Treatment of chronic pruritus with unknown origin

Abstract

The present disclosure provides pharmaceutical compositions for preventing or treating chronic pruritus of unknown origin (CPUO), the pharmaceutical compositions including an anti-IL-31 receptor A antibody as an active ingredient.

Description

Atty. Dkt. No.: 105153-2851TREATMENT OF CHRONIC PRURITUS WITH UNKNOWN ORIGIN CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U. S. C. § 119(a) of J. P. Application No.2024-208081, filed November 29, 2024, the entire contents of which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to pharmaceutical compositions and methods for preventing or treating chronic pruritus of unknown origin (CPUO), the pharmaceutical compositions including an anti-IL-31 receptor A antibody as an active ingredient.BACKGROUND

[0003] Chronic pruritus is defined by the International Forum for the Study of Itch (IFSI) as itch that lasts 6 weeks or longer (NPL1), and chronic severe pruritus has significant adverse effects on quality of life (QOL). Its causes include various primary cutaneous disorders including atopic dermatitis (AD) and prurigo nodularis, and systemic diseases including chronic renal diseases, hepatobiliary diseases, nervous diseases, pregnancy and infection. However, there are cases of chronic pruritus where the disease cause cannot be identified even though such causative diseases are ruled out. It is proposed to define such chronic pruritus with unknown cause as chronic pruritus of unknown origin (CPUO) (NPL2).

[0004] For diagnosing CPUO, it is important to exclude primary cutaneous disorders or other underlying diseases that can cause itch. A subject is diagnosed as having CPUO if the causes cannot be identified after confirming, for example, disease history, examining cutaneous findings, performing blood examination (NPL3). However, scratching may cause secondary skin lesions such as scratch marks and pigmentation. The prevalence of CPUO among patients who show pruritus systemically is 3.6% to 44.5%, and is reported to be high for the elderly (NPL4).Atty. Dkt. No.: 105153-2851

[0005] It is reported that CPUO patients can have stronger itch compared to atopic dermatitis (AD) patients. In addition, CPUO patients often suffer from intense pruritus even when administered with a potent immunosuppressant, and this has significant adverse effects on their quality of life (QOL) (NPL3).

[0006] Clear causes that induce strong pruritus in CPUO are unknown, but the presence of cutaneous and systemic type 2 immune deviation has been suggested (NPLs 5, 6). The skin of CPUO patients has a gene pattern similar to that of AD patients (NPL7), reflecting type 2 immune response, and also often shows eosinophilia in the blood and a mild spongiotic dermatitis pattern accompanied by eosinophilic infiltration into dermis (NPL2). Moreover, the serum interleukin-31 (IL-31) concentration of CPUO patients has been reported to show higher values compared to that of healthy adults (NPL8).

[0007] Although CPUO is intensely pruritic, effective treatments are few due to its unknown pathophysiology. Topical steroids, antihistaminic agents and such, which have been frequently used conventionally but are generally not effective for treating CPUO (NPLs 9, 10), and even the administration of immunosuppressants does not improve pruritus in some patients, posing difficulties in treatment (NPL3). There have been reports that dupilumab (NPLs 11, 12), pregabalin (NPL13) and μ opioid antagonist (NPL14), can be effective for treating CPUO, but the evidence levels of successful treatment are low because of the low numbers of administered patients. As described above, there is no established therapy for CPUO, and thus an effective and safe therapeutic agent having novel action mechanism is desired.

[0008] [Non Patent Literature]

[0009] [NPL1] 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.[NPL2] Kim B. S., Berger T. G., 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): 1223-1224Atty. Dkt. No.: 105153-2851[NPL3] Yozo Ishiuji. Current Status and Therapy of Chronic Pruritus of Unknown Origin (CPUO). The Journal of Japanese Dermatological Association. 2022; 132(4): 639-642.[NPL4] Elke Weisshaar, Florence Dalgard. Epidemiology of Itch: Adding to the Burden of Skin Morbidity. Acta dermato-Venereologica. 2009; 89(4): 339-350.[NPL5] Berger T. G., Steinhoff M. Pruritus in elderly patients-eruptions of senescence.Seminars in cutaneous medicine and surgery. 2011 Jun 1; 30(2): 113-117.[NPL6] Adam Reich, Sonja Stander, Jacek C Szepietowski. Pruritus in the elderly. Clinics in Dermatology. 2010 Dec 10; 29: 15-23.[NPL7] Landon K Oetjen, Madison R Mack, Jing Feng, Timothy M Whelan, Haixia Niu, Changxiong J Guo, et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017 Sep 7; 171(1): 217-228.[NPL8] Kanin Salao, Kittisak Sawanyawisuth, Kengkart Winaikosol, Charoen Choonhakam, Suteerapom Chaowattanapanit. Interleukin-31 and Chronic Pruritus of Unknown Origin. Biomarker Insights. 2020 Jul 8; 15.1-4.[NPL9] Michael O'Donoghue, Michael D Tharp. Antihistamines and their role as antipruritics. Dermatologic Therapy. 2005 Jul 1; 18(4): 333-340.[NPL10] Matthew J. Zirwas, Mark P Seraly. Pruritus of unknown origin: A retrospective study. Journal of the American Academy of dermatology. 2001 Jan 1; 45(6): 892-896.[NPL11] Lisa L. Zhai, Kevin T. Savage, Connie C. Qiu, Annie Jin, Rodrigo Valdes-Rodriguez, Nicholas K. Mollanazar. Chronic Pruritus Responding to Dupilumab-A Case Series. Medicines. 2019 Jun 29; 6(3)[NPL12] Jiehyun Jeona, Fang Wang, Asima Badic, Brian S. Kim. Treatment of patients with chronic pruritus of unknown origin with dupilumab. Journal of dermatological Treatment. 2021 Feb 8; 33(3): 1754-1757.[NPL13] JaeIn Lee, DongHyek Jang, JooYoon Bae, HyeJung Jung, MiYoun Park, JiYoung Ahn. Efficacy of pregabalin for the treatment of chronic pruritus of unknown origin, assessed based on electric current perception threshold. Scientific Reports. 2020 Jan 23; 10(1): 1022.[NPL14] Ngoc Quan Phan, Jeffrey D Bernhard, Thomas A Luger, Sonja Stander. Antipruritic treatment with systemic μ-opioid receptor antagonists: A review. Journal of the American Academy of Dermatology. 2010 May 11; 63(4): 680-688.Atty. Dkt. No.: 105153-2851SUMMARY

[0010] Technical Problem: The present disclosure was made in view of the above circumstances. In one embodiment, an objective of the disclosure is to provide novel means for treating CPUO. Furthermore, In some embodiments, an objective of the present disclosure is to provide novel means for treating CPUO for which existing treatments are insufficiently effective.

[0011] Solution to Problem:

[0012] The present disclosure provides an investigation of the efficacy and safety of nemolizumab, a humanized anti-human IL-31 receptor A (IL-31RA) monoclonal antibody, in CPUO patients. The present disclosure found that the antibody was effective for treating or preventing CPUO.

[0013] The present disclosure is based on such findings, and specifically includes embodiments as exemplary described below, but is not limited thereto. The present disclosure relates to pharmaceutical compositions (preventive or therapeutic agents) for preventing or treating chronic pruritus of unknown origin (CPUO), the compositions (agents) comprising an antibody against interleukin-31 (herein below, IL-31) receptor A as an active ingredient. In another embodiment, the present disclosure relates to methods of preventing or treating CPUO, the methods comprising administering an antibody against IL-31 receptor A. In addition, in another embodiment, the present disclosure relates to antibodies against IL-31 receptor A for use in prevention or treatment of CPUO. Furthermore, in another embodiment, the present disclosure relates to uses of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating CPUO. In some embodiments, CPUO is CPUO for which existing treatments are insufficiently effective. In some embodiments, the antibody against IL-31 receptor A is nemolizumab.

[0014] In an aspect, the present disclosure provides preventive or therapeutic agent for chronic pruritus of unknown origin (CPUO) in a subject, the agent comprising an antibody against IL-31 receptor A as an active ingredient.Atty. Dkt. No.: 105153-2851

[0015] In some embodiments, the antibody is an antibody having a neutralizing activity against IL-31 receptor A. In some embodiments, the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0016] In some embodiments, the CPUO is CPUO for which an existing treatment is insufficiently effective.

[0017] In some embodiments, the subject is a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents. In some embodiments, the subject is a CPUO patient having pruritus of moderate or higher severity. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher. In some embodiments, the subject is a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher.

[0018] In some embodiments, the subject has chronic pruritus of unknown origin at any one of: (i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or (iii) only a pubic region.

[0019] In some embodiments, the subject has chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk. In some embodiments, the subject has chronic pruritus of unknown origin only at a head region. In some embodiments, the subject has chronic pruritus of unknown origin only at a pubic region.Atty. Dkt. No.: 105153-2851

[0020] In some embodiments, a dose of the antibody against IL-31 receptor A 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.

[0021] In some embodiments, the preventive or therapeutic agent is used such that the agent is administered to the subject once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks or once per eight weeks.

[0022] In some embodiments, the preventive or therapeutic agent as disclosed herein comprising 30 mg or 60 mg of the antibody against IL-31 receptor A.

[0023] In some embodiments, the preventive or therapeutic agent is used such that the agent is administered to the subject once per four weeks.

[0024] In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at an initial dose of 60 mg / body, and at a second and subsequent doses of 30 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks.

[0025] In some embodiments, the agent shows improvement in at least one of the following indexes compared to that before administration: (a) iItch score; (b) peak pruritus-NRS (PP-NRS); (c) sleep disturbance scale; (d) DLQI score; (e) CDLQI score; (f) ISI sum score; and (g) 5-D Itch Scale score.

[0026] In some embodiments, the CPUO is CPUO with an iItch score of 3 or higher, and the iItch score improves to 1.8 or improves by 1.2 or more compared to the score before administration of the antibody four months after the administration. In some embodiments, the CPUO is CPUO with a pruritus NRS of 5 or higher, and the pruritus NRS score improves by 3 or more compared to the score before administration of the antibody four months after the administration.Atty. Dkt. No.: 105153-2851

[0027] In an aspect, the present disclosure provides a method of preventing or treating chronic pruritus of unknown origin (CPUO) in a subject, the method comprising administering an antibody against IL-31 receptor A to the subject.

[0028] In some embodiments, the antibody is an antibody having a neutralizing activity against IL-31 receptor A. In some embodiments, the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0029] In some embodiments, the CPUO is CPUO for which an existing treatment is insufficiently effective. In some embodiments, the subject is a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents. In some embodiments, the subject is a CPUO patient having pruritus of moderate or higher severity. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher. In some embodiments, the subject is a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher. In some embodiments, the subject has chronic pruritus of unknown origin at any one of: (i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or (iii) only a pubic region. In some embodiments, the subject has chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk. In some embodiments, the subject has chronic pruritus of unknown origin only at a head region. In some embodiments, the subject has chronic pruritus of unknown origin only at a pubic region.Atty. Dkt. No.: 105153-2851

[0030] In some embodiments, a dose of the antibody against IL-31 receptor A 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.

[0031] In some embodiments, the antibody against IL-31 receptor A is administered to the subject once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks or once per eight weeks.

[0032] In some embodiments, a dose of the antibody against IL-31 receptor A is 30 mg or 60 mg. In some embodiments, the antibody against IL-31 receptor A is administered to the subject once per four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at an initial dose of 60 mg / body and at a second and subsequent doses of 30 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. In some embodiments, the subject shows improvement in at least one of the following indexes compared to that before administration: (a) iItch score; (b) peak pruritus-NRS (PP-NRS); (c) sleep disturbance scale; (d) DLQI score; (e) CDLQI score; (f) ISI sum score; and (g) 5-D Itch Scale score.

