Pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition for preventing or treating chronic pruritus of unknown cause (CPUO). [Solution] A preventive or therapeutic agent containing an anti-IL-31 receptor A antibody as an active ingredient is provided.

Description

Technical Field

[0001] In one aspect, the present disclosure relates to a pharmaceutical composition (prevention or treatment agent) for preventing or treating chronic pruritus of unknown origin (CPUO) containing an antibody against interleukin-31 (hereinafter, IL-31) receptor A as an active ingredient. In another aspect, the present disclosure relates to a method for preventing or treating CPUO including administering an antibody against IL-31 receptor A. In yet another aspect, the present disclosure relates to an antibody against IL-31 receptor A for use in the prevention or treatment of CPUO. In still yet another aspect, the present disclosure relates to the use of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating CPUO. In a specific aspect, CPUO is CPUO with insufficient efficacy in existing treatments. In a specific aspect, the antibody against IL-31 receptor A is nemolizumab.

Background Art

[0002] 〔Chronic pruritus of unknown origin〕 Chronic pruritus is defined by the International Forum for the Study of Itch (IFSI) as pruritus lasting for 6 weeks or more (Non-Patent Document 1), and chronic severe pruritus has a great adverse impact on quality of life (QOL). As its causes, various primary skin diseases such as atopic dermatitis (AD) and prurigo nodularis, as well as systemic diseases including chronic kidney disease, hepatobiliary disease, neurological disease, pregnancy, and infection can be mentioned. However, even when such causative diseases are excluded, the etiology may not be identified in some cases. It has been proposed to define such chronic pruritus with unknown etiology as Chronic pruritus of unknown origin (CPUO) (Non-Patent Document 2).

[0003] In diagnosing CPUO, it is important to rule out primary skin diseases or other underlying conditions that may cause itching. A diagnosis of CPUO is made when the cause cannot be identified after reviewing the medical history, examining the skin, and performing blood tests (Non-Patent Literature 3). However, secondary skin lesions such as scratch marks and hyperpigmentation may occur due to scratching. The prevalence of CPUO in patients with generalized pruritus is 3.6% to 44.5%, and it is said to be more common in the elderly (Non-Patent Literature 4).

[0004] It is said that CPUO patients experience more severe itching than AD patients. Furthermore, even when administered with strong immunosuppressants, CPUO patients often suffer from severe itching, which significantly negatively impacts their quality of life (Non-Patent Document 3).

[0005] The clear etiology of severe itching in CPUO is unknown, but the presence of type 2 immune deviations in the skin and systemically has been suggested (Non-Patent Literature 5, 6). The genetic pattern of the skin of CPUO patients is similar to that of AD patients (Non-Patent Literature 7), and a mild cavernous dermatitis pattern with eosinophilia in the blood and eosinophilic infiltration in the dermis is often observed, reflecting a type 2 immune response (Non-Patent Literature 2). Furthermore, serum interleukin-31 (IL-31) concentrations in CPUO patients have been reported to be higher than in healthy adults (Non-Patent Literature 8).

[0006] [Treatment methods for CPUO and their problems] Despite the severe itching associated with CPUO, effective treatments are scarce due to the lack of understanding of its pathophysiology. While topical steroids and antihistamines have been frequently used, they have shown little effect on CPUO (Non-Patent Documents 9, 10), and treatment remains challenging, with some patients not experiencing improvement in itching even with immunosuppressant therapy (Non-Patent Document 3). Although there are reports of dupilumab (Non-Patent Documents 11, 12), pregabalin (Non-Patent Document 13), and μ-opioid antagonists (Non-Patent Document 14) being effective for CPUO when used off-label, the number of cases is small, and the level of evidence for all of these is low. As mentioned above, there is no established treatment for CPUO, so there is a need for effective and safe therapeutic drugs with novel mechanisms of action. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Sonja Stander, Elke Weisshaar, Thomas Mettang, Jacek C Szepietowski, Earl Carstens, Akihiko Ikoma, et al: Clinical Classification of Itch: a Position Paper of the International Forum for the Study of Itch, Acta Dermato-Venereologica, 2007; 87: 291-294. [Non-Patent Document 2] Kim BS, Berger TG, Yosipovitch G. Chronic pruritus of unknown origin (CPUO): Uniform nomenclature and diagnosis as a pathway to standardized understanding and treatment. Journal of the American Academy of Dermatology. 2019 Jun 22;81(5):1223-1224 [Non-Patent Document 3] Ishi, Yozo. The reality and treatment of Chronic pruritus of unknown origin (CPUO). Japanese Journal of Dermatology. 2022;132(4):639-642. [Non-Patent Document 4] Elke Weisshaar, Florence Dalgard. Epidemiology of Itch: Adding to the Burden of Skin Morbidity. Acta dermato-Venereologica. 2009; 89(4):339-350. [Non-Patent Document 5] Berger TG, Steinhoff M. Pruritus in elderly patients with eruptions of senescence. Seminars in Cutaneous Medicine and Surgery. 2011 Jun 1;30(2):113-117.

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[0008] The inventions in this disclosure have been made in view of the above circumstances and, in one embodiment, aim to provide a new means for treating CPUO. In a particular embodiment, the inventions in this disclosure aim to provide a new means for treating CPUO that is not adequately treated by existing therapies. [Means for solving the problem]

[0009] The inventors investigated the efficacy and safety of nemolizumab, a humanized anti-human IL-31 receptor A (IL-31RA) monoclonal antibody, in patients with CPUO and found that the antibody is effective in treating or preventing CPUO.

