A method for treating atopic dermatitis by administering an IL-4R antagonist.

Abstract

Methods for treating moderate to severe atopic dermatitis in a pediatric subject are provided. In one embodiment, the methods comprise administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application was filed as a PCT international patent application on March 26, 2021, claiming priority to U.S. Provisional Patent Application No. 63 / 001,224, filed on March 27, 2020, and European Patent Application No. 21315010.5, filed on January 28, 2021, the contents of each of which are incorporated herein by reference.

[0002] This disclosure relates to the use of interleukin - 4 receptor (IL - 4R) antagonists for treating atopic dermatitis.

Background Art

[0003] Atopic dermatitis (AD) is one of the most common skin diseases in infants and children, with 45% of all cases occurring in children under 6 months of age, 60% in children under 1 year of age, and 89% occurring within the first 5 years (Non - Patent Document 1; Non - Patent Document 2). The prevalence is estimated to be 15 - 38% in children under 5 years of age in the United States (Non - Patent Document 3) and 21.5% in children under 2 years of age in Germany (Non - Patent Document 4).

[0004] AD has a significant impact on the quality of life (QoL) of both children and their families. In one study, nearly two - thirds of children with severe AD had moderately to highly impaired QoL (Non - Patent Document 5). In infants, the greatest impacts of AD include itching, sleep deprivation, and changes in mood and behavior. In children, AD disrupts sleep, increases economic costs, parental fatigue, and irritability, impairs daily activities, and reduces leisure and family time, as well as psychological and emotional well - being. See, for example, Non - Patent Document 6.

[0005] The so-called "atopic march" in some younger children is due to the increased risk of developing asthma and / or allergic rhinitis in children with a history of AD and food allergies, suggesting that AD can be a "gateway" to subsequent allergic diseases. It is estimated that 60% of infants and toddlers with severe AD and 30% with mild AD will develop asthma (Non-Patent Literature 7). Despite the immunomodulatory disorders common to all atopic diseases, standard treatment focuses on the long-term use of different topical products for the skin, inhalants for asthma, nasal sprays for rhinitis, and oral antihistamines for itching. These related conditions are often managed in isolation. Therefore, there is a great need for therapies that treat co-occurring diseases simultaneously in an effective manner.

[0006] Pharmacological management of Alzheimer's disease (AD) in children is primarily limited to topical corticosteroids (TCS). While clinically relevant side effects are rare, younger children are at the highest risk of systemic absorption, with potential growth retardation and suppression of the hypothalamic-pituitary axis, due to their growth stage and high body surface area (BSA) ratio. To minimize chronic TCS exposure in AD, non-corticosteroid alternatives such as the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are used; however, the use of these therapies is often restricted by insurers based on the prescribing information for children over 2 years of age. Other systemic immunosuppressants such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil have been used off-label despite significantly higher potential side effects (e.g., growth retardation in children, Cushing's syndrome, hypertension, impaired glucose tolerance, muscle damage, osteonecrosis, glaucoma, and cataracts), but the use of systemic corticosteroids is strongly discouraged in AD. See, for example, Non-Patent Literature 8. Furthermore, the use of systemic immunosuppressants carries the risk of a rebound phenomenon, where disease symptoms significantly worsen after discontinuation of treatment. Thus, in children with Alzheimer's disease (AD), the need for a treatment with a favorable risk-benefit profile that can lead to rapid disease improvement is completely unmet. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Mortz et al., Allergy 2015,70:836-845 [Non-Patent Document 2] Kay et al., J Am Acad Dermatol 1994, 30:35-39 [Non-Patent Document 3] Al-Naqeeb et al., J Am Board Fam Med 2019,32:191-200 [Non-Patent Document 4] Ili et al., J Allergy Clin Immunol 2004, 113:925-931 [Non-Patent Document 5] Ricci et al., Pediatr Allergy Immunol 2007,18:245-249 [Non-Patent Document 6] Ramirez et al., JAMA Dermatol, 2019, 155:556-563 [Non-Patent Document 7] Ricci et al., J Am Acad Dermatol 2006,55:765-771 [Non-Patent Document 8] Lebwohl et al., 2019, J Drugs Dermatol, 18:122-129 [Overview of the Initiative]

[0008] In one embodiment, a method for treating atopic dermatitis (AD) or a method for improving AD-related parameters in a subject is provided. In some embodiments, the method comprises administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a child subject having moderate to severe or severe AD that is not adequately controlled by topical AD therapeutic agents, wherein the subject is between 6 months and 6 years of age. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof.

[0009] In some embodiments, this method (a) Select subjects with moderate to severe or severe AD that is not adequately controlled by topical AD medications, wherein the subjects are between 6 months and 6 years of age; and (b) Administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. Includes.

[0010] In some embodiments, the subjects are those with severe Alzheimer's disease (AD). In some embodiments, the subjects have an inadequate response to treatment with moderate or higher-potency topical corticosteroids (TCS). In some embodiments, the subjects have been previously administered systemic AD medications.

[0011] In some embodiments, the subjects are between 6 months and under 2 years of age at the start of treatment. In some embodiments, the subjects are between 2 years and under 6 years of age at the start of treatment.

[0012] In some embodiments, the subject is (i) Has a baseline Investigator's Global Assessment (IGA) score of 4; (ii) Having a baseline eczema area and severity index (EASI) score of ≥21; and / or (iii) Having baseline AD-affected body surface area (BSA) ≥ 15%.

[0013] In some embodiments, the subject has at least one concurrent atopic or allergic condition. In some embodiments, the subject has a concurrent atopic or allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergy, allergic conjunctivitis, urticaria, chronic rhinosinusitis, nasal polyps, and eosinophilic esophagitis.

[0014] In some embodiments, the IL-4R antagonist is administered subcutaneously at a dose of 3 mg / kg. In some embodiments, the IL-4R antagonist is administered subcutaneously at a dose of 6 mg / kg. In some embodiments, the method includes administering multiple doses of the IL-4R antagonist. In some embodiments, the IL-4R antagonist is administered once a week or once every two weeks.

[0015] In some embodiments, the subject is administered an IL-4R antagonist in combination with a topical treatment (e.g., a topical corticosteroid (TCS) or a topical nonsteroidal anti-steroid). In some embodiments, the subject 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 administered to the subject compared to baseline.

[0016] In some embodiments, treatment with an IL-4R antagonist results in a reduction of the level of one or more type 2 inflammatory biomarkers in the subject relative to baseline levels. In some embodiments, treatment with an IL-4R antagonist results in a reduction of serum TARC and / or serum total IgE levels in the subject relative to baseline levels, e.g., a reduction of at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more relative to baseline levels.

[0017] In some embodiments, as a result of treatment with an IL-4R antagonist, (i) Achieving an IGA score of 0 or 1 by 4 weeks after administration of the first dose of the IL-4R antagonist; (ii) A reduction of at least 50% from baseline in the EASI score (EASI-50) by 3 weeks after administration of the initial dose of the IL-4R antagonist; (iii) A reduction of at least 75% from baseline in the EASI score (EASI-75) by 3 weeks after administration of the initial dose of the IL-4R antagonist; (iv) A reduction of less than 40% in the percentage of BSAs affected by AD by 3 weeks after administration of the initial dose of an IL-4R antagonist; and (v) 35% reduction from baseline in AD-affected BSA by 3 weeks after administration of the initial dose of IL-4R antagonist. The AD-related parameters selected from this list will be improved.

[0018] In some embodiments, one or more AD-related parameters are assessed by the caregiver. In some embodiments, improvement in one or more AD-related parameters is based on caregiver-reported assessments. In some embodiments, the caregiver-reported assessment is the Caregiver-Reported Peak Pruritus Numerical Rating Scale (NRS). In some embodiments, treatment with an IL-4R antagonist results in an improvement in the caregiver-reported peak pruritus NRS score.

[0019] In some embodiments, treatment with an IL-4R antagonist results in improvement in itching (e.g., by a change in NRS score or by a change in SCORAD score or its components). In some embodiments, baseline levels of itching and / or improvement in itching are assessed by a caregiver. In some embodiments, improvement in itching is assessed by a caregiver-reported peak pruritus NRS score.

[0020] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody that specifically binds to IL-4R, or an antigen-binding fragment thereof. In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment includes a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody includes a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab or its bioequivalent.

[0021] In some embodiments, the IL-4R antagonist (e.g., an anti-IL-4R antibody or its antigen-binding fragment disclosed herein) is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pen-type delivery device (e.g., a pre-filled pen).

[0022] Other embodiments will become apparent from the subsequent detailed description of the invention. [Brief explanation of the drawing]

[0023] [Figure 1A] This figure shows the pharmacokinetics of a single dose of dupilumab over time in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (1A) Mean (SD) concentrations by dose group and nominal time on a log-linear scale. Samples below LLoQ were set to LLoQ / 2. In the older cohort, dupilumab was undetectable at all time points in one patient receiving a 3 mg / kg dose. This patient was excluded from all summary figures and descriptive statistics. (1B) Mean (SD) concentrations by dose group and nominal time on a linear scale. Samples below LLoQ were set to 0. In the older cohort, dupilumab was undetectable at all time points in one patient receiving a 3 mg / kg dose. This patient was excluded from all summary figures and descriptive statistics. LLoQ, lower limit of quantification; n = number of patients; SD, standard deviation. [Figure 1B]This figure shows the pharmacokinetics of a single dose of dupilumab over time in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (1A) Mean (SD) concentrations by dose group and nominal time on a log-linear scale. Samples below LLoQ were set to LLoQ / 2. In the older cohort, dupilumab was undetectable at all time points in one patient receiving a 3 mg / kg dose. This patient was excluded from all summary figures and descriptive statistics. (1B) Mean (SD) concentrations by dose group and nominal time on a linear scale. Samples below LLoQ were set to 0. In the older cohort, dupilumab was undetectable at all time points in one patient receiving a 3 mg / kg dose. This patient was excluded from all summary figures and descriptive statistics. LLoQ, lower limit of quantification; n = number of patients; SD, standard deviation. [Figure 2A] This figure shows the efficacy results in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (2A) Mean percentage change in EASI from baseline to week 4; (2B) Mean percentage change in SCORAD score from baseline to week 4; (2C) Percentage of patients with EASI-50; (2D) Percentage of patients with EASI-75; (2E) Mean percentage change in caregiver-reported peak pruritus NRS from baseline to week 4. EASI: Eczema Area and Severity Index; EASI-50 / -75: Improvement of ≥50% / ≥75% from baseline in EASI; NRS: Numerical Rating Scale; SCORAD: Scoring Atopic Dermatitis; SD: Standard Deviation. [Figure 2B]This figure shows the efficacy results in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (2A) Mean percentage change in EASI from baseline to week 4; (2B) Mean percentage change in SCORAD score from baseline to week 4; (2C) Percentage of patients with EASI-50; (2D) Percentage of patients with EASI-75; (2E) Mean percentage change in caregiver-reported peak pruritus NRS from baseline to week 4. EASI: Eczema Area and Severity Index; EASI-50 / -75: Improvement of ≥50% / ≥75% from baseline in EASI; NRS: Numerical Rating Scale; SCORAD: Scoring Atopic Dermatitis; SD: Standard Deviation. [Figure 2C] This figure shows the efficacy results in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (2A) Mean percentage change in EASI from baseline to week 4; (2B) Mean percentage change in SCORAD score from baseline to week 4; (2C) Percentage of patients with EASI-50; (2D) Percentage of patients with EASI-75; (2E) Mean percentage change in caregiver-reported peak pruritus NRS from baseline to week 4. EASI: Eczema Area and Severity Index; EASI-50 / -75: Improvement of ≥50% / ≥75% from baseline in EASI; NRS: Numerical Rating Scale; SCORAD: Scoring Atopic Dermatitis; SD: Standard Deviation. [Figure 2D]This figure shows the efficacy results in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (2A) Mean percentage change in EASI from baseline to week 4; (2B) Mean percentage change in SCORAD score from baseline to week 4; (2C) Percentage of patients with EASI-50; (2D) Percentage of patients with EASI-75; (2E) Mean percentage change in caregiver-reported peak pruritus NRS from baseline to week 4. EASI: Eczema Area and Severity Index; EASI-50 / -75: Improvement of ≥50% / ≥75% from baseline in EASI; NRS: Numerical Rating Scale; SCORAD: Scoring Atopic Dermatitis; SD: Standard Deviation. [Figure 2E] This figure shows the efficacy results in two age cohorts (6 months to under 2 years and 2 years to under 6 years). (2A) Mean percentage change in EASI from baseline to week 4; (2B) Mean percentage change in SCORAD score from baseline to week 4; (2C) Percentage of patients with EASI-50; (2D) Percentage of patients with EASI-75; (2E) Mean percentage change in caregiver-reported peak pruritus NRS from baseline to week 4. EASI: Eczema Area and Severity Index; EASI-50 / -75: Improvement of ≥50% / ≥75% from baseline in EASI; NRS: Numerical Rating Scale; SCORAD: Scoring Atopic Dermatitis; SD: Standard Deviation.

