Treatment methods for atopic dermatitis and related disorders

Abstract

The present invention relates to methods of treating atopic dermatitis and related disorders in a subject using interleukin-13 (IL-13) binding proteins, such as anti-IL-13 antibodies or IL-13-binding fragments thereof.

Description

[Technical Field]

[0001] The present invention relates to a method for treating atopic dermatitis in a subject using an interleukin-13 (IL-13) binding protein, such as an anti-IL-13 antibody or its IL-13 binding fragment. [Background technology]

[0002] Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease resulting from genetic and environmental factors that disrupt the skin's barrier function and immune response (Leung, D. and Guttman-Yassky, E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134:769-779). Current management generally involves a combination of treatments to suppress inflammation, restore skin barrier function, and prevent co-infections (Wollenberg, A., Oranje, A., Deleuran, M., Simon, D., Szalai, Z., Kunz, B. et al. ETFAD / EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol. 2016;30:729-747).

[0003] Topical corticosteroids (TCS) are by far the most frequently prescribed class of drugs for patients with Alzheimer's disease (AD), but long-term use of TCS is not recommended. Topical calcineurin inhibitors (TCIs) are generally effective and safe as short-term treatments. Due to the increased risk of cutaneous malignancies and lymphomas, regulatory authorities have instructed, for example, to mandate warnings about the long-term safety of topical tacrolimus and pimecrolimus in prescribing information. First-generation antihistamines are widely prescribed for the acute symptomatic treatment of pruritus, but their effectiveness is limited and mainly attributable to their sedative effect. Oral immunosuppressants and glucocorticoids are effective, but their use is limited to short-term and / or intermittent therapy due to the potential for severe toxicity and side effects.

[0004] Cyclosporine A (CSA) is a treatment for severe Alzheimer's disease (AD) in some regions. It is an immunosuppressant that affects both humoral and cellular immune responses, increasing susceptibility to infection and reducing immune surveillance for cancer. Other commonly recognized toxicity includes hypertension and impaired renal and hepatic function. Furthermore, CSA may interact with other commonly used medications, affecting their metabolism and efficacy. Systemic immunosuppressants are usually limited to the treatment of moderate to severe AD because they are associated with adverse events and are not suitable for long-term use (Wollenberg, A., Oranje, A., Deleuran, M., Simon, D., Szalai, Z., Kunz, B. et al. ETFAD / EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol. 2016;30:729-747). Therefore, there is a need for more effective and tolerable therapies that target the pathophysiological mechanisms of Alzheimer's disease, rather than simply alleviating symptoms.

[0005] One important feature of AD is the upregulation of IL-13 and interleukin-4 (IL-4) in lesional and non-lesional skin, suggesting that both cytokines may contribute to the pathogenesis of AD (see Nomura, I., Goleva, E., Howell, MD, Hamid, QA, Ong, PY, Hall, C et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262-3269; Tazawa, T., Sugiura, H., Sugiura, Y., and Uehara, M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295:459-464). Furthermore, while the severity of AD is associated with increased levels of IL-13 and related chemokine mRNA and serum levels, decreased IL-13 levels correlate with improved treatment response and clinical outcomes. Treatment with dupilumab, a human mAb that inhibits both IL-4 and IL-13 signaling, has shown improvement in AD symptoms, but the relative contributions of each of these cytokines to the pathogenesis of AD remain unclear.

[0006] In actual clinical practice, the prevalence of conjunctivitis in patients receiving dupilumab is estimated to be 26% based on a systematic review of the literature (Halling AS et al. Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis. J Am Acad Dermatol 2020), and it can persist despite appropriate ophthalmic treatment (Achten R et al. Long-term follow-up and treatment outcomes of conjunctivitis during dupilumab treatment in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Pract 2020). Furthermore, studies have shown that the incidence of ocular complications with dupilumab, such as conjunctivitis, increases with the severity of Alzheimer's disease (Simpson EL et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2017;376:1090-1091; Thyssen JP et al. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol 2017;77:280-286 e281).Ophthalmic side effects during dupilumab treatment have been observed only in AD patients and not in trials involving nasal polyps, asthma, or chronic sinusitis with eosinophilic esophagitis (Bachert C et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 2016;315:469-479; Castro M et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018;378:2486-2496; Hirano I et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology). (2020;158:111-122.e110) This suggests the existence of an AD-specific predisposition. Since dupilumab was introduced as a treatment for AD, conjunctivitis has been identified as an important adverse event, and as a result, collaboration with ophthalmologists has been strengthened (Agnihotri G et al. A Clinician's Guide to the Recognition and Management of Dupilumab-Associated Conjunctivitis. Drugs in R&D 2019;19:311-318, Wollenberg et al. 2018, Wollenberg A et al. Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab - clinical characteristics and treatment. J Allergy Clin Immunol Pract 2018).

[0007] IL-13 is a cytokine consisting of 114 amino acids, with an unmodified molecular weight of approximately 12 kDa. IL-13 is most closely related to IL-4, sharing 30% sequence homology at the amino acid level. The human IL-13 gene is located on chromosome 5q31, adjacent to the IL-4 gene. Initially identified as a cytokine derived from Th2 CD4+ lymphocytes, IL-13 is also produced by Th1 CD4+ T cells, CD8+ T lymphocytes, NK cells, and non-T cell populations, such as mast cells, basophils, eosinophils, macrophages, monocytes, and airway smooth muscle cells. IL-13 is associated with multiple diseases, particularly those caused by inflammatory responses. For example, administration of recombinant IL-13 to the airways of naive, unsensitized rodents has been shown to induce many aspects of the asthmatic phenotype, including airway inflammation, mucus production, and airway hyperresponsiveness. A similar phenotype was observed in transgenic mice that specifically overexpressed IL-13 in the lungs. In this model, more chronic exposure to IL-13 also resulted in fibrosis.

[0008] Multiple genetic polymorphisms of the IL-13 gene have also been linked to allergic diseases. In particular, the IL-13 gene variant in which 130 amino acid arginine residues are substituted with glutamine (Q130R) has been associated with bronchial asthma, atopic dermatitis, and elevated serum IgE levels. This particular IL-13 variant is also called the Q110R variant (in which 110 amino acid arginine residues are substituted with glutamine) by several groups that exclude 20 amino acid signal sequences from its amino acid count.

[0009] Tralokinumab (also known as CAT-354 and BAK502G9) is a fully human therapeutic antibody that binds to and neutralizes IL-13, including the Q130R variant (see Popovic et al., J. Mol. Biol. (2017) 429(2):208-219, May, R.D., Monk, P.D., Cohen, E.S., Manuel, D., Dempsey, F., Davis, N.H. et al., Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma. Br J Pharmacol. 2012;166:177-193).

[0010] Tralokinumab has previously been tested in a Phase 2b trial for the treatment of AD in 204 adult subjects. In this trial, patients received 45 mg, 150 mg, or 300 mg of subcutaneous tralokinumab or placebo every 2 weeks for 12 weeks in combination with topical glucocorticoids. Compared with placebo, an improvement in the change from baseline in the Eczema Area and Severity Index (EASI) score was observed, along with improvements in Scoring Atopic Dermatitis (SCORAD), the Dermatology Life Quality Index (DLQI), and numerical rating scale scores for pruritus (Wollenberg, J. Allergy Clin. Immunol. (2019) 143(1):135-141).

[0011] For example, there remains a need in the art for further improved treatments for AD that address at least some of the problems mentioned above. Summary of the Invention

[0012] The present inventors have found that patient response to an IL-13 binding protein (e.g., an anti-IL-13 antibody such as tralokinumab) is maintained even when the administration frequency of the antibody is reduced. Reducing administration frequency is associated with many advantages, for example, improved patient compliance (e.g., reduced number of injections), reduction in the total amount of drug required per patient, and reduced involvement of clinicians (e.g., when treatment cannot be self-administered). Patients may develop antibodies against therapeutic proteins, which neutralize the therapeutic effect. This tends not to be a problem for short-term use (e.g., cancer treatment), but the likelihood increases with duration of use and drug exposure. Reducing drug exposure by lowering administration frequency may help prevent this effect. Increased drug exposure also increases the likelihood of side effects. Reducing administration frequency may reduce side effects. Accordingly, tolerability (the balance between therapeutic efficacy and its side effects) can also be improved.

[0013] Accordingly, in one aspect, the present invention provides an interleukin-13 (IL-13) binding protein (e.g., an anti-IL-13 antibody or an IL-13 binding fragment thereof) for use in a method of treating atopic dermatitis in a subject, the method comprising the steps of: (a) administering a first dose of the IL-13 binding protein to the subject; and (b) administering one or more further doses of the IL-13 binding protein to the subject, provided that each further dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0014] In another aspect, the present invention provides a method of treating atopic dermatitis in a subject in need thereof, comprising the steps of: (a) administering a first dose of an IL-13 binding protein (e.g., an anti-IL-13 antibody or an IL-13 binding fragment thereof) to the subject; and (b) administering one or more further doses of the IL-13 binding protein to the subject, provided that each further dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0015] In a further embodiment, the present invention provides the use of an IL-13 binding protein (e.g., an anti-IL-13 antibody or its IL-13 binding fragment) in the manufacture of a pharmacopoeia for the treatment of atopic dermatitis in a subject, the method comprising (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0016] In another embodiment, the present invention provides an interleukin-13 (IL-13) binding protein for use in a method of treating skin infections in subjects with moderate to severe or severe Alzheimer's disease, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0017] In another embodiment, the present invention provides an interleukin-13 (IL-13) binding protein for use in a method for treating a skin infection in a subject, the method comprising (a) selecting a subject having moderate to severe or severe AD and a microbial skin infection, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0018] In another embodiment, the present invention provides a method for treating a skin infection in a subject with moderate to severe or severe Alzheimer's disease, the method comprising administering the subject the IL-13 binding protein. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0019] In another embodiment, the present invention provides a method for treating a skin infection in a subject, the method comprising the steps of (a) selecting a subject having moderate to severe or severe AD and a microbial skin infection, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0020] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a pharmacopoeia for the treatment of skin infections in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0021] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of a skin infection in a subject, the method comprising (a) selecting a subject having moderate to severe or severe AD and a microbial skin infection, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0022] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for treating pruritus in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0023] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for treating pruritus in a subject, the method comprising the steps of (a) selecting a subject having moderate to severe or severe AD and pruritus, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0024] In another embodiment, the present invention provides a method for treating pruritus in subjects with moderate to severe or severe Alzheimer's disease, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0025] In another embodiment, the present invention provides a method for treating pruritus in a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and is experiencing pruritus, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0026] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of pruritus in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0027] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of pruritus in a subject, the method comprising (a) selecting a subject that has moderate to severe or severe AD and is pruritic, and (b) administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0028] In another embodiment, the present invention provides an IL-13 binding protein for use in a method of treating eczema-related sleep disturbance in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0029] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for treating eczema-related sleep disturbances in subjects, the method comprising (a) selecting a subject who has moderate to severe or severe AD and eczema-related sleep disturbances, and (b) administering the IL-13 binding protein to the subject.

[0030] In another embodiment, the present invention provides a method for treating eczema-related sleep disturbances in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0031] In another embodiment, the present invention provides a method for treating eczema-related sleep disturbance in a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and eczema-related sleep disturbance, and (b) administering the IL-13 binding protein to the subject.

[0032] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of eczema-related sleep disturbance in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. Preferably, the IL-13 binding protein is not administered in combination with a topical corticosteroid.

[0033] In another aspect, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of eczema-related sleep disturbance in a subject, the method comprising (a) selecting a subject who has moderate to severe or severe AD and eczema-related sleep disturbance, and (b) administering the IL-13 binding protein to the subject.

[0034] In another embodiment, the present invention provides an IL-13 binding protein for use in a method of treating anxiety and / or depression in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0035] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for treating anxiety and / or depression in a subject, the method comprising (a) selecting a subject who has moderate to severe or severe AD and anxiety and / or depression, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0036] In another embodiment, the present invention provides a method for treating anxiety and / or depression in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0037] In another embodiment, the present invention provides a method for treating anxiety and / or depression in a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and anxiety and / or depression, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0038] In another embodiment, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of anxiety and / or depression in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0039] In another embodiment, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of anxiety and / or depression in a subject, the method comprising (a) selecting a subject who has moderate to severe or severe AD and is also anxious and / or depressed, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the subject may have a baseline HADS score of 8 or higher.

[0040] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the subject's health status and / or quality of life may be determined by an improvement in the subject's (i) SF-36 score, e.g., SF-36 physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, (iii) DLQI score and / or PGI-B score.

[0041] In another embodiment, the present invention provides an IL-13 binding protein for use in a method for improving the health status and / or quality of life of a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and is experiencing a decline in health status and / or quality of life, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the health status and / or quality of life of the subject may be determined by an improvement in the subject's (i) SF-36 score, e.g., physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, and (iii) DLQI score and / or PGI-B score.

[0042] In another embodiment, the present invention provides a method for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the subject's health status and / or quality of life may be determined by an improvement in the subject's (i) SF-36 score, e.g., SF-36 physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, (iii) DLQI score and / or PGI-B score.

[0043] In another embodiment, the present invention provides a method for improving the health status and / or quality of life of a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and is experiencing a decline in health status and / or quality of life, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the health status and / or quality of life of the subject may be determined by an improvement in the subject's (i) SF-36 score, e.g., SF-36 physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, (iii) DLQI score and / or PGI-B score.

[0044] In another embodiment, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, the method comprising administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the health status and / or quality of life of the subject may be determined by an improvement in the subject's (i) SF-36 score, e.g., SF-36 physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, (iii) DLQI score and / or PGI-B score.

[0045] In another embodiment, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for improving the health status and / or quality of life in a subject, the method comprising the steps of (a) selecting a subject who has moderate to severe or severe AD and has a reduced health status and / or quality of life, and (b) administering the IL-13 binding protein to the subject. In some embodiments, the improvement in the health status and / or quality of life of the subject may be determined by an improvement in the subject's (i) SF-36 score, e.g., SF-36 physical component score and / or SF-36 mental component score, (ii) EQ-5D-5L score, (iii) DLQI score and / or PGI-B score. [Brief explanation of the drawing]

[0046] [Figure 1] This is the percentage of patients who achieved IGA-0 / 1 and EASI-75 after 16 weeks of administration of tralokinumab / TCS or placebo / TCS (control). * = statistically significant difference compared to the control (p<0.05). [Figure 2] These are patient-reported outcome scores at baseline and 2 weeks after administration of tralokinumab / TCS or placebo / TCS (control). ERSI = Eczema-related sleep disturbance, POEM = Patient self-assessment of eczema, DLQI = Questionnaire on skin condition. * = Significant difference compared to control (p<0.05). [Figure 3]This represents the percentage of patients who achieved IGA-0 / 1 after 16 weeks of treatment with tralokinumab monotherapy or placebo (control) in the ECZTRA1 and ECZTRA2 trials. * = statistically significant difference compared to the control (p<0.05). [Figure 4] This represents the percentage of patients who achieved EASI-75 after 16 weeks of treatment with tralokinumab monotherapy or placebo (control) in the ECZTRA1 and ECZTRA2 trials. * = statistically significant difference compared to the control (p<0.05). [Figure 5] In the ECZTRA1 and ECZTRA2 trials, patient-reported outcome scores were measured at baseline and 2 weeks after administration of tralokinumab monotherapy or placebo (control). * = statistically significant difference compared to the control (p < 0.05). A ERSI = Eczema-Related Sleep Disturbance Score, B POEM = Patient Self-Assessment Score for Eczema, C DLQI = Questionnaire Score on Skin Condition. [Figure 6] This represents the percentage of patients who achieved IGA-0 / 1 and EASI-75 at week 32. Patients were responders to tralokinumab / TCS at week 16. At week 16, responders were divided into two groups, and tralokinumab / TCS was administered every two weeks (Q2W) or every four weeks (Q4W) for the remainder of the study. [Figure 7] This represents the percentage of patients who achieved IGA-0 / 1 and EASI-75 at week 52 in the ECZTRA1 and ECZTRA2 trials. Patients were responders to tralokinumab at week 16. At week 16, responders were divided into groups and received tralokinumab every two weeks (Q2W) or every four weeks (Q4W) for the remainder of the trial. †Evaluated patients who achieved IGA-0 / 1 at week 16 without receiving salvage therapy after initial randomization to tralokinumab.‡Evaluated patients who achieved EASI-75 at week 16 without receiving salvage therapy after initial randomization to tralokinumab. Patients who received salvage therapy after week 16 or transitioned to open-label treatment were considered non-responders at week 52. Missing values ​​were attributed as non-responders. [Figure 8]These are the scores for secondary endpoints (SCORAD, pruritus, DLQI, and EASI) at baseline and 16 weeks after administration of tralokinumab or placebo (control) in the ECZTRA1 and ECZTRA2 trials. SCORAD = Atopic Dermatitis Scoring (SCORAD), DLQI = Questionnaire on Skin Condition, EASI = Eczema Area Severity Index. [Figure 9] This is the mean percentage change from baseline of the highest daily value of the pruritus NRS score (weekly average from weeks 0 to 16). [Figure 10] Achievement of EASI-50 and EASI-90 after 16 weeks of administration with tralokinumab / TCS or placebo / TCS (control) (ECZTRA3 trial). Patients with missing data were attributed to non-responders. *p<0.05 compared to placebo+TCS, **p<0.01 compared to placebo+TCS, ***p<0.001 compared to placebo+TCS. EASI-50: at least 50% reduction in EASI score. EASI-90: at least 90% reduction in EASI score. [Figure 11] Eczema-related sleep disturbance (ERSI) scores after 16 weeks of treatment in the ECZTRA1-3 trials. *P<0.05, **P<0.01, ***P<0.001. [Figure 12] Patient-assigned eczema assessment (POEM) scores after 16 weeks of treatment in the ECZTRA1-3 trials. *P<0.05, **P<0.01, ***P<0.001. [Figure 13] Adjusted mean weekly change from baseline in HADS total score for pivotal Phase 3 trials and ECZTRA1+2, initial treatment duration: FAS. [Figure 14] In the ECZTRA1+2 trial, this refers to the percentage of patients who reported no sleep disturbances, 1-2 days, 3-4 days, 5-6 days, or daily sleep disturbances. [Figure 15] Comparison of S. aureus colony formation in EASI-75 responders in the tralokinumab group and the placebo group. [Modes for carrying out the invention]

[0047] The present invention relates to a method for treating atopic dermatitis in a subject using an interleukin-13 (IL-13) binding protein (e.g., an anti-IL-13 antibody or its IL-13 binding fragment).

[0048] Atopic dermatitis As used herein, “atopic dermatitis” (AD) means an inflammatory skin disease characterized by severe itching (e.g., severe itching) and scaly and dry eczematous lesions.

[0049] The term "atopic dermatitis" includes AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, maids, dust mites, animals, etc.), radiation exposure, and / or asthma. In some embodiments, the present invention relates to moderate to severe or severe AD.

[0050] As used herein, “moderate to severe AD” is characterized by widespread, severely itchy skin lesions, often complicated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD, which often involves thickened plaques, lichenification, and fibrous papules of the skin. Generally, patients with moderate to severe AD also have more than 20% of their body skin, or more than 10% of their skin area, affected, in addition to involvement of wrinkles around the eyes, hands, and body. Moderate to severe AD is also thought to be present in patients who frequently require treatment with topical corticosteroids. In the clinical trials reported herein, subjects with “moderate to severe AD” were those with an IGA score of 3–4.

[0051] As used herein, “severe AD” refers to chronic relapsing Alzheimer's disease (AD) that is resistant to treatment with moderate- and high-potency TCS and / or immunosuppressive therapy. Severe AD is also characterized by chronic, severe pruritic lesions affecting more than 20% of the body surface area. According to the Eichenfield criteria (Eichenfield et al 2014, J.Am.Acad.Dermatol.70:338-351), subjects with chronic AD may be considered to have severe AD, for which treatment with potent topical corticosteroids (TCS) is indicated, and / or the subjects are resistant to treatment with systemic corticosteroids and / or nonsteroidal immunosuppressants. In the clinical trials reported herein, subjects with “severe AD” were subjects with an IGA score of 4. Thus, in certain embodiments, the method treats severe AD in subjects who have an IGA score of 4 at baseline. Subjects with "severe AD" may have AD covering at least 10% of their body surface area at screening and baseline, an EASI score of 20 or higher at screening and baseline, and an IGA score of 3 or higher at screening and baseline.

[0052] subject As used herein, the term “subject” includes humans and non-human animals, particularly mammals. Typically, the subject is a human, as shown in the following examples.

[0053] Patients with AD (particularly moderate to severe AD or severe AD) may be resistant, unresponsive, or poorly responsive to treatment with nonsteroidal systemic immunosuppressants. The term “nonsteroidal systemic immunosuppressants” includes cyclosporine A (CSA), methotrexate, mycophenolate mofetil, azathioprine, and interferon-gamma. In certain embodiments, the term also includes immunobiological agents, such as tumor necrosis factor alpha (TNFa) inhibitors (e.g., anti-TNFa antibodies such as infliximab), CD11a inhibitors (e.g., anti-CD11a antibodies such as efalizumab), IgE inhibitors (e.g., omalizumab), and CD20 inhibitors (e.g., rituximab). Accordingly, in some cases, the methods described herein may treat AD in patients who are resistant, unresponsive (refractory), or poorly responsive to treatment with systemic immunosuppressants. The term "resistant, unresponsive, or poorly responsive to systemic immunosuppressants" refers to patients with Alzheimer's disease (AD) who have been treated with systemic immunosuppressants and have not shown a therapeutic effect, for example, patients with moderate to severe AD or severe AD (e.g., patients with chronic relapsing AD) who have been treated with nonsteroidal immunosuppressants (NSAIDs) for 1–3 months and have not seen a reduction in one or more AD-related parameter scores. The time for evaluating the therapeutic effect varies depending on the typical time frame for the onset of action of NSAIDs. Such time frames are well known. For example, in the case of cyclosporine, the onset of action is usually 2–6 weeks, while for other NSAIDs, it is usually about 8–12 weeks.

[0054] In some embodiments, immunosuppressant therapy is considered medically undesirable by the physician for the subject. Such subjects may be identified by the following criteria: (1) no prior exposure to immunosuppressants; (2) not currently a candidate for immunosuppressant therapy due to medical contraindications, hypersensitivity to the immunosuppressant or excipient(s), use of drugs prohibited for concomitant use with immunosuppressants, increased susceptibility to renal impairment or increased risk of serious infection due to immunosuppressants; (3) prior intolerance and / or unacceptable toxicity from previous exposure to immunosuppressants; and / or (4) a request for immunosuppressants exceeding the dose or duration specified in the prescribing information.

[0055] In any of the methods described herein for treating atopic dermatitis, for example, severe atopic dermatitis, the subjects may be those whose atopic dermatitis is not adequately controlled by cyclosporine A (CSA), for example, oral cyclosporine A, or the subjects may be those for whom cyclosporine A (CSA), for example, oral cyclosporine A, is contraindicated.

[0056] An inadequate response to CSA is defined as a relapse of AD on tapering of CSA up to a maintenance dose (2-3 mg / kg / day) after a maximum of 6 weeks of high dose (5 mg / kg / day), or a relapse at least 3 months after the maintenance dose. A relapse is defined as an increase in signs or symptoms that may lead to an expansion of treatment, which may involve dose increase, switching to a higher potency class TCS, or initiation of another systemic nonsteroidal immunosuppressant.

[0057] The following are contraindications for CSA: i. Medical contraindications (e.g., poorly controlled hypertension due to medication) or hypersensitivity to the active substance or excipients of CSA, ii. Use of prohibited concomitant medications (e.g., statins, digoxin, macrolides, antibiotics, barbiturates, anticonvulsants, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, St. John's wort), iii. Increased susceptibility to renal impairment (elevated creatinine) and hepatic impairment (elevated functional test results) due to CSA, or increased risk of serious infection. iv. Intolerance or unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, poorly controlled hypertension, paresthesia, headache, nausea, hirsutism), or v. The required dose of CSA exceeding 5 mg / kg / day, or the need for a duration of administration (more than 1 year) exceeding that specified in the prescription information.

[0058] Treatment for Alzheimer's disease The methods described herein treat Alzheimer's disease (AD). Generally, terms such as “treat,” “medicate,” and “cure” mean to temporarily or permanently alleviate (reduce, minimize, or eliminate) symptoms, or to reduce, minimize, or eliminate the cause of symptoms.

[0059] AD-related parameters Various AD-related parameters are available to measure the severity of AD and the effect of drugs on AD. These include the Investigator General Assessment (IGA), the Area-Based Severity Index (EASI), the Scorading of Atopic Dermatitis (SCORAD), and / or the Numerical Stimulation Scale (NRS). The methods described herein may improve the AD-related parameters of interest. Alternatively, the methods may maintain the improvement of the AD-related parameters of interest. The AD-related parameters may be selected from the Investigator General Assessment (IGA), the Area-Based Severity Index (EASI), the Scorading of Atopic Dermatitis (SCORAD), and / or the Numerical Stimulation Scale (NRS).

[0060] IGA is a tool used in clinical trials to assess the overall severity of Alzheimer's disease in subjects, and is based on a 5-point scale from 0 (clear) to 4 (severe) based on the disease state at the time of assessment. [Table 1]

[0061] The EASI is a validated scale used in clinical practice and clinical trials to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al. "The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Experimental dermatology" (2001) 10(1):11-18). SCORAD is one of the most commonly used disease severity scores in clinical trials and clinical practice for AD (see "European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European task force on atopic dermatitis" Dermatology (1993) 186(1):23-31).

[0062] The diurnal peak score for pruritus (NRS) is established in accordance with FDA and EMA recommendations (see, for example, FDA “The Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009” and EMA “Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQoL) measures in the evaluation of medicinal products. EMEA / CHMP / EWP / 139391 / 2004.2005”). For pruritus (NRS), subjects assess the severity of their worst itchiness over the past 24 hours using an NRS score of 11 points, ranging from 0 (no itchiness) to 10 (worst imaginable itchiness) ("Dilnal Peak Score for Pruritus").

[0063] For each AD-related parameter, improvement or maintenance of improvement is measured relative to baseline. Related improvements may include a decrease in IGA score, a decrease in EASI score, a decrease in SCORAD score (≥50 for severe, 25-50 for moderate, <25 for mild), and a decrease in pruritus NRS score. Each score is compared to baseline.