[0010] This disclosure is based on such findings and includes, but is not limited to, the following exemplary aspects. [A1] A prophylactic or therapeutic agent for chronic pruritus of unknown cause (CPUO) in the target population, containing an antibody against IL-31 receptor A as an active ingredient. [A2] The prophylactic or therapeutic agent according to [A1], wherein the antibody is an antibody having neutralizing activity against IL-31 receptor A. [A3] The antibody is (1) An antibody comprising a heavy chain variable region containing a CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region containing a CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) An antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) An antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10 which is the prophylactic or therapeutic agent described in [A1] or [A2]. [A4] The prophylactic or therapeutic agent according to any one of [A1] to [A3], wherein the CPUO is a CPUO with insufficient efficacy in existing treatments. [A5] The prophylactic or therapeutic agent according to any one of [A1] to [A4], wherein the subject is a CPUO patient with insufficient efficacy with oral antihistamines or anti-allergy drugs, or a CPUO patient who cannot take them. [A6] The prophylactic or therapeutic agent according to any one of [A1] to [A5], wherein the subject is a CPUO patient with moderate to severe pruritus. [A7] The prophylactic or therapeutic agent according to any one of [A1] to [A6], wherein the subject is a CPUO patient with a pruritus score of ³3. [A8] The prophylactic or therapeutic agent according to any one of [A1] to [A7], wherein the subject is a CPUO patient with a Peak pruritus-NRS [PP-NRS] of ³5. [A9] The prophylactic or therapeutic agent according to any one of [A1] to [A8], wherein the subject is a CPUO patient with a pruritus score of ³3 and a Peak pruritus-NRS [PP-NRS] of at least 5. [A10] The subject is (i) at least two of the three sites of the upper limb, lower limb, and trunk (ii) only the head, or (iii) only the genital area A preventive or therapeutic agent according to any one of [A1] to [A9], which has an unexplained chronic pruritus in any one of the following: [A11] A preventive or therapeutic agent according to any one of [A1] to [A9], wherein the subject has an unexplained chronic pruritus in at least two of the three parts: the upper limb, the lower limb, and the trunk. [A12] A preventive or therapeutic agent according to any one of [A1] to [A9], wherein the subject has an unexplained chronic pruritus only in the head. [A13] A preventive or therapeutic agent according to any one of [A1] to [A9], wherein the subject has an unexplained chronic pruritus only in the genital area. [A14] The dosage of the antibody against the IL-31 receptor A per administration is 0.1 mg to 1000 mg / body, or 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, or about 90 mg. A preventive or therapeutic agent according to any one of [A1] to [A13]. [A15] The preventive or therapeutic agent is used so as to be administered to the subject 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. A preventive or therapeutic agent according to any one of [A1] to [A14]. [A16] A preventive or therapeutic agent according to any one of [A1] to [A15], which contains an antibody against the IL-31 receptor A at 30 mg or 60 mg. [A17] The preventive or therapeutic agent is used so as to be administered to the subject once every four weeks. A preventive or therapeutic agent according to any one of [A1] to [A16]. [A18] The antibody against the IL-31 receptor A is administered to the subject at 60 mg / body per administration every four weeks. A preventive or therapeutic agent according to any one of [A1] to [A17]. [A19] A prophylactic or therapeutic agent according to any of [A1] to [A17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 60 mg / body for the first dose and 30 mg / body per dose every four weeks thereafter. [A20] A prophylactic or therapeutic agent according to any one of [A1] to [A17], wherein an antibody against the IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. [A21] A prophylactic or therapeutic agent described in any of [A1] to [A20] that shows improvement in at least one of the following indicators compared to before administration: (a) Itch score (b) Peak pruritus-NRS (PP-NRS) (c) Sleep Disorder Scale (d) DLQI score (e) CDLQI score (f) Total ISI score (g) 5-D Itch Scale score [A22] The prophylactic or therapeutic agent according to any of [A1] to [A21], wherein the CPUO has an itching score of 3 or higher, and four months after administration of the antibody, the itching score improves to 1.8, or improves by 1.2 or more compared to before administration. [A23] The prophylactic or therapeutic agent according to any of [A1] to [A22], wherein the CPUO is 5 or higher on the NRS scale for pruritus, and four months after administration of the antibody, the NRS score for pruritus improves by 3 or more compared to before administration.

[0011] [B1] A method for preventing or treating chronic pruritus of unknown cause (CPUO) in a subject, comprising administering an antibody against IL-31 receptor A to the subject. [B2] The method according to [B1], wherein the antibody is an antibody having neutralizing activity against IL-31 receptor A. [B3] The antibody is (1) An antibody comprising a heavy chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6; (2) An antibody comprising a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8; or (3) An antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO: 10. The method according to [B1] or [B2]. [B4] The method according to any one of [B1] to [B3], wherein the CPUO is a CPUO that is not adequately controlled by existing treatments. [B5] The method according to any of [B1] to [B4], wherein the subject is a CPUO patient whose condition is not adequately controlled by oral antihistamines or anti-allergic drugs, or a CPUO patient who is unable to take such drugs. [B6] The method according to any one of [B1] to [B5], wherein the subject is a CPUO patient with moderate to severe pruritus. [B7] The method according to any of [B1] to [B6], wherein the subject is a CPUO patient with an itching score of 3 or higher. [B8] The method according to any of [B1] to [B7], wherein the subject is a CPUO patient with a Peak pruritus-NRS [PP-NRS] of 5 or higher. [B9] The method according to any one of [B1] to [B8], wherein the subject is a CPUO patient whose itching score is 3 or higher and whose Peak pruritus-NRS [PP-NRS] is 5 or higher. [B10] The above object is (i) At least two of the three areas: upper limbs, lower limbs, and trunk. (ii) Head only, or (iii) Genitals only The method according to any of [B1] to [B9] for any of the following, which involves chronic itching of unknown cause. [B11] The method according to any one of [B1] to [B9], wherein the subject has chronic itching of unknown cause in at least two of the three areas of the upper limbs, lower limbs, and trunk. [B12] The method according to any one of [B1] to [B9], wherein the subject has chronic itching of unknown cause only on the head. [B13] The method according to any one of [B1] to [B9], wherein the subject has chronic itching of unknown cause only in the genital area. [B14] The method according to any of [B1] to [B13], wherein the dose of the antibody against the IL-31 receptor A per dose is 0.1 mg to 1000 mg / body, or approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, or approximately 90 mg. [B15] The method according to any one of [B1] to [B14], wherein the antibody against the IL-31 receptor A is administered to the subject 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. [B16] The method according to any one of [B1] to [B15], wherein the dose of the antibody against the IL-31 receptor A administered per dose is 30 mg or 60 mg. [B17] The method according to any one of [B1] to [B16], wherein the antibody against the IL-31 receptor A is administered to the subject once every four weeks. [B18] The method according to any one of [B1] to [B17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks. [B19] The method according to any of [B1] to [B17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 60 mg / body for the first dose and 30 mg / body per dose every four weeks thereafter. [B20] The method according to any one of [B1] to [B17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. [B21] The method described in any of [B1] to [B20], which shows improvement in at least one of the following indicators compared to before administration: (a) Itch score (b) Peak pruritus-NRS (PP-NRS) (c) Sleep Disorder Scale (d) DLQI score (e) CDLQI score (f) Total ISI score (g) 5-D Itch Scale score [B22] The method according to any of [B1] to [B21], wherein the CPUO has an itching score of 3 or higher, and four months after administration of the antibody, the itching score improves to 1.8, or improves by 1.2 or more compared to before administration. [B23] The method according to any one of [B1] to [B22], wherein the CPUO has an pruritus NRS score of 5 or higher, and four months after administration of the antibody, the pruritus NRS score improves by 3 or more compared to before administration.

