Nemolizumab in the treatment of moderate to severe excoriation-associated atopic dermatitis

Abstract

Disclosed herein are methods for selectively treating atopic dermatitis (AD) in subjects with skin abrasions, pharmaceutical compositions for use in treating atopic dermatitis in subjects with skin abrasions, the use of nemolizumab or an equivalent thereof in the manufacture of a medicament for treating atopic dermatitis in subjects with skin abrasions, and methods for identifying subjects with atopic dermatitis who are likely to respond to nemolizumab treatment or an equivalent thereof.

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 628,714, filed February 9, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Field As used herein, skin Scratch marks Methods for selectively treating atopic dermatitis (AD) in a subject having skin Scratch marks A pharmaceutical composition for use in treating atopic dermatitis in a subject having skin Scratch marks The use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of atopic dermatitis in a subject with atopic dermatitis, and a method for identifying a subject with atopic dermatitis who is likely to respond to nemolizumab treatment or an equivalent thereof are described. [Background technology]

[0003] background The following discussion is intended to aid the reader in understanding the present disclosure and is not intended to describe or constitute prior art to the present disclosure.

[0004] Atopic dermatitis ("AD," also known as atopic eczema) is a chronic inflammation of the skin that can result in itchy (pruritic), swelling, redness, and / or cracked skin. AD can be triggered by an immune response to an antigen, irritant, or mechanical stimulus. AD patients with pruritus may exhibit behaviors such as scratching or rubbing their skin. In some cases, AD patients with pruritus may refrain from rubbing or scratching. Continued skin scratching behavior can lead to exacerbation of AD, disruption of sleep, and negative impacts on the patient's psychosocial well-being. Some AD patients experience pruritus even when other symptoms are effectively managed through treatment.

[0005] Approved treatments for pruritus include topical glucocorticoids and antihistamines, but these treatments have limited efficacy and / or significant side effects in patients with AD. Approved AD treatments include calcineurin inhibitors, emollients, and topical glucocorticoids. However, these treatments have limited efficacy among patients with moderate to severe AD. Oral antihistamines are often prescribed for atopic dermatitis, but these medications have little or no effect in reducing pruritus. Nemolizumab (CIM331) is a humanized monoclonal antibody that inhibits interleukin-31 signaling by binding to interleukin-31 receptor A (IL-31RA) on cells, including neurons. Interleukin-31 is thought to be involved in the pathogenesis of AD, and therefore may be effective in treating AD. However, AD patients, especially those with AD, are at increased risk of developing pruritus. Scratch marks There remains a need to develop novel treatment regimens for treating AD patients with insomnia and for identifying patients who are likely to respond to AD treatment. Summary of the Invention

[0006] overview As used herein, skin Scratch marks A method for selectively treating atopic dermatitis (AD) in a subject having one or more skin Scratch marks A pharmaceutical composition for use in treating atopic dermatitis in a subject having skin Scratch marks The present invention provides the use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of atopic dermatitis in a subject with atopic dermatitis, and a method for identifying a subject with atopic dermatitis who is likely to respond to nemolizumab treatment or an equivalent thereof.

[0007] According to some embodiments, the skin Scratch marks The present invention provides a method for selectively treating atopic dermatitis in a subject having the above-mentioned condition, the method comprising, consisting of, or consisting essentially of administering to said subject an effective amount of nemolizumab or an equivalent thereof.

[0008] In some embodiments of the aforementioned method, Scratch marks The severity of the nemolizumab or its equivalent is moderate to severe. In some embodiments of the method, the effective amount of nemolizumab or its equivalent is in the range of about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In some embodiments of the method, the nemolizumab or its equivalent is administered by a topical or parenteral route. In some embodiments of the method, the nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

[0009] According to some embodiments, there is provided a pharmaceutical composition for use in treating atopic dermatitis in a subject, said subject having one or more skin conditions comprising: Scratch marks and a composition comprising, consisting of, or consisting essentially of nemolizumab or an equivalent thereof.

[0010] In some embodiments of the aforementioned pharmaceutical composition, Scratch marks moderate to severe skin Scratch marks In some embodiments, the pharmaceutical composition further comprises a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier.

[0011] According to some embodiments, one or more skin Scratch marksIn some embodiments, the use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of atopic dermatitis in a subject having the aforementioned skin is provided. Scratch marks moderate to severe skin Scratch marks is.

[0012] According to some embodiments, there is provided a method of identifying a subject with atopic dermatitis who is likely to respond to nemolizumab treatment or its equivalent, comprising: Scratch marks In accordance with the present invention, a method is provided comprising, consisting of, or consisting essentially of detecting

[0013] In some embodiments, the method further comprises: Scratch marks as mild, moderate, or severe.

[0014] In some embodiments, the aforementioned methods include treating one or more moderate to severe Scratch marks and identifying the subject as likely to respond to nemolizumab treatment or its equivalent if

[0015] According to some embodiments, there is provided a method of treating a patient with atopic dermatitis, comprising: (a) treating said patient with atopic dermatitis with one or more skin irritants; Scratch marks and (b) treating the patient screened in step (a) by administering an effective amount of nemolizumab or an equivalent thereof.

[0016] In some embodiments of the aforementioned method, Scratch marksThe severity of the nemolizumab or its equivalent is moderate to severe. In some embodiments of the method, the effective amount of nemolizumab or its equivalent is in the range of about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In some embodiments of the method, the nemolizumab or its equivalent is administered by a topical or parenteral route. In some embodiments of the method, the nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

[0017] According to some embodiments, a person suffering from atopic dermatitis and having one or more skin Scratch marks The present invention provides a method for improving the sleep quality of a subject having a sleep disorder, comprising administering to the subject an effective amount of nemolizumab or its equivalent. In some embodiments, the improvement of sleep quality is determined by detecting an improvement in one or more of sleep onset latency, total sleep time, sleep efficiency, or wake-after-sleep time.

[0018] In some embodiments of the method, the skin excoriation is moderate to severe. In some embodiments of the method, the effective amount of nemolizumab or its equivalent is in the range of about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In some embodiments of the method, the nemolizumab or its equivalent is administered topically or parenterally. In some embodiments of the method, the nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1001] A method for selectively treating atopic dermatitis in a subject having one or more skin excoriations, comprising administering to the subject an effective amount of nemolizumab or its equivalent. [The present invention 1002] The method of claim 1001, wherein the skin scratch is moderate to severe. [The present invention 1003] The method of claim 1001 or 1002, wherein the skin scratch is assigned a score of at least 2 on the SCORAD scale. [The present invention 1004] Any of the methods of the present invention, wherein the effective amount of nemolizumab or its equivalent is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [The present invention 1005] Any of the aforementioned methods of the present invention, wherein nemolizumab or its equivalent is administered by topical or parenteral route. [The present invention 1006] Any of the aforementioned methods of the present invention, wherein nemolizumab or its equivalent is administered subcutaneously. [The present invention 1007] Any of the methods of the present invention, wherein nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1008] A pharmaceutical composition comprising nemolizumab or an equivalent thereof for use in treating atopic dermatitis in a subject determined to have one or more skin excoriations. [The present invention 1009] The pharmaceutical composition of the present invention 1008, wherein the skin excoriation is moderate to severe. [The present invention 1010] The pharmaceutical composition of invention 1008 or invention 1009, wherein said skin excoriation is assigned a score of at least 2 on the SCORAD scale. [The present invention 1011] The pharmaceutical composition of any one of claims 1008 to 1010, further comprising a carrier. [The present invention 1012] 1008. The pharmaceutical composition of the present invention, wherein said carrier is a pharmaceutically acceptable carrier. [The present invention 1013] Use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of atopic dermatitis in a subject having one or more skin excoriations. [The present invention 1014] The use of the present invention 1013, wherein the skin scratch is moderate to severe. [The present invention 1015] The use of invention 1013 or invention 1014, wherein said skin scratch is assigned a score of at least 2 on the SCORAD scale. [The present invention 1016] A method for identifying a subject with atopic dermatitis who is likely to respond to treatment with nemolizumab or its equivalent, the method comprising detecting one or more scratch marks on the subject's skin. [The present invention 1017] The method of claim 1016, further comprising scoring the scratch as mild, moderate, or severe. [The present invention 1018] The method of claim 1016, further comprising scoring the scratch as 1, 2, or 3 according to the SCORAD scale. [The present invention 1019] The method of claim 1017, further comprising identifying the subject as likely to respond to treatment with nemolizumab or its equivalent if one or more moderate to severe excoriations are detected. [The present invention 1020] The method of claim 1018, further comprising identifying the subject as likely to respond to treatment with nemolizumab or its equivalent if one or more scratch marks are scored as 2 or 3 according to the SCORAD scale. [The present invention 1021] The method of claim 1019, further comprising administering to said subject identified as likely to respond to treatment with nemolizumab or its equivalent an effective amount of nemolizumab or its equivalent. [The present invention 1022] The method of the present invention 1021, wherein the effective amount of nemolizumab or its equivalent is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [The present invention 1023] The method of claim 1021 or claim 1022, wherein nemolizumab or its equivalent is administered by topical or parenteral route. [The present invention 1024] The method of any of claims 1021 to 1023, wherein nemolizumab or its equivalent is administered subcutaneously. [The present invention 1025] Any of the methods of claims 1021 to 1024, wherein nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1026] 1. A method for treating a patient with atopic dermatitis, comprising: (a) screening said patient with atopic dermatitis for one or more skin scratches; (b) treating the patient screened in step (a) by administering an effective amount of nemolizumab or its equivalent; A method comprising: [The present invention 1027] The method of claim 1026, wherein the skin scratch is moderate to severe. [The present invention 1028] The method of claim 1026, wherein the skin scratch is assigned a score of at least 2 on the SCORAD scale. [The present invention 1029] Any of the methods of present inventions 1026 to 1028, wherein the effective amount of nemolizumab or its equivalent is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [The present invention 1030] 1029. The method of any of claims 1026 to 1029, wherein said effective amount of nemolizumab or its equivalent is administered by topical or parenteral route. [The present invention 1031] The method of any of claims 1026 to 1030, wherein said effective amount of nemolizumab or its equivalent is administered subcutaneously. [The present invention 1032] Any of the methods of claims 1026 to 1031, wherein the effective amount of nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1033] A method for improving sleep quality in a subject suffering from atopic dermatitis and having one or more skin scratches, comprising administering to the subject an effective amount of nemolizumab or its equivalent. [The present invention 1034] The method of claim 1033, wherein the skin scratch is moderate to severe. [This invention 1035] The method of claim 1033, wherein the skin scratch is assigned a score of at least 2 on the SCORAD scale. [The present invention 1036] The method of any one of invention 1033 and invention 1035, wherein the effective amount of nemolizumab or its equivalent is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [This invention 1037] The method of any of claims 1033 to 1036, wherein nemolizumab or its equivalent is administered by topical or parenteral route. [The present invention 1038] The method of any of claims 1033 to 1037, wherein nemolizumab or its equivalent is administered subcutaneously. [This invention 1039] Any of the methods of claims 1033 to 1038, wherein nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1040] The method of any one of claims 1033 to 1039, wherein the improvement in sleep quality is determined by detecting an improvement in one or more of sleep onset latency, total sleep time, sleep efficiency, or wake-after-sleep time. [Brief explanation of the drawings]