[0064] The baseline is an initial measurement of an AD-related parameter or patient-related outcome (or any other parameter) taken before the initiation of administration according to the method described herein, i.e., before the “baseline dose” (as defined elsewhere).

[0065] A Principal Investigator's Global Assessment (IGA) score of 0 or 1 (IGA 0 / 1, skin with no or near-no signs of inflammation) and / or an improvement of 75% or more in the Eczema Area Severity Index (EASI-75) is the primary efficacy endpoint by regulatory authorities in Phase 3 clinical trials of Alzheimer's disease (AD). Accordingly, the methods described herein can preferably achieve or maintain an IGA score of 0 or 1 and / or an improvement of 75% or more in the Eczema Area Severity Index (EASI-75) compared to baseline (e.g., as shown in Examples 1 and 4 herein). In some embodiments, the methods can achieve or maintain an improvement of 50% or more in the Eczema Area Severity Index (EASI-50) compared to baseline (e.g., as shown in Example 3).

[0066] Furthermore, or alternatively, the methods described herein may improve at least one patient-related outcome (PRO) selected from the group consisting of the highest diurnal score on the Nutritional Rating Scale (NRS) (see Nutritional Rating Scale above), eczema-related sleep disturbance, Patient Self-Assessment of Eczema (POEM), Skin Condition Questionnaire (DLQI), Patient's General Perception of Troubles (PGI-B), Hospital Anxiety and Depression Questionnaire (HADS), Short-Response (36-item) Health Status Questionnaire (SF-36), and Eurocol 5-Item Health Survey 5-Level (EQ-5D-5L).

[0067] In the case of eczema-related sleep disturbance NRS, subjects rate how much eczema disturbed their sleep the previous night using an 11-point NRS scale from 0 (no disturbance) to 10 (complete disturbance). POEM is a validated questionnaire used to assess disease symptoms in both clinical practice and clinical trials for patients with AD (see Charman et al. "The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients' perspective" Arch Dermatol. (2004) 140(12):1513-1519). DLQI is a validated patient-reported questionnaire that includes content specific to subjects with skin conditions (see Finlay et al. "Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use" Clin Exp Dermatol. (1994) 19(3):210-216). The Patient's General Trouble Impression (PGI-B) is designed to capture the subject's perception of how much they were troubled by AD over the past 24 hours at the time of completion. A five-category response scale is used ("None at all", "Slightly", "Somewhat", "Quite a bit", "Very much"). The Hospital Anxiety and Depression Scale (HADS) is a Likert scale tool widely used to detect anxiety and depression in a typical hospital setting (see Zigmond AS, Snaith RP. "The hospital anxiety and depression scale". Acta Psychiatr Scand. 1983;67(6):361-70). This tool consists of 14 items that assess a subject's anxiety (7 items) and depression (7 items) over the past week. Each item is scored from 0 to 3, with higher scores indicating more severe anxiety or depression.The 36-item Short-Form Health Questionnaire (SF-36) is a patient-reported survey designed to assess health status by generating scores for eight health domains (physical functioning, role functioning (physical), physical pain, overall health perception, vitality, social functioning, functioning in daily living (mental), and mental health), as well as two summary scores (physical health and mental health) obtained through psychometrics (see Ware JEJ, Sherbourne CD, "The 36-item Short-Form Health Questionnaire (SF-36). I. Conceptual framework and item selection," Med Care. 1992;30(6):473-83). The Eurocol 5-Item Health Survey 5-Level (EQ-5D-5L) is a standardized measure of health status developed by the Eurocol Group, providing a simple and general health scale for clinical and economic assessment (see Greiner W et al., "A single European currency for EQ-5D health states. Results from a six-country study," The European Journal of Health Economics: HEPAC: health economics in prevention and care. 2003;4(3):222-31). The EQ-5D-5L is a self-administered questionnaire used to assess health status "today" and is divided into two sections. The first section includes five items (mobility, self-care, daily living, pain / discomfort, and anxiety / depression), each of which is rated by the subject using a five-point scale ("no problem," "slight problem," "moderate problem," "severe problem," and "extreme problem"). The second section consists of a vertical visual analog scale fixed at 0 ("the worst health imaginable") and 100 ("the best health imaginable").

[0068] The method may maintain improvement in at least one patient-related outcome (PRO) selected from a group consisting of the highest diurnal score on the Numerical Rating Scale (NRS), eczema-related sleep disturbance, patient self-assessment of eczema (POEM), skin condition questionnaire (DLQI), patient's general impression of trouble (PGI-B), hospital anxiety and depression questionnaire (HADS), short-response (36-item) health status questionnaire (SF-36), and Eurocol 5-item health survey 5 levels (EQ-5D-5L). For each PRO, improvement or maintenance of improvement is defined as a decrease compared to baseline. This improvement may be a decrease in the PRO score (e.g., a decrease of 3 points or more) (or, e.g., a decrease of 4 points or more on the DLQI), and the score is compared to baseline.

[0069] In some embodiments, the methods described herein may achieve: (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50); (b) a decrease of 2 or more points in the IGA score; (c) a decrease of 3 or more points in the Pruritus NRS; (d) a decrease of 4 or more points in the POEM score; (e) a decrease of 4 or more points in the DLQI score; (f) a decrease of 0.4 or more points in Eczema-Related Sleep Disturbance; (g) a decrease of 1 or more points in the PGI-B score; (h) a decrease of 2 or 3 or more points in the HADS score; (i) an increase of 4 or more points in the SF-36 Physical Health score and / or an increase of 2 or more points in the SF-36 Mental Health score; and / or (j) an increase of 0.2 or more points in the EQ-5D-5L Index score. In some embodiments, the method may maintain: (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50), (b) a decrease of 2 or more points in the IGA score, (c) a decrease of 3 or more points in the pruritus NRS, (d) a decrease of 4 or more points in the POEM score, (e) a decrease of 4 or more points in the DLQI score, (f) a decrease of 0.4 or more points in Eczema-Related Sleep Disturbance, (g) a decrease of 1 or more points in the PGI-B score, (h) a decrease of 2 or 3 or more points in the HADS score, (i) an increase of 4 or more points in the SF-36 Physical Health score and / or an increase of 2 or more points in the SF-36 Mental Health score, and / or (j) an increase of 0.2 or more points in the EQ-5D-5L index score.

[0070] For example, the methods described herein may achieve one or more (in particular all): (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50), (b) a decrease of 2 or more points in the IGA score, (c) a decrease of 4 or more points in the POEM score, and (d) a decrease of 4 or more points in the DLQI score. The methods may maintain one or more (or all) of the following: (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50), (b) a decrease of 2 or more points in the IGA score, (c) a decrease of 4 or more points in the POEM score, and (d) a decrease of 4 or more points in the DLQI score.

[0071] In preferred embodiments, the methods described herein may achieve: (a) a reduction of 4 or more points in the pruritus NRS score, (b) a reduction of 4 or more points in the POEM score, (c) a reduction of 4 or more points in the DLQI score, and / or (d) a reduction of 2 or more points in eczema-related sleep disturbance (e.g., after 2 or 3 weeks, as shown in Example 2).

[0072] In preferred embodiments, the methods described herein may achieve: (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50), (b) a 3 or greater reduction in the Pruritus NRS score, (c) a 4 or greater reduction in the POEM score, (d) a 4 or greater reduction in the DLQI score, and / or (e) a 1 or greater reduction in the PGI-B score (e.g., after 12 weeks, as shown in Example 3).

[0073] In preferred embodiments, the methods described herein may achieve: (a) a 50% or greater improvement in the Eczema Area Severity Index (EASI-50), and / or (b) a 75% or greater improvement in the Eczema Area Severity Index (EASI-75) (for example, after 24 weeks, as shown in Example 3, or after 16 weeks, as shown in Example 11).

[0074] In preferred embodiments, the methods described herein may achieve: (a) a reduction of 4 or more points in the pruritus NRS score, (b) a reduction of 4 or more points in the POEM score, (c) a reduction of 4 or more points in the DLQI score, and / or (d) a reduction of about 1 or more points in eczema-related sleep disturbance (e.g., after 2 or 3 weeks, as shown in Example 5).

[0075] In preferred embodiments, the methods described herein may achieve: (a) a decrease of 2 or more points in the HADS score, or a decrease of 3 or more points; (b) an increase of 4 or more points in the SF-36 physical health score and / or an increase of 2 or more points in the SF-36 mental health score; and / or (c) an increase of 0.2 or more points in the EQ-5D-5L index score (e.g., after 16 weeks, as shown in Examples 9 and 10).

[0076] In preferred embodiments, the methods described herein may achieve: (a) an IGA score of 0 or 1, (b) a reduction in the SCORAD score, (c) a reduction of 4 or more points in the pruritus NRS, and / or (d) an improvement in the DLQI score (e.g., after 16 or 26 weeks, as shown in Example 11).

[0077] In some embodiments, the method may achieve 1, 2, 3, 4, 5, 6, 7, 8, 9 or all of the following: (a) improvement of 50% or more in the Eczema Area Severity Index (EASI-50), (b) a decrease of 2 or more points in the IGA score, (c) a decrease of 3 or more points in the Pruritus NRS, (d) a decrease of 4 or more points in the POEM score, (e) a decrease of 4 or more points in the DLQI score, (f) a decrease of 0.4 or more points in Eczema-Related Sleep Disturbance, (g) a decrease of 1 or more points in the PGI-B score (e.g., as shown in Examples 1-3), (h) a decrease of 2 or 3 or more points in the HADS score, (i) an increase of 4 or more points in the SF-36 Physical Health score and / or an increase of 2 or more points in the SF-36 Mental Health score, and / or (j) an increase of 0.2 or more points in the EQ-5D-5L index score.

[0078] In some embodiments, the methods described herein may maintain 1, 2, 3, 4, 5, 6, 7, 8, 9 or all of the following: (a) improvement of 50% or more in the Eczema Area Severity Index (EASI-50), (b) a decrease of 2 or more points in the IGA score, (c) a decrease of 3 or more points in the Pruritus NRS, (d) a decrease of 4 or more points in the POEM score, (e) a decrease of 4 or more points in the DLQI score, (f) a decrease of 0.4 or more points in Eczema-Related Sleep Disturbance, (g) a decrease of 1 or more points in the PGI-B score, (h) a decrease of 2 or 3 or more points in the HADS score, (i) an increase of 4 or more points in the SF-36 Physical Health score and / or an increase of 2 or more points in the SF-36 Mental Health score, and / or (j) an increase of 0.2 or more points in the EQ-5D-5L index score.

[0079] TCS dependency Long-term use of TCS is not recommended due to the risk of skin atrophy, hyperpigmentation abnormalities, acneiform rash, and systemic absorption-related risks (e.g., effects on the hypothalamic-pituitary axis, Cushing's disease, etc.). Prolonged or repeated application of any topical therapy to a large surface area may also lead to decreased patient compliance.

[0080] The methods described herein may reduce topical corticosteroid (TCS) dependence in subjects with AD (particularly moderate to severe or severe AD).

[0081] The reduction in dependence can be assessed by comparing the cumulative amount (grams) of the TCS-containing formulation applied by subjects over a specific time interval (e.g., 16 weeks) after the initiation of the method described herein with that of subjects who received a placebo. For example, subjects may use at least 0.2 g less, at least 0.3 g less, at least 0.4 g less, or at least 0.5 g less per day than subjects who received a placebo. Typically, subjects may use at least 0.5 g less per day than subjects who received a placebo (e.g., in Example 1).

[0082] The reduction in dependence can also be assessed by the number of days without TCS (which may include low-potency TCS and TCI) compared to the same measurement performed at baseline after the initiation of the method.

[0083] TCS can be classified as topical corticosteroids of Group I, Group II, Group III, and Group IV. According to the World Health Organization's Anatomical and Therapeutic Chemistry Classification, corticosteroids are classified into weak / low potency (Group I), moderate potency (Group II), high potency (Group III), and very high potency (Group IV) based on their activity compared to hydrocortisone. Group IV TCS (very high potency) are up to 600 times potent than hydrocortisone and include clobetasol propionate and hallucinonide. Group III TCS (high potency) are 50 to 100 times potent than hydrocortisone and include betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (medium-high potency) is 2 to 25 times potent than hydrocortisone and contains clobetasone butyrate and triamcinolone acetonide. Group I TCS (low potency) contains hydrocortisone.

[0084] The term "TCS-free day" refers to a day on which a subject does not use TCS in Group II, Group III, or Group IV.

[0085] For example, the number of days a subject does not use TCS may increase by an average of approximately 0.5 days, 0.75 days, 1 day, 1.5 days, 2 days, 3 days, or more per week compared to a placebo-treated subject. Typically, the number of days a subject does not use TCS may increase by approximately 0.5 days compared to a placebo-treated subject (as shown, for example, in Example 1).

[0086] As shown in the following examples, the IL-13 binding protein may be administered as monotherapy, i.e., without TCS, so that it can be used to discontinue the use of TCS in subjects. Accordingly, in the methods described herein, a medium-to-high potency or high-potency TCS may also be administered in parallel with the IL-13 binding protein. The amount of TCS can then be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or about 100% compared to the baseline amount of TCS, after the start of the method (for example, over a period of 3-4 months).

[0087] Treatment of skin infections In some embodiments, the methods described herein treat skin infections. Generally, terms such as “treat,” “medicate,” and “cure” mean to temporarily or permanently alleviate (reduce, minimize, or eliminate) symptoms, or to reduce, minimize, or eliminate the cause of symptoms.

[0088] Patients receiving treatment have microbial skin infections such as bacterial, fungal, or viral infections. For example, such skin infections may include Staphylococcus aureus infection, Streptococcus infection, impetigo, cellulitis, infectious dermatitis, herpetic eczema, folliculitis, infectious vesicles, mycosis, and tinea versicolor.

[0089] In some embodiments, the IL-13 binding protein is not administered in combination with a topical corticosteroid. “Not administered in combination with” means “not administered in the same therapeutic course.” In some embodiments, the IL-13 binding protein is administered as monotherapy for treating skin infections in subjects with moderate to severe Alzheimer's disease (AD).

[0090] In some embodiments, the IL-13 conjugate is administered together with a second therapeutic agent, such as an antibacterial agent, antiviral agent, antifungal agent, another IL-13 antagonist, IgE inhibitor, nonsteroidal anti-inflammatory drug (NSAID), or interferon-gamma (IFNγ). The second therapeutic agent may be administered to the subject before, after, or concurrently with the IL-13 conjugate protein.

[0091] Treatment for itching In some embodiments, the methods described herein treat pruritus (i.e., itchiness).

[0092] Treatment of pruritus means a reduction in the diurnal peak of the pruritus numerical score (NRS) compared to baseline, for example, before treatment. In some embodiments, treatment of pruritus is characterized by a reduction of 1 or more points, 2 or more points, 3 or more points, or 4 or more points in the diurnal peak of the pruritus NRS compared to baseline, for example, before treatment.

[0093] The diurnal peak of the pruritus NRS is determined according to FDA and EMA recommendations (see, for example, FDA “The Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009” and EMA “Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQoL) measures in the evaluation of medicinal products. EMEA / CHMP / EWP / 139391 / 2004.2005”). For the pruritus NRS, subjects rate the severity of their worst itchiness over the past 24 hours ("diurnal peak of the pruritus NRS") using an NRS score of 11 points from 0 (no itchiness) to 10 (worst itchiness imaginable).

[0094] In some embodiments, the IL-13 binding protein is not administered in combination with a topical corticosteroid. “Not administered in combination with” means “not administered in the same therapeutic course.” In some embodiments, the IL-13 binding protein is administered as monotherapy for the treatment of pruritus in subjects with moderate to severe Alzheimer's disease (AD).

[0095] In some embodiments, the subjects may be those whose atopic dermatitis is not adequately controlled by cyclosporine A (CSA), such as oral cyclosporine A, or they may be those who have contraindications to cyclosporine A (CSA), such as oral cyclosporine A.

[0096] Treatment of eczema-related sleep disturbances In some embodiments, the methods described herein treat eczema-related sleep disturbances.

[0097] In the case of the Eczema-Related Sleep Disturbance Quantification Score (NRS), subjects rate how much their eczema disrupted their sleep the previous night using an NRS of 11 points, ranging from 0 (no disruption) to 10 (complete disruption).

[0098] Treatment of eczema-related sleep disturbance means a reduction in the eczema-related sleep disturbance NRS compared to baseline, e.g., before treatment. In some embodiments, treatment of eczema-related sleep disturbance NRS is characterized by a reduction of 0.4 points or more, 1 point or more, 2 points or more, or 4 points or more from baseline, e.g., before treatment.

[0099] Treatment of anxiety and depression In some embodiments, the methods described herein treat anxiety and / or depression.

[0100] When using the HADS to assess anxiety and / or depression, patients rate the 14 items on the questionnaire from 0 to 3, resulting in a total score of 0 to 21 for anxiety or depression.

[0101] Treatment of anxiety and / or depression means a decrease in HADS scores, e.g., a decrease in the HADS anxiety score and / or HADS depression score, compared to baseline, e.g., pre-treatment. In some embodiments, treatment of anxiety and / or depression is characterized by a decrease of 1 or more points, 2 or more points, 3 or more points, or 4 or more points in the HADS score from baseline, e.g., pre-treatment.

[0102] In some embodiments, the methods described herein treat anxiety and / or depression in subjects having AD, for example, moderate to severe AD. In some preferred embodiments, the subjects may have a baseline (e.g., pre-treatment) HADS score of 8 or higher, for example, a baseline HADS anxiety score and / or HADS depression score of 8 or higher.

[0103] Treatment of patients with conjunctivitis In some embodiments, the present invention provides an IL-13 binding protein for use in a method for treating atopic dermatitis in subjects who have previously experienced conjunctivitis when treated with an IL-13 binding protein in combination with a topical corticosteroid, the method comprising: (a) administering to the subject a first dose of the IL-13 binding protein, wherein the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid; and (b) administering to the subject one or more second doses of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose, and the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose.

[0104] In some embodiments, the present invention provides an IL-13 binding protein for use in a method for treating atopic dermatitis in subjects, the method comprising: (a) selecting subjects who have experienced conjunctivitis when treated with an IL-13 binding protein in combination with a topical corticosteroid; (b) administering a first dose of the IL-13 binding protein to the subjects, wherein the IL-13 binding protein is not administered to the subjects in combination with a topical corticosteroid; and (c) administering one or more second doses of the IL-13 binding protein to the subjects, wherein each second dose is administered to the subjects 12 to 35 days after the previous dose, and the IL-13 binding protein is not administered to the subjects in combination with a topical corticosteroid. Preferably, each second dose is administered to the subject 12 to 16 days after the previous dose, for example, 14 days after the previous dose, or 25 to 31 days after the previous dose, for example, about 4 weeks after the previous dose.

[0105] In some embodiments, the present invention provides a method for treating atopic dermatitis in subjects who have previously experienced conjunctivitis when treated with IL-13 binding protein in combination with topical corticosteroids, the method comprising: (a) administering to the subject a first dose of the IL-13 binding protein, wherein the IL-13 binding protein is not administered to the subject in combination with topical corticosteroids; and (b) administering to the subject one or more second doses of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose, and the IL-13 binding protein is not administered to the subject in combination with topical corticosteroids. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose.

[0106] In some embodiments, the present invention provides a method for treating atopic dermatitis in subjects, the method comprising: (a) selecting subjects who have experienced conjunctivitis when treated with IL-13 binding protein in combination with topical corticosteroids; (b) administering a first dose of the IL-13 binding protein to the subjects, wherein the IL-13 binding protein is not administered to the subjects in combination with topical corticosteroids; and (c) administering one or more second doses of the IL-13 binding protein to the subjects, wherein each second dose is administered to the subjects 12 to 35 days after the preceding dose, and the IL-13 binding protein is not administered to the subjects in combination with topical corticosteroids. Preferably, each second dose is administered to the subjects 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose.

[0107] In some embodiments, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis in subjects who have previously experienced conjunctivitis when treated with an IL-13 binding protein in combination with a topical corticosteroid, the method comprising: (a) administering to the subject a first dose of the IL-13 binding protein, wherein the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid; and (b) administering to the subject one or more second doses of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose, and the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. Preferably, each second dose is administered to the subject 12 to 16 days after the previous dose, for example, 14 days after the previous dose, or 25 to 31 days after the previous dose, for example, about 4 weeks after the previous dose.

[0108] In some embodiments, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis in a subject, the method comprising: (a) selecting a subject that has experienced conjunctivitis when treated with the IL-13 binding protein in combination with a topical corticosteroid; (b) administering to the subject a first dose of the IL-13 binding protein, wherein the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid; and (c) administering to the subject one or more second doses of the IL-13 binding protein, wherein each second dose is administered to the subject 12 to 35 days after the previous dose, and the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. Preferably, each second dose is administered to the subject 12 to 16 days after the previous dose, for example, 14 days after the previous dose, or 25 to 31 days after the previous dose, for example, about 4 weeks after the previous dose.

[0109] In some embodiments, the present invention provides an IL-13 binding protein for use in a method of treating atopic dermatitis in subjects who have experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, for example, dupilumab, the method comprising: (a) administering a first dose of the IL-13 binding protein to the subject; and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0110] In some embodiments, the present invention provides an IL-13 binding protein for use in a method for treating atopic dermatitis in subjects, the method comprising: (a) selecting subjects who have experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, such as dupilumab; (b) administering a first dose of the IL-13 binding protein to the subjects; and (c) administering one or more second doses of the IL-13 binding protein to the subjects, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subjects in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0111] In some embodiments, the present invention provides a method for treating atopic dermatitis in subjects who have previously experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, such as dupilumab, the method comprising: (a) administering a first dose of the IL-13 binding protein to the subject; and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0112] In some embodiments, the present invention provides a method for treating atopic dermatitis in subjects, the method comprising: (a) selecting subjects who have experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, such as dupilumab; (b) administering a first dose of IL-13 binding protein to the subjects; and (c) administering one or more second doses of the IL-13 binding protein to the subjects, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subjects in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0113] In some embodiments, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis in subjects who have experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, for example, dupilumab, the method comprising the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0114] In some embodiments, the present invention provides the use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis in a subject, the method comprising: (a) selecting a subject who has experienced conjunctivitis when treated with an anti-IL4Rα antibody or an antibody that inhibits IL4 / IL13 signaling, such as dupilumab; (b) administering a first dose of the IL-13 binding protein to the subject; and (c) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose. Preferably, the IL-13 binding protein is not administered to the subject in combination with a topical corticosteroid. In some embodiments, the subjects discontinued dupilumab therapy as a result of experiencing conjunctivitis.

[0115] In some embodiments of the above-described method relating to the treatment of AD patients experiencing conjunctivitis after treatment with alternative therapies, the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) the step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each dose administered after the first dose of the one or more prior doses (prior doses, first dose, and second doses) is approximately 300 mg of the IL-13 binding protein.

[0116] In some embodiments of the above-described method relating to the treatment of AD patients experiencing conjunctivitis after treatment with alternative therapies, the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the most recent dose. (ii) the step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering to the subject one or more second doses of the IL-13 binding protein for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject about two weeks or about four weeks after the preceding dose, where the first dose of the one or more prior doses is about 600 mg of the IL-13 binding protein, and each dose administered after the first of the one or more prior doses (prior doses, first dose, and second doses) is about 300 mg of the IL-13 binding protein.

[0117] IL-13 binding protein IL-13 binding proteins are proteins that specifically bind to human IL-13 and neutralize it.

[0118] In this specification, the term “specifically binds” means that a protein (e.g., an antibody or its antigen-binding fragment) forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether a protein specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance (e.g., using the BIAcore 200 biosensor (BIAcore AB)). For example, an IL-13 binding protein that “specifically binds” to IL-13 (e.g., an anti-IL-13 antibody or its IL-13-binding fragment) can be measured by surface plasmon resonance at 25°C, and K D It can bind to IL-13 at concentrations of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 100 nM, less than approximately 50 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 1 nM, less than approximately 0.5 nM, less than approximately 0.25 nM, less than approximately 0.1 nM, or less than approximately 0.05 nM. Tralokinumab, an exemplary antibody, can be measured by surface plasmon resonance (see WO2005 / 007699 for detailed methods), K D It binds to human-conjugated human IL-13 at 178 pM. Therefore, in a preferred embodiment, the anti-IL-13 antibody is measured by surface plasmon resonance at 37°C or 25°C, and K DIt has a concentration of less than approximately 200 pM. IL-13 binding proteins specifically bind to human IL-13, but may also exhibit cross-reactivity to other antigens, such as IL-13 from other (non-human) species.

[0119] Methods for measuring neutralizing activity are well known in the art. Neutralizing activity can be measured by an IL-13-dependent TF-1 cell proliferation assay compared to a control antibody not directed towards IL-13, as described in WO2005 / 007699. In this assay, inhibition of IL-13-dependent proliferation is determined by measuring the decrease in the uptake of tritiated thymidine into newly synthesized DNA of dividing cells. Briefly, commercially available TF-1 cells are maintained according to the provided protocol. The assay medium contains RPMI-1640 supplemented with GLUTAMAX I (Invitrogen) containing 5% FBS and 1% sodium pyruvate. Before each assay, TF-1 cells are pelleted by centrifugation at 300xg for 5 minutes, the medium is aspirated and removed, and the cells are resuspended in the assay medium. This process is repeated for 10 minutes. 5The procedure is repeated twice with cells resuspended in assay medium at a final concentration of cells / mL. Test antibody solutions (in triplicate) are diluted to the desired concentration with assay medium. An antibody not directed against IL-13 is used as a negative control. Human or mouse IL-13 derived from recombinant bacteria is added to a final concentration of 50 ng / mL when mixed with an appropriate test antibody at a total volume of 100 µL / well in a 96-well assay plate. The concentration of IL-13 used in the assay is selected such that the final assay concentration provides a dose that gives approximately 80% of the maximal proliferative response. All samples are incubated for 30 minutes at room temperature. Next, 100 µL of the resuspended cells are added to each assay point to bring the total assay volume to 200 µL / well. The assay plate is incubated for 72 hours at 37°C under 5% CO₂. 25 µL of tritiated thymidine (10 µCi / mL) is then added to each assay point, and the assay plate is returned to the incubator for an additional 4 hours. Cells are harvested onto a glass fiber filter plate (Perkin Elmer) using a cell harvester. Thymidine incorporation is measured using a Packard TopCount microplate liquid scintillation counter.