[0033] In some embodiments, the CPUO is CPUO with an iItch score of 3 or higher, and the iItch score improves to 1.8 or improves by 1.2 or more compared to the score before administration of the antibody four months after the administration. In some embodiments, the CPUO is CPUO with a pruritus NRS of 5 or higher, and the pruritus NRS score improves by 3 or more compared to the score before administration of the antibody four months after the administration.

[0034] In an aspect, the present disclosure provides an antibody against IL-31 receptor A for use in prevention or treatment of chronic pruritus of unknown origin (CPUO) in a subject.

[0035] In some embodiments, the antibody is an antibody having a neutralizing activity against IL-31 receptor A. In some embodiments, the antibody is: (1) an antibody comprisingAtty. Dkt. No.: 105153-2851a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0036] In some embodiments, the CPUO is CPUO for which an existing treatment is insufficiently effective.

[0037] In some embodiments, the subject is a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents. In some embodiments, the subject is a CPUO patient having pruritus of moderate or higher severity. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher. In some embodiments, the subject is a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher.

[0038] In some embodiments, the subject has chronic pruritus of unknown origin at any one of: (i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or (iii) only a pubic region.

[0039] In some embodiments, the subject has chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk. In some embodiments, the subject has chronic pruritus of unknown origin only at a head region. In some embodiments, the subject has chronic pruritus of unknown origin only at a pubic region.

[0040] In some embodiments, a dose of the antibody against IL-31 receptor A is 0.1 mg to 1000 mg / body, or about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, aboutAtty. Dkt. No.: 105153-285130 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.

[0041] In some embodiments, the antibody is used such that it is administered to the subject once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks or once per eight weeks.

[0042] In some embodiments, a dose of the antibody against IL-31 receptor A is 30 mg or 60 mg. In some embodiments, the antibody is used to be administered to the subject once per four weeks. In some embodiments, the antibody is administered to the subject at a dose of 60 mg / body every four weeks. In some embodiments, the antibody is administered to the subject at an initial dose of 60 mg / body and at a second or subsequent doses of 30 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. In some embodiments, the subject shows improvement in at least one of the following indexes compared to that before administration: (a) iItch score; (b) peak pruritus-NRS (PP-NRS); (c) sleep disturbance scale; (d) DLQI score; (e) CDLQI score; (f) ISI sum score; and (g) 5-D Itch Scale score.

[0043] In some embodiments, the CPUO is CPUO with an iItch score of 3 or higher, and the iItch score improves to 1.8 or improves by 1.2 or more compared to the score before administration of the antibody four months after the administration. In some embodiments, the CPUO is CPUO with a pruritus NRS of 5 or higher, and the pruritus NRS score improves by 3 or more compared to the score before administration of the antibody four months after the administration.

[0044] In an aspect, the present disclosure provides use of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating chronic pruritus of unknown origin (CPUO) in a subject.

[0045] In some embodiments, the antibody is an antibody having a neutralizing activity against IL-31 receptor A. In some embodiments, the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having theAtty. Dkt. No.: 105153-2851amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0046] In some embodiments, the CPUO is CPUO for which an existing treatment is insufficiently effective. In some embodiments, the subject is a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents. In some embodiments, the subject is a CPUO patient having pruritus of moderate or higher severity. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher. In some embodiments, the subject is a CPUO patient with a peak pruritus-NRS (PP-NRS) of 5 or higher. In some embodiments, the subject is a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS (PP-NRS) of 5 or higher.

[0047] In some embodiments, the subject has chronic pruritus of unknown origin at any one of: (i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or (iii) only a pubic region.

[0048] In some embodiments, the subject has chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk. In some embodiments, the subject has chronic pruritus of unknown origin only at a head region. In some embodiments, the subject has chronic pruritus of unknown origin only at a pubic region. In some embodiments, a dose of the antibody against IL-31 receptor A 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.

[0049] In an aspect, the present disclosure provides the use of the antibody in the manufacture of a medicament. In some embodiments, the medicament is administered to theAtty. Dkt. No.: 105153-2851subject once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks or once per eight weeks.

[0050] In some embodiments, wherein a dose of the antibody against IL-31 receptor A is 30 mg or 60 mg. In some embodiments, the medicament is administered to the subject once per four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at an initial dose of 60 mg / body and at a second and subsequent doses of 30 mg / body every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks. In some embodiments, the subject shows improvement in at least one of the following indexes compared to that before administration: (a) iItch score; (b) peak pruritus-NRS (PP-NRS); (c) sleep disturbance scale; (d) DLQI score; (e) CDLQI score; (f) ISI sum score; and (g) 5-D Itch Scale score.

[0051] In some embodiments, the CPUO is CPUO with an iItch score of 3 or higher, and the iItch score improves to 1.8 or improves by 1.2 or more compared to the score before administration of the antibody four months after the administration. In some embodiments, the CPUO is CPUO with a pruritus NRS of 5 or higher, and the pruritus NRS score improves by 3 or more compared to the score before administration of the antibody four months after the administration.

[0052] In an aspect, the present disclosure provides Nemolizumab for use in prevention or treatment of CPUO in a subject.

[0053] In some embodiments, for use in prevention or treatment of CPUO for which an existing treatment is insufficiently effective in a subject.

[0054] In some embodiments, for use in prevention or treatment of CPUO in a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents.Atty. Dkt. No.: 105153-2851

[0055] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having pruritus of moderate or higher severity.

[0056] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher.

[0057] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher.

[0058] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher.

[0059] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk.

[0060] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a head region.

[0061] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a pubic region.

[0062] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a subject, wherein nemolizumab is administered to the subject at a dose of 30 mg once per four weeks.Atty. Dkt. No.: 105153-2851

[0063] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a subject, wherein nemolizumab is administered to the subject at a dose of 60 mg once per four weeks.

[0064] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a subject, wherein nemolizumab is administered to the subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0065] In some embodiments, for use in prevention or treatment of CPUO in a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0066] In some embodiments, for use in prevention or treatment of CPUO in a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0067] In some embodiments, for use in prevention or treatment of CPUO in a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0068] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having pruritus of moderate or higher severity, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0069] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having pruritus of moderate or higher severity, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.Atty. Dkt. No.: 105153-2851

[0070] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having pruritus of moderate or higher severity, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0071] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0072] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0073] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0074] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0075] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0076] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.Atty. Dkt. No.: 105153-2851

[0077] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0078] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0079] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS [PP-NRS] of 5 or higher, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0080] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body drunk, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0081] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body drunk, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0082] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body drunk, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.Atty. Dkt. No.: 105153-2851

[0083] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a head region, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0084] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a head region, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0085] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a head region, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0086] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a pubic region, wherein nemolizumab is administered to a subject at a dose of 30 mg once per four weeks.

[0087] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a pubic region, wherein nemolizumab is administered to a subject at a dose of 60 mg once per four weeks.

[0088] In some embodiments, for use in prevention or treatment of CPUO (optionally CPUO for which an existing treatment is insufficiently effective) in a CPUO patient having chronic pruritus of unknown origin only at a pubic region, wherein nemolizumab is administered to a subject at an initial dose of 60 mg and at a second and subsequent doses of 30 mg once per four weeks.

[0089] In some embodiments, the subject is greater than or equal to 18 years old.Atty. Dkt. No.: 105153-2851

[0090] In some embodiments, the antibody against IL-31 receptor A is administered subcutaneously.

[0091] In some embodiments, the antibody against IL-31 receptor A is administered once every four weeks (Q4W).

[0092] In some embodiments, the antibody against IL-31 receptor A is administered at a dose of about 30 mg.

[0093] In some embodiments, the antibody against IL-31 receptor A is administered according to a flat dose regimen.

[0094] In some embodiments, the subject is greater than or equal to 90 kg.

[0095] In some embodiments, the antibody against IL-31 receptor A is administered according to a loading dose regimen. In some embodiments, the loading dose comprises about 60 mg of the antibody against IL-31 receptor A. In some embodiments, the about 60 mg of the antibody against IL-31 receptor A is administered as two about 30 mg doses.

[0096] In some embodiments, the subject has had CPUO for at least 6 months. In some embodiments, the subject has pruritus at one or more of left lower limb, right lower limb, left upper limb, right upper limb, anterior trunk, posterior trunk. In some embodiments, the subject has an improved Peak Pruritus Numeric Rating Scale (PP-NRS) score after at least one dose. In some embodiments, the subjects weekly average Peak Pruritus Numeric Rating Scale (PP-NRS) score is improved compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Peak Pruritus Numeric Rating Scale (PP-NRS) score compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score. In some embodiments, the subject has a Peak Pruritus Numeric Rating Scale (PP-NRS) score of less than 2 after the last dose. In some embodiments, the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose. In some embodiments, the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Sleep Disturbance NumericAtty. Dkt. No.: 105153-2851Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose. In some embodiments, the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Sleep Disturbance Numeric Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improved Dermatology Life Quality Index (DLQI) score after at least one dose. In some embodiments, the subjects Dermatology Life Quality Index (DLQI) score is improved compared to a baseline Dermatology Life Quality Index (DLQI) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Dermatology Life Quality Index (DLQI) score compared a baseline Dermatology Life Quality Index (DLQI) score. In some embodiments, the subject has a Dermatology Life Quality Index (DLQI) score of 0 or 1 after the last dose. In some embodiments, has an improved ItchyQoL™ score compared to a baseline ItchyQoL™ score.

[0097] The present disclosure also provides methods of treating CPUO with an antibody disclosed herein, for example, according to any of the foregoing aspects or embodiments, as well as uses of the antibodies disclosed herein for treating or preventing CPUO.DETAILED DESCRIPTION

[0098] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology.

[0099] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Many modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to thoseAtty. Dkt. No.: 105153-2851enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0100] The present disclosure provides preventive or therapeutic agents of CPUO (herein also referred to as pharmaceutical compositions for preventing or treating CPUO), the agents (pharmaceutical compositions) comprising an antibody against IL-31 receptor A as an active ingredient. In another embodiment, the present disclosure relates to methods of preventing or treating CPUO, the methods comprising administering an antibody against IL-31 receptor A. In addition, in another embodiment, the present disclosure relates to antibodies against IL-31 receptor A for use in prevention or treatment of CPUO. Furthermore, in another embodiment, the present disclosure relates to uses of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating CPUO. Herein, the above-mentioned various embodiments of the present disclosure are collectively referred to as the preventive or therapeutic agents of the present disclosure or the preventive or treatment methods of the present disclosure. Subjects who receive the preventive or therapeutic agent of the present disclosure, or prevention or treatment by the preventive or treatment method of the present disclosure are subjects potentially with CPUO or subjects with CPUO, and in some embodiments, CPUO patients for whom oral antihistaminic agents or antiallergic agents are insufficiently effective, or CPUO patients who cannot take these agents.

[0101] In some embodiments, CPUO is CPUO for which existing treatments are insufficiently effective. In some embodiments, the antibody against IL-31 receptor A is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the aminoAtty. Dkt. No.: 105153-2851acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody against IL-31 receptor A is nemolizumab. In some embodiments, the antibody against IL-31 receptor A is administered at a dose (per dose) of 30 mg / body or 60 mg / body. In some embodiments, the antibody against IL-31 receptor A is administered every four weeks. In some embodiments, the antibody against IL-31 receptor A is administered subcutaneously. In some embodiments, the antibody against IL-31 receptor A is administered to patients having pruritus of moderate or higher severity. In some embodiments, the antibody against IL-31 receptor A is administered to patients with an iItch score of 3 or higher. In some embodiments, the antibody against IL-31 receptor A is administered to patients with a PP-NRS of 5 or higher. In some embodiments, the antibody against IL-31 receptor A is administered to patients with an iItch score of 3 or higher and a PP-NRS of 5 or higher.Definitions

[0102] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0103] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 1, 5, or 10%. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about.” It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0104] As used herein, the term “approximately” or “about” means plus or minus 10% as well as the specified number. For example, “about 10” should be understood as both “10” and a range encompassing “9-11”.Atty. Dkt. No.: 105153-2851

[0105] As used herein, comparative terms as used herein, such as high, low, increase, decrease, reduce, or any grammatical variation thereof, can refer to certain variation from the reference. In some embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1 fold, or about 2 folds, or about 3 folds, or about 4 folds, or about 5 folds, or about 6 folds, or about 7 folds, or about 8 folds, or about 9 folds, or about 10 folds, or about 20 folds, or about 30 folds, or about 40 folds, or about 50 folds, or about 60 folds, or about 70 folds, or about 80 folds, or about 90 folds, or about 100 folds or more higher than the reference. In some embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 0%, or about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.