[0019] [Figure 1A]Figures 1A-1C show representative images of scratch marks and their corresponding Scoring Atopic Dermatitis Index (SCORAD) scores. The images are taken from the Consensus Report of the European Task Force on Atopic Dermatitis, entitled "Severity Scoring of Atopic Dermatitis: The SCORAD Index" (Stalder, JF et al., Dermatology (1993), 186:23-31). Figure 1A shows a mild scratch mark with a score of 1. Figure 1B shows a moderate scratch mark with a score of 2. Figure 1C shows a severe scratch mark with a score of 3. White arrows point to exemplary scratches. [Figure 1B] See legend to Figure 1A. [Figure 1C] See legend to Figure 1A. [Figure 2] Figures 2A-2D. Representative images of scratch marks on a subject's wrist. Scratch marks were scored according to the SCORAD system as indicated: Figure 2A shows none (i.e., no scratch marks) with a score of 0; Figure 2B shows mild scratch marks with a score of 1; Figure 2C shows moderate scratch marks with a score of 2; and Figure 2D shows severe scratch marks with a score of 3. [Figure 3] Figures 3A-3D show illustrations of representative images of scratch marks and their corresponding Eczema Area and Severity Index (EASI) scores. Scratch marks were scored according to the EASI method as indicated: Figure 3A shows none (i.e., no scratch marks) with a score of 0; Figure 3B shows mild scratch marks with a score of 1; Figure 3C shows moderate scratch marks with a score of 2; and Figure 3D shows severe scratch marks with a score of 3. [Figure 4]Diagram of study design. *In Part A, patients in the nemolizumab 2.0 mg / kg Q8W group received placebo at week 4; in Part B, patients received placebo at week 12 and nemolizumab at week 16, with placebo and nemolizumab alternating thereafter. **Number of patients randomized to Part B. †Number of patients at week 64. ‡Safety follow-up was conducted 12 weeks after the last dose of study drug. FU, follow-up; TCI, topical calcineurin inhibitor; TCS, topical glucocorticosteroid; w, week. [Figure 5] Graphical representation of results from Parts A and B of the Phase II study. [Figure 6] Figure 6 shows itch visual analog scale (VAS) scores. Figure 6A shows the percent change from baseline in itch VAS scores. Data are presented as mean (SE). Figure 6B shows the proportion of patients with itch VAS scores less than 30 mm (post-hoc analysis). [Figure 7] Graphical representation of percent change from baseline in key secondary and exploratory endpoints for the intention-to-treat (ITT) population receiving nemolizumab in Part A (including data after rescue treatment). Figure 7A shows the percent change (mean ± SE) in EASI score. Figure 7B shows the percentage (%) of patients with an sIGA score of 0 or 1. Figure 7C shows the percent change (mean ± SE) from baseline in the sleep disturbance visual analog scale (VAS). Figure 7D shows the percentage (%) of patients with a 4-point or greater reduction in DLQI (post-hoc analysis). DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description The following provides a more complete description of embodiments according to the present disclosure. However, each aspect of the present disclosure may be embodied in different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0021] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, it should be understood that terms defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of this application and the related art, and should not be interpreted in an idealized or overly formal way unless expressly defined as such herein. Unless expressly defined below, such terms should be interpreted according to their ordinary meaning.

[0022] The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0023] Unless the context indicates otherwise, it is expressly intended that the various features of the invention described herein can be used in any and all combinations. Furthermore, it is contemplated by the present disclosure that in some embodiments, any feature or combination of features described herein can be excluded or omitted. For example, if a composite is described herein as comprising component A, component B, and component C, it is expressly contemplated that any of A, B, or C, or any combination thereof, singly or in any combination, can be omitted or excluded.

[0024] Unless otherwise specified, all specific embodiments, features, and terms are intended to encompass both the recited embodiment, feature, or term and its biological equivalents.

[0025] definition As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless expressly stated to refer to the singular only.

[0026] It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about." The term "about" means that the encompassed values ​​include, but are not limited to, the exact values ​​set forth herein, and are intended to refer not only to the set forth values, but also to values ​​substantially surrounding the set forth values, to the extent that they do not depart from the scope of the present invention. As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are unclear to a person of ordinary skill in the art given the context in which it is used, "about" will mean up to ±15%, ±10%, ±5%, ±1%, or ±0.1% of the particular term.

[0027] Also, as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted as an alternative ("or").

[0028] The terms "administer," "administration," or "administering," as used herein, mean (1) providing, administering, dispensing, and / or prescribing, such as by or under the direction of a healthcare professional or their designated representative, and (2) administering, taking, or consuming, such as by a healthcare professional or a subject. Administration is intended to include, but is not limited to, oral administration, parenteral administration (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation spray, nasal, vaginal, rectal, sublingual, intraurethral administration (e.g., urethral suppository), or topical routes of administration (e.g., gels, ointments, creams, aerosols, etc.), and may be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and bases appropriate for each administration route. The present invention is not limited to the aforementioned administration routes, formulations, or administration schedules.

[0029] The terms "treat," "treating," or "treatment," as used herein, include alleviating, ameliorating, or ameliorating AD, pruritus, or one or more symptoms thereof, regardless of whether the AD and / or pruritus is considered "cured" or "cured," and whether all symptoms have been resolved. These terms also include reducing or inhibiting the progression of AD and / or pruritus, or one or more symptoms thereof, interfering with or inhibiting the pathogenesis of AD and / or pruritus, or one or more symptoms thereof, and achieving any therapeutic and / or prophylactic effect.

[0030] The interleukin-31 receptor α subunit (IL-31RA, also known as NR10, glm-r, or GPL) is a protein that functions as an IL-31 receptor by forming a heterodimer with the oncostatin M receptor (OSMR). Many splicing variants of human IL-31RA are known (WO 00 / 075314). NR10.1 consists of 662 amino acids and contains a transmembrane domain. NR10.2 consists of 252 amino acids and is a soluble receptor-like protein that does not contain the aforementioned transmembrane domain. On the other hand, known IL-31RA splicing variants that function as transmembrane receptor proteins include NR10.3 and IL-31RAv3. Preferred IL-31RA variants include NR10.3 (also known as ILRAv4 (Nat Immunol 5, 752-60, 2004)) and IL-31RAv3. NR10.3 (IL31RAv4) consists of 662 amino acids (WO 00 / 075314; Nat Immunol 5, 752-60, 2004), and IL31RAv3 consists of 732 amino acids (GenBank Accession No. NM-139017).

[0031] The amino acid sequence of IL31RAv4 is as follows: TIFF0007777921000001.tif73156

[0032] The amino acid sequence of IL31RAv3 is as follows: TIFF0007777921000002.tif80156

[0033] Mouse-derived IL-31RA includes a protein comprising the following amino acid sequence: TIFF0007777921000003.tif80156

[0034] Cynomolgus monkey-derived IL-31RA includes a protein comprising the following amino acid sequence: TIFF0007777921000004.tif80156

[0035] As used herein, the term "subject" is used synonymously with "patient" and refers to a mammal, particularly a human, horse, cow, pig, cat, dog, mouse, rat, or non-human primate. In a preferred embodiment, the subject is a human. The subject may exhibit skin-scratching behavior and / or skin Scratch marks In some embodiments, the subject may or may not be in need of evaluation for skin scratching behavior and / or skin irritation prior to administration of nemolizumab treatment. Scratch marks In some embodiments, the subject is a child, under 13 years old, under 8 years old, under 5 years old, under 3 years old, under 2 years old, or under 1 year old. In other embodiments, the subject is an adult.

[0036] The term "atopic dermatitis" (i.e., "AD") is used herein as it is used in the art to refer to chronic inflammation of the skin. The cause of AD is unknown, but genetics, immune system dysfunction, environmental exposure, and / or impaired skin permeability may be involved. Symptoms of AD include, but are not limited to, itching, dry skin, itching that can be particularly severe at night, reddish to brownish-gray patches of skin, especially on the hands, feet, ankles, wrists, neck, upper chest, eyelids, inside the crooks of the elbows and knees, and in infants, on the face and scalp; raised bumps that may leak fluid and form scabs when scratched; thickened, cracked, scaly, peeling, sensitive skin; swollen skin; and sleep disruption and / or insomnia. AD most often begins before age 5 and can persist into adolescence and adulthood. In some patients, AD periodically flares up, followed by periods of clearance that can last for several years.

[0037] The term "pruritus" is used herein as it is used in the art to refer to itchy skin and / or an itchy sensation. Itching can be caused by AD or other diseases or conditions, such as dry skin. In some cases, itching involves generalized itchy skin over the entire body. In some cases, itching is localized to a specific body area, such as an arm or leg. Itching can be chronic or acute. Symptoms of itching include itchy skin, ... Scratch marks Symptoms of pruritus include, but are not limited to, redness, bumps, patches, blisters, dry skin, cracked skin, and leathery or scaly skin texture. In some cases, pruritus does not cause detectable changes to the skin. Behavioral responses to pruritus include, but are not limited to, scratching and / or rubbing of the skin. In some cases, skin scratching ranges from mild to severe. Scratch marks In some cases, patients with pruritus refrain from scratching and / or rubbing their skin. Conventional treatments for pruritus include, but are not limited to, skin moisturizers, topical emollients, antihistamines (such as diphenhydramine), corticosteroids (such as topical hydrocortisone cream), counterirritants (such as peppermint oil, menthol, or camphor), crotamiton, antipruritics often used in the treatment of scabies, local anesthetics (such as topical benzocaine cream), and phototherapy. The usual type of light used in phototherapy is UVB.

[0038] As used herein, the term "antibody" refers generically to immunoglobulin or immunoglobulin-like molecules, non-limiting examples of which include IgA, IgD, IgE, IgG, and IgM, combinations thereof, or fragments thereof. Non-limiting examples of antibody fragments include Fab fragments and single-chain variable fragments (scFv), and similar molecules produced during the immune response in any vertebrate, e.g., mammals such as humans, goats, rabbits, and mice, as well as non-mammalian species (e.g., shark immunoglobulins).

[0039] Regarding antibody structure, immunoglobulins generally have heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chains: lambda (λ) and kappa (κ). There are five major classes (or isotypes) of heavy chains, which determine the functional activity of antibody molecules (IgM, IgD, IgG, IgA, and IgE). Each heavy and light chain contains a constant region and a variable region (these regions are also known as "domains"). These heavy and light chain variable regions, collectively known as the "Fab region," specifically bind to antigens. The light and heavy chain variable regions contain "framework" regions, also known as "complementarity-determining regions" or "CDRs," between which three hypervariable regions are inserted. The extent of the framework regions and CDRs has been defined (see Kabat et al., Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, 1991, incorporated herein by reference). The Kabat database is currently maintained online. The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework regions of antibodies, which are the combined framework regions of the constituent light and heavy chains, largely adopt a β-sheet conformation, with the CDRs forming loops that connect and, in some cases, form part of this β-sheet structure. That is, the framework regions act as a scaffold that allows the CDRs to be positioned in the correct orientation through non-covalent interactions between the chains.

