IL-13 antibody for the treatment of atopic dermatitis

Abstract

To provide safer and more effective therapies and treatment regimens for moderate to severe atopic dermatitis (AD). [Solution] Provided herein are methods, uses, and pharmaceutical compositions of an antibody that binds to human IL-13 ("anti-IL-13 antibody") for the treatment of atopic dermatitis. Also provided herein are drug regimens for methods and uses of anti-IL-13 antibodies for the treatment of atopic dermatitis.

Description

[Technical Field]

[0001] (Sequence Listing) This application is filed together with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled "X23063_SequenceListing" created on August 3, 2022, and has a size of 15 kilobytes. The Sequence Listing information in ST.26 XML format is incorporated herein by reference in its entirety.

[0002] (Field of the Invention) The present invention relates to methods, uses, and pharmaceutical compositions of an antibody that binds to human IL-13 ("anti-IL-13 antibody") for treating atopic dermatitis. The present invention also relates to dosing regimens for methods and uses of an anti-IL-13 antibody for treating atopic dermatitis. [Background Art]

[0003] Atopic dermatitis (AD) is a chronic, relapsing, and remittent inflammatory skin disorder affecting all age groups. Clinically, AD is characterized by xerosis, erythematous crusted rash, lichenification, impaired skin barrier, and severe itching (Bieber T., N Engl J Med 2008;358:1483-94). Patients with AD have a high disease burden, and their quality of life is significantly affected. One study showed that AD has a greater negative impact on patients' mental health than diabetes and hypertension (Zuberbier T, et al., J Allergy Clin Immunol 2006;118:226-32). Patients with moderate to severe Alzheimer's disease (AD) have a higher prevalence of social dysfunction and sleep disorders, which are directly related to the severity of the disease (Williams H, et al., J Allergy Clin Immunol 2008;121:947-54.e15). Depression, anxiety, and social dysfunction affect not only AD patients but also their caregivers (Zuberbier T, et al., J Allergy Clin Immunol 2006;118:226-32).

[0004] Interleukin (IL)-13 is a key mediator of T-helper type 2 (Th2) inflammation, transmitting signals via the heterodimeric receptor IL-4Rα / IL-13Rα1. A summary of several pieces of evidence suggests that IL-13 is a major pathogenic component in Alzheimer's disease (AD). Increased IL-13 expression has been consistently reported in AD skin (Hamid Q, et al., J Allergy Clin Immunol 98:225-31

[1996] , Jeong CW, et al., Clin Exp Allergy 33:1717-24

[2003] , Tazawa T, et al., Arch Dermatol Res 295:459-64

[2004] , Neis MM, et al., J Allergy Clin Immunol 118:930-7

[2006] , Suarez-Farinas M, et al., J Allergy Clin Immunol 132:361-70

[2013] , Choy DF, et al., J Allergy Clin Several reports, including Immunol. 130:1335-43 (2012), suggest a relationship between IL-13 expression and disease severity (La Grutta S, et al., Allergy 60:391-5 (2005)). Increased IL-13 levels have also been reported in the serum of AD patients (Novak N, et al., J Invest Dermatol 2002;119:870-5, International Publication No. 2016149276), and several studies have reported increased IL-13-expressing T cells in the blood of AD patients (Akdis M, et al., J Immunol 1997;159:4611-9, Aleksza M, et al., Br J Dermatol 2002;147:1135-41, La Grutta S, et al., Allergy 2005;60:391-5).

[0005] Treatment approaches for Alzheimer's disease (AD) primarily include trigger avoidance, skin moisturizing through bathing, and the use of anti-inflammatory therapies such as emollients and topical corticosteroids (TCS). In many patients, treatment with TCS provides some symptom relief but does not adequately control the patient's disease. In addition, the use of TCS is associated with many comorbidities and limitations, including a high patient burden. Long-term application of TCS is not recommended due to the risk of cutaneous atrophy, hyperpigmentation abnormalities, acneiform rash, and risks associated with systemic absorption (e.g., hypothalamic-pituitary axial effect, Cushing's disease). Topical calcineurin inhibitors (TCIs) are generally effective and safe as short-term treatments, but due to concerns about an increased risk of cutaneous malignancies and lymphomas, regulatory authorities now require warnings regarding the long-term safety of topical tacrolimus and pimecrolimus in their prescribing information. Prolonged or repeated application of any topical therapy to a large surface area also leads to decreased patient compliance.

[0006] For patients with persistent moderate to severe AD who do not respond well to TCS, several step-up treatment options are available (Ring J, et al., J Eur Acad Dermatol Venereol 2012;26:1176-93, Schneider L, et al., J Allergy Clin Immunol 2013;131:295-9.e1-27). Oral immunosuppressants (Schmitt et al 2007, JEADV 21:606-619) and glucocorticoids are effective, but they can be associated with severe toxicity and side effects, and therefore their use is limited to short-term and / or intermittent therapy. Cyclosporine is approved in many European countries for the treatment of moderate to severe AD, but it is not approved in the United States, and its use is limited to patients 16 years of age or older (for a maximum of 8 weeks) [NEORAL®]. Even when cyclosporine shows substantial efficacy, approximately 50% of patients relapse within two weeks and 80% within six weeks after discontinuation of treatment (Amor KT, et al., J Am Acad Dermatol 2010;63:925-46). Cyclosporine A (CsA) is a potent immunosuppressant that affects both humoral and cellular immune responses, potentially leading to increased susceptibility to infection and decreased cancer immune surveillance. Other commonly recognized toxicities of CsA include hypertension and renal and hepatic impairment. Furthermore, CsA may interact with other commonly used medications, potentially affecting their metabolism and effects.

[0007] There remains an unmet medical need for safer and more effective therapies and treatment regimens for moderate to severe Alzheimer's disease (AD). There is also a need for therapeutic interventions and medication regimens that offer greater tolerability and convenience, as well as lower risks, thereby improving patient compliance and satisfaction. [Overview of the Initiative]

[0008] Provided herein are methods, uses, and pharmaceutical compositions of an anti-IL-13 antibody (e.g., levukizumab) for the treatment of atopic dermatitis. Also provided herein are drug regimens for methods and uses of an anti-IL-13 antibody (e.g., levukizumab) for the treatment of atopic dermatitis. The methods and drug regimens provided herein have one or more advantages: optimized and improved dosing frequency that enables higher patient compliance and higher patient satisfaction while maintaining the desired efficacy, a lower risk of injection site reactions, and / or lower manufacturing costs.

[0009] In one embodiment, the foregoing provides a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks) every four weeks. In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0010] In some embodiments, what is provided herein is a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, the method comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4–16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2–14, and then administering 250 mg of the anti-IL-13 antibody to the patient every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0011] Furthermore, provided herein is a method for treating moderate to severe atopic dermatitis in patients requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein during the induction period (or first period), the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14, and the patient undergoes the induction period (or first period) The method comprises determining whether the patient is a responder to the anti-IL-13 antibody after an induction period, and if the patient is a responder, administering the patient 250 mg of the anti-IL-13 antibody every two weeks, every four weeks, or every eight weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks), and if the patient is not a responder, administering the patient 250 mg of the anti-IL-13 antibody every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. Whether a patient is a responder to anti-IL-13 antibodies can be determined by assessing the patient's skin clearance, skin improvement, and / or improvement in itching, sleep, or quality of life. For example, skin clearance and skin improvement can be measured by the Investigator Global Assessment (IGA) or the Eczema Area and Severity Index (EASI) score.Itching, sleep loss, and quality of life can be measured using the Pruritus Numerical Rating Scale (NRS), sleep loss score, and the DLQI (Dermatology Life Quality Index) or CDLQI (Children's Dermatology Life Quality Index) scales, respectively. In some embodiments, a patient is a responder if their EASI score, determined after the induction period (or first period), is 75% or greater compared to their baseline EASI score. In some embodiments, a patient is a responder if their IGA score is 0 or 1 after the induction period (or first period). In some embodiments, a patient is a responder if their IGA score is 0 or 1 after the induction period (or first period) and their IGA score, determined after the induction period (or first period), is 2 points or greater compared to their baseline IGA score. In some embodiments, if the patient is a responder, the anti-IL-13 antibody is administered at a dose of 250 mg once every four weeks over the maintenance period (or second period). In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0012] In some embodiments, the foregoing provides a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, comprising administering an anti-IL-13 antibody to the patient over a first period of 4 to 16 weeks, wherein during the first period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, and further comprising administering 250 mg of the anti-IL-13 antibody to the patient over a second period of 8 to 36 weeks, where the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6.

[0013] In some embodiments, provided herein is a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, comprising administering an anti-IL-13 antibody to the patient over a first period of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at baseline (week 0) and week 2 at 500 mg, and thereafter at 250 mg every two weeks for 2 to 14 weeks, and determining whether the patient is a responder to the anti-IL-13 antibody after the first period, and if the patient is a responder, a second period of 8 to 36 weeks The method comprises administering an anti-IL-13 antibody to the patient at a dose of 250 mg once every 4 weeks or once every 8 weeks over a period of time, and, if the patient is not a responder, administering an anti-IL-13 antibody to the patient at a dose of 250 mg once every 2 weeks over a second period of 8 to 36 weeks, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and VL comprising LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6.

[0014] In some embodiments, the patient has moderate to severe atopic dermatitis for at least one year at baseline. Moderate to severe atopic dermatitis can be determined by criteria known in the art, for example, the American Academy of Dermatology Consensus Criteria for Chronic Atopic Dermatitis. In some embodiments, the patient has an EASI score of 16 or higher, an IGA score of 3 or higher, and more than 10% of body surface area (BSA) affected by atopic dermatitis at baseline. In some embodiments, the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or crisabolol, or topical corticosteroids, topical calcineurin inhibitors, or crisabolol are not medically recommended for the patient. In some embodiments, the patient is 12 years of age or older.

[0015] In some embodiments, the methods described herein further include determining one or more of the following patient characteristics at baseline and during and after the induction period (or first period): EASI score, IGA score, percentage of BSAs affected by atopic dermatitis, pruritus NRS score, SCORAD (Scoring of Atopic Dermatitis) score, sleep loss score, POEM (Patient-Oriented Eczema Measure) total score, DLQI (Dermatological Quality of Life Index) or CDLQI (Careful Developmental Dermatological Quality of Life Index) score, EQ-5D (European Quality of Life-5 Dimension), ACQ-5 (Asthma Control Questionnaire), PROMIS (Patient-Reported Outcomes Measurement Information System) anxiety and depressive symptoms.

[0016] In some embodiments, the methods described herein further include determining one or more of the following patient characteristics during and after the maintenance period (or second period): EASI score, IGA score, percentage of BSA affected by atopic dermatitis, pruritus NRS score, SCORAD score, sleep loss score, POEM total score, DLQI or CDLQI score, EQ-5D, ACQ-5, PROMIS anxiety, and depressive symptoms.

[0017] In another embodiment, the foregoing provides a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient in a loading dose of 500 mg at baseline (week 0) and week 2, and a subsequent dose of 250 mg every two weeks thereafter. In some embodiments, the anti-IL-13 antibody is administered to the subject over a period of 4 to 52 weeks. In some embodiments, the anti-IL-13 antibody is administered to the subject over a period of 4 to 16 weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment is reduced by 2 points or more compared to the patient's sleep score at baseline.

[0018] Also provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of 8 to 36 weeks, at a dose every two weeks, every four weeks, or every eight weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment is reduced by 2 points or more compared to the patient's sleep score at baseline.

[0019] Furthermore, provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes determining whether the patient is a responder to the anti-IL-13 antibody after an induction period (or first period), administering the patient 250 mg of the anti-IL-13 antibody every two weeks, every four weeks, or every eight weeks for a maintenance period of 8 to 36 weeks (or second period) if the patient is a responder, and administering the patient 250 mg of the anti-IL-13 antibody every two weeks for a maintenance period of 8 to 36 weeks (or second period) if the patient is not a responder. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment decreases by 2 points or more compared to the patient's sleep score at baseline.