[0024] Detailed description of the invention Before describing the present invention, it will be understood that the present invention is not limited to the specific methods and experimental conditions described, and that such methods and conditions may vary. Furthermore, since the scope of the present invention is limited only by the appended claims, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit them.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains.

[0026] As used herein, the term “about” means, when used in relation to a specific stated number, that the value may vary by no more than 1% from the stated value. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0027] As used herein, the terms “to treat,” “to treat,” etc., mean to alleviate symptoms, to temporarily or permanently remove the cause of symptoms, or to prevent or delay the appearance of symptoms of a named disorder or condition.

[0028] As used herein, “atopic dermatitis” or “AD” means an inflammatory skin disease characterized by severe itching (e.g., severe itch) and scaly, dry, eczematous lesions. The term “atopic dermatitis” includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. This disclosure encompasses methods for treating patients with moderate to severe or severe AD. As used herein, “moderate to severe AD” is characterized by widespread, severely itchy skin lesions, often concomitant with persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. Often, chronic lesions include hypertrophic plaques, lichenification, and fibrous papules. In patients with moderate to severe Alzheimer's disease (AD), more than 20% or 10% of the skin on the body is affected, in addition to lesions of the eyes, hands, and body wrinkles. Moderate to severe AD is also considered to be seen in patients who require frequent treatment with topical corticosteroids. Patients may also be said to have moderate to severe AD if they are resistant or refractory to treatment with either topical corticosteroids or calcineurin inhibitors. As used herein, “severe AD” is characterized by the presence of widespread skin lesions, persistent itching, or physical or mental impairment that significantly impairs the patient’s quality of life. In some embodiments, patients with severe AD also exhibit one or more symptoms such as abrasions, skin excisions, widespread skin thickening, skin bleeding, capillary bleeding, and / or cracks, as well as changes in pigmentation. In some embodiments, severe Alzheimer's disease is refractory to treatment with topical therapies (e.g., topical corticosteroids, calcineurin inhibitors, or crisabolol).

[0029] As used herein, the term “subject requiring it” refers to a human or non-human animal having AD (e.g., moderate to severe AD or severe AD). In some embodiments, the term “subject requiring it” refers to a patient having moderate to severe or severe AD, where the patient is between 6 months and under 6 years of age, for example, a subject between 6 months and under 2 years of age or a subject between 2 years and under 6 years of age. The terms “subject” and “patient” are used interchangeably herein.

[0030] In some embodiments, the term “subjects requiring it” includes patients with moderate to severe or severe Alzheimer's disease who are between 6 months and 6 years of age and have previously received systemic therapy. As used herein, the term “systemic therapy” refers to a therapeutic agent administered systemically (e.g., orally administered corticosteroids). This term includes systemic immunosuppressants or immunomodulators. In the context of this disclosure, the term “systemic immunosuppressant” includes, but is not limited to, cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, and interferon-gamma. In certain embodiments, this term also includes immunobiological agents such as tumor necrosis factor alpha (TNFα) inhibitors (e.g., anti-TNFα antibodies such as infliximab), CD11a inhibitors (e.g., anti-CD11a antibodies such as efalizumab), IgE inhibitors (e.g., omalizumab), and CD20 inhibitors (e.g., rituximab). Systemic therapies, including systemic immunosuppressants, can be used for the short-term treatment of erythema or as a temporary means to suppress the disease, but their use is limited by serious 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, in which the symptoms of the disease may worsen significantly after discontinuation of treatment. In certain embodiments, the terms “systemic therapy,” “systemic therapeutic agent,” and “systemic immunosuppressant” are used interchangeably throughout this disclosure.

[0031] As used herein, the term "TCS" includes topical corticosteroids of Groups I, II, III, and IV. According to the World Health Organization's Anatomical Therapeutic Classification System, corticosteroids are classified into weak (Group I), moderately potent (Group II), potent (Group III), and very potent (Group IV) based on their activity compared to hydrocortisone. Group IV TCS (very potent) are up to 600 times potent than hydrocortisone and include clobetasol propionate and halcionide. Group III TCS (strong) has 50 to 100 times the potency of hydrocortisone and includes, but is not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent; also referred to herein interchangeably as "medium potency") has 2 to 25 times the potency of hydrocortisone and includes, but is not limited to, clobetazone butyrate and triamcinolone acetonide. Group I TCS (mild; also referred to herein interchangeably as "low potency") includes hydrocortisone.

[0032] Any methods and materials similar to or equivalent to those described herein may be used in carrying out this disclosure, but typical methods and materials are described herein. All publications described herein are incorporated herein by reference in their entirety.

[0033] Treatment method In one embodiment, a method for treating atopic dermatitis (AD) or a method for improving AD-related parameters in a subject is provided. In some embodiments, the method comprises administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject aged 6 months to under 6 years having moderate to severe or severe AD. In some embodiments, the IL-4R antagonist is administered in combination with a topical therapy for AD, such as a topical corticosteroid (TCS) or a topical nonsteroidal anti-steroid (e.g., a calcineurin inhibitor or crisabolol). In some embodiments, the subject is aged 6 months to under 1 year. In some embodiments, the subject is aged 6 months to under 2 years. In some embodiments, the subject is aged 1 year to under 2 years. In some embodiments, the subject is aged 2 years to under 4 years. In some embodiments, the subject is aged 4 years to under 6 years. In some embodiments, the subject is aged 3 years to under 6 years. In some embodiments, the subject is aged 2 years to under 6 years. In some embodiments, the subject is aged 1 year to under 6 years.

[0034] In some embodiments, subjects treated according to the methods disclosed herein are subjects aged 6 months to under 6 years (e.g., subjects aged 6 months to under 6 years, or subjects aged 2 years to under 6 years) with severe AD who have an inadequate response to topical therapy (e.g., TCS with or without topical calcineurin inhibitors (TCIs)), or subjects with severe AD for whom topical therapy is not recommended (e.g., due to side effects or safety risks). In some embodiments, subjects have a demonstrated history of an inadequate response to a sufficient course of outpatient treatment with topical AD medications. As used herein, “inadequate response” means the inability to achieve and maintain remission or a state of low disease activity (investigator’s global assessment [IGA] 0 = clear to 2 = mild) despite treatment for at least 28 days with topical therapy (e.g., a regimen of moderate to high-potency TCS, ± TCI as needed). In some embodiments, subjects have an “inadequate response” if the patient has received demonstrated systemic treatment for AD.

[0035] In some embodiments, treatment with an IL-4R antagonist improves, alleviates, or reduces one or more symptoms of AD in a subject, including but not limited to pruritus (i.e., itching), xerosis (dry skin), eczematous lesions, erythema, papulogenesis, edema, exudation / crusting, epidermal exfoliation, lichenification, sleep disturbances, anxiety, and depression.

[0036] In some embodiments, treatment with an IL-4R antagonist improves one or more AD-related parameters in subjects. Examples of AD-related parameters include, but are not limited to, (a) Investigators' Global Assessment (IGA); (b) Body Surface Area Involvement of Atopic Dermatitis (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Pruritus Numeric Rating Scale (NRS). "Improvement in AD-related parameters" means a decrease from baseline in one or more of the following: IGA, BSA, EASI, SCORAD, 5-D pruritus scale, NRS / worst itch score, patient's overall impression of the disease, patient's overall impression of change, Children's Dermatology Life Quality Index (CDLQI), Patient-Oriented Eczema Measure (POEM), Dermatitis Family Index (DFI) score, or Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and / or depression scores. The term "baseline" as used with respect to AD-related parameters means the numerical value of the AD-related parameter for the subject before or at the time of administration of the pharmaceutical composition disclosed herein.

[0037] To determine whether AD-related parameters have “improved,” the parameters are quantified at baseline and at one or more time points after administration of the pharmaceutical composition of this disclosure. For example, AD-related parameters may be measured on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, and 85, or at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or any further period after the initial treatment with the pharmaceutical composition of the Disclosure. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to determine whether there has been an “improvement” (e.g., a decrease) in the AD-related parameter. The AD-related parameter is described in its entirety in U.S. Patent Publication No. US2014 / 0072583, which is incorporated herein by reference.

[0038] In some embodiments, AD-related parameters are assessed by caregivers. In some embodiments, parameters are quantified at baseline and one or more time points after administration of the pharmaceutical composition, based on caregiver assessments of AD-related parameters. In some embodiments, caregiver-reported assessments are used to assess AD-related parameters in patients aged between 6 months and under 6 years, e.g., patients aged between 6 months and under 4 years, or patients aged between 6 months and under 2 years. In some embodiments, caregiver-reported assessments are used to assess improvements in peak pruritus NRS scores, the patient's overall impression of the disease, the patient's overall impression of change, the Childhood Atopic Dermatitis Quality of Life Assessment Scale (CDLQI), Patient-Oriented Eczema Measure (POEM), Dermatitis Family Index (DFI) scores, or Patient-Reported Outcome Measurement Information System (PROMIS) anxiety and / or depression scores. In some embodiments, improvement in pruritus is determined based on caregiver-reported assessments. In some embodiments, improvement in pruritus is assessed by the caregiver-reported peak pruritus NRS score.