[0040] The CDRs are primarily responsible for binding to the epitope of an antigen. The CDRs of each chain are usually referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus, and are typically identified by the chain in which the particular CDR is located. H CDR3 is located in the variable domain of the heavy chain of the antibody in which it is contained, while V LCDR1 is the CDR1 of the variable domain of the light chain of the antibody in which it is contained. Antibodies that bind to IL-31RA have a specific V H Area array and V L Each antibody has a unique CDR sequence and therefore has a unique CDR sequence. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although CDRs vary among antibodies, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity-determining residues (SDRs). The base of the antibody plays a role in regulating immune cell activity. This region, called the Fc fragment region (Fc), is composed of two heavy chains, which provide two or three constant domains depending on the antibody class. The Fc region functions by binding to specific classes of proteins called "Fc receptors" present on specific cells, such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, and neutrophils, enabling each antibody to mount an appropriate immune response to a given antigen. Because the constant domains of the heavy chains make up the Fc region of an antibody, the class of heavy chains within an antibody determines its class effect. Heavy chains in antibodies include α, γ, δ, ε, and μ, which are associated with the antibody isotypes IgA, G, D, E, and M, respectively. This suggests that antibodies of different isotypes have different class effects because their different Fc regions bind to and activate different types of receptors.

[0041] IgG, the most abundant antibody isotype in human serum, has four highly conserved subclasses: IgG1, IgG2, IgG3, and IgG4. For a general discussion, see the World Wide Web at: ncbi.nlm.nih.gov / pmc / articles / PMC4202688 / . The amino acid sequences of the constant regions of these peptides are known in the art; see, for example, Rutishauser, U. et al. (1968) "Amino acid sequence of the Fc region of a human gamma G-immunoglobulin" PNAS 61(4):1414-1421; Shinoda et al. (1981) "Complete amino acid sequence of the Fc region of a human delta chain" PNAS 78(2):785-789; and Robinson et al. (1980) "Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511)" PNAS 77(8):4909-4913.

[0042] therapeutic antibodies "Nemolizumab" is a humanized monoclonal antibody that binds to IL-31RA. Nemolizumab is annotated as follows: immunoglobulin G2-κ, anti-[human IL31RA (interleukin-31 receptor α subunit)], humanized monoclonal antibody; γ2 heavy chain (1-445) [humanized VH (human IGHV1-2)] * 02(83.70%)-(IGHD)-IGHJ5 * 01)[8.8.14](1-121)-Human IGHG2 *01 (CH1 C10>S(135), R12>K(137), E16>G(141), S17>G(142)(122-219), hinge C4>S(223)(220-231), CH2 H30>Q(268)(232-340), CH3 R11>Q(355), Q98>E(419)(341-445))(122-445)], (224-214')-κ light chain (1'-214') and disulfide [humanized V-KAPPA (human IGKV1-39)]. * 01(82.10%)-IGKJ4 * 01)[6.3.9](1'-107')-Human IGKC * 01(108'-214')]; dimer (227-227":230-230")-bisdisulfide. Nemolizumab has disulfide bridges at the following positions: Intra-H (C23-C104) 22-96 148-204 261-321 367-425 22''-96'' 148''-204'' 261''-321'' 367''-425''; Intra-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194'''; Inter-HL (h 5-CL 126) 224-214' 224''-214''''; Inter-HH (h 8, h 11) 227-227'' 230-230''. Nemolizumab has N-glycosylation sites at the following positions: H CH2 N84.4:297, 297''. Nemolizumab lacks glycine and lysine at the C-terminus of the heavy chain (CHS G1>del, K2>del).

[0043] Nemolizumab heavy chain amino acid sequence: TIFF0007777921000005.tif59134

[0044] Nemolizumab light chain amino acid sequence: TIFF0007777921000006.tif31134

[0045] The variable domains of the heavy and light chain sequences are shown above in bold, and the CDR sequences are underlined.

[0046] Antibodies equivalent to nemolizumab include (i) antibodies having a heavy chain with at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the heavy chain sequence of nemolizumab; (ii) antibodies having a light chain with at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the light chain sequence of nemolizumab; and (iii) antibodies having at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the variable region sequence of nemolizumab. (iv) antibodies having CDRs that comprise at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the CDR sequences of nemolizumab; (v) antibodies that bind to the same IL-31RA isoform as nemolizumab (e.g., IL31-RAv3), optionally the same epitope of IL-31RA; (vi) antibodies that block or neutralize IL-31RA; (vii) antibodies that bind to the oncostatin M receptor (OSMR); and (viii) combinations thereof. For example, suitable equivalents include immunoglobulins or immunoglobulin-like molecules having heavy chain and light chain amino acid sequences that are the same as or substantially similar to those of nemolizumab. Further examples of nemolizumab equivalents are described, for example, in WO 2010 / 064697.

[0047] Nemolizumab equivalents can be monoclonal or polyclonal antibodies. Monoclonal antibodies that bind to and / or neutralize IL31-RA can be obtained, for example, by the following method: Anti-IL31-RA monoclonal antibodies are produced using IL31-RA or a fragment thereof derived from a mammal, such as a human or mouse, as an antigen by known methods, and then antibodies that bind to and / or neutralize IL31-RA are selected from the anti-IL31-RA monoclonal antibodies thus obtained. Specifically, for immunization, a target antigen or cells expressing the target antigen are used as a sensitizing antigen according to conventional immunization methods. The resulting immune cells are fused with known parent cells using conventional cell fusion methods, and then screened for monoclonal antibody-producing cells (hybridomas) using conventional screening methods, thereby obtaining anti-IL31-RA monoclonal antibodies. Examples of animals to be immunized include mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cattle, horses, and pigs. The antigen can be produced using a known IL31-RA gene sequence according to a known method, for example, by a method using baculovirus (eg, WO 98 / 46777).

[0048] Hybridomas can be prepared, for example, according to the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46). When an antigen has low immunogenicity, it may be conjugated to an immunogenic macromolecule (e.g., albumin) prior to inoculation. The antigen used to prepare a monoclonal antibody that binds to and / or neutralizes human IL31-RA is not particularly limited, as long as it allows the preparation of an antibody that binds to and / or neutralizes human IL31-RA. For example, several variants of human IL31-RA are known to exist, and any of these variants can be used as an immunogen as long as it allows the preparation of an antibody that binds to and / or neutralizes human IL31-RA. Alternatively, under the same conditions, a peptide fragment of IL31-RA or a protein in which artificial mutations have been introduced into the native IL31-RA sequence may be used as an immunogen. Human IL31-RA.3 is one of the preferred immunogens for producing antibodies having binding and / or neutralizing activity against IL31-RA in the present disclosure.

[0049] The IL31-RA binding activity of an equivalent antibody can be determined by methods known to those skilled in the art. Methods for determining the antigen-binding activity of an antibody include, for example, ELISA (enzyme-linked immunosorbent assay), EIA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay), and fluorescent antibody techniques. For example, when using enzyme immunoassay, an antibody-containing sample (such as a purified antibody or culture supernatant of antibody-producing cells) is added to a plate coated with the antigen. A secondary antibody labeled with an enzyme (such as alkaline phosphatase) is added, and the plate is incubated. After washing, an enzyme substrate (such as paranitrophenyl phosphate) is added, and the antigen-binding activity is assessed by measuring the absorbance. The binding and / or neutralizing activity of an equivalent antibody to IL31-RA can be measured, for example, by observing the effect of inhibiting the proliferation of an IL-31-dependent cell line. For example, the activity of a purified mouse IL-31 antibody can be assayed by evaluating the IL-31-dependent proliferation of Ba / F3 cells transfected with mouse IL-31 receptor α and mouse OSMR genes.

[0050] as a biomarker for response to nemolizumab treatment Scratch marks The inventors hypothesized that antipruritic drugs would have a greater effect on AD in patients who scratch their skin due to pruritus than in patients who do not scratch. Without being limited by theory, the vicious cycle of itch and scratching is thought to be not only a symptom of AD, but also an exacerbating factor for some AD patients who scratch their skin in response to itch. In the vicious cycle of itch and scratching, strong scratching behavior increases itch and Scratch marks This makes it easier for the skin lesions called psoriasis to worsen.

[0051] An objective method to identify subjects who scratch their skin due to itching is to measure the amount of scratching-induced Scratch marks The purpose is to identify objects that have the following characteristics. Scratch marks refers to skin damage caused by trauma such as scratching or abrasion. In some embodiments of the methods described herein, Scratch marks It can be identified by the presence, number, and / or intensity of lesions with one or more of the following characteristics: lines, cracks or breaks in the skin surface, crusting, serous crusts, bleeding, redness, skin abrasions, or cracks in the skin. Scratch marks involves a linear tear through the epidermis to the underlying dermis Scratch marks is.

[0052] In some embodiments, Scratch marks are scored as none, mild, moderate, or severe. "None," "mild," "moderate," and "severe" are Scratch marks These are terms of art used to describe the presence, extent, and / or intensity of a condition. Those skilled in the art will understand the boundaries of these terms. For example, they are used by medical professionals and Scratch marks Methods for assessing atopic dermatitis, including scoring the condition as absent, mild, moderate, and severe, include, but are not limited to, the Atopic Dermatitis Assessment Measure (ADAM), the Eczema Area and Severity Index (EASI), the self-administered EASI (SA-EASI), SCORing Atopic Dermatitis (SCORAD), the Six Area Six Sign Atopic Dermatitis Index (SASSAD), the Simple Scoring System (SSS), and the Three Item Severity Score (TIS). In some embodiments, a score of absent is represented by the number zero, a score of mild is represented by the number one, a score of moderate is represented by the number two, and a score of severe is represented by the number three.

[0053] As used herein, the term "none to mild" refers to skin that is scored as none, mild, or somewhere in between. Scratch marksIn some embodiments, "none to mild" refers to skin that is scored as 0, 1, 1.5, 0-1, 1 or less, or less than 2. Scratch marks In some embodiments, "none to mild" refers to a range of skin conditions from approximately 0 to approximately 1. Scratch marks As used herein, the term "moderate to severe" refers to skin that is scored as moderate, severe, or somewhere in between. Scratch marks In some embodiments, "moderate to severe" refers to skin that is scored as 2, 2.5, 3, 2-3, or 2 or greater. Scratch marks In some embodiments, "moderate to severe" refers to a range of skin conditions from about 2 to about 3. Scratch marks Point to the score.