[0106] As will be understood by one skilled in the art, for any and all purposes, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Furthermore, as will be understood by one skilled in the art, a range includes each individual member.

[0107] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0108] 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 in the alternative (“or”).

[0109] The terms “administer,” “administration,” or “administering” as used herein refer to (1) providing, giving, dosing and / or prescribing, such as by either a health professional or his or her authorized agent or under his direction, and (2) putting into, taking or consuming, such as by a health professional, the subject or the subject’s caregiver. Administration shall include without limitation, administration by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection,Atty. Dkt. No.: 105153-2851or implant), by inhalation spray nasal, vaginal, rectal, sublingual, urethral (e.g., urethral suppository) or topical routes of administration (e.g., gel, ointment, cream, aerosol, etc.) and can be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration.

[0110] The terms “treat”, “treating” or “treatment”, as used herein, include alleviating, abating, or ameliorating chronic pruritus of unknown origin (CPUO) or one or more symptoms thereof, whether or not CPUO is considered to be “cured” or “healed” and whether or not all symptoms are resolved. The terms also include reducing or preventing progression of CPUO or one or more symptoms thereof, impeding or preventing an underlying mechanism of CPUO or one or more symptoms thereof, and achieving any therapeutic benefit. As used herein, the phrase “symptoms of CPUO” encompasses clinical signs of CPUO as well (e.g., clinical signs of CPUO including, but not limited to: itchiness (pruritus), dry and cracked skin, raw and sensitive skin due to scratching, rash or patches of discolored skin, scaly patches, thickened skin, oozing and crusting, and / or darkened skin surrounding the eyes).[OHl] The terms “prevent”, “preventing” or “prevention”, as used herein, include avoiding a flare, breakout, or recurrence of chronic pruritus of unknown origin (CPUO) or one or more symptoms thereof, whether or not CPUO is considered to be “cured” or “healed” and whether or not all symptoms are resolved.

[0112] As used herein, an “effective amount” is an amount sufficient to effect beneficial or desired results such as alleviating at least one or more symptom of CPUO. An effective amount as used herein would also include an amount sufficient to delay the development of CPUO, alter the course of an CPUO symptom (for example, hardening and tightening of the skin), or reverse a symptom of CPUO.

[0113] The term “Chronic pruritus of unknown origin (CPUO)” as used herein is defined as chronic pruritus of which cause cannot be identified even after causative diseases such as various primary cutaneous diseases including atopic dermatitis (AD) and prurigo nodularis, and systemic diseases including chronic renal disease, hepatobiliary disease, nervous disease,Atty. Dkt. No.: 105153-2851pregnancy and infection are ruled out (NPL2). Chronic pruritus of unknown origin (CPUO) includes, for example, chronic pruritus that is not any one of pruritus associated with primary cutaneous lesion, pruritus associated with visceral diseases, neurogenic or psychogenic pruritus, and drug-induced pruritus. Herein, “chronic pruritus” means pruritus that lasts 6 weeks or longer, according to the definition by the International Forum for the Study of Itch (IF SI) (NPL1).

[0114] The term “IL-31” as used herein refers to a new member of IL-6 cytokine family that was originally reported as an inducer of dermatitis in mice. IL-31 is mainly produced by Th2 cells and is expressed in a variety of cells, including fibroblasts, keratinocytes, and macrophages. Binding of IL-31 to the IL-31 receptor complex on cell surface activates JAK / STAT, PI3K / AKT, and other intracellular signaling pathways, leading to a wide range of immune responses. Interleukin 31 receptor subunit alpha (IL-31 receptor a, IL-3 IRA, IL-31 a, IL-3 la, also known as NR10, glm-r, and GPL) is a protein that forms a heterodimer with oncostatin M receptor (OSMR) and functions as an IL-31 receptor.

[0115] The IL-31 receptor complex is a heterodimer consisting of “IL-31 receptor A (IL-3 IRA)” and “oncostatin M receptor”. IL-3 IRA is unique to the IL-31 receptor, whereas oncostatin M receptor is shared by a receptor complex for oncostatin M. Within these two receptor subunits, IL-31 binds predominantly to IL-3 IRA.

[0116] The terms “anti-IL-31 receptor A antibody” and “antibody against IL-31 receptor A” as used herein are used synonymously and refer to an antibody capable of specifically binding to IL-31 receptor A (IL-3 IRA). As disclosed herein, an antibody against IL-31 receptor A is preferably an antibody that has a neutralizing activity against IL-31 receptor A. Herein, a “neutralizing activity against IL-31 receptor A” is an activity of inhibiting the binding of IL-31 receptor A with its ligand, IL-31, and preferably is an activity of suppressing a biological activity based on IL-31 receptor A. Therefore, an “antibody having a neutralizing activity against IL-31 receptor A” can inhibit the binding of IL-3 IRA with IL-31 and thereby suppress, inhibit, or block intracellular signaling caused via IL-3 IRA.

[0117] The term “antibody” as used herein refers to a molecule that specifically binds to a certain antigen determinant (epitope). Antibodies include various antibody structures,Atty. Dkt. No.: 105153-2851including monoclonal antibodies (mAb), polyclonal antibodies (pAb), and antibody fragments, but are not limited thereto.

[0118] As used herein, the term “subject” is used interchangeably with “patient,” and indicates a mammal who is 18 years or older, in particular a human, equine, bovine, porcine, feline, canine, murine, rat, or non-human primate. In some embodiments, the subject has been diagnosed with CPUO for at least 6 months.Therapeutic Antibodies of the Disclosed Treatments

[0119] As disclosed herein, an antibody against IL-31RA is preferably an antibody against mammalian IL-31RA, and more preferably an antibody against human IL-31RA.

[0120] Neutralizing antibodies against human IL-3 IRA include, for example, nemolizumab. Nemolizumab has been shown to improve the symptoms of atopic dermatitis in clinical trials. Nemolizumab comprises a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6. Nemolizumab comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. Nemolizumab comprises a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0121] Nemolizumab is a humanized monoclonal antibody that binds to IL-3 IRA.Nemolizumab is annotated as follows: immunoglobulin G2 -kappa, anti-[Homo sapiens IL31RA (interleukin 31 receptor subunit alpha)], humanized monoclonal antibody; gamma2 heavy chain (1-445) [humanized VH (Homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -Homo sapiens IGHG2*01 (CHI 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')-disulfideAtty. Dkt. No.: 105153-2851with kappa light chain (E-214’) [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (82.10%) - IGKJ4*01) [6.3.9] (l'-107') -Homo sapiens IGKC*01 (108'- 214')]; dimer (227-227":230-230")-bisdisulfide. Nemolizumab has disulfide bridges at the following locations: Intra-H (C23-C104) 22-96 148-204261-321 367-42522"-96" 148"-204" 261"-321" 367"-425"; Intra-L (C23-C104) 23'-88' 134'-194' 23"'-88'" 134"'-194'"; Inter-H-L (h 5-CL 126) 224-214' 224"-214'"; Inter-H-H (h 8, h 11) 227-227" 230-230". Nemolizumab has N-glycosylation sites at the following locations: H CH2 N84.4: 297, 297". Nemolizumab lacks H chain C-terminal glycine and lysine (CHS Gl>del, K2>del).

[0122] Nemolizumab heavy chain amino acid sequence:QVQLVQSGAEVKKPGASVKVSCKASGYTFT**GYIMN**WVRQAPGQGLEWMG**LIN PYNGGTDYNPQFQD**RVTITADKSTSTAYMELSSRLSEDTAVYYCAR**DGYDDGPYT LET**WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPMLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 9)

[0123] Nemolizumab light chain amino acid sequence:DIQMTQSPSSLSASVGDRVTITC**QASEDIYSFVA**WYQQKPGKAPKLLIY**NAQTEAQ** GVPSRFSGSGSGTDFTLTISSLQPEDFATYYYC**QHHYDSPLT**FGGGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10)

[0124] The variable domains of the heavy and light chain sequences are shown in bold above, and the CDR sequences are italicized.

[0125] Equivalents of nemolizumab may be monoclonal or polyclonal antibodies. Such monoclonal antibodies having IL31-RA -binding and / or neutralizing activity can be obtained, for example, by the following procedure: anti-IL31-RA monoclonal antibodies are prepared by using as an antigen IL31-RA or a fragment thereof that is derived from a mammal such asAtty. Dkt. No.: 105153-2851human or mouse by known methods, and then antibodies having IL31-RA-binding and / or neutralizing activity are selected from the thus obtained anti-IL31-RA monoclonal antibodies. Specifically, a desired antigen or cells expressing the desired antigen are used as a sensitizing antigen for immunization according to conventional immunization methods. Anti-IL31-RA monoclonal antibodies can be prepared by fusing the obtained immune cells with known parental cells using conventional cell fusion methods, and screening them for monoclonal antibody-producing cells (hybridomas) by conventional screening methods. Animals to be immunized include, for example, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses, and pigs. The antigen can be prepared using the known IL31-RA gene sequence according to known methods, for example, by methods using baculovirus (for example, WO 98 / 46777).

[0126] The IL31-RA-binding activity of the equivalent antibodies 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 immunoassay), RIA (radioimmunoassay), and fluorescent antibody method. For example, when enzyme immunoassay is used, antibody-containing samples, such as purified antibodies and culture supernatants of antibody-producing cells, are added to antigen-coated plates. A secondary antibody labeled with an enzyme, such as alkaline phosphatase, is added and the plates are incubated. After washing, an enzyme substrate, such as p-nitrophenyl phosphate, is added, and the absorbance is measured to evaluate the antigenbinding activity. The binding and / or neutralizing activity of an equivalent antibody against IL31-RA can be measured, for example, by observing the effect of suppressing the growth of the IL-31 -dependent cell line. For example, the activity of a purified mouse IL-3 lantibody can be assayed by assessing the IL-31 -dependent growth of Ba / F3 cells transfected with mouse IL-3 IRA and mouse OSMR genes.Treatment for Chronic Pruritus of Unknown Origin (CPUO),

[0127] As disclosed herein, a methods for the prevent and treatment of chronic pruritus of unknown origin (CPUO). In some embodiments the treating or preventing chronic pruritus of unknown origin (CPUO) is in a subject greater than or equal to 18 years old, comprisingAtty. Dkt. No.: 105153-2851administering to the subject, for example, about 30 mg of an antibody against IL-31 receptor A as an active ingredient as disclosed herein.