[0039] In some embodiments, treatment with an IL-4R antagonist by the method of the present disclosure results in an improvement in the subject's IGA score relative to baseline. A method for determining the IGA score for a subject is described in the following Examples section. In some embodiments, the subject to be treated has a baseline IGA score ≥ 3 (e.g., IGA score 3 or IGA score 4). In some embodiments, treatment with an IL-4R antagonist results in a decrease of at least 1 point in the IGA score from baseline (e.g., from baseline IGA score ≥ 3 or baseline IGA score = 4) by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a decrease from baseline (e.g., from IGA score ≥ 3 or IGA score = 4) to IGA score 0 or 1 by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist.

[0040] In some embodiments, treatment with an IL-4R antagonist by the method of the present disclosure results in an improvement in the subject's EASI score relative to baseline. A method for determining the EASI score for a subject is described in the following Examples section. In some embodiments, the subject to be treated has a baseline EASI score ≥ 21 (e.g., 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% in the EASI score from baseline by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in subjects achieving an EASI-75 response (i.e., ≥75% improvement from baseline) by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in subjects achieving an EASI-50 response (i.e., ≥50% improvement from baseline) by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist.

[0041] In some embodiments, treatment with an IL-4R antagonist by the method of the present disclosure results in an improvement in the subject's BSA score relative to baseline. A method for determining the BSA score for a subject is described in the Examples section below. In some embodiments, the subject being treated has a baseline BSA score of ≥15% (e.g., ≥20%, ≥30%, ≥40%, ≥50%, ≥75%, or ≥90%). In some embodiments, the subject 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 in the percentage of AD-affected BSA by week 3, week 4, week 8, week 12, or week 16, following the administration of the initial dose of the IL-4R antagonist.

[0042] In some embodiments, treatment with an IL-4R antagonist by the method of the present disclosure results in an improvement in the subject's pruritus score, such as the subject's “worst pruritus scale” score (also referred herein to as the peak pruritus numerical rating scale (NRS) score), relative to baseline. Methods for determining the pruritus score are described in the following Examples section. In some embodiments, the subject to be treated has a weekly mean score of the worst pruritus score at baseline with maximum pruritus intensity, which is ≥4 (e.g., ≥7). In some embodiments, treatment with an IL-4R antagonist results in a weekly mean reduction of ≥3 points (e.g., ≥4 points) from baseline in the daily pruritus score (e.g., worst pruritus score) by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist.

[0043] In some embodiments, treatment with an IL-4R antagonist by the method of the present disclosure results in an improvement in the subject's SCORAD score relative to baseline. A method for determining the SCORAD score for a subject is described in the Examples section below. In some embodiments, the subject to be treated has a baseline SCORAD score ≥ 40 (e.g., SCORAD score ≥ 50, ≥ 60, or ≥ 70). In some embodiments, treatment with an IL-4R antagonist results in a reduction in the SCORAD score of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% from baseline by week 3, week 4, week 8, week 12, or week 16 after administration of the initial dose of the IL-4R antagonist.

[0044] In some embodiments, treatment with an IL-4R antagonist enhances the efficacy and / or safety of topical therapy for AD. As used herein, a topical therapy (e.g., TCS) regimen is “enhanced” if one or more of the following results or phenomena are observed or achieved in a subject: (1) a reduction in the amount of topical agent (e.g., TCS) administered concomitantly; (2) a reduction in the number of days for which the topical agent (e.g., TCS) is administered concomitantly; (3) a reduction in the patient's dose of a lower-potency topical agent (e.g., a patient is switched from a moderate-potency TCS to a lower-potency TCS); (4) a reduction or elimination of one or more side effects of the topical agent (e.g., TCS); or (5) a reduction in toxicity of the topical agent (e.g., TCS). In some embodiments, the amount of topical agent (e.g., TCS) administered concomitantly to a subject is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more compared to the subject's baseline value or compared to a subject not receiving an IL-4R inhibitor. In some embodiments, concomitant treatment with the topical agent (e.g., TCS) can be gradually reduced or discontinued by treatment with an IL-4R antagonist.

[0045] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure involve administering an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof (e.g., a subject with moderate to severe AD between 6 months and under 6 years of age, e.g., a subject between 6 months and under 2 years of age, or a subject between 2 years and under 6 years of age). As used herein, an "IL-4R antagonist" (also referred herein as an "IL-4R inhibitor," "IL-4R blocker," or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand to inhibit or attenuate the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. The type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an aγc chain. The type 2 IL-4 receptor is a dimeric receptor containing an IL-4Rα chain and an IL-13Rα1 chain. While the type 1 IL-4 receptor interacts with and is stimulated by IL-4, the type 2 IL-4 receptor interacts with both IL-4 and IL-13 and is stimulated by IL-13. Therefore, IL-4R antagonists usable in the methods of this disclosure 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 this disclosure can prevent interaction between IL-4 and / or IL-13 and type 1 or type 2 receptors.

[0046] Non-limiting examples of the category of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor bodies" (e.g., modified molecules containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments thereof that specifically bind to human IL-4Rα. As used herein, an IL-4R antagonist also includes an antigen-binding protein that specifically binds to IL-4 and / or IL-13.

[0047] Anti-IL-4Rα antibodies and antigen-binding fragments thereof In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains and two light (L) chains linked to each other by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or V H for short) and a heavy chain constant region. The heavy chain constant region includes three domains, C H 1, C H 2 and C H 3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or V L for short) and a light chain constant region. The light chain constant region includes one domain (C L 1). The V H and V L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) and more conserved regions called framework regions (FRs). The V H and V[[ID=2S]] LEach consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or its antigen-binding moiety) are identical to those of the human germline sequence. In some embodiments, one or more FRs of the anti-IL-4R antibody (or its antigen-binding moiety) are naturally or artificially modified.

[0048] As used herein, the term “antibody” includes the antigen-binding fragment of a complete antibody molecule. As used herein, the terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, etc., include any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived, for example, from a complete antibody molecule using some appropriate standard technique such as proteolytic digestion, or recombinant genetic engineering techniques including the manipulation and expression of DNA encoding the antibody’s variable and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA may be sequenced and manipulated using chemical or molecular biological techniques, for example, to position one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

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

[0050] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or within one or more framework sequences. L Domain and related V H In antigen-binding fragments having domains, the VH and VL domains can be positioned relative to each other in some appropriate arrangement. For example, the variable region may be a dimer, and V H -V H , V H -V L or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may be a monomer V H or V L You may include a domain name.

[0051] In certain embodiments, the antigen-binding fragment of the antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting and exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody of this disclosure include: (i)V H -C H 1;(ii)V H -C H 2; (iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C LThis includes. In any configuration of the variable domain and constant domain, including any of the exemplary configurations listed above, the variable domain and constant domain may be directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that result in a mobile or semi-mobile link between adjacent variable domains and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody of this disclosure is non-covalently linked to and / or one or more monomers V H Or V L Depending on the domain (for example, by disulfide bonds), the material may contain homodimers or heterodimers (or other polymers) of any of the variable domains and constant domains listed above.

[0052] The constant region of an antibody is crucial for its ability to immobilize complement and mediate cell-dependent cytotoxicity. Therefore, in some embodiments, the antibody isotype may be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0053] As used herein, the term “antibody” also includes polyspecific (e.g., bispecific) antibodies. A polyspecific antibody or antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, each variable domain capable of specifically binding to separate antigens or to different epitopes on the same antigen. Any polyspecific antibody format can be adapted for use in the context of antibodies or antigen-binding fragments of antibodies of this disclosure using common techniques available in the art. For example, in some embodiments, the methods of this disclosure involve the use of a bispecific antibody in which one arm of immunoglobulin is specific to IL-4Rα or a fragment thereof, and the other arm of immunoglobulin is specific to a second therapeutic target or conjugated to a therapeutic site. Exemplary bispecificity forms that can be used in the context of this disclosure include, but are not limited to, scFv-based or diabody bispecificity forms, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knobs-into-holes, common light chains (e.g., common light chains having knobs-into-holes), CrossMab, CrossFab, (SEED) bodies, leucine zippers, duobody, IgG1 / IgG2, dual-acting Fab (DAF)-IgG, and Mab 2 Bispecificity forms (for example, see Klein et al., 2012, mAbs 4:6, 1-11, and the references cited therein for a review of the aforementioned forms). Bispecificity antibodies can also be constructed using peptide / nucleic acid conjugations, for example, by using non-natural amino acids with orthogonal chemical reactivity to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into multimeric complexes with defined composition, valency, and shape. (See, for example, Kazane et al., J.Am.Chem.Soc. [Epub:Dec.4,2012]).

[0054] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. As used herein, the term “human antibody” includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo), for example, in CDRs, particularly CDR3. However, as used herein, the term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been transplanted into a human framework sequence.

[0055] The antibodies used in the methods of this disclosure may be recombinant human antibodies. As used herein, “recombinant human antibody” includes all human antibodies prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (further described below), antibodies isolated from recombinant combinatorial human antibody libraries (further described below), antibodies isolated from animals transgenic for human immunoglobulin genes (e.g., mice) (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created or isolated by any other means, including splicing of 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, if using animals transgenic for human Ig sequences, in vivo somatic mutation), thus affecting the V of the recombinant antibody. H and V L The amino acid sequence of the region is human germ cell V H and V LThis sequence, while derived from and related to other sequences, may not naturally exist within the human antibody repertoire in vivo.

[0056] An “isolated antibody” is an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody separated or removed from at least one component of an organism, or from a tissue or cell in which antibodies are naturally present or naturally produced, is an “isolated antibody.” Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody may substantially contain no other cellular material and / or chemical substances.

[0057] According to certain embodiments, the antibody used in the method of this disclosure specifically binds to IL-4Rα. As used herein, “specifically binds” means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. In some embodiments, antibodies that "specifically bind" to IL-4Rα, when measured in a surface plasmon resonance assay (e.g., BIAcore®, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ), show a high equilibrium dissociation constant (K) of IL-4Rα or a portion thereof, less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 1 nM, less than approximately 0.5 nM, less than approximately 0.25 nM, less than approximately 0.1 nM, or less than approximately 0.05 nM. D) binds. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα may exhibit cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0058] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment, comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing the amino acid sequence of any of the anti-IL-4R antibodies described herein by reference, U.S. Patent No. 7,608,693. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment, comprising a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0059] In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 3, 4, 5, 6, 7, and 8, respectively, and further includes HCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO. 1 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO. 1) and LCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO. 2 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment includes HCVR containing SEQ ID NO. 1 and LCVR containing SEQ ID NO. 2.

[0060] In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0061] An exemplary antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of this disclosure involve the use of dupilumab. As used herein, “dupilumab” also includes bioequivalents of dupilumab. As used herein with respect to dupilumab, “bioequivalent” refers to a pharmacopoeial or pharmacopoeial equivalent or substitute anti-IL-4R antibody or IL-4R-binding protein or fragment thereof that, when administered in the same molar dose under similar experimental conditions, whether single-dose or multi-dose, exhibits no significant difference in absorption rate and / or degree compared to that of dupilumab. In some embodiments, it refers to an antigen-binding protein that binds to IL-4R and has no clinically significant difference from dupilumab in terms of safety, purity and / or potency.