[0020] In some embodiments, the methods described herein further include determining one or more of the following patient characteristics: EASI score, IGA score, percentage of BSA affected by atopic dermatitis, pruritus NRS score, SCORAD score, sleep loss score, POEM total score, DLQI or CDLQI score, EQ-5D, ACQ-5, PROMIS anxiety, and depressive symptoms.

[0021] In some embodiments, the anti-IL-13 antibody binds to IL-13 with high affinity and blocks signaling via the active IL-4R alpha / IL-13R alpha 1 heterodimer. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises a VH containing SEQ ID NO: 7 and a VL containing SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody is lebrikizumab.

[0022] In another embodiment, the foregoing provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in the treatment of moderate to severe atopic dermatitis in a patient.

[0023] In another embodiment, provided herein is a pharmaceutical composition comprising an anti-IL-13 antibody or an anti-IL-13 antibody for use in a method for reducing sleep loss in patients with moderate to severe atopic dermatitis. In another embodiment, provided herein is a pharmaceutical composition comprising an anti-IL-13 antibody or an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis.

[0024] In some embodiments, provided herein is an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, and the anti-IL-13 antibody or the pharmaceutical composition is for administration at a loading dose of 500 mg at baseline (week 0) and week 2, followed by a subsequent dose of 250 mg once every two weeks.

[0025] In some embodiments, provided herein is an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, the VL comprises LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, the anti-IL-13 antibody or the pharmaceutical composition is for administration over an induction period of 4 to 16 weeks (or a first period), during the induction period (or the first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, followed by 250 mg once every two weeks for 2 to 14 weeks, and the anti-IL-13 antibody is for administration at 250 mg once every four weeks over a maintenance period of 8 to 36 weeks (or a second period).

[0026] In another aspect, provided herein is the use of an anti-IL-13 antibody in the manufacture of a medicament for the treatment of moderate to severe atopic dermatitis in a patient. Also provided herein is the use of an anti-IL-13 antibody in the manufacture of a medicament for reducing sleep loss in patients with moderate to severe atopic dermatitis.

[0027] In some embodiments, the methods, uses, and pharmaceutical compositions described herein further comprise administering one or more topical corticosteroids to the patient. In some embodiments, the topical corticosteroid is triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone. In some embodiments, the topical corticosteroid is administered concurrently with the anti-IL-13 antibody. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] [Figure 1] It is a schematic diagram of the phase 3 study design described in Example 1. [Figure 2A] It shows baseline demographics of participants in ADvocate 1. [Figure 2B] It shows baseline demographics of participants in ADvocate 1. [Figure 2C] It shows baseline disease characteristics of participants in ADvocate 1. AD=atopic dermatitis, ITT=Intent-to-Treat, LEB=lebrikizumab, Q2W=every 2 weeks, PBO=placebo, SD=Standard Deviation, BMI=Body-Mass Index, BSA=body surface area, DLQI=Dermatology Life Quality Index, EASI=Eczema Area and Severity Index, IGA=Investigator's Global Assessment, IQR (Interquartile Range)=interquartile range, NRS=numeric rating scale, POEM=Patient-Oriented Eczema Measure, SCORAD=Scoring Atopic Dermatitis. [Figure 3A] It provides a summary of adverse events up to week 16 in ADvocate 1. [Figure 3B] It shows serious adverse events up to week 16 in ADvocate 1. [Figure 3C] It shows TEAEs within special safety topics up to week 16 in ADvocate 1. [Figure 3D]This shows injection site reactions up to week 16 in ADvocate 1. AE = Adverse Event, LEB = Lebrikizumab, Q2W = Every 2 weeks, PBO = Placebo, TEAE = Treatment-Emergent Adverse Event. [Figure 4A] This section outlines the achievement of key efficacy endpoints in ADvocate 1. [Figure 4B] This shows the IGA response rate at week 16 in ADvocate 1, which measures the percentage of IGA (0, 1) that improved by ≥2 points from baseline at week 16. [Figure 4C] This shows the EASI-75 response rate at week 16 in ADvocate 1. [Figure 4D] This shows the time-dependent IGA response rate up to week 16 in ADvocate 1. [Figure 4E] This shows the EASI-75 response rate over time up to week 16 in ADvocate 1. [Figure 4F] This shows the EASI-90 response rate over time up to week 16 in ADvocate 1. [Figure 4G] This shows the percentage change from baseline in EASI over time up to week 16 in ADvocate 1. [Figure 5A] ADvocate 1 shows a temporal improvement of ≥4 points in pruritus NRS from baseline up to week 16. [Figure 5B] This shows the percentage change from baseline in pruritus NRS over time up to week 16 in ADvocate 1. [Figure 5C] ADvocate 1 shows a longitudinal improvement of ≥2 points in the sleep loss score from baseline up to week 16. [Figure 5D] This shows the change from baseline in sleep loss scores over time up to week 16 in ADvocate 1. [Figure 5E] This shows a longitudinal improvement of ≥4 points in DLQI from baseline up to week 16. [Figure 5F] This shows the temporal change from baseline in DLQI up to week 16 in ADvocate 1. [Figure 6A] This shows the IGA response rates at week 52 in ADvocate 1(6A) and ADvocate 2(6B), which measure the percentage of patients who achieved IGA(0,1). [Figure 6B] This shows the IGA response rates at week 52 in ADvocate 1(6A) and ADvocate 2(6B), which measure the percentage of patients who achieved IGA(0,1). [Figure 6C] This shows the EASI-75 response rate at week 52 in ADvocate 1(6C) and ADvocate 2(6D), which measures the percentage of patients who achieved EASI-75. [Figure 6D] This shows the EASI-75 response rate at week 52 in ADvocate 1(6C) and ADvocate 2(6D), which measures the percentage of patients who achieved EASI-75. [Figure 6E] This shows the pruritus response rate at week 52 in ADvocate 1(6E) and ADvocate 2(6F), which measures the percentage of patients who had a pruritus NRS ≥ 4 at baseline and achieved an improvement of ≥ 4 points. [Figure 6F] This shows the pruritus response rate at week 52 in ADvocate 1(6E) and ADvocate 2(6F), which measures the percentage of patients who had a pruritus NRS ≥ 4 at baseline and achieved an improvement of ≥ 4 points. [Figure 7] This section summarizes the adverse events observed in ADvocate 1 and ADvocate 2 from week 16 to week 52. [Figure 8A] This is a graph of the final PK-PD model in Example 2. [Figure 8B] The estimated model parameters for the final PK-PD model are shown. [Figure 9]This chart shows simulated EASI-75 response rates for week 16 responders who transitioned to various maintenance medication regimens between weeks 16 and 52. The line represents the median across 500 simulations. [Figure 10] This chart shows simulated EASI-75 response rates for responders at week 16 who transitioned to the lebrikizumab 250 mg Q4W or 250 mg Q8W maintenance regimen between weeks 16 and 52. The line represents the median over 500 simulations, and the shaded area represents the 95% confidence interval. [Figure 11] This graph shows simulated EASI-90 response rates for week 16 responders who transitioned to various medication regimens between weeks 16 and 52. The line represents the median across 500 simulations. [Figure 12] This chart shows simulated EASI-90 response rates for responders at week 16 who transitioned to the lebrikizumab 250 mg Q4W or 250 mg Q8W maintenance regimen between weeks 16 and 52. The line represents the median over 500 simulations, and the shaded area represents the 95% confidence interval. [Modes for carrying out the invention]

[0029] Provided herein are methods, uses, and pharmaceutical compositions of anti-IL-13 antibodies for the treatment of atopic dermatitis. Also provided herein are dosing regimens for methods and uses of anti-IL-13 antibodies for the treatment of atopic dermatitis. The methods and dosing regimens provided herein have one or more of the following advantages: optimized and / or improved dosing frequency that enables higher patient compliance and higher patient satisfaction while maintaining the desired efficacy, a lower risk of injection site reactions, and lower manufacturing costs.

[0030] In one embodiment, the foregoing provides a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks over weeks 2 to 14 weeks, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks) every four weeks. In some embodiments, the induction period (or first period) is 16 weeks. During the 16-week induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0031] In one embodiment, the foregoing provides a method for treating moderate to severe atopic dermatitis in a patient requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks over weeks 2 to 14 weeks, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks) once every eight weeks. In some embodiments, the induction period (or first period) is 16 weeks. During the 16-week induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0032] In some embodiments, provided herein are methods for treating moderate to severe atopic dermatitis in patients requiring treatment, the methods comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4–16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks over weeks 2–14 weeks, and then administering 250 mg of the anti-IL-13 antibody to the patient every two weeks over a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks). In some embodiments, the induction period (or first period) is 16 weeks, during which the anti-IL-13 antibody is administered at baseline (week 0) and week 2 at 500 mg, and then at 250 mg every two weeks for the following 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0033] Furthermore, provided herein is a method for treating moderate to severe atopic dermatitis in patients requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14, and the patient undergoes an induction period (or The method comprises determining whether the patient is a responder to the anti-IL-13 antibody after a first period, administering the patient 250 mg of the anti-IL-13 antibody every two weeks or every four weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks), and administering the patient 250 mg of the anti-IL-13 antibody every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0034] Furthermore, provided herein is a method for treating moderate to severe atopic dermatitis in patients requiring treatment, comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14, and the patient undergoes an induction period (or The method comprises determining whether the patient is a responder to the anti-IL-13 antibody after a first period, administering the patient 250 mg of the anti-IL-13 antibody every two weeks or every eight weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks), and administering the patient 250 mg of the anti-IL-13 antibody every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8–36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0035] Whether a patient is a responder to anti-IL-13 antibodies can be determined by assessing the patient's skin clearance, skin improvement, and / or improvement in itching, sleep, or quality of life. For example, skin clearance and skin improvement can be measured by the IGA or EASI score. Itching, sleep loss, and quality of life can be measured by the pruritus NRS, sleep loss score, and DLQI or CDLQI scale, respectively. In some embodiments, a patient is a responder if their EASI score, determined after the induction period (or first period), is 75% or greater compared to their baseline EASI score. In some embodiments, a patient is a responder if their IGA score is 0 or 1 after the induction period (or first period). In some embodiments, a patient is a responder if their IGA score is 0 or 1 after the induction period (or first period) and their IGA score, determined after the induction period (or first period), is 2 points or greater compared to their baseline IGA score. In some embodiments, if the patient is a responder, the anti-IL-13 antibody is administered at a dose of 250 mg once every four weeks over the maintenance period (or second period). In some embodiments, if the patient is a responder, the anti-IL-13 antibody is administered at a dose of 250 mg once every eight weeks over the maintenance period (or second period).

[0036] In another embodiment, the foregoing provides a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient in a loading dose of 500 mg at baseline (week 0) and week 2, and then in a subsequent dose of 250 mg every two weeks thereafter. In some embodiments, the anti-IL-13 antibody is administered to the patient over a period of 4 to 52 weeks (e.g., about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, or about 52 weeks). In some embodiments, the anti-IL-13 antibody is administered to the patient over a period of 4 to 16 weeks (e.g., approximately 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and 16 weeks). In some embodiments, sleep loss is determined by the patient's sleep loss score, as described herein, for example. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment is reduced by 2 points or more compared to the patient's baseline sleep score.