[0054] In some embodiments, Scratch marksScoring is performed according to one or more of the following methods: SCORAD (disclosed in Stalder, JF et al., Dermatol (1993), 186: 23-31, the disclosure of which is incorporated herein by reference in its entirety), Patient-Oriented SCORAD (disclosed in Vourc'h-Jourdain, M. et al., Dermatology (2009) 218: 246-51, the disclosure of which is incorporated herein by reference in its entirety), ADAM (disclosed in Charman, D. et al., J. Outcome Meas. (1999) 3: 21-34, the disclosure of which is incorporated herein by reference in its entirety), EASI (Tofte, SJ et al., J Eur Acad Dermatol Venereol (1998) 11: S197, the entire disclosure of which is incorporated herein by reference), SA-EASI (disclosed in Housman TS et al., Br J Dermatol (2002) 147:1192-8, the entire disclosure of which is incorporated herein by reference), SASSAD (disclosed in Berth-Jones, J., Br J Dermatol (1996) 135: 25-30, the entire disclosure of which is incorporated herein by reference), SSS (disclosed in Costa, C. et al., Acta Derm Venereol (1989) 69: 42-5, the entire disclosure of which is incorporated herein by reference), and TIS (disclosed in Wolkerstorfer, A. et al., Acta Derm. Venereol. (1999) 79: 356-59, the entire disclosure of which is incorporated herein by reference). In a preferred embodiment, Scratch marks Scoring is performed according to the SCORAD and / or PO-SCORAD methods.

[0055] The SCORAD method (SCORAD and PO-SCORAD) is a representative Scratch marks In the area Scratch marksBased on the presence and intensity of Scratch marks This method involves scoring the severity of AD as absent (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3). Scratch marks The area is the average intensity of the target. Scratch marks This is the site containing the SCORAD method. Scratch marks SCORAD does not include scoring based on fractions (e.g., half-point scoring such as 0.5, 1.5, or 2.5). Scratch marks Scored according to law Scratch marks Exemplary images are shown in Figures 1A-1C and 2A-2D (Stalder et al. (1993), and Oranje, AP et al. (Pediatr. Allergy Immunol. (1997) 8: 28-34, the disclosures of which are incorporated herein by reference in their entirety).

[0056] The EASI methods (EASI and SA-EASI) measure the average score in each of four body regions (head and neck, trunk, upper limbs, and lower limbs). Scratch marks Based on the strength, Scratch marks This is a method for determining the severity of eczema, which involves scoring the skin as absent (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3). Scratch marks Body areas where no stimuli are present are scored as absent (score = 0), and areas where only barely perceptible, sparsely populated, and / or superficial stimuli are present are scored as absent (score = 0). Scratch marks was scored as mild (score = 1), with many superficial Scratch marks and / or some deep Scratch marks Contains Scratch marks was scored as moderate (score = 2), with diffuse, widespread superficial Scratch marks and / or many deep Scratch marks is scored as severe (score = 3). Half scores (e.g., 2.5) are acceptable in the EASI system. However, Scratch marksThe minimum score for the presence of EASI is mild (score = 1), so a score of 0.5 is unacceptable. Scratch marks Illustrative images of representative images are shown in Figures 3A-3D.

[0057] The ADAM method comprises administering to a subject a sample present in the skin of the subject. Scratch marks Based on the total number of Scratch marks A method for assessing the severity of AD includes scoring the following: Scratch marks is scored as 0, and 5 to 20 Scratch marks is scored as 1, and more than 20 Scratch marks The cracked area was scored as 2. Scratch marks is scored as a 3.

[0058] The SASSAD method involves measuring the following within each of six target areas (hands, arms, feet, legs, head and neck, and trunk): Scratch marks In the most severe areas Scratch marks Based on the salience of Scratch marks The SASSAD method involves scoring the severity of AD as absent (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3). Scratch marks is defined as any damage to the skin caused by scratching, not due to erythema or urticaria. Scratch marks Absence means that the condition cannot be detected reliably even with careful testing, and is mild. Scratch marks requires careful examination to observe Scratch marks The presence of moderate Scratch marks is immediately apparent Scratch marks The presence of severe Scratch marks is very noticeable Scratch marks The existence of

[0059] The SSS method ranks the severity of pain in 20 target areas (scalp, ears, peri-cheek, peri-orbital, face, neck, chest, abdomen, back, elbows, arms, axillae, hands and dorsal wrists, palms and wrists, buttocks and groin, popliteal fossae, thighs, legs, arches, and soles) based on the severity of the pain. Scratch marksand scoring the clefts as absent (score=0), mild (score=1), moderate (score=2), or severe (score=3).

[0060] Like SCORAD, the TIS method is the most representative Scratch marks In the area Scratch marks Based on the presence and intensity of Scratch marks This is a method for assessing the severity of AD, which involves scoring the condition on a scale of none (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3). Scratch marks The area is the average intensity of the target. Scratch marks This is the area containing the TIS method. Scratch marks Scoring does not include scoring based on fractions (e.g., half-point scoring such as 0.5, 1.5, or 2.5).

[0061] To test the hypothesis that AD patients who scratch their skin due to pruritus represent a subpopulation of responders to nemolizumab treatment, published data from a study of subcutaneously administered nemolizumab in adults with moderate to severe AD (Ruzicka, T. et al. N. Engl. J. Med. (2017), 376: 826-35, the entire disclosure of which is incorporated herein by reference) were analyzed to determine the effect of treatment in patients with scratching. AD patients in the Ruzicka et al. nemolizumab study had skin scratching. Scratch marks Based on the results, (i) none to mild symptoms at baseline Scratch marks and (ii) AD patients with moderate to severe AD at baseline. Scratch marks Patients with AD were divided into two groups. Scratch marks was scored according to the SCORAD method. Each parameter in this study was then reanalyzed to compare the relative treatment effects in each population compared with placebo.

[0062] The Ruzicka et al. nemolizumab study was a 12-week, phase 2, randomized, double-blind, placebo-controlled trial involving 264 patients (clinical trial number NCT01986933). Eligible patients were adults with moderate to severe atopic dermatitis not adequately controlled with topical therapy. Patients were ineligible for the study if they had active skin disease associated with AD. Enrolled patients received nemolizumab or placebo subcutaneously at doses of 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg every 4 weeks. Some patients instead received 2.0 mg / kg every 8 weeks. The primary endpoint of the study was improvement in pruritus visual analog scale (VAS) scores. Additional endpoints included improvement in atopic dermatitis body surface area and Eczema Area and Severity Index (EASI). At the end of the study, at week 12, the greatest percent change in EASI score, -42.3%, occurred in patients receiving 0.5 mg / kg nemolizumab every four weeks. This dose also offered the best benefit-risk profile. However, improvements in EASI score were also seen in the other dose groups (-23.0% in the 0.1 mg group and -40.9% in the 2.0 mg group). Improvements in VAS scores were also seen at each dose.

[0063] The results of our analysis of the Ruzicka et al. nemolizumab trial are shown in Tables 1 and 2 below. Pruritus VAS scores ranged from 0 (no itch) to 100 (worst itch imaginable) and were recorded daily by patients using an electronic recording tool. A negative change in the VAS score indicated improvement. EASI scores ranged from 0 to 72, with higher scores indicating greater disease severity. Investigator Global Assessment (IGA) scores ranged from 0 (none) to 5 (very severe) and were expressed as the percentage of patients in a designated population. Sleep refers to sleep measurements recorded by actigraphy, a motion-detection method that records whole-body movement and is effective in recording sleep metrics, including sleep efficiency. Sleep efficiency is total time asleep divided by total time in bed. Dermatology Life Quality Index (DLQI) scores ranged from 0 to 30, with higher scores indicating lower quality of life. To be eligible for the Ruzicka et al. study, patients were required to have a baseline EASI score of at least 10, a baseline pruritus VAS score of at least 50 mm, and a baseline IGA score of at least 3.

[0064] As shown in Table 1, the two AD patient groups in this study had similar scores for pruritus, DLQI, and sleep efficiency. Although the EASI and IGA were not balanced between the two groups, these two parameters were Scratch marks This was expected, as the effect of the presence or absence of

[0065] Table 1. Clinical characteristics at baseline TIFF0007777921000007.tif79147

[0066] As shown in Table 2, Scratch marks The presence of nemolizumab affected the efficacy of treatment in patients with moderate to severe AD. Scratch marksIn the patient population with nemolizumab, treatment outcomes improved in all parameters at week 12. These results were obtained by comparing the net effect (effect of nemolizumab minus effect of placebo) between the two groups. For example, after treatment with nemolizumab, there was no to mild Scratch marks Patients with moderate to severe sleep apnea showed a 13% improvement in sleep efficiency. Scratch marks Patients with sleep apnea showed a 39% improvement in sleep efficiency, with none to mild Scratch marks The response was three times better than that of the control group.

[0067] (Table 2) Treatment results TIFF0007777921000008.tif91157

[0068] The data presented in Table 2 are for moderate to severe Scratch marks The presence of α-glucan-1 is a biomarker for predicting the efficacy of nemolizumab treatment in AD patients.

[0069] Thus, provided herein is a method for identifying a subject with atopic dermatitis who is likely to respond to treatment with nemolizumab or its equivalent, comprising: Scratch marks In some embodiments, a method for determining whether a subject with atopic dermatitis is likely to respond to treatment with nemolizumab or its equivalent, comprising detecting one or more Scratch marks In some embodiments, a method for predicting whether a subject with atopic dermatitis is likely to respond to treatment with nemolizumab or its equivalent, comprising detecting one or more of the following on the skin of the subject: Scratch marks Provided herein are methods comprising, consisting of, or consisting essentially of detecting Scratch marksis caused by itching.

[0070] In some embodiments, the methods described above involve treating 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more skin Scratch marks In some embodiments, the method comprises detecting a skin Scratch marks The extent of is detected by detecting the total lesioned skin surface area, the number and / or size of lesioned areas, or the percent body surface area of ​​lesions. Scratch marks is the average intensity of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the subject's skin is detected in a specific area or region, including: Scratch marks is the worst (i.e., most severe) intensity of the aforementioned subject Scratch marks representing Scratch marks In some embodiments, the average intensity or worst intensity is detected in a specific area or region of the subject's skin, including Scratch marks is detected in one or more of the following areas of the subject: hands, arms, feet, legs, head, neck, head and neck, trunk, upper limbs, lower limbs, scalp, ears, peri-cheek, peri-orbital, face, neck, chest, abdomen, back, elbows, arms, axillae, hands and dorsal wrists, palms and wrists, buttocks and groin, popliteal fossae, thighs, legs, arches, and soles. Scratch marks In some embodiments, the aforementioned Scratch marks is detected by said subject or by an adult guardian of said subject.

[0071] In some embodiments, the method comprises: Scratch marks In some embodiments, the method further comprises scoring the above-mentioned condition as mild, moderate, or severe. Scratch marksis scored as absent (scored as 0), mild (scored as 1), moderate (scored as 2), or severe (scored as 3) according to the SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS instruments. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks is scored by a medical professional. Scratch marks is scored by the subject or by the subject's adult guardian.