[0120] Anti-IL-13 antibody and IL-13 binding thereof Typically, said IL-13 binding protein is an anti-IL-13 antibody or an IL-13 binding fragment thereof.

[0121] As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains interconnected by disulfide bonds, that is, two heavy (H) chains and two light (L) chains, as well as multimers thereof (e.g., IgM). In a conventional antibody, each heavy chain comprises a heavy chain variable region (herein abbreviated as HCVR or V H ) and a heavy chain constant region. The heavy chain constant region comprises three domains, that is, C H 1, C H 2 and C H 3. Each light chain comprises a light chain variable region (herein abbreviated as LCVR or V LIt includes a light chain steady region (abbreviated as C). The light chain steady region consists of one domain (C L 1) includes the V H and V L It is further divided into a more conserved region called the framework region (FR) and a highly variable region called the complementarity-determining region (CDR). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some cases, the FRs of the anti-IL-13 antibody (or its IL-13 binding fragment or derivative) may be identical to the human germline sequence, or they may be naturally or artificially modified.

[0122] The heavy chain constant region of the antibody may originate from any type of constant region, such as IgG, IgM, IgD, IgA, and IgE. Generally, the antibody is IgG (e.g., isotype IgG1, IgG2, IgG3, or IgG4). Preferably, the antibody is IgG4, as illustrated herein.

[0123] The antibody may be mouse, human, primate, humanized, or chimeric. The antibody may be polyclonal or monoclonal. Monoclonal and human (or humanized) antibodies are preferred for therapeutic applications. In a particularly preferred embodiment, the antibody is human or humanized and monoclonal.

[0124] The antibody may be a multispecific (e.g., bispecific) antibody. A multispecific antibody or antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, each of which can specifically bind to a distinct antigen or a different epitope of the same antigen. Any multispecific antibody format can be adapted for use in association with the antibodies or antigen-binding fragments of antibodies described herein using common techniques available in the art. For example, a method using a bispecific antibody in which one arm of the immunoglobulin is specific to IL-13 and the other arm of the immunoglobulin is specific to or bound to a second therapeutic target or therapeutic moiety.

[0125] The IL-13 binding fragment of an anti-IL-13 antibody may be any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide. Such fragments may be obtained from a complete antibody molecule using any suitable standard technique, such as recombinant genetic engineering techniques, including, for example, proteolytic digestion or manipulation and expression of DNA encoding an antibody variable domain and optionally a constant domain. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or using molecular biological techniques, for example, by arranging one or more variable and / or constant domains into a suitable configuration, or by introducing codons, creating cysteine ​​residues, modifying, adding, or deleting amino acids, etc.

[0126] Non-limiting examples of IL-13 binding fragments include Fab, Fab', F(ab')2, Fd, Fv, single-chain Fv(scFv), disulfide-bonded Fv, dAb fragments, and other manipulated molecules such as domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR-transplant antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunoassays (SMIPs), and shark variable IgNAR domains.

[0127] The IL-13 binding fragment of an anti-IL-13 binding antibody typically contains at least one variable domain. This variable domain may be of any size or amino acid composition and typically contains at least one CDR, which is either adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In antigen-binding fragments having a domain, the V H Domain and V L The domains can be located relative to each other in any suitable arrangement. For example, the variable region may be a dimer, and V H -V H , V H -V L or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may be a monomer V. H or V L It may include a domain name.

[0128] The anti-IL-13 antibody, or its IL-13 binding fragment, may include a heavy chain complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determination region 1 (LCDR1) containing the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determination region 2 (LCDR2) containing the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determination region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 6. The anti-IL-13 antibody, or its IL-13 binding fragment, may include a heavy chain variable region (HCVR) and a light chain variable region (LCVR), where (i) the heavy chain variable region includes a heavy chain complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 2, and a heavy chain complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 3; and (ii) the light chain variable region includes a light chain complementarity determination region 1 (LCDR1) containing the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determination region 2 (LCDR2) containing the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determination region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 6. Furthermore, the anti-IL-13 antibody, or its IL-13 binding fragment, may further include (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain variable region sequence of SEQ ID NO: 8, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain variable region sequence of SEQ ID NO: 10. The anti-IL-13 antibody, or its IL-13 binding fragment, may include the heavy chain variable region sequence of SEQ ID NO: 8 and the light chain variable region sequence of SEQ ID NO: 10.

[0129] The anti-IL-13 antibody, or its IL-13-binding fragment, may include (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain sequence of SEQ ID NO: 11, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain sequence of SEQ ID NO: 12. In some cases, the anti-IL-13 antibody, or its IL-13-binding fragment or IL-13-binding derivative, may include the heavy chain sequence of SEQ ID NO: 11 and the light chain sequence of SEQ ID NO: 12.

[0130] One such antibody that may be used in the methods described herein is tralokinumab, an anti-IL-13 antibody (as listed in “International Nonproprietary Names for Pharmaceutical Substances (INN)” list 102 (WHO Drug Information (2009) 23(4): pp 348)). Tralokinumab is a fully human IgG4-lambda antibody that specifically binds to and neutralizes human IL-13. [Table 2-1] [Table 2-2]

[0131] Methods for identifying, isolating, and testing (e.g., conjugating and neutralizing) antibodies and their fragments are well known in the art. See WO2005 / 007699, which discloses the identification and characterization of various anti-IL-13 antibodies and fragments and provides appropriate methods for doing so.

[0132] Dosage and administration plan The present invention provides the above-mentioned interleukin-13 (IL-13) binding protein (e.g., an anti-IL-13 antibody or its IL-13 binding fragment) for use in any therapeutic method described herein, the method comprising: (a) administering a first dose of the IL-13 binding protein to a subject; and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the preceding dose. Preferably, each second dose is administered to the subject 12 to 16 days after the preceding dose, for example, 14 days after the preceding dose, or 25 to 31 days after the preceding dose, for example, about 4 weeks after the preceding dose.

[0133] The term "dose" refers to the amount (mass) of IL-13 binding protein administered to a subject on a particular treatment day. For example, a dose of 300 mg of IL-13 binding protein means that a total of 300 mg of IL-13 binding protein is given to the subject on a treatment day. Typically, the dose is administered in a single administration step (e.g., one injection). However, in some embodiments, one, two, three or more administration steps (e.g., one, two, three or more injections) may be used to provide the subject with the desired dose.

[0134] The terms “prior dose,” “first dose,” “second dose,” and “third dose” refer to the time series of IL-13 binding protein administrations. The term “first dose” refers to a single dose of IL-13 binding protein, followed by one or more second doses. The first dose may be preceded by one or more prior doses, or the “first dose” may be the initiation of treatment by the method described herein (in the latter case, this dose may therefore be called the “baseline dose”). The first dose is followed by one or more second doses, which may be followed by one or more third doses.

[0135] The expression "immediately preceding dose" refers to the dose of IL-13 binding protein administered to a patient in a series of multiple doses, without any intervening doses of IL-13 binding protein before subsequent doses in the series.

[0136] "Dosage frequency" refers to the frequency with which the dose of the IL-13 binding protein is administered. Therefore, a decrease in dosage frequency means an increase in the time interval between doses. Common terms used in relation to dosage frequency are QW (once a week), Q2W (once every two weeks), Q3W (every three weeks), or Q4W (every four weeks).

[0137] The first dose may be about 10 mg to about 600 mg of the IL-13 binding protein, about 50 mg to about 500 mg, about 100 mg to about 400 mg, about 250 mg to about 350 mg, or about 280 mg to about 320 mg. For example, the first dose is about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. In some cases, the first dose is 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, the first dose is about 300 mg of the IL-13 binding protein (for example, as shown in the examples).

[0138] Each second dose may be administered to the subject 18–35 days, 21–35 days, 22–34 days, 24–32 days, 25–31 days, 26–30 days, or 27–29 days after the previous dose. In certain cases, each second dose may be administered to the subject approximately 28 days after the previous dose (as illustrated herein).

[0139] The methods described herein may be carried out until an improvement in the AD-related parameters and / or patient-related outcomes described herein is obtained. In some cases, the methods may result in improvements in AD-related parameters and / or patient-related outcomes in about 2 weeks, about 3 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, or about 52 weeks. In preferred embodiments, the improvement in AD-related parameters and / or patient-related outcomes is obtained in about 16 weeks (e.g., improvements in IGA and EASI scores, Examples 1 and 4, etc.).

[0140] In some cases, the method may be continued until the subject reaches a low-disease state. For example, the subject may reach a low-disease state in about 4 weeks, about 8 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, or about 52 weeks. In a preferred embodiment, the subject may reach a low-disease state in about 16 weeks (as in Examples 1 and 4, etc.).

[0141] In some cases, the method may be carried out for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 24 weeks, at least 6 months, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer. In some cases, the method may be carried out for about 2 weeks, about 3 weeks, about 12 weeks, about 3 months, about 16 weeks, about 24 weeks, about 6 months, about 32 weeks, about 36 weeks, about 1 year, or about 52 weeks. In a preferred embodiment, the method may be carried out for at least 16 weeks (e.g., in Examples 1 and 4, etc.), at least 32 weeks (e.g., in Example 1, etc.), or at least 52 weeks (e.g., in Example 4, etc.).

[0142] In this specification, the term "low disease state" refers to an Investigator Global Assessment (IGA) score of 0 or 1 and / or a 75% or greater improvement in the Eczema Area Severity Index (EASI-75) compared to baseline.

[0143] Step (b) of the method (i.e., administering one or more second doses of the IL-13 binding protein to the subject) may be continued for 8 to 52 weeks, 12 to 40 weeks, or 16 to 36 weeks (i.e., by administering multiple second doses). The one or more second doses may be administered for at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 6 months, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 1 year, at least 52 weeks, or longer. Step (b) of the method may be continued for about 8 weeks, about 12 weeks, about 3 months, about 16 weeks, about 20 weeks, about 24 weeks, about 6 months, about 28 weeks, about 32 weeks, about 36 weeks, about 1 year, about 52 weeks, or longer (i.e., by administering multiple second doses). In a preferred embodiment, the one or more second doses are administered for at least 16 weeks (e.g., in Example 1) or at least 36 weeks (e.g., in Example 4). Furthermore, or alternatively, step (b) may be continued until the method results in improvement of the AD-related parameters and / or patient-related outcomes described herein. Step (b) may be continued to maintain the improvement of the AD-related parameters and / or patient-related outcomes described herein. In particular cases, step (b) may be continued until the subject reaches a low-disease state.

[0144] Each second dose may be approximately 10 mg to 600 mg of the IL-13 binding protein, approximately 50 mg to 500 mg, approximately 100 mg to 400 mg, approximately 250 mg to 350 mg, or approximately 280 mg to 320 mg. For example, each second dose may be approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg. In some cases, each second dose may be 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, each second dose is approximately 300 mg of the IL-13 binding protein (for example, in the Examples). Typically, the first dose and one or more second doses are equal amounts (i.e., milligrams) of IL-13 binding protein.

[0145] In a preferred embodiment, the method includes (a) administering a first dose of about 300 mg of IL-13 binding protein (e.g., tralokinumab) to a subject, and (b) administering one or more second doses of about 300 mg of the IL-13 binding protein (e.g., tralokinumab) to the subject, wherein each second dose is administered to the subject about four weeks after the immediately preceding dose, and optionally, the method is carried out for about 12 weeks (i.e., about 300 mg of the IL-13 binding protein (e.g., tralokinumab) is administered to the subject at week 0, week 4, week 8 and week 12). Preferably, each dose is administered by subcutaneous injection.

[0146] In the methods described herein, prior to step (a) (i.e., administering a first dose of the IL-13 binding protein to a subject), the method may further include administering one or more prior doses of the IL-13 binding protein to the subject. Each prior dose may be administered to the subject 3 to 6 weeks after the immediately preceding prior dose, for example, 1 to 6 weeks, 1 to 4 weeks, 1 to 3 weeks, or 1 to 2 weeks after the immediately preceding prior dose. In preferred embodiments, each prior dose is administered to the subject 12 to 16 days (e.g., about 2 weeks) after the immediately preceding prior dose (as shown in the examples).

[0147] The method may include administering one or more prior doses of the IL-13 binding protein to the subject for 2 to 36 weeks, 4 to 20 weeks, 8 to 16 weeks, or 12 to 16 weeks, for example, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, or longer. Preferably, the method includes administering one or more prior doses of the IL-13 binding protein to the subject for about 16 weeks or less (for example, in Examples 1 and 4). Furthermore, or alternatively, the administration of one or more prior doses of the IL-13 binding protein may be continued until the method results in improvement of the AD-related parameters and / or patient-related outcomes described herein (by administering multiple prior doses). In certain cases, the administration of one or more prior doses of the IL-13 binding protein may be continued until the subject reaches a low disease state. For example, if a subject shows partial improvement in the AD-related parameters and / or patient-related outcomes described herein after being administered one or more prior doses of the IL-13 binding protein for about 16 weeks, the administration of one or more prior doses of the IL-13 binding protein to the subject may be continued beyond 16 weeks, for example, for about 20 weeks or more, about 24 weeks or more, about 28 weeks or more, about 32 weeks or more, about 36 weeks or more, about 40 weeks or more, about 44 weeks or more, about 48 weeks or more, or about 52 weeks or more, until the method yields the desired improvement in the AD-related parameters and / or patient-related outcomes described herein. In a preferred embodiment, each prior dose is administered to the subject 12 to 16 days (e.g., about 2 weeks) after the immediately preceding prior dose. Preferably, administering one or more prior doses 12 to 16 days (e.g., about two weeks) after the most recent prior dose is continued until the subject achieves an Investigator's Global Assessment (IGA) score of 0 or 1 and / or an eczema area severity index improvement of 75% or more compared to the subject's baseline (EASI-75).After the subject has achieved the desired response, one or more second doses of the IL-13 binding protein may be administered to the subject 15 to 35 days after the previous dose, preferably 28 days after the previous dose.

[0148] Each pre-dose may be approximately 10 mg to 600 mg of the IL-13 binding protein, approximately 50 mg to 500 mg, 100 mg to 400 mg, approximately 250 mg to 350 mg, or approximately 280 mg to 320 mg. For example, each pre-dose may be approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg. In some cases, the dose may be 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, each pre-dose is approximately 300 mg of the IL-13 binding protein (as shown, for example, in the examples).

[0149] If administering one or more prior doses results in improvement of one or more AD-related parameters or patient-related outcomes as described herein, steps (a) and (b) of the method (i.e., administering a first dose and one or more second doses of the IL-13 binding protein to the subject) may further improve or maintain the one or more AD-related parameters or patient-related outcomes. If the subject reaches a low-disease state by administering one or more prior doses, steps (a) and (b) of the method (i.e., administering a first dose and one or more second doses of the IL-13 binding protein to the subject) may maintain the low-disease state. Preferably, administering one or more prior doses may result in achieving an Investigator Global Assessment (IGA) score of 0 or 1 and / or an improvement of 75% or more in the Eczema Area Severity Index (EASI-75) compared to the subject's baseline, which is then maintained by method steps (a) and (b) (for example, as shown in Examples 1 and 4).

[0150] If the method includes one or more prior doses of the IL-13 binding protein, the first of these prior doses is the first dose in a time series of administrations of the IL-13 binding protein, indicating the initiation of treatment by the method described herein. In these cases, the “first” prior dose may therefore also be called the “baseline dose.”

[0151] For example, the method described herein may include the steps of (i) administering one or more prior doses of the IL-13 binding protein to the subject for about two weeks to 36 weeks, wherein each prior dose is administered three days to two weeks after the most recent dose; (ii) administering a first dose of the IL-13 binding protein to the subject; and (iii) administering one or more second doses of the IL-13 binding protein to the subject for at least eight weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 days to 35 days after the most recent dose, where each dose (prior dose(s), first dose, and second dose(s)) is about 10 mg to about 600 mg of the IL-13 binding protein.

[0152] The methods described herein may also include the steps of (i) administering one or more prior doses of the IL-13 binding protein to the subject for about 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose; (ii) administering a first dose of the IL-13 binding protein to the subject; and (iii) administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered 12 to 16 days (e.g., 14 days) or 26 to 30 days (e.g., 28 days) after the most recent dose, where each dose (prior dose(s), first dose, and second dose(s)) is 250 mg to 350 mg of the IL-13 binding protein.

[0153] The methods described herein may also include the steps of (i) administering one or more prior doses of the IL-13 binding protein to the subject for about 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose; (ii) administering a first dose of the IL-13 binding protein to the subject; and (iii) administering one or more second doses of the IL-13 binding protein to the subject for at least 8 weeks, wherein the first dose of the one or more prior doses is about 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is about 300 mg of the IL-13 binding protein.

[0154] The methods described herein may also include the steps of (i) administering one or more prior doses of the IL-13 binding protein to the subject for about 12 to 16 weeks, wherein each prior dose is administered about two weeks after the most recent dose; (ii) administering a first dose of the IL-13 binding protein to the subject; and (iii) administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered about two or four weeks after the most recent dose, where each dose (prior dose(s), first dose, and second dose(s)) is about 300 mg of the IL-13 binding protein.

[0155] The methods described herein may also include the steps of (i) administering one or more prior doses of the IL-13 binding protein to the subject for about 12 to 16 weeks, wherein each prior dose is administered about two weeks after the most recent dose; (ii) administering a first dose of the IL-13 binding protein to the subject; and (iii) administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered about two to four weeks after the most recent dose, where the first dose of the one or more prior doses is about 600 mg of the IL-13 binding protein, and each dose administered after the first of the one or more prior doses (prior doses, first dose, and second dose) is about 300 mg of the IL-13 binding protein.

[0156] In the uses and methods described herein, following step (b) (i.e., administering one or more second doses of the IL-13 binding protein to a subject), the method may further include the step of (c) administering one or more third doses of the IL-13 binding protein to the subject.

[0157] Each third dose may be administered to the subject 3 to 6 weeks after the immediately preceding third dose, for example, 1 to 6 weeks, 1 to 4 weeks, 1 to 3 weeks, or 1 to 2 weeks after the immediately preceding third dose. In a preferred embodiment, each third dose is administered to the subject 12 to 16 days (e.g., about 2 weeks) after the immediately preceding third dose.

[0158] The method may include administering to the subject one or more third doses of the IL-13 binding protein for 2 to 36 weeks, 4 to 20 weeks, 8 to 16 weeks, or about 12 to 16 weeks, for example, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks, or about 20 weeks or longer. Furthermore, or alternatively, the administration of one or more third doses of the IL-13 binding protein may be continued (by administering multiple third doses) until the method results in improvement of the AD-related parameters and / or patient-related outcomes described herein. In certain cases, the administration of one or more third doses of the IL-13 binding protein may be continued until the subject reaches a low-disease state.

[0159] Each third dose may be approximately 10 mg to 600 mg of the IL-13 binding protein, approximately 50 mg to 500 mg, approximately 100 mg to 400 mg, approximately 250 mg to 350 mg, or approximately 280 mg to 320 mg. For example, each third dose may be approximately 10 mg, approximately 25 mg, approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg. In some cases, the dose may be 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In a preferred embodiment, each third dose is approximately 300 mg of the IL-13 binding protein.

[0160] If steps (a) and (b) (and optionally any prior dose) result in improvement of one or more AD-related parameters / or patient-related outcomes described herein, step (c) (i.e., administering one or more third doses of the IL-13 binding protein to the subject) may further improve or maintain the one or more AD-related parameters or patient-related outcomes. If the subject reaches a low-disease state by administering the first dose and one or more second doses (and optionally any prior doses) of the IL-13 binding protein to the subject, step (c) (i.e., administering one or more third doses of the IL-13 binding protein to the subject) may maintain the low-disease state. For example, the first dose and one or more second doses (and optionally any prior doses) may result in an Investigator Global Assessment (IGA) score of 0 or 1 and / or an improvement of 75% or more in the Eczema Area Severity Index (EASI-75) compared to the baseline of the subject, which is then maintained by method step (c).

[0161] In the methods described herein, following step (c), the method may further include one or more repetitions of steps (a), (b), and (c), for example, a series of administration steps may continue to repeat steps (a), step (b), step (c), step (a), step (b), step (c), etc. For example, if step (c) results in an improvement in one or more AD-related parameters and / or patient-related outcomes described herein, one or more repetitions of steps (a) and (b) may maintain the one or more AD-related parameters or patient-related outcomes. If administering one or more third doses of the IL-13 binding protein to the subject results in the subject reaching a low-disease state, one or more repetitions of steps (a) and (b) may maintain the low-disease state. For example, one or more third doses may achieve an Investigator Global Assessment (IGA) score of 0 or 1 and / or an improvement of 75% or more in the Eczema Area Severity Index (EASI-75) compared to the baseline of the subject, which is then maintained by one or more repetitions of method steps (a) and (b).

[0162] In some embodiments, each dose (the first dose and one or more second doses, and optionally one or more prior doses and / or one or more third doses) is an equal amount (milligrams) of the IL-13 binding protein, for example, about 10 mg to about 600 mg of the IL-13 binding protein, about 50 mg to about 500 mg of the IL-13 binding protein, about 100 mg to about 400 mg, about 250 mg to about 350 mg, or about 280 mg to about 320 mg. In particular, each dose may be about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. In some cases, the dose may be 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, or 200 mg or less. In preferred embodiments, each dose (i.e., the first dose and one or more second doses, and optionally one or more prior doses and / or one or more third doses) is about 300 mg of IL-13 binding protein (for example, as shown in the examples).

[0163] In some embodiments, the first dose of the one or more prior doses and / or the one or more third doses is a bolus dose, which is twice the dose following the bolus dose.

[0164] In some embodiments, the first dose of the one or more prior doses and / or the one or more third doses is a 600 mg dose, and the subsequent dose(s) are 300 mg doses(s).

[0165] In some embodiments, the bolus dose is given as the first dose of the “one or more prior doses” described above, or as the first dose of step (c). The bolus is typically twice the dose to be administered in the next dose. For example, if the next dose to be administered is 300 mg, a dose of 600 mg is used as the bolus dose, and if the next dose to be administered is 600 mg, a dose of 300 mg is used as the bolus dose.

[0166] In some cases, the one or more prior doses and the one or more third doses may be administered to the subject at the same administration interval (for example, approximately two weeks after the most recent dose).

[0167] Administration In the methods described herein, the IL-13 binding protein (e.g., an anti-IL-13 antibody or its IL-13 binding fragment) may be administered by any suitable method. Typically, administration is parenteral, such as intradermal, intramuscular, intravenous, and subcutaneous. Subcutaneous administration is particularly preferred (e.g., as shown in the examples). Accordingly, each dose of the IL-13 binding protein may be administered subcutaneously.

[0168] The administration is preferably in a “therapeutic effective dose,” which is sufficient to demonstrate improvement or maintenance of improvement, or achievement of a low disease state, of one or more AD-related parameters or patient-related outcomes as described herein.

[0169] Administration may be by any convenient route, for example, by infusion or bolus injection, or by absorption through the epithelial or mucosal layers of the skin (e.g., oral mucosa, rectal and intestinal mucosa).

[0170] Subcutaneous or intravenous delivery may be performed using standard needles and syringes (e.g., including pre-filled syringes). The methods described herein are not intended to be limited to use in a clinic. Therefore, subcutaneous injection using needleless devices is also desirable. Such delivery devices may be reusable or disposable. Numerous reusable pen and auto-injector delivery devices are known in the art and may find applications in the present invention. Examples include AUTOPEN (trademark) (Owen Mumford, Inc., Woodstock, UK), DISETRONIC (trademark) pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 (trademark) pen, HUMALOG (trademark) pen, HUMALIN 70 / 30 (trademark) pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN (trademark) 1, 11 and 111 (Nova Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (trademark) (Nova Nordisk, Copenhagen, Denmark), BD (trademark) pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN (trademark), OPTIPEN PRO (trademark), OPTIPEN Examples include STARLET® and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany). Exemplary disposable pen delivery devices for subcutaneous delivery that may be used in the applications of the present invention include SOLOSTAR® pen (Sanofi-Aventis), FLEXPEN® (Nova Nordisk), KWIKPEN® (Eli Lilly), SURECLICK® Autoinjector (Amgen, Thousand Oaks, CA), PENLET® (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA® pen (Abbott Labs, Abbott Park, IL).

[0171] Each dose of IL-13 binding protein is not necessarily administered in a single dosing step (e.g., one injection or one tablet). In fact, depending on the concentration of the IL-13 binding protein (e.g., contained in the pharmaceutical composition), one, two, three, or more dosing steps (e.g., one, two, three, or more injections) may be required to provide the required amount of IL-13 binding protein to the subject (e.g., a 300 mg dose). Therefore, in some embodiments, each dose of IL-13 binding protein is administered in one or two injections (e.g., subcutaneously). Typically, a subcutaneous injection has a volume of about 1.5 mL or less, for example, 0.2 to 1.5 mL, for example, about 1 mL.

[0172] Monotherapy and combination therapy The methods described herein may also be monotherapy (for example, in Examples 4 and 5, etc.). As used herein, the term “monotherapy” refers to a therapy that uses a single drug to treat a disease or condition. Thus, a subject treated with monotherapy is administered only a single drug to treat an associated disorder, e.g., AD, skin infection, itching, or eczema-related sleep disturbance. For example, anti-IL-13 antibody monotherapy refers to a monotherapy that involves administering an anti-IL-13 antibody to a subject as the sole drug for the treatment of AD or a skin infection.

[0173] The methods described herein may also be combination therapies (for example, as in Examples 1-3). As used herein, the term “combination therapy” refers to a therapy that uses multiple drugs to treat a disease or condition. For example, a subject treated with combination therapy is administered multiple drugs (e.g., two, three, or more) to treat Alzheimer's disease (AD).

[0174] In some embodiments, the IL-13 binding protein is administered in combination with topical therapy (e.g., topical corticosteroids or topical calcineurin inhibitors). In some cases, the additional therapy (e.g., TCS or TCI) is administered as needed for the patient.

[0175] In some cases, the IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of topical corticosteroids, topical calcineurin inhibitors, antihistamines, emollients, or antibacterial agents. In some cases, the IL-13 binding protein is administered in combination with a corticosteroid of group I, group II, group III, or group IV. Preferably, the IL-13 binding protein may be administered in combination with mometasone furoate (e.g., 0.1% cream), as shown in Example 1.

[0176] Pharmaceutical compositions and preparations The present invention envisions a method in which each dose of an IL-13 binding protein (e.g., an anti-IL-13 antibody or its IL-13 binding fragment) is administered as a pharmaceutical composition.