[0037] Also provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of 8 to 36 weeks, every two weeks or every four weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment is reduced by 2 points or more compared to the patient's sleep score at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which the anti-IL-13 antibody is administered at baseline (week 0) and week 2 at 500 mg, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0038] Also provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody (e.g., levukizumab) to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, and then administering 250 mg of the anti-IL-13 antibody to the patient over a maintenance period (or second period) of 8 to 36 weeks, once every eight weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment is reduced by 2 points or more compared to the patient's sleep score at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which the anti-IL-13 antibody is administered at baseline (week 0) and week 2 at 500 mg, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0039] Also provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, the method comprising determining whether the patient is a responder to the anti-IL-13 antibody after the induction period (or first period), and if the patient is a responder, administering the patient 250 mg of the anti-IL-13 antibody every two weeks or every four weeks over a maintenance period (or second period) of 8 to 36 weeks, and if the patient is not a responder, administering the patient 250 mg of the anti-IL-13 antibody every two weeks over a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment decreases by 2 points or more compared to the patient's sleep score at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0040] Also provided herein is a method for reducing sleep loss in patients with moderate to severe atopic dermatitis, the method comprising administering an anti-IL-13 antibody to the patient over an induction period (or first period) of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14, the method comprising determining whether the patient is a responder to the anti-IL-13 antibody after the induction period (or first period), and if the patient is a responder, administering the patient 250 mg of the anti-IL-13 antibody every eight weeks over a maintenance period (or second period) of 8 to 36 weeks, or if the patient is not a responder, administering the patient 250 mg of the anti-IL-13 antibody every two weeks over a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, sleep loss is determined by the patient's sleep loss score. In some embodiments, the patient's sleep loss score after anti-IL-13 antibody treatment decreases by 2 points or more compared to the patient's sleep score at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which the anti-IL-13 antibody is administered at 500 mg at baseline (week 0) and week 2, and then at 250 mg every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient.

[0041] In some embodiments, the patient has moderate to severe atopic dermatitis for at least one year at baseline. In some embodiments, the patient has an EASI score of 16 or higher, an IGA score of 3 or higher, and more than 10% BSA with atopic dermatitis at baseline. In some embodiments, the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or crisabolol, or topical corticosteroids, topical calcineurin inhibitors, or crisabolol are not medically recommended for the patient. In some embodiments, the patient is 12 years of age or older. In some embodiments, the patient is 18 years of age or older.

[0042] In some embodiments, moderate to severe atopic dermatitis can be determined by criteria known in the art, such as the Hanifin and Rajka criteria (Acta Derm Venereol (Stockh) 1980; Suppl 92:44-7), the Rajka and Langeland criteria (Rajka G and Langeland T, Acta Derm Venereol (Stockh) 1989; 144 (Suppl): 13-4), or the American Academy of Dermatology Consensus Criteria for Chronic Atopic Dermatitis (Eichenfield LF, et al. J Am Acad Dermatol. 2014; 70(2): 338-351). In some embodiments, moderate to severe atopic dermatitis can be determined by the American Academy of Dermatology Consensus Criteria for Chronic Atopic Dermatitis. Under these criteria, essential features of atopic dermatitis include: pruritus, eczema (acute, subacute, chronic), typical morphology and age-specific pattern, and chronic or recurrent history. Typical morphology and age-specific pattern includes: involvement of the face, neck, and extensor muscles in infants and children, current or previous flexion lesions in any age group, and preservation of the groin and axillary regions. Other important features that support the diagnosis include: juvenile onset, atopy, personal and / or family history, immunoglobulin E reactivity, and xerosis. Related features that may be helpful in suggesting a diagnosis of atopic dermatitis but are not specific to be used to define or detect atopic dermatitis for research and epidemiological studies include: atypical vascular response (e.g., pallor, white skin depiction, delayed white response), keratosis pilaris / pityriasis leukorrhea / hyperlinear palmar / ichthyosis, periorbital / perifollicular changes, and perifollicular intensification / lichenification / pruritic lesions. In some cases, skin biopsy specimens or other tests (such as serum immunoglobulin E, potassium hydroxide preparations, patch tests, and / or genetic tests) may be useful in ruling out other or related skin conditions.Exclusion criteria include: scabies, seborrheic dermatitis, contact dermatitis (irritant or allergic), ichthyosis, cutaneous T-cell lymphoma, psoriasis, photosensitive dermatitis, immunodeficiency disorders, and erythroderma of other causes.

[0043] Suitable anti-IL-13 antibodies for use in the methods and uses provided herein have been previously described, for example, in International Publication No. 2005062967. In some embodiments, the anti-IL-13 antibody binds to IL-13 with high affinity and blocks signaling via the active IL-4R alpha / IL-13R alpha 1 heterodimer. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH containing SEQ ID NO: 7 and VL containing SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody is lebrikizumab. Table 1 provides the amino acid sequence of lebrikizumab. C-terminal clipping of IgG antibodies can occur when one or two C-terminal amino acids are removed from the heavy chain of the IgG antibody. For example, if C-terminal lysine (K) is present, it may be truncated or cleaved from the heavy chain. The second-to-last glycine (G) may similarly be truncated or cleaved from the heavy chain. Modification of the N-terminal amino acids of IgG can also occur. For example, N-terminal glutamine (Q) or glutamic acid (E) can spontaneously cyclize to pyroglutamic acid (pE). Sequence ID 9 reflects these potential modifications of the lebrikizumab heavy chain.

[0044] Table 1. Lebrikizumab sequences [Table 1]

[0045] Anti-IL-13 antibodies, such as lebrikizumab, can be formulated with suitable carriers or excipients into pharmaceutical compositions suitable for administration to patients. For example, anti-IL-13 antibodies, such as lebrikizumab, can be formulated in pharmaceutical compositions such as those described in International Publication No. 2013 / 066866. The pharmaceutical composition may contain 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg or 500 mg of anti-IL-13 antibody. In some embodiments, the concentration of anti-IL-13 antibody in the pharmaceutical composition is 100 mg / mL to 150 mg / mL, for example, 125 mg / mL. The pharmaceutical composition may also contain 5 mM to 40 mM histidine acetate buffer, pH 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., sugar) having a concentration of 100 mM to 200 mM, and / or a surfactant (e.g., polysorbate 20) having a concentration of 0.01% to 0.1%. In one embodiment, the pharmaceutical composition comprises 125 mg / mL of anti-IL-13 antibody (e.g., levukizumab), 20 mM histidine acetate buffer, pH 5.7, 175 mM sucrose, and 0.03% polysorbate 20.

[0046] In some embodiments, the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is administered subcutaneously to the patient. In some embodiments, the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks. In some embodiments, the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is administered to the patient at a dose of 250 mg once every two weeks or once every four weeks. In some embodiments, the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every two weeks. In some embodiments, the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every four weeks.

[0047] In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to a patient using a subcutaneous administration device. The subcutaneous administration device can be selected from pre-filled syringes, disposable pen-type injectors, microneedle devices, micro-injection devices, needle-free injectors, or automated injectors. Various subcutaneous administration devices, including automated injectors, are known and commercially available in the art. Examples of devices include, but are not limited to, pre-filled syringes (e.g., BD HYPAK SCF®, READYFILL®, and STERIFILL SCF® from Becton Dickinson, CLEARSHOT® copolymer-filled syringes from Baxter, and Daikyo Seiko CRYSTAL ZENITH® pre-filled syringes available from West Pharmaceutical Services), disposable pen-type injection devices such as the BD Pen from Becton Dickinson, ultra-sharp and microneedle devices (e.g., INJECT-EASE® and micro-injection devices from Becton Dickinson, and H-PATCH® available from Valeritas), and needle-free injection devices (e.g., BIOJECTOR® and IJECT® available from Bioject, and SOF-SERTER® and patch devices available from Medtronic). In some embodiments, the subcutaneous administration device is an automated injection device described in International Publication No. 2008 / 112472, International Publication No. 2011 / 109205, International Publication No. 2014 / 062488, and / or International Publication No. 2016 / 089864.

[0048] In some embodiments, patients may be treated with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for a period of up to 52 weeks, for example, about 4 to 52 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, or about 52 weeks.

[0049] In some embodiments, the patient is treated with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody over an induction period (or first period) of up to 16 weeks (e.g., about 4–16 weeks, about 6–16 weeks, about 8–16 weeks, about 10–16 weeks, about 12–16 weeks, about 4–12 weeks, about 6–12 weeks, about 8–12 weeks, about 4–8 weeks, about 4–10 weeks, about 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks). During the induction period (or first period), the anti-IL-13 antibody is administered as a loading dose of 500 mg at baseline (week 0) and week 2, and then as a subsequent dose of 250 mg every two weeks for 2–14 weeks (e.g., approximately 4–14 weeks, 6–14 weeks, 8–14 weeks, 10–14 weeks, 12–14 weeks, 4–12 weeks, 6–12 weeks, 8–12 weeks, 10–12 weeks, 4–6 weeks, 4–8 weeks, 4–10 weeks, 6–10 weeks, 8–10 weeks, approximately 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks). In some embodiments, the induction period (or first period) is 4–16 weeks. In some embodiments, the induction period (or first period) is 16 weeks. In this embodiment, during the induction period (or first period), the anti-IL-13 antibody is administered as a loading dose of 500 mg at baseline (week 0) and week 2, followed by a subsequent dose of 250 mg every two weeks for 14 weeks.

[0050] Before, during, and after treatment with anti-IL-13 antibodies, patients may evaluate one or more features of the Atopic Dermatitis Disease Severity Measures (ADDSM) to determine specific signs, symptoms, characteristics, or parameters associated with atopic dermatitis that can be assessed quantitatively or qualitatively. Examples of ADDSM include, but are not limited to, the Eczema Area and Severity Index (EASI), Investigator's Comprehensive Assessment (IGA), Body Surface Area (BSA), Scoring for Atopic Dermatitis (SCORAD), Numerical Rating Scale for Pruritus (NRS), Sleep Loss Scale, Skin Pain NRS Score, Patient-Directed Eczema Scale (POEM) Total Score, Dermatology Quality of Life Index (DLQI) or Pediatric Dermatology Quality of Life Index (CDLQI), DLQI-Related (DLQI-R) Score, Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety and Depression Symptoms, EQ-5D (European Quality of Life 5-Dimensional), ACQ-5 (Asthma Control Questionnaire-5), World Health Organization-Five Well-Being Index (WHO-5) Score, Recap of Atopic Eczema (RECAP) Score, and Treatment Satisfaction Questionnaire for Medication-9 Examples include the TSQM-9 score. ADDSM can be measured at baseline and at one or more time points after administration of an anti-IL13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. The difference between the ADDSM value at a specific time point after the start of treatment and the ADDSM value at baseline is used to establish whether there has been an improvement (e.g., a decrease) in ADDSM.

[0051] In some embodiments, the methods and therapeutic uses described herein further include determining the following characteristics of a patient at baseline, during and after the induction period (or first period): EASI score, IGA score, percentage of BSA affected by atopic dermatitis, pruritus NRS score, SCORAD score, sleep loss score, POEM total score, DLQI or CDLQI score, EQ-5D, ACQ-5, PROMIS anxiety, and depressive symptoms.

[0052] In some embodiments, the patient's EASI score is determined after an induction period (or first period). In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 50% or more compared to the patient's baseline EASI score, meaning the patient has achieved "EASI-50". In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 75% or more compared to the patient's baseline EASI score, meaning the patient has achieved "EASI-75". In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 90% or more compared to the patient's baseline EASI score, meaning the patient has achieved "EASI-90". If a patient reaches EASI-75 after the induction period (or first period), the patient is considered a responder to the anti-IL13 antibody.

[0053] In some embodiments, the patient's IGA score is determined after an induction period (or first period). A patient is considered a responder to anti-IL13 antibodies if their IGA score after the induction period (or first period) is 0 or 1. In some embodiments, a patient is considered a responder to anti-IL13 antibodies if their IGA score is 0 or 1 after the induction period (or first period) and the patient's IGA score after the induction period (or first period) is 2 points or more lower than the patient's IGA score determined at baseline.