[0012] [C1] An antibody against IL-31 receptor A for use in the prevention or treatment of chronic pruritus of unknown cause (CPUO) in the subject. [C2] The antibody according to [C1], wherein the antibody is an antibody having neutralizing activity against IL-31 receptor A. [C3] The antibody is (1) An antibody comprising a heavy chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6; (2) An antibody comprising a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8; or (3) An antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO: 10. The antibody described in [C1] or [C2]. [C4] The antibody described in any of [C1] to [C3], wherein the CPUO is a CPUO that is inadequately controlled by existing treatments. [C5] The antibody described in any of [C1] to [C4], wherein the subject is a CPUO patient whose condition is not adequately controlled by oral antihistamines or anti-allergic drugs, or a CPUO patient who is unable to take such drugs. [C6] The antibody described in any of [C1] to [C5], wherein the subject is a CPUO patient with moderate to severe pruritus. [C7] The antibody described in any of [C1] to [C6], wherein the subject is a CPUO patient with an itching score of 3 or higher. [C8] The antibody described in any of [C1] to [C7], wherein the subject is a CPUO patient with a Peak pruritus-NRS [PP-NRS] of 5 or higher. [C9] The antibody described in any of [C1] to [C8], wherein the subject is a CPUO patient with an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher. [C10] The above object is (i) At least two of the three areas: upper limbs, lower limbs, and trunk. (ii) Head only, or (iii) Genitals only An antibody described in any of [C1] to [C9], which is present in any of the following cases with chronic itching of unknown cause. [C11] The antibody described in any of [C1] to [C9], wherein the subject has chronic itching of unknown cause in at least two of the three sites: the upper limbs, lower limbs, and trunk. [C12] The antibody described in any of [C1] to [C9], wherein the subject has chronic itching of unknown cause only on the head. [C13] The antibody described in any of [C1] to [C9], wherein the subject has chronic itching of unknown cause only in the genital area. [C14] The antibody described in any of [C1] to [C13], wherein the dose of the antibody against the IL-31 receptor A per administration is 0.1 mg to 1000 mg / body, or approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, or approximately 90 mg. [C15] An antibody according to any one of [C1] to [C14], characterized in that it is used to administer to a target once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. [C16] The antibody according to any one of [C1] to [C15], wherein the dose of the antibody against the IL-31 receptor A per administration is 30 mg or 60 mg. [C17] An antibody according to any one of [C1] to [C16], characterized in that it is used to be administered to a subject once every four weeks. [C18] An antibody described in any of [C1] to [C17], administered to the subject at a dose of 60 mg / body every four weeks. [C19] The antibody described in any of [C1] to [C17] is administered to the subject at a dose of 60 mg / body for the first dose, and 30 mg / body every four weeks thereafter. [C20] The antibody described in any of [C1] to [C17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. [C21] An antibody listed in any of [C1] to [C20] that shows improvement in at least one of the following indicators compared to before administration: (a) Itch score (b) Peak pruritus-NRS (PP-NRS) (c) Sleep Disorder Scale (d) DLQI score (e) CDLQI score (f) Total ISI score (g) 5-D Itch Scale score [C22] The antibody described in any of [C1] to [C21], wherein the CPUO has an itchiness score of 3 or higher, and four months after administration of the antibody, the itchiness score improves to 1.8, or improves by 1.2 or more compared to before administration. [C23] The antibody described in any of [C1] to [C22], wherein the CPUO is 5 or higher on the pruritus NRS scale, and four months after administration of the antibody, the pruritus NRS score improves by 3 or more compared to before administration.

[0013] [D1] Use of an antibody against IL-31 receptor A in the manufacture of a pharmaceutical product for the prevention or treatment of chronic pruritus of unknown cause (CPUO) in a subject. [D2] The use according to [D1], wherein the antibody is an antibody having neutralizing activity against IL-31 receptor A. [D3] The antibody is (1) An antibody comprising a heavy chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6; (2) An antibody comprising a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8; or (3) An antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO: 10. The use described in [D1] or [D2]. [D4] Use as described in any of [D1] to [D3], wherein the CPUO is a CPUO that is not adequately controlled by existing treatments. [D5] Use as described in any of [D1] to [D4], wherein the subject is a CPUO patient whose condition is not adequately controlled by oral antihistamines or anti-allergic drugs, or a CPUO patient who is unable to take such drugs. [D6] Use as described in any of [D1] to [D5], wherein the subject is a CPUO patient with moderate to severe pruritus. [D7] Use as described in any of [D1] to [D6], wherein the subject is a CPUO patient with an itching score of 3 or higher. [D8] Use as described in any of [D1] to [D7], wherein the subject is a CPUO patient with a Peak pruritus-NRS [PP-NRS] of 5 or higher. [D9] Use as described in any of [D1] to [D8], wherein the subject is a CPUO patient with an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher. [D10] The above object is (i) At least two of the three areas: upper limbs, lower limbs, and trunk. (ii) Head only, or (iii) Genitals only Use as described in any of [D1] to [D9] for chronic itching of unknown cause in any of the following cases. [D11] Use according to any of [D1] to [D9], wherein the subject has chronic itching of unknown cause in at least two of the three areas of the upper limbs, lower limbs, and trunk. [D12] Use according to any of [D1] to [D9], wherein the subject has chronic itching of unknown cause only on the head. [D13] Use according to any of [D1] to [D9], wherein the subject has chronic itching of unknown cause only in the genital area. [D14] Use as described in any of [D1] to [D13], wherein the dose of the antibody against the IL-31 receptor A per administration is 0.1 mg to 1000 mg / body, or approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, or approximately 90 mg. [D15] The use described in any of [D1] to [D14], wherein the pharmaceutical is administered to the subject 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. [D16] The use described in any of [D1] to [D15], wherein the dose of the antibody against IL-31 receptor A per administration is 30 mg or 60 mg. [D17] The use described in any of [D1] to [D16], wherein the pharmaceutical agent is administered to the subject once every four weeks. [D18] The use described in any of [D1] to [D17], wherein the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks. [D19] The use described in any of [D1] to [D17], wherein the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body for the first dose and 30 mg / body per dose every four weeks thereafter. [D20] The use described in any of [D1] to [D17], wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. [D21] Use as described in any of [D1] to [D20], showing improvement in at least one of the following indicators compared to before administration: (a) Itch score (b) Peak pruritus-NRS (PP-NRS) (c) Sleep Disorder Scale (d) DLQI score (e) CDLQI score (f) Total ISI score (g) 5-D Itch Scale score [D22] The use described in any of [D1] to [D21], wherein the CPUO has an itching score of 3 or higher, and four months after administration of the antibody, the itching score improves to 1.8, or improves by 1.2 or more compared to before administration. [D23] The use described in any of [D1] to [D22], wherein the CPUO is 5 or higher on the pruritus NRS scale, and four months after administration of the antibody, the pruritus NRS score improves by 3 or more compared to before administration.