[0177] The pharmaceutical composition may be formulated using appropriate carriers, excipients, and other agents that provide appropriate mobility, delivery, tolerance, etc. Numerous formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, a prescription collection known to all pharmacists.

[0178] The dose administered to a patient according to the methods described herein may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. The dose may be calculated based on body weight or surface area.

[0179] Accordingly, the pharmaceutical composition may contain, in addition to the active ingredient (i.e., the IL-13 binding protein), pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The detailed properties of the carrier or other materials depend on the route of administration, which may be oral or by injection, e.g., intravenous or subcutaneous. Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders, or liquids. Tablets may contain a solid carrier, e.g., gelatin or an adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier, e.g., water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. They may also contain saline solution, dextrose or other sugar solutions, or glycols, e.g., ethylene glycol, propylene glycol, or polyethylene glycol.

[0180] For intravenous or subcutaneous injection, the pharmaceutical composition may be a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability. Those skilled in the art can easily prepare a suitable solution using, for example, an isotonic medium such as sodium chloride injection, Ringer's solution, or Ringer's lactate solution. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as needed.

[0181] The pharmaceutical composition may be in the form of a liquid formulation or a lyophilized formulation that is reconstituted before use. For lyophilized formulations, for example, sugar alcohols or sugars (e.g., mannitol or glucose) may be used as excipients. In the case of a liquid formulation, the pharmaceutical composition is usually provided in the form of containers of a specified volume, including sealed and sterile plastic or glass vials, ampoules and syringes, as well as in the form of large-capacity containers such as bottles. Preferably, in the method described herein, the pharmaceutical composition is a liquid formulation.

[0182] Exemplary pharmaceutical compositions that may be used in light of the present invention are disclosed, for example, in WO2007 / 036745 and WO2018 / 158332.

[0183] Preferably, the IL-13 binding protein may be included in the pharmaceutical composition at a concentration of 1 mg / mL to 200 mg / mL, more preferably 150 mg / mL.

[0184] Preferably, the pharmaceutical composition can be buffered to a pH of 5.2 to 5.7, most preferably 5.5 (e.g., ±0.1). Such a pH selection provides great stability to the pharmaceutical composition. Examples of alternative buffers that can control the pH within this range include succinic acid, gluconic acid, histidine, citric acid, phosphoric acid, glutaric acid, cacodylic acid, sodium hydrogen maleate, tris(hydroxymethyl)aminomethane (Tris), 2-(N-morpholino)ethanesulfonic acid (MES), and imidazole. Preferably, the buffer is an acetate buffer, more preferably a sodium acetate buffer.

[0185] Preferably, the acetate buffer is included in the pharmaceutical composition in an amount of 1 mM to 100 mM, more preferably 30 mM to 70 mM, and particularly 50 mM.

[0186] It should be understood that the reference to “medically acceptable excipients” includes any excipients conventionally used in pharmaceutical compositions. Such excipients may typically include one or more surfactants, inorganic or organic salts, stabilizers, diluents, solubilizers, reducing agents, antioxidants, chelating agents, preservatives, etc.

[0187] Typical examples of surfactants include nonionic surfactants (HLB 6-18), such as sorbitan fatty acid esters (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), glycerin fatty acid esters (e.g., glycerin monocaprylate, glycerin monomyristate, glycerin monostearate), polyglycerin fatty acid esters (e.g., decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate), and polyoxyethylene sorbitan fatty acid esters. (For example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate), polyoxyethylene sorbitol fatty acid esters (for example, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerin fatty acid esters (for example, polyoxyethylene sorbitol Polyethylene glyceryl monostearate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol distearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxypropylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkylphenyl ethers (e.g., polyoxyethylene nonylphenyl ether), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax), polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin), and polyoxyethylene fatty acid amides (e.g., polyoxyethylene stearyl amide), anionic surfactants, e.g., C10-C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate,Examples include polyoxyethylene C10-C18 alkyl ether sulfates (e.g., polyoxyethylene sodium lauryl sulfate) and C8-C18 alkyl sulfosuccinate esters (e.g., sodium lauryl sulfosuccinate ester) containing an average of 2-4 moles of ethylene oxide, as well as natural surfactants such as lecithin, glycerophospholipids, sphingophospholipids (e.g., sphingomyelin), and sucrose C12-C18 fatty acid esters. The surfactant may be selected from polyoxyethylene sorbitan fatty acid esters. Preferred surfactants are polysorbate 20, 21, 40, 60, 65, 80, 81, and 85, most preferably polysorbate 20 and 80, and especially polysorbate 80.

[0188] Preferably, the surfactant is included in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w), more preferably 0.005% and 0.05% (w / w), and particularly 0.01% (w / w).

[0189] Typical examples of inorganic salts include sodium chloride, potassium chloride, calcium chloride, sodium phosphate, sodium sulfate, ammonium sulfate, potassium phosphate, and sodium bicarbonate, or any other sodium, potassium, or calcium salt. Preferably, the inorganic salt is sodium chloride.

[0190] Preferably, the inorganic salt is included in the pharmaceutical composition in an amount of 10 mM to 200 mM, more preferably 60 mM to 130 mM, and particularly 85 mM.

[0191] Examples of reducing agents include N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and C1-C7 thioalkanoates.

[0192] Examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, alpha-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, triamyl gallate, and propyl gallate.

[0193] Examples of chelating agents include disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

[0194] Examples of stabilizers include amino acids selected from creatinine, histidine, alanine, glutamic acid, glycine, leucine, phenylalanine, methionine, isoleucine, proline, aspartic acid, arginine, lysine, and threonine; carbohydrates selected from sucrose, trehalose, sorbitol, xylitol, and mannose; surfactants selected from polyethylene glycol (PEG, e.g., PEG3350 or PEG4000) or polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20 or polysorbate 80); or any combination thereof.

[0195] In one preferred embodiment, the stabilizer comprises a single carbohydrate (e.g., trehalose).

[0196] In alternative, preferred embodiments, the stabilizer comprises an amino acid in combination with a carbohydrate (e.g., trehalose and alanine, or trehalose, alanine, and glycine).

[0197] In further alternative preferred embodiments, the stabilizer comprises an amino acid in combination with a carbohydrate and a surfactant (e.g., trehalose, alanine and PEG3350, trehalose, proline and PEG3350, trehalose, alanine and polysorbate 80, trehalose, proline and polysorbate 80, trehalose, alanine, glycine and PEG3350, trehalose, alanine, glycine and polysorbate 80).

[0198] Furthermore, in a further alternative preferred embodiment, the stabilizer comprises an amino acid in combination with a surfactant (for example, alanine and PEG3350 or alanine, glycine and PEG3350).

[0199] Furthermore, in a further alternative preferred embodiment, the stabilizer comprises a carbohydrate in combination with a surfactant (e.g., trehalose and PEG3350 or trehalose and polysorbate 80).

[0200] Examples of preservatives include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl group is a long-chain compound), benzethonium chloride, aromatic alcohols such as phenol, butyl alcohol and benzyl alcohol, alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. In preferred embodiments, the pharmaceutical composition comprises the IL-13 binding protein, surfactant and inorganic salt described herein, and is buffered to pH 5.5 ± 0.1 in acetate buffer.

[0201] In a more preferred embodiment, the pharmaceutical composition comprises the IL-13 binding protein described herein, sodium chloride, and polysorbate 80, and is buffered to pH 5.5 ± 0.1 with sodium acetate buffer.

[0202] In a more preferred embodiment, the pharmaceutical composition comprises an IL-13 binding protein as described herein (e.g., tralokinumab), 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, wherein the pharmaceutical composition has a pH of 5.5.

[0203] In a more preferred embodiment, the pharmaceutical composition comprises 150 mg / mL of IL-13 antibody (e.g., tralokinumab), 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, wherein the pharmaceutical composition has a pH of 5.5.

[0204] Other definitions Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention belongs.

[0205] The articles "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, "element" means one or more elements.

[0206] The terms "comprise" and "comprising" are used in a comprehensive and open sense, meaning that they may include additional elements.

[0207] Generally, a method that "includes" several steps does not require those steps to be performed in a specific order. If a method includes several sequentially numbered or alphabetically ordered steps (e.g., (1), (2), (3), (i), (ii), (iii), or (a), (b), (c), etc.), this means that the steps must be performed in a predetermined order unless otherwise specified.

[0208] The term "including" is used herein to mean "including, but not limited to."

[0209] The term "approximately" in relation to a numerical value x is arbitrary and can mean, for example, x ± 10%.

[0210] In general, terms such as “to treat,” “to treat,” and “treatment” mean to alleviate (reduce, minimize, or eliminate) symptoms, either temporarily or permanently, or to reduce, minimize, or eliminate the cause of symptoms. All publications referenced herein are incorporated as a whole by reference. [Examples]

[0211] The present invention will be further illustrated by the following embodiments. These embodiments are for illustrative purposes only and should not be understood as limiting the present invention. Further modifications may be made without departing from the spirit of the invention.

[0212] Example 1: Tralokinumab / TCS combination therapy is effective in treating moderate to severe atopic dermatitis. A Phase 3 trial (ECTZRA3) was conducted to evaluate the efficacy and safety of tralokinumab in combination with (if necessary) topical corticosteroids (TCS) in patients with moderate to severe Alzheimer's disease (AD).

[0213] method This was a double-blind, randomized 32-week trial (NCT03363854). Patients with moderate to severe AD (IGA 3 or 4) were randomized in a 2:1 ratio and received either subcutaneous tralokinumab 300 mg (Q2W + TCS) or a control (placebo Q2W + TCS) every two weeks. A loading dose of 600 mg of tralokinumab or placebo was administered on day 0. Throughout the entire treatment period, all patients applied a thin layer of TCS (mometasone furoate 0.1% cream, Europe: Class 3 [high potency], USA: Class 4 [moderate potency]), provided in kit sizes of 180-200 g per visit, once daily to areas with active lesions. Further lower-potency TCS or topical calcineurin inhibitors [TCIs] were prescribed when necessary for use in areas of the body where the prescribed TCS was unsuitable, areas of thin skin (e.g., face, skin folds, genitals), or areas where continued treatment with TCS was unsafe. TCS use was continuously monitored for safety and appropriateness and gradually discontinued once control was achieved. Patients were instructed to return used and unused tubes at each trial visit to measure TCS usage. Emulsifiers were applied twice daily (or more if necessary) for at least 14 days prior to randomization and throughout the trial (including safety follow-up). In cases of lesioned skin, emollients were applied only if TCS was not applied. Relief treatment in the form of topical and systemic medications was permitted to control unacceptable AD symptoms. Patients receiving high-potency TCS (Europe: Class 3 or higher, US: Class 4 or lower) continued treatment, but patients receiving systemic corticosteroids or nonsteroidal systemic immunosuppressants temporarily interrupted treatment until the rescue therapy was discontinued (and until the systemic therapy was washed out at 5 half-lifes).

[0214] The primary endpoints were a 16-week Investigator Global Assessment (IGA) score of 0 or 1 (IGA-0 / 1, skin with no or near-no signs of inflammation) and a 75% or greater improvement in the Eczema Area Severity Index (EASI-75). At baseline, 46.3% of the 380 randomized patients had severe AD (IGA-4). The mean baseline EASI score was 29.4. Additional secondary endpoints included TCS use and TCS-free days.

[0215] At week 16, tralokinumab responders (IGA-0 / 1 and / or EASI-75) were re-randomized in a 1:1 ratio for an additional 16 weeks to receive either tralokinumab Q2W or every 4 weeks (Q4W) + TCS. Placebo responders continued with placebo Q2W + TCS. All non-responders received tralokinumab Q2W + TCS. [Table 3-1] [Table 3-2]

[0216] result Tralokinumab treatment significantly improved IGA and EASI scores after 16 weeks. During the initial treatment period, 380 patients were randomized: 253 to receive tralokinumab plus TCS every other week, and 127 to receive placebo plus TCS every other week. One patient from each treatment group withdrew from the study before receiving treatment. Therefore, the 252 patients who received tralokinumab plus TCS every other week and the 126 patients who received placebo plus TCS every other week were included in the largest analysis control population and safety analysis population. Continued treatment (based on response at 16 weeks and initial treatment) was assigned to 353 patients.

[0217] Baseline demographics and disease characteristics were well-balanced across all treatment groups. At baseline, approximately half of patients had severe disease (IGA-4), the median duration of AD was 26.0 years, and the median surface lesion area was 41%. Many patients had concomitant atopic diseases. All patients had received prior treatment; almost all (98.2%) had received TCS, and 61.6% had used systemic steroids. Cyclosporine was the most common oral immunosuppressant previously used (31.1%).

[0218] Significant differences were observed between tralokinumab plus TCS and placebo plus TCS for both primary endpoints. At 16 weeks, more patients achieved IGA-0 / 1 and EASI-75 with tralokinumab plus TC compared to placebo plus TCS. IGA-0 / 1 was achieved in 38.9% of patients treated with tralokinumab plus TCS compared to 26.2% of patients treated with placebo plus TCS (p=0.015). EASI-75 was achieved in 56% of patients treated with tralokinumab plus TCS compared to 35.7% of patients treated with placebo plus TCS (p<0.001). Sensitivity, secondary, and tertiary analyses supported the results of the primary analysis (Figure 1).

[0219] Regardless of baseline IGA severity and history of atopic diseases (asthma, food allergies, and hay fever), the proportion of IGA-0 / 1 and EASI-75 responders was higher in tralokinumab plus TCS than in placebo plus TCS. IGA-0 / 1 and EASI-75 response rates were higher in female patients and patients aged 65 years or older (tralokinumab plus TCS group only). The use of rescue therapy was higher in placebo plus TCS (10.2%) than in tralokinumab plus TCS (2.8%).

[0220] Tralokinumab administration reduced the need for TCS use. Salvage treatment was reported in 10.2% of control patients compared to 2.8% of tralokinumab patients. Over 16 weeks, significantly fewer TCSs were used cumulatively in tralokinumab patients than in control patients (134.9g vs. 193.5g, Δ58.6g, p=0.004). The number of TCS-free days (weekly mean from eDiary, including low-potency TCSs and TCIs) was significantly higher in tralokinumab patients compared to control patients at week 7 (Δ0.6 days, p=0.040) and weeks 9–15 (range: Δ1.0 days, p=0.001–Δ0.6 days, p=0.045). Tralokinumab patients also had an average of 0.5 more TCS-free days at week 16 (p=0.17).

[0221] At week 16, subjects in the tralokinumab group used 50% less of the prescribed TCS compared to subjects in the placebo group (p<0.001) [data not shown]. In the tralokinumab plus TCS group, the proportion of patients using less than 5g of TCS at weeks 15-16 was higher (55.3%) compared to placebo plus TCS (36.7%). The reduction in TCS use in the tralokinumab plus TCS group was not compensated for by the use of low-potency TCS or TCIs.

[0222] The results for week 16 can be seen in Table 3 below. [Table 4-1] [Table 4-2] [Table 4-3]

[0223] The results for other evaluation items may be shown in Table 4 below: [Table 5]

[0224] Table 5 may show the results of other evaluation items for patients who achieved a clinical response at week 16: [Table 6]

[0225] The response to tralokinumab was maintained for 32 weeks. At week 16, the majority of tralokinumab responders maintained their response to tralokinumab, regardless of the administration frequency (every two weeks or every four weeks). Among tralokinumab responders, those who received tralokinumab every two weeks (Q2W+TCS) maintained an IGA-0 / 1 score and 92.5% maintained an EASI-75 score at week 32. In the case of tralokinumab Q4W+TCS, 77.6% achieved IGA-0 / 1 and 90.8% achieved an EASI-75 score at week 32. The results are shown in Figure 6.

[0226] Among all subjects who achieved either IGA 0 or 1 or EASI-75 at week 16, the mean percentage improvement in EASI score from baseline was 93.5% at week 32 for subjects maintaining tralokinumab 300 mg Q2W + TCS, and 91.5% at week 32 for subjects on tralokinumab 300 mg Q4W + TCS.

[0227] Among patients who did not achieve IGA-0 / 1 and / or EASI-75 at 16 weeks with tralokinumab (Q2W+TCS), 30.5% and 55.8% achieved IGA-0 / 1 and EASI-75, respectively, at 32 weeks after continuing tralokinumab Q2W+TCS administration.

[0228] In patients receiving tralokinumab plus TCS every other week, the majority who achieved an EASI-75 or IGA-0 / 1 response at week 16 also achieved an EASI-90 response and maintained that response until week 32, regardless of whether the treatment was continued every other week or every four weeks. Patients who did not achieve either an EASI-75 or IGA-0 / 1 response at week 16 continued to improve with tralokinumab plus TCS every other week.

[0229] Other evaluation items at 16 and 32 weeks are shown in Tables 6 and 7: [Table 7] [Table 8]

[0230] Tralokinumab has a desirable safety profile. Table 8 shows the overall frequency and severity of adverse events over 16 weeks. [Table 9-1] [Table 9-2]

[0231] Overall, the safety profile at 32 weeks was comparable to that of the initial treatment period, as shown in Table 9 below. [Table 10-1] [Table 10-2]

[0232] Overall, tralokinumab used in combination with TCS for up to 32 weeks was well-tolerated and demonstrated an acceptable safety profile in adults with moderate to severe Alzheimer's disease (AD). The most frequent adverse events (AEs) occurring in patients treated with tralokinumab Q2W plus TCS (≥5% of patients in any treatment group) compared to placebo Q2W plus TCS were viral upper respiratory tract infections, conjunctivitis, headache, upper respiratory tract infections, and injection site reactions. Conjunctivitis (as a basic term) occurred in 10.9% of patients treated with tralokinumab plus TCS (all, i.e., the entire tralokinumab group over the entire treatment period). This is higher than the 2.6% of patients who experienced conjunctivitis with tralokinumab (whole) in the Phase 2 trial (Wollenberg et al., The Journal of Allergy and Clinical Immunology 2019;143:135-141) and the 4.0% and 3.8% who experienced conjunctivitis with dupilumab monotherapy (whole) in SOLO1 and SOLO2, respectively (Simpson et al., The New England Journal of Medicine 2016;375:2335-2348), but lower than the 17.8% who experienced conjunctivitis with dupilumab plus TCS (whole) in LIBERTY AD CHRONOS (Blauvelt et al., Lancet 2017;389:2287-2303). Unlike dupilumab, tralokinumab specifically binds to IL-13 cytokines and does not affect IL-4 signaling. However, the causal relationship of the mechanisms leading to ocular complications remains unclear. As for AESIs, conjunctivitis was reported more frequently in tralokinumab Q2W plus TCS at 16 weeks than in placebo Q2W plus TCS (13.1% vs. 5.6%), but all of these were mild or moderate and most resolved. In particular, tralokinumab Q2W plus TCS had a lower incidence of skin infections requiring systemic treatment compared to placebo Q2W plus TCS.

[0233] These findings support clinical trial and real-world data of dupilumab showing that patients with moderate to severe atopic dermatitis (AD) are at higher risk of developing conjunctivitis compared to placebo patients (Akinlade B et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol 2019;181:459-473; Ferreira S, Torres T. Conjunctivitis in patients with atopic dermatitis treated with dupilumab. Drugs Context 2020;9:2020-2022-2023; Halling AS et al. Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis. J Am Acad Dermatol 2020). Similarly, most cases of conjunctivitis with dupilumab were mild to moderate and resolved during the course of treatment with ophthalmic care.The risk factors identified in this analysis are consistent with those identified in clinical trials and real-world data of dupilumab (Akinlade B et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol 2019;181:459-473, Ferreira S, Torres T. Conjunctivitis in patients with atopic dermatitis treated with dupilumab. Drugs Context 2020;9:2020-2022-2023, Thyssen JP et al. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol 2017;77:280-286 e281, Treister AD et al. Risk Factors for Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis. JAMA Dermatol 2018;154:1208-1211, Wollenberg A et al. Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS). Br J Dermatol 2020;182:1120-1135). However, compared with dupilumab clinical trials, the overall incidence of conjunctivitis is considered to be lower.

[0234] Tralokinumab + TCS was associated with a lower incidence of severe and serious infections requiring systemic treatment, herpetic eczema, and skin infections compared with placebo + TCS.

[0235] Conclusion Tralokinumab 300 mg Q2W + TCS is effective for the treatment of moderate to severe atopic dermatitis, and also has a desirable safety profile. TCS usage is significantly lower in tralokinumab-administered patients than in placebo, demonstrating the potential steroid-sparing effect of tralokinumab. Tralokinumab maintained efficacy in responders when administered once every 2 weeks. Surprisingly, response was also maintained with an administration frequency of once every 4 weeks.

[0236] Example 2: Tralokinumab / TCS combination therapy improves short-term patient-reported outcomes Patient-reported outcomes (PROs) were used to evaluate the benefits of these treatment regimens experienced by patients.

[0237] Methods Patient-reported outcomes (PROs) experienced by patients were investigated during the tralokinumab / TCS combination therapy trial described in Example 1. PROs included a reduction of 4 or more points in the daily peak pruritus numerical rating scale (NRS), reduction in eczema-related sleep disturbance, Patient-Oriented Eczema Measure (POEM), and changes in Dermatology Life Quality Index (DLQI) score.

[0238] At baseline, the mean eczema-related sleep disturbance was 6.9, the mean POEM was 22.3, and the mean DLQI score was 17.6. The baseline daily peak pruritus score was 7.7.

[0239] Results After two weeks of administration, changes in eczema-related sleep disturbances, patient-reported eczema assessment (POEM), and skin condition questionnaire (DLQI) scores were significantly reduced in tralokinumab / TCS patients compared to placebo / TCS patients (Figure 2). The mean eczema-related sleep disturbance decreased by 2.3 points in the tralokinumab / TCS group compared to 1.9 points in the control group (p=0.037) (Figure 2). The mean POEM score decreased significantly in the tralokinumab / TCS group (-7.9 compared to -5.9 in placebo / TCS, p=0.006). The mean reported DLQI score decreased by 8.9 points after tralokinumab / TCS administration (-7.3 compared to placebo / TCS, p=0.011). The mean improvement from baseline in DLQI and POEM reached the minimum clinically important change (MCID) in addition to statistical significance.

[0240] By week 3, the proportion of patients receiving tralokinumab who experienced a reduction of 4 or more points in their diurnal peak pruritus from baseline was significantly higher compared to the control group (27.3% compared to 17.5%, p=0.029).

[0241] Figures 9, 11, and 12 show that tralokinumab / TCS significantly improved all secondary endpoints compared to placebo / TCS at 16 weeks.

[0242] conclusion Significant early improvement in PRO was observed with tralokinumab / TCS combination therapy. Patients felt the effects of tralokinumab immediately after starting treatment and experienced significant improvement after just two weeks of treatment.

[0243] Example 3: Further analysis of the efficacy of tralokinumab / TCS combination therapy The investigator's overall rating of 0 or 1 (IGA 0 / 1, skin with no or near-no signs of inflammation) and / or improvement of 75% or more in the Eczema Area Severity Index (EASI-75), as evaluated in Example 1 above, are the primary efficacy endpoints set by regulatory authorities in Phase 3 clinical trials for Alzheimer's disease (AD). However, these endpoints do not comprehensively capture the full burden of AD.

[0244] Further analyses were used to evaluate the response to treatment with tralokinumab / TCS based on targets and time points typically used in clinical practice.

[0245] method The data from the experiment described in Example 1 were further analyzed to evaluate patient responses at 3 and 6 months after treatment with tralokinumab / TCS. Responses were based on clinician-assessed signs (EASI), patient-reported symptoms (pruritus and POEM), and patient-reported quality of life scores (DLQI) and patient overall trouble impression (PGI-B). The selected time points reflect the usual follow-up of adult AD patients initiating a new treatment. All 252 patients who received tralokinumab / TCS in Example 1 were included in this analysis.

[0246] result Table 10 shows the percentage of tralokinumab / TCS-treated patients who achieved the target outcome at week 12. [Table 11]

[0247] A high percentage of patients (79.4%, 196 out of 247 evaluated) achieved both a reduction of 1 point or more on the PGI-B and at least one other endpoint shown in Table 10.

[0248] At 24 weeks, 81.0% (204 / 252) achieved EASI-50 (an improvement of 50% or more from EASI), and 69.0% achieved EASI-75. Among the lower group of patients (n=196) who had a PGI-B score decrease of 1 point or more at 12 weeks and had any of the other evaluation items shown in Table 10, 90.8% achieved EASI-50 and 75.5% achieved EASI-75 at 24 weeks.

[0249] Improvement in DLQI was maintained beyond 16 weeks in all dose groups. Maintenance of high-level response with tralokinumab every other week or every 4 weeks was not associated with an increase in TCS use. The peak daily pruritus NRS score decreased from 2.6 to 2.2 between week 16 and week 32 in the tralokinumab plus TCS every other week group, and decreased from 3.0 to 2.7 in the tralokinumab plus TCS every 4 weeks group.

[0250] As shown in Figure 10, at week 16, more patients achieved EASI-50 and EASI-90 with tralokinumab / TCS versus placebo / TCS.

[0251] Conclusions Tralokinumab / TCS combination therapy is associated with a higher proportion of patients achieving and maintaining improvement in AD symptoms and AD-related quality of life at 3 and 6 months after treatment, which is the usual follow-up period in clinical practice. Therefore, tralokinumab combination therapy provides measurable benefits to patients at clinically meaningful time points.

[0252] Example 4: Tralokinumab monotherapy is effective in the treatment of moderate-to-severe atopic dermatitis To evaluate the efficacy of tralokinumab alone, two 52-week trials (ECZTRA1 and ECZTRA2) of tralokinumab monotherapy in moderate-to-severe AD were conducted.

[0253] Methods Patients were enrolled for two double-blind, randomized, placebo-controlled 52-week trials of tralokinumab monotherapy in moderate-to-severe AD across Europe (ECZTRA1: Germany, France and Spain; plus ECZTRA2: United Kingdom, Italy, Poland and Russia), North America (ECZTRA1: United States; ECZTRA2: United States and Canada), Asia (ECZTRA1: Japan; ECZTRA2: South Korea), and Australia (ECZTRA2). Inclusion criteria: diagnosis of AD for more than 1 year, baseline EASI score of 16 or higher, baseline IGA score of 3 or higher, and mean pruritus NRS score of 4 or higher before baseline.