[0054] After the induction period (or first period) is completed, the patient enters the maintenance period (or second period). During the maintenance period (or second period), the patient is further treated with a pharmaceutical composition containing an anti-IL13 antibody or anti-IL-13 antibody. The medication regimen for the maintenance period (or second period) may be selected based on the patient's ADDSM assessment and response to IL-13 antibodies after the induction period (or first period), e.g., the patient's IGA or EASI score after the induction period (or first period), and / or the patient's own characteristics, e.g., weight, age, race.

[0055] The maintenance period (or second period) is a maximum of 36 weeks (for example, approximately 4-36 weeks, 8-36 weeks, 12-36 weeks, 16-36 weeks, 20-36 weeks, 24-36 weeks, 28-36 weeks, 4-32 weeks, 8-32 weeks, 12-32 weeks, 16-32 weeks, 20-32 weeks, 24-32 weeks, 28-32 weeks, 4-24 weeks, 8-24 weeks). The interval can be approximately 12-24 weeks, 16-24 weeks, 20-24 weeks, 4-20 weeks, 8-20 weeks, 12-20 weeks, 16-20 weeks, 4-16 weeks, 8-16 weeks, 12-16 weeks, 4-12 weeks, 8-12 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, or 36 weeks. In some embodiments, the maintenance period (or second period) is 8-36 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks.

[0056] In some embodiments, the methods and therapeutic uses described herein further include determining one or more of the following characteristics of the patient during and after the maintenance period (or second period): EASI score, IGA score, percentage of BSA affected by atopic dermatitis, pruritus NRS score, SCORAD score, sleep loss score, POEM total score, DLQI or CDLQI score, EQ-5D, ACQ-5, PROMIS anxiety, and depressive symptoms. Similarly, the patient's EASI score can be assessed during and after the maintenance period (or second period) to determine whether the patient has reached EASI-50, EASI-75, or EASI-90. The patient's IGA score can also be assessed during and after the maintenance period (or second period) to determine whether the patient's IGA score is 0 or 1, and whether the patient's IGA score has decreased by 2 points or more.

[0057] The Investigator's Comprehensive Assessment (IGA), or Investigator's Assessment (IGA), is a globally used assessment scale for evaluating the severity of a patient's Alzheimer's disease (AD) (Simpson E, et al. J Am Acad Dermatol. 2020;;83(3):839-846). It is based on a 5-point scale ranging from 0 (no abnormality) to 4 (severe), with scores selected using descriptors that best describe the overall appearance of the lesion at a given time (see Table 2). Not all characteristics under the morphological description need to be present. The IGA can be performed before the EASI and BSA assessments.

[0058] Table 2. Investigator's Comprehensive Assessment (IGA) [Table 2]

[0059] The Eczema Area and Severity Index, or EASI, is a scale used in clinical settings to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al., Exp Dermatol. 2001;10:11-18). The EASI is a composite index with a score ranging from 0 to 72, where higher values ​​indicate a more severe and / or widespread disease. The severity of erythema, induration / papulogenesis, abrasions, and lichenification can be assessed by a clinician or other healthcare professional on a scale of 0 (none) to 3 (severe) for each of the four body regions: head and neck, torso, upper extremities, and lower extremities, with half a score being acceptable. Furthermore, the degree of AD involvement in each of the four body regions can be assessed as a percentage of the body surface area of ​​the head, torso, upper extremities, and lower extremities, which can be converted to a score of 0 to 6. The total score (0 to 72) is assigned based on the total score for each of the four body region scores.

[0060] Body surface area (BSA) assessment estimates the degree of disease or skin involvement in Alzheimer's disease (AD) and is expressed as a percentage of total body surface area. BSA is determined by a clinician or other healthcare professional using the patient's palm and is approximately 1% BSA.

[0061] The "Atopic Dermatitis Scoring" or "SCORAD" is an effective clinical tool for assessing the degree and severity of AD, developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31). There are three components to the assessment: (i) the degree of AD is assessed as a percentage of each defined body area and reported as the sum of all areas having a score ranging from 0 to 100 (assigned as "A" in the overall SCORAD calculation); and (ii) the severity of the six symptoms of AD is assessed as redness, swelling, exudation / crusting, abrasion, skin thickening / lichenification, and dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a total of up to 18 points, which are assigned as "B" in the entire SCORAD calculation), (iii) subjective assessments of itching and insomnia are recorded for each symptom using a visual analogue scale (VAS), where 0 is no itching (or insomnia) and 10 is the worst itching (or insomnia) imaginable, with a maximum possible score of 20 (assigned as "C" in the entire SCORAD calculation). The formula for the SCORAD index is A / 5 + 7B / 2 + C. The maximum score for the SCORAD index is 103.

[0062] The Numerical Rating Scale for Pruritus (NRS) is an 11-point scale used by patients (and, if applicable, with the help of a parent / caregiver if necessary) to assess the severity of their worst itching over the past 24 hours, where 0 indicates "no itching" and 10 indicates "worst imaginable itching" (Phan NQ, et al. Acta Derm Venereol 2012;92:502-507). Assessments are recorded daily by patients using an electronic diary. The baseline pruritus NRS is determined based on the mean of the daily pruritus NRS scores over the 7 days immediately preceding baseline. This calculation requires scores for at least 4 of those 7 days immediately preceding baseline.

[0063] The sleep loss scale assesses sleep loss due to itching using a 5-point Likert scale (scores ranging from 0 [none], 1 [slight], 2 [moderate], 3 [very slight] to 4 [unable to sleep at all]). Assessments are recorded daily by the patient using an electronic diary.

[0064] The Skin Pain NRS is an 11-point scale completed by the patient (and, if applicable, with the help of a parent / caregiver if necessary) to assess the severity of the patient's worst skin pain (e.g., discomfort or pain) over the past 24 hours, where 0 indicates "no pain" and 10 indicates "worst imaginable pain" (Newton L, et al. J Patient Rep Outcomes. 2019 Jul 16;3:42). Assessments are recorded by the patient daily using an electronic diary until week 16, and weekly thereafter. The baseline Skin Pain NRS is determined based on the mean of the daily Skin Pain NRS scores for the 7 days immediately preceding baseline. This calculation requires scores for at least 4 of the 7 days immediately preceding baseline.

[0065] The Patient-Oriented Eczema Measure (POEM) is a seven-item validated questionnaire completed by the patient (and, if applicable, with the help of a parent / caregiver if necessary) over a week to assess disease symptoms (Centre of Evidence Based Dermatology. POEM - Patient-Oriented Eczema Measure. Available at: https: / / www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx). Patients are asked to answer seven questions about dry skin, itching, peeling, cracking, sleep loss, bleeding, and tearing. All seven responses have equal weights with a total possible score of 0 to 28 (responses are scored as follows: no days = 0, 1-2 days = 1, 3-4 days = 2, 5-6 days = 3, daily = 4). Higher scores indicate poor quality of life. POEM responses are captured weekly using an electronic diary.

[0066] The Dermatological Quality of Life Index (DLQI) is a 10-item validated questionnaire completed by patients or caregivers and used to assess the impact of skin disease on a patient's quality of life (Finlay, AY and Khan, GK 1994. Clinical and Experimental Dermatology 1993 Sep 23;19:210-216). The 10 questions cover the following topics: symptoms over the past week, functional impairment, shopping and home care, clothing, social and leisure, sports, work or research, close relationships, sex, and treatment. Each question is scored from 0 to 3 ("none at all," "a little," "a lot," and "very much"), giving a total score ranging from 0 to 30. A higher score indicates a poorer quality of life.

[0067] For adolescents under 16 years of age, a different Pediatric DLQI (CDLQI) is used, which consists of a set of 10 questions, distinct from the DLQI (Lewis-Jones MS, Finlay AY. British Journal of Dermatology, 1995;132:942-949).

[0068] DLQI-Relevant (DLQI-R) is a recently developed scoring system that adjusts the total score of the DLQI questionnaire for the number of not relevant responses (NRRs) indicated by the patient (Rencz F, et al. Br J Dermatol. 2020;182(5):1167-1175).

[0069] The Patient-Reported Outcome Measurement Information System (PROMIS) is a people-centered set of scales for assessing and monitoring physical, mental, and social health in adults and children. The PROMIS® measures used in this study include short forms of anxiety and depression, which assess a patient's symptoms over the preceding week. Patients aged 17 years or younger will complete the pediatric version during the study period.

[0070] The PROMIS Anxiety Short Form v1.0-Anxiety 8a is a participant management questionnaire that assesses the following items in adults: self-reported phobias (fear, panic), anxious misery (worry, fear), hyperarousal (tension, nervousness, restlessness), and arousal-related physical symptoms (palpitations, dizziness) (PROMIS Anxiety 2019, published March 1, 2019. Accessed March 8, 2021. Available at: https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Anxiety_Scoring_Manual.pdf). Each question has five answer choices with a score ranging from 1 to 5. The total score ranges from 8 to 40, with higher scores indicating a higher level of anxiety. The adult self-report assesses anxiety over the "past 7 days".

[0071] The PROMIS Depression Short Form v1.0-Depression 8a is a participant management questionnaire that assesses the following items in adults: self-reported negative mood (sadness, guilt), self-perception (self-criticism, worthlessness), social cognition (isolation, social alienation), and decreased positive feelings and engagement (loss of interest, meaning, and purpose) (PROMIS Depression 2019, published February 28, 2019; accessed March 8, 2021; available at: https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Depression_Scoring_Manual.pdf). Physical symptoms (such as changes in appetite or sleep patterns) are not included. This helps to eliminate potential confounding effects of these items when assessing participants with comorbid physical conditions. Each question has five answer choices with scores ranging from 1 to 5. The total score ranges from 8 to 40, with higher scores indicating a higher level of depression. Adult self-report assessments depression over the past seven days.

[0072] The EQ-5D (European Quality of Life Five Dimensions) includes five dimensions: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. The EQ VAS records a patient's self-reported health on a vertical visual analog scale. The scores for these five dimensions can be presented as a health profile or converted into a single summary index number (usefulness) that reflects preferences compared to other health profiles. The EQ-5D is completed by patients in research clinics.

[0073] The European Quality of Life-5 Dimensions-5 Levels (EuroQol-5D-5L or EQ-5D-5L) is a participant-managed, five-question plus-one visual analog scale (VAS) standardized scale of health status in adults, providing a simple and general measure of health for clinical and economic assessment. EQ-5D-5L consists of two components: a respondent's health descriptive system and an assessment of the respondent's current health status using a VAS (20cm) ranging from 0 to 100mm. This descriptive system includes the following five dimensions: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, minor problem, moderate problem, serious problem, and extreme problem. Respondents are asked to indicate their health status by checking (or crossing) the box associated with the most appropriate statement for each of the five dimensions. Note that the numbers 1-5 do not have arithmetic properties and should not be used as ordinal scores. The EQ-5D-5L health status, as defined by the EQ-5D-5L descriptive system, can be converted into a single summary index by applying a formula that essentially adds a value (also called a weight) to each level in each dimension. The VAS records the respondent's self-reported health on a vertical VAS, with assessment items labeled “best imagined health status” and “worst imagined health status.” This information can be used as a quantitative measure of health outcomes (Herdman et al., Qual Life Res. 2011;20(10):1727-1736; EuroQol Group, EQ-5D-5L User Guide. Version 2.1. April 2015. Accessed January 14, 2021. Available at: https: / / euroqol.org / wp-content / uploads / 2016 / 09 / EQ-5D-5L_UserGuide_2015.pdf). Self-reported health status captured by EQ-5D-5L is related to the participant's status at completion. No attempts are made to recall health status in the preceding days or weeks (EuroQol Group 2015).