[0014] [E1] Nemolizumab for use in the prevention or treatment of CPUO in the target population. [E2] Nemolizumab for use in the prevention or treatment of CPUO in patients who are inadequately controlled by existing therapies. [E3] Nemolizumab for use in the prevention or treatment of CPUO in CPUO patients who are not adequately controlled by oral antihistamines or antiallergic drugs, or who are unable to take such drugs. [E4] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with moderate to severe pruritus. [E5] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with an itching score of 3 or higher. [E6] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in patients with a Peak pruritus-NRS [PP-NRS] of 5 or higher. [E7] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher. [E8] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic pruritus of unknown cause in at least two of three sites: the upper limbs, lower limbs, and trunk. [E9] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with chronic itching of unknown cause confined to the scalp. [E10] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with chronic pruritus of unknown cause confined to the genital area. [E11] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in subjects, wherein 30 mg is administered to the subject once every four weeks. [E12] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in subjects, wherein 60 mg is administered to the subject once every four weeks. [E13] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in subjects, wherein the subject is administered 60 mg as the first dose and 30 mg every four weeks thereafter. [E14] Nemolizumab for use in the prevention or treatment of CPUO in CPUO patients who are not adequately controlled by oral antihistamines or antiallergic drugs, or who are unable to take such drugs, wherein 30 mg is administered to the patient once every four weeks. [E15] Nemolizumab for use in the prevention or treatment of CPUO in CPUO patients who are not adequately controlled by oral antihistamines or antiallergic drugs, or who are unable to take such drugs, wherein 60 mg is administered to the patient once every four weeks. [E16] Nemolizumab for use in the prevention or treatment of CPUO in CPUO patients who are not adequately controlled by oral antihistamines or antiallergic drugs, or who are unable to take such drugs, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E17] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with moderate to severe pruritus, wherein 30 mg is administered to the patient once every four weeks. [E18] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with moderate to severe pruritus, wherein 60 mg is administered to the patient once every four weeks. [E19] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with moderate to severe pruritus, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E20] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients with an itching score of 3 or higher, wherein 30 mg is administered to the patient once every four weeks. [E21] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients with an itching score of 3 or higher, wherein 60 mg is administered to the patient once every four weeks. [E22] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients with an itching score of 3 or higher, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E23] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in patients with a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein 30 mg is administered to the patient once every four weeks. [E24] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in patients with a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein 60 mg is administered to the patient once every four weeks. [E25] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in patients with a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E26] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients having an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein 30 mg is administered to the patient once every four weeks. [E27] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients having an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein 60 mg is administered to the patient once every four weeks. [E28] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatment) in CPUO patients with an itching score of 3 or higher and a Peak pruritus-NRS [PP-NRS] of 5 or higher, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E29] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients having chronic pruritus of unknown cause in at least two of three sites: the upper limbs, lower limbs, and trunk, wherein 30 mg is administered to the patient once every four weeks. [E30] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients having chronic pruritus of unknown cause in at least two of three sites: the upper limbs, lower limbs, and trunk, wherein 60 mg is administered to the patient once every four weeks. [E31] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic pruritus of unknown cause in at least two of three sites: the upper limbs, lower limbs, and trunk, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E32] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic itching of unknown cause confined to the scalp, wherein 30 mg is administered to the patient once every four weeks. [E33] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic itching of unknown cause confined to the scalp, wherein 60 mg is administered to the patient once every four weeks. [E34] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with chronic pruritus of unknown cause confined to the scalp, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [E35] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic itching of unknown cause only in the genital area, wherein 30 mg is administered to the patient once every four weeks. [E36] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients who have chronic itching of unknown cause confined to the genital area, wherein 60 mg is administered to the patient once every four weeks. [E37] Nemolizumab for use in the prevention or treatment of CPUO (optionally, CPUO that is inadequately controlled by existing treatments) in CPUO patients with chronic pruritus of unknown cause confined to the genital area, wherein the patient is administered 60 mg initially and 30 mg once every four weeks thereafter. [Modes for carrying out the invention]

[0015] [Detailed explanation] In one embodiment, the Disclosure provides a prophylactic or therapeutic agent for CPUO (also referred to herein as a pharmaceutical composition for the prophylactic or therapeutic of CPUO) containing an antibody against IL-31 receptor A as an active ingredient. In another embodiment, the Disclosure relates to a method for the prophylactic or therapeutic of CPUO, comprising administering an antibody against IL-31 receptor A. In yet another embodiment, the Disclosure relates to an antibody against IL-31 receptor A for use in the prophylactic or therapeutic of CPUO. In yet another embodiment, the Disclosure relates to the use of an antibody against IL-31 receptor A in the manufacture of a pharmaceutical for the prophylactic or therapeutic of CPUO. In this specification, the various embodiments of the Disclosure described above may be collectively referred to as the Prophylactic or Therapeutic Agent or the Prophylactic or Therapeutic Method of the Disclosure. The subjects receiving prevention or treatment with the Prophylactic or Therapeutic Agent or the Prophylactic or Therapeutic Method of the Disclosure are subjects at risk of having CPUO, or subjects who have had CPUO, and in certain embodiments, CPUO patients who are not adequately controlled by oral antihistamines or anti-allergic drugs, or who are unable to take them.

[0016] In certain embodiments, CPUO is a CPUO that is inadequately controlled by existing therapies. In certain embodiments, the antibody against IL-31 receptor A is (1) an antibody comprising a heavy chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO: 10. In certain embodiments, the antibody against IL-31 receptor A is nemolizumab. In certain embodiments, the antibody against IL-31 receptor A is administered at a dose of 30 mg / body or 60 mg / body per dose (per single dose). In certain embodiments, antibodies against IL-31 receptor A are administered every four weeks. In certain embodiments, antibodies against IL-31 receptor A are administered subcutaneously. In certain embodiments, antibodies against IL-31 receptor A are administered to patients with moderate to severe pruritus. In certain embodiments, antibodies against IL-31 receptor A are administered to patients with an itchiness score of 3 or higher. In certain embodiments, antibodies against IL-31 receptor A are administered to patients with a PP-NRS score of 5 or higher. In certain embodiments, antibodies against IL-31 receptor A are administered to patients with an itchiness score of 3 or higher AND a PP-NRS score of 5 or higher.

[0017] [Chronic pruritus of unknown origin (CPUO)] "Chronic pruritus of unknown cause (CPUO)" is defined as chronic pruritus in which the etiology cannot be identified even after excluding various primary skin diseases such as atopic dermatitis (AD) and prurigo nodule, as well as systemic diseases including chronic kidney disease, hepatobiliary tract disease, neurological disorders, pregnancy, and infection (Non-Patent Literature 2). Chronic pruritus of unknown cause (CPUO) includes, for example, chronic pruritus that is not associated with primary skin lesions, pruritus associated with visceral diseases, neurogenic or psychogenic pruritus, or drug-induced pruritus. In this specification, "chronic pruritus" means pruritus that lasts for six weeks or more, in accordance with the definition of the International Forum for the Study of Itch (IFSI) (Non-Patent Literature 1).

[0018] [IL-31] IL-31 is a new member of the IL-6 cytokine family and was initially reported as an inducer of mouse dermatitis. IL-31 is primarily produced by Th2 cells but is expressed in various cell types, including fibroblasts, keratinocytes, and macrophages. When IL-31 binds to the IL-31 receptor complex on the cell surface, it activates JAK / STAT, PI3K / AKT, and other intracellular signaling pathways, leading to a broad immune response.

[0019] The IL-31 receptor complex is a heterodimer consisting of "IL-31 receptor A (IL-31RA)" and "oncostatin M receptor." While the oncostatin M receptor is also present in the receptor complex for oncostatin M, IL-31RA is specific to the IL-31 receptor. IL-31 primarily binds to IL-31RA, one of these two receptor subunits.