[0128] Dose / Dosage

[0129] In a non-limiting embodiment, for a subject with or potentially with CPUO, for example, a human adult and / or child, one dosage may be selected from 0.1 mg to 1000 mg / body, for example, 0.2 mg to 360 mg / body, and 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 to 40 mg / body, 10 mg to 39.5 mg / body, 10 mg to 39 mg / body, 10 mg to 38.5 mg / body, 10 mg to 38 mg / body, 10 mg to 37.5 mg / body, 15 mg to 100 mg / body, 15 mg to 75 mg / body, 15 mg to 50 mg / body, 15 mg to 40 mg / body, 15 mg to 39.5 mg / body, 15 mg to 39 mg / body, 15 mg to 38.5 mg / body, 15 mg to 38 mg / body, 15 mg to 37.5 mg / body, 17.5 mg to 100 mg / body, 17.5 mg to 75 mg / body, 17.5 mg to 50 mg / body, 17.5 mg to 40 mg / body, 17.5 mg to 39.5 mg / body, 17.5 mg to 39 mg / body, 17.5 mg to 38.5 mg / body, 17.5 mg to 38 mg / body, 17.5 mg to 37.5 mg / body, 20 mg to 100 mg / body, 20 mg to 75 mg / body, 20 mg to 50 mg / body, 20 mg to 40 mg / body, 20 mg to 39.5 mg / body, 20 mg to 39 mg / body, 20 mg to 38.5 mg / body, 20 mg to 38 mg / body, 20 mg to 37.5 mg / body, 22.5 mg to 100 mg / body, 22.5 mg to 75 mg / body, 22.5 mg to 50 mg / body, 22.5 mg to 40 mg / body, 22.5 mg to 39.5 mg / body, 22.5 mg to 39 mg / body, 22.5 mg to 38.5 mg / body, 22.5 mg to 38 mg / body, 22.5 mg to 37.5 mg / body, 25 mg to 500 mg / body, 25 mg to 200 mg / body, 25 mg to 120 mg / body, 25 mg to 110 mg / body, 25 mg to 100 mg / body, 25 mg to 90 mg / body, 25 mg to 80 mg / body, 25 mg to 79 mg / body, 25 mg to 78 mg / body, 25 mg to 77 mg / body, 25 mg to 76 mg / body, 25 mg to 75 mg / body, 25 mg to 74 mg / body, 25 mg to 73 mg / body, 25 mg to 72 mg / body, 25 mg to 71 mg / body, 25 mg to 70 mg / body, 25 mg to 50 mg / body, 30 mg to 50 mg / body, 30 mg to 75 mg / body, 30 mg to 100 mg / body, 30 mg to 150 mg / body, 30 mg to 200 mg / body, 30 mg to 250 mg / body, 30 mg to 300 mg / body, 40 mg to 70 mg / body, 40 mg to 71 mg / body, 40 mg to 72 mg / body, 40 mg to 73 mg / body, 40 mg to 74 mg / body, 40 mg to 75 mg / body, 40 mg to 76 mg / body, 40 mg to 77 mg / body, 40 mg to 78 mg / body, 40 mg to 79 mg / body, 40 mg to 80 mg / body, 40 mg to 90 mg / body, 40 mg to 100 mg / body, 40 mg to 110 mg / body, 40 mg to 120 mg / body, 42.5 mg to 70 mg / body, 42.5 mg to 71 mg / body, 42.5 mg to 72 mg / body, 42.5Atty. Dkt. No.: 105153-2851mg to 73 mg / body, 42.5 mg to 74 mg / body, 42.5 mg to 75 mg / body, 42.5 mg to 76 mg / body, 42.5 mg to 77 mg / body, 42.5 mg to 78 mg / body, 42.5 mg to 79 mg / body, 42.5 mg to 80 mg / body, 42.5 mg to 90 mg / body, 42.5 mg to 100 mg / body, 42.5 mg to 110 mg / body, 42.5 mg to 120 mg / body, 45 mg to 70 mg / body, 45 mg to 71 mg / body, 45 mg to 72 mg / body, 45 mg to 73 mg / body, 45 mg to 74 mg / body, 45 mg to 75 mg / body, 45 mg to 76 mg / body, 45 mg to 77 mg / body, 45 mg to 78 mg / body, 45 mg to 79 mg / body, 45 mg to 80 mg / body, 45 mg to 90 mg / body, 45 mg to 100 mg / body, 45 mg to 110 mg / body, 45 mg to 120 mg / body, 47.5 mg to 70 mg / body, 47.5 mg to 71 mg / body, 47.5 mg to 72 mg / body, 47.5 mg to 73 mg / body, 47.5 mg to 74 mg / body, 47.5 mg to 75 mg / body, 47.5 mg to 76 mg / body, 47.5 mg to 77 mg / body, 47.5 mg to 78 mg / body, 47.5 mg to 79 mg / body, 47.5 mg to 80 mg / body, 47.5 mg to 90 mg / body, 47.5 mg to 100 mg / body, 47.5 mg to 110 mg / body, 47.5 mg to 120 mg / body, 50 mg to 70 mg / body, 50 mg to 71 mg / body, 50 mg to 72 mg / body, 50 mg to 73 mg / body, 50 mg to 74 mg / body, 50 mg to 75 mg / body, 50 mg to 76 mg / body, 50 mg to 77 mg / body, 50 mg to 78 mg / body, 50 mg to 79 mg / body, 50 mg to 80 mg / body, 50 mg to 90 mg / body, 50 mg to 100 mg / body, 50 mg to 110 mg / body, 50 mg to 120 mg / body, 50 mg to 150 mg / body, 50 mg to 200 mg / body, 50 mg to 250 mg / body, 50 mg to 300 mg / body, 52.5 mg to 70 mg / body, 52.5 mg to 71 mg / body, 52.5 mg to 72 mg / body, 52.5 mg to 73 mg / body, 52.5 mg to 74 mg / body, 52.5 mg to 75 mg / body, 52.5 mg to 76 mg / body, 52.5 mg to 77 mg / body, 52.5 mg to 78 mg / body, 52.5 mg to 79 mg / body, 52.5 mg to 80 mg / body, 52.5 mg to 90 mg / body, 52.5 mg to 100 mg / body, 52.5 mg to 110 mg / body, 52.5 mg to 120 mg / body, 75 mg to 100 mg / body, 75 mg to 150 mg / body, 75 mg to 200 mg / body, 75 mg to 250 mg / body, 75 mg to 300 mg / body, 100 mg to 150 mg / body, 100 mg to 200 mg / body, 100 mg to 250 mg / body, 100 mg to 300 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, and 200 mg to 300 mg / body, as the dosage of the IL-31 antagonist (e.g., an antibody against IL-31 receptor A, such as Nemolizumab) of the present disclosure, and may be repeatedly administered using the above-described dosing interval, in equal amounts at the same dosing interval. An initial administration dose may be a different dose from that of subsequent administration(s).

[0130] In another non-limiting embodiment, for a subject with or potentially with CPUO, for example, a human adult and / or child, one dosage may be selected from 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, andAtty. Dkt. No.: 105153-2851preferably, 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, 0.1 mg to 3 mg / kg, 0.125 mg to 0.25 mg / kg, 0.125 mg to 0.3 mg / kg, 0.125 mg to 0.5 mg / kg, 0.125 mg to 0.75 mg / kg, 0.125 mg to 1 mg / kg, 0.125 mg to 1.5 mg / kg, 0.125 mg to 2 mg / kg, 0.125 mg to 3 mg / kg, 0.2 mg to 0.3 mg / kg, 0.2 mg to 0.5 mg / kg, 0.2 mg to 0.75 mg / kg, 0.2 mg to 1 mg / kg, 0.2 mg to 1.5 mg / kg, 0.2 mg to 2 mg / kg, 0.2 mg to 3 mg / kg, 0.25 mg to 0.3 mg / kg, 0.25 mg to 0.5 mg / kg, 0.25 mg to 0.75 mg / kg, 0.25 mg to 1 mg / kg, 0.25 mg to 1.5 mg / kg, 0.25 mg to 2 mg / kg, 0.25 mg to 3 mg / kg, 0.3 mg to 0.5 mg / kg, 0.3 mg to 0.75 mg / kg, 0.3 mg to 1 mg / kg, 0.3 mg to 1.5 mg / kg, 0.3 mg to 2 mg / kg, 0.3 mg to 3 mg / kg, 0.5 mg to 0.75 mg / kg, 0.5 mg to 1 mg / kg, 0.5 mg to 1.5 mg / kg, 0.5 mg to 2 mg / kg, 0.5 mg to 3 mg / kg, 0.75 mg to 1 mg / kg, 0.75 mg to 1.5 mg / kg, 0.75 mg to 2 mg / kg, 0.75 mg to 3 mg / kg, 1 mg to 1.5 mg / kg, 1 mg to 2 mg / kg, 1 mg to 3 mg / kg, 1.5 mg to 2 mg / kg, 1.5 mg to 3 mg / kg, 2 mg to 3 mg / kg, 0.15 mg to 2.9 mg / kg, 0.2 mg to 2.8 mg / kg, 0.25 mg to 2.7 mg / kg, 0.3 mg to 2.6 mg / kg, 0.35 mg to 2.5 mg / kg, 0.4 mg to 2.4 mg / kg, 0.425 mg to 2.3 mg / kg, 0.45 mg to 2.2 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, as the dosage of the IL-31 antagonist (e.g., an antibody against IL-31 receptor A, such as Nemolizumab) of the present disclosure, and may be repeatedly administered using the above-described dosing interval, in equal amounts at the same dosing interval.

[0131] In one embodiment, an anti-IL-31 receptor A antibody is administered to a subject (herein, may also be referred to as a patient or a test subject) about 5 mg / body, about 10 mg / body, about 15 mg / body, about 20 mg / body, about 25 mg / body, about 30 mg / body, about 35 mg / body, about 40 mg / body, about 45 mg / body, about 50 mg / body, about 55 mg / body, about 60 mg / body, about 65 mg / body, about 70 mg / body, about 75 mg / body, about 80 mg / body, about 85 mg / body or about 90 mg / body per dose. In some embodiments, an anti-IL-31 receptor A antibody is administered to a subject about 30 mg / body or about 60 mg / body per dose. In some embodiments, an anti-IL-31 receptor A antibody is administered to a subject at an initial dose of about 60 mg / body and at a second and subsequent doses of about 30 mg / body. In one embodiment, an anti-IL-31 receptor A antibody is administered to a subject once per about one week, once per about two weeks, once per about three weeks, once per about four weeks, once per about five weeks, once per about six weeks, once per about seven weeks or once per about eight weeks. In some embodiments, an anti-IL-31Atty. Dkt. No.: 105153-2851receptor A antibody (e.g., Nemolizumab) is administered to a subject every about four weeks. In some embodiments, an anti-IL-31 receptor A antibody (e.g., Nemolizumab) is administered subcutaneously. In some embodiments, an anti-IL-31 receptor A antibody (e.g., Nemolizumab) is administered subcutaneously to a subject every about four weeks at about 60 mg / body per dose. In some embodiments, an anti-IL-31 receptor A antibody (e.g., Nemolizumab) is administered subcutaneously to a subject every about four weeks at about 30 mg / body per dose. In another embodiment, an anti-IL-31 receptor A antibody (e.g., Nemolizumab) is administered subcutaneously to a subject at an initial dose of about 60 mg / body and at a second and subsequent doses of about 30 mg / body every about four weeks.

[0132] In some embodiments, the dose is administered to the subject at about 30 mg. In some embodiments, the dose is administered according to a loading dose. In some embodiments, the loading dose is about 60 mg. In some embodiments, the loading dose is two doses of 30 mg. In some embodiments, the subject is greater than or equal to 90 kg and receives the loading dose. In some embodiments, the subject is less than 90 kg and does not receive the loading dose.

[0133] Age:

[0134] In some embodiments, the subject is greater than or equal to 18 years old. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is about 20 years old, about 22 years old, about 24 years old, about 26 years old, about 28 years old, about 30 years old, about 32 years old, about 34 years old, about 36 years old, about 38 years old, about 40 years old, about 42 years old, about 44 years old, about 48 years old, about 50 years old, about 52 years old, about 54 years old, about 56 years old, about 58 years old, about 60 years old, about 62 years old, about 64 years old, about 66 years old, about 68 years old, about 70 years old, about 72 years old, about 74 years old, about 76 years old, about 78 years old, about 80 years old, about 82 years old, about 84 years old, about 86 years old, about 88 years old, about 90 years old, about 92 years old, about 94 years old, about 96 years old, about 98 years old, or about 100 or more years old.