[0072] In some embodiments, the foregoing method comprises administering to a patient having a condition scored as moderate to severe. Scratch marks In some embodiments, the method further comprises identifying the subject as likely to respond to nemolizumab treatment or an equivalent thereof if a score of moderate to severe is detected. Scratch marks In some embodiments, the method further comprises determining that the subject with atopic dermatitis is likely to respond to treatment with nemolizumab or its equivalent when a score of moderate to severe is detected. Scratch marks The method further includes predicting that the subject with atopic dermatitis is likely to respond to treatment with nemolizumab or its equivalent if

[0073] In some embodiments, the foregoing methods involve the determination of the severity of a condition scored as none to mild. Scratch marks In some embodiments, the method further comprises determining the subject as unlikely to respond to nemolizumab treatment or its equivalent if no response is detected. Scratch marks In some embodiments, the method further comprises determining that the subject with atopic dermatitis is unlikely to respond to treatment with nemolizumab or its equivalent if no response is detected in the subject scored as none to mild. Scratch marks is not detected, the subject having atopic dermatitis is predicted to be unlikely to respond to treatment with nemolizumab or its equivalent.

[0074] Pharmaceutical Composition As used herein, one or more skin Scratch marks The present disclosure also provides a pharmaceutical composition for use in treating atopic dermatitis in a subject determined to have AD, the pharmaceutical composition comprising, consisting of, or consisting essentially of nemolizumab or an equivalent thereof. The present disclosure also provides a therapeutic agent for AD, comprising nemolizumab or an equivalent thereof as an active ingredient.

[0075] In some embodiments, the aforementioned Scratch marks has been previously detected and / or scored by a medical professional, the subject, or an adult guardian of the subject. Scratch marks is scored according to one or more of the following methods: SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks In some embodiments, the aforementioned Scratch marks In some embodiments, the subject has a skin condition scored as none to mild. Scratch marks In some embodiments, the aforementioned Scratch marks does not have a score of 0 to 1. In some embodiments, Scratch marks In some embodiments, the aforementioned scored Scratch marks is the average intensity of the aforementioned object Scratch marks representing Scratch marksIn some embodiments, the scored Scratch marks is the worst case strength of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the skin of the subject is present in a specific area or region comprising: Scratch marks In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin rashes. Scratch marks It has.

[0076] The phrase "comprising nemolizumab or its equivalent as an active ingredient" means that nemolizumab or its equivalent is contained as at least one active ingredient, and the proportion of the antibody is not limited. Furthermore, the therapeutic agent for AD in the present disclosure may contain other ingredients that enhance the treatment of AD in combination with nemolizumab or its equivalent. For example, the composition may contain one or more calcineurin inhibitors (e.g., topical calcineurin inhibitors), emollients, topical steroids (e.g., topical glucocorticoids), and oral antihistamines.

[0077] Pharmaceutical compositions of nemolizumab or its equivalents disclosed herein can be prepared as formulations according to standard methods (see, for example, Remington's Pharmaceutical Sciences, Mark Publishing Company, Easton, USA). In some embodiments, the pharmaceutical compositions include a carrier and / or an additive. In some embodiments, the carrier is a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical compositions include one or more of surfactants (e.g., PEG and Tween), excipients, antioxidants (e.g., ascorbic acid), colorants, flavoring agents, preservatives, stabilizers, buffers (e.g., phosphoric acid, citric acid, and other organic acids), chelating agents (e.g., EDTA), suspending agents, isotonicity agents, binders, disintegrants, lubricants, flow enhancers, flavoring agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, and inorganic salts. In some embodiments, the pharmaceutical compositions include one or more other low molecular weight polypeptides, proteins (such as serum albumin, gelatin, and immunoglobulins), and amino acids (such as glycine, glutamine, asparagine, arginine, and lysine).

[0078] When preparing nemolizumab or its equivalent as an aqueous solution for injection, nemolizumab or its equivalent can be dissolved in an isotonic solution containing, for example, physiological saline, glucose, or other auxiliary agents. Examples of the auxiliary agents include D-sorbitol, D-mannose, D-mannitol, and sodium chloride. In addition, suitable solubilizers, such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol and PEG), and nonionic surfactants (polysorbate 80 and HCO-50), can be used in combination.

[0079] Optionally, nemolizumab or its equivalent may be entrapped in microcapsules (microcapsules composed of hydroxymethylcellulose, gelatin, polymethylmethacrylate, etc.) and may be a component of colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, e.g., "Remington's Pharmaceutical Science 16th edition" & Oslo Ed. (1980)). Furthermore, methods for preparing sustained-release formulations are known and can be applied to nemolizumab or its equivalents (Langer et al., J. Biomed. Mater. Res. (1981) 15, 167-277; Langer, Chem. Tech. (1982) 12, 98-105; U.S. Pat. No. 3,773,919; European Patent Application (EP) No. 58,481; Sidman et al., Biopolymers (1983) 22, 547-56; European Patent Application No. 133,988).

[0080] The pharmaceutical composition of the present disclosure can be administered either orally or parenterally, but is preferably administered parenterally. Specifically, the pharmaceutical composition is administered to a patient by injection or transdermal administration. Injections include, for example, intravenous injection, intramuscular injection, and subcutaneous injection, and may be administered systemically or locally. The pharmaceutical composition may be administered by local injection or intramuscular injection to the site where inflammation is to be suppressed or the surrounding area of ​​the site. In some embodiments, the pharmaceutical composition is administered by injection into one or more skin. Scratch marks on or in one or more areas of the skin Scratch marks The administration is proximal to the site of

[0081] The administration method can be appropriately selected depending on the age and condition of the patient. The single dose can be selected, for example, within the range of 0.0001 to 100 mg of active ingredient per kg of body weight. Alternatively, for example, when the above-mentioned drug is administered to a human patient, the dose of the active ingredient can be selected within the range of 0.001 to 1,000 mg / kg of body weight. In some embodiments, the composition may be administered in a dose range of, for example, about 0.01 to 50 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.05 mg / kg to 0.15 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 0.75 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 1.8 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.8 mg / kg to about 2.2 mg / kg, about 1 mg / kg to about 2.5 mg / kg, or about 1 mg / kg to about 3.5 mg / kg. The formulation is formulated to administer a dose containing nemolizumab or its equivalent of about 1 mg / kg, about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 20 mg / kg to about 50 mg / kg, about 25 mg / kg to about 75 mg / kg, about 50 mg / kg to about 100 mg / kg, about 100 mg / kg to about 500 mg / kg, or about 100 mg / kg to about 1000 mg / kg of body weight. In preferred embodiments, the aforementioned doses range from about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.In some embodiments, the aforementioned doses are about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, g / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In a preferred embodiment, the dose is about 0.5 mg / kg.

[0082] In some embodiments, the single-administration dose can be selected from, for example, 1 to 100 mg, or more specifically, about 10 to about 90 mg, about 20 to about 80 mg, about 25 to about 70 mg, or about 30 to about 60 mg of the active ingredient (i.e., nemolizumab or its equivalent). For example, in some embodiments, the single-administration dose can be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

[0083] In some embodiments, the single dose may vary over time. For example, a subject may initially receive a "loading dose" that is higher than a subsequent "maintenance dose." In some embodiments, a subject may receive one or more initial loading doses of 60 mg of nemolizumab (or its equivalent), followed by a maintenance dose of 30 mg. In other embodiments, the initial dose and subsequent doses may be the same. For example, the initial dose and subsequent doses may be 60 mg. In any of these embodiments, the antibody (nemolizumab or its equivalent) may be administered to a subject together with a second active agent, such as a topical steroid or a topical calcineurin inhibitor, or alone.

[0084] Treatment method In some embodiments, one or more skin Scratch marks The present invention provides a method for selectively treating atopic dermatitis in a subject having the above-mentioned condition, the method comprising, consisting of, or consisting essentially of administering to said subject an effective amount of nemolizumab or an equivalent thereof.

[0085] In some embodiments, the aforementioned Scratch marks has been previously detected and / or scored by a medical professional, the subject, or an adult guardian of the subject. Scratch marksis scored according to one or more of the following methods: SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks In some embodiments, the aforementioned Scratch marks In some embodiments, the subject has a skin condition scored as none to mild. Scratch marks In some embodiments, the aforementioned Scratch marks does not have a score of 0 to 1. In some embodiments, Scratch marks In some embodiments, the aforementioned scored Scratch marks is the average intensity of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the scored Scratch marks is the worst case strength of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the skin of the subject is present in a specific area or region comprising: Scratch marks In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin conditions. Scratch marks It has.

[0086] An "effective amount" is an amount sufficient to produce a beneficial or desired result, such as at least alleviating one or more symptoms of AD and / or pruritus. As used herein, an effective amount also includes an amount sufficient to delay the onset of AD and / or pruritus, change the course of symptoms of AD and / or pruritus (e.g., sleep efficiency), or improve symptoms of AD and / or pruritus. That is, an exact "effective amount" cannot be specified. However, in any given case, a person skilled in the art can determine a suitable "effective amount" using only routine experimentation.

[0087] An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery depends on several variables, including, for example, the duration for which the individual dosage units are used, the bioavailability of the therapeutic agent, and the route of administration. However, it should be understood that the specific dosage level of the therapeutic agent of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the subject's age, weight, general health, sex, and diet, the timing of administration, the rate of excretion, the drug combination, the severity of the particular disorder being treated, and the form of administration. Therapeutic dosages can generally be titrated to optimize safety and efficacy. Dosages can be determined by a physician and adjusted accordingly to accommodate observed therapeutic effects. Typically, dosage-effect relationships obtained in in vitro and / or in vivo studies can provide useful guidance initially regarding appropriate dosages for patient administration. Generally, it is desirable to administer an amount of the compound effective to achieve serum concentrations corresponding to concentrations determined to be effective in vitro. Determining these parameters is well within the skill of one of ordinary skill in the art. These concepts, as well as effective formulations and administration methods, are well known in the art and are described in standard textbooks.

[0088] In some embodiments, the dose of nemolizumab or its equivalent administered to the subject is within the range of 0.001 to 1,000 mg / kg of the subject's body weight. In some embodiments, the dose is about 0.01 to 50 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.05 mg / kg to 0.15 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 0.75 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 1.8 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.8 mg / kg to about 2.2 mg / kg, about 1 mg / kg to about 2.5 mg / kg, or about 1 mg / kg to about 2.5 mg / kg. Nemolizumab or its equivalent is administered in the range of about 3.5 mg / kg, about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 20 mg / kg to about 50 mg / kg, about 25 mg / kg to about 75 mg / kg, about 50 mg / kg to about 100 mg / kg, about 100 mg / kg to about 500 mg / kg, or about 100 mg / kg to about 1000 mg / kg of body weight. In preferred embodiments, the aforementioned doses range from about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.In some embodiments, the aforementioned doses are about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, g / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In a preferred embodiment, the dose is about 0.5 mg / kg.