[0020] [Anti-IL-31 receptor A antibody] In this specification, "anti-IL-31 receptor A antibody" and "antibody against IL-31 receptor A" are used synonymously and refer to an antibody that has the ability to specifically bind to IL-31 receptor A (IL-31RA). In relation to the invention of this disclosure, the antibody against IL-31 receptor A is preferably an antibody having neutralizing activity against IL-31 receptor A. In this specification, "neutralizing activity against IL-31 receptor A" is an activity that inhibits the binding of IL-31 receptor A to its ligand IL-31, and preferably an activity that suppresses physiological activity based on IL-31 receptor A. Therefore, an "antibody having neutralizing activity against IL-31 receptor A" can inhibit the binding of IL-31RA to IL-31, thereby suppressing, inhibiting, or blocking intracellular signal transduction mediated by IL-31RA.

[0021] In this specification, "antibody" refers to a molecule that specifically binds to a particular antigenic determinant (epitope), and includes, but is not limited to, various antibody structures, including monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), and antibody fragments.

[0022] In relation to the inventions of this disclosure, the antibody against IL-31RA is preferably an antibody against mammalian IL-31RA, and more preferably an antibody against human IL-31RA. An example of a neutralizing antibody against human IL-31RA is nemolizumab. In clinical trials, nemolizumab has been shown to improve the symptoms of atopic dermatitis. Nemolizumab comprises a heavy chain variable region containing CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region containing CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6. Nemolizumab also comprises a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8. Furthermore, nemolizumab comprises a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO: 10.

[0023] [Dosage and usage] In one non-limiting embodiment, for subjects affected or at risk of developing CPUO, such as adult and / or child humans, the dosage is 0.1 mg to 1000 mg / body, for example, 0.2 mg to 360 mg / body, preferably, for example, 5 mg to 100 mg / body, 5 mg to 75 mg / body, 5 mg to 60 mg / body, 5 mg to 30 mg / body, 5 mg to 20 mg / body, 10 mg to 100 mg / body, 10 mg to 75 mg / body, 10 mg to 60 mg / body, 10 mg~40mg / body, 10mg~39.5mg / body, 10mg~39mg / body, 10mg~38.5mg / body, 10mg~38mg / body, 10mg~37.5mg / body, 15mg~100mg / body, 15mg~ 75mg / body, 15mg~50mg / body, 15mg~40mg / body, 15mg~39.5mg / body, 15mg~39mg / body, 15mg~38.5mg / body, 15mg~38mg / body, 15mg~37.5mg / body, 17.5mg~100mg / body, 17.5mg~75mg / body, 17.5mg~50mg / body, 17.5mg~40mg / body, 17.5mg~39.5mg / body, 17.5mg~39mg / body, 17.5mg~38.5mg / body, 17.5mg~38mg / body, 17.5mg~37.5mg / body, 20mg~100mg / body, 20mg~75mg / body, 20mg~50mg / body, 20mg~40mg / body, 20 mg~39.5mg / body, 20mg~39mg / body, 20mg~38.5mg / body, 20mg~38mg / body, 20mg~37.5mg / body, 22.5mg~100mg / body, 22.5mg~75mg / body, 2 2.5mg~50mg / body, 22.5mg~40mg / body, 22.5mg~39.5mg / body, 22.5mg~39mg / body, 22.5mg~38.5mg / body, 22.5mg~38mg / body, 22.5mg~37.5mg / body、25mg~500mg / body、25mg~200mg / body、25mg~120mg / body、25mg~110mg / body、25mg~100mg / body、25mg~90mg / body、25mg~80mg / body、25mg~79mg / body、25mg~78mg / body、25mg~77mg / body、25mg~76mg / body、25mg~75mg / body、25mg~74mg / body、25mg~73mg / body、25mg~72mg / body、25mg~71mg / body、25mg~70mg / body、25mg~50mg / body、30mg~50mg / body、30mg~75mg / body、30mg~100mg / body、30mg~150mg / body、30mg~200mg / body、30mg~250mg / body、30mg~300mg / body、40mg~70mg / body、40mg~71mg / body、40mg~72mg / body、40mg~73mg / body、40mg~74mg / body、40mg~75mg / body、40mg~76mg / body、40mg~77mg / body、40mg~78mg / body、40mg~79mg / body、40mg~80mg / body、40mg~90mg / body、40mg~100mg / body、40mg~110mg / body、40mg~120mg / body、42.5mg~70mg / body、42.5mg~71mg / body、42.5mg~72mg / body、42.5mg~73mg / body、42.5mg~74mg / body、42.5mg~75mg / body、42.5mg~76mg / body、42.5mg~77mg / body、42.5mg~78mg / body、42.5mg~79mg / body、42.5mg~80mg / body、42.5mg~90mg / body、42.5mg~100mg / body、42.5mg~110mg / body、42.5mg~120mg / body、45mg~70mg / body、45mg~71mg / body、45mg~72mg / body、45mg~73mg / body、45mg~74mg / body、45mg~75mg / body、45mg~76mg / body、45mg~77mg / body、45mg~78mg / body、45mg~79mg / body、45mg~80mg / body、45mg~90mg / body、45mg~100mg / body、45mg~110mg / body、45mg~120mg / body、47.5mg~70mg / body、47.5mg~71mg / body、47.5mg~72mg / body、47.5mg~73mg / body、47.5mg~74mg / body、47.5mg~75mg / body、47.5mg~76mg / body、47.5mg~77mg / body、47.5mg~78mg / body、47.5mg~79mg / body、47.5mg~80mg / body、47.5mg~90mg / body、47.5mg~100mg / body、47.5mg~110mg / body、47.5mg~120mg / body、50mg~70mg / body、50mg~71mg / body、50mg~72mg / body、50mg~73mg / body、50mg~74mg / body、50mg~75mg / body、50mg~76mg / body、50mg~77mg / body、50mg~78mg / body、50mg~79mg / body、50mg~80mg / body、50mg~90mg / body、50mg~100mg / body、50mg~110mg / body、50mg~120mg / body、50mg~150mg / body、50mg~200mg / body、50mg~250mg / body、50mg~300mg / body、52.5mg~70mg / body、52.5mg~71mg / body、52.5mg~72mg / body、52.5mg~73mg / body、52.5mg~74mg / body、52.5mg~75mg / body、52.5mg~76mg / body、52.5mg~77mg / body、52.5mg~78mg / body、52.5mg~79mg / body、52.5mg~80mg / body、52.5mg~90mg / body、52.5mg~100mg / body, 52.5mg~110mg / body, 52.5mg~120mg / body, 75mg~100mg / body, 75mg~150mg / body, 75mg~200mg / body, 75mg~250mg / body, 75mg~300mg / body, 100mg~150mg / body, 100mg~200mg / body, 100mg~250mg / body, 100mg~3 A single dose selected from among 00 mg / body, 150 mg to 200 mg / body, 150 mg to 250 mg / body, 150 mg to 300 mg / body, 200 mg to 250 mg / body, 200 mg to 300 mg / body, etc., may be selected as the dose of the IL-31 antagonist (antibody against IL-31 receptor A) in this disclosure and repeatedly administered at the same dose interval as described below. In this case, the initial dose may be different from subsequent doses.