[0254] Of the 802 patients randomized in ECZTRA1 and the 794 patients randomized in ECZTRA2, 50.7% and 48.7%, respectively, had severe AD (IGA-4), and the mean EASI was 32.4 and 32.2 at baseline. Patients enrolled in ECZTRA1 and ECZTRA2 had similar baseline disease characteristics, although some baseline measurements differed by region. For example, the proportion of patients with severe AD (IGA-4) was 50.7% (ECZTRA1) and 48.7% (ECZTRA2) across the entire study population, but severe AD was higher in Japan (66.1%) and Australia (63.6%) compared to Europe (52.6% / 51.3%), North America (36.4% / 43.2%), and South Korea (43.6%). Among patients with severe AD (IGA-4) at baseline, higher median baseline EASI scores were observed in Japan (46.6%) and Australia (47.2%) compared to Europe (35.6% / 41.2%), North America (35.3% / 32.6%), and South Korea (37.2%). These regional differences may explain the slight differences in treatment response observed between ECZTRA1 and ECZTRA2.

[0255] Table 11 shows the baseline demographic and clinical characteristics of the randomized patients. [Table 12]

[0256] This study consisted of an initial 16-week treatment period and a 36-week maintenance treatment period. Following a 2-week washout period for TCS and other topical treatments, tralokinumab or placebo was administered subcutaneously every other week for 16 weeks. Patients were randomized in a 3:1 ratio to receive tralokinumab 300 mg or placebo subcutaneously every two weeks (Q2W) for 16 weeks. The primary endpoints were IGA-0 / 1 and EASI-75 achieved without the use of salvage therapy.

[0257] Depending on the randomization scheme, patients received either a loading dose of tralokinumab (600 mg) or placebo on day 0.

[0258] Patients were instructed to use a stable dose of emollient applied at least twice daily as needed for two weeks prior to baseline visit and throughout the study. Salvage treatment for AD was available at the discretion of the principal investigator when medically necessary to control unacceptable symptoms and did not prevent transition to maintenance or open-label treatment. However, patients who received salvage treatment were considered non-responders in the primary analysis (see statistical analysis below). When systemic corticosteroids or nonsteroidal immunosuppressants were used as salvage, patients had to temporarily discontinue administration (see the Methods section of the online supplemental appendix for details), but when salvage was limited to topical medication, patients continued with the study.

[0259] After the initial 16-week treatment period, tralokinumab-treated patients who achieved pre-specified clinical response criteria, defined as achieving IGA 0 (clear) or 1 (nearly clear), or a 75% or greater improvement in the Eczema Area Severity Index (EASI-75), transitioned to the maintenance phase, re-randomized in a 2:2:1 ratio, and received either tralokinumab 300 mg every other week or every four weeks, or placebo for a further 36 weeks. Patients who achieved clinical response criteria with placebo continued with placebo every other week to maintain blinding of the study. The placebo cohort from week 16 was not randomized to the 36-week maintenance period and was not included in these analyses. Patients who did not achieve clinical response criteria at week 16 optionally transitioned to open-label tralokinumab 300 mg every other week using TCS. Furthermore, if the specified clinical response criteria were not met over a four-week period, patients transitioned from maintenance to open-label tralokinumab after week 16. Unless they proceeded to the long-term ECZTEND trial (NCT03587805), all patients received final safety follow-up 16 weeks after the last dose of the study drug.

[0260] Patients were evaluated every two weeks for clinical efficacy and safety measures, and clinical tests were performed every four weeks throughout the trial. Serum samples to determine the presence or absence of anti-drug antibodies (ADAs) were collected at weeks 0, 4, 16, 28, 52, and 66. Samples confirmed to be ADA-positive at the confirmation stage were analyzed for the presence of neutralizing antibodies (nABs) by measuring ADA endpoint titers.

[0261] result Tralokinumab monotherapy significantly improved IGA and EASI scores after 16 weeks. At 16 weeks, the IGA-0 / 1 response was reported in significantly more tralokinumab-treated patients compared to the placebo control, in both ECZTRA1 (7.1% placebo compared to 15.8% tralokinumab, p=0.002) and ECZTRA2 (10.9% placebo compared to 22.2% tralokinumab, p<0.001) (see Figure 3). The EASI-75 response was 12.7% in placebo (ECZTRA1) compared to 25.0% in tralokinumab, and 11.4% in placebo (ECZTRA2) compared to 33.2% in tralokinumab (both p<0.001) (see Figure 4).

[0262] The results for both primary and secondary outcomes at week 16 can be seen in Table 12 below: [Table 13-1] [Table 13-2] [Table 13-3]

[0263] Tralokinumab monotherapy maintained IGA and EASI scores after 52 weeks. In ECZTRA1 and ECZTRA2, after an initial 16-week treatment period, 185 and 227 patients, respectively, were randomized in a 2:2:1 ratio to continue tralokinumab every other week, reduce the frequency of tralokinumab administration to every four weeks, or switch to placebo every two weeks.

[0264] The results for IGA and EASI75 may be included in Table 13 below: [Table 14]

[0265] At 52 weeks, 51.3% (ECZTRA1) and 59.3% (ECZTRA2) of patients maintained an IGA-0 / 1 response with tralokinumab Q2W. The response at Q4W was similar, with 38.9% (ECZTRA1) and 44.9% (ECZTRA2) maintaining an IGA-0 / 1 response. The results are shown in Figure 7. Among patients re-randomized to placebo, 47.4% and 25.0% maintained a response at 52 weeks in ECZTRA1 and ECZTRA2, respectively. In ECZTRA1, there was no statistically significant difference in the proportion of patients maintaining an IGA-0 / 1 response at 52 weeks between patients who continued tralokinumab every other week and patients who received tralokinumab initially and switched to placebo at 16 weeks. In ECZTRA2, the difference in the proportion of patients maintaining IGA 0 / 1 at week 52 with tralokinumab every other week compared to placebo was statistically significant. However, there was no statistically significant difference in IGA 0 / 1 response between tralokinumab every four weeks and placebo (P=0.084).

[0266] In ECZTRA1 and ECZTRA2, among patients who achieved EASI-75 at week 16 with tralokinumab without salvage therapy, the proportion of patients who maintained EASI-75 at week 52 was 59.6% and 55.8% in patients who continued tralokinumab every other week, 49.1% and 51.4% in patients re-randomized to tralokinumab every four weeks, and 33.3% and 21.4% in patients re-randomized to placebo.

[0267] Among subjects randomized to tralokinumab who did not achieve IGA 0 or 1 or EASI-75 at week 16 and who received open-label tralokinumab 300 mg Q2W + optional transition to TCS, 20.8% in ECZTRA1 and 19.3% in ECZTRA2 achieved IGA 0 or 1 at week 52, and 46.1% in ECZTRA1 and 39.3% in ECZTRA2 achieved EASI-75 at week 52. Clinical response was primarily facilitated by continued tralokinumab administration rather than optional TCS administration. Subjects with IGA 2 or EASI-50 at week 16 had a higher rate of achieving IGA 0 or 1 or EASI-75 compared to subjects with IGA 3 or 4 or <EASI-50 at week 16.

[0268] In both trials, tralokinumab administration resulted in higher EASI-50 and EASI-90 responses at week 16 compared to placebo, with a greater rate of change in EASI scores at week 16, and segregation between treatment groups (P<0.05) occurred from week 2 onwards.

[0269] The proportion of patients achieving EASI-50 was higher in the tralokinumab group compared to placebo at each periodic evaluation time during the initial treatment period, and segregation between treatment groups occurred from week 2. EASI-90 was achieved more frequently in tralokinumab patients than in placebo patients from weeks 4 to 16, and segregation between treatment groups occurred from week 6 onwards. The percentage change from baseline in EASI score was greater in the tralokinumab group compared to placebo at each evaluation time, including week 16 in both trials, and segregation between treatment groups (P<0.05) occurred from week 2 onwards.

[0270] Tralokinumab monotherapy has a desirable safety profile over 52 weeks. Adverse events (AEs) were similar between tralokinumab Q2W and placebo over 16 weeks, and the adverse event profile over 52 weeks was comparable to that of the initial 16 weeks.

[0271] The incidence of adverse events (AEs) was similar for tralokinumab and placebo during the initial treatment period in both studies. Most AEs were not serious, were mild to moderate in severity, and most recovered or improved by the end of the treatment period. Very few patients experienced AEs that led to permanent discontinuation of the investigational drug (IMP). The most common AEs during the initial treatment period were exacerbations of Alzheimer's disease (AD) and upper respiratory tract infections (mostly reported as the common cold).

[0272] During the initial treatment period in both trials, the frequency of serious adverse events (SAEs) was low and similar in both treatment groups. The majority of patients who reported SAEs recovered from those events. No significant differences in SAEs were observed between treatment groups within each treatment period or between treatment periods, and there was no clustering with respect to specific organ-specific classifications or types of events.

[0273] Conjunctivitis, reported as part of standard adverse event (AE) reporting and particularly as a significant AE, occurred more frequently in tralokinumab-treated patients than in placebo-treated patients. Most cases of conjunctivitis were mild and resolved by the end of the treatment period. One case led to discontinuation of treatment. Tralokinumab was associated with a lower incidence of herpetic eczema (0.5% for tralokinumab versus 1.0% for placebo in ECZTRA1, and 0.3% for tralokinumab versus 2.5% for placebo in ECZTRA2).

[0274] Skin infections requiring systemic treatment, which were reported as particularly important adverse events (AEs), occurred more frequently in patients receiving placebo than in those receiving tralokinumab in ECZTRA2. In ECZTRA1, the frequency was similar between the two groups. In ECZTRA1, the reduction in Staphylococcus aureus colonization, as assessed by qPCR in lesional skin from baseline to week 16, was more than 10-fold greater in tralokinumab patients compared to those receiving placebo, with a median of 969 to 22 gene copies / cm² in tralokinumab patients. 2 In comparison, the placebo group had 649 to 238 gene copies / cm². 2 That was the case.

[0275] Overall, the rate of reported adverse events (AEs) during the maintenance period was lower compared to the initial treatment period of tralokinumab administered every other week, and the pattern of events was similar to that of the initial treatment period. AEs were reported more frequently in the tralokinumab every other week group than in the tralokinumab every four weeks group. In total, four patients experienced SAEs in ECZTRA1 (one patient receiving tralokinumab every other week and three patients receiving tralokinumab every four weeks), and in ECZTRA2, three patients, all in the tralokinumab every four weeks group, showed SAEs. Two and three patients in ECZTRA1 and ECZTRA2, respectively, experienced AEs leading to permanent discontinuation of tralokinumab.

[0276] Positive broad-spectrum neutralizing antibody (nAB) reactions were observed in 3 patients receiving tralokinumab in ECZTRA1 and in 8 patients receiving tralokinumab in ECZTRA2. Based on inter-study tralokinumab concentration, ADA reaction, AE, and IGA / EASI score testing, the presence of nAB was considered not to affect the efficacy and safety of tralokinumab in any of the subjects. There were no notable differences between the treatment groups in laboratory values, vital signs, or electrocardiogram assessments. More tralokinumab-treated subjects experienced eosinophilia during the initial treatment period, but eosinophil levels returned to baseline values ​​during the maintenance period, with eosinophilia (>1.5x10) being reduced. 9 The safety profile of subject L) was comparable to that of the overall study population. Table 14 shows the overall frequency and severity of adverse events over 16 weeks. [Table 15-1] [Table 15-2]

[0277] Table 15 shows the overall frequency and severity of adverse events during the 36-week maintenance period. [Table 16-1] [Table 16-2]

[0278] The incidence of ocular complications was collected as a particularly important adverse event due to the increased incidence of ocular complications observed in clinical trials of dupilumab. Conjunctivitis occurred in less than 8% of patients treated with tralokinumab in any trial during the initial treatment period and in less than 6% of patients in any tralokinumab treatment group during the maintenance period. Almost all cases of conjunctivitis were mild to moderate, and one case led to discontinuation of the drug.

[0279] conclusion Both trials demonstrate that tralokinumab monotherapy significantly improves IGA and EASI scores at 16 weeks in patients with moderate to severe Alzheimer's disease (AD), and exhibits a favorable safety profile. Tralokinumab monotherapy maintained efficacy for 52 weeks in responders when administered every two weeks, and remarkably, a similar response was maintained even with a four-week administration frequency.

[0280] Example 5: Tralokinumab monotherapy improves patient-reported outcomes As described above, Alzheimer's disease (AD) is a burdensome disease for patients, involving symptoms including pain, itching, and sleep disturbances. The impact of tralokinumab monotherapy on patient-reported outcomes (PROs) was evaluated in phase 3 trials (ECZTRA1: NCT03131648, ECZTRA2: NCT03160885).

[0281] method PROs were analyzed for patients in the ECZTRA1 and ECZTRA2 trials described in Example 4. Evaluated PROs included a decrease of 4 points or more in the diurnal peak score of the Nutritional Rating Scale (NRS), a reduction in eczema-related sleep disturbances, changes in patient-reported eczema (POEM), SCORAD, and DLQI scores.

[0282] Baseline eczema-related sleep disturbance scores were 6.3 (ECZTRA1) and 6.9 (ECZTRA2). The mean baseline POEM score was 22.8 for both ECZTRA1 and ECZTRA2. The mean baseline DLQI values ​​were 16.8 (ECZTRA1) and 17.7 (ECZTRA2). The baseline diurnal peak pruritus score was 7.7 (ECZTRA1) and 7.9 (ECZTRA2).

[0283] result In both trials, there were significant differences between the tralokinumab group and the placebo group for all secondary endpoints of Example 4.

[0284] The results for other evaluation items can be shown in Table 16 below. [Table 17]

[0285] In the tralokinumab group, a significantly greater reduction in SCORAD was achieved at 16 weeks compared to the placebo group (P<0.001 compared to placebo in both trials). The change from baseline in SCORAD was greater with tralokinumab compared to placebo throughout the initial treatment period, and the segregation between treatment groups (P<0.001) was observed from week 2 onwards (Figure 8). The change from baseline in SCORAD sleep score was greater with tralokinumab compared to PBO at each week, and the segregation between treatment groups (p<0.01) was observed from week 2 onwards.

[0286] In ECZTRA1 (P=0.002) and ECZTRA2 (P<0.001), a significantly higher proportion of patients achieved a reduction of 4 or more in the diurnal peak score (weekly mean) of pruritus with tralokinumab at 16 weeks compared to placebo (10.3% and 9.5%) (20% and 25%, respectively). The reduction in the diurnal peak score (weekly mean) of pruritus was greater with tralokinumab compared to placebo throughout the initial treatment period, and the separation between treatment groups (P<0.05) was observed from week 1 onward (Figure 8). By week 3, the proportion of patients with tralokinumab whose diurnal peak pruritus score decreased by 4 points or more from baseline (7.7 / 7.9) was significantly higher in ECZTRA1 (8.1% compared to 1.5%, p<0.001) and ECZTRA2 (7.5% compared to 3.0%, p=0.021) compared to placebo.

[0287] Eczema-related sleep NRS (weekly mean) improved in both treatment groups in both the ECZTRA1 and ECZTRA2 trials. The adjusted mean change from baseline (standard error [SE]) at week 16 was greater with tralokinumab compared to placebo: -2.6 (0.12) vs. -1.9 (0.23), p=0.007 in ECZTRA1, and -2.9 (0.12) vs. -1.5 (0.22), p<0.001 in ECZTRA2.

[0288] The change from baseline in eczema-related sleep NRS was greater with tralokinumab compared to placebo each week, and the separation between treatment groups (p<0.001) was observed from week 1.

[0289] In both trials, by week 2, eczema-related sleep disturbance scores decreased in patients treated with tralokinumab, and this was significantly different from the control group. In ECZTRA1, eczema-related sleep disturbance decreased by 0.9 with tralokinumab compared to 0.4 in the control group (p<0.001). In the ECZTRA2 trial, the change in eczema-related sleep disturbance was -1.1 in the tralokinumab group compared to -0.4 in the control group (p<0.001).

[0290] SCORAD sleep scores improved in both treatment groups in both trials. The adjusted mean change (SE) from baseline at week 16 was greater with tralokinumab compared to placebo, at -1.8 (0.26) versus -2.6 (0.14) in ECZTRA1 (p=0.004) and at -1.8 (0.28) versus -3.0 (0.14) in ECZTRA2 (p<0.001), with the groups separating from week 2.

[0291] POEM sleep scores improved significantly with tralokinumab compared to PBO from week 2 onward (p<0.001). The adjusted mean change (SE) from baseline to week 16 was greater with tralokinumab than with PBO, at -0.6 (0.13) versus -1.2 (0.07) for ECZTRA1 and -0.6 versus -1.3 (0.07) for ECZTRA2 (both p<0.001). At week 16, the proportion of tralokinumab patients reporting "no" or "1-2 days" of sleep disturbance (35.9-39.1%) was higher than in placebo (see Figure 14).

[0292] At 16 weeks, the change from baseline in DLQI was greater with tralokinumab than with placebo in ECZTRA1 (-5.0 vs. -7.1, P=0.02) and ECZTRA2 (-4.9 vs. -8.8, P<0.001), and the results were separated between the treatment groups from week 2 onward at each planned evaluation time throughout the initial treatment period (P<0.05).

[0293] In both trials, by week 2, POEM and DLQI scores decreased in patients treated with tralokinumab, and this was significantly different from placebo.

[0294] In the ECZTRA1 group, the DLQI decreased by 4.4 with tralokinumab compared to 2.5 in the control group (p<0.001), and in the ECZTRA2 group, it decreased by 4.7 with tralokinumab compared to 2.2 in the control group (p<0.001). The mean improvement in DLQI from baseline reached the minimum clinically important change (MCID) in addition to statistical significance.

[0295] The mean POEM was significantly reduced from baseline compared to placebo in ECZTRA1 (-4.0 with tralokinumab compared to -1.3 in control, p<0.001) and ECZTRA2 (-4.6 with tralokinumab compared to -1.6 in control, p<0.001). The mean improvement in POEM from baseline reached the minimum clinically important change (MCID) in addition to statistical significance.

[0296] Figures 8, 11, and 12 show data for secondary endpoints up to 16 weeks. Improvements in SCORAD, pruritus, DLQI, ERSI, and POEM were observed early in the trial (see Figures 8, 11, and 12). Improvement in EASI began immediately after the start of administration, and was greater with tralokinumab than with placebo in both trials (Figure 8).

[0297] conclusion Tralokinumab monotherapy results in significant early improvement in PROs, as observed in two trials. In particular, patients experience early effects after initiating tralokinumab monotherapy, with substantial improvement as early as two weeks later.

[0298] Example 6: Conjunctivitis in adult patients with moderate to severe atopic dermatitis treated with tralokinumab: Integrated results from five clinical trials Materials and methods Patients receiving tralokinumab 300 mg or placebo (PBO) every two weeks were integrated from five trials: Phase 3 ECZTRA1 / 2 (tralokinumab monotherapy) and ECZTRA3 (tralokinumab with topical corticosteroids), Phase 2 ECZTRA5 (vaccine response in tralokinumab-treated AD patients), and Phase 2b (evaluation of tralokinumab efficacy and safety). Adverse events (AEs) during the initial treatment period (16 weeks in ECZTRA and 12 weeks in Phase 2b) were summarized. Conjunctivitis was defined as a particularly important AESI (AESI). Events were extracted from AE reports (ECZTRA) or the International Medical Terminology Search (Phase 2b). Adjusted AE incidence rates were calculated using Cochran-Mantel-Haenszel weighting, taking into account the different randomization rates between tralokinumab and PBO.

[0299] result Adult patients treated with tralokinumab (n=1605) or PBO (n=680) were included in this analysis. During the initial treatment period, conjunctivitis-associated adverse events (AESI) (basic terms: conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis) occurred in 126 patients (7.5%) treated with tralokinumab, compared to 21 patients (3.2%) treated with PBO. Overall, 145 and 23 conjunctivitis events occurred in the tralokinumab and PBO groups, respectively, the majority of which were mild (68% and 65%) or moderate (30% and 35%). Ophthalmologists confirmed 30% of conjunctivitis events across the tralokinumab (39 events) and PBO (6 events) groups. Similar percentages of events in the tralokinumab and PBO groups recovered (78.6% and 73.9%) or improved (2.8% and 4.3%) during the initial treatment period. There were no serious events, and two events led to permanent discontinuation of tralokinumab. Higher baseline AD severity and a history of allergic conjunctivitis were associated with a higher incidence of conjunctivitis. The median time to the first event was similar in both groups (50.0 days and 51.5 days), but the duration of conjunctivitis was longer in the tralokinumab group (21.0 days and 14.5 days). The majority of patients received treatment for conjunctivitis (81% of tralokinumab patients and 63% of PBO patients). Common treatments included ophthalmic antiallergic drugs (28% and 42%), anti-infective drugs (30% and 11%), corticosteroids (22% and 11%), and combination therapy of corticosteroids and anti-infective drugs (13.5% and 15.8%).

[0300] A comparison of the incidence of conjunctivitis in patients treated with dupilumab (300 mg q2w) after 16 weeks of administration showed that dupilumab had a higher overall incidence (9.3% vs. 7.5%) and a higher percentage of moderate or severe events compared to tralokinumab (Akinlade et al. 2019). This suggests that specific IL-13 neutralization is associated with a lower risk of conjunctivitis than IL-4 / IL-13 double blockade, and that blocking IL-4 signaling, which is known to shift T cells toward a Th1 / Th17 phenotype, may lead to more severe conjunctivitis (Reyes et al. 2014, Stern et al. 2005).

[0301] conclusion The overall incidence of conjunctivitis identified as an AESI during the initial treatment period of the AD pool was higher with tralokinumab than with PBO, although the majority of cases were mild to moderate in severity. Most conjunctivitis events resolved or improved with concurrent treatment during the study.

[0302] Example 7: Clinical response to tralokinumab in atopic dermatitis patients who initially achieved a response below optimal and continued treatment. Materials and Methods: Patients who did not achieve a clinical response, i.e., IGA0 / 1 or EASI-75, at 16 weeks in the ECZTRA1 and ECZTRA2 trials were advanced to open-label tralokinumab 300 mg q2w plus an additional 36 weeks of optional TCS. This post-hoc analysis of data integrated from both trials evaluated the clinical response during open-label treatment in patients who initially achieved a suboptimal response to tralokinumab at 16 weeks.

[0303] Results: In this pooled analysis, 686 out of 1196 patients (57.4%) receiving tralokinumab (360 from ECZTRA1 and 326 from ECZTRA2, respectively) transitioned to open-label treatment at week 16. The proportion of patients achieving IGA0 / 1 or EASI-75 with open-label tralokinumab plus any TCS continued to increase, with 20.1% and 42.9% of these patients achieving IGA0 / 1 and EASI-75, respectively, at week 52. More than half of these responders achieved this within 8 weeks of initiating open-label treatment, and 11.4% and 31.9% achieved IGA0 / 1 and EASI-75 by week 24. In an alternative analysis, patients using concomitant anti-inflammatory therapy (including TCS) (49.1%) were classified as non-responders. In patients who did not receive concomitant anti-inflammatory therapy, the response rates for IGA0 / 1 and EASI-75 were 13.9% and 25.7%, respectively. Considering the level of AD disease activity at 16 weeks, 53.2% of patients with EASI-50 to EASI-74 at 16 weeks achieved EASI-75 at 52 weeks, and 36.5% of the lower group of patients with IGA2 at 16 weeks achieved IGA0 / 1 at 52 weeks. Among patients with EASI25-50% at 16 weeks, 40.7% achieved EASI-75 at 52 weeks, and among patients with IGA3 at 16 weeks, 17.1% achieved IGA0 / 1 at 52 weeks.

[0304] Among patients with an EASI of less than 25 at week 16, 29.3% achieved EASI-75 at week 52, and among patients with an IGA of 4 at week 16, 7.6% achieved IGA0 / 1 at week 52.

[0305] Discussion: These data indicate that the majority of patients who initially had a suboptimal response to tralokinumab subsequently achieved an EASI-75 with continued treatment, and this response correlated with the disease activity of AD achieved by week 16. Furthermore, the clinical response with continued treatment did not appear to be enhanced by the addition of any TCS.

[0306] Example 8: Effect of IL-13 targeting on colony formation in Staphylococcus aureus Materials and Methods: In the ECZTRA1 Phase III trial, patients with moderate to severe Alzheimer's disease (AD) were randomized in a 3:1 ratio to receive either subcutaneous tralokinumab 300 mg or placebo (PBO) every two weeks for the first 16 weeks. The exploratory endpoint was the change in S. aureus skin colonization in patients at week 16. The absolute abundance of S. aureus on diseased skin was assessed by rtPCR of DNA extracted after rotating a sterile cotton swab over the skin. The association between S. aureus colonization and disease severity and selected biomarkers was evaluated. The ratio of the relative decrease in S. aureus colonization from baseline to week 16 between treatment groups was assessed by a t-test of the change in log-transformed values.

[0307] Results: 802 patients were randomized to tralokinumab:PBO in a ratio of 603 to 199. 50.7% had severe AD (IGA-4) at baseline, with a mean EASI score of 32.4. S. aureus colonization correlated with disease severity (EASI score) at baseline and at 16 weeks. S. aureus colonization was further significantly correlated with the gene expression of biomarkers, including IL-13, IL-22, and hBD2, at baseline and at 16 weeks. The median abundance of S. aureus from baseline to 16 weeks was 238 gene copies / cm³ in patients treated with PBO (n=184, 649 to 16 weeks). 2 Patients who received tralokinumab (n=555, 22 gene copies / cm² from 969) 2 The reduction was greater in the tralokinumab-treated patients compared to the PBO group, with a 10-fold greater reduction in PBO patients (ratio = 0.09, p < 0.0001). The use of salvage therapy did not affect the outcome.

[0308] In patients not receiving salvage therapy (64.2% of tralokinumab patients and 53.8% of placebo patients did not receive salvage therapy), the reduction was significantly greater in tralokinumab patients compared to placebo (ratio = 0.12, p < 0.0001).

[0309] Comparing EASI-75 responders in the tralokinumab group and the placebo group, the median colonization of S. aureus at week 16 was lower in tralokinumab patients than in placebo patients. See Figure 15.

[0310] Compared to placebo, tralokinumab significantly reduced the median count from baseline to week 16 (-96.6%, p<0.0001 vs. +34.2%, no significant difference).