[0135] Severity of CPUO:Atty. Dkt. No.: 105153-2851

[0136] In one embodiment, severity of CPUO can be assessed by a peak pruritus-NRS (herein below, PP-NRS), iItch score, sleep disturbance scale by CPUO, ISI score, DLQI / CDLQI score, 5-D Itch Scale score, and such. Assessment methods of these assessment items are known in the art, and see also Examples described herein.

[0137] Treatment target:

[0138] In one embodiment, patients (herein may also be referred to as treatment subjects or subjects) who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are CPUO patients for whom existing treatments (for example, oral antihistaminic agents or antiallergic agents) are insufficiently effective. In another embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are CPUO patients who cannot receive existing treatments (for example, CPUO patients who cannot take oral antihistaminic agents or antiallergic agents). In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are CPUO (for example, CPUO for which existing treatments are insufficiently effective) patients having pruritus of moderate or higher severity. In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are CPUO patients (for example, CPUO for which existing treatments are insufficiently effective) with an iItch score of 3 or higher. In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure (herein may also be referred to as treatment subjects or subjects)are CPUO patients (for example, CPUO for which existing treatments are insufficiently effective) patients with a PP-NRS of 5 or higher. In some embodiments, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are CPUO patients (for example, CPUO for which existing treatments are insufficiently effective) patients with an iItch score of 3 or higher and a PP-NRS of 5 or higher. In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or theAtty. Dkt. No.: 105153-2851preventive or treatment method of the present disclosure are CPUO patients having chronic pruritus of unknown origin at any one of: (i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or (iii) only a pubic region.

[0139] In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are patients who do not have pruritus associated with primary cutaneous lesion, pruritus associated with visceral diseases, neurogenic or psychogenic pruritus, and drug-induced pruritus. In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are patients having diabetes complication but diabetes is not a cause of pruritus. In another embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are patients who do not have diabetes complication. In one embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are patients who have iron deficiency complication. In another embodiment, patients who receive administration of the preventive or therapeutic agent of the present disclosure or the preventive or treatment method of the present disclosure are patients who do not have iron deficiency complication.

[0140] Efficacy:

[0141] In one embodiment, efficacy of the preventive or therapeutic agents of the present disclosure or the preventive or treatment methods of the present disclosure can be assessed by severity of CPUO compared to a control. In the context of the invention of the present disclosure, a control refers to, in one embodiment, severity of CPUO in a CPUO patient who does not receive administration of the preventive or therapeutic agent of the present disclosure or treatment by the treatment method of the present disclosure or in a population of the patients. In some embodiments, a control refers to severity of CPUO in a CPUO patient before receiving administration of the preventive or therapeutic agent of the presentAtty. Dkt. No.: 105153-2851disclosure or treatment by the treatment method of the present disclosure or in a population of the patients.

[0142] In one embodiment, the preventive or therapeutic agents of the present disclosure or the preventive or treatment methods of the present disclosure reduce a PP-NRS by 2 to 5. In one embodiment, the preventive or therapeutic agents of the present disclosure or the preventive or treatment methods of the present disclosure reduce an iItch score by 1 to 2 or more.

[0143] In some embodiments, the subject has Peak Pruritus Numeric Rating Scale (PP-NRS) score of greater than or equal to 7 at least 24 hours prior to administering. In some embodiment, the subject has Peak Pruritus Numeric Rating Scale (PP-NRS) score of greater than or equal to 7 at least 7 days prior to administering. In some embodiments, the subject has an improved Peak Pruritus Numeric Rating Scale (PP-NRS) score after at least one dose. In some embodiments, the subjects weekly average Peak Pruritus Numeric Rating Scale (PP-NRS) score is improved compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score. In the subject has an improvement of greater than or equal to 4 Peak Pruritus Numeric Rating Scale (PP-NRS) score compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score. In some embodiments, the subject has a Peak Pruritus Numeric Rating Scale (PP-NRS) score of less than 2 after the last dose.

[0144] In some embodiments, the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose. In some embodiments, the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Sleep Disturbance Numeric Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose. In some embodiments, the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score. In some embodiments, the subject has an improvement of greater than orAtty. Dkt. No.: 105153-2851equal to 4 Sleep Disturbance Numeric Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score.

[0145] In some embodiments, the subject has an improved Dermatology Life Quality Index (DLQI) score after at least one dose. In some embodiments, the subjects Dermatology Life Quality Index (DLQI) score is improved compared to a baseline Dermatology Life Quality Index (DLQI) score. In some embodiments, the subject has an improvement of greater than or equal to 4 Dermatology Life Quality Index (DLQI) score compared a baseline Dermatology Life Quality Index (DLQI) score. In some embodiments, the subject has a Dermatology Life Quality Index (DLQI) score of 0 or 1 after the last dose.

[0146] In some embodiments, the subjects had an improved ItchyQoL™ score compared to a baseline ItchyQoL™ score.Pharmaceutical Compositions

[0147] The present disclosure provides for pharmaceutical compositions comprising the antibody against IL-31RA is preferably an antibody against mammalian IL-31RA, and more preferably an antibody against human IL-31RA as disclosed herein. In some embodiments, the pharmaceutical composition is for treating and preventing chronic pruritus of unknown origin (CPUO).

[0148] The pharmaceutical compositions as disclosed herein can be prepared as formulations according to standard methods (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). In some embodiments, the pharmaceutical compositions comprise a carrier and / or additive. In some embodiments, the carrier is a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (for example, PEG and Tween), excipients, antioxidants (for example, ascorbic acid), coloring agents, flavoring agents, preservatives, stabilizers, buffering agents (for example, phosphoric acid, citric acid, and other organic acids), chelating agents (for example, EDTA), suspending agents, isotonizing agents, binders, disintegrators, lubricants, fluidity promoters, corrigents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmelose calcium, carmelose sodium, hydroxypropylcellulose,Atty. Dkt. No.: 105153-2851hydroxypropylmethylcellulose, polyvinylacetaldiethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salt. In some embodiments, the pharmaceutical composition comprises one or more other low-molecular-weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulin, and amino acids such as glycine, glutamine, asparagine, arginine, and lysine.

[0149] When the pharmaceutical composition as disclosed herein is prepared as an aqueous solution for injection, the antibody as disclosed herein may be dissolved in an isotonic solution containing, for example, physiological saline, dextrose, or other adjuvants. The adjuvants may include, for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride. In addition, appropriate solubilizing agents, for example, alcohols (for example, ethanol), polyalcohols (for example, propylene glycols and PEGs), and non-ionic detergents (polysorbate 80 and HCO-50) may be used concomitantly.

[0150] In some embodiments, the antibody as disclosed herein may be encapsulated in microcapsules (microcapsules made of hydroxymethylcellulose, gelatin, polymethylmethacrylate, and the like), and made into components of colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) (for example, see “Remington's Pharmaceutical Science 16th edition” &, Oslo Ed. (1980)). Moreover, methods for making sustained-release drugs are known, and these can be applied for nemolizumab or an equivalent thereof (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; EP 133,988).

[0151] The pharmaceutical compositions of the present disclosure can be administered either orally or parenterally. Specifically, the pharmaceutical compositions are administered to patients by injection or percutaneous administration. Injections include, for example, intralesional injections, intravenous injections, intramuscular injections, and subcutaneous injections, for systemic or local administration. The pharmaceutical compositions may beAtty. Dkt. No.: 105153-2851given to sites where inflammation is to be suppressed, or areas surrounding the sites by local infusion or intramuscular injection.

[0152] All prior art references cited herein are incorporated by reference in their entirety.EXAMPLES

[0153] . Herein below, the present disclosure will be described in detail with reference to the Examples, but it is not to be construed as being limited thereto.Example 1: Anti-human IL-31RA antibody

[0154] Nemolizumab (specified by the amino acid sequences of H chain: SEQ ID NO: 9; and L chain: SEQ ID NO: 10), which is an anti-human IL-31RA antibody, was prepared according to the method known in the art. As described in WO 2010 / 064697, nemolizumab has a neutralizing activity against human IL-31RA and cynomolgus monkey IL-31RA.Example 2 Randomized, placebo-controlled, double-blind, dose-response, multicenter study of nemolizumab targeting CPUO patients

[0155] Objective of clinical study. Efficacy and safety are confirmed when 30 mg (60 mg for only an initial dose) or 60 mg of nemolizumab is administered to CPUO patients at a four-week interval (Q4W) for 16 weeks, and optimal dose is evaluated.Table 1:Clinical study design _Phase of clinical study Phase IIType of clinical study Randomized, placebo-controlled, double-blind, dose-response, multicenter study Target patients CPUO patients aged 13 years or older having pruritus of moderate or higher severity (Peak pruritus-NRS [PP-NRS] is 5 or higher and iItch score is 3 or higher)Target test 62 cases (Generalized CPUO: 42 cases (each 14 cases for nemolizumab 60 mg group / subject number 30 mg group / placebo group), head region / pubic region CPUO: 20 cases(15 cases for nemolizumab 60 mg group, 5 cases for placebo group))Atty. Dkt. No.: 105153-2851

[0156] Considering effects of body weight on efficacy, body weight (60 kg or higher / less) was set as a stratification factor to make body weight distribution among administration groups be uniform as much as possible.

[0157] Use of the following drugs is allowed if a clinical investigator judges as being necessary.-Use of an oral antihistaminic agent(s) or antiallergic agent(s) for CPUO at a fixed dose / dosage.-Use of a moisturizing / protecting agent(s) at a fixed dosage.-Use of topical corticosteroids (TCS) of Strong class or below at a fixed dosage for secondary skin lesions due to scratching.

[0158] Target disease. CPUO for which existing treatments are insufficiently effective.

[0159] Selection criteria:(1) Patients aged 13 years or older who are diagnosed as CPUO(2) Patients who fall under any one of the followinga) Generalized CPUOPatients having chronic pruritus of unknown origin at least two areas among upper limb, lower limb and body trunk (three areas)b) CPUO at a head region or a pubic regionPatients having chronic pruritus of unknown origin only at a head region or only at a pubic region. However, patients having chronic pruritus of unknown origin at regions other than a head region or other than a pubic region but for whom a clinical investigator judges that the pruritus does not affect assessment of pruritus at the head region or at the pubic region are also included.(3) Patients who fall under any one of the following.1) Patients who had continuously taken oral antihistaminic agents or antiallergic agents for CPUO for two weeks or longer according to medical doctor’s instruction but efficacy was insufficient (medical doctor judges that pruritus corresponding to an iItch score of 3 or higher remains)Atty. Dkt. No.: 105153-28512) Patients who cannot take oral antihistaminic agents or antiallergic agents (hypersensitivity / contraindication)(4) Patients who meet all the following criteria at a start day of a screening period1) an iItch score of 3 or higher2) a PP-NRS of 5 or higher.

[0160] Exclusion criteria:(1) Patients who are undergoing hemodialysis or peritoneal dialysis(2) Patients having any one of the following pruritusa) pruritus associated with primary cutaneous lesionb) pruritus associated with a visceral disease(s)c) neurogenic or psychogenic pruritusd) drug-induced pruritus* Even if a subject is also suffered from a disease that may invoke pruritus (diabetes, iron deficiency, or such), inclusion of such subject into clinical trial is allowed if the subject meets all the following conditions:- clinical investigator judges that the disease is not a major cause of pruritus;- control of the disease is good; and- treatment of the disease can appropriately be continued according to a medical doctor’s instruction during a clinical study period.(3) Patients who are administered with the following systemically-administered drugs within 28 days counted from randomizationa) steroidb) immunodepressantc) JAK inhibitord) PDE4 inhibitore) NK (neurokinin) 1 receptor antagonistf) selective κ-opioid receptor agonistg) μ-opioid antagonisth) gabapentine, pregabalin, mirogabalini) antidepressantj) following Chinese herbal medicineAtty. Dkt. No.: 105153-2851- Unseiin extract- Orengedokuto extract- Goshajinkigan extract- Tokiinshi extract- Hachimijiogan extract- Rokumigan extract(4) Patients who have received ultraviolet therapy / photodynamic therapy aiming at treating pruritus within 28 days counted from randomization.