[0074] The ACQ-5 is an asthma control questionnaire. Patients who report comorbid asthma before enrollment will complete the ACQ-5 in addition to the outcomes reported by other patients in this trial. The ACQ-5 has been shown to reliably measure asthma control and distinguish patients with well-controlled asthma (score ≤ 0.75 points) from patients with uncontrolled asthma (score ≥ 1.5 points). It consists of five questions scored on a 7-point Likert scale over a one-week recall period. The total ACQ-5 score is the average score of all questions. A lower score indicates better asthma control. The ACQ-5 is completed by patients at the research clinic.

[0075] In another embodiment, the foregoing provides an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in the treatment of moderate to severe atopic dermatitis in a patient.

[0076] In another aspect, what is provided herein is the use of an anti-IL-13 antibody in the manufacture of a pharmaceutical product for the treatment of moderate to severe atopic dermatitis in a patient.

[0077] In some embodiments, the methods and uses described herein further include administering one or more topical corticosteroids to a patient. Examples of topical corticosteroids include, but are not limited to, triamcinolone acetonide, hydrocortisone, and combinations of triamcinolone acetonide and hydrocortisone. Triamcinolone acetonide is typically formulated at a concentration of 0.1% in a cream, and hydrocortisone is typically formulated at a concentration of 1% or 2.5% in a cream. Certain topical corticosteroids, such as betamethasone dipropionate, clobetasol propionate, diflorasone acetate, fluocinonide, and halobetazole propionate, are considered to be of very high potency. Certain topical corticosteroids, such as amcinonides, desoximethasone, halcinonide, and triamcinolone acetonide, are considered to be of high potency. For example, certain topical corticosteroids such as betamethasone valerate, crocoltron pivalate, fluocinolone acetonide, flurandrenolide, fluocinonide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and prednicarbate are considered to have moderate potency. For example, certain topical corticosteroids such as alclomethasone dipropionate, desonide, and hydrocortisone are considered to have low potency. TCS can be applied to the affected area once daily, twice daily, three times daily, or as needed. In some embodiments, patients are not adequately controlled by topical corticosteroids. In some embodiments, the topical corticosteroid is triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone. In some embodiments, the topical corticosteroid is administered simultaneously with or consecutively with an anti-IL-13 antibody. In some embodiments, topical corticosteroids are administered simultaneously with anti-IL-13 antibodies.

[0078] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both singular and plural forms, unless otherwise specified herein or unless the context clearly contradicts this.

[0079] When used herein, the term "approximately" means a figure that is sufficiently close to the stated figure, for example, within ±10% of the stated figure.

[0080] As used herein, the term “antibody” refers to an immunoglobulin molecule that binds to an antigen. Embodiments of an antibody include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugate antibodies. Antibodies may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0081] An exemplary antibody is an immunoglobulin G (IgG) type antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) crosslinked via interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of approximately 100 to 125 or more amino acids, primarily involved in antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region, primarily involved in effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

[0082] The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which contain scattered, more conserved regions called framework regions (FRs). CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen-binding specificity. Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Hereinafter, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain the majority of the residues that form specific interactions with the antigen.The assignment of amino acid residues to CDRs is attributed to Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics This can be done according to well-known schemes, including those described in the database (available at www.imgt.org, see Lefranc et al., Nucleic Acids Res. 1999;27:209-212).

[0083] Exemplary embodiments of the antibodies of this disclosure also include antibody fragments or antigen-binding fragments, which include at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as Fab, Fab', F(ab')2, Fv fragment, scFv, scFab, disulfide-linked Fv(sdFv), Fd fragment, and linear antibodies.

[0084] As used herein, the term “baseline” means before or at the time of administration of the first dose (week 0) of the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody. For example, the Atopic Dermatitis Disease Severity Scale (ADDSM) score before or at the time of administration of the first dose of the anti-IL-13 antibody or the pharmaceutical composition containing the anti-IL-13 antibody is considered the baseline value of that ADDSM.

[0085] As used herein, the term “to bind” is intended, unless otherwise specified, to mean the ability of a protein or molecule to form a chemical bond or an attractive interaction with another protein or molecule, resulting in proximity of two proteins or molecules as determined by common methods known in the art.

[0086] As used herein, the term “initial redness” refers to an increase in signs and / or symptoms that result in an increase in treatment, which may be due to an increase in dose, a switch to a higher potency class of drug, or the initiation of another drug.

[0087] The term "high affinity" as used herein means approximately 10 -8 Less than M, for example, 10 -15 M~10 -8 M, or 10 -12 M~10 -9 The equilibrium dissociation constant (K) of M D This refers to the binding strength of antibodies to human IL-13 that possess the characteristic (IQ).

[0088] The term "human IL-13" refers to human interleukin-13 (also known as P600), an immunomodulatory cytokine primarily produced by activated Th2 cells. Two known human IL-13 isoforms exist: isoform a and isoform b. As used herein, the term "human IL-13" refers collectively to all human IL-13 isoforms. The amino acid sequence of human IL-13 isoform a can be found at NCBI accession number NP_002179.2. The amino acid sequence of human IL-13 isoform b can be found at NCBI accession number NP_001341922.1.

[0089] As used herein, the term “inadequate response” refers to the failure to achieve good disease control of atopic dermatitis after using the treatment for the period recommended by the product prescription information (e.g., failure to achieve IGA ≤ 2 or EASI 75), or the occurrence of redness of atopic dermatitis during treatment.

[0090] As used herein, the terms "intolerance" or "intolerance" refer to unacceptable toxicity (e.g., elevated creatinine, elevated liver function test results, uncontrolled hypertension, paresthesia, headache, nausea, hirsutism), or the need for a dose or duration of the drug exceeding those specified in the prescribing information.

[0091] As used herein, the term "patient" refers to a human patient.

[0092] As used herein, the terms “topical corticosteroid” or “TCS” include topical corticosteroids of Group I, II, III, and IV. According to the World Health Organization’s Anatomical Therapeutic Chemical (ATC) 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 and hallucinonide. Group III TCS (potent) are 50 to 100 times potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent) is 2 to 25 times potent than hydrocortisone and includes, but is not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (weak or mild) includes hydrocortisone, prednisolone, and methylprednisolone.

[0093] As used herein, the terms “topical calcineurin inhibitor” or “TCI” include pimecrolimus, tacrolimus, and other inhibitors that suppress calcineurin activity and can be applied topically to the skin of a patient.

[0094] As used herein, “to treat,” “to treat,” or “to treat” means any process that can slow, control, delay, or halt the progression of a disorder or disease disclosed herein, or improve the symptoms of a disorder or disease, but does not necessarily mean the complete disappearance of all symptoms of the disorder or disease. Treatment includes the administration of proteins, nucleic acids, vectors, or compositions for the treatment of a patient, in particular a disease or condition in a human. [Examples]

[0095] Example 1. Two randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of leburikizumab in patients with moderate to severe atopic dermatitis. Two identical phase 3 randomized, double-blind, placebo-controlled, parallel-group studies were conducted to evaluate the safety and efficacy of lebrikizumab as monotherapy for moderate to severe atopic dermatitis (ADvocate 1 and ADvocate 2, i.e., NCT04146363 and NCT04178967). Each trial had a duration of 52 weeks, including a 16-week induction period (or period 1) and a 36-week maintenance period (or period 2).

[0096] Patient population Eligible adult and adolescent (12 to under 18 years old, weight ≥ 40 kg) patients with moderate to severe atopic dermatitis for at least one year, as defined by the American Academy of Dermatology Consensus Criteria, an Eczema Area and Severity Index score (EASI) of ≥ 16, an Investigator's Comprehensive Assessment (IGA) score of ≥ 3, and a Body Surface Area (BSA) of ≥ 10%.

[0097] Inclusion Criteria: Patients must meet all of the following criteria to be eligible to participate in the study: 1. Adults and young people (ages 12 to under 18, weighing 40 kg or more). 2. Chronic AD (according to the American Academy of Dermatology Consensus Criteria for Chronic Atopic Dermatitis) that has been present for more than one year prior to the screening visit. 3. Eczema area and severity index (EASI) score ≥ 16 at baseline visit. 4. Investigator's Comprehensive Assessment (IGA) score at baseline visit ≥ 3 (on a scale of 0-4). 5. Body surface area (BSA) of patients with concomitant atopic dermatitis (AD) at baseline visit ≥ 10%. 6. Determine that there is a history of inadequate response to topical medication, or that topical treatment is otherwise not medically recommended. 7. Before baseline visit, apply a stable dose of a non-medicinal topical moisturizer at least twice daily for ≥7 days. 8. Completed an electronic diary recording itching and sleep loss for at least four days during the seven days prior to randomization. 9. I am willing and able to follow all clinic visit and research-related procedures and questionnaires. 10. Women of childbearing potential agree to remain abstinent or use highly effective contraception during the treatment period and for at least 18 weeks after the last dose of lebrikizumab or placebo. 11. Male patients who are sexually active with women of potential pregnancy must agree to use an effective barrier method of contraception during the study and for at least 18 weeks after the last dose of the study drug. 12. Provide signed informed consent / agreement.

[0098] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. Previous participation in a leburikizumab clinical study. 2. A history of anaphylaxis as defined by the Sampson criteria (Sampson et al., J Allergy Clin Immunol. 2006;117(2):391-397). 3. Treatment with topical corticosteroids, calcineurin inhibitors, or phosphodiesterase-4 inhibitors, such as crisabolol, within one week prior to baseline visit. 4. Prior treatment with dupilumab or tralokinumab. 5. Treatment with any of the following medications within 4 weeks prior to baseline visit: a. Immunosuppressants / immunomodulators (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, methotrexate), b. Phototherapy and photochemotherapy (PUVA) for Alzheimer's disease (AD). 6. The following treatments performed before baseline visit a. The longer of the following two periods: within 8 weeks or within 5 half-lives (if known). b. B-cell depletion biological agents containing rituximab within the last 6 months. c.5 Another biological agent with a half-life (if known) or within 16 weeks, whichever is longer. 7. Use of prescribed moisturizer within 7 days of baseline visit. 8. Regular use of tanning booths / halls within 4 weeks of a screening visit (more than 2 visits per week). 9. Treatment with a planned live (attenuated) vaccine within 12 weeks of baseline visit or during the study. 10. Uncontrolled chronic conditions that may require a burst of oral corticosteroids, e.g., comorbid severe uncontrolled asthma (defined by an ACQ-5 score of ≥1.5, or a history of ≥2 asthma exacerbations within the past 12 months requiring systemic [oral and / or parenteral] corticosteroid treatment or hospitalization for >24 hours). 11. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, anthelmintics, antiparasitic agents, or antifungals within two weeks prior to baseline visit, or superficial skin infection within one week prior to baseline visit. 12. Evidence of active acute or chronic hepatitis (as defined by the Department of Health & Human Services Centers for Disease Control and Prevention) or known cirrhosis. 13. A diagnosed active endoparasitic infection or a high risk of such infection. 14. A known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, pneumocystisosis, and aspergillosis), despite the resolution of the infection, or an unusually frequent, recurrent, or prolonged infection as determined by the principal investigator. 15. History of human immunodeficiency virus (HIV) infection or positive HIV serology at the time of screening. 16. Any clinically significant test result obtained from chemical, blood, or urine tests at the time of the screening visit, as determined by the principal investigator. 17. The presence of comorbid skin conditions that may interfere with the evaluation of the study. 18. A history of malignant tumors, including mycosis fungoides, within 5 years prior to the screening visit, excluding cured insight cervical cancer, cured and remission of non-metastatic cutaneous squamous cell carcinoma, or basal cell carcinoma. 19. Severe comorbidities that, in the judgment of the Principal Investigator, would adversely affect a patient's participation in the study. Any other medical or psychological condition that, in the opinion of the Principal Investigator, suggests a new disease and / or a disease that is not well understood, could present an unreasonable risk to the patient for participation in this clinical trial, make patient participation unreliable, or interfere with the evaluation of the study. 20. Women who are pregnant or breastfeeding, or who plan to become pregnant or breastfeed during the study.