[0062] Other anti-IL-4Rα antibodies that can be used in the context of the methods of this disclosure include, for example, antibodies known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med, 181(8):788-796) or MEDI 9314, or any of the anti-IL-4Rα antibodies described in U.S. Patent Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, 8,877,189, 10,774,141, or International Patent Publication No. WO2020 / 096381, the contents of each of these are incorporated herein by reference.

[0063] In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment for use in the methods of the present disclosure comprises one or more CDR, HCVR, and / or LCVR sequences listed in Table 7 below.

[0064] In some embodiments, the anti-IL-4Rα antibody is (i) SEQ ID NOs: 32 (SCB-VH-59), 33 (SCB-VH-60), 34 (SCB-VH-61), 35 (SCB-VH-62), 36 (SCB-VH-63), 37 (SCB-VH-64), 38 (SCB-VH-65), 39 (SCB-VH-6) 6) Sequence ID 40 (SCB-VH-67), Sequence ID 41 (SCB-VH-68), Sequence ID 42 (SCB-VH-69), Sequence ID 43 (SCB-VH-70), Sequence ID 44 (SCB-VH-71), Sequence ID 45 (SCB-VH-72), Sequence ID 46 (SCB-VH-73), Sequence ID 47 (SCB-VH-74), Sequence ID 48 (SCB-VH-75), Sequence ID 49 (SCB-VH-76), SEQ ID NO: 50 (SCB-VH-77), SEQ ID NO: 51 (SCB-VH-78), SEQ ID NO: 52 (SCB-VH-79), SEQ ID NO: 53 (SCB-VH-80), SEQ ID NO: 54 (SCB-VH-81), SEQ ID NO: 55 (SCB-VH-82), SEQ ID NO: 56 (SCB-VH-83), SEQ ID NO: 57 (SCB-VH-84), SEQ ID NO: 58 (SCB HCVRs containing the amino acid sequences of SEQ ID NO: -VH-85), SEQ ID NO: 59 (SCB-VH-86), SEQ ID NO: 60 (SCB-VH-87), SEQ ID NO: 61 (SCB-VH-88), SEQ ID NO: 62 (SCB-VH-89), SEQ ID NO: 63 (SCB-VH-90), SEQ ID NO: 64 (SCB-VH-91), SEQ ID NO: 65 (SCB-VH-92), or SEQ ID NO: 66 (SCB-VH-93);and (ii) SEQ ID NOs: 12 (SCB-VL-39), 13 (SCB-VL-40), 14 (SCB-VL-41), 15 (SCB-VL-42), 16 (SCB-VL-43), 17 (SCB-VL-44), 18 (SCB-VL-45), 19 (SCB-VL-46), 20 (SCB-VL-47), 21 (SCB-VL-48), 22 The LCVR includes the amino acid sequence of (SCB-VL-49), SEQ ID NO: 23 (SCB-VL-50), SEQ ID NO: 24 (SCB-VL-51), SEQ ID NO: 25 (SCB-VL-52), SEQ ID NO: 26 (SCB-VL-53), SEQ ID NO: 27 (SCB-VL-54), SEQ ID NO: 28 (SCB-VL-55), SEQ ID NO: 29 (SCB-VL-56), SEQ ID NO: 30 (SCB-VL-57), or SEQ ID NO: 31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα antibody includes the HCVR including the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91) and the LCVR including the amino acid sequence of SEQ ID NO: 17 (SCB-VL-44), SEQ ID NO: 27 (SCB-VL-54), or SEQ ID NO: 28 (SCB-VL-55).

[0065] In some embodiments, the anti-IL-4Rα antibody is represented by SEQ ID NOs. 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NOs. 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NOs. 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NOs. 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NOs. 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NOs. 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NOs. 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NOs. 8 1 / 82(MEDI-8-VH / MEDI-8-VL); Sequence ID 83 / 84(MEDI-9-VH / MEDI-9-VL); Sequence ID 85 / 86(MEDI-10-VH / MEDI-10-VL); Sequence ID 87 / 88(MEDI-11-VH / MEDI-11 / VL); Sequence ID 89 / 90(MEDI-12-VH / MEDI-12-VL); Sequence ID 91 / 92(MEDI-13-VH / MEDI-13-VL); Sequence ID 93 / 94(MEDI-14-VH / MEDI-14-VL); Sequence ID 95 / 96(MEDI-15-VH / MEDI -15-VL); SEQ ID NO: 97 / 98 (MEDI-16-VH / MEDI-16 / VL); SEQ ID NO: 99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NO: 101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NO: 103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NO: 105 / 106 (MEDI-20-VH / MEDI-20-VL); SEQ ID NO: 107 / 108 (MEDI-21-VH / MEDI-21-VL); SEQ ID NO: 109 / 110 (MEDI-22-VH / MEDI-22-V L); Sequence ID 111 / 112 (MEDI-23-VH / MEDI-23-VL); Sequence ID 113 / 114 (MEDI-24-VH / MEDI-24-VL); Sequence ID 115 / 116 (MEDI-25-VH / MEDI-25-VL); Sequence ID 117 / 118 (MEDI-26-VH / MEDI-26-VL); Sequence ID 119 / 120 (MEDI-27-VH / MEDI-27-VL); Sequence ID 121 / 122 (MEDI-28-VH / MEDI-28-VL); Sequence ID 123 / 124 (MEDI-29-VH / MEDI-29-VL);Sequence ID 125 / 126 (MEDI-30-VH / MEDI-30-VL); Sequence ID 127 / 128 (MEDI-31-VH / MEDI-31-VL); Sequence ID 129 / 130 (MEDI-32-VH / MEDI-32-VL); Sequence ID 131 / 132 (MEDI-33-VH / MEDI-33-VL); Sequence ID 133 / 134 (MEDI-34-VH / MEDI-34-VL); Sequence ID 135 / 136 (MEDI-35-VH / MEDI-35-VL); Sequence ID 137 / 138 (MEDI-36-VH / MEDI-36-VL); Sequence ID 139 / 140 (ME This includes amino acid sequence pairs selected from the group consisting of DI-37-VH / MEDI-37-VL); SEQ ID NOs. 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NOs. 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NOs. 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NOs. 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NOs. 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NOs. 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0066] In some embodiments, the anti-IL-4Rα antibody is (i) SEQ ID NO: 153 (AJOU-1-VH), SEQ ID NO: 154 (AJOU-2-VH), SEQ ID NO: 155 (AJOU-3-VH), SEQ ID NO: 156 (AJOU-4-VH), SEQ ID NO: 157 (AJOU-5-VH), SEQ ID NO: 158 (AJOU-6-VH), SEQ ID NO: 159 (AJOU-7-VH), SEQ ID NO: 160 HCVR containing the amino acid sequence of (AJOU-8-VH), SEQ ID NO: 161 (AJOU-9-VH), SEQ ID NO: 162 (AJOU-10-VH), SEQ ID NO: 163 (AJOU-69-VH), SEQ ID NO: 164 (AJOU-70-VH), SEQ ID NO: 165 (AJOU-71-VH), SEQ ID NO: 166 (AJOU-72-VH), or SEQ ID NO: 167 (AJOU-83-VH); and (ii) SEQ ID NOs. 168 (AJOU-33-VL), 169 (AJOU-34-VL), 170 (AJOU-35-VL), 171 (AJOU-36-VL), 172 (AJOU-37-VL), 173 (AJOU-38-VL), 174 (AJOU-39-VL), 175 (AJOU-40-VL), 176 (AJOU-41-VL), 177 (AJOU-42-VL), 17 Contains LCVRs including the amino acid sequence of 8(AJOU-77-VL), SEQ ID NO: 179(AJOU-78-VL), SEQ ID NO: 180(AJOU-79-VL), SEQ ID NO: 181(AJOU-80-VL), SEQ ID NO: 182(AJOU-86-VL), SEQ ID NO: 183(AJOU-87-VL), SEQ ID NO: 184(AJOU-88-VL), SEQ ID NO: 185(AJOU-89-VL), SEQ ID NO: 186(AJOU-90-VL), or SEQ ID NO: 187(AJOU-91-VL).

[0067] In some embodiments, the anti-IL-4Rα antibody is (i) an amino acid combination of (i) SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163). (ii) HCVRs containing the sequence; and (ii) LCVRs containing the amino acid sequence of SEQ ID NO: 198 (REGN-VL-11), SEQ ID NO: 199 (REGN-VL-27), SEQ ID NO: 200 (REGN-VL-43), SEQ ID NO: 201 (REGN-VL-59), SEQ ID NO: 202 (REGN-VL-75), SEQ ID NO: 203 (REGN-VL-91), SEQ ID NO: 204 (REGN-VL-107), SEQ ID NO: 205 (REGN-VL-123), SEQ ID NO: 206 (REGN-VL-155), or SEQ ID NO: 207 (REGN-VL-171).

[0068] In some embodiments, anti-IL-4Rα antibodies used in the methods disclosed herein may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use as disclosed herein may exhibit decreased binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use as disclosed herein may exhibit enhanced binding to the antigen at acidic pH compared to neutral pH. The term “acidic pH” includes pH values ​​less than about 6.2, for example, about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the term “neutral pH” means pH from about 7.0 to about 7.4. The term "neutral pH" includes pH values ​​of approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0069] In a particular embodiment, "decreased binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K of the antibody that binds to IL-4Rα at neutral pH. D K of the antibody that binds to IL-4Rα at acidic pH relative to the value D It is expressed by the ratio of values ​​(or vice versa). For example, an antibody or its antigen-binding fragment has an acidic / neutral potassium (K) of approximately 3.0 or higher. D Where a ratio is given, for the purposes of this disclosure, it may be considered to indicate "a decrease in binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K of the antibody or antigen-binding fragment of this disclosure D The ratio can be approximately 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or higher.

[0070] Antibodies with pH-dependent binding properties can be obtained, for example, by screening an antibody population for decreased (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. Furthermore, antibodies with pH-dependent properties may be obtained by modifying the antigen-binding domain at the amino acid level. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody may be obtained in which antigen binding decreases at acidic pH compared to neutral pH.

[0071] Preparation of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used in the context of this disclosure to produce human antibodies that specifically bind to human IL-4R.

[0072] Using VELOCIMMUNE® technology (see, for example, US6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R is first isolated, possessing both a human variable region and a mouse constant region. VELOCIMMUNE® technology involves generating a transgenic mouse having a genome containing human heavy and light chain variable regions operably ligated to an endogenous mouse constant region locus, such that the mouse produces an antibody containing both the human variable region and the mouse constant region in response to antigen stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably ligated to the DNA encoding the human heavy and light chain constant regions. This DNA is then expressed in cells capable of expressing a fully human antibody.

[0073] Generally, VELOCIMMUNE® mice are administered the target antigen, and lymphocytes (e.g., B cells) expressing the antibody are collected from the mice. These lymphocytes are fused with myeloma cell lines to prepare immortal hybridoma cell lines, and such hybridoma cell lines can be screened to identify hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains may be isolated and ligated to the constant regions of the desired isotypes of the heavy and light chains. Such antibody proteins may be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies, or DNA encoding the variable domains of the light and heavy chains, may be isolated directly from antigen-specific lymphocytes.