[0024] In a non-limiting embodiment, for subjects affected or at risk of developing CPUO, such as adult and / or child humans, the dosage may be 0.01 mg to 10 mg / kg, for example, 0.05 mg to 7.5 mg / kg, 0.075 mg to 5 mg / kg, or 0.1 mg to 3 mg / kg, preferably for example, 0.1 mg to 0.25 mg / kg, 0.1 mg to 0.3 mg / kg, 0.1 mg to 0.5 mg / kg, 0.1 mg to 0.75 mg / kg, 0.1 mg to 1 mg / kg, 0.1 mg to 1.5 mg / kg, 0.1 mg to 2 mg / kg, or 0.1 mg to 3 mg. / kg, 0.125mg~0.25mg / kg, 0.125mg~0.3mg / kg, 0.125mg~0.5mg / kg, 0.125mg~0.75mg / kg, 0.125mg~1mg / kg, 0.125mg~1.5mg / kg, 0.125mg~2mg / kg, 0.125mg~3mg / kg, 0.2mg~0.3mg / kg, 0.2mg~0.5mg / kg, 0.2mg~0.75mg / kg, 0.2mg~1mg / kg, 0.2mg~1.5mg / kg, 0.2mg~2mg / kg, 0.2mg~3mg / kg, 0.25mg~0.3mg / kg, 0.25mg~0.5mg / kg, 0.25mg~0.75mg / kg, 0.25mg~1mg / kg, 0.25mg~1.5mg / kg, 0.25mg~2mg / kg, 0.25mg~3mg / kg, 0.3mg~0.5mg / kg, 0.3mg~0.75mg / kg , 0.3mg~1mg / kg, 0.3mg~1.5mg / kg, 0.3mg~2mg / kg, 0.3mg~3mg / kg, 0.5mg~0.75mg / kg, 0.5mg~1mg / kg, 0.5mg~1.5mg / kg, 0.5mg~2mg / kg, 0.5mg~3mg / kg, 0.75mg~1mg / kg, 0.75mg~1.5mg / kg, 0.75mg~2mg / kg, 0.75mg~3mg / kg, 1mg~1.5mg / kg, 1mg~2mg / kg, 1mg~3mg / kg, 1.5mg~2mg / kg, 1.5mg~3mg / kg, 2mg~3 mg / kg, 0.15mg~2.9mg / kg, 0.2mg~2.8mg / kg, 0.25mg~2.7mg / kg, 0.3mg~2.6mg / kg, 0.35mg~2.5mg / kg, 0.4mg~2.4mg / kg, 0.425mg~2.3mg / kg, 0.45mg~2.A single dose selected from 2 mg / kg, 0.475 mg to 2.1 mg / kg, 0.5 mg to 2 mg / kg, or 0.5 mg to 1.5 mg / kg may be used as the dose of the IL-31 antagonist (antibody against IL-31 receptor A) in this disclosure, and repeated administration of the same dose at the same interval as described below.

[0025] In one embodiment, the anti-IL-31 receptor A antibody is administered to a subject (which may be referred to herein as a patient or subject) in doses of approximately 5 mg / body, 10 mg / body, 15 mg / body, 20 mg / body, 25 mg / body, 30 mg / body, 35 mg / body, 40 mg / body, 45 mg / body, 50 mg / body, 55 mg / body, 60 mg / body, 65 mg / body, 70 mg / body, 75 mg / body, 80 mg / body, 85 mg / body, or 90 mg / body. In a particular embodiment, the anti-IL-31 receptor A antibody is administered to a subject in doses of approximately 30 mg / body or 60 mg / body. In a particular embodiment, the anti-IL-31 receptor A antibody is administered to a subject in doses of approximately 60 mg / body for the first dose and approximately 30 mg / body for subsequent doses. In one embodiment, the anti-IL-31 receptor A antibody is administered to the subject approximately 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. In a specific embodiment, the anti-IL-31 receptor A antibody is administered to the subject approximately every four weeks. In one embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously. In certain embodiments, the anti-IL-31 receptor A antibody is administered subcutaneously to the subject at a dose of approximately 60 mg / body every four weeks. In certain embodiments, the anti-IL-31 receptor A antibody is administered subcutaneously to the subject at a dose of approximately 30 mg / body every four weeks. In another specific embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously to the subject at an initial dose of approximately 60 mg / body, followed by subsequent doses of approximately 30 mg / body every four weeks.

[0026] [Severity of CPUO] In one embodiment, the severity of CPUO can be evaluated using the Peak pruritus-NRS (PP-NRS), itch score, CPUO-based sleep disturbance scale, ISI score, DLQI / CDLQI score, 5-D Itch Scale score, etc. The evaluation methods for these evaluation items are known to those skilled in the art, and please refer to the examples in this specification.

[0027] [Target for treatment] In one embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure (which may also be referred to herein as the "treatment subject" or "subject") is a CPUO patient who is inadequately controlled by existing treatments (e.g., oral antihistamines or antiallergic drugs). In another embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient who is unable to receive existing treatments (e.g., taking oral antihistamines or antiallergic drugs). In one embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient with moderate to severe pruritus (e.g., a CPUO who is inadequately controlled by existing treatments). In one embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient with an itch score of 3 or higher (e.g., a CPUO who is inadequately controlled by existing treatments). In one embodiment, the patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient with a PP-NRS score of 5 or higher (e.g., a CPUO patient whose treatment is inadequate with existing therapies). In a particular embodiment, the patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient with an itchiness score of 3 or higher and a PP-NRS score of 5 or higher (e.g., a CPUO patient whose treatment is inadequate with existing therapies). In one embodiment, the patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a CPUO patient having chronic pruritus of unknown cause in at least two of three sites: (i) the upper limbs, lower limbs, and trunk; (ii) the head only; or (iii) the genitals only.

[0028] In one embodiment, patients receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure are patients who do not have pruritus associated with primary skin lesions, pruritus associated with visceral diseases, neurogenic or psychogenic pruritus, or drug-induced pruritus. In one embodiment, the patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a patient with diabetes mellitus, but diabetes mellitus is not the cause of the itching. In another embodiment, the patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a patient without diabetes mellitus. In one embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a patient with a concomitant iron deficiency. In another embodiment, a patient receiving the prophylactic or therapeutic agent of the Disclosure or the prophylactic or therapeutic method of the Disclosure is a patient without a concomitant iron deficiency.

[0029] [Efficacy] In one embodiment, the effectiveness of the preventive or therapeutic agent or preventive or therapeutic method of the Disclosure may be evaluated by the severity of CPUO compared to a control. In relation to the invention of the Disclosure, the control means, in one embodiment, the severity of CPUO in a patient or patient population who does not receive the preventive or therapeutic agent or treatment by the treatment method of the Disclosure. In a particular embodiment, the control means the severity of CPUO in a patient or patient population before receiving the preventive or therapeutic agent or treatment by the treatment method of the Disclosure.