[0311] Conclusion: Tralokinumab administration was associated with a significant reduction in S. aureus colonization on lesional skin compared to protanopia in adult patients with moderate to severe Alzheimer's disease (AD). This suggests that the reduction in S. aureus colonization due to IL-13 neutralization contributes to the effects of tralokinumab in improving the characteristics of AD and breaking the cycle of itching, scratching, impaired skin barrier function, and immune-mediated inflammation.

[0312] Example 9: Effects of IL-13 targeting on anxiety and depression Materials and Methods: Patients in the ECZTRA Phase III trials (1-3) were assessed for anxiety and depression using the Hospital Anxiety and Depression Questionnaire (HADS).

[0313] Results: The results of HADS are summarized in Table 17 below regarding ECZTRA1-3 and monotherapy integration (initial administration period: FAS). [Table 18]

[0314] Among subjects with baseline HADS anxiety or HADS depression subscale scores of 8 or higher, the proportion of responders with HADS anxiety and HADS depression scores below 8 at week 16 was higher in the tralokinumab group compared to the placebo group across all trials (p=0.52 in ECZTRA1, p<0.001 in ECZTRA2, and p=0.003 in ECZTRA3). The difference between tralokinumab and placebo was similar in ECZTRA2 (21.2%) and ECZTRA3 (24.8%), but less in ECZTRA1 (3.0%) (see Table 17).

[0315] Furthermore, in all pivotal phase 3 trials, the mean total HADS score from baseline to week 16 was even lower in the tralokinumab group compared to placebo (p=0.38 in ECZTRA1, p=0.001 in ECZTRA2 and 3) (see Table 17).

[0316] In all pivotal phase 3 trials, the mean change from baseline in the tralokinumab group was greater than that of the placebo group from week 4 onward (Figure 13). The same pattern was observed when examining the two individual components of the HADS total score, namely the HADS anxiety score and the HADS depression score.

[0317] In ECZTRA5, the mean change in total HADS score from baseline to week 16 was higher with tralokinumab compared to placebo. The adjusted mean change was -2.4 in the tralokinumab group and -0.6 in the placebo group, with a difference of -1.8 between the treatment groups (p=0.033).

[0318] Conclusion: Tralokinumab administration was associated with a significant reduction in anxiety and depression as measured by HADS compared to PBO in adult patients with moderate to severe Alzheimer's disease (AD).

[0319] Example 10: Effects of IL-13 targeting on health-related quality of life Short-answer format (36 items) health status questionnaire (SF-36) Materials and Methods: The SF-36 short-answer (36-item) health status questionnaire was evaluated for patients in the Phase III trials of ECZTRA1 and ECZTRA2 described above.

[0320] Results: In both trials, both SF-36 physical and mental health scores improved throughout the initial treatment period in both treatment groups.

[0321] In ECZTRA1, the mean physical health score increased from 44.5 at baseline to 51.3 at week 16 in the tralokinumab group, and from 44.7 to 50.2 in the placebo group. The mean mental health score increased from 43.6 at baseline to 48.2 at week 16 in the tralokinumab group, and from 42.4 to 46.0 in the placebo group.

[0322] In the ECZTRA2 study, the mean physical health score increased from 44.3 at baseline to 51.5 at week 16 in the tralokinumab group, and from 43.4 to 48.6 in the placebo group. The mean mental health score increased from 43.6 at baseline to 48.4 at week 16 in the tralokinumab group, and from 43.2 to 44.8 in the placebo group.

[0323] Table 18 below shows that in both trials, the change from baseline in both physical and mental health scores at week 16 was greater in the tralokinumab group compared to the placebo group. [Table 19]

[0324] In ECTZRA1, the adjusted mean change in the SF-36 physical health score was 4.5 in the tralokinumab group compared to 2.9 in the placebo group, with a difference of 1.6 (p=0.013). The adjusted mean change in the SF-36 mental health score was 2.5 in the tralokinumab group compared to 0.3 in the placebo group, with a difference of 2.3 (p=0.010). In ECTZRA2, the adjusted mean change in the SF-36 physical health score was 5.8 in the tralokinumab group compared to 3.2 in the placebo group, with a difference of 2.6 (p<0.001). The adjusted mean change in the SF-36 mental health score was 3.5 in the tralokinumab group compared to 0.5 in the placebo group, with a difference of 3.0 (p<0.001).

[0325] Conclusion: Tralokinumab administration was associated with significant improvement in SF-36 physical and mental health scores compared to PBO in adult patients with moderate to severe Alzheimer's disease (AD).

[0326] Eurocol 5-item health survey with 5 levels (EQ-5D-5L) Materials and Methods: The Eurocol 5-item health questionnaire (EQ-5D-5L) was evaluated in patients participating in the ECZTRA Phase III trials 1-3.

[0327] Results: In all trials, subjects' health perception improved throughout the initial treatment period, based on both parts of EQ-5D-5L (i.e., EQ-5D-5L index score and EQ-5D-5L VAS).

[0328] In ECZTRA1, the mean EQ-5D-5L index score increased from 0.553 at baseline to 0.787 at week 16 in the tralokinumab group, and from 0.571 to 0.739 in the placebo group. The mean EQ-5D-5L VAS score increased from 53.8 at baseline to 72.7 at week 16 in the tralokinumab group, and from 54.7 to 69.4 in the placebo group.

[0329] In the ECZTRA2 study, the mean EQ-5D-5L index score increased from 0.544 at baseline to 0.779 at week 16 in the tralokinumab group, and from 0.543 to 0.683 in the placebo group. The mean EQ-5D-5L VAS score increased from 58.0 at baseline to 74.4 at week 16 in the tralokinumab group, and from 55.7 to 68.0 in the placebo group.

[0330] In ECZTRA3, the mean EQ-5D-5L index score increased from 0.561 at baseline to 0.839 at week 16 in the tralokinumab + TCS group, and from 0.589 to 0.766 in the placebo + TCS group. The mean EQ-5D-5L VAS score increased from 59.1 at baseline to 76.1 at week 16 in the tralokinumab + TCS group, and from 59.4 to 72.8 in the placebo + TCS group.

[0331] The changes from the baseline in both sections of EQ-5D-5L for ECZTRA1-3 are summarized in Table 19 below. [Table 20]

[0332] Across all trials, subjects' health perception improved based on their EQ-5D-5L index scores. The change in EQ-5D-5L index scores from baseline to week 16 was higher in the tralokinumab group compared to the placebo group across all trials, with similar inter-group differences between trials (p=0.004 for ECZTRA1, p<0.001 for ECZTRA2 and ECZTRA3). Differences were observed from the first assessment after week 4 in all trials.

[0333] Furthermore, subjects' health perception improved across all trials based on the EQ-5D-5L VAS. The change in EQ-5D-5L VAS from baseline to week 16 was higher in the tralokinumab group compared to the placebo group across all trials, with a larger inter-group difference in ECZTRA2 compared to ECZTRA1 and ECZTRA3 (p=0.016 for ECZTRA1, p<0.001 for ECZTRA2, and p=0.12 for ECZTRA3). Differences were observed from week 4 onwards in all pivotal trials.

[0334] In the ECZTRA5 study, the mean change in EQ-5D-5L index scores from baseline to week 16 was higher in the tralokinumab group compared to placebo, with an adjusted mean change of 0.130 in the tralokinumab group and 0.097 in the placebo group, resulting in a difference of 0.034 (p=0.19). The mean change in EQ-5D-5L VAS was 8.3 in the tralokinumab group and 0.6 in the placebo group, resulting in a difference of 7.6 (p=0.004).

[0335] Conclusion: Tralokinumab administration was associated with a significant improvement in subjects' health perception compared to PBO, as measured by EQ-5D-5L, in adult patients with moderate to severe Alzheimer's disease (AD).

[0336] Example 11: Use of tralokinumab in AD patients who are not adequately controlled by cyclosporine A or who have contraindications to cyclosporine A. This example reports the initial results of the ECZTRA7 trial of tralokinumab in combination with topical corticosteroids in subjects with severe atopic dermatitis that is not adequately controlled with oral cyclosporine A or who have contraindications to oral cyclosporine A.

[0337] This was an international, multicenter, phase 3 trial. The trial was randomized, double-blind, and placebo-controlled. [Table 21-1] [Table 21-2]

[0338] Test design This trial consisted of a 2-6 week screening period and a 26-week administration period. After completing the 26-week visit or safety follow-up visit, eligible subjects were invited to participate in a long-term extension study conducted under a different protocol (LP0162-1337, ECZTEND). Subjects who did not transition to ECZTEND after completing the 26-week visit were required to complete a 14-week drug-free follow-up period for evaluation of safety, pharmacokinetics (PK), and anti-drug antibodies (ADA). Subjects deemed eligible after the screening period were randomized in a 1:1 ratio to receive either tralokinumab 300 mg + TCS or placebo + TCS every two weeks (Q2W). Randomization was stratified by prior cyclosporine A (CSA) use (yes / no), country (Germany / not Germany), and baseline disease severity (Investigator Global Assessment [IGA] = 3 or 4).

[0339] A total of 250 subjects were planned to be randomized. 277 subjects were randomized, and 275 received the investigational drug (IMP, tralokinumab, or placebo). All 275 subjects were included in the largest control and safety analysis populations.

[0340] Selection Criteria In order for a subject to be included in this study, they had to meet all of the following criteria: 1. Signed and dated informed consent has been obtained prior to any protocol-related procedure. 2. Must be 18 years of age or older. 3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria (27). 4. A history of Alzheimer's disease lasting 1 year or more. 5. Subjects with a recent medical history (within one year prior to the screening visit) of insufficient response to topical medication. An insufficient response was defined as the failure to achieve or maintain remission or a state of low disease activity (equivalent to IGA 0 = clear to 2 = mild) despite daily prescription treatment with a moderate to high-potency TCS (±TCI as needed) for at least 28 days or the longest period recommended by the product's prescription information (e.g., 14 days for super-potent TCS), whichever is shorter. • Subjects with a documented history of systemic treatment for AD within the past year were also considered to be inadequate responders to topical treatment and were potentially eligible for tralokinumab treatment after an appropriate washout period. 6. AD lesions covering 10% or more of the body surface at the time of screening using SCORAD component A and at baseline. 7. EASI score of 20 or higher at screening and baseline. 8. IGA score of 3 or higher at screening and baseline. 9. The mean score of the highest diurnal pruritus score (NRS) in the week prior to baseline is 4 or higher. • The highest daily pruritus NRS score at baseline was calculated from the daily assessment of the most severe itching during the 7 days immediately preceding randomization (days -6 to 0) (highest daily pruritus NRS score). To calculate the mean baseline score, at least four highest daily pruritus NRS scores were required within the 7 days. For subjects who did not report at least four scores during the 7 days immediately preceding the scheduled randomization date, randomization was delayed until this requirement was met, but not exceeding the maximum screening period of 6 weeks. 10. Subjects applied a stable dose of emollient twice daily (or more if necessary) for at least 14 days prior to randomization. 11. Women who may become pregnant should not be highly effective throughout the entire study and at least 16 weeks (5 half-lives) after the last IMP dose. * It was necessary to use a specific form of contraception (confirmed by the principal investigator). *Highly effective contraception was defined as a method with a low failure rate (less than 1% in one year), such as bilateral tubal occlusion, intrauterine devices (IUDs), intrauterine hormone-releasing systems (IUSs), combination hormonal contraception (including estrogen and progestogen) associated with ovulation suppression (oral, vaginal, transdermal), hormonal contraception using only progestogen associated with ovulation suppression (oral, injectable, implantable), sexual abstinence (if this aligns with the subject's preferred normal lifestyle), and a vasectomized partner (if the subject is monogamous). Subjects had to have been using contraception continuously for at least one month prior to the baseline pregnancy test. Women were defined as having no potential for pregnancy if they were postmenopausal (no menstruation for at least 12 months prior to screening without other medical causes) or surgically infertile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). 12. Any of the following medical histories recorded by a physician: • No prior exposure to CSA, and not a candidate for CSA treatment due to any of the following: i. Medical contraindications (e.g., poorly controlled hypertension due to medication) or hypersensitivity to the active substance or excipients of the CSA. ii. Use of prohibited concomitant medications (e.g., statins, digoxin, macrolides, antibiotics, barbiturates, anticonvulsants, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors, St. John's wort). iii. Increased susceptibility to renal impairment (elevated creatinine) and hepatic impairment (elevated functional test results) due to CSA, or an increased risk of serious infection. • You have been previously exposed to CSA and should not continue or resume CSA treatment for any of the following reasons: i. Intolerance or unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, poorly controlled hypertension, paresthesia, headache, nausea, hirsutism). ii. Inadequate response to CSA (defined as a relapse of AD with tapering of CSA up to 6 weeks at a high dose [5 mg / kg / day] followed by a maintenance dose [2–3 mg / kg / day], or a relapse at least 3 months after the maintenance dose). A relapse was defined as an increase in signs or symptoms leading to an expansion of treatment, which may involve dose increase, switching to a high-potency class TCS, or initiation of another systemic nonsteroidal immunosuppressant. iii. A required dose of CSA exceeding 5 mg / kg / day, or a duration of administration exceeding that specified in the prescription information (more than 1 year).

[0341] Exclusion criteria A subject was deemed ineligible to participate in the study based on any of the following criteria: 1. Subjects for whom TCS is medically unsuitable, in the opinion of the principal investigator, for example, due to serious side effects or safety risks (treatment intolerance, hypersensitivity reaction, severe skin atrophy, systemic effects, etc.). 2. Simultaneous enrollment in another interventional clinical trial. 3. Previous randomization in clinical trials of tralokinumab. 4. Active skin conditions that may be confused with the diagnosis of Alzheimer's disease or may interfere with the evaluation of treatment, such as scabies, cutaneous lymphoma, or psoriasis. 5. Known active allergic or irritant contact dermatitis that is likely to interfere with the assessment of the severity of AD. 6. Use of a tanning bed or phototherapy (narrowband ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]) within 6 weeks prior to randomization. 7. Treatment with the following medications within 4 weeks prior to randomization: • Systemic immunosuppressants / immunomodulators (e.g., methotrexate, CSA, azathioprine, mycophenolate mofetil, Janus kinase inhibitors). • Use of systemic corticosteroids (excluding topical, inhaled, or intranasal administration). • Bleach baths three or more times in any week within a four-week period. 8. Treatment with a topical PDE-4 inhibitor within two weeks prior to randomization. 9. Administration of attenuated live vaccine within 30 days prior to the randomization date and during the trial, including the safety follow-up period. • Inactive / dead-cell vaccines (e.g., inactive influenza) were permitted, provided they were not administered within 5 days before or after any trial visit. 10. Administration of commercially available biological therapies (e.g., immunoglobulins, anti-IgE) including dupilumab or investigational biological agents: • Any cell depletion agent, including but not limited to rituximab: within 6 months prior to randomization, or until lymphocyte count returns to normal, whichever is longer. • Other biologics: Whichever is longer, within 3 months prior to randomization or within 5 half-lives. 11. Administration of non-biological investigational drugs with a half-life of less than 5 months prior to randomization. 12. Administration of blood products within 4 weeks prior to screening. 13. You have undergone major surgery within 8 weeks prior to screening, or you have scheduled hospitalization for surgery or hospitalization during the trial period. 14. You have a known or suspected allergy or reaction to any component of an IMP or AxMP formulation. 15. History of any active skin infection within one week prior to randomization. 16. A history of a clinically significant infection within four weeks prior to randomization, in the opinion of the principal investigator or the sponsor's medical professional, that could potentially impair the subject's safety during the study, interfere with the assessment of IMP, or reduce the subject's ability to participate in the study. A clinically significant infection was defined as follows: ·Systemic infection. • Severe skin infections requiring parenteral (intravenous or intramuscular) antibiotics, antiviral drugs, or antifungal drugs. 17. Parasitic helminth infection within six months prior to the date informed consent was obtained, which was either not treated with standard treatment or did not respond to it. 18. A history of anaphylaxis following any biological therapy. 19. History of immune complex disease. 20. Cancer history: Subjects with a history of basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix are eligible, provided that they are in remission and have completed curative therapy at least 12 months prior to the date informed consent was obtained. Subjects with a history of other malignant tumors are eligible provided they are in remission and have completed curative therapy at least five years prior to the date informed consent was obtained. 21. Tuberculosis requiring treatment within 12 months prior to screening. Evaluation was based on the standard treatment of the implementing facility, in accordance with the facility's guidelines. 22. Subjects with a history of any known primary immunodeficiency disorder, including a positive human immunodeficiency virus (HIV) test, or who are taking antiretroviral drugs as determined by their medical history and / or oral reports. 23. A history of chronic alcohol or drug abuse within 12 months prior to screening, or any condition associated with low compliance as determined by the principal investigator. 24. History of suicide attempt or significant risk of suicide (in the opinion of the principal investigator, or by answering "yes" to question 4 or 5 regarding suicidal ideation, or by answering "yes" to suicidal behavior on the Columbia Suicide Severity Rating Scale [C-SSRS] Screening Version). 25. Any major physical disability, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, immunological, psychiatric, or unstable as determined by the Principal Investigator, which may include: • It may affect the safety of subjects during the trial. • It may affect the results or interpretation of the test. • It hinders the subject's ability to complete the entire duration of the study. 26. Any clinically significant abnormal findings in the opinion of the principal investigator during the screening period, including physical examination, vital signs, electrocardiogram (ECG), hematology, clinical chemistry, or urinalysis, may endanger participation in the study or affect the study results or the subject's ability to complete the entire duration of the study. 27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are 2.0 times or higher than the upper limit of normal (ULN) at the time of screening. 28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (anti-HCV) serology at the time of screening. Subjects who are HBsAb positive may be randomized under the condition that they have a history of hepatitis B vaccination and negative HBsAg and HBcAb serology. 29. Subjects who do not refrain from donating blood and / or plasma for 16 weeks (5 half-lives) after the last dose of IMP from the time of informed consent. 30. Subjects legally confined to a facility. 31. Pregnant, breastfeeding, or lactating women. 32. An employee of the testing facility, or any other individual directly involved in the planning or execution of the test, or a close relative of such individual.

[0342] Tralokinumab - Duration of Administration • First day of administration (Day 0 = 3rd visit, baseline): Four subcutaneous (SC) injections of tralokinumab, 600 mg, and 150 mg (1.0 mL each). Subsequent visits leading up to the final IMP administration scheduled for week 24: Tralokinumab, 300 mg Q2W, and two SC injections of 150 mg tralokinumab (1.0 mL each).

[0343] Placebo-dosage period • First day of administration (Day 0 = 3rd visit, baseline): Placebo, 4 SC injections (1.0 mL each). Subsequent visits up to the 24th week visit: Placebo, Q2W, two SC injections (1.0 mL each).

[0344] statistical methods In this study, four estimates were defined, incorporating three main types of comorbidities that influenced the estimation of treatment efficacy: initiation of rescue therapy, permanent discontinuation of IMP, and onset of COVID-19 in the subject. Overall Type I error in the primary analysis of primary estimates for the primary and secondary endpoints was prevented by a hierarchical testing procedure. These endpoints were tested sequentially at a 5% significance level.

[0345] No interim analysis was performed.

[0346] Primary endpoint (EASI 75 at 16 weeks) Differences in response rates between treatment groups were analyzed using Mantel-Haenszel risk differences and associated standard errors, stratified by prior CSA use (with / without) and baseline disease severity (IGA=3 or 4), and multiple estimates were combined using Rubin's rule.

[0347] Concomitant events were processed based on the first event to occur. Salvage treatment, permanent discontinuation of IMP, and missing data at week 16 visit not attributable to the COVID-19 pandemic were analyzed as non-responders. Subject onset of COVID-19 pandemic and missing data at week 16 visit attributable to the COVID-19 pandemic were imputed using a stepwise multiple imputation procedure.

[0348] Secondary outcome items At 26 weeks, an EASI of 75, at 16 / 26 weeks an IGA of 0 / 1, and a decrease of 4 or more in the weekly mean of the diurnal peak pruritus NRS from baseline to 16 / 26 weeks were analyzed as described for the primary endpoints.

[0349] Changes in SCORAD and DLQI scores from baseline to weeks 16 and 26 were analyzed using a repeated measures model of post-baseline response up to week 26, including only data prior to concomitant events.

[0350] Medical resource utilization (use of TCS) The amount of TCS used was analyzed using a repeated measures model. To account for missing data due to unreturned tubes, the amount of TCS used was analyzed based on two different approaches: 1) no TCS was used from unreturned tubes, or 2) all TCS was used from unreturned tubes.

[0351] Summary of results Treatment duration: 277 subjects were randomized in a 1:1 ratio, with 140 subjects randomized to tralokinumab + TCS and 137 subjects randomized to placebo + TCS. Two subjects in the tralokinumab + TCS group did not receive treatment.

[0352] 125 subjects (89.3%) in the tralokinumab + TCS group and 120 subjects (87.6%) in the placebo + TCS group completed 26 weeks of treatment.

[0353] Demographics and Baseline Characteristics Overall, demographic and baseline characteristics were well-balanced between the tralokinumab + TCS and placebo + TCS groups. The mean age at baseline was 36.5 years (SD: 14.1), mean weight was 75.7 kg (SD: 16.3), and 59.6% of subjects were male. The mean BSA of AD lesions at baseline was 54.7% (SD: 22.2), the mean age to AD onset was 10.3 years (SD: 15.4), and the mean duration of AD was 26.2 years (SD: 13.9). Disease severity at baseline was similar between the treatment groups. All subjects had severe AD (baseline EASI score ≥ 20). The average EASI score was 32.95 (SD: 12.54), the average SCORAD score was 70.51 (SD: 12.43), the average DLQI score was 16.11 (SD: 6.43), and the average diurnal peak (weekly average) of the pruritus NRS was 7.37 (SD: 1.41).

[0354] The types of previous AD treatments, the proportion of subjects who had used those treatments, and the history of atopic dermatitis were similar across the treatment groups and were as expected in the long-term and severe AD population.

[0355] Exposure and compliance during administration The majority of subjects were exposed to IMP for 16 weeks or more (93.5% in the tralokinumab + TCS group and 95.6% in the placebo + TCS group). 79.7% and 71.5% of subjects received all planned doses of IMP (tralokinumab + TCS or placebo + TCS, respectively) until the end of the study or permanent discontinuation of IMP. The impact of the COVID-19 pandemic was limited, with only 24 subjects (8.7%) missing one or two IMP dose opportunities due to the COVID-19 pandemic (10 in the tralokinumab + TCS group and 14 in the placebo + TCS group), and one subject (0.7%) in the placebo + TCS group missing more than three IMP dose opportunities due to the COVID-19 pandemic.

[0356] Efficacy Results The efficacy of tralokinumab in combination with TCS in treating adult patients with severe Alzheimer's disease who are ineligible for CSA treatment was demonstrated during the administration period of this randomized, placebo-controlled phase 3 clinical trial. The results of the primary and secondary endpoints are summarized below.

[0357] The clinical efficacy of tralokinumab administration was evaluated by three different investigator assessments (EASI, IGA, and SCORAD). EASI was used for primary and secondary endpoints, while IGA and SCORAD were used for secondary endpoints. Several validated patient-reported questionnaires were included to assess the efficacy of tralokinumab on PROs and health-related quality of life (HRQoL).

[0358] Primary endpoint (EASI 75 at 16 weeks) At week 16, the proportion of EASI75 responders was statistically significantly higher in the tralokinumab + TCS group compared to the placebo + TCS group. The difference between the treatment groups was 14.1% (95% CI: 2.5–25.7, p=0.018) at week 16, with 64.2% responders in the tralokinumab + TCS group and 50.5% in the placebo + TCS group (primary analysis of primary estimates). Primary analyses of secondary, tertiary, and quaternary estimates, as well as sensitivity analyses, yielded the same conclusions as the primary analysis of primary estimates (p<0.05, overall analysis).

[0359] Secondary outcome items No secondary endpoints were confirmed by the successive testing hierarchy as a reduction of 4 or more points in the diurnal peak score (weekly mean) of the primary secondary endpoint, pruritus NRS, from baseline to week 16, and therefore could not be statistically significant (p=0.106). However, these results seemed to indicate different responses between the treatment groups, as 45.5% of tralokinumab + TCS patients achieved a reduction of 4 points in the diurnal peak score of pruritus NRS at week 16 (compared to 35.6% for placebo + TCS at week 16) (47.2% for tralokinumab + TCS and 39.7% for placebo + TCS at week 26). Nevertheless, regardless of the confirmatory testing hierarchy, all other secondary endpoints showed greater improvement with tralokinumab + TCS in adult subjects with severe AD at both week 16 and week 26 (P<0.05). At 26 weeks, the proportion of EASI75 responders was higher in the tralokinumab + TCS group compared to the placebo + TCS group. The difference between the treatment groups was 14.1% (95% CI: 2.9~25.3, p=0.014) at 26 weeks, with 68.8% responders in the tralokinumab + TCS group and 55.3% in the placebo + TCS group (primary analysis of primary estimates). Primary analyses of secondary, tertiary, and quaternary estimates, as well as sensitivity analyses, yielded the same conclusions as the primary analysis of primary estimates (p<0.05, overall analysis). • The proportion of IGA0 / 1 responders at weeks 16 and 26 was higher in the tralokinumab + TCS group compared to the placebo + TCS group. Based on the primary analysis of primary estimates, the differences between treatment groups were as follows: ○At 16 weeks, the response rate was 15.6% (95% CI: 4.8~26.3, p=0.005), with 40.9% in the tralokinumab + TCS group and 26.0% in the placebo + TCS group. ○At 26 weeks, the response rate was 14.3% (95% CI: 2.9~25.6, p=0.014), with 47.0% in the tralokinumab + TCS group and 33.4% in the placebo + TCS group. Primary analyses of secondary, tertiary, and quaternary estimates, as well as sensitivity analyses, yielded the same conclusions at 16 and 26 weeks as the primary analysis of the primary estimate (p<0.05, overall analysis). • Changes in SCORAD from baseline to weeks 16 and 26 were greater in the tralokinumab + TCS group compared to the placebo + TCS group. Based on the primary analysis of primary estimates, the differences between treatment groups were as follows: ○At 16 weeks, the average change was -8.6 (95% CI: -13.0 to -4.2, p<0.001), with an adjusted mean change of -42.7 (SE: 1.6) in the tralokinumab + TCS group and -34.1 (SE: 1.6) in the placebo + TCS group. ○At 26 weeks, the average change was -8.9 (95% CI: -13.2 to -4.6, p<0.001), with an adjusted mean change of -46.3 (SE: 1.5) in the tralokinumab + TCS group and -37.3 (SE: 1.6) in the placebo + TCS group. Primary analyses of secondary, tertiary, and quaternary estimates, as well as sensitivity analyses, yielded the same conclusions at 16 and 26 weeks as the primary analysis of the primary estimate (p<0.05, overall analysis). • Changes in DLQI from baseline to weeks 16 and 26 were greater in the tralokinumab + TCS group than in the placebo + TCS group. Based on the primary analysis of primary estimates, the differences between treatment groups were as follows: ○At 16 weeks, the adjusted mean change was -1.5 (95% CI: -2.6 to -0.4, p<0.009) in the tralokinumab + TCS group and -9.6 (SE: 0.4) in the placebo + TCS group. ○At 26 weeks, the adjusted mean change was -1.6 (95% CI: -2.7 to -0.5, p<0.005), with an adjusted mean change of -11.5 (SE: 0.4) in the tralokinumab + TCS group and -9.9 (SE: 0.4) in the placebo + TCS group. At 26 weeks, the primary analysis of secondary and tertiary estimates, as well as the sensitivity analysis, yielded the same conclusions as the primary analysis of primary estimates (p<0.05, all analyses). At 16 weeks, no differences between treatment groups were observed based on the analysis of secondary and tertiary estimates (p≧0.05, all analyses).