[0074] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. This antibody is then characterized and selected for desirable properties, including affinity, selectivity, and epitopes, using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to produce the fully human antibody of this disclosure, e.g., wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the specific application, but the high-affinity antigen-binding properties and target specificity properties reside in the variable region.

[0075] Generally, antibodies usable in the methods of this disclosure have the high affinity described above when measured by binding to an antigen immobilized on either a solid phase or in a solution phase. A fully human antibody of this disclosure is generated by substituting a mouse constant region with a desired human constant region. The selected constant region may vary depending on the specific application, but the high affinity antigen-binding properties and target specificity properties reside in the variable region.

[0076] In one embodiment, a human antibody or its antigen-binding fragment that specifically binds to IL-4R and can be used in the manner disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify the identified CDRs within the HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. For example, this is described in 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 to identify CDR sequences within antibodies.

[0077] Pharmaceutical composition In one embodiment, the present disclosure provides a method comprising administering an IL-4R antagonist to a subject, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained in a pharmaceutical composition comprising one or more pharmaceutically acceptable media, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0078] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by absorption through the epithelium or the lining of the mucous membrane (e.g., oral mucosa, rectal mucosa, and intestinal mucosa) via any convenient route, such as injection or bolus injection, or may be administered together with other biologically active agents. In some embodiments, pharmaceutical compositions such as those disclosed herein are administered intravenously. In some embodiments, pharmaceutical compositions such as those disclosed herein are administered subcutaneously.

[0079] In some embodiments, the pharmaceutical composition includes injectable formulations such as dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, as well as intravenous infusions. These injectable formulations can be prepared by known methods. For example, an injectable formulation may be prepared, for example, by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous injectable media include physiological saline, isotonic solutions containing glucose and other adjuvants, which may be used in combination with a suitable solubilizer, such as alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), or nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injectable formulation thus prepared can be filled into a suitable ampoule.

[0080] The dose of antibody administered to a subject by the method of this disclosure may vary depending on the subject's age and size, symptoms, condition, and route of administration. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment may be adjusted according to the severity of symptoms. Effective doses and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies may be determined empirically, for example, by monitoring the subject's progress through periodic evaluations and adjusting the dose accordingly. Furthermore, interspecies scaling of doses can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses of anti-IL4R antibodies and administration regimens containing them that can be used in the context of this disclosure are disclosed elsewhere in this specification.

[0081] In some embodiments, the IL-4R antagonist or pharmaceutical composition of this disclosure is contained in a container. Thus, in another embodiment, a container containing the IL-4R antagonist or pharmaceutical composition disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of glass vials, syringes, pen-type delivery devices, and auto-injectors.

[0082] In some embodiments, the pharmaceutical compositions of the Disclosure are 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-type delivery device or auto-injector is used to deliver the pharmaceutical compositions of the Disclosure (for example, for subcutaneous delivery). The pen-type delivery device may be reusable or disposable. Typically, a reusable pen-type delivery device utilizes a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge is administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. In disposable pen-type delivery devices, there is no replaceable cartridge. Rather, disposable pen-type delivery devices are pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition in the reservoir is empty, the entire device is discarded.

[0083] Examples of suitable pens and auto-injector delivery devices include 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®, and OPTIPEN®. Examples of disposable pen-type delivery devices for use in subcutaneous delivery of the pharmaceutical compositions of this disclosure include, but are not limited to, STARLET® and OPTICLIK® (sanofi-aventis, Frankfurt, Germany).

[0084] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, cited above; Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201). In another embodiment, a polymer material may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, the controlled-release system may be positioned near the target of the composition and therefore require only a fraction of the systemic dose (see, for example, Goodson, 1984, Medical Applications of Controlled Release, cited above, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533. Other delivery systems are known and can be used to administer pharmaceutical compositions, such as liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

[0085] In some embodiments, the pharmaceutical compositions for use as described herein are prepared into unit dose dosage forms suitable for the dose of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[0086] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the context of this disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0087] Dosage and administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject (e.g., a subject between 6 months and under 6 years of age) in a therapeutically effective dose according to the method of this disclosure. As used herein with respect to an IL-4R antagonist, “therapeutably effective dose” means a dose of an IL-4R antagonist that results in one or more of the following: (a) improvement in one or more AD-related parameters (as referred to elsewhere herein), and / or (b) a detectable improvement in one or more symptoms or signs of atopic dermatitis.

[0088] For anti-IL-4R antibodies, the therapeutically effective dose ranges from approximately 0.05 mg to approximately 600 mg, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, and 27 mg. The anti-IL-4R antibody can be administered in amounts of 0 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, 590 mg, or approximately 600 mg. In some embodiments, the therapeutically effective dose is approximately 50 mg to approximately 600 mg, or approximately 100 mg to approximately 600 mg, or approximately 200 mg to approximately 600 mg. In specific embodiments, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of anti-IL-4R antibody is administered to the target.

[0089] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in individual doses can be expressed in milligrams of antibody per kilogram of body weight (i.e., mg / kg). For example, an IL-4R antagonist may be administered to a subject in doses ranging from approximately 0.0001 to approximately 10 mg / kg of body weight, for example, from approximately 1 mg / kg to approximately 10 mg / kg, from approximately 2 mg / kg to approximately 9 mg / kg, or from approximately 3 mg / kg to approximately 8 mg / kg. In some embodiments, an IL-4R antagonist may be administered to a subject in doses of approximately 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. In some embodiments, an IL-4R antagonist is administered to a subject in a dose of approximately 3 mg / kg. In some embodiments, the IL-4R antagonist is administered to subjects at a dose of approximately 6 mg / kg. In some embodiments, the IL-4R antagonist is administered to subjects at a dose of 5 mg / kg to 10 mg / kg. In some embodiments, the IL-4R antagonist is administered to subjects at a dose of at least approximately 5 mg / kg, for example, at least 6 mg / kg.

[0090] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to the subject (e.g., subcutaneously) in an amount that results in the maximum serum concentration (i.e., Cmax) of the IL-4R antagonist in the subject, such as at least 20 mg / L, for example, at least 25 mg / L, 30 mg / L, at least 35 mg / L, at least 40 mg / L, or at least 45 mg / L. In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered subcutaneously in an amount that results in a total exposure to the IL-4R antagonist in the subject (i.e., AUC) of at least 120 days·mg / L, for example, at least 125 days·mg / L, at least 130 days·mg / L, at least 150 days·mg / L, at least 200 days·mg / L, at least 250 days·mg / L, at least 300 days·mg / L, at least 350 days·mg / L, at least 400 days·mg / L, at least 450 days·mg / L, at least 500 days·mg / L, at least 550 days·mg / L, at least 600 days·mg / L, or at least 650 days·mg / L.

[0091] In some embodiments, the methods disclosed herein involve administering an IL-4R antagonist to a target at a frequency of administration of approximately four times a week, twice a week, once a 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, as long as a therapeutic response is achieved.

[0092] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject (e.g., subcutaneously) at a frequency that causes the subject to maintain a serum concentration of at least 25 mg / L, e.g., at least 30 mg / L, at least 35 mg / L, at least 40 mg / L, or at least 45 mg / L of the IL-4R antagonist over a defined period (e.g., over a period of at least 4 weeks, or over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer). In some embodiments, multiple doses of the IL-4R antagonist are administered (e.g., subcutaneously) at a frequency such that the subject maintains a total exposure to the IL-4R antagonist for at least one week, at least two weeks, at least three weeks, at least four weeks or longer (e.g., at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months or longer), and at least 130 days·mg / L (e.g., at least 150 days·mg / L, at least 200 days·mg / L, at least 250 days·mg / L, at least 300 days·mg / L, at least 350 days·mg / L, at least 400 days·mg / L, at least 450 days·mg / L, at least 500 days·mg / L, at least 550 days·mg / L, at least 600 days·mg / L, or at least 650 days·mg / L).

[0093] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a predetermined period of time. In some embodiments, the method of the present disclosure includes sequential administration of multiple doses of an IL-4R antagonist to a subject. As used herein, “sequential administration” means that each dose of the IL-4R antagonist is administered to the subject at different points in time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the method of the present disclosure includes sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL-4R antagonist, and optionally one or more tertiary doses of the IL-4R antagonist.

[0094] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of administration of the IL-4R antagonist. Thus, the “initial dose” is the first dose administered in the treatment regimen (also called the “loading dose”), the “secondary dose” is the dose administered after the initial dose, and the “tertiary dose” is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but generally they may differ from one another in terms of administration frequency. However, in certain embodiments, the amounts of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses may differ from one another during the course of treatment (e.g., adjusted up or down as needed). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5 times) are administered as a “loading dose” at the start of the treatment regimen, followed by subsequent doses administered at a less frequent frequency (e.g., “maintenance doses”). In some embodiments, the initial dose and one or more secondary doses each contain the same amount of IL-4R antagonist. In other embodiments, the initial dose contains a first amount of IL-4R antagonist, and one or more secondary doses each contain a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist can be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times or more than the second amount of IL-4R antagonist. In some embodiments, one or more maintenance doses of IL-4R antagonist are administered without a loading dose.

[0095] In some embodiments, the loading dose is a “split dose” administered as two or more doses (e.g., 2, 3, 4, or 5 doses) given on separate days. In some embodiments, the loading dose is administered as a split dose, with two or more doses given at least about one week apart. In some embodiments, the loading dose is administered as a split dose, with two or more doses given at about one, two, three, or four weeks apart. In some embodiments, the loading dose is evenly divided over two or more doses (e.g., half of the loading dose is given as the first part and half of the loading dose is given as the second part). In some embodiments, the loading dose is unevenly divided over two or more doses (e.g., more than half of the loading dose is given as the first part and less than half of the loading dose is given as the second part).

[0096] In some embodiments, each secondary and / or tertiary dose is administered 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, or more) weeks after the preceding dose. As used herein, “previous dose” means a dose of the IL-4R antagonist administered to the patient in a series of consecutive doses, without any doses intervening in the sequence, and immediately before the administration of the next dose.

[0097] The methods of the present disclosure may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight, or more) tertiary doses are administered to the patient.

[0098] 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 to 2 weeks after the previous 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 to 4 weeks after the previous 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. Furthermore, the frequency of administration may be adjusted by the physician during the course of treatment, according to the individual patient's needs, after clinical examinations.

[0099] Combination therapy In some embodiments, the methods of the present disclosure include administering an IL-4R antagonist (e.g., an anti-IL-4R antibody) according to the present disclosure to a subject (e.g., a subject aged 6 months to under 6 years) in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agents are topical therapeutic agents, e.g., TCS, or topical nonsteroidal therapeutic agents such as TCI or crisabolol. As used herein, the expression “in combination with” means that the topical therapeutic agent (e.g., TCS) is administered before, after, or concurrently with the IL-4R inhibitor. The term “in combination with” also includes administering the IL-4R inhibitor and the topical therapy (e.g., TCS) sequentially or concurrently.

[0100] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before the administration of the pharmaceutical composition containing the IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after the administration of the pharmaceutical composition containing the IL-4R antagonist. Administering "concurrently" with or together with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form less than 5 minutes (before, after, or concurrently) with the administration of the pharmaceutical composition containing the IL-4R antagonist, or that the additional therapeutic agent is administered to the subject as a single combination containing both the additional therapeutic agent and the IL-4R antagonist.