[0161] Discontinuance criteria: If a cause of chronic pruritus is revealed after starting clinical study, the clinical study of the test subject will be discontinued.

[0162] Investigational drug: nemolizumab: Nemolizumab, which is an investigational drug of this clinical study, is a humanized anti-human interleukin-31 (herein below, IL-31) receptor A (IL-31RA) monoclonal antibody that inhibits binding of IL-31 to IL-31 receptor and downstream signaling. On March 28, 2022, manufacture and sales of the injection " Mitchga Subcutaneous Injection 60 mg Syringe", of which active ingredient is nemolizumab, was approved for pruritus associated with atopic dermatitis for adults and children aged 13 years or older (restricted to cases where efficacy is insufficient with preexisting treatment) as the indications. On March 26, 2024, manufacture and sales of the injection " Mitchga Subcutaneous Injection 30 mg Vial", of which active ingredient is nemolizumab, was approved for pruritus associated with prurigo nodularis aged 13 years or older (restricted to cases for which existing treatments are insufficiently effective) and for pruritus associated with atopic dermatitis for children aged 6-12 years (restricted to cases for which existing treatments are insufficiently effective) as the indications.

[0163] Reference drug: Placebo is used.

[0164] Administration method: Two syringes of administration solution (nemolizumab or placebo), 0.6 mL per syringe, are subcutaneously administered slowly to test subjects for each group at a four week-interval (Q4W). Skin with no lesion among a brachial region, abdominal region and femoral region is selected as an administration region. First andAtty. Dkt. No.: 105153-2851second syringes are administered at the same region, but the sites are separated by at least about 5 cm.

[0165] Restriction of Concomitant Drug / Therapy: If a clinical investigator judges that use of the following drug / therapy is necessary for CPUO, the use at a fixed dose / dosage is allowed.(1) Oral antihistaminic agent / antiallergic agent for CPUO(2) Moisturizing / protecting agent.(3) TCS of Strong class or below for secondary cutaneous lesion due to scratching.

[0166] Rescue treatment: If a secondary cutaneous lesion due to scratching worsens on Day 2 or thereafter and a clinical investigator judges that this is an adverse event, concomitant use of TCS (rank is not restricted) additionally is allowed for that adverse event according to the judgement of the clinical investigator.

[0167] Assessment items (exploratory assessment items):(1) Time course of the following up to 16 weeks after administrationWeekly mean PP-NRS, weekly mean iItch score, weekly mean sleep disturbance scale by CPUO, DLQI / CDLQI score, ISI sum score, 5-D Itch Scale score(2) Time course of the following up to 2 weeks after administration for each dayPP-NRS, sleep disturbance scale by CPUO

[0168] Efficacy assessment (patient assessment): Test subjects are assessed with the following items(1) PP-NRS(2) IItch score(3) Sleep disturbance scale by CPUO

[0169] (1) PP-NRS: In order to assess efficacy of nemolizumab on CPUO, an NRS was employed, which is pruritus assessment index commonly used in clinical studies, and time course of the degree of peak pruritus in the last 24 hours (PP-NRS) up to 16 weeks after administration. Furthermore, in order to confirm early pruritus improvement effects, time course of daily PP-NRS up to two weeks after administration was set. Test subjects areAtty. Dkt. No.: 105153-2851assessed for their degree of peak CPUO pruritus in the last 24 hours by 11 scales, from "0 = no itch" to "10 = worst imaginable itch".

[0170] (2) IItch score: It has been recommended to assess pruritus with multiple assessment items, and thus an iItch score, which is commonly used in clinical studies that assesses pruritus, was set. Test subjects are assessed for their degree of peak CPUO pruritus in the last 24 hours by 5 scales, from "0 = none" to "4 = severe" according to Table 2. If the scores differ between daytime and nighttime, the higher score is chosen.Table 2:Itch scoreScore Intensity Daytime Nighttime0 None Almost no itch Almost no itch1 Slight Sometimes itching, but not itching to scratch Can sleep without scratching 2 Mild Sometimes scratch slightly with hand Can sleep with scratching 3 Moderate Scratch even in public with substantial itching Wake up with itching4 Severe Unbearable itching Hardly sleep with itching

[0171] (3) Sleep disturbance scale by CPUO: According to the guidelines of clinical assessment methods of sleep medicine, it is important to appropriately assess subjective improvement effects of sleep disturbance under daily living environment. Sleep disturbance scale by CPUO was set to investigate subjective assessment by patients relating to sleep by CPUO. Furthermore, in order to confirm sleep disturbance improvement effects by early improvement of pruritus, time course of daily sleep disturbance scale by CPUO up to two weeks after administration was set. Test subjects are assessed for their degree of sleep disturbance by CPUO the night before by 11 scales, from "0 = no problem with sleep" to "10 = cannot sleep at all".

[0172] Efficacy assessment (patient QOL assessment): Test subjects are assessed with the following items.(1) ISI(2) DLQI(3) CDLQI(4) 5-D Itch ScaleAtty. Dkt. No.: 105153-2851

[0173] (1) ISI: According to the guidelines of clinical assessment methods of sleep medicine, it is important to appropriately assess subjective improvement effects of sleep disturbance under daily living environment. ISI was set to investigate subjective assessment of patients for sleep by CPUO. Test subjects are assessed for their degree of sleep disturbance 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.).

[0174] (2) DLQI: DLQI was set since it is a QOL scale specific to cutaneous diseases and commonly used in clinical studies. Test subjects aged 16 years or older at the date of obtaining consent are assessed for effects on their quality of life 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.)

[0175] (3) CDLQI: CDLQI was set since it is a QOL scale specific to cutaneous diseases and commonly used in clinical studies. Test subjects aged below 16 years at the date of obtaining consent are assessed for effects on their quality of life 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.)

[0176] (4) 5-D Itch Scale: 5-D itch scale can readily assess and quantify multiple aspects such as pruritus duration, intensity, progress, adverse effects and body distribution. In addition, it can comprehensively assess multiple elements associated with pruritus compared with widely-used assessment scales such as VAS. 5-D itch scale was set to assess severity of pruritus in primary diseases in more detail. Test subjects are assessed with their pruritus severity using the 5-D Itch Scale questionnaire. (See S. Elman, L. S. Hynan, V. Gabriel, M. J. Mayo. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010 Mar; 162(3): 587-593.).

[0177] Industrial Applicability: The present invention provides novel means (preventive or therapeutic agents, drugs, or pharmaceutical compositions) for preventing or treating CPUO (particularly CPUO for which existing treatments are insufficiently effective), which comprises an antibody against IL-31 receptor A as an active ingredient. The presentAtty. Dkt. No.: 105153-2851invention further provides methods of preventing or treating CPUO (particularly CPUO for which existing treatments are insufficiently effective) by administering an antibody against IL-31 receptor A to a subject in need thereof.Example 3: Phase 2, multi-center, parallel group, randomized, double-blind, placebo-controlled study to assess the PK / PD relationship of nemolizumab in CPUO patients.

[0178] Study Design: This phase 2, multi-center, parallel group, randomized, double-blind, placebo-controlled, exploratory proof of concept study is designed to assess the PK / PD relationship of nemolizumab in participants > 18 years of age with CPUO during a 16-week treatment period. Approximately 50 participants with CPUO will be randomized 4: 1 to receive either nemolizumab or placebo by SC injection. Dosing will be defined according to patient body weight tiered groups. Participants weighing < 90 kg at baseline will receive either 30 mg nemolizumab (with 60 mg loading dose at baseline) or placebo Q4W at Wk 4, Wk 8, and Wk 12. Participants weighing > 90 kg at baseline will receive either 60 mg nemolizumab or placebo Q4W at Wk 4, Wk 8, and Wk 12 (without loading dose at baseline). Each participant is expected to be in the study for up to 28 weeks. The study consists of a 2 to 4-week screening period, a 16-week intervention (treatment) period, and an 8-week follow up period (12 weeks after last study intervention injection).

[0179] The length of CPUO diagnosis of at least 6 months is necessary to allow for the testing and exclusion of other potential diagnoses, as itch is a symptom of many conditions. To ensure participants have CPUO without a clear association to another condition, patients with uncontrolled conditions will be excluded. Additionally, uncontrolled conditions are excluded to avoid confounding of the safety assessment.

[0180] The study population will include participants with generalized itch affecting at least 4 of 6 prespecified areas (i.e., left lower limb, right lower limb, left upper limb, right upper limb, anterior trunk, posterior trunk). The aim is to include participants with generalized pruritus as this indicates a certain widespread manifestation of disease.

[0181] Justification for Dose: The SC dose to be tested is an initial loading dose of 60 mg, followed by 30 mg Q4W for patients with a body weight <90 kg or a 60 mg dose given Q4WAtty. Dkt. No.: 105153-2851for participants with body weight >90 kg. Nemolizumab has been demonstrated to achieve rapid and meaningful reduction in pruritus and results were consistent across subgroups (< 90 kg and >90 kg). The body weight dose tiered groups was further supported by PopPK model. A PopPK model was built from pooled nemolizumab evaluable PK data obtained in 1952 subjects enrolled across Phase 1 to Phase 3 clinical studies in AD and PN indications. PK profile of nemolizumab was not impacted by the disease status (AD or PN). A significant impact of body weight was identified, with increasing body weight resulting in a decrease in the nemolizumab systemic exposure for subjects receiving a flat dose. Steady state systemic C trough exposure was predicted to be 1.7-fold lower between the upper body weight quartile (87 to 181 kg: 1.72 µg / mL) and the lower body weight quartile (31 to 62 kg: 2.92 µg / mL). Overall, considering that 1) the PopPK analysis showed an impact of body weight on nemolizumab PK profile and 2) the impact of this variability on efficacy cannot be assessed using PK / PD simulations in this indication, a conservative approach was adopted in patients with CPUO. Therefore, the proposed dosing regimens were selected to achieve matching systemic exposure in participants with body weight <90 kg and >90 kg. Overall, similar mechanism of action (IL-31 receptor inhibition) is expected in both PN and CPUO; therefore, the same therapeutic concentrations range are expected to result in similar pharmacological activity. Therefore, the dose approved for the treatment of PN will be tested in the CPUO population in this study.

[0182] End of Study Definition: A participant is considered to have completed the study if the participant has completed all periods of the study including the follow-up visit (defined as 12 weeks after the last dose of study intervention) or the last scheduled procedure shown in the SoA (Table 7). The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the SoA (Table 7) for the last participant in the study globally, including the last follow-up visit.

[0183] Study Population:

[0184] Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply:AgeAtty. Dkt. No.: 105153-28511. Participant must be 18 years of age or older, at the time of signing the informed consent.Type of Participant and Disease Characteristics1. Participants with chronic pruritus on normal-appearing skin (except for dry skin or excoriations) for at least 6 months before the screening visit.2. Chronic pruritus considered of unknown origin (i.e., without a clear association to another condition or medication) as assessed by the investigator at baseline.3. The pruritus must affect at least 4 of the following body areas: left lower limb, right lower limb, left upper limb, right upper limb, anterior trunk, posterior trunk.4. History of insufficient control of the chronic pruritus with prior treatment.5. Peak Pruritus Numeric Rating Scale (PP-NRS) score > 7 in the 24-hour period prior to the Screening visit.6. Weekly average Peak Pruritus Numeric Rating Scale (PP-NRS) score > 7 in the week (7 days) immediately prior to randomization, as recorded in the patient diary. Note: PPNRS score should be measured on at least 4 days during the week preceding the baseline visit. Rounding of the mean PP-NRS score is not permitted.Sex and Contraceptive / Barrier Requirements1. Women of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile) must agree to use at least 1 adequate and approved method of contraception throughout the study and for 12 weeks after the last study intervention injection.