[0089] In some embodiments, the single-administration dose can be selected from, for example, 1 to 100 mg, or more specifically, about 10 to about 90 mg, about 20 to about 80 mg, about 25 to about 70 mg, or about 30 to about 60 mg of the active ingredient (i.e., nemolizumab or its equivalent). For example, in some embodiments, the single-administration dose can be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

[0090] In some embodiments, the single dose may vary over time. For example, a subject may initially receive a "loading dose" that is higher than a subsequent "maintenance dose." In some embodiments, a subject may receive one or more initial loading doses of 60 mg of nemolizumab (or its equivalent), followed by a maintenance dose of 30 mg. In other embodiments, the initial dose and subsequent doses may be the same. For example, the initial dose and subsequent doses may be 60 mg. In any of these embodiments, the antibody (nemolizumab or its equivalent) may be administered to a subject together with a second active agent, such as a topical steroid or a topical calcineurin inhibitor, or alone.

[0091] In some embodiments of the method, the nemolizumab or its equivalent is administered by a topical or parenteral route. In some embodiments of the method, the nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the dosage is administered subcutaneously or via one or more intravenous routes. Scratch marks The therapeutic agent is administered at or proximal to the site of the injury.

[0092] In some embodiments, nemolizumab or its equivalent is administered daily, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, twice a year, once a year, and / or as needed based on the symptomatic status of atopic dermatitis or pruritus. In a preferred embodiment, nemolizumab or its equivalent is administered every four weeks or every eight weeks.

[0093] In certain embodiments, both the dosage and dosing schedule can be determined before initiating a treatment method. For example, a subject can receive about 30 to about 60 mg of nemolizumab or its equivalent once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W), alone or in combination with a second active agent (e.g., a topical steroid or a topical calcineurin inhibitor). In some embodiments, a subject can receive a loading dose of 60 mg of nemolizumab or its equivalent, followed by a maintenance dose of 30 mg of nemolizumab or its equivalent once every four weeks (Q4W). In some embodiments, the maintenance dose can be administered as infrequently as once every eight weeks (Q8W). In such a treatment regimen, administration may be performed with or without a topical steroid or a topical calcineurin inhibitor. In another embodiment, a subject may receive a 60 mg dose of nemolizumab or its equivalent once every four weeks (Q4W) without reducing the dose over time. In some embodiments, the aforementioned dose may be administered as infrequently as once every eight weeks (Q8W). In such a treatment regimen, administration may be performed with or without a topical steroid or a topical calcineurin inhibitor.

[0094] Alternatively, the dosage in a particular dosing regimen may be based on the subject's body weight (e.g., mg / kg) rather than a predetermined dose. For example, a subject may receive about 0.1 to about 2.0 mg / kg of nemolizumab or its equivalent once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W), alone or in combination with a second active agent (e.g., a topical steroid or a topical calcineurin inhibitor). In some embodiments, a subject may receive a loading dose of 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg of nemolizumab or its equivalent, followed by a maintenance dose of nemolizumab or its equivalent that is less than the loading dose once every four weeks (Q4W). In some embodiments, the aforementioned maintenance dose may be administered as infrequently as once every eight weeks (Q8W). Such a treatment regimen may be administered with or without a topical steroid or a topical calcineurin inhibitor. In another embodiment, a subject may receive a dose of 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg of nemolizumab or its equivalent once every four weeks (Q4W) without reducing the dose over time. In some embodiments, the aforementioned dose may be administered as infrequently as once every eight weeks (Q8W). Such a treatment regimen may be administered with or without a topical steroid or a topical calcineurin inhibitor.

[0095] In some embodiments, the treatment period is about 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or as needed based on the symptomatic status of the atopic dermatitis. In preferred embodiments, the treatment period is about 12 to about 24 weeks, about 12 to about 36 weeks, about 12 to about 48 weeks, or about 24 to about 36 weeks.

[0096] In some embodiments, one or more skin Scratch marks In some embodiments, the use of nemolizumab or an equivalent thereof in the manufacture of a medicament for treating atopic dermatitis in a subject having Scratch marks has been previously detected and / or scored by a medical professional, the subject, or an adult guardian of the subject. Scratch marks is scored according to one or more of the following methods: SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks In some embodiments, the aforementioned Scratch marks In some embodiments, the subject has a skin condition scored as none to mild. Scratch marks In some embodiments, the aforementioned Scratch marks does not have a score of 0 to 1. In some embodiments, Scratch marks In some embodiments, the aforementioned scored Scratch marks is the average intensity of the aforementioned object Scratch marksrepresenting Scratch marks In some embodiments, the scored Scratch marks is the worst case strength of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the skin of the subject is present in a specific area or region comprising: Scratch marks In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin rashes. Scratch marks It has.

[0097] In some embodiments, there is provided a method of treating a patient with atopic dermatitis, comprising: (a) treating said patient with atopic dermatitis with a skin Scratch marks and (b) treating said patient screened in step (a) by administering an effective amount of nemolizumab or an equivalent thereof. In some embodiments, said patient screened in step (a) is Scratch marks In some embodiments, the screening comprises: Scratch marks In some embodiments, the method includes detecting and / or scoring: Scratch marks is scored according to one or more of the following methods: SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks In some embodiments, the aforementioned Scratch marks In some embodiments, the patient has a skin rash scored as none to mild. Scratch marksIn some embodiments, the aforementioned Scratch marks does not have a score of 0 to 1. In some embodiments, Scratch marks In some embodiments, the aforementioned Scratch marks is the average intensity of the aforementioned patient Scratch marks representing Scratch marks In some embodiments, the patient is screened in a specific area or region of the skin, including Scratch marks is the worst intensity of the patient mentioned above. Scratch marks representing Scratch marks In some embodiments, the skin is screened in a specific area or region of the patient's skin, including Scratch marks In some embodiments, the patient has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin rashes. Scratch marks It has.

[0098] In some embodiments, a person suffering from atopic dermatitis and having one or more skin Scratch marks The present invention provides a method for improving sleep quality in a subject having a sleep disorder, the method comprising administering to the subject an effective amount of nemolizumab or its equivalent. In some embodiments, the improvement in sleep quality is determined by detecting an improvement in one or more of sleep onset latency, total sleep time, sleep efficiency, or wake-after-sleep time. As described above, sleep efficiency is defined as total sleep time divided by total time in bed. In some embodiments, sleep quality is recorded or detected by one or more of actigraphy, motion detection, video monitoring, and / or self-reporting ... Scratch marks has been previously detected and / or scored by a medical professional, the subject, or an adult guardian of the subject. Scratch marksis scored according to one or more of the following methods: SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and / or TIS. Scratch marks is scored according to the SCORAD or PO-SCORAD method. Scratch marks In some embodiments, the aforementioned Scratch marks In some embodiments, the subject has a skin condition scored as none to mild. Scratch marks In some embodiments, the aforementioned Scratch marks does not have a score of 0 to 1. In some embodiments, Scratch marks In some embodiments, the aforementioned scored Scratch marks is the average intensity of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the scored Scratch marks is the worst case strength of the aforementioned object Scratch marks representing Scratch marks In some embodiments, the skin of the subject is present in a specific area or region comprising: Scratch marks In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin rashes. Scratch marks It has.

[0099] The success of treatment with nemolizumab or its equivalent can be determined or assessed by detecting improvement, reduction, elimination, or amelioration of AD, pruritus, or one or more symptoms thereof. For example, success can be determined by detecting improvement in one or more of the following: skin Scratch marks Number of skin Scratch marksThe strength of Scratch marks score, a subject's pruritus VAS score, a subject's DLQI score, sleep efficiency, sleep onset latency, total sleep time, awakenings during sleep, percent body surface area affected, a subject's EASI score, a subject's IGA score, the degree or amount of dry skin, the frequency or presence of pruritus, the severity of pruritus, skin redness, the frequency of raised bumps, the degree or amount of skin thickening, the degree or amount of skin cracking, the degree or amount of skin scaling, the degree or amount of peeling skin, the degree or amount of sensitive skin, and / or the degree or amount of skin swelling. In some embodiments, success does not depend on whether AD and / or pruritus is considered "cured" or "cured" and whether all symptoms have resolved. [Example]

[0100] A randomized, double-blind, placebo-controlled, dose-ranging study was conducted to evaluate the long-term efficacy and safety of continuous subcutaneous administration of nemolizumab, injected every 4 weeks (Q4W) or every 8 weeks (Q8W), in patients with moderate to severe atopic dermatitis inadequately controlled with topical therapy. This study was published in Kabashima, et al., J Allergy Clin Immunol (2018) 142(4)1121, which is incorporated by reference in its entirety, including any figures. The primary endpoint analysis demonstrated a significant improvement in pruritus from baseline at week 12 when nemolizumab was administered every 4 weeks (Q4W), as assessed using the pruritus visual analog scale (VAS). The reductions in reported pruritus VAS scores were -44% in the 0.1 mg / kg group, -60% in the 0.5 mg / kg group, and -63% in the 2.0 mg / kg group, compared with -21% in the placebo group (P < .01 for all comparisons). Improvements in AD disease severity and body surface lesions, as well as sleep disturbance, compared with placebo, were also observed at week 12.

[0101] method Study design This study was conducted in two parts (Figure 4). In Part A, nemolizumab was evaluated over 12 weeks at four dosing regimens: 0.1 mg / kg, 0.5 mg / kg, or 2.0 mg / kg subcutaneously (Q4W), and 2.0 mg / kg subcutaneously (Q8W), or subcutaneous placebo (Q4W). After completion of Part A, patients entered a double-blind extension period where they continued receiving nemolizumab at their pre-assigned dose for an additional 52 weeks (Weeks 12–64, Part B). Patients randomized to placebo in Part A were re-randomized in a 1:1:1 ratio to nemolizumab (0.1, 0.5, or 2.0 mg / kg subcutaneously, Q4W) in Part B using a centralized interactive voice response or online response system (placebo-treated patients were not re-randomized to nemolizumab 2.0 mg / kg Q8W). All patients were required to cross over to Part B within 7 days of their last visit in Part A. To maintain blinding in Part B, the study monitoring team, study site personnel, and other site / company personnel were not informed of treatment assignment until the final database was locked after study completion. The study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki guidelines. Approval was obtained from the institutional review board or institutional review board at each study center. Written informed consent was obtained from all patients.

[0102] Study population Key eligibility criteria are listed in Figure 4. To enter Part B, patients were required to have completed the Part A treatment period and provided written informed consent to participate in the extension phase.