[0101] In some embodiments, the additional therapeutic agent is 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, the additional therapeutic agent is a TCI. In some embodiments, the additional therapeutic agent is crisabolol.

[0102] Examples The following examples are provided to those skilled in the art to provide a complete disclosure and explanation of how the methods and compositions of this disclosure are prepared and used, and are not intended to limit the scope of what the inventors consider to be the invention. While efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), some experimental error and deviation should be taken into consideration. Unless otherwise specified, parts are parts by weight, molecular weight is the average molecular weight, temperature is Celsius, and pressure is at or near air pressure.

[0103] Example 1: Clinical trial to investigate the pharmacokinetics, efficacy, and safety of dupilumab in children aged 6 months to under 6 years with severe, uncontrolled atopic dermatitis. Study design and objectives This was an open-label, multicenter, phase 2, sequential, two-age cohort, two-dose-level study (LIBERTY AD PRE-SCHOOL; NCT03346434) investigating the pharmacokinetics, safety, and efficacy of subcutaneous dupilumab. Dupilumab is a fully human anti-IL-4R antibody containing a heavy chain with the amino acid sequence of SEQ ID NO: 9, a light chain with the amino acid sequence of SEQ ID NO: 10, an HCVR / LCVR amino acid sequence pair with SEQ ID NO: 1 / 2, and heavy and light chain CDR sequences with SEQ ID NOs: 3-8. Older patients (ages 2 to under 6 years) were enrolled first, followed by younger cohorts (ages 6 months to under 2 years). A subgroup of 10 patients in each cohort was treated with a lower dose (3 mg / kg) based on body weight, followed by another subgroup being treated with a higher dose (6 mg / kg). To ensure adequate distribution of patients within each age cohort, the maximum number of patients enrolled at a given dose level was limited to seven patients in each subgroup: 2 to under 4 years and 4 to under 6 years in the older cohort, and 6 months to under 1 year and 1 to under 2 years in the younger cohort.

[0104] The trial consisted of a screening period (-35 to -1 day), baseline visit (day 1), a single-dose treatment on day 1, and a subsequent 4-week PK sampling period. Patients were then offered the opportunity to enroll in the open-label extension (OLE) trial R668-AD-1434 (LIBERTY AD PED-OLE, NCT02612454). Patients who declined or were ineligible to participate in the OLE were followed for an additional 4 weeks.

[0105] This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (IMMED) guidelines for good clinical practices, and applicable regulatory requirements. The protocol was reviewed and approved by the institutional review boards / ethics boards of all sites. Written informed consent was obtained from the parent or legal guardian of all patients.

[0106] Patient group In this study, we enrolled pediatric patients (boys or girls between 6 months and 6 years of age at the time of screening) with severe Alzheimer's disease (AD) and a recent history of inadequate response to topical AD medications.

[0107] Inclusion Criteria: To participate in this study, patients had to meet the following criteria: (1) Male or female, between 6 months and under 6 years of age at the time of screening; (2) Diagnosis of Alzheimer's disease (AD) according to the American Academy of Dermatology consensus criteria (Eichenfield 2003) at the time of screening; (3) Record of a history of inadequate response to topical AD medications in recent years (within 6 months prior to the screening visit); (4) IGA = 4 at the time of screening and at baseline; (5) EASI ≥ 21 at screening and at baseline; (6) BSA ≥ 15% at screening and at baseline; (7) Application of a stable dose of topical emollient (moisturizer) twice daily for at least 7 consecutive days immediately prior to the baseline visit (Part B of the study only); (8) Where applicable, a parent or legal guardian was able to understand and complete the study requirements and study-related questionnaires.

[0108] Note: Patients who fail to achieve and / or maintain remission and low disease activity (IGA score <3) despite receiving treatment with moderate to high-potency TCS (±TCI as needed) daily for 28 days or more, or for the maximum duration recommended by the product's prescribing information, whichever is shorter, will be considered to meet the definition of an inadequate response for the purposes of this study. Patients who have received systemic treatment for AD within the past six months will also be considered to have an inadequate response to topical treatment and may be eligible for treatment with dupilumab after appropriate washout. Acceptable documentation includes prescriptions for topical treatments and synchronous medical records documenting treatment results, or documentation from the principal investigator based on communication with the treating physician. If documentation is insufficient, potential patients may be offered a course of treatment with moderate to high-potency TCS (±TCI as needed) daily for at least 28 days during the screening period, or for the maximum duration recommended by the product's prescribing information, whichever is shorter. Patients who demonstrate an inadequate response during this period will be eligible to participate in this study.

[0109] Exclusion Criteria: The following were excluded from this study: (1) Participation in a previous dupilumab clinical trial; (2) A history of significant adverse events with moderate-potency topical corticosteroids as assessed by the principal investigator or the physician treating the patient (e.g., intolerance to treatment, hypersensitivity reaction, significant skin atrophy, systemic effects, etc.); (3) More than 30% of the total lesion surface being in areas of thin skin that cannot be safely treated with moderate-potency TCS at baseline (e.g., face, neck, intertriginous area, genital area, skin graft area) (in this study) Applicable only to Part B); (4) Treatment with the investigational drug at any point before baseline visit; (5) Treatment with TCI within two weeks before baseline visit (applicable only to Part B of this study); (6) Treatment within four weeks before baseline visit, or within a period equal to five times the drug's half-life, whichever is longer, including: (a) Immunosuppressants / immunomodulators (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon (b) A history of receiving any of the following phototherapy for AD: (a) Treatment with a biologic agent, including but not limited to rituximab: within 6 months prior to baseline visit or until lymphocyte and CD19+ lymphocyte counts return to normal, whichever is longer; (b) Other biologic agents: within 5 half-lives (if known) or within 16 weeks prior to baseline visit, whichever is longer; (8) Treatment with crisabolol within 2 weeks prior to baseline visit; (9) Treatment with a live (attenuated) vaccine within 4 weeks prior to baseline visit [Note: For patients scheduled to receive a live attenuated vaccine during the study period (based on the national immunization schedule / local guidelines), consult with a pediatrician to determine whether the vaccine can be postponed until after the study or brought forward to before the start of the study without compromising the patient's health: (a) Patients who can safely postpone the administration of the live (attenuated) vaccine are considered eligible for enrollment in this study. (b) Patients who have received vaccination earlier may only participate in this study after a 4-week interval following vaccine administration. (10) The use of any of the prohibited therapeutic agents and procedures is planned or anticipated during the study procedure. (11) Initiation of AD treatment with prescribed moisturizers or moisturizers containing additives such as ceramides, hyaluronic acid, urea, filaggrin hydrolysates, etc., during the screening period (if initiated before the screening visit, the patient may continue using a stable amount of such moisturizer) (for Part B of the study only); (12) Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitic agents, or antifungals within two weeks prior to the baseline visit [Note: Patients may be rescreened after the infection has subsided. Patients with mild localized superficial infections may be included in this study at the discretion of the principal investigator]. (13) A confirmed diagnosis of primary immunodeficiency disorder (such as severe combined immunodeficiency, Wiscott-Aldrich syndrome, DiGeorge syndrome, X-linked agamaglobulinemia, unclassified immunodeficiency), or secondary immunodeficiency. Patients suspected of having immunodeficiency based on clinical symptoms (such as a history of invasive opportunistic infections like tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, or chronic mucocutaneous candidiasis, as determined by the principal investigator) will also be excluded from this study. (14) Eczema, which is part of the hereditary skin disease syndromes such as Netherton syndrome, hyper-IgE syndrome, and Wiscott-Aldrich syndrome; (15) A known history of human immunodeficiency virus (HIV) infection, or HIV seropositive at the time of screening; (16) A confirmed diagnosis of hepatitis B virus infection at the time of screening, or positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at the time of screening [Note: Patients who are HBsAg negative and HBsAb positive are considered to have immunity after natural infection has cleared, or have been vaccinated against hepatitis B. Therefore, they are eligible to participate in this study.]These patients will be eligible to enroll in this study but will be followed up with routine clinical and liver function tests. (17) A confirmed diagnosis of hepatitis C virus infection at screening, or positive for hepatitis C antibodies at screening; (18) A history of past or present tuberculosis or other mycobacterial infection; (19) Having a known liver disease, or currently being treated for a liver disease including but not limited to acute or chronic hepatitis, cirrhosis, or hepatic failure, or having evidence of liver disease as indicated by persistently elevated transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) >3 times the upper limit of normal (ULN) during the screening period (confirmed by repeated testing at ≥2 weeks intervals); (20) Any abnormalities in the clinical laboratory results at screening: (i) Platelets ≤ 100 × 10. 3 / μL; (ii) For patients under 1 year of age, neutrophils ≤ 1.0 × 10 3 / μL; For patients aged 1 to under 6 years, neutrophils ≤ 1.5 × 10⁻¹⁰ 3(iii) Eosinophils ≥ 5000 / μL; (iv) Creatine phosphokinase (CPK) > 5 × ULN; (v) Serum creatinine > 1.5 × ULN; [Note: If abnormal values ​​are detected during screening, repeat the test to confirm the abnormality. If an abnormality is confirmed by repeat testing, it will be classified as a screening failure] having one or more of these; (21) Presence of a skin comorbidity that may interfere with the evaluation of the study, including but not limited to scabies, seborrheic dermatitis, cutaneous T-cell lymphoma, and psoriasis; (22) History of malignancy prior to baseline visit; (23) Diagnosis of active endoparasitic infection; suspected or at high risk of endoparasitic infection, except if active infection has been ruled out by clinical and (if necessary) laboratory evaluation prior to randomization; (24) A serious comorbidity that, in the judgment of the principal investigator, would adversely affect the patient's participation in the study. For example, patients with a short life expectancy, significant congenital malformations, cardiovascular conditions (e.g., clinically significant congenital cardiovascular anomalies), severe renal or hepatobiliary conditions (e.g., ChildePugh classification B or C), active and significant autoimmune diseases (e.g., lupus, inflammatory bowel disease, etc.), and other serious endocrine, gastrointestinal, metabolic, pulmonary, neurological, or lymphatic disorders are included, but are not limited to these. The specific justification for patients excluded under these criteria will be documented in the trial documentation (e.g., medical record notes, case report forms [CRFs]). (25) In the opinion of the principal investigator, any other medical or psychological condition, including related laboratory abnormalities at screening, that may pose an undue risk to the patient by participating in this clinical trial, make the patient's participation unreliable, or interfere with the evaluation of the trial, suggesting a new and / or poorly understood disease; (26) The patient is scheduled to undergo a major surgical procedure while participating in this trial; (27) The patient or a close relative is a member of the dupilumab research team.