[0099] Research drugs: The pharmaceutical composition containing 125 mg / mL of lebrikizumab or placebo is supplied for subcutaneous administration to patients as sterile, pre-filled syringes equipped with a pre-assembled needle safety device (PFS-NSD). The lebrikizumab sequence is shown in Table 1. The placebo solution is identical in appearance and volume to the active solution, except that it does not contain lebrikizumab.

[0100] Research design: This research design is shown in Figure 1.

[0101] In each trial, approximately 400 patients will be stratified during a 16-week induction period (or period 1) and randomized in a 2:1 ratio to receive either 250 mg of lebrikizumab (with a 500 mg loading dose at baseline (week 0) and week 2) or placebo via subcutaneous (SC) injection every two weeks (Q2W). All study drug injections will be administered in a clinic setting.

[0102] After completing the 16-week visit, patients who have responded to treatment [defined as having 0 or 1 IGA, or a 75% reduction in EASI from baseline to week 16 (EASI-75)] will enter the maintenance period (or second period) and be re-randomized in a 2:2:1 ratio to one of the following treatment groups: lebrikizumab 250 mg every two weeks (Q2W), lebrikizumab 250 mg every four weeks (Q4W), or placebo Q2W. Patients will be instructed to self-administer the investigational drug at home.

[0103] Respondents who received placebo during the first 16 weeks of the study and were re-randomized to the leburikizumab group will receive a loading dose of either 500 mg of leburikizumab at week 16 or 500 mg at weeks 16 and 18, based on their assigned active treatment group at maintenance.

[0104] Patients who do not achieve an IGA of 0 or 1 or an EASI-75 at week 16, and patients who do not maintain an EASI-50 response after re-randomization at weeks 24, 32, 40, or 48, will be assigned to the Escape Arm and will receive lebrikizumab 250 mg Q2W as long-term treatment until week 52. Patients in the Escape Arm who do not achieve an EASI-50 response after 8 weeks of treatment will be terminated from the study.

[0105] Efficacy is measured by IGA, EASI, BSA, SCORAD, pruritus, and sleep loss scores.

[0106] Safety is assessed by monitoring adverse events, serological, hematological, and urinalysis laboratory tests, physical examinations, pulse, and blood pressure. An independent Data Safety Monitoring Board monitors patient safety by conducting formal reviews of safety data accumulated regularly throughout the trial. In addition, adolescents are monitored for hormone levels.

[0107] Quality of life and the impact of the disease will be assessed using the POEM, DLQI / CDLQI, EQ-5D, and PROMIS® Anxiety and Depression Scales. Patients who reported comorbid asthma at the start of the study will complete the ACQ-5.

[0108] Serum samples are collected for pharmacokinetic analysis and immunogenicity testing.

[0109] Patients who complete this 52-week study will be offered the option of continued treatment in a separate, longer-term extension study. Patients who choose to terminate early or not participate in a longer-term extension study will have a safety follow-up visit approximately 12 weeks after their last study drug injection.

[0110] Objectives and evaluation items The primary objective of this study is to evaluate the safety and efficacy of leburikizumab compared to placebo in patients with moderate to severe Alzheimer's disease (AD).

[0111] In the United States, the primary efficacy endpoint is the percentage of patients with an IGA score of 0 or 1 and a reduction of ≥2 points from baseline to week 16. Secondary objectives include: (1) the percentage of patients achieving EASI-75 (≥75% reduction from baseline in EASI score) at week 16; (2) the percentage of patients achieving EASI-90 (≥90% reduction from baseline in EASI score) at week 16; (3) the percentage change in Numerical Rating Scale (NRS) score from baseline to week 16; (4) the percentage of patients with a ≥4 point pruritus NRS at baseline who achieved a reduction of ≥4 points from baseline to week 16; the percentage change in EASI score from baseline to week 16; and (6) the percentage change in baseline BSA percentage to week 16. (7) the percentage of patients who achieved EASI-90 at week 4, (8) the percentage change in sleep loss score from baseline up to week 16, (9) the change in sleep loss score from baseline at week 16, (10) the percentage of patients who had a pruritus NRS of ≥4 points at baseline and achieved a reduction of ≥4 points from baseline to week 4, (11) the percentage of patients who had a pruritus NRS of ≥4 points at baseline and achieved a reduction of ≥4 points from baseline to week 2, and (12) the percentage of patients who had a pruritus NRS of ≥4 points at baseline and achieved a reduction of ≥4 points from baseline to week 1. During the maintenance period, secondary objectives include: (1) the percentage of re-randomized patients who achieve EASI-75 at week 16 and continue to show EASI-75 at week 52 (EASI-75 calculated relative to baseline EASI score); and (2) the percentage of randomized patients who achieve IGA 0 or 1 and an improvement of ≥2 points from baseline at week 16 and continue to show IGA 0 or 1 and an improvement of ≥2 points from baseline at week 52.

[0112] For Europe, the co-primary endpoints are (1) the percentage of patients with an IGA score of 0 or 1 and a reduction of ≥2 points from baseline to week 16, and (2) the percentage of patients who achieved EASI-75 (≥75% reduction from baseline in the EASI score) at week 16. Secondary objectives include: (1) the percentage of patients who achieved EASI-90 (≥90% reduction from baseline in EASI score) at week 16; (2) the percentage change in pruritus numerical rating scale (NRS) score from baseline up to week 16; (3) the percentage of patients who had a pruritus index (NRS) of ≥5 points at baseline and achieved a reduction of ≥4 points from baseline to week 16; (4) the percentage of patients who had a pruritus NRS of ≥4 points at baseline and achieved a reduction of ≥4 points from baseline to week 16; (5) the percentage change in EASI score from baseline up to week 16; and (6) the percentage of patients who achieved EASI-90 at week 4. (7) Percentage of patients who achieved the following: (8) Change from baseline in DLQI at week 16; (9) Percentage of patients who achieved an improvement of ≥4 points in DLQI from baseline to week 16; (10) Percentage of change in sleep loss score from baseline up to week 16; (11) Change from baseline in sleep loss score at week 16; (12) Percentage of patients who had a pruritus NRS score of ≥5 points at baseline and achieved a reduction of ≥4 points from baseline to weeks 1, 2, and 4; (13) Percentage of patients who had a pruritus NRS score of ≥4 points at baseline and achieved a reduction of ≥4 points from baseline to weeks 1, 2, and 4.During the maintenance period, secondary objectives include: (1) the percentage of re-randomized patients who achieve EASI-75 at week 16 and continue to show EASI-75 (EASI-75 calculated relative to baseline EASI score) at week 52; and (2) re-randomized patients who achieve IGA 0 or 1 and an improvement of ≥2 points from baseline at week 16 and maintain an IGA at week 52. (3) Percentage of patients who continue to show improvement of 0 or 1 and ≥2 points from baseline; (4) Percentage of patients who had a pruritus NRS score of ≥4 points at baseline after re-randomization, achieved a reduction of ≥4 points from baseline at week 16, and continued to show a reduction of ≥4 points from baseline at week 52; (5) Percentage of patients who had a pruritus NRS score of ≥5 points at baseline after re-randomization, achieved a reduction of ≥4 points from baseline at week 16, and continued to show a reduction of ≥4 points from baseline at week 52; (6) Percentage change in SCORAD (achieved EASI-75 at week 16) from baseline at week 52.

[0113] To evaluate the pharmacokinetics of leburikizumab, the mean serum leburikizumab concentration is measured.

[0114] Other secondary endpoints include: the proportion of patients with EASI-75, EASI-90, and EASI-50 scores upon visit; the proportion of patients with an IGA score of 0 or 1 and a reduction of ≥2 points from baseline upon visit; the percentage change in EASI score from baseline upon visit; the percentage change in pruritus NRS from baseline upon visit; the percentage of patients with a pruritus NRS change of ≥4 points from baseline upon visit; and patients with a pruritus NRS score of ≥4 points at baseline and a reduction of ≥4 points from baseline upon visit. Percentage of patients who achieved the following: Change from baseline in sleep loss score upon visit, Change from baseline in DLQI / CDLQI upon visit, Change from baseline in EQ5D upon visit, Change from baseline in POEM upon visit, Change from baseline in PROMIS anxiety scale upon visit, Change from baseline in PROMIS depression scale upon visit, Change from baseline in ACQ-5 score from baseline to week 16 in patients with self-reported comorbid asthma, Percentage of change from baseline up to week 16 in SCORAD.

[0115] Statistical analysis will be performed on the primary and secondary outcome measures. Estimation and missing data imputation methods will include Markov Chain Monte Carlo Multiple Imputation (MCMC-MI) and non-responder imputation (NRI).

[0116] result In the ADvocate 1 trial, all primary and important secondary endpoints, including improvement in skin and itching, were met at week 16 (Figures 4A-4G and 5A-5F).

[0117] Figures 2A to 2C show the baseline demographics and disease characteristics of participants in ADvocate 1. Figures 3A to 3C show adverse events up to week 16. Figure 3D shows injection site reactions up to week 16.

[0118] Compared to the placebo group, a statistically significantly higher percentage of participants in the leburikizumab treatment group achieved skin clearance and skin improvement as early as week 4, as measured by IGA 0 / 1, EASI-75, and EASI-90 (see Figures 4D-4G). A statistically significantly higher percentage of participants in the leburikizumab treatment group achieved improvement in itching as early as week 2, as measured by the pruritus NRS (Figures 5A-5B). A statistically significantly higher percentage of participants in the leburikizumab treatment group experienced improvements in sleep and quality of life, as measured by the sleep loss score and DLQI scale, respectively (Figures 5C-5F).

[0119] At the 16-week evaluation, lebrikizumab remained well-tolerated, with adverse events occurring at a frequency comparable to placebo, including a low frequency of injection site reactions. The overall frequency of discontinuation due to SAEs and AEs was low, and there were no deaths.

[0120] Similar results were observed in the ADvocate 2 trial, where all primary and important secondary endpoints, including improvement in skin and itching, were met at week 16.

[0121] Therefore, lebrikizumab treatment met the primary endpoint and all important secondary endpoints, including itching, itching-related sleep interference, and quality of life at week 16, in two critical Phase 3 clinical trials.

[0122] Based on an interim analysis of the data at week 16, in ADvocate 1, the proportion of patients treated with lebrikizumab 250 mg (N=283) and placebo (N=141) who achieved IGA 0 / 1 at week 16 was 43.0% and 12.8% (p<0.001), respectively, and the EASI-75 response was 59.3% and 16.4% (p<0.001). The proportion of patients with an improvement of ≥4 points in pruritus NRS from baseline (P≧4) was 46.3% and 12.7% (p<0.001), respectively. The mean baseline DLQI scores in patients treated with lebrikizumab 250 mg (N=283) and placebo (N=141) were 15.3 and 15.7, respectively. The corresponding baseline mean EQ-5D VAS scores were 68.2 and 67.0, respectively, and the US Health State Index for EQ-5D-5L was 0.7 and 0.7, respectively. At week 16, the proportion of patients whose week 16 DLQI score improved by ≥4 points from baseline was 71.2% in the lebrikizumab group and 29.3% in the placebo group, among patients with a baseline DLQI score of ≥4. The proportion of patients receiving lebrikizumab and placebo who had a DLQI(0,1) response was 26.3% and 4.2%, among patients with a baseline DLQI >1, respectively. The mean total DLQI score CFB at week 16 improved by -10.0 in lebrikizumab-treated patients and -4.4 in placebo-treated patients. Statistical significance was achieved as early as week 4, the first assessment after baseline, and continued to week 16 for all DLQI analyses. There were also significant differences at week 16 between the mean EQ-5D VAS score CFB (10.5 and 2.2, respectively) and the EQ-5D-5L U.S. Health Status Index CFB (0.13 and 0.03, respectively) in patients assigned to lebrikizumab and placebo.