[0103] Test Procedure In Part B of the study, patients received one of three doses of nemolizumab (0.1, 0.5, or 2.0 mg / kg) subcutaneously administered Q4W or 2.0 mg / kg subcutaneously administered Q8W for 52 weeks. To maintain blinding, patients receiving nemolizumab Q8W received placebo at Week 12 (the last visit in Part A) and nemolizumab at Week 16, alternating between placebo and nemolizumab thereafter. Patients were permitted to use emollients, topical treatments (e.g., eye drops), weak topical glucocorticosteroids (including prednisolone), topical calcineurin inhibitors, and antihistamines (nonselective H1 antihistamines were excluded). Patients with, in the investigator's opinion, minimal improvement in pruritus VAS scores (range, 0 mm [no itch] to 100 mm [worst itch imaginable]) and static Investigator's Global Assessment (sIGA) scores (range, 0 [none] to 5 [very severe]) were permitted to use "strong" topical glucocorticosteroids (e.g., mometasone furoate 0.1%) as rescue treatment in Part A (after week 4) and "strong" or "very strong" topical glucocorticosteroids (e.g., clobetasol propionate 0.05%) in Part B.

[0104] Test evaluation Baseline assessments for patients re-randomized from placebo to nemolizumab in Part B were conducted at the last visit in Part A or at a separate visit. Patients attended study visits every 4 weeks from Weeks 12 to 64, with a safety follow-up visit 12 weeks (± 5 days) after their last dose of study drug. For consistency, patients were assessed by the same assessor at all visits (when possible). Rater training was conducted to minimize variability across locations and investigators. Efficacy assessments were conducted every 4 weeks from Weeks 16 to 64 and at the earliest possible withdrawal visit after discontinuation of study drug. The pruritus VAS, the pruritus verbal rating scale (VRS; measuring pruritus intensity on a scale ranging from 0 (no itch) to 4 (very severe itch)), and the sleep disturbance VAS (ranging from 0 (no insomnia) to 100 (complete insomnia)) were completed by patients every 7 days in Part B.

[0105] Test evaluation items The primary efficacy outcome, the rate of improvement from baseline in pruritus VAS score at week 12, was assessed in Part A. Secondary efficacy outcomes evaluated in Part B (weeks 12 to 64) included improvements from baseline in the following: pruritus VAS score, Eczema Area and Severity Index (EASI) score (range, 0-72; higher scores indicate greater disease severity), Scoring of Atopic Dermatitis (SCORAD; range, 0-103; higher scores indicate greater severity), body surface area (BSA) of AD lesions, and sleep disturbance VAS score. Secondary outcomes included the proportion of patients achieving 25%, 50%, and 75% improvement from baseline in pruritus VAS score and EASI score; the proportion of patients achieving a ≥2-point improvement from baseline in sIGA score and pruritus VRS score; and the proportion of patients receiving rescue treatment. The proportion of patients achieving an itch VAS score of less than 30 mm (no itch or mild itch) was investigated in a post-hoc analysis. Exploratory efficacy endpoints in Part B included the frequency, duration, and amount of topical glucocorticosteroids used as rescue treatment, as well as the Dermatological Life Quality Index score (DLQI; measured on a scale of 0 to 30, with higher scores indicating greater functional impairment). A change of 4 or more points in the DLQI score, considered the minimal clinically important difference, was investigated in a post-hoc analysis. The long-term safety profile was also evaluated.

[0106] statistical analysis Secondary and exploratory endpoints in Part B were summarized using descriptive statistics, and no formal statistical comparisons were performed in Part B. Missing values ​​were not imputed. Data measured after rescue treatment were included in the analysis. The intention-to-treat population, which included all randomized patients who received at least one dose of nemolizumab in Part A or Part B and had at least one post-dose efficacy assessment, was used for efficacy analyses. All patients who received at least one dose of nemolizumab in Part A or Part B were included in safety analyses. Separate efficacy and safety analyses were performed for patients who received nemolizumab throughout the entire 64-week study period (patients randomized to nemolizumab in Parts A and B) and patients who switched from placebo to nemolizumab at Week 12 (patients randomized to placebo in Part A and re-randomized to nemolizumab in Part B).

[0107] result In total, 264 patients were randomized to Part A; of these, 216 completed Part A and 191 entered Part B, including 38 patients who were randomly reassigned from the placebo group (see Figure 5). Of the 191 patients who entered Part B, 131 (69%) completed Part B. The most common reason for discontinuation in Part B was patient withdrawal from the study (33 / 191 [17%]), followed by lack of efficacy (10 / 191 [5%]) and AEs (8 / 191 [4%]). The intention-to-treat population included 248 patients (211 patients randomized to nemolizumab in Part A and 37 patients randomized to nemolizumab who had received placebo in Part A [one randomly reassigned patient did not have evaluable post-treatment efficacy data]). The safety population included 249 patients (211 randomized to nemolizumab in Part A and 38 who received placebo in Part A and were re-randomized to nemolizumab). Overall, 84% (222 / 264) of patients enrolled in the study in Part A or Part B completed the safety follow-up 12 weeks after their last study drug dose.

[0108] Patients had intense itch at baseline according to the itch visual analog scale (VAS) score and moderate to severe itch according to the investigator's static global assessment (sIGA) score, AD-occupied body surface area (BSA) score, and Eczema Area and Severity Index (EASI) score. Mean baseline total serum IgE values ​​are listed in Table 3. The most common concomitant allergy was allergic rhinitis (n = 91), and the most common history of allergy was asthma (n = 34). Among patients who received placebo in Part A and were then re-randomized to nemolizumab Q4W in Part B, demographics, baseline characteristics, and baseline AD severity were similar between groups.

[0109] Table 3. Baseline total serum IgE values ​​in the intention-to-treat (ITT) population TIFF0007777921000009.tif40161

[0110] In patients randomized to receive nemolizumab throughout the 64-week study, the improvements from baseline in pruritus VAS scores observed in Part A were maintained or increased from Week 12 to Week 64 (see Figure 6). The greatest improvements throughout the study were observed in the 0.5 mg / kg nemolizumab group (see Table 4). The proportion of patients achieving an pruritus VAS score of less than 30 mm was maintained through Week 64 (Figure 6B and Figure 4). In patients receiving nemolizumab in Part A, the mean ± SD percent changes from baseline in the EASI score, Scoring of Atopic Dermatitis (SCORAD) score, lesion BSA, and sleep disturbance VAS score, as well as the proportion of patients achieving a 2-point or greater improvement in the sIGA score or pruritus verbal rating score (VRS), were also maintained or increased from Week 12 to Week 64 (Figures 7A-7C and Table 4 below). Approximately two-thirds (68%, 68%, and 66%) of patients in the 0.1 mg / kg Q4W nemolizumab group, the 0.5 mg / kg Q4W nemolizumab group, and the 2.0 mg / kg Q4W nemolizumab group, and almost three-quarters (74%) of patients in the 2.0 mg / kg Q8W group who remained on treatment at week 64 showed a 75% improvement in EASI score (Table 5 below).

[0111] Table 4. Percent changes from baseline in secondary and exploratory endpoints at Weeks 12 and 64 in the intention-to-treat (ITT) population receiving nemolizumab in Part A TIFF0007777921000010.tif69167TIFF0007777921000011.tif189167 * Post-mortem analysis

[0112] Table 5. For the intention-to-treat (ITT) population who received nemolizumab in Part A, patients who experienced a 25%, 50%, and 75% improvement from baseline in pruritus VAS score and EASI score at Weeks 12 and 64 (data shown as percentages). Data after rescue treatment are included. TIFF0007777921000012.tif83163

[0113] In Part A, patients who received placebo and were switched to nemolizumab at Week 12 experienced a treatment response in pruritus VAS scores by Week 16 (i.e., 4 weeks after switching to active treatment) that was maintained through Week 64 (1 year after switching to active treatment; see Table 6 below). The mean ± SD percent change from baseline at Week 12 to Week 16 in SCORAD score, EASI score, lesion BSA, and sleep disturbance VAS score generally showed improvement and were maintained or increased from Week 16 to Week 64 (see Table 6). However, these data were affected by outliers in a small number of patients in each group, and a high degree of variability was observed across visits (see Table 6).

[0114] Table 6. Percent changes from baseline (Week 12) in secondary and exploratory endpoints at Week 16 (4 weeks after the first nemolizumab dose in Part B) and Week 64 in the intention-to-treat (ITT) population receiving placebo in Part A (including data after rescue treatment) TIFF0007777921000013.tif104150 * Post-mortem analysis

[0115] Among patients randomized to receive nemolizumab throughout the 64-week study period, the median duration of topical glucocorticosteroid use decreased with increasing nemolizumab dose above 0.5 mg / kg, from 27.0 weeks (range, 1–62 weeks) in the 0.1 mg / kg Q4W group to 8.0 weeks (range, 1–57 weeks) in the 0.5 mg / kg Q4W group, 7.5 weeks (range, 1–59 weeks) in the 2.0 mg / kg Q4W group, and 3.0 weeks (range, 1–48 weeks) in the 2.0 mg / kg Q8W group (see Table 7).

[0116] Table 7. Overall and efficacy (%) in the intention-to-treat population receiving nemolizumab in Part A * ) for each baseline ( * Duration and cumulative dose of topical glucocorticosteroids throughout the study period from baseline to end of treatment (data shown as median and range) TIFF0007777921000014.tif137163 † The effectiveness of topical glucocorticosteroids as defined by the UK National Institute for Health and Care Excellence (see Atopic eczema in children: Management of atopic eczema in children from birth up to the age of 12 years. Clinical guideline. 2007). * Baseline values ​​were not available (zero) because patients were not permitted to use potent and very potent topical glucocorticosteroids within 2 weeks before randomization, or weak and moderately potent topical glucocorticosteroids within 1 week before randomization. Use of topical glucocorticosteroids was not permitted during Part A of the study, except as rescue treatment after week 4.

[0117] The median cumulative dose of topical glucocorticosteroid therapy also decreased with increasing nemolizumab dose above 0.5 mg / kg, from 137.4 g (range, 2 to 2,245 g) in the 0.1 mg / kg Q4W group to 60.7 g (range, 2 to 822 g) in the 0.5 mg / kg Q4W group, 55.8 g (range, 1 to 1,174 g) in the 2.0 mg / kg Q4W group, and 44.7 g (range, 10 to 250 g) in the 2.0 mg / kg Q8W group (see Table 7). However, there was considerable interpatient variability in the duration and dose of topical glucocorticosteroid therapy, limiting the number of evaluable patients included in the total number of patients receiving glucocorticosteroid therapy (18 / 30 in the 0.1 mg / kg Q4W group, 17 / 24 in the 0.5 mg / kg Q4W group, 20 / 27 in the 2.0 mg / kg Q4W group, and 11 / 24 in the 2.0 mg / kg Q8W group). The proportion of patients receiving "very potent" topical glucocorticosteroids was similar between groups, but the proportion of patients receiving "potent" agents was highest in the lowest-dose nemolizumab Q4W group (63% [19 / 30] in the 0.1 mg / kg group, 42% [10 / 24] in the 0.5 mg / kg group, and 56% [15 / 27] in the 2.0 mg / kg group). Among patients receiving "potent," "moderately potent," and "weak" agents, the duration of use and cumulative dose of topical glucocorticosteroids in evaluable patients tended to decrease with increasing dose (see Table 7); limited data were available for "very potent" agents.