[0185] Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply:Medical Condition1. Known dermatologic, systemic, neurologic or psychiatric condition(s), other than dry skin, that is considered by the investigator to be the primary cause of current pruritus.Atty. Dkt. No.: 105153-28512. Documented parasitic infection, including skin parasites such as scabies, within 12 weeks prior to randomization.3. Cutaneous infection within 1 week before the baseline visit, any infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks before the baseline visit.4. Diagnosis of chronic pruritus of neuropathic origin including but not limited to scalp dysesthesia, brachioradial pruritus, generalized neuropathic pruritus or chronic pruritus of psychogenic origin (pruritus associated with psychological disorders such as delusional parasitosis or Morgellons disease).5. Any medical or psychological condition or any clinically relevant laboratory abnormalities that may put the participant at significant risk according to the investigator’s judgment, if he / she participates in the clinical study, or may interfere with study assessments. Examples (non-exhaustive) include uncontrolled diabetes (hemoglobin A1c >8%, untreated iron deficiency, cardiovascular conditions (e.g., Class III or IV heart failure according to the New York Heart Association classification), hepato-biliary conditions (e.g., Child-Pugh Class B or C, autoimmune hepatitis, Wilson disease), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis), other severe endocrinological, gastrointestinal, metabolic, pulmonary (e.g., uncontrolled asthma), or lymphatic diseases, chronic kidney disease stage 4 or 5 (eGFR<30 ml / min / 1.732), recent infections (e.g., respiratory infections) unless resolved or uncomplicated and adequately treated. Patients should receive optimal treatment for concomitant conditions that could impact pruritus (e.g., diabetes mellitus, iron deficiency) prior to enrollment in the trial.6. History of bullous pemphigoid or positive bullous pemphigoid autoantibodies at screening.7. History of mastocytosis or serum total tryptase >20 ng / ml at screening.8. Active TB or non-tuberculosis mycobacterial infection, or a history of incompletely treated TB, unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent.Atty. Dkt. No.: 105153-28519. Positive serology results (hepatitis B surface antigen [HbsAg] or hepatitis B core antibody [HbcAb], hepatitis C [HCV] antibody with positive confirmatory test for HCV [e.g., polymerase chain reaction [PCR], or HIV antibody) at the screening visit. Note: Participants with a positive HbcAb and a negative HbsAg can be included in this clinical study if hepatitis B surface antibody is positive (considered immune after a natural infection). Participants with negative confirmatory test for HCV RNA can be included in this clinical study.10. Known or suspected immunodeficiency.11. Lymphoproliferative disease or malignancy within the last 5 years, except for:Cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma in situ (Bowen’s disease), or carcinoma in situ of the cervix that have been treated and have no evidence of recurrence in the last 12 weeks before the screening visit, orActinic keratoses that have been treated.12 Presence of major psychiatric diagnosis, clinically significant dementia, intellectual impairment, or any medical condition or disability which, in the investigator’s opinion, may confound the assessment of nemolizumab’s safety or efficacy or interfere with the participant’s ability to comply with protocol-mandated activities.Weight1. Body weight < 30kg.Other Exclusion Criteria1. Prior treatment with commercially available nemolizumab.2. Hypersensitivity to the active substance (nemolizumab) or to any of the excipients of the study intervention.3. Requiring rescue therapy for pruritus during the screening period.4. Alcohol and / or substance abuse within 6 months of the screening visit.Atty. Dkt. No.: 105153-28515. Planned or anticipated major surgical procedure or other activity that would interfere with the participant’s ability to comply with protocol -mandated assessments (e.g., extended international travel).6. Pregnant or breastfeeding female, or female planning a pregnancy during the study.7. Vulnerable subject as defined by ICH GCP.

[0186] Study Intervention AdministeredTable 3:Intervention Label Active PlaceboIntervention Name nemolizumab placeboIntervention Description SC injections of 30 mg each 2 SC injections at baseline (60mg loading dose) at followed by 1 SC injection baseline followed by 1 SC every 4 weeks at Wk 4, Wk injection of 30 mg every 4 8, Wk 12 for a treatment weeks at Wk 4, Wk 8, Wk duration of 16 weeks for 12 for a treatment duration participants weighing < 90 of 16 weeks for participants kg at baseline; weighing < 90 kg atbaseline; 2 SC injections at baseline and every 4 weeks at Wk 4, 2 SC injections of 30 mg Wk 8, Wk 12 for a treatment each (60mg) at baseline and duration of 16 weeks for every 4 weeks at Wk 4, Wk participants weighing > 90 8, Wk 12 for a treatment kg at baseline.duration of 16 weeks forparticipants weighing > 90kg at baselineType Combination product n / aDose Formulation lyophilized powder and walyophilized powder and water for injection for solution ter forfor injection in a Singleinjection for solution for indose, Single-use, Pre-filled jection in a Single-dose, SinDual chamber Al gle-use, Pre-filled DualchamberAlAtty. Dkt. No.: 105153-2851Unit Dose Strength(s) 30 mg n / aDosage Level(s) 60 mg loading dose at basen / aline followed by 30 mgevery 4 weeks for participants weighing < 90 kg atbaseline; 60 mg at baselineand every 4 weeks for participants weighing > 90 kgatbaselineRoute of Administration SC SC

[0187] Efficacy Assessments: Subjects will be assessed using 1) Peak Pruritus Numeric Rating Scale (PP-NRS); 2) Sleep Disturbance Numeric Rating Scale (SD-NRS); 3) Dermatology Life Quality Index (DLQI); and 4) ItchyQoL™

[0188] Peak Pruritus Numeric Rating Scale (PP-NRS): The PP-NRS is a single question validated PRO assessment that participants will use to report the maximum intensity of their pruritus (itch). The PP-NRS consists of the following question: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, how would you rate your itch at the worst moment during the previous 24 hours?”

[0189] Sleep Disturbance Numeric Rating Scale (SD-NRS): The SD-NRS is a single-item PRO for quantifying sleep disturbance that has been validated in PN patients. In this study, participants will use the SD-NRS to report the degree of sleep loss they experience due to their CPUO. The SD-NRS consists of the following question: “On a scale of 0 to 10, with 0 being ‘no sleep loss related to the symptoms of my skin disease (chronic pruritus of unknown origin)’ and 10 being ‘I did not sleep at all due to the symptoms of my skin disease (chronic pruritus of unknown origin)’, how would you rate your sleep last night?”

[0190] Dermatology Life Quality Index (DLQI): The DLQI is a validated general dermatology quality of life PRO instrument used in routine clinical practice and clinical trials to assess the impact of disease symptoms and treatment on QOL. The format is a simpleAtty. Dkt. No.: 105153-2851response to 10 items which assess QOL over the past week, with an overall scoring system of 0 to 30; a high total score indicates a poor QOL.

[0191] ItchyQoL™: The ItchyQoL™ is a validated pruritus-specific QOL PRO instrument. The format is a simple response of “Never”, “Rarely”, “Sometimes”, “Often”, or “All the Time” to 22 statements related to the participant’s itchy skin condition over the past week. Each statement is assigned a score from 1 (Never) to 5 (All the Time). Scores from the 22 statements are summed to determine the total score, which can range from 22 to 110; higher scores indicate greater impact on quality of life.

[0192] Adverse Events (AEs) and Serious Adverse Events (SAEs)

[0193] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can be 1) Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from Baseline, considered clinically significant in the medical and scientific judgment of the investigator (i.e., not related to progression of underlying disease, or more severe than expected for the participant’s condition); 2) Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition; 3) New condition detected or diagnosed after study intervention administration even though it may have been present before the start of the study; 4) Signs, symptoms, or the clinical sequelae of a suspected drugdrug interaction; 5) Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication; 6) Overdose in and of itself is not considered an SAE and is not required to be reported as an SAE for the purpose of this study unless it is an intentional overdose or suicide attempt; 7) Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and / or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE.Atty. Dkt. No.: 105153-2851

[0194] An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of:1) Results in death;2) Is life threatening: The term life threatening in the definition of serious refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.3) Requires inpatient hospitalization or prolongation of existing hospitalization: In general, hospitalization signifies that the participant has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious.4) Results in persistent or significant disability / incapacity: The term disability means a substantial disruption of a person’s ability to conduct normal life functions.5) Is a congenital anomaly / birth defect.

[0195] Pharmacokinetics

[0196] PK Blood Samples: Blood samples will be collected for measurement of serum concentrations of nemolizumab at the timepoints specified in the SoA (Table 7). At each sampling time point for PK assessments, the collected blood will be placed to clot at room temperature (no less than 30 minutes and no more than 60 minutes after collection) and then centrifuged. The serum will be collected into storage tubes. As a guideline, PK samples should be collected at approximately the same time of day throughout the study, to the extent possible, before IP injection (pre-dose samples).

[0197] Nemolizumab Quantification in Blood Sample

[0198] Concentration of nemolizumab in the serum will be determined by the designated contract research organization (CRO) using a validated ELISA method. Details related to theAtty. Dkt. No.: 105153-2851processing of serum samples and the assessments of nemolizumab will be described in a bioanalytical plan, which will be finalized before the beginning of sample analysis.

[0199] Immunogenicity Assessments

[0200] ADA / NAb Blood Samples

[0201] Blood samples will be collected for analysis of anti-drug antibodies (ADA) and their neutralizing potential (NAb) in serum at the timepoints specified in the SoA. At each sampling time point for ADA / NAb assessments, the collected blood will be placed to clot at room temperature (no less than 30 minutes and no more than 60 minutes after collection) and then centrifuged. The serum will be collected into storage tubes.

[0202] ADA / NAb Assessment in Blood Samples

[0203] The ADA will be determined by the designated CRO using a validated ECLIA. The serum concentration will be assessed using a multi-tiered approach. If serum circulating ADA is detected, presence will be confirmed and characterized (e.g., for titer and neutralizing potential). Neutralizing potential will be determined by the designated CRO using a validated cell-based assay. The immunogenicity variables are ADA status, titer, Nab status, and each time-point.

[0204] Analysis Sets

[0205] Intent to treat (ITT) population: This will include all randomized patients. This will be the primary population for efficacy analyses.

[0206] Safety population (SAF): This will include all patients who received at least one dose of any investigational product (placebo or active). This will be the primary population for safety analyses.

[0207] PK population: This will include all patients who received at least one dose of active investigational product and who provide at least one post-baseline evaluable drug concentration value. This will be the primary population for the popPK analysis.Atty. Dkt. No.: 105153-2851

[0208] PK / PD population:

[0209] This will include all patients who received at least one dose of active investigational product or placebo and who provide at least one post-baseline evaluable drug concentration value and at least one post-baseline weekly average PP-NRS value. This will be the primary population for the PK / PD analysis.

[0210] Main Analytical Approach: Pharmacokinetics of nemolizumab, i.e., the time course of nemolizumab concentrations (Ctrough) during the 16-week treatment period, will be described by a designated CRO, using a non-linear mixed effect modeling approach with NONMEM software. A pre-specified PopPK model based on existing information from previous studies in adults (first-order absorption and a 1 -compartment distribution model) will be used to fit the nemolizumab serum concentrations obtained in this study. In addition, PK / PD analysis will be conducted to describe the relationship between the time course of nemolizumab concentrations (Ctrough) and the effect on pruritus (weekly average PP-NRS) during the 16-week treatment period. See Table 4 for Primary Outcome Measures.