[0123] Based on an interim analysis of the data at week 16, in ADvocate 2 (lebrikizumab, N=281, placebo, N=146), the corresponding rates for IGA 0 / 1 were 33.1% and 10.9% (p<0.001), respectively; the EASI-75 response was 50.8% and 18.2% (p<0.001); and the rates of improvement of 4 points or more on the pruritus NRS from baseline (P≧4) were 38.3% and 11.3% (p<0.001), respectively. The mean baseline DLQI scores were 15.4 and 15.9, respectively; the EQ-5D VAS scores were 66.7 and 68.6; and the EQ-5D-5L U.S. Health Status Index was 0.8 and 0.7, respectively. At week 16, the proportion of patients whose week 16 DLQI score improved by ≥4 points from baseline was 60.5% in the lebrikizumab group and 31.3% in the placebo group, respectively, among patients with a baseline DLQI score of ≥4. The proportion of patients assigned to lebrikizumab and placebo who achieved a DLQI(0,1) response was 16.1% and 7.7%, respectively, among patients with a baseline DLQI >1. The mean total DLQI score CFB at week 16 improved by -9.3 in lebrikizumab-treated patients and -4.9 in placebo-treated patients. Statistical significance was achieved early, at week 4, the first assessment after baseline, and persisted to week 16 for DLQI ≥4 point improvement and total score CFB. Significant differences were observed at week 16 in the mean EQ-5D VAS score CFB (9.0 and 5.2, respectively) and the EQ-5D-5L U.S. Health Status Index CFB (0.08 and 0.03, respectively) in patients receiving leburikizumab and placebo.

[0124] The percentage of patients reporting TEAEs of ≥1 was similar in ADvocate 1 (lebrikizumab 45.4%, placebo 51.1%) and ADvocate 2 (lebrikizumab 53.0%, placebo 66.2%).

[0125] Following the final database lock, several updates regarding concomitant medications, such as emergency drugs, were considered for efficacy and safety endpoints. In ADvocate 1 (43.1% vs. 12.7% [p<0.001]) and ADvocate 2 (33.2% vs. 10.8% [p<0.001]), a statistically higher percentage of patients receiving lebrikizumab 250 mg versus placebo achieved IGA(0,1) with an improvement of ≥2 points from baseline at week 16. Furthermore, in ADvocate 1 (58.8% vs. 16.2% [p<0.001]) and ADvocate 2 (52.1% vs. 18.1% [p<0.001]), the percentage of patients achieving an EASI-75 response at week 16 was also higher in the lebrikizumab versus placebo groups. The corresponding proportion of EASI-90 at week 16 was 38.3% vs. 9.0% (p<0.001) in ADvocate 1 and 30.7% vs. 9.5% (p<0.001) in ADvocate 2. The percentage change in least-squares mean (LSM) from baseline in EASI scores up to week 16 was significantly greater in lebrikizumab-treated patients (ADvocate 1 -64.3% vs. ADvocate 2 -61.5% vs. ADvocate 2, p<0.001) compared to placebo-treated patients (ADvocate 1 -26.0% vs. ADvocate 2 -28.0% vs. ADvocate 2, p<0.001). A significantly larger proportion (p<0.001) of patients receiving lebrikizumab 250 mg versus placebo achieved at least a 4-point improvement from baseline in the pruritus NRS score at week 16 (ADvocate 1: 45.9% vs. 13% and ADvocate 2: 39.8% vs. 11.5%), a ≥2-point improvement in the sleep loss scale (ADvocate 1: 39% vs. 4.7% and ADvocate 2: 28% vs. 8.2%), and a ≥4-point improvement in the DLQI. In addition, lebrikizumab demonstrated clinically significant improvements compared to the placebo group at week 16 in the percentage change from baseline in LSM of the pruritus NRS score, the change from baseline in LSM of the sleep loss scale, and the DLQI.

[0126] Lebrikizumab 250 mg demonstrated rapid onset of action. In both studies, statistical significance compared to placebo was achieved at week 4 for IGA(0,1), with improvements of ≥2 points, EASI-90, and ≥4 points on the pruritus NRS, all of which were controlled for multiplicity.

[0127] The use of emergency medications was approximately 3 times and 2 times greater in placebo-treated patients (ADvocate 1 and ADvocate 2) compared to leburikizumab-treated patients. Patients assigned to placebo required emergency treatment earlier than those treated with leburikizumab. The percentage of placebo-treated patients requiring local and / or systemic salvage therapy as early as week 2 was 5.0% in ADvocate 1 (compared to 1.4% in leburikizumab-treated patients) and 10.3% in ADvocate 2 (compared to 3.9% in leburikizumab-treated patients). Emergency patients received primarily local treatment, in contrast to systemic therapy.

[0128] Treatment-induced adverse events (TEAEs) were reported in 51.8% (N=73) and 66.2% (N=96) of patients receiving placebo, respectively, compared to 45.7% (N=129) and 53.4% ​​(N=150) of patients receiving lebrikizumab 250 mg in ADvocate 1 and ADvocate 2, respectively. Most TEAEs were mild to moderate in severity, and the frequency of treatment discontinuation was low. In both studies, low-frequency injection site reactions (1.1% for ADvocate 1, 2.1% for ADvocate 2), serious adverse events (2.1% for ADvocate 1, 0.7% for ADvocate 2), and TEAEs leading to study discontinuation (1.1% for ADvocate 1, 3.2% for ADvocate 2) were reported in patients treated with lebrikizumab 250 mg, comparable to the proportion of patients in the placebo group. One death occurred in the placebo group for ADvocate 2. The most common TEAE (incidence ≥5% in the lebrikizumab group, consistently reported at a higher frequency than in the placebo group) was conjunctivitis in ADvocate 1 (7.4%) and ADvocate 2 (7.5%). All conjunctivitis-related TEAEs were mild to moderate in severity.

[0129] Improvements in anxiety and depression were measured in ADvocate 1 and ADvocate 2 using the Patient-Reported Outcomes Measurements Information Systems (PROMIS) scale for anxiety and depression in adults. Missing data were imputed by last observation carried forward (LOCF). In ADvocate 1, baseline anxiety scores were 52.9 and 54.3 for patients receiving lebrikizumab 250 mg (N=246) or placebo (N=123), respectively, and baseline depression scores were 49.8 and 50.0, respectively. The change from baseline (CFB) of anxiety at week 16 was -3.99 in the lebrikizumab 250 mg group compared to -0.62 in the placebo group (p<0.001), and the depression CFB was -3.16 vs. -0.40, respectively (p=0.002). In ADvocate 2, baseline anxiety scores were 54.4 and 55.0 in the lebrikizumab 250 mg group (N=251) and the placebo group (N=129), respectively, while depression scores were 51.3 and 51.2. At week 16, the anxiety CFB was -3.00 in the lebrikizumab 250 mg group compared to -0.43 in the placebo group (p<0.001), and the depression CFB was -2.38 and 0.19, respectively (p=0.13).

[0130] Throughout the maintenance period, in patients who received lebrikizumab treatment during the induction period (or first period) and were considered responders at week 16, both lebrikizumab Q4W and Q2W maintenance dosing surprisingly preserved the response in a clinically meaningful percentage of patients at week 52, as measured by IGA, EASI-75, and pruritus NRS (see Figures 6A–6F). In ADvocate 1, 79% of patients who received lebrikizumab Q4W and 79% of patients who received lebrikizumab Q2W maintained an EASI-75 at week 52 (see Figure 6C), and 74% of patients who received lebrikizumab Q4W and 76% of patients who received lebrikizumab Q2W maintained an IGA of 0 or 1 with an improvement of ≥2 points at week 52. In addition, in ADvocate 2, 85% of patients who received lebrikizumab Q4W and 77% of patients who received lebrikizumab Q2W maintained an EASI-75 response at week 52 (see Figure 6D), and 81% of patients who received lebrikizumab Q4W and 65% of patients who received lebrikizumab Q2W maintained an IGA of 0 or 1, with an improvement of ≥2 points at week 52. In ADvocate 1 and ADvocate 2, 81.2% and 90.3% of patients who received lebrikizumab Q2W maintained an improvement of 4 points or more from baseline to week 52 on the Numeric Rating Scale (NRS), compared to 80.4% and 88.1%, respectively, for patients who received lebrikizumab Q4W. Overall, approximately 80% of leburikizumab responders in ADvocate 1 and 2 maintained improved skin clearance and disease severity at week 52, and sustained improvement in itching was also observed at week 52 in patients treated with leburikizumab. Unexpectedly, the loss of response after leburikizumab withdrawal was relatively slow, with approximately half of patients re-randomized to placebo during the maintenance period ("leburikizumab withdrawal group") still having a response at week 52 (see Figures 6A–6F). In ADvocate 1 and ADvocate 2, 61% and 72% of patients in the leburikizumab withdrawal group, respectively, continued to meet EASI-75 criteria at week 52.The proportion of patients in the leburikizumab withdrawal group who maintained a pruritus NRS response was 65.4% (ADvocate 1) and 67.6% (ADvocate 2). Across the treatment groups, the proportion of patients who used any emergency therapy was 14.0% (ADvocate 1) and 16.4% (ADvocate 2).

[0131] The overall safety profiles for leburikizumab Q2W and Q4W were comparable, and no new safety findings were observed during the maintenance period (see Figure 7). Low-frequency SAEs and AEs led to discontinuation, and no deaths were reported. Most reported adverse events were mild to moderate in severity. The overall incidence of conjunctivitis in the leburikizumab treatment group was 14.5%. Only one injection site reaction was reported.

[0132] Following 16 weeks of induction with lebrikizumab Q2W, both lebrikizumab Q2W and lebrikizumab Q4W maintained improvement in the signs and symptoms of moderate to severe atopic dermatitis with a favorable safety profile.

[0133] Example 2. Exposure Response Modeling and Simulation The exposure-response relationship for leburikizumab was evaluated in a combined PK-PD analysis of five randomized, double-blind, placebo-controlled studies in AD patients (induction period data (week 16) from ADvocate 1 and ADvocate 2, NCT04250337, NCT03443024, NCT02340234). The relationship between leburikizumab exposure and the eczema area and severity index (EASI) response was evaluated based on data from these double-blind, placebo-controlled phase 2 and phase 3 AD studies. Since EASI is a continuous variable, EASI was selected for modeling. A high agreement of 88% was observed between EASI90 and IGA(0,1) in the leburikizumab phase 3 data, further confirming the appropriateness and usefulness of the EASI endpoint for this type of modeling.

[0134] The long-term EASI response to lebrikizumab was well explained by an indirect effects model that included the lebrikizumab effect, placebo effect, and time-varying TCS effect. The following covariates did not have significant effects in the ER model: age, sex, weight (continuous and categorical), race, and baseline IGA (moderate vs. severe). The model diagram is shown in Figure 8A, and the model parameters are shown in Figure 8B.

[0135] Following the development of the final emergency response (ER) model, this model was used to investigate different aspects of exposure and dose-response for lebrikizumab. Simulations using the ER model were performed to explore maintenance dosing options for participants who achieved EASI-75 at week 16 with the induction regimen (loading doses of 500 mg at weeks 0 and 2, followed by 250 mg Q2W until week 14). Each dosing regimen was simulated for a group of n=125 patients, and the simulations were repeated 500 times. n=125 was selected based on the typical sample size per treatment group in a phase 3 study. In the simulations, patients who met the EASI-75 response at week 16 were divided into either responder or non-responder categories, and data for responders and non-responders were summarized separately for each dosing regimen.

