (17) 2 ± 2 (17) 5 ± 3 (18) 4 ± 2 (19) 6 ± 2 (16) 3 ± 2 (16) 3 ± 2 (16) Mean % change in NRS maximum pruritus from baseline in trial 2a ± SD (N1) -17 ± 46 (17) -42 ± 35 (16) -9 ± 39 (17) -50 ± 42 (17) -70 ± 32 (17) -20 ± 47 (18) -40 ± 41 (19) 5 ± 68 (16) -51 ± 44 (16) -58 ± 33 (16) Patients with NRS improvement in maximum pruritus ≥3 from baseline in phase 2a trial, n/N (%) 4/18 (22) 7/18 (39) 4/17 (24) 11/17 (65) 14/17 (82) 7/19 (37) 10/19 (53) 6/16 (38) 11/16 (69) 11/16 (69) Patients with NRS improvement in maximum pruritus ≥4 from baseline in phase 2a trial, n/N (%) 2/18 (11) 5/18 (28) 1/17 (6) 9/17 (53) 11/17 (65) 5/19 (26) 9/19 (47) 3/16 (19) 11/16 (69) 11/16 (69) Mean SCORAD ± SD (N1) 51 ± 20 (17) 28 ± 15 (16) 52 ± 17
(17) 26 ± 20
(17) 14 ± 11
(17) 52 ± 15
(18) 38 ± 17
(19) 67 ± 18
(16) 29 ± 15
(15) 24 ± 14
(16) Mean % change in SCORAD from baseline in phase 2a trial ± SD (N1) -25 ± 21 (17) -58 ± 23 (16) -22 ± 20
(17) -61 ± 31 (17) -79 ± 16 (17) -28 ± 19 (18) -47 ± 24 (19) -10 ± 23
(16) -62 ± 18 (15) -67 ± 19 (16)

EASI, Eczema Area and Severity Index; EASI-50/75/90, ≥50/75/90% improvement in EASI from baseline; IGA, investigator global assessment; N1, patients with available time-point measurements; NRS, Numerical Rating Scale; OLE, Open-label extension; SCORAD, Scoring of Atopic Dermatitis; SD, standard deviation.

^a The median duration of the interval between the last dose in the Phase 2a trial and the first dose in the Phase 3 OLE was 118 and 97 days for the 2 mg/kg and 4 mg/kg dose groups, respectively.

Discussion

[0224] In pediatric patients aged ≥6-<12 years with severe AD, dupilumab was well tolerated for up to 52 weeks 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 no serious TEAEs were reported that were considered related to dupilumab.

[0225] Although the incidence of TEAEs was higher in the 4 mg/kg versus 2 mg/kg dose group in the Phase 2a trial, the incidence of TEAEs was comparable in the OLE. No significant differences in SAEs or TEAEs leading to treatment discontinuation were observed between the two dose regimens. Furthermore, patients in this sequential arm trial were not randomized to dosing regimens, resulting in differences in disease severity at baseline in the OLE, and the numbers of patients in each dosing regimen were small; thus, precise comparisons between dosing regimens were not possible. Although a higher incidence of skin infections was observed with the 4 mg/kg versus 2 mg/kg dose in the Phase 2a trial, the rates were similar in the OLE. Skin infections occurred primarily in patients who were not receiving dupilumab at the time of TEAE onset (patients were in Part A or B observation periods). Many patients with AD have skin colonization with Staphylococcus aureus , and patients with AD are prone to developing skin infections. Dupilumab, through the treatment of AD, should result in a reduction in skin infections. Phase 3 trials in adults and adolescents with AD demonstrated that the incidence of skin infections was numerically lower in patients in the dupilumab versus placebo groups. See, Simpson et al, JAMA Dermatol 2020, 156:44-56.

[0226]Signs and symptoms AD, including pruritus, demonstrated rapid improvement with a single dose of dupilumab in a phase 2a trial at 2 mg/kg and 4 mg/kg doses. Improvements in clinical scores (EASI, SCORAD) and NRS for maximum pruritus were observed as early as week 2, with further improvements with continued treatment through week 52 in OLE. QoL also improved with long-term treatment. The PK profile of severe AD was similar to that of adults and adolescents with moderate to severe AD, and was characterized by non-linear target-mediated kinetics. These safety and efficacy results support the use of dupilumab as continuous long-term treatment for pediatric patients aged ≥6 to <12 years with severe AD.

[0227] The scope of the present invention is not limited to 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 following description and the accompanying drawings. Such modifications are intended to be within the scope of the appended claims.

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LIST OF SEQUENCES

<110> RIGENERON PHARMACEUTICALS, INC.