[0030] In one embodiment, the preventive or therapeutic agent or preventive or therapeutic method of the present disclosure reduces the PP-NRS score by 2 to 5. In one embodiment, the preventive or therapeutic agent or preventive or therapeutic method of the present disclosure reduces the itching score by 1 to 2 or more.

[0031] All technical references cited herein are incorporated herein by reference in their entirety. [Examples]

[0032] The present disclosure will be described in detail below with reference to examples, but the present disclosure is not limited to these examples.

[0033] [Example 1] Anti-human IL-31RA antibody Nemolizumab (identified by the amino acid sequences of H chain: SEQ ID NO: 9; L chain: SEQ ID NO: 10), an anti-human IL-31RA antibody, was prepared by methods known to those skilled in the art. As described in WO2010 / 064697, nemolizumab has neutralizing activity against human IL-31RA and cynomolgus monkey IL-31RA.

[0034] [Example 2] A randomized, placebo-controlled, double-blind, dose-response, multicenter trial of nemolizumab in CPUO patients. [Purpose of the clinical trial] This study aims to confirm the efficacy and safety of administering nemolizumab 30 mg (60 mg for the first dose only) or 60 mg every four weeks (Q4W) for 16 weeks to CPUO patients, and to determine the optimal dose.

[0035] [Table 1]

[0036] To consider the impact of body weight on efficacy and to ensure the weight distribution is as even as possible across treatment groups, body weight (≥60 kg / ≤60 kg) was set as a stratification factor.

[0037] The use of the following medications may be permitted if the clinical trial physician deems it necessary. • Use oral antihistamines or anti-allergic drugs for CPUO in a fixed dosage and administration manner. • Use moisturizing and protective agents according to their prescribed usage instructions. • For secondary skin lesions caused by scratching, use topical corticosteroids (TCS) of the Strong class or lower in a fixed manner.

[0038] [Target Diseases] CPUO with insufficient response to existing treatments

[0039] [Selection Criteria] (1) Patients aged 13 years or older diagnosed with CPUO (2) Patients who fall under any of the following categories a) Generalized CPUO Patients who have chronic itching of unknown cause in at least two of the following three areas: upper limbs, lower limbs, and trunk. b) CPUO of the head or genitals Patients experiencing chronic itching of unknown cause, confined to either the scalp or genital area. However, this also includes patients experiencing chronic itching of unknown cause in areas other than the scalp or genital area, but whose condition is deemed by the clinical trial physician not to affect the assessment of scalp or genital itching. (3) Patients who fall under any of the following categories 1) Patients who have previously used oral antihistamines or anti-allergic drugs for CPUO for more than two weeks as directed by a physician, but whose condition was insufficiently improved (the physician determined that itching equivalent to an itchiness score of 3 or higher remained). 2) Patients who cannot take oral antihistamines or anti-allergic drugs (hypersensitivity / contraindications) (4) Patients who meet all of the following criteria on the start date of the screening period 1) Itch score of 3 or higher 2) PP-NRS is 5 or higher

[0040] [Exclusion criteria] (1) Patients undergoing hemodialysis or peritoneal dialysis (2) Patients who have any of the following itching symptoms a) Itching associated with primary skin lesions b) Itching associated with internal organ diseases c) Neurogenic or psychogenic pruritus d) Drug-induced itching * Even if the patient has a co-existing condition that may cause itching (such as diabetes or iron deficiency), they may be included if all of the following conditions are met. • The clinical trial physician has determined that the disease in question is not the primary cause of the itching. • The disease is well under control. • During the clinical trial period, the patient can continue appropriate treatment for the disease in accordance with the doctor's instructions. (3) Patients who received any of the following systemic drugs within 28 days from the start of randomization. a) Steroid drugs b) Immunosuppressants c) JAK inhibitors d) PDE4 inhibitors e) NK (neurokinin) 1 receptor antagonists f) Selective κ-opioid receptor agonists g) μ-opioid antagonists h) Gabapentin, pregabalin, mirogabalin i) Antidepressants j) The following herbal medicines ·Hot drink ·Orenkadokuto ·Goshisha Jinkigan Toki-inshi ·Hachimijiomaru ·Rokumimaru (4) Patients who underwent ultraviolet therapy or photodynamic therapy for the treatment of itching within 28 days from the start of randomization.

[0041] [Cancellation Criteria] If the cause of chronic pruritus is identified after the start of the clinical trial, the trial will be terminated for that subject.

[0042] [Investigational drug: nemolizumab] The investigational drug in this clinical trial, nemolizumab, is a humanized anti-human interleukin-31 receptor A (IL-31RA) monoclonal antibody that inhibits the binding of IL-31 to the interleukin-31 (IL-31) receptor and its downstream signaling. On March 28, 2022, "Michiga 60 mg subcutaneous injection syringe," an injectable formulation containing nemolizumab as the active ingredient, was approved for manufacture and sale for the treatment of pruritus associated with atopic dermatitis in adults and children aged 13 years and older (limited to cases where existing treatments are insufficient). On March 26, 2024, "Michiga Subcutaneous Injection 30 mg Vial," an injectable drug containing nemolizumab as the active ingredient, received manufacturing and marketing approval for the treatment of pruritus associated with nodular prurigo in patients aged 13 years and older (limited to cases where existing treatments are insufficient) and pruritus associated with atopic dermatitis in children aged 6 to under 13 years (limited to cases where existing treatments are insufficient).

[0043] [Comparator drug] This will be treated as a placebo.

[0044] [Method of administration] Each group will receive two 0.6 mL syringes of the administration solution (nemolizumab or placebo) slowly subcutaneously at 4-week intervals (Q4W). The administration site will be selected from the upper arm, abdomen, or thigh, choosing skin free from lesions. The first and second injection sites will be the same, separated by at least 5 cm.

[0045] [Contraindicated drugs and therapies] If the clinical trial physician determines that the use of the following drugs / therapies is necessary for CPUO, their use in a fixed dosage and administration method is permitted. (1) Oral antihistamines and antiallergic drugs for CPUO (2) Moisturizers and protective agents (3) Strong class or lower TCS for secondary skin lesions caused by scratching

[0046] [Rescue treatment] If, from Day 2 onward, secondary skin lesions caused by scratching worsen and the investigator determines this to be an adverse event, the investigator may, at their discretion, add TCS (regardless of rank) to the treatment for that adverse event.

[0047] [Evaluation items (exploratory evaluation items)] (1) The following time course up to 16 weeks after administration Weekly average PP-NRS score, weekly average itch score, weekly average sleep disturbance scale score based on CPUO, DLQI / CDLQI score, ISI total score, 5-D Itch Scale score (2) The following time course for each day up to 2 weeks after administration Sleep Disorder Scale using PP-NRS and CPUO

[0048] [Efficacy evaluation (patient evaluation)] The subjects will evaluate the following items. (1) PP-NRS (2) Itch score (3) CPUO scale for sleep disturbance

[0049] (1) PP-NRS To evaluate the efficacy of nemolizumab in relation to CPUO, the NRS, a commonly used pruritus assessment index in clinical trials, was adopted, and the time course of the maximum pruritus intensity (PP-NRS) over the past 24 hours up to 16 weeks after administration was recorded. In addition, to confirm the early improvement in pruritus, the time course of PP-NRS for each day up to 2 weeks after administration was recorded. Participants rate the severity of itching on an 11-point scale from "0 = no itching" to "10 = worst possible itching" based on their highest CPUO over the past 24 hours.