[0360] Utilization of medical resources Regardless of the analytical approach (e.g., whether to assume no or all TCS used from unreturned tubes), the amount of TCS supplied was less with tralokinumab than with placebo over 26 weeks. • Cumulative TCS use was lower with tralokinumab compared to placebo at weeks 15-16 (p=0.006) and 25-26 (p=0.002). Over the periods of weeks 0-16 and 0-26, subjects receiving tralokinumab used approximately 30% less of the provided TCS compared to subjects receiving placebo. At weeks 15-16, approximately 60-65% of tralokinumab subjects and approximately 50-55% of placebo subjects either did not use TCS or used a limited amount (0-15g). At weeks 25-26, the percentages were approximately 55-60% for tralokinumab and approximately 45-50% for placebo. The average number of days without local treatment (weekly average) was already higher in the tralokinumab + TCS group from week 3 onwards than in the placebo + TCS group (p<0.05). The proportion of subjects who did not use local treatment for 5–7 days was higher with tralokinumab compared to placebo at both week 16 (43.8% vs. 21.1%, p<0.001) and week 26 (39.8% vs. 24.1%, p=0.006). Sensitivity analysis yielded the same conclusion at both week 16 and week 26 (p<0.05).

[0361] Safety performance Overall, tralokinumab administration in combination with TCS for up to 26 weeks was well-tolerated and demonstrated an acceptable safety profile in adults with severe Alzheimer's disease who were ineligible for treatment with CSA.

[0362] Summary of adverse events • Throughout the study period and across all treatment groups, the incidence of adverse events (AEs) was comparable between tralokinumab + TCS and placebo + TCS. The majority of reported AEs were not serious, were mild to moderate in severity, and were considered unrelated to IMP by the investigators. Most events resolved by the end of the study. During the administration period (weeks 0-26), adverse events (AEs) were reported at similar incidence and proportions in tralokinumab + TCS (77.5% of subjects, 589.1 events per 100 PYE) and placebo + TCS (78.8% of subjects, 646.7 events per 100 PYE, P=0.795). In both treatment groups, the most frequently reported SOC for AEs was "infections and parasitic diseases" in over 50% of subjects in each group. Within this SOC, the most frequently reported PT was "viral upper respiratory tract infections" in 26.8% of subjects in tralokinumab + TCS (81.10 events per 100 PYE) and in 25.5% of subjects in placebo + TCS (70.33 events per 100 PYE). In the State of Computing (SOC) category, 15.2% of subjects in the tralokinumab + TCS group reported headache at a rate of 38.25 events per 100 PYE, compared to 9.5% of subjects in the placebo + TCS group at a rate of 27.52 events per 100 PYE. During the safety follow-up period, four events (5.3%, 33.95 events per 100 PYE) were reported in four subjects treated with tralokinumab + TCS and twelve events (7.2%, 91.66 events per 100 PYE) were reported in six subjects treated with placebo + TCS prior to the occurrence of an adverse event (AE). No patterns were observed in either group, neither in terms of situational awareness (SOC) nor post-operative period (PT).

[0363] Death, other serious adverse events, and other clinically significant events There were no reports of deaths during the test. A small number of SAEs were reported during the trial (11 events in total from 7 subjects), and most events occurred with placebo + TCS rather than tralokinumab + TCS (1 SAE in 1 subject [0.7%], PT “appendicitis”) (10 SAEs in 6 subjects [4.4%], including 1 event “pyelonephritis” that occurred during safety follow-up in 1 subject who received placebo + TCS before the event occurred). Of these 11 SAEs, 6 events were severe (PT “appendicitis”, “cerebrovascular disorder”, “seizure”, “anaphylactic reaction”, “atopic dermatitis”, and “pyelonephritis”). Three SAEs led to permanent discontinuation of IMP (PT “cerebrovascular disorder”, “depressed mood”, and “suicidal ideation” [all placebo + TCS]), and of these, the “cerebrovascular disorder” event also led to withdrawal from the trial. These three SAEs were thought to be related to IMP, while the other SAEs were not assessed as being related to IMP in the study. With the exception of one subject with the PT “Peripheral Nerve Injury” event ("not recovered / not resolved") and one subject with the PT “Depressed Mood” and “Suicidal Ideation” events, which were reported as “unconfirmed” because they dropped out of follow-up, most subjects recovered from SAEs by the end of the study. There were only a few adverse events (AEs) during the administration period that led to permanent discontinuation of IMP (a total of 5 events in 4 subjects): 1 subject (0.7%) in the tralokinumab + TCS group experienced 1 PT ("injection site pain"), and 3 subjects (2.2%) in the placebo + TCS group experienced 4 AEs, 3 of which led to withdrawal from the study. Of these 5 events, 3 were serious (PT: "cerebrovascular disorder" [severe], "depressed mood," "suicidal ideation" [moderate severity]), and 2 were not serious (PT: "atopic dermatitis" [moderate severity] and "injection site pain" [mild severity]). With the exception of the PT "atopic dermatitis" event, all events were considered to be IMP-related, probably / with high certainty. The events of "cerebrovascular disease," "atopic dermatitis," and "injection site pain" that led to permanent discontinuation of IMP also resulted in withdrawal from the study during the treatment period, and these outcomes were reported as "recovered / resolved." Two particularly important adverse event (AESI), herpetic eczema, were reported in one subject receiving tralokinumab + TCS during the treatment period. Neither event was severe, both were mild in severity, and were thought to be potentially related to IMP. Their outcomes were reported as "recovered / resolved." • No cases of AESI (Antimicrobial Stem Infection) of malignant tumors diagnosed after randomization were reported in this trial. Fourteen AESIs related to skin infections requiring systemic treatment were reported in the trial. One AESI (PT: "Infectious Dermatitis") occurred in one subject (0.7%) in the tralokinumab + TCS group, and 13 AESIs occurred in nine subjects (6.6%) in the placebo + TCS group (including one AESI during the safety follow-up period). None of the events were severe or critical, and six of the 14 events were considered potentially related to IMP. With the exception of one event, "Staphylococcal Skin Infection," in the placebo + TCS group, which was reported as "not resolved / not recovered" at the end of the trial, most subjects recovered from their events by the end of the trial. • Twenty-six AESIs related to predefined eye disorders (conjunctivitis, keratoconjunctivitis, and keratitis) were reported in this study (all reported during the treatment period). The majority of events were classified as conjunctivitis and were more frequent in tralokinumab + TCS (15 events in 13 subjects [9.4%]) than in placebo + TCS (8 events in 6 subjects [4.4%]) (PT "conjunctivitis," "allergic conjunctivitis," and "viral conjunctivitis"). One event classified as keratoconjunctivitis (PT "atopic keratoconjunctivitis") was reported in one subject (0.7%) in the tralokinumab + TCS group. Two events classified as keratitis were reported (1 event in 1 subject [0.7%] in each treatment group). Of these 26 AESIs related to predefined eye disorders, none were severe or serious, and none resulted in withdrawal from the study. Eleven of the 26 events were thought to be related to IMP. For all but six events (three in each treatment group), the outcome was reported as "recovered / resolved" or "recovering / resolving" at the end of the study. Seventeen adverse events (AEs) related to injection site reactions were reported during the administration period (12 events in 9 subjects in the tralokinumab + TCS group and 5 events in 3 subjects in the placebo + TCS group). The majority of events were "injection site reactions." None of the 17 events were serious or severe. With the exception of one event in the tralokinumab + TCS group, no subjects withdrew from the study due to "injection site reactions." All events were thought to be related to IMP, and their outcomes were reported as "recovered / resolved." Aside from one event of "elevated eosinophil count" reported during the screening period (recovered / resolved before the first IMP administration), no eosinophilia-related adverse events were reported during the study.

[0364] pregnancy No pregnancies were reported during the trial.

[0365] Clinical Laboratory Evaluation Aside from eosinophil levels, no other clinically relevant laboratory parameters were observed in any of the treatment groups during the study. • At baseline, the mean eosinophil level was 0.454 × 10⁻¹⁰ in the tralokinumab + TCS group. 9 / L[SD:0.355×10 9 / L]) and placebo + TCS group (0.543 × 10 9 / L[SD:0.410×10 9 In both subjects ([L]), the levels were within the normal range. From week 4 onwards, mean eosinophil levels remained higher in subjects receiving tralokinumab + TCS than in subjects receiving placebo + TCS. At week 16, the mean change from baseline was 0.140 × 10⁻⁶ in the tralokinumab + TCS group. 9 / L(SD:0.459×10 9 / L) and placebo + TCS was -0.148 × 10 9 / L(SD:0.305×10 9 The average count was 0.593 × 10⁻¹⁰ for tralokinumab + TCS. 9 / L(SD:0.510×109 / L) and placebo + TCS was 0.409 × 10 9 / L(SD:0.262×10 9 The result was / L). At 26 weeks, the mean change from baseline was 0.112 × 10 for tralokinumab + TCS. 9 / L(SD:0.465×10 9 / L) and placebo + TCS was -0.171 × 10 9 / L(SD:0.365×10 9 The average count was 0.565 × 10⁻¹⁰ for tralokinumab + TCS. 9 / L(SD:0.514×10 9 / L) and placebo + TCS was 0.394 × 10 9 / L(SD:0.317×10 9 It was / L).

[0366] Other safety evaluations • No clinically relevant changes were observed in vital signs, physical examination findings, or electrocardiogram findings in any of the treatment groups. The majority of subjects did not develop anti-tralokinumab antibodies or nABs. In total, two subjects (1.4%) in the tralokinumab + TCS group and three subjects (2.2%) in the placebo + TCS group tested positive for ADA.

[0367] conclusion This Phase 3 randomized, double-blind, placebo-controlled trial demonstrated the efficacy and safety of tralokinumab in combination with TCS in adult subjects with severe Alzheimer's disease who were ineligible for CSA treatment. These results support the following conclusions: The EASI75 response rate (primary endpoint) at 16 weeks was statistically significantly higher with tralokinumab + TCS than with placebo + TCS (p<0.05), demonstrating that tralokinumab + TCS is superior to placebo + TCS in the treatment of severe AD. The primary secondary outcome measure addressing itching (a decrease of 4 or more points in the weekly mean of the diurnal peak pruritus NRS score from baseline to week 16) was not statistically significant (p=0.106), and the remaining hierarchies could not be confirmed. On the other hand, regardless of the hierarchy of the confirmatory sequential test: ○At 16 weeks, 45.5% of subjects treated with tralokinumab + TCS achieved a 4-point reduction in their diurnal peak pruritus NRS score (compared to 35.6% at 16 weeks with placebo + TCS) (at 26 weeks, the figures were 47.2% for tralokinumab + TCS and 39.7% for placebo + TCS). Improvements in other secondary endpoints related to AD severity and degree (EASI75 at 26 weeks, IGA0 / 1 at 16 / 26 weeks, and SCORAD at 16 / 26 weeks) and HRQoL (DLQI at 16 / 26 weeks) were greater with tralokinumab + TCS than with placebo + TCS (p<0.05). • The amount of TCS provided and the amount of rescue therapy used were lower in tralokinumab-treated subjects than in placebo-treated subjects at both weeks 16 and 26, supporting the demonstrated efficacy of tralokinumab. More tralokinumab-treated subjects than placebo-treated subjects had 5 to 7 days without topical treatment at both weeks 16 and 26. PRO (POEM, a decrease of 4 points or more in POEM, and the Physical Health Scales EQ-5D-5L and SF-36) showed greater improvement with tralokinumab + TCS than with placebo + TCS, and the subjects' own perception of treatment effectiveness was consistent with the demonstrated clinical response (EASI75 or IGA0 / 1) obtained with tralokinumab + TCS. Tralokinumab + TCS was well-tolerated and demonstrated an acceptable safety profile in adults with severe Alzheimer's disease who were ineligible for treatment with CSA.

[0368] List of abbreviations AD, atopic dermatitis AE, Adverse Events AESI, particularly important adverse events BSA, lesions on the body surface CI, confidence interval DLQI, a questionnaire about skin condition. EASI, Eczema Area Severity Index EASI-50, the eczema area severity index score, decreases by at least 50%. EASI-75, the eczema area severity index score, decreased by at least 75%. EASI-90, the eczema area severity index score, decreases by at least 90%. EQ-5D-5L, Eurocol 5-item health survey, 5 levels FAS, the largest group of analysis subjects HADS = Hospital-Associated Anxiety and Depression Questionnaire HRQoL (Health-related Quality of Life) IGA, Overall evaluation by the principal investigator IGA-0 / 1, Principal Investigator's Global Assessment Score: 0 (disappeared) or 1 (almost disappeared) IMP, investigational drug IQR, Interquartile Range MedDRA, International Medical Terminology Glossary NRS, Numerical Rating Scale PT, basic word PYE, patient year Q2W, every other week, that is, every two weeks. Q4W, every 4 weeks R, the rate (the number of AEs divided by PYE and multiplied by 100) SAE, serious adverse event SCORAD, a scoring system for atopic dermatitis SE, standard error SF-36, Short-answer (36-item) Health Status Questionnaire TCS, topical corticosteroids

[0369] The following numbered clauses describing aspects of the present invention are part of this specification.

[0370] 1. An interleukin-13 (IL-13) binding protein for use in a method for treating atopic dermatitis (AD) in a subject, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0371] 2. A method for treating a subject in need of treatment for atopic dermatitis (AD), comprising the steps of (a) administering a first dose of IL-13 binding protein to the subject, and (b) administering one or more second doses of IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0372] 3. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis (AD) in a subject, the method comprising: (a) administering a first dose of the IL-13 binding protein to the subject; and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose.

[0373] 4. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the AD is moderate to severe or severe AD.

[0374] 5. IL-13 binding protein, method or use for use as described in any one of the preceding clauses, wherein each second dose is administered to the subject 25 to 31 days after the immediately preceding dose.

[0375] 6. IL-13 binding protein, method or use for use as described in any one of the preceding clauses, wherein each second dose is administered to the subject approximately four weeks after the immediately preceding dose.

[0376] 7. An IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, wherein the method is carried out for at least two weeks, at least three weeks, at least twelve weeks, at least three months, at least sixteen weeks, at least twenty-four weeks, at least six months, at least thirty-two weeks, at least thirty-six weeks, at least one year, or at least fifty-two weeks or longer.

[0377] 8. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the method is continued until the subject reaches a low disease state.

[0378] 9. An IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, wherein step (b) is performed for at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 6 months, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer.

[0379] 10. The IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, comprising the steps of (a) administering to the subject a first dose of about 300 mg of the IL-13 binding protein, and (b) administering to the subject one or more second doses of about 300 mg of the IL-13 binding protein, wherein each second dose is administered to the subject about four weeks after the immediately preceding dose.

[0380] 11. The IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, comprising the steps of (a) subcutaneously administering a first dose of approximately 300 mg of the IL-13 binding protein to the subject, and (b) subcutaneously administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately four weeks after the immediately preceding dose.

[0381] 12. The IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, wherein the method comprises (a) subcutaneously administering a first dose of approximately 300 mg of the IL-13 binding protein to the subject, and (b) subcutaneously administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately four weeks after the immediately preceding dose, and the method is performed for approximately 12 weeks.

[0382] 13. An IL-13 binding protein, method, or use for use according to any one of the preceding clauses, wherein the method further comprises the step of administering one or more prior doses of the IL-13 binding protein to the subject prior to step (a).

[0383] 14. The IL-13 binding protein, method, or use described in Clause 13, wherein each prior dose of the IL-13 binding protein is administered to the subject 3 days to 6 weeks after the immediately preceding prior dose.

[0384] 15. Prior to step (a) described above, the method further comprises administering one or more prior doses of the IL-13 binding protein to the subject for about two weeks, about four weeks, about six weeks, about eight weeks, about twelve weeks, about sixteen weeks, or about twenty weeks or longer, the IL-13 binding protein, method, or use described in Clause 13 or Clause 14.

[0385] 16. The method, method, or use described in any one of the preceding clauses, comprising the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for 2 to 36 weeks, wherein each prior dose is administered 3 days to 2 weeks after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least eight weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 15 to 35 days after the immediately preceding dose. Here, each dose corresponds to approximately 10 to 600 mg of IL-13 binding protein.

[0386] 17. The IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, wherein the method further comprises (c) administering one or more third doses of the IL-13 binding protein to the subject, following step (b) above.

[0387] 18. The IL-13 binding protein, method or use described in Clause 17, wherein each third dose of the IL-13 binding protein is administered 1 to 6 weeks after the immediately preceding dose.

[0388] 19. The IL-13 binding protein, method, or use described in Clause 18, wherein each of the one or more third doses of the IL-13 binding protein is administered to the subject two weeks after the immediately preceding dose.

[0389] 20. The method, method, or use described in any one of the preceding clauses, comprising the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 26 to 30 days after the immediately preceding dose. Here, each dose corresponds to approximately 250 to 350 mg of IL-13 binding protein.

[0390] 21. The method, method, or use described in any one of the preceding clauses, comprising the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second doses) is approximately 300 mg of the IL-13 binding protein.

[0391] 22. The method, method, or use described in any one of the preceding clauses, comprising the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately 4 weeks after the immediately preceding dose. Here, each dose is approximately 300 mg of IL-13 binding protein.

[0392] 23. The method, method, or use described in any one of the preceding clauses, comprising the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately 4 weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second doses) is approximately 300 mg of the IL-13 binding protein.

[0393] 24. IL-13 binding protein, method or use for use as described in any one of the preceding clauses, wherein the first dose, one or more second doses, one or more prior doses, and / or one or more third doses are approximately 10 mg to approximately 600 mg of IL-13 binding protein.

[0394] 25. IL-13 binding protein, method or use for use as described in any one of the preceding clauses, wherein the first dose, the second dose, one or more prior doses and / or one or more third doses are approximately 300 mg of IL-13 binding protein.

[0395] 26. IL-13 binding protein, method or use for use as described in any one of the preceding clauses, wherein the first dose of the one or more prior doses and / or the first dose of the one or more third doses is a dose of 600 mg, and the dose(s) following the 600 mg dose(s) is a dose(s) of 300 mg.

[0396] 27. An interleukin-13 (IL-13) binding protein for use in a method of treating a skin infection in a subject with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject.

[0397] 28. A method for treating a skin infection in a subject with moderate to severe or severe Alzheimer's disease, comprising administering a therapeutically effective amount of IL-13 binding protein to the subject.

[0398] 29. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of a skin infection in a subject with moderate to severe or severe AD, wherein the method for treating the skin infection comprises administering the IL-13 binding protein to the subject.

[0399] 30. IL-13 binding protein, method or use for use according to any of Clauses 27 to 29, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0400] 31. The method, method, or use described in Clause 30, where the method is defined in any one of Clauses 5 to 26, and the IL-13 binding protein is used for the purposes described in Clause 30.

[0401] 32. The binding protein, method or use for use described in Clause 31, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0402] 33. An IL-13 binding protein, method, or use for use according to any one of clauses 27 to 32, wherein the IL-13 binding protein is not administered in combination with a topical corticosteroid in a method for treating the skin infection.

[0403] 34. The IL-13 binding protein, method or use for use as described in any one of the clauses 27 to 33, wherein the skin infection is a bacterial infection.

[0404] 35. The IL-13 binding protein, method or use for use as described in any one of the clauses 27 to 33, wherein the skin infection is a viral infection.

[0405] 36. The IL-13 binding protein, method or use for use as described in any one of Clauses 27 to 35, wherein the skin infection is selected from the group consisting of Staphylococcus aureus infection, Streptococcus infection, impetigo, cellulitis, infectious dermatitis, herpetic eczema, folliculitis, infectious vesicles, mycosis and tinea versicolor.

[0406] 37. The IL-13 binding protein, method or use described in Clause 36, wherein the skin infection is a Staphylococcus aureus infection.

[0407] 38. An IL-13 binding protein, method or use for use as described in any one of Clauses 27 to 37, wherein the second therapeutic agent is administered to the subject before, after, or concurrently with the IL-13 binding protein.

[0408] 39. The IL-13 binding protein, method or use for use as described in Clause 38, wherein the second therapeutic agent is selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, another IL-13 antagonist, IgE inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and IFNγ.

[0409] 40. The IL-13 binding protein, method, or use described in any one of Clauses 27 to 39, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0410] 41. The IL-13 binding protein, method, or use described in any one of Clauses 27 to 40, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0411] 42. An IL-13 binding protein for use in a method for treating pruritus in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject.

[0412] 43. A method for treating pruritus in a subject with moderate to severe or severe AD, comprising administering an IL-13 binding protein to the subject.

[0413] 44. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of pruritus in subjects with moderate to severe or severe AD, wherein the method for treating the pruritus comprises administering the IL-13 binding protein to the subject.

[0414] 45. IL-13 binding protein, method or use for use according to any of Clauses 42 to 44, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0415] 46. ​​The method, method, or use described in Clause 45, where the method is defined in any one of Clauses 5 to 26, and the IL-13 binding protein is used for the purposes described in Clause 45.

[0416] 47. The binding protein, method or use for use described in Clause 46, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0417] 48. The IL-13 binding protein, method, or use for use according to any one of the clauses 42 to 47, wherein the IL-13 binding protein is not administered in combination with a topical corticosteroid in the method for treating pruritus.

[0418] 49. The IL-13 binding protein, method, or use described in any one of Clauses 42 to 48, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0419] 50. The IL-13 binding protein, method, or use described in any one of Clauses 42 to 49, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0420] 51. The IL-13 binding protein, method or use for use according to any one of the clauses 42 to 50, wherein the method achieves a baseline of the highest diurnal score on the Numerical Rating Scale (NRS), for example, a decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points from before treatment with the IL-13 binding protein.

[0421] 52. An IL-13 binding protein for use in a method for treating eczema-related sleep disturbance in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject.

[0422] 53. A method for treating eczema-related sleep disturbance in a subject with moderate to severe or severe AD, comprising administering the IL-13 binding protein to the subject.

[0423] 54. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of eczema-related sleep disturbance in subjects with moderate to severe or severe AD, wherein the method for treating the eczema-related sleep disturbance comprises administering the IL-13 binding protein to the subject.

[0424] 55. The IL-13 binding protein, method, or use for use according to any one of Clauses 52 to 54, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0425] 56. The binding protein, method or use for use described in Clause 55, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0426] 57. The method, method, or use described in Clause 56, where the method is defined in any one of Clauses 5 to 26, and the IL-13 binding protein is used for the purposes described in Clause 56.

[0427] 58. The IL-13 binding protein, method, or use described in any one of Clauses 54 to 56, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0428] 59. The IL-13 binding protein, method, or use described in any one of Clauses 54 to 57, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0429] 60. The IL-13 binding protein, method or use for use as described in any one of Clauses 52 to 59, wherein the method achieves a reduction of at least 0.4 points, at least 1 point, at least 2 points, or at least 4 points in baseline eczema-related sleep disturbance compared to pre-treatment with the IL-13 binding protein.

[0430] 61. An IL-13 binding protein for use in a method of treating anxiety and / or depression in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject.

[0431] 62. A method for treating anxiety and / or depression in a subject with moderate to severe or severe AD, comprising administering an IL-13 binding protein to the subject.

[0432] 63. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of anxiety and / or depression in subjects with moderate to severe or severe AD, wherein the method for treating the anxiety and / or depression comprises administering the IL-13 binding protein to the subject.

[0433] 64. The IL-13 binding protein, method, or use for use according to any one of Clauses 53 to 55, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0434] 65. The binding protein, method or use for use described in Clause 64, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0435] 66. The method, method, or use described in Clause 65, where the method is defined in any one of Clauses 5 to 26.

[0436] 67. The IL-13 binding protein, method, or use described in any one of clauses 61 to 66, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0437] 68. The IL-13 binding protein, method, or use described in any one of clauses 61 to 67, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0438] 69. Anxiety and / or depression in the subject is determined by the Hospital Anxiety and Depression Questionnaire (HADS), and the IL-13 binding protein, method or use for use as described in any one of Clauses 61-68.

[0439] 70. The IL-13 binding protein, method, or use described in Clause 69, wherein the subject has a baseline score of 8 or higher.

[0440] 71. The IL-13 binding protein, method or use described in Clause 69 or 70, wherein the method achieves a reduction of at least 1 point, at least 2 points, at least 3 points or at least 4 points in the HADS score compared to a baseline, for example, a reduction of at least 4 points compared to before treatment with the IL-13 binding protein.

[0441] 72. An IL-13 binding protein for use in a method for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject.

[0442] 73. A method for improving the health status and / or quality of life of a subject with moderate to severe or severe Alzheimer's disease, comprising administering an IL-13 binding protein to the subject.

[0443] 74. Use of IL-13 binding protein in the manufacture of a drug for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, wherein the method for improving the health status and / or quality of life comprises administering the IL-13 binding protein to the subject.

[0444] 75. IL-13 binding protein, method or use for use according to any one of Clauses 72 to 74, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0445] 76. The binding protein, method or use for use described in Clause 75, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0446] 77. The method, method, or use described in Clause 56, where the method is defined in any one of Clauses 5 to 26.