[0110] Test treatment The 6 mg / kg dose was expected to result in drug exposure comparable to a single 300 mg dose of dupilumab in adult patients. To assess safety before transitioning to the 6 mg / kg dose, the 3 mg / kg dose was initially evaluated in each age group. The results of this Phase 2 trial will provide information for dose selection in the important randomized, double-blind, parallel-group, placebo-controlled Phase 3 trial (LIBERTY AD INFANT) evaluating the efficacy, safety, and immunogenicity of multiple doses of dupilumab administered in combination with TCS over 16 weeks. Standardized low-to-moderate potency TCS and TCI combinations or non-combination were permitted, while high-potency TCS, systemic nonsteroidal immunosuppressants, and systemic corticosteroids were permitted only as life-saving measures. The use of crisabolol was also permitted in accordance with local guidelines and product prescribing information, except for the two weeks leading up to baseline visits. The use of prescribed moisturizers and moisturizers containing additives such as ceramides, hyaluronic acid, urea, or filaggrin degradation products was permitted only if the use of such moisturizers had already been initiated before the screening visit. Initiating treatment for AD with such moisturizers during the trial was not permitted. Medications used to treat chronic diseases such as diabetes, hypertension, and asthma were also permitted.

[0111] Evaluation results The primary endpoints were serum concentrations of functional dupilumab over time and PK parameters (summary statistics of drug concentration and PK parameters), as well as the incidence and severity of treatment-induced adverse events (TEAEs) during the study period.

[0112] Secondary endpoints included the incidence of serious adverse events (SAEs) and severe TEAEs up to week 4; percentage changes in EASI (scale 0-72) and SCORing Atopic Dermatitis (SCORAD) scores (scale 0-103) from baseline to week 4; and the proportion of patients with an IGA score of 0 or 1 (on a 5-point scale) at week 4.

[0113] Other endpoints included: the percentage of patients with a ≥75% improvement from baseline in the EASI (EASI-75) or a ≥50% improvement from baseline in the EASI (EASI-50) at week 4; the percentage change in the caregiver-reported peak pruritus numerical rating scale (NRS) (scale 0-10) from baseline to week 4; and the change in BSA affected from baseline to week 4. For each protocol, the week 3 trial visit was defined as day 18 ± 3 days, and the week 4 visit was defined as day 29 ± 3 days.

[0114] Procedures for evaluating effectiveness (e.g., using EASI, SCORAD, IGA, BSA, NRS, or other evaluation methods) are described below and are also described in WO2018 / 057776, which are incorporated herein by reference.

[0115] Overall Assessment by the Principal Investigator: IGA is an assessment tool used in clinical trials to comprehensively assess the severity of Alzheimer's disease (AD) based on a 5-point scale from 0 (clear) to 4 (severe). The IGA score can be assessed at screening, baseline, and on specific days during and / or after treatment.

[0116] The Eczema Area and Severity Index (EASI) is a valid scale used in clinical practice and clinical trials to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al. 2001, Exp. Dermatol. 10:11-18). The EASI is a composite index with a score from 0 to 72. The four AD disease features (erythema, thickness [induration, papules, edema], scratching [excision], lichenification) are each assessed by the investigator or designated person on a scale from "0" (none) to "3" (severe). In addition, the area of ​​AD lesions is assessed as a percentage for each body part (head, trunk, upper and lower extremities) and converted to a score from 0 to 6. For each body part, the area is expressed as 0, 1 (1%-9%), 2 (10%-29%), 3 (30%-49%), 4 (50%-69%), 5 (70%-89%), or 6 (90%-100%). The EASI score can be evaluated at screening, baseline, and on specific days during and / or after the procedure.

[0117] Atopic Dermatitis Score Assessment: The Atopic Dermatitis Score Assessment (SCORAD) is a valid tool used in clinical research and practice, developed to standardize the assessment of the degree and severity of AD (European Task Force on Atopic Dermatitis 1993, Dermatol. 186:23-31). The assessment has three elements: A = extent or affected BSA, B = severity, and C = subjective symptoms. The degree of AD is assessed as a percentage for each defined body area and reported as the sum of all areas, with the highest score being 100% (assigned as "A" in the SCORAD overall calculation). The severity of the six symptoms of AD (redness, swelling, exudation / crusting, abrasions, skin thickening / lichenification, and dryness) is assessed using the following scale: none (0), mild (1), moderate (2), and severe (3) (a maximum total score of 18 is assigned as a B in the overall SCORAD calculation). Subjective assessments of itching and insomnia are recorded by the patient or a relative for each symptom using a Visual Analogue Scale, where 0 is no itching (or insomnia) and 10 is the worst itching (or insomnia) imaginable, with a maximum possible score of 20. This parameter is assigned as a "C" in the overall SCORAD calculation. The SCORAD is calculated as A / 5 + 7B / 2 + C, where the maximum is 103. The SCORAD score can be assessed at screening, baseline, and on specific days during and / or after treatment.

[0118] Atopic dermatitis lesion surface area: The body surface area (BSA) affected by AD is assessed for each body part using the rule of nine (the highest possible scores for each part are: head and neck [9%], anterior trunk [18%], back [18%], upper extremities [18%], lower extremities [36%], and genitals [1%]), and reported as a percentage of all major body parts combined. BSA can be assessed at screening, baseline, and on specific days during and / or after treatment.

[0119] Peak Itch Numerical Rating Scale: The Peak Itch Numerical Rating Scale (NRS) is a validated patient-reported scale for assessing the worst itch intensity (Yosipovitch et al., Br J Dermatol, 2019, 181:761-769). It is an 11-point scale (0-10), where 0 indicates no itching and 10 indicates the worst itch, and patients (or caregivers) assess the intensity of their peak (worst) itch over the past 24 hours.

[0120] Pharmacokinetic analysis Serum functional dupilumab concentrations were analyzed using validated enzyme-linked immunosorbent assay (ELISA), as previously described. The limit of quantification (LLoQ) of dupilumab in undiluted human serum is 0.0780 mg / L. Serum for PK analysis was collected at baseline (before dupilumab injection) and on days 3, 8, 18, and 29 of the study.

[0121] Maximum concentration (C max ), dose normalized C max (C max (dose), time to maximum concentration (t) max ), final observed concentration (C last ), time to the final observed concentration (t last ), area under the curve (AUC) from time zero to the final observed concentration, dose-normalized AUC last (AUC last PK parameters such as (dose / particle) were determined using a non-compartmental method and actual sampling times. The mean concentration-time profile is presented using nominal sampling times.

[0122] Biomarker analysis For CCL17 / TARC measurement, serum samples were assayed using a valid commercially available ELISA (Human CCL17 / TARC Quantikine ELISA Kit #SDN00, R&D Systems Inc, Minneapolis, MN, USA) according to the manufacturer's instructions. Total IgE was assessed using an immunoturbidimetric methodology with a BN II instrument. Serum eosinophil counts were measured using a Coulter LH 750 Hematology Analyzer with volume, conductivity, and scatter (VCS) flow technology.

[0123] statistical analysis Since the primary objective was to evaluate safety and PK, formal power calculations based on efficacy endpoints were not performed. A total of 10 patients in each dose group was considered sufficient to characterize the safety and PK profiles. Descriptive statistics of functional dupilumab serum concentrations at each time point by dose were reported from the PK analysis set (all treated patients who received either study drug and did not miss at least one functional dupilumab measurement after administration). Safety and efficacy were evaluated in the safety analysis set, consisting of all treated patients who received one or more doses of dupilumab. Efficacy analyses were performed observationally without censoring. Due to the small cohort size, inferential statistical analyses were not reported, and all efficacy results were summarized as descriptive statistics. All analyses were performed using SAS Version 9.4 (Cary, NC, USA) or later.

[0124] result Forty patients were screened and enrolled (20 aged 2 to under 6 years, and 20 aged 6 months to under 2 years; 10 patients at each dose level within the age cohort). Patient screening was performed at 21 of 30 sites initiated in the United States, the United Kingdom, and Germany. In the older cohort, all patients completed the trial and moved to the OLE trial. In the younger cohort, one patient withdrew consent during the safety follow-up period and discontinued the trial early, and two patients completed the trial but did not continue to the OLE. All patients were included in the safety analysis set.

[0125] Of all patients in the study, 10 were between 4 and 6 years old, 10 were between 2 and 4 years old, 14 were between 1 and 2 years old, and 6 were between 6 months and 1 year old. Baseline demographic features and characteristics were generally similar across treatment groups within each age cohort. Overall, disease features were consistent with severe AD (Table 1). In the older cohort, 40% had previously used systemic AD medications, of which 25% had used corticosteroids and 20% had used nonsteroidal immunosuppressants. All patients had one or more comorbid atopic / allergic conditions at baseline, and more than half had food allergies or allergic rhinitis. In the younger cohort, 40% of patients had previously used systemic medications for AD, of which 35% had used corticosteroids and 5% had used nonsteroidal immunosuppressants (Table 1). Most patients had one or more comorbid atopic / allergic conditions at baseline, and more than half of them had food allergies (Table 1).

[0126] [Table 1-1] [Table 1-2]

[0127] Dupilumab pharmacokinetics Within each age cohort, higher dupilumab doses of 6 mg / kg resulted in higher serum concentrations that lasted longer than lower doses of 3 mg / kg. Maximum serum concentrations of dupilumab were similar across age cohorts at each dose level and were observed 2 days after injection in most patients (Figure 1A). Mean C in the 3 mg / kg and 6 mg / kg dose groups of the older cohort. max The doses were 25.2 mg / L and 49.8 mg / L, respectively, and 20.1 mg / L and 46.1 mg / L, respectively, in the younger cohort (Table 2). Total dupilumab exposure increased more than proportionally with dose between dose levels within each age cohort, and was slightly higher in the older cohort at each dose level. Mean AUC last In the older cohort, the dose increased from 215 days·mg / L at the 3 mg / kg dose to 670 days·mg / L at the 6 mg / kg dose, while in the younger cohort, it increased from 133 days·mg / L at the 3 mg / kg dose to 519 days·mg / L at the 6 mg / kg dose (Table 2, Figure 1B). The mean serum dupilumab concentration fell below LLoQ by week 4 in the 3 mg / kg dose group, but remained measurable in the 6 mg / kg dose group.

[0128] [Table 2]

[0129] Effectiveness In the older cohort, both doses of dupilumab led to improvements in clinical AD signs and symptoms at week 3, as assessed by reductions from baseline in mean EASI, total SCORAD, SCORAD Visual Analog Scale (VAS) pruritus score (Table 3, Figures 2A-2B), and lesion BSA range. SCORAD VAS sleep score also improved at week 3, but only at the 6 mg / kg dose. The apparent lack of response at the 3 mg / kg dose was due to one patient with abnormal values ​​(Table 3). EASI scores decreased by 44.6% at the 3 mg / kg dose and 49.7% at the 6 mg / kg dose (Table 3). Improvement in AD signs was also demonstrated by the percentage of patients with EASI-50 (50% and 50%) and EASI-75 (30% and 20%) at week 3 after a single dose of 3 mg / kg and 6 mg / kg, respectively (Table 3; Figures 2C-2D). Furthermore, itching improved, as indicated by a mean reduction in caregiver-reported peak pruritus NRS scores from baseline at week 3 for doses of 3 mg / kg and 6 mg / kg, respectively (Table 3, Figure 2E).