[0136] Based on simulations, a high level of EASI response was predicted for responders at week 16 who transitioned to a 250 mg Q2W (once every two weeks) or 250 mg Q4W (once every four weeks) maintenance regimen between weeks 16 and 52. EASI-75 and EASI-90 simulations are shown in Figures 9 to 12. These simulations were consistent with the data observed from phase 3 (comparison data are not shown).

[0137] Based on simulations, a long-term EASI response was predicted for responders who switched to placebo at week 16 (Figures 9 and 11). The observed efficacy data for placebo (leburikizumab withdrawal group) were consistent with simulations using the ER model (data not shown). The long-lasting effect is attributed to the long PK half-life of leburikizumab and the indirect ER relationship.

[0138] We investigated additional dosing regimen options not studied in Phase 3, including a 250 mg Q8W (once every eight) maintenance regimen at 16 weeks. High levels of efficacy were predicted for responders who continued the 250 mg Q8W maintenance regimen at week 16. EASI-75 and EASI-90 simulations are shown in Figures 9–12. Simulations for EASI-75 and EASI-90 show a slight reduction for Q8W administration compared to Q4W, but Q8W still demonstrates high levels of response (Figures 9–12). There is some overlap in the 95% confidence intervals between Q4W and Q8W (Figures 10 and 12), suggesting that both of these dosing regimens yield high levels of efficacy and are equivalent to each other.

Claims

1. A method for treating moderate to severe atopic dermatitis in patients requiring treatment, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and then at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes administering 250 mg of the anti-IL-13 antibody to the patient once every four weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

2. A method for treating moderate to severe atopic dermatitis in patients requiring treatment, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes administering 250 mg of the anti-IL-13 antibody to the patient once every two weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

3. A method for treating moderate to severe atopic dermatitis in patients requiring treatment, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. To determine whether the patient is a responder to the anti-IL-13 antibody after the induction period, If the patient is a responder, the patient shall be administered 250 mg of the anti-IL-13 antibody once every four weeks for a maintenance period of 8 to 36 weeks. If the patient is not a responder, the treatment includes administering the patient 250 mg of the anti-IL-13 antibody once every two weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

4. A method for reducing sleep loss in patients with moderate to severe atopic dermatitis, The treatment involves administering an anti-IL-13 antibody to the patient at a loading dose of 500 mg at baseline (week 0) and week 2, followed by a subsequent dose of 250 mg every two weeks thereafter. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

5. A method for reducing sleep loss in patients with moderate to severe atopic dermatitis, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes administering 250 mg of the anti-IL-13 antibody to the patient once every four weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

6. A method for reducing sleep loss in patients with moderate to severe atopic dermatitis, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. To determine whether the patient is a responder to the anti-IL-13 antibody after the induction period, If the patient is a responder, the patient shall be administered 250 mg of the anti-IL-13 antibody once every four weeks for a maintenance period of 8 to 36 weeks. If the patient is not a responder, the treatment includes administering the patient 250 mg of the anti-IL-13 antibody once every two weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

7. A method for treating moderate to severe atopic dermatitis in patients requiring treatment, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes administering 250 mg of the anti-IL-13 antibody to the patient once every 8 weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

8. A method for treating moderate to severe atopic dermatitis in patients requiring treatment, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. To determine whether the patient is a responder to the anti-IL-13 antibody after the induction period, If the patient is a responder, the patient shall be administered 250 mg of the anti-IL-13 antibody once every 8 weeks for a maintenance period of 8 to 36 weeks. If the patient is not a responder, the treatment includes administering the patient 250 mg of the anti-IL-13 antibody once every two weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

9. A method for reducing sleep loss in patients with moderate to severe atopic dermatitis, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. The procedure includes administering 250 mg of the anti-IL-13 antibody to the patient once every 8 weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

10. A method for reducing sleep loss in patients with moderate to severe atopic dermatitis, The patient is administered an anti-IL-13 antibody over an induction period of 4 to 16 weeks, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg every two weeks for weeks 2 to 14. To determine whether the patient is a responder to the anti-IL-13 antibody after the induction period, If the patient is a responder, the patient shall be administered 250 mg of the anti-IL-13 antibody once every 8 weeks for a maintenance period of 8 to 36 weeks. If the patient is not a responder, the treatment includes administering the patient 250 mg of the anti-IL-13 antibody once every two weeks for a maintenance period of 8 to 36 weeks. A method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6.

11. The method according to any one of claims 1 to 10, wherein the patient has moderate to severe atopic dermatitis for at least one year at baseline.

12. The method according to any one of claims 1 to 10, wherein the moderate to severe atopic dermatitis is determined by the American Academy of Dermatology Consensus Criteria for Chronic Atopic Dermatitis.

13. The method according to any one of claims 1 to 10, wherein the patient has an EASI score of 16 or higher, an IGA score of 3 or higher, and a body surface area (BSA) of more than 10% affected by atopic dermatitis at baseline.

14. The method according to any one of claims 1 to 13, wherein the patient has an insufficient response to a topical corticosteroid, a topical calcineurin inhibitor, or crisabolol, or topical corticosteroids, topical calcineurin inhibitors, or crisabolol are not medically recommended for the patient.

15. The method according to any one of claims 1 to 14, wherein the patient is 12 years of age or older.

16. The method according to any one of claims 1 to 3, 5 to 15, further comprising determining the patient's EASI score at baseline, during and after the induction period.

17. The method according to any one of claims 1 to 3, 5 to 15, further comprising determining the patient's IGA score at baseline, during and after the induction period.

18. The method according to any one of claims 1 to 3, 5 to 17, further comprising determining one or more of the following characteristics of the patient at baseline and during and after the induction period: the percentage of BSAs affected by atopic dermatitis, the pruritus NRS score, the SCORAD score, the sleep loss score, the POEM total score, the DLQI or CDLQI score, the EQ-5D, ACQ-5, the PROMIS anxiety, and depressive symptoms.

19. The method according to any one of claims 3 and 6 to 18, wherein the patient is a responder if the patient's EASI score determined after the induction period is 75% or more lower than the patient's EASI score at baseline.

20. The method according to any one of claims 3 and 6 to 18, wherein the patient is a responder if the patient's IGA score is 0 or 1 after the induction period.

21. The method according to claim 20, wherein the patient's IGA score determined after the induction period is 2 points or more lower than the patient's IGA score at baseline.

22. The method according to any one of claims 1 to 3, 5 to 21, wherein the induction period is 16 weeks.

23. The method according to claim 22, wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg once every two weeks for 14 weeks.

24. The method according to any one of claims 1 to 3, 5 to 23, wherein the maintenance period is 36 weeks.

25. The method according to any one of claims 1 to 3, 5 to 24, further comprising determining the patient’s EASI score during and after the maintenance period.

26. The method according to any one of claims 1 to 3, 5 to 25, further comprising determining the patient's IGA score during and after the maintenance period.

27. The method according to any one of claims 1 to 3, 5 to 26, further comprising determining one or more of the following characteristics of the patient during and after the maintenance period: the percentage of BSA with atopic dermatitis, the pruritus NRS score, the SCORAD score, the sleep loss score, the POEM total score, the DLQI or CDLQI score, the EQ-5D, ACQ-5, the PROMIS anxiety, and depressive symptoms.

28. The method according to claim 4, further comprising determining the EASI score of the patient.

29. The method according to claim 4, further comprising determining the IGA score of the patient.

30. The method according to claim 4, further comprising determining one or more of the following characteristics of the patient: the percentage of BSA affected by atopic dermatitis, the pruritus NRS score, the SCORAD score, the sleep loss score, the POEM total score, the DLQI or CDLQI score, the EQ-5D, ACQ-5, the PROMIS anxiety, and depressive symptoms.

31. The method according to claim 4, wherein the anti-IL-13 antibody is administered to the patient over a period of 4 to 52 weeks.

32. The method according to claim 4, wherein the anti-IL-13 antibody is administered to the patient over a period of 4 to 16 weeks.

33. The method according to any one of claims 4 to 32, wherein the sleep loss is determined by the patient's sleep loss score.

34. The method according to claim 33, wherein the patient's sleep loss score after treatment with the anti-IL-13 antibody has decreased by 2 points or more compared to the patient's sleep score at baseline.

35. The method according to any one of claims 16, 25, or 28, further comprising determining whether the patient's EASI score has decreased by 50%, 75%, 90%, or more compared to the patient's baseline EASI score.

36. The method according to any one of claims 17, 26, or 29, further comprising determining whether the patient's IGA score is 0 or 1, and whether the patient's IGA score has decreased by 2 points or more compared to the patient's baseline IGA score.

37. The method according to any one of claims 1 to 36, wherein the antibody comprises VH containing SEQ ID NO: 7 and VL containing SEQ ID NO:

8.

38. The method according to any one of claims 1 to 37, wherein the antibody comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO:

10.

39. The method according to any one of claims 1 to 38, wherein the antibody is leburikizumab.

40. The method according to any one of claims 1 to 39, wherein the anti-IL-13 antibody is administered subcutaneously to the patient.

41. The method according to any one of claims 1 to 40, wherein the anti-IL-13 antibody is administered to the patient using a subcutaneous administration device.

42. The method according to claim 41, wherein the subcutaneous administration device is selected from a pre-filled syringe, a disposable pen-type injection device, a microneedle device, a micro-injection device, a needle-free injection device, or an automated injection device.

43. The method according to any one of claims 1 to 42, further comprising administering one or more topical corticosteroids to the patient.

44. The method according to claim 43, wherein the one or more topical corticosteroids are triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone.

45. The method according to claim 43 or 44, wherein one or more local corticosteroids are administered simultaneously with the antibody.

46. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in the treatment of moderate to severe atopic dermatitis in a patient, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprising LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, and the anti An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody, wherein the anti-IL-13 antibody is to be administered over an induction period of 4 to 16 weeks, during which the anti-IL-13 antibody is to be administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg once every two weeks for weeks 2 to 14, and the anti-IL-13 antibody is to be administered at a dose of 250 mg once every four weeks for a maintenance period of 8 to 36 weeks.

47. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, the VL comprises LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO: 6, and the anti-IL-13 antibody or pharmaceutical composition is to be administered as a loading dose of 500 mg at baseline (week 0) and week 2, and thereafter as a subsequent dose of 250 mg once every two weeks.

48. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprising LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6. The anti-IL-13 antibody or pharmaceutical composition comprising the anti-IL-13 antibody is for administration over an induction period of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg once every two weeks for weeks 2 to 14, and the anti-IL-13 antibody is administered at a dose of 250 mg once every four weeks for a maintenance period of 8 to 36 weeks.

49. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in the treatment of moderate to severe atopic dermatitis in a patient, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, and HCDR3 comprising SEQ ID NO: 3, and the VL comprising LCDR1 comprising SEQ ID NO: 4, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, and the anti An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody, wherein the anti-IL-13 antibody is to be administered over an induction period of 4 to 16 weeks, during which the anti-IL-13 antibody is to be administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg once every two weeks for weeks 2 to 14, and the anti-IL-13 antibody is to be administered at a dose of 250 mg once every eight weeks for a maintenance period of 8 to 36 weeks.

50. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep loss in patients with moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 2, and HCDR3 containing SEQ ID NO: 3, and the VL comprising LCDR1 containing SEQ ID NO: 4, LCDR2 containing SEQ ID NO: 5, and LCDR3 containing SEQ ID NO:

6. The anti-IL-13 antibody or pharmaceutical composition comprising the anti-IL-13 antibody is for administration over an induction period of 4 to 16 weeks, during which the anti-IL-13 antibody is administered at a dose of 500 mg at baseline (week 0) and week 2, and thereafter at a dose of 250 mg once every two weeks for weeks 2 to 14, and the anti-IL-13 antibody is administered at a dose of 250 mg once every eight weeks for a maintenance period of 8 to 36 weeks.

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