[0447] 78. The IL-13 binding protein, method, or use described in any one of Clauses 75 to 77, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0448] 79. The IL-13 binding protein, method, or use described in any one of Clauses 75-78, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0449] 80. IL-13 binding protein, method or use for use as described in any one of Clauses 72-79, wherein the health status and / or quality of life of the subject is determined by the subject's SF-36 score.

[0450] 81. The IL-13 binding protein, method or use for use as described in Clause 80, wherein the SF-36 score is the SF-36 physical component score and / or the SF-36 mental component score.

[0451] 82. The IL-13 binding protein, method or use for use as described in Clause 80 or 81, wherein the method achieves an increase of at least 4 points in the SF-36 physical health score and / or an increase of at least 2 points in the SF-36 mental health score compared to a baseline, for example, before treatment with the IL-13 binding protein.

[0452] 83. IL-13 binding protein, method or use for use as described in any one of Clauses 72 to 82, wherein the health status and / or quality of life of the subject is determined by the EQ-5D-5L score of the subject.

[0453] 84. The IL-13 binding protein, method or use described in Clause 83, wherein the method achieves an increase of at least 0.2 points in the EQ-5D-5L index score compared to baseline, for example, before treatment with the IL-13 binding protein.

[0454] 85. IL-13 binding protein, method or use for use as described in any one of Clauses 72-84, wherein the health status and / or quality of life of the subject is determined by the DLQI score of the subject.

[0455] 86. The IL-13 binding protein, method or use described in Clause 85, wherein the method achieves a reduction of at least 4 points in the DLQI score compared to baseline, for example, before treatment with the IL-13 binding protein.

[0456] 87. IL-13 binding protein, method or use for use as described in any one of Clauses 72 to 86, wherein the health status and / or quality of life of the subject is determined by the PGI-B score of the subject.

[0457] 88. The IL-13 binding protein, method, or use described in Clause 87, wherein the method achieves a reduction of at least one point in the PGI-B score compared to baseline, for example, before treatment with the IL-13 binding protein.

[0458] 89. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein each dose of the IL-13 binding protein is administered by one or two injections.

[0459] 90. IL-13 binding protein, method or use for use as described in Clause 89, each injection having a volume of approximately 1 mL.

[0460] 91. Each dose of the IL-13 binding protein is administered subcutaneously, as described in any one of the preceding clauses, for use of the IL-13 binding protein, method, or use.

[0461] 92. Each dose of the IL-13 binding protein is administered as a pharmaceutical composition comprising 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, wherein the pharmaceutical composition has a pH of 5.5, the IL-13 binding protein, method, or use described in any one of the preceding clauses.

[0462] 93. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the IL-13 binding protein is an anti-IL-13 antibody or its IL-13 binding fragment.

[0463] 94. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the IL-13 binding protein is a monoclonal anti-IL-13 antibody or its IL-13 binding fragment.

[0464] 95. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the IL-13 binding protein is a human anti-IL-13 antibody or its IL-13 binding fragment.

[0465] 96. The IL-13 binding protein, method, or use for use according to any one of clauses 93 to 95, wherein the IL-13 antibody is an IgG4 antibody.

[0466] 97. An IL-13 binding protein, method or use for use according to any one of clauses 93 to 96, wherein the IL-13 binding fragment is selected from Fab, Fab', F(ab')2, Fd, Fv, single-chain Fv(scFv), or disulfide-bonded Fv(sdFv).

[0467] 98. The anti-IL-13 antibody, or its IL-13 binding fragment, is an IL-13 binding protein, method, or use for the use described in any one of clauses 93 to 97, comprising: Heavy chain complementarity determination region 1 (HCDR1), which contains the amino acid sequence of SEQ ID NO: 1, Heavy chain complementarity determination region 2 (HCDR2), which contains the amino acid sequence of SEQ ID NO: 2, Heavy chain complementarity determination region 3 (HCDR3), which contains the amino acid sequence of SEQ ID NO: 3, Light chain complementarity determination region 1 (LCDR1), which contains the amino acid sequence of SEQ ID NO: 4, Light chain complementarity determination region 2 (LCDR2), which includes the amino acid sequence of SEQ ID NO: 5, and Light chain complementarity determination region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 6.

[0468] 99. The anti-IL-13 antibody, or its IL-13 binding fragment, comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and is an IL-13 binding protein, method, or use described in any one of the clauses 93 to 98. (i) The heavy chain variable region is Heavy chain complementarity determination region 1 (HCDR1), which contains the amino acid sequence of SEQ ID NO: 1, Heavy chain complementarity determination region 2 (HCDR2), which includes the amino acid sequence of SEQ ID NO: 2, and It contains heavy chain complementarity determination region 3 (HCDR3) which includes the amino acid sequence of SEQ ID NO: 3, (ii) The light chain variable region is Light chain complementarity determination region 1 (LCDR1), which contains the amino acid sequence of SEQ ID NO: 4, Light chain complementarity determination region 2 (LCDR2), which includes the amino acid sequence of SEQ ID NO: 5, and Including the light chain complementarity determination region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 6, IL-13 binding protein, method, or use for the aforementioned use.

[0469] 100. The anti-IL-13 antibody, or its IL-13 binding fragment, further (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain variable region sequence of SEQ ID NO: 8, and / or (ii) An IL-13 binding protein, method, or use for use as described in any one of clauses 93 to 99, comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain variable region sequence of SEQ ID NO: 10.

[0470] 101. The IL-13 binding protein, method, or use for use according to any one of the clauses 93 to 100, wherein the anti-IL-13 antibody or its IL-13 binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 8 and the light chain variable region sequence of SEQ ID NO: 10.

[0471] 102. An IL-13 binding protein, method, or use for use according to any one of clauses 93 to 101, wherein the anti-IL-13 antibody or its IL-13 binding fragment comprises (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain sequence of SEQ ID NO: 11, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain sequence of SEQ ID NO: 12.

[0472] 103. The anti-IL-13 antibody, or its IL-13 binding fragment, comprises the heavy chain sequence of SEQ ID NO: 11 and the light chain sequence of SEQ ID NO: 12, for use according to any one of Clauses 93 to 102, IL-13 binding protein, method, or use.

[0473] 104. The IL-13 binding protein, method, or use described in any one of the preceding clauses, wherein the IL-13 binding protein is administered as monotherapy.

[0474] 105. The IL-13 binding protein, method, or use for the use described in any one of the preceding clauses, wherein the IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, a emollient, or an antibacterial therapeutic agent.

[0475] 106. The IL-13 binding protein, method or use described in Clause 105, wherein the IL-13 binding protein is administered in combination with a topical corticosteroid.

[0476] 107. An interleukin-13 (IL-13) binding protein for use in a method of treatment for subjects with severe AD, wherein the AD is not adequately controlled by cyclosporine A, or the subject has a contraindication to cyclosporine A, and the method comprises administering the IL-13 binding protein to the subject.

[0477] 108. A method for treating a subject with severe AD, wherein the AD is not adequately controlled by cyclosporine A, or the subject has a contraindication to cyclosporine A, and the method comprises administering a therapeutically effective amount of IL-13 binding protein to the subject.

[0478] 109. Use of an IL-13 binding protein in the manufacture of a drug for the treatment of a subject with severe AD, wherein the AD is not adequately controlled by cyclosporine A, or the subject has a contraindication to cyclosporine A, and the method of treating the AD comprises administering the IL-13 binding protein to the subject.

[0479] 110. IL-13 binding protein, method or use for use according to any one of clauses 107 to 109, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 12 to 35 days after the immediately preceding dose.

[0480] 111. The IL-13 binding protein, method, or use described in Clause 110, where the method is defined in any one of Clauses 5-26, 89-92, and 104-106.

[0481] 112. The IL-13 binding protein, method, or use described in Clause 110, wherein the IL-13 binding protein is defined in any one of Clauses 93 to 103.

[0482] 113. The binding protein, method or use for use described in Clause 110, wherein step (b) comprises administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately two weeks after the immediately preceding dose.

[0483] 114. The IL-13 binding protein, method, or use described in any one of Clauses 107 to 113, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 12 to 16 days after the preceding dose or 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0484] 115. The IL-13 binding protein, method, or use described in any one of Clauses 107 to 114, wherein the method includes the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately two weeks or approximately four weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second dose) is approximately 300 mg of the IL-13 binding protein.

[0485] 116. The IL-13 binding protein, method or use for the use described in any one of the clauses 107 to 115, wherein the IL-13 binding protein is administered in combination with a topical corticosteroid.

[0486] 117. By the above method, a. Improvement of 50% or more compared to baseline in the Eczema Area Severity Index (EASI-50), b. A decrease of at least 2 points in the IGA score compared to the baseline. c. A decrease of at least 4 points in the POEM score compared to baseline. d. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the diurnal highest score on the Numerical Rating Scale (NRS) compared to baseline. e. A reduction of at least 0.4 points in eczema-related sleep disturbances compared to baseline. f. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the Hospital Anxiety and Depression Scale (HADS) score compared to baseline. g. An increase of at least 4 points in the SF-36 Physical Health Score compared to baseline and / or an increase of at least 2 points in the SF-36 Mental Health Score compared to baseline. h. An increase of at least 0.2 points in the EQ-5D-5L index score compared to the baseline. i. A decrease of at least 4 points in the DLQI score compared to baseline, and / or j. An IL-13 binding protein, method, or use for use as described in any one of the preceding clauses, which achieves a reduction of at least one point in the PGI-B score compared to baseline.

[0487] 118. IL-13 binding protein, method, or use for the use described in any one of the preceding clauses, for the treatment of skin infections (e.g., Staphylococcus aureus infection), pruritus, eczema-related sleep disturbances, anxiety and / or depression, or for the improvement of health condition and / or quality of life. Further aspects of the present invention will be described in the following sections. [Section 1] An interleukin-13 (IL-13) binding protein for use in a method of treating atopic dermatitis (AD) in a subject, wherein the method comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose. [Section 2] A method for treating atopic dermatitis (AD) in a subject requiring treatment, comprising the steps of (a) administering a first dose of IL-13 binding protein to the subject, and (b) administering one or more second doses of IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose. [Section 3] The use of an IL-13 binding protein in the manufacture of a drug for the treatment of atopic dermatitis (AD) in a subject, wherein the method of treating the AD comprises the steps of (a) administering a first dose of the IL-13 binding protein to the subject, and (b) administering one or more second doses of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject 15 to 35 days after the immediately preceding dose. [Section 4] By the above method, a. Improvement of 50% or more compared to baseline in the Eczema Area Severity Index (EASI-50), b. A decrease of at least 2 points in the IGA score compared to the baseline. c. A decrease of at least 4 points in the POEM score compared to baseline. d. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the diurnal highest score on the Numerical Rating Scale (NRS) compared to baseline. e. A reduction of at least 0.4 points in eczema-related sleep disturbances compared to baseline. f. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the Hospital Anxiety and Depression Scale (HADS) score compared to baseline. g. An increase of at least 4 points in the SF-36 Physical Health Score compared to baseline and / or an increase of at least 2 points in the SF-36 Mental Health Score compared to baseline. h. An increase of at least 0.2 points in the EQ-5D-5L index score compared to the baseline. i. A decrease of at least 4 points in the DLQI score compared to baseline, and / or j. A reduction of at least 1 point in the PGI-B score compared to the baseline is achieved. IL-13 binding protein, method, or use for use as described in any one of the preceding paragraphs. [Section 5] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs, wherein the AD is moderate to severe or severe AD. [Section 6] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs is for the treatment of skin infections (e.g., Staphylococcus aureus infection), itching, eczema-related sleep disturbances, anxiety and / or depression, or for the improvement of health status and / or quality of life. [Section 7] Each second dose is administered to the subject 25 to 31 days after the immediately preceding dose, the IL-13 binding protein, method, or use described in any one of the preceding paragraphs. [Section 8] Each second dose is administered to the subject approximately four weeks after the immediately preceding dose, the IL-13 binding protein, method, or use described in any one of the preceding paragraphs. [Section 9] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs, wherein step (b) is performed for at least 8 weeks, at least 12 weeks, at least 3 months, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 6 months, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer. [Section 10] The IL-13 binding protein, method, or use for use according to any one of the preceding paragraphs, wherein the method comprises the steps of (a) administering to the subject a first dose of about 300 mg of the IL-13 binding protein, and (b) administering to the subject one or more second doses of about 300 mg of the IL-13 binding protein, wherein each second dose is administered to the subject about four weeks after the immediately preceding dose. [Section 11] The IL-13 binding protein, method, or use for use according to any one of the preceding paragraphs, wherein the method comprises the steps of (a) subcutaneously administering a first dose of about 300 mg of the IL-13 binding protein to the subject, and (b) subcutaneously administering one or more second doses of about 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject about four weeks after the immediately preceding dose. [Section 12] The method comprises (a) subcutaneously administering a first dose of approximately 300 mg of the IL-13 binding protein to the subject, and (b) subcutaneously administering one or more second doses of approximately 300 mg of the IL-13 binding protein to the subject, wherein each second dose is administered to the subject approximately four weeks after the immediately preceding dose, and the method is performed for approximately 12 weeks, wherein the IL-13 binding protein, method, or use described in any one of the preceding paragraphs is described. [Section 13] Prior to step (a), the method further comprises administering one or more prior doses of the IL-13 binding protein to the subject, the IL-13 binding protein, method, or use according to any one of the preceding clauses. [Section 14] The IL-13 binding protein, method, or use for use according to item 13, wherein each prior dose of the IL-13 binding protein is administered to the subject 3 days to 6 weeks after the immediately preceding prior dose. [Section 15] Prior to step (a), the method further comprises administering one or more prior doses of the IL-13 binding protein to the subject for about two weeks, about four weeks, about six weeks, about eight weeks, about twelve weeks, about sixteen weeks, or about twenty weeks or longer, the IL-13 binding protein, method, or use for use according to item 13 or 14. [Section 16] The method, method, or use described in any one of the preceding paragraphs comprises the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for 2 to 36 weeks, wherein each prior dose is administered 3 days to 2 weeks after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least eight weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 15 to 35 days after the immediately preceding dose. Here, each dose corresponds to approximately 10 to 600 mg of IL-13 binding protein. [Section 17] The IL-13 binding protein, method, or use for use according to any one of the preceding paragraphs, further comprising the step of (c) administering one or more third doses of the IL-13 binding protein to the subject, following step (b). [Section 18] The IL-13 binding protein, method, or use described in item 17 above, wherein each third dose of the IL-13 binding protein is administered 1 to 6 weeks after the immediately preceding dose. [Section 19] The IL-13 binding protein, method, or use described in paragraph 18, wherein each of the one or more third doses of the IL-13 binding protein is administered to the subject two weeks after the immediately preceding dose. [Section 20] The method, method, or use described in any one of the preceding paragraphs comprises the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 26 to 30 days after the immediately preceding dose. Here, each dose corresponds to approximately 250 to 350 mg of IL-13 binding protein. [Section 21] The method, method, or use described in any one of the preceding paragraphs comprises the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 8 to 16 weeks, wherein each prior dose is administered 12 to 16 days after the most recent dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 12 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject 26 to 30 days after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second doses) is approximately 300 mg of the IL-13 binding protein. [Section 22] The method, method, or use described in any one of the preceding paragraphs comprises the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately 4 weeks after the immediately preceding dose. Here, each dose is approximately 300 mg of IL-13 binding protein. [Section 23] The method, method, or use described in any one of the preceding paragraphs comprises the following steps: (i) A step of administering one or more prior doses of the IL-13 binding protein to the subject for approximately 12 to 16 weeks, wherein each prior dose is administered approximately two weeks after the previous dose. (ii) The step of administering a first dose of the IL-13 binding protein to the subject, (iii) The step of administering one or more second doses of the IL-13 binding protein to the subject for at least 16 weeks, wherein each second dose of the IL-13 binding protein is administered to the subject approximately 4 weeks after the preceding dose, where the first dose of the one or more prior doses is approximately 600 mg of the IL-13 binding protein, and each subsequent dose of the one or more prior doses (prior doses, first dose, and second doses) is approximately 300 mg of the IL-13 binding protein. [Section 24] An interleukin-13 (IL-13) binding protein for use in a method of treating a skin infection in a subject with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject. [Section 25] A method for treating a skin infection in a subject with moderate to severe or severe Alzheimer's disease, comprising administering a therapeutically effective amount of IL-13 binding protein to the subject. [Section 26] The use of an IL-13 binding protein in the manufacture of a drug for the treatment of a skin infection in a subject with moderate to severe or severe AD, wherein the method of treating the skin infection comprises administering the IL-13 binding protein to the subject. [Section 27] The method described above involves an IL-13 binding protein for use as defined in any one of sections 4 to 23 above, the method described in section 25 above, or the use described in section 26 above. [Section 28] An IL-13 binding protein for use in a method for treating pruritus in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject. [Section 29] A method for treating pruritus in a subject with moderate to severe or severe AD, comprising administering an IL-13 binding protein to the subject. [Section 30] The use of an IL-13 binding protein in the manufacture of a drug for the treatment of pruritus in subjects with moderate to severe or severe AD, wherein the method for treating the pruritus comprises administering the IL-13 binding protein to the subject. [Section 31] The method described above involves an IL-13 binding protein for use as defined in any one of sections 4 to 23 above, the method described in section 29 above, or the use described in section 30 above. [Section 32] An IL-13 binding protein for use in a method for treating eczema-related sleep disturbance in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject. [Section 33] A method for treating eczema-related sleep disturbances in subjects with moderate to severe or severe AD, comprising administering the IL-13 binding protein to the subject. [Section 34] The use of an IL-13 binding protein in the manufacture of a drug for the treatment of eczema-related sleep disturbance in subjects with moderate to severe or severe AD, wherein the method for treating the eczema-related sleep disturbance comprises administering the IL-13 binding protein to the subject. [Section 35] The method described above involves an IL-13 binding protein for use as defined in any one of sections 4 to 23 above, the method described in section 33 above, or the use described in section 34 above. [Section 36] An IL-13 binding protein for use in a method of treating anxiety and / or depression in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject. [Section 37] A method for treating anxiety and / or depression in a subject with moderate to severe or severe AD, comprising administering an IL-13 binding protein to the subject. [Section 38] The use of an IL-13 binding protein in the manufacture of a drug for the treatment of anxiety and / or depression in subjects with moderate to severe or severe AD, wherein the method of treating the anxiety and / or depression comprises administering the IL-13 binding protein to the subject. [Section 39] The method described above involves an IL-13 binding protein for use as defined in any one of sections 4 to 23 above, the method described in section 37 above, or the use described in section 38 above. [Section 40] An IL-13 binding protein for use in a method of improving the health status and / or quality of life in subjects with moderate to severe or severe AD, wherein the method comprises administering the IL-13 binding protein to the subject. [Section 41] A method for improving the health status and / or quality of life of a subject with moderate to severe or severe Alzheimer's disease, comprising administering an IL-13 binding protein to the subject. [Section 42] The use of an IL-13 binding protein in the manufacture of a drug for improving the health status and / or quality of life in subjects with moderate to severe or severe AD, wherein the method for improving the health status and / or quality of life comprises administering the IL-13 binding protein to the subject. [Section 43] The method described above involves an IL-13 binding protein for use as defined in any one of the above sections 4 to 23, the method described in section 41, or the use described in section 42. [Section 44] Each dose of the IL-13 binding protein is administered by one or two injections, as described in any one of the preceding paragraphs, for use of the IL-13 binding protein, method, or use. [Section 45] Each dose of the IL-13 binding protein is administered subcutaneously, according to the method, method, or use of the IL-13 binding protein described in any one of the preceding paragraphs. [Section 46] Each dose of the IL-13 binding protein is administered as a pharmaceutical composition comprising 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, wherein the pharmaceutical composition has a pH of 5.5, and the IL-13 binding protein, method, or use described in any one of the preceding items. [Section 47] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs, wherein the IL-13 binding protein is an anti-IL-13 antibody or its IL-13 binding fragment. [Section 48] The IL-13-binding protein, method, or use described in any one of the preceding paragraphs, wherein the IL-13-binding protein is a monoclonal anti-IL-13 antibody or its IL-13-binding fragment. [Section 49] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs, wherein the IL-13 binding protein is a human anti-IL-13 antibody or its IL-13 binding fragment. [Section 50] The IL-13 binding protein, method, or use for use according to any one of the above sections 47 to 49, wherein the IL-13 antibody is an IgG4 antibody. [Section 51] An IL-13 binding protein, method, or use for use according to any one of the above sections 47 to 50, wherein the IL-13 binding fragment is selected from Fab, Fab', F(ab')2, Fd, Fv, single-chain Fv(scFv), or disulfide-bonded Fv(sdFv). [Section 52] The anti-IL-13 antibody, or its IL-13 binding fragment, comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and is an IL-13 binding protein, method, or use for the purposes described in any one of the above sections 47 to 51. (i) The heavy chain variable region is Heavy chain complementarity determination region 1 (HCDR1), which contains the amino acid sequence of SEQ ID NO: 1, Heavy chain complementarity determination region 2 (HCDR2), which includes the amino acid sequence of SEQ ID NO: 2, and It contains heavy chain complementarity determination region 3 (HCDR3) which includes the amino acid sequence of SEQ ID NO: 3, (ii) The light chain variable region is Light chain complementarity determination region 1 (LCDR1), which contains the amino acid sequence of SEQ ID NO: 4, Light chain complementarity determination region 2 (LCDR2), which includes the amino acid sequence of SEQ ID NO: 5, and Light chain complementarity determination region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 6 The IL-13 binding protein, method, or use for the aforementioned use, including the IL-13 binding protein for the aforementioned use. [Section 53] The anti-IL-13 antibody, or its IL-13 binding fragment, further... (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain variable region sequence of SEQ ID NO: 8, and / or (ii) An IL-13 binding protein, method, or use for use according to any one of items 47 to 52 above, comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain variable region sequence of SEQ ID NO: 10. [Section 54] The IL-13 binding protein, method, or use described in any one of the above items 47 to 53, wherein the anti-IL-13 antibody or its IL-13 binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 8 and the light chain variable region sequence of SEQ ID NO: 10. [Section 55] An IL-13 binding protein, method, or use for use according to any one of the above paragraphs 47 to 54, wherein the anti-IL-13 antibody or its IL-13 binding fragment comprises (i) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the heavy chain sequence of SEQ ID NO: 11, and / or (ii) an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the light chain sequence of SEQ ID NO: 12. [Section 56] The IL-13 binding protein, method, or use described in any one of the above items 47 to 55, wherein the anti-IL-13 antibody or its IL-13 binding fragment comprises the heavy chain sequence of SEQ ID NO: 11 and the light chain sequence of SEQ ID NO: 12. [Section 57] The IL-13 binding protein, method, or use described in any one of the preceding paragraphs, wherein the IL-13 binding protein is administered as monotherapy. [Section 58] The IL-13 binding protein, method, or use for use according to any one of the preceding paragraphs, wherein the IL-13 binding protein is administered in combination with a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, a emollient, or an antibacterial therapeutic agent.

Claims

1. A pharmaceutical composition for the treatment of atopic dermatitis (AD) in a subject, wherein the pharmaceutical composition comprises an IL-13 binding protein, and the subject is administered (a) a first dose comprising 300 mg of the IL-13 binding protein, and (b) one or more second doses each comprising 300 mg of the IL-13 binding protein, wherein each second dose is administered to the subject for at least 12 weeks, 4 weeks after the immediately preceding dose. Prior to the administration of (a), the IL-13 binding protein is administered to the subject in a first prior dose containing 600 mg of the IL-13 binding protein, and one or more subsequent prior doses of 300 mg of the IL-13 binding protein, wherein each of the prior doses of the IL-13 binding protein is administered to the subject two weeks after the immediately preceding dose for at least 16 weeks. Each dose of the aforementioned pharmaceutical composition is administered subcutaneously. A pharmaceutical composition wherein the IL-13 binding protein is tralokinumab.

2. The administration of the aforementioned pharmaceutical composition a. Improvement of 50% or more compared to baseline in the Eczema Area Severity Index (EASI-50), b. A decrease of at least 2 points in the Investigator's Global Assessment (IGA) score compared to baseline. c. A decrease of at least 4 points in the POEM score compared to the baseline. d. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the diurnal peak score of the Numerical Stimulation Scale (NRS) compared to baseline. e. A reduction of at least 0.4 points in eczema-related sleep disturbances compared to baseline. f. A decrease of at least 1 point, at least 2 points, at least 3 points, or at least 4 points in the Hospital Anxiety and Depression Scale (HADS) score compared to baseline. g. An increase of at least 4 points on the SF-36 Physical Health Score compared to baseline and / or an increase of at least 2 points on the SF-36 Mental Health Score compared to baseline. h. An increase of at least 0.2 points in the EQ-5D-5L index score compared to the baseline. i. A decrease of at least 4 points in the DLQI score compared to the baseline, and / or j. Achieve a reduction of at least 1 point in the PGI-B score compared to the baseline. The pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 1 or 2, wherein the AD is moderate to severe or severe AD.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is for the treatment of skin infections or Staphylococcus aureus skin infections, itching, eczema-related sleep disturbances, anxiety and / or depression, or for improving health and / or quality of life.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the administration of the dose of (b) is continued for at least 3 months, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 6 months, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 1 year, or at least 52 weeks or longer.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered to the subject in one or more prior doses for 20 weeks or longer.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is administered to the subject in one or more second doses for at least 16 weeks.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the administration of one or more prior doses is continued in the subject until an improvement of 75% or more in the eczema area severity index (EASI-75) is achieved in the subject with an IGA score of 0 or 1 and / or baseline.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein each dose of the pharmaceutical composition is administered by one or two injections.

10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising 50 mM sodium acetate buffer, 85 mM sodium chloride, and 0.01% (w / v) polysorbate 80, and having a pH of 5.

5.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered as monotherapy.

12. The pharmaceutical composition according to any one of claims 1 to 11, further comprising, or administered in combination with, a second therapeutic agent selected from the group consisting of a topical corticosteroid, a topical calcineurin inhibitor, an antihistamine, a emollient, or an antibacterial therapeutic agent.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject has a contraindication to cyclosporine A, or AD is not adequately controlled by cyclosporine A.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject has experienced conjunctivitis when treated with (i) an IL-13 binding protein in combination with a topical corticosteroid, (ii) an anti-IL4Rα antibody, or (iii) an antibody that inhibits IL4 / IL13 signaling, or dupilumab.

Images