[0118] In patients randomized to nemolizumab Q4W and nemolizumab Q8W throughout the 64-week period, Dermatology Life Quality Index (DLQI) total scores gradually decreased throughout the study, with a greater proportion of patients showing a 4-point or greater decrease in total scores at Week 64 compared with Week 12 (Figure 7, and Table 4). A similar trend was observed in patients receiving placebo in Part A (see Table 6).

[0119] Overall, no new safety concerns were identified after long-term use of nemolizumab. Among patients randomized to receive nemolizumab throughout the entire study period (64 weeks), the proportion of patients with at least one AE (83% to 89%) and at least one treatment-related AE (37% to 48%) remained similar throughout the study (see Table 8 below). The most common AEs among these patients (≥5% of patients randomized to nemolizumab throughout the entire study period) were nasopharyngitis (27%), AD exacerbation (25%), increased blood creatine phosphokinase (11%), upper respiratory tract infection (9%), headache (8%), peripheral edema (6%), and impetigo (6%). The most common treatment-related AEs (occurring in ≥2% of patients randomized to nemolizumab throughout the entire study period) were exacerbation of AD (8%), upper respiratory tract infection (4%), nasopharyngitis (4%), peripheral edema (3%), increased blood creatine phosphokinase levels (3%), and injection site reactions (2%). All treatment-related AEs, except for nasopharyngitis and injection site reactions, occurred at a slightly higher incidence in the 2.0 mg / kg Q4W group than in the other study groups. The proportion of patients randomized to receive nemolizumab throughout the 64-week study period who experienced a first-time AE decreased over time, with the majority of AEs reported during the first 12 weeks of the study (see Table 9 below). Most AEs during the study were mild or moderate in intensity. Nine patients (17%) receiving 2.0 mg / kg nemolizumab Q8W experienced an SAE compared with three to four patients (6% to 8%) in the Q4W treatment group (see Table 8). Six SAEs reported in five patients were considered related to study treatment. Five patients (one in the 0.5 mg / kg Q4W group, two in the 2.0 mg / kg Q4W group, and two in the 2.0 mg / kg Q8W group) experienced one SAE, AD exacerbation, which was considered treatment-related in one patient.

[0120] Table 8. Adverse events (AEs) during the 64-week study period in patients randomized to nemolizumab throughout the entire study period TIFF0007777921000015.tif150150 * Patients who received placebo during Part A

[0121] The proportion of patients experiencing a first-ever SAE was evenly distributed over the study period (see Table 9 below). Adjusting for duration of drug exposure, the rates of AEs and SAEs among patients randomized to nemolizumab over the 64-week study period were higher in the 2.0 mg / kg Q8W group than in the 0.1 mg / kg Q4W, 0.5 mg / kg Q4W, and 2.0 mg / kg Q4W groups (Table 10), although no increase in specific AEs was observed. Discontinuation of study treatment due to AEs among patients randomized to receive nemolizumab throughout the 64-week study period occurred in 7 (13%), 3 (6%), 5 (10%), and 6 (12%) patients in the 0.1 mg / kg nemolizumab Q4W, 0.5 mg / kg nemolizumab Q4W, 2.0 mg / kg nemolizumab Q4W, and 2.0 mg / kg nemolizumab Q8W groups, respectively (see Table 11). Ten patients discontinued the study due to worsening AD, all during Part A.

[0122] Table 9. First-time adverse events (AEs) and serious adverse events (SAEs) by time point in patients randomized to receive nemolizumab throughout the study period (safety analysis population) TIFF0007777921000016.tif218163

[0123] Table 10. Exposure-adjusted adverse events (AEs) expressed as events per 100 person-years based on a ration of observed events over total person-years of exposure. TIFF0007777921000017.tif132163 * Patients who received nemolizumab in Part A and Part B † Patients who received placebo in Part A

[0124] Table 11. Adverse events (AEs) leading to treatment discontinuation in patients randomized to nemolizumab throughout the study period TIFF0007777921000018.tif108163 * One patient discontinued the study due to an AE after the last study drug injection, which is not listed.

[0125] Among patients re-randomized from placebo to nemolizumab in Part B, AEs were reported in 67% to 92% of patients across treatment groups (see Table 12). The most common AEs were similar to those seen throughout the study overall (see Table 12). One SAE was reported in one patient receiving placebo in Part A. Two patients who received placebo in Part A discontinued treatment due to AEs after being randomized to nemolizumab in Part B. Most injection-related reactions (IRRs) occurred in Part A of the study, with no trend toward a dose-related effect (12 patients experienced 13 events in Part A and 4 patients experienced 5 events in Part B). Nearly all IRRs were primarily local reactions of mild severity, and most were considered treatment-related. One IRR led to discontinuation of study treatment (exfoliative dermatitis).

[0126] Table 12. Adverse events (AEs) in Part B patients (safety population) randomized to receive placebo in Part A TIFF0007777921000019.tif138163 * SAE of diverticulitis, † asthma, ‡ Bronchial hyperresponsiveness

[0127] Consideration This study evaluated the efficacy and tolerability of nemolizumab, an anti-IL-31 receptor A mAb, in treating patients with AD inadequately controlled with topical therapy. The study demonstrated that improvements in pruritus, dermatitis, and sleep measures compared with placebo in the 12-week placebo-controlled portion of the study (Part A) were maintained or progressively increased with extended treatment (Extension Phase: Part B) up to 64 weeks. Although the study was not designed to formally compare different dose groups, consistent with the results obtained in Part A, there was no evidence that 2.0 mg / kg nemolizumab administered Q4W or Q8W was more effective than the 0.5 mg / kg dose. In Part B, patients were permitted to use mild topical glucocorticosteroids, and potent or very potent topical glucocorticosteroids were permitted as rescue treatment. Throughout this study, the higher the dose of nemolizumab administered to patients (≥0.5 mg / kg), the shorter the duration and cumulative dose of concomitant topical glucocorticosteroid therapy, but the limited number of patients precludes conclusions. These findings suggest that the dose-dependent response, which would have increased efficacy with higher doses of nemolizumab, may not have been present due to the use of higher doses of topical glucocorticosteroid therapy in patients in the 0.1 mg / kg group.

[0128] AD and associated pruritus impair the quality of life (QoL) of patients with the disease. The reductions in Dermatological Life Quality Index (DLQI) scores observed in Part A of this study were maintained during the long-term extension period, suggesting a long-term reduction in the impact of symptoms on daily life. These findings are consistent with the early improvement in pruritus observed during the first week of nemolizumab treatment in Part A of this study.

[0129] Overall, nemolizumab was well tolerated over 64 weeks. The safety profile was similar to that observed in Part A, and no new AEs were observed in the extension study. The incidence of IRRs was lower in Part B, suggesting that tolerability of nemolizumab injections improved over time.

[0130] In summary, nemolizumab was effective and generally well-tolerated when administered for up to 64 weeks to patients with moderate to severe AD inadequately controlled with conventional topical therapies. Treatment with nemolizumab significantly suppressed clinical pruritus and dermatitis. No new safety concerns were identified with long-term use of nemolizumab.

Claims

1. A pharmaceutical composition for selectively treating atopic dermatitis in a subject having one or more moderate to severe skin excoriations, comprising an effective amount of nemolizumab, The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. The pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein the skin scratch is moderate.

3. The pharmaceutical composition of claim 1, wherein the skin scratch is severe.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the effective amount of nemolizumab is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that said pharmaceutical composition is adapted to be administered by topical or parenteral route.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pharmaceutical composition is administered subcutaneously.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

8. A pharmaceutical composition comprising nemolizumab for use in treating atopic dermatitis in a subject determined to have one or more moderate to severe skin excoriations, The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. The pharmaceutical composition.

9. The pharmaceutical composition of claim 8, wherein the skin scratch is moderate.

10. The pharmaceutical composition of claim 8, wherein the skin scratch is severe.

11. The pharmaceutical composition according to any one of claims 8 to 10, further comprising a pharmaceutically acceptable carrier.

12. 1. Use of nemolizumab in the manufacture of a medicament for the treatment of atopic dermatitis in a subject having one or more moderate to severe skin excoriations, comprising: The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. The above use.

13. The use according to claim 12, wherein the skin scratch is moderate.

14. The use according to claim 12, wherein the skin excoriation is severe.

15. 1. A method for identifying a subject with atopic dermatitis who is likely to respond to treatment with nemolizumab, comprising: detecting one or more scratches on the subject's skin; scoring the scratch as mild, moderate, or severe; and Identifying the subject as likely to respond to treatment with nemolizumab if one or more moderate to severe excoriations are detected. Including, The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. The method.

16. 16. The method of claim 15, further comprising scoring the scratch as a 2 or 3 according to the SCORAD scale.

17. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is identified as likely to respond to treatment with nemolizumab by the method according to any one of claims 15 to 16.

18. A pharmaceutical composition for treating a patient with atopic dermatitis, comprising an effective amount of nemolizumab, The patient with atopic dermatitis is a patient who has been screened for one or more moderate to severe skin excoriations; The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. Pharmaceutical compositions.

19. 19. The pharmaceutical composition of claim 18, wherein the skin scratch is moderate.

20. 19. The pharmaceutical composition of claim 18, wherein the skin excoriation is severe.

21. The pharmaceutical composition of any one of claims 18 to 20, wherein the effective amount of nemolizumab is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.

22. The pharmaceutical composition according to any one of claims 18 to 21, characterized in that it is adapted to be administered by topical or parenteral route.

23. The pharmaceutical composition according to any one of claims 18 to 22, characterized in that the pharmaceutical composition is used for subcutaneous administration.

24. The pharmaceutical composition according to any one of claims 18 to 23, wherein the pharmaceutical composition is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

25. A pharmaceutical composition for improving sleep quality in a subject suffering from atopic dermatitis and having one or more moderate to severe skin excoriations, comprising an effective amount of nemolizumab, The one or more moderate to severe skin scratches are assigned a score of at least 2 on the SCORAD scale. The pharmaceutical composition.

26. 26. The pharmaceutical composition of claim 25, wherein the skin scratch is moderate.

27. 26. The pharmaceutical composition of claim 25, wherein the skin excoriation is severe.

28. The pharmaceutical composition of any one of claims 25 to 27, wherein the effective amount of nemolizumab is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.

29. The pharmaceutical composition according to any one of claims 25 to 28, characterized in that it is adapted to be administered by topical or parenteral route.

30. The pharmaceutical composition according to any one of claims 25 to 29, characterized in that the pharmaceutical composition is used for subcutaneous administration.

31. The pharmaceutical composition according to any one of claims 25 to 30, wherein the pharmaceutical composition is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

32. The pharmaceutical composition according to any one of claims 25 to 31, wherein the improvement in sleep quality is an improvement in one or more of sleep onset latency, total sleep time, sleep efficiency, or wake-after-sleep time.

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