[0050] (2) Itch score It is recommended to evaluate pruritus using multiple assessment criteria, and we established an itch score that is commonly used in clinical trials to evaluate pruritus. Participants rate the severity of itching on a 5-point scale from "0 = none" to "4 = severe" according to Table 2, based on their maximum CPUO over the past 24 hours. If daytime and nighttime scores differ, the higher score should be selected.

[0051] [Table 2]

[0052] (3) CPUO scale for sleep disturbance Guidelines for the clinical evaluation of hypnotics emphasize the importance of appropriately assessing the improvement in subjective sleep disturbances in everyday living environments. To investigate patients' subjective evaluations of sleep using CPUO, a CPUO-based sleep disturbance scale was established. Furthermore, to confirm the effect of early pruritus relief on improving sleep disturbances, the time course of the CPUO-based sleep disturbance scale was recorded for each day up to two weeks after administration. Participants evaluate the degree of sleep disturbance based on CPUO (Coefficient of Sleep Oscillation) from the previous night on an 11-point scale ranging from "0 = no sleep problems" to "10 = unable to sleep at all."

[0053] [Efficacy evaluation (Patient QOL evaluation)] The subjects will evaluate the following items. (1) ISI (2) DLQI (3) CDLQI (4) 5-D Itch Scale

[0054] (1) ISI Guidelines for the clinical evaluation of sleep medications emphasize the importance of appropriately assessing the improvement of subjective sleep disorders in everyday living environments. To investigate patients' subjective assessments of sleep using the CPUO (Cognitive Pulmonary Occupation) scale, the ISI (Instantaneous Sleep Intake) was established. Participants assess the severity of their sleep disorder using the ISI questionnaire. (See Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001; 2(4): 297-307)

[0055] (2) DLQI The DLQI was established because it is a QOL scale specific to skin diseases and is widely used in clinical trials. For subjects aged 16 or older on the date of informed consent, the impact on their quality of life will be assessed using the DLQI questionnaire. (See Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: 210-216)

[0056] (3) CDLQI The CDLQI was established because it is a QOL scale specific to skin diseases and is widely used in clinical trials. For subjects under 16 years of age on the date of consent, the impact on quality of life will be assessed using the CDLQI questionnaire. (See Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): Initial validation and practical use. Br J Dermatol 1995; 132: 942-949)

[0057] (4) 5-D Itch Scale The 5-Ditch scale allows for the simple assessment and quantification of multiple aspects of pruritus, including duration, intensity, course, adverse effects, and physical distribution. Compared to widely used assessment scales such as VAS, it provides a more comprehensive evaluation of multiple elements associated with pruritus. It was developed to provide a more detailed assessment of the severity of pruritus in the underlying disease. Participants assessed the severity of their itching using the 5-D Itch Scale questionnaire. (See S. Elman, LS Hynan, V. Gabriel, MJ Mayo. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010 Mar; 162(3): 587-593) [Industrial applicability]

[0058] The present invention provides a novel means (a preventive or therapeutic agent, a pharmaceutical, or a pharmaceutical composition) for preventing or treating CPUO (particularly CPUO that is inadequately controlled by existing therapies), comprising an antibody against IL-31 receptor A as an active ingredient. The present invention further provides a method for preventing or treating CPUO (particularly CPUO that is inadequately controlled by existing therapies) by administering an antibody against IL-31 receptor A to a subject in need thereof.

Claims

1. A prophylactic or therapeutic agent for chronic pruritus of unknown cause (CPUO) in the target population, containing an antibody against IL-31 receptor A as an active ingredient.

2. The prophylactic or therapeutic agent according to claim 1, wherein the antibody is an antibody having neutralizing activity against IL-31 receptor A.

3. The aforementioned antibody (1) An antibody comprising a heavy chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 1, CDR2 having the amino acid sequence described in SEQ ID NO: 2, and CDR3 having the amino acid sequence described in SEQ ID NO: 3, and a light chain variable region including CDR1 having the amino acid sequence described in SEQ ID NO: 4, CDR2 having the amino acid sequence described in SEQ ID NO: 5, and CDR3 having the amino acid sequence described in SEQ ID NO: 6; (2) An antibody comprising a heavy chain variable region having the amino acid sequence described in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence described in SEQ ID NO: 8; or (3) An antibody comprising a heavy chain having the amino acid sequence described in SEQ ID NO: 9 and a light chain having the amino acid sequence described in SEQ ID NO:

10. The preventive or therapeutic agent according to claim 1 or 2.

4. The preventive or therapeutic agent according to claim 1 or 2, wherein the CPUO is a CPUO that is insufficiently controlled by existing treatments.

5. The preventive or therapeutic agent according to claim 1 or 2, wherein the target is a CPUO patient whose condition is not adequately controlled by oral antihistamines or anti-allergic drugs, or a CPUO patient who is unable to take such drugs.

6. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject is a CPUO patient with moderate to severe pruritus.

7. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject is a CPUO patient with an itching score of 3 or higher.

8. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject is a CPUO patient with a Peak pruritus-NRS [PP-NRS] score of 5 or higher.

9. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject is a CPUO patient whose itching score is 3 or higher and whose Peak pruritus-NRS [PP-NRS] is 5 or higher.

10. The aforementioned subject is, (i) At least two of the three areas: upper limbs, lower limbs, and trunk. (ii) Head only, or (iii) Genitals only A preventive or therapeutic agent according to claim 1 or 2, wherein any of the following has chronic itching of unknown cause.

11. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject has chronic itching of unknown cause in at least two of the three areas: the upper limbs, lower limbs, and trunk.

12. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject has chronic itching of unknown cause only on the head.

13. The preventive or therapeutic agent according to claim 1 or 2, wherein the subject has chronic itching of unknown cause only in the genital area.

14. The prophylactic or therapeutic agent according to claim 1 or 2, wherein the dose of the antibody against the IL-31 receptor A administered per dose is 0.1 mg to 1000 mg / body.

15. The preventive or therapeutic agent according to claim 1 or 2, characterized in that the preventive or therapeutic agent is used to administer to a target 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.

16. A prophylactic or therapeutic agent according to claim 1 or 2, comprising 30 mg or 60 mg of the antibody against the IL-31 receptor A.

17. The preventive or therapeutic agent according to claim 1 or 2, characterized in that the preventive or therapeutic agent is used to be administered to a subject once every four weeks.

18. The prophylactic or therapeutic agent according to claim 1 or 2, wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks.

19. The prophylactic or therapeutic agent according to claim 1 or 2, wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks.

20. The prophylactic or therapeutic agent according to claim 1 or 2, wherein the antibody against the IL-31 receptor A is administered to the subject at a dose of 60 mg / body for the first dose and 30 mg / body per dose every four weeks thereafter.

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