[0130] AD clinical signs improved in both dose groups in the younger cohort. EASI scores decreased by a mean 42.7% and 38.8% at week 3 for the 3 mg / kg and 6 mg / kg doses, respectively (Table 3, Figure 2A). Total SCORAD scores, as well as SCORAD VAS scores for sleep and pruritus, and the proportion of affected BSAs also decreased at week 3 for both dupilumab doses (Table 3, Figure 2B). The proportion of patients with EASI-50 was 50% and 40% at week 3 after the 3 mg / kg and 6 mg / kg doses, respectively, and the proportion of patients with EASI-75 was 20% and 0%. Caregiver-reported peak pruritus NRS scores decreased by a mean 11.1% and 18.2% (Table 3, Figures 2C-2E).

[0131] At week 4, the decline in efficacy outcomes, including EASI, SCORAD, and caregiver-reported peak pruritus NRS scores, began to reverse, but in both age groups, the higher dose group maintained better results. All efficacy outcomes improved overall compared to baseline (Table 3, Figures 2A-2E) and were generally numerically higher in the 6 mg / kg group (Table 3).

[0132] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0133] safety In the older cohort, five cases of TEAEs were reported in the 3 mg / kg group and three cases in the 6 mg / kg group. The incidence of TEAEs was similar between treatment groups (Table 4), and the severity of all TEAEs was mild or moderate. One case of SAE (anaphylactic reaction) with dupilumab 3 mg / kg was reported immediately after a meal that was thought to contain nuts in a patient with a history of peanut anaphylaxis and recorded food allergies to eggs, peanuts, dairy products, and soy. This SAE was not considered treatment-related based on the history of food allergy and anaphylaxis, and the time of onset after administration. No more than one AE was reported per treatment group and none were considered treatment-related. No conjunctivitis or superficial eye disease, herpesvirus infection, or injection site reactions were reported.

[0134] The number of TEAEs was higher in the younger cohort (11 in each dose group; Table 4). Most were mild to moderate. Two patients in the 6 mg / kg dose group experienced drug-related AEs (diarrhea and injection site erythema), but neither was severe or critical. One patient in the 3 mg / kg dose group experienced a severe TEAE and anaphylactic reaction, which occurred immediately after eating crab and more than two weeks after administration, and was therefore considered unrelated to dupilumab. Aside from nasopharyngitis, no AEs were reported in one or more patients in any treatment group (Table 3). No conjunctivitis, superficial eye diseases, or herpesvirus infections were reported. There were also no deaths during the study period.

[0135] [Table 4-1] [Table 4-2]

[0136] Biomarker analysis In both older and younger patients, dupilumab significantly suppressed serum TARC and total IgE at both doses (Table 5). Serum eosinophil counts at week 4 increased slightly in older patients in the 3 mg / kg group, but decreased in younger patients; in both older and younger cohorts, there was no change after dupilumab 6 mg / kg (Table 5).

[0137] [Table 5-1] [Table 5-2]

[0138] Combination therapy with TCS for AD The majority of patients in both the younger cohort (80% and 60% at 3 mg / kg and 6 mg / kg, respectively) and the older cohort (90% and 80% at 3 mg / kg and 6 mg / kg, respectively) used concomitant TCS for AD during the study (Table 6). Most of the concomitant TCS were of moderate potency (Group II), and no patients used very potent potency (Group IV) TCS during the study (Table 6).

[0139] [Table 6]

[0140] Consideration Both age cohorts and both dose groups experienced improvement in AD signs and symptoms at week 3, as measured by EASI, total SCORAD, SCORAD VAS for sleep and pruritus, and caregiver-reported peak pruritus NRS scores. However, there was a tendency for slightly better responses in the older cohort compared to the younger cohort, particularly when comparing the 6 mg / kg dose groups. At week 4, not all effects persisted in either age group, and loss of efficacy was more pronounced in the lower dose groups. These findings suggest potential benefits of repeated administration.

[0141] Dupilumab exhibits a non-linear, target-mediated pharmacokinetic (PK) as previously characterized in adult and adolescent patients with moderate to severe AD, and supported by the dose-inflated increase in AUC observed in this study. In this study, slightly lower exposure was observed in younger patients than in older patients at the same mg / kg dose level. It has been previously noted that drug dose clearance is not proportional to body weight for monoclonal antibodies in general, especially dupilumab. This manifests as faster clearance per kg of total body weight in smaller individuals. Therefore, in pediatric populations, using the same mg / kg dose regimen across a wide body weight range may result in over-correction of the dose for the effect of body weight, leading to lower exposure in younger patients.

[0142] Maintaining sufficient concentrations of antagonistic antibodies like dupilumab is crucial for blocking the target pathway during the intended treatment period. When administered in similar multi-dose plans, younger populations may require larger, weight-normalized doses to maintain similar trough concentrations due to the rapid excretion per kg of total body weight. This is supported by the fact that a single dose of 300 mg of dupilumab in adults, equivalent to less than 5 mg / kg in adults weighing 60 kg or more, results in similar exposure to the 6 mg / kg dose used in this study. Other mechanisms, such as higher IL-13 gene expression levels in non-lesional AD skin in children compared to adults, may also contribute to more rapid drug elimination via receptor-mediated pathways in infants.

[0143] Overall, single-dose dupilumab treatment suppressed serum type 2 inflammatory biomarkers TARC and total IgE, consistent with findings in adolescents and adults, suggesting a common underlying mechanism of inflammation involving interleukin-4 and interleukin-13 as mediators. Indeed, even recently diagnosed pediatric AD patients under 2 years of age showed a strong Th2-heavy immune response. There was no clear effect of a single dose of dupilumab on serum eosinophil counts.

[0144] The safety profile of dupilumab in children aged 6 months to under 6 years was comparable to that observed in adults, adolescents, and children over 6 years of age. There were no dupilumab-related events of serious infection or systemic hypersensitivity.

[0145] Numerous adverse events in the younger cohort did not appear to be attributable to any specific event, and the majority were considered unrelated to dupilumab. Furthermore, the acceptable safety profile was reassuring considering the theoretical associations with the use of immunomodulatory treatments in infants. Supported by safety data after multiple dose treatments, the use of targeted immunomodulators like dupilumab would differentiate it from the broad range of immunosuppressants currently used off-label in infants.

[0146] conclusion A single subcutaneous dose of dupilumab in children aged 6 months to under 6 years with severe Alzheimer's disease (AD) resulted in substantial clinical benefit in reducing AD signs and symptoms, although a clear dose-response was not observed at week 3. However, at week 4, improvements in most efficacy responses began to reverse, particularly in lower dose groups. Additionally, exposure and efficacy tended to be slightly higher in older children (2 years to under 6 years) compared to younger children (6 months to under 2 years). Dupilumab was generally well-tolerated in the pediatric population, and its safety profile was similar to that in adults, adolescents, and children over 6 years of age.

[0147] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14] [Table 7-15] [Table 7-16]

[0148] The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications shall be included within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in a method of treating atopic dermatitis (AD) or improving AD-related parameters in subjects aged 6 months to under 6 years with moderate to severe or severe AD that is not adequately controlled by topical AD treatments, The method comprises administering to a subject one or more times a dose of an IL-4R antagonist ranging from 3 mg / kg to 8 mg / kg, The pharmaceutical composition wherein the IL-4R antagonist is dupilumab.

2. The pharmaceutical composition according to claim 1, wherein the subject is a subject having severe AD.

3. The pharmaceutical composition according to claim 1 or 2, wherein the subject is insufficiently responsive to treatment with a moderate or higher potency topical corticosteroid (TCS).

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject has previously been administered a systemic AD treatment drug.

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the target is 6 months to under 2 years of age.

6. A pharmaceutical composition according to any one of claims 1 to 4, wherein the target population is 2 years of age or older but under 6 years of age.

7. The target is, (i) Has a baseline Investigator Global Assessment (IGA) score of 4; (ii) Having a baseline eczema area and severity index (EASI) score of ≥ 21; and / or (iii) Having baseline AD-affected body surface area (BSA) ≥ 15%, A pharmaceutical composition according to any one of claims 1 to 6.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the IL-4R antagonist is administered subcutaneously at a dose of 3 mg / kg.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the IL-4R antagonist is administered subcutaneously at a dose of at least 6 mg / kg.

10. The pharmaceutical composition according to claim 9, wherein the IL-4R antagonist is administered subcutaneously at a dose of 6 mg / kg.

11. The pharmaceutical composition according to any one of claims 1 to 7, wherein the IL-4R antagonist is administered subcutaneously in an amount such that the total exposure of the subject to the IL-4R antagonist is at least 130 days / mg / L.

12. A pharmaceutical composition according to any one of claims 1 to 11, comprising administering multiple doses of an IL-4R antagonist to a target.

13. The pharmaceutical composition according to claim 12, wherein the IL-4R antagonist is administered subcutaneously in an amount such that the total exposure of the IL-4R antagonist to the subject is at least 130 days / mg / L for a period of at least two weeks.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein an IL-4R antagonist is administered to the subject once a week or once every two weeks.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein an IL-4R antagonist is administered in combination with a topical AD treatment drug.

16. The pharmaceutical composition according to claim 15, wherein the topical AD treatment drug is a moderate-potency TCS or a low-potency TCS.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein treatment with an IL-4R antagonist results in a reduction in the level of one or more type 2 inflammatory biomarkers in a subject compared to baseline levels.

18. The pharmaceutical composition according to claim 17, wherein treatment with an IL-4R antagonist results in a reduction in serum TARC and / or serum total IgE levels in the subject compared to baseline levels.

19. Treatment with an IL-4R antagonist is as follows: (i) A reduction from baseline in the IGA score to achieve an IGA score of 0 or 1 by the fourth week following the administration of the initial dose of an IL-4R antagonist; (ii) A reduction of at least 50% from baseline in the EASI score (EASI-50) by three weeks after the administration of the initial dose of the IL-4R antagonist; (iii) A reduction of at least 75% from baseline in the EASI score (EASI-75) by three weeks after the administration of the first dose of the IL-4R antagonist; (iv) A reduction in the percentage of BSAs affected by AD to less than 40% within three weeks after administration of the initial dose of an IL-4R antagonist; and (v) A 35% reduction from baseline in BSAs affected by AD by 3 weeks after administration of the first dose of an IL-4R antagonist; A pharmaceutical composition according to any one of claims 1 to 18, which results in improvement of one or more AD-related parameters selected from.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein AD-related parameters are determined based on caregiver-reported evaluations.

21. A pharmaceutical composition according to any one of claims 1 to 20, wherein treatment with an IL-4R antagonist results in an improvement in the caregiver-reported peak pruritus numerical rating scale (NRS) score.

22. A pharmaceutical composition according to any one of claims 1 to 21, wherein treatment with an IL-4R antagonist results in improvement of itching.

23. The pharmaceutical composition according to claim 22, wherein improvement in itching is evaluated by the caregiver-reported peak pruritus NRS score.

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector.

25. The pharmaceutical composition according to claim 24, wherein an IL-4R antagonist is contained in a pre-filled syringe.

26. The pharmaceutical composition according to claim 25, wherein the pre-filled syringe is a single-dose pre-filled syringe.

27. The pharmaceutical composition according to claim 24, wherein an IL-4R antagonist is contained in an auto-injector.

28. The pharmaceutical composition according to claim 24, wherein an IL-4R antagonist is contained in a pen-type delivery device.

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