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<223>LCVR

<400> 2

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 3

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223>HCDR1

<400> 3

Gly Phe Thr Phe Arg Asp Tyr Ala

1 5

<210> 4

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223>HCDR2

<400> 4

Ile Ser Gly Ser Gly Gly Asn Thr

1 5

<210> 5

<211> 18

<212> PROTEIN

<213> Artificial sequence

<220>

<223>HCDR3

<400> 5

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

1 5 10 15

Asp Val

<210> 6

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR1

<400> 6

Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr

1 5 10

<210> 7

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR2

<400> 7

Leu Gly Ser

1

<210> 8

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR3

<400> 8

Met Gln Ala Leu Gln Thr Pro Tyr Thr

1 5

<210> 9

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<223>HC

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 10

<211> 219

<212> PROTEIN

<213> Artificial sequence

<220>

<223>LC

<400> 10

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 11

<211> 207

<212> PROTEIN

<213> Artificial sequence

<220>

<223> hIL-4R alpha

<400> 11

Met Lys Val Leu Gln Glu Pro Thr Cys Val Ser Asp Tyr Met Ser Ile

1 5 10 15

Ser Thr Cys Glu Trp Lys Met Asn Gly Pro Thr Asn Cys Ser Thr Glu

20 25 30

Leu Arg Leu Leu Tyr Gln Leu Val Phe Leu Leu Ser Glu Ala His Thr

35 40 45

Cys Ile Pro Glu Asn Asn Gly Gly Ala Gly Cys Val Cys His Leu Leu

50 55 60

Met Asp Asp Val Val Ser Ala Asp Asn Tyr Thr Leu Asp Leu Trp Ala

65 70 75 80

Gly Gln Gln Leu Leu Trp Lys Gly Ser Phe Lys Pro Ser Glu His Val

85 90 95

Lys Pro Arg Ala Pro Gly Asn Leu Thr Val His Thr Asn Val Ser Asp

100 105 110

Thr Leu Leu Leu Thr Trp Ser Asn Pro Tyr Pro Pro Asp Asn Tyr Leu

115 120 125

Tyr Asn His Leu Thr Tyr Ala Val Asn Ile Trp Ser Glu Asn Asp Pro

130 135 140

Ala Asp Phe Arg Ile Tyr Asn Val Thr Tyr Leu Glu Pro Ser Leu Arg

145 150 155 160

Ile Ala Ala Ser Thr Leu Lys Ser Gly Ile Ser Tyr Arg Ala Arg Val

165 170 175

Arg Ala Trp Ala Gln Cys Tyr Asn Thr Thr Trp Ser Glu Trp Ser Pro

180 185 190

Ser Thr Lys Trp His Asn Ser Tyr Arg Glu Pro Phe Glu Gln His

195 200 205

<---

Claims (35)

1. A method for treating atopic dermatitis (AD) in an individual having moderate to severe AD or severe AD, wherein the individual is ≥6 years old to <12 years old, the method comprising administering to the individual an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof that comprises 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; wherein the IL-4R antagonist is administered subcutaneously in an initial dose followed by one or more booster doses, wherein: (i) for an individual weighing <30 kg, the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg every four weeks (Q4W); or (ii) for an individual weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at an initial dose of 400 mg followed by one or more booster doses of 200 mg every two weeks (Q2W); or (iii) for an individual weighing ≥60 kg, the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q2W. 2. The method of claim 1, wherein the individual is an individual with severe AD that is not adequately controlled with topical anti-AD medications or for whom topical treatment is not medically recommended. 3. The method of claim 2, wherein the individual is insufficiently responsive to treatment with a topical corticosteroid (TCS). 4. The method according to any one of claims 1-3, wherein the individual is an individual with severe AD who is a candidate for systemic therapy. 5. The method according to any one of paragraphs 1-3, wherein the individual: (i) has a baseline Investigator Global Assessment (IGA) score of 4; (ii) has a baseline Eczema Area and Severity Index (EASI) score ≥ 21; (iii) has a baseline body surface area (BSA) affected by AD ≥ 15%; and/or (iv) has chronic AD diagnosed at least one year before starting treatment. 6. The method of claim 1, wherein the individual has a body weight <30 kg and the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q4W. 7. The method of claim 6, wherein the individual has a body weight of ≥15 kg to <30 kg. 8. The method of claim 1, wherein the individual has a body weight of ≥30 kg to <60 kg, and the IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more booster doses of 200 mg Q2W. 9. The method of claim 1, wherein the individual has a body weight of ≥60 kg and the IL-4R antagonist is administered at an initial dose of 600 mg followed by one or more booster doses of 300 mg Q2W. 10. The method of any one of claims 1 to 9, wherein the individual has a concomitant allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergy, allergic conjunctivitis, urticaria, chronic rhinosinusitis, nasal polyps and eosinophilic esophagitis. 11. The method according to any one of claims 1 to 10, wherein the IL-4R antagonist is administered in combination with TCS. 12. The method of claim 11, wherein the TCS is a medium efficiency TCS. 13. The method of claim 11, wherein the TCS is a low efficiency TCS. 14. The method according to any one of claims 11-13, wherein treatment with an IL-4R antagonist reduces the amount of TCS administered to the individual relative to the baseline level. 15. The method according to any one of claims 1-14, wherein treatment with an IL-4R antagonist results in an improvement in an AD-associated parameter in the individual. 16. The method according to claim 15, wherein the improvement of the AD associated parameter is selected from: (i) a reduction from baseline IGA to an IGA of 0 or 1 by week 16 after the first dose of IL-4R antagonist; and (ii) a reduction of at least 75% from baseline in EASI (EASI-75) score by 16 weeks after the first dose of the IL-4R antagonist. 17. The method according to any one of claims 1 to 16, wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. 18. The method according to any one of claims 1 to 17, wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and comprises an LCVR comprising the amino acid sequence of SEQ ID NO: 2. 19. The method according to any one of claims 1 to 18, wherein the antibody against IL-4R 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. 20. The method according to any one of claims 1 to 19, wherein the IL-4R antagonist is dupilumab or a bioequivalent thereof. 21. The method according to any one of claims 1 to 20, 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 autoinjector. 22. The method according to claim 21, wherein the IL-4R antagonist is contained in a pre-filled syringe. 23. The method of claim 22, wherein the pre-filled syringe is a single dose pre-filled syringe. 24. The method according to claim 21, wherein the IL-4R antagonist is contained in an autoinjector. 25. The method according to claim 21, wherein the IL-4R antagonist is contained in a delivery device in the form of a pen.