[0211] Analysis Supporting Secondary Objective s): Nemolizumab model-derived PK parameters (Cl / F, Vd / F, Ka, Cmax, Tmax, Ctrough, AUCT, and 11 / 2) will be summarized descriptively based on the PK population as n, arithmetic mean, standard deviation, coefficient of variation (CV)% geometric mean, median, minimum, maximum. The observed Ctrough concentrations at each time point will be summarized based on the PK population as n, arithmetic mean, standard deviation, coefficient of variation (CV)% geometric mean, median, minimum, maximum, and number of samples below the limit of quantification. See Table 5 for secondary outcome measures.

[0212] Secondary Endpoints(s): All efficacy data will be summarized descriptively on the ITT population. Binary endpoints will be summarized including frequency and (exact) 95% confidence interval using non-responder imputation and observed case (OC). Continuous endpoints will be summarized descriptively including n, mean, standard deviation, median, 25% and 75% quantiles, minimum, maximum, and 95% confidence interval. Time to event endpoint will be analyzed using Kaplan-Meier (KM) method (Table 5).Atty. Dkt. No.: 105153-2851Table 4: Primary Outcome MeasuresOutcome Measure Measure Description Time Frame Population Point Estimate of Population From Baseline up to Week Pharmacokinetics (PopPK) Total Clearance (Cl / F) of 16.Model of the Elimination of nemolizumab will benemolizumab During the 16- reported.week Treatment PeriodPoint.Population Point Estimate of Population From Baseline up to Week Pharmacokinetics (PopPK) Volume of Distribution 16.Model of the Distribution of (Vd / F) of nemolizumab willnemolizumab During the 16- be reported.week Treatment PeriodPoint.Population Point Estimate of From Baseline up to Week Pharmacokinetics (PopPK) Absorption Rate Constant 16.Model of the Absorption of (Ka) of nemolizumab will benemolizumab During the 16- reported.week Treatment PeriodPoint.Pharmacokinetic Point Estimate of population From Baseline up to Week (PK) / Pharmacodynamic IC50 of nemolizumab, i.e. 16.(PD) Model of the Effect of the drug concentrationnemolizumab Systemic required to produce 50% ofExposure on Pruritus during the maximal inhibition of16-week Treatment Period. Average Peak Pruritus, willbe reported.Table 5: Secondary Outcome MeasuresOutcome Measure Measure Description Time Frame Individual Observed Ctrough Average of individual observed Ctrough Week 16 Concentrations of concentrations of nemolizumab at week nemolizumab 16 will be reported.Individual Model - derived Average of individual model-derived Week 16 Ctrough Concentrations of Ctrough concentrations of nemolizumabnemolizumab at week 16 will be reported.Individual Total Clearance Average of individual model-derived From Baseline (Cl / F) of nemolizumab estimates of Cl / F will be reported. up to Week 16Atty. Dkt. No.: 105153-2851Individual Volume of Average of individual model-derived From Baseline Distribution (Vd / F) of estimates of Vd / F will be reported. up to Week 16 nemolizumabIndividual Absorption Rate Average of individual model-derived From Baseline Constant (Ka) of estimates of Ka will be reported. up to Week 16 nemolizumabIndividual Maximum Serum Average of individual model-derived From Baseline Concentration (Cmax) of estimates of Cmax will be reported. up to Week 16 nemolizumabIndividual Time to Reach Average of individual model-derived From Baseline Maximum Serum estimates of Tmax will be reported. up to Week 16 Concentration (Tmax) ofnemolizumabIndividual Area Under the Average of individual model-derived From Baseline Concentration-time Curve estimates of AUCtau will be reported. up to Week 16 Within a Dosing Interval(AUCtau) of nemolizumabTerminal Half-life (tl / 2) of Average of individual model-derived From Baseline nemolizumab estimates of tl / 2 will be reported. up to Week 16 Change From Baseline in PP NRS is a scale that will be used by Up to Week 16 Weekly Average Peak the participants to report the intensity ofPruritus Numeric Rating their pruritus (itch) during the last 24Scale (PP NRS) hours. For maximum itch intensity: thescores are provided on a scale of 0 to10, with 0 being 'no itch' and 10 being'worst itch imaginable'. Higher scoresindicate worse outcome. Participant willreport PP NRS via daily e-PRO diary.Number of Participants With AE defined as any untoward medical From start of Adverse Events (AEs), occurrence in clinical study participant study up to Treatment Emergent administered a medicinal product which follow-up period Adverse Events (TEAEs), does not necessarily have causal (Week 24) Adverse Events of Special relationship with this treatment. TEAEsInterest (AESIs), and defined as AEs occurring after firstSerious Adverse Events administration of study drug during the(SAEs), AEs Leading to study. SAE was any untoward medicalStudy Intervention occurrence, in view of eitherWithdrawal, AEs Leading to Investigator or Sponsor, that resulted inStudy Discontinuation death, was life-threatening, resulted ininpatient hospitalisation or prolongationof existing hospitalisation, resulted inpersistent or significantdisability / incapacity, was congenitalanomaly / birth defect or was importantmedical event. AESI was noteworthyAtty. Dkt. No.: 105153-2851TEAE for study drug that was to bemonitored closely and reportedpromptly. Relatedness to study drugwas based on Investigator's discretion.AEs Leading to study treatmentwithdrawal and AEs Leading to studywithdrawal will also be reported.Table 6: Schedule of Activities (So A)Procedure ScreeningVisit VIWeek 2 to 4 weeks before DI Informed consent XInclusion and exclusion criteria X Demography XMedical history, previous therapies and procedures Xreview, smoking statusContraceptive counseling (participants of child-bearXing potential only)Screening visit PP-NRS XHeight XWeight XComplete physical examination XVital signs X12-lead ECG (locally performed and read) XBlood sample for virology (HIV, Hepatitis B and C) XBlood samples for hematology and biochemistry XBlood samples for bullous pemphigoid autoantibodies Xand tryptaseSerum pregnancy test (women of child-bearing potenXtial only)FSH (postmenopausal participants only) XAdverse event reporting X Concomitant therapies and procedures review X Moisturizer use Daily for at least 14 days prior to day 1PP-NRS / SD-NRS on participant diary Daily throughout screening periodAtty. Dkt. No.: 105153-2851Table 7: Schedule of Activities (So A)Procedure Intervention Period Follow-up Early TermiUnscheduled nation Visit Visit V2 V3 V4 V5 V6 V7(if applicable) (if applicable) Week BaseW4 W8 W12 W16 W24line (EOT) (EOS)12weeksafterlast doseDay DI D29 D57 D85 D113 D169Visit Window (days) — ±3 ± 3 ± 3 ±3 ± 7Inclusion and exclusion criXteriaContraceptive counselX (X) ing (women of childXbearing potential only)Moisturizer use X (X) X PP-NRS / SD-NRS on parXticipant diary XDLQI / ItchyQoL X X X X (X) Weight XComplete physical examinaX X X X X (X) tionVital signs X X X X X X X (X) Blood samples for hematolX X X X X X (X) ogy and biochemistryUrine pregnancy test X X X X X X X (X) (women of child-bearing potential only)12-lead ECG (locally perX X X (X) formed and read) (for participants withclinicallysignificantabnormalECG findings duringthe study)Adverse event reporting X X X X X X X (X) Concomitant therapies and X X X X X X X (X) proceduresreviewBlood sample for PK X X X X X (X) (X) (pie(pre(pre(pre(pre-dose) (pre-dose) dose) dose) dose) dose)Blood sample for ADA / Nab X (beX X (X) (X)foreAtty. Dkt. No.: 105153-2851firstdose)Randomization XStudy intervention injection X X X X (X) (Baselineweight based)PP-NRS, SD-NRS, DLQI, ItchyQoL AE reporting, and concomitant therapies / procedures review will occur before ECG, laboratory sample collections, and study intervention injection.

Claims

Atty. Dkt. No.: 105153-2851WHAT IS CLAIMED IS:

1. A preventive or therapeutic agent for chronic pruritus of unknown origin (CPUO) in a subject, the agent comprising an antibody against IL-31 receptor A as an active ingredient.

2. The preventive or therapeutic agent of claim 1, wherein the antibody is an antibody having a neutralizing activity against IL-31 receptor A.

3. The preventive or therapeutic agent of claim 1 or 2, wherein the antibody is:(1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6;(2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or(3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

4. The preventive or therapeutic agent of any one of claims 1-3, wherein the CPUO is CPUO for which an existing treatment is insufficiently effective.

5. The preventive or therapeutic agent of any one of claims 1-4, wherein the subject is a CPUO patient for whom an oral antihistaminic agent or antiallergic agent is insufficiently effective, or a CPUO patient who cannot take these agents.

6. The preventive or therapeutic agent of any one of claims 1-5, wherein the subject is a CPUO patient having pruritus of moderate or higher severity.

7. The preventive or therapeutic agent of any one of claims 1-6, wherein the subject is a CPUO patient with an iItch score of 3 or higher.Atty. Dkt. No.: 105153-28518. The preventive or therapeutic agent of any one of claims 1-7, wherein the subject is a CPUO patient with a peak pruritus-NRS [PP-NRS] of 5 or higher.

9. The preventive or therapeutic agent of any one of claims 1-8, wherein the subject is a CPUO patient with an iItch score of 3 or higher and a peak pruritus-NRS (PP-NRS) of 5 or higher.

10. The preventive or therapeutic agent of any one of claims 1-9, wherein the subject has chronic pruritus of unknown origin at any one of:(i) at least two areas among the following three areas: upper limb, lower limb and body trunk; (ii) only a head region; or(iii) only a pubic region.

11. The preventive or therapeutic agent of any one of claims 1-10, wherein the subject has chronic pruritus of unknown origin at least two areas among the following three areas: upper limb, lower limb and body trunk.

12. The preventive or therapeutic agent of any one of claims 1-11, wherein the subject has chronic pruritus of unknown origin only at a head region.

13. The preventive or therapeutic agent of any one of claims 1-12, wherein the subject has chronic pruritus of unknown origin only at a pubic region.

14. The preventive or therapeutic agent of any one of claims 1-13, wherein a dose of the antibody against IL-31 receptor A is 0.1 mg to 1000 mg / body.

15. The preventive or therapeutic agent of any one of claims 1-14, characterized in that the preventive or therapeutic agent is used such that the agent is administered to the subject once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks or once per eight weeks.

16. The preventive or therapeutic agent of any one of claims 1-15, comprising 30 mg orAtty. Dkt. No.: 105153-285117. The preventive or therapeutic agent of any one of claims 1-16, characterized in that the preventive or therapeutic agent is used such that the agent is administered to the subject once per four weeks.

18. The preventive or therapeutic agent of any one of claims 1-17, wherein the antibody against IL-31 receptor A is administered to the subject at a dose of 60 mg / body every four weeks.

19. The preventive or therapeutic agent of any one of claims 1-18, wherein the antibody against IL-31 receptor A is administered to the subject at a dose of 30 mg / body every four weeks.

20. The preventive or therapeutic agent of any one of claims 1-19, wherein the antibody against IL-31 receptor A is administered to the subject at an initial dose of 60 mg / body, and at a second and subsequent doses of 30 mg / body every four weeks.

21. The preventative or therapeutic agent of any one of claims 1-20, wherein the subject is greater than or equal to 18 years old.

22. The preventative or therapeutic agent of any one of claims 1-21, wherein the antibody against IL-31 receptor A is administered subcutaneously.

23. The preventative or therapeutic agent of any one of claims 1-22, wherein the antibody against IL-31 receptor A is administered once every four weeks (Q4W).

24. The preventative or therapeutic agent of any one of claims 1-23, wherein the antibody against IL-31 receptor A is administered at a dose of about 30 mg.

25. The preventative or therapeutic agent of claim 24, wherein the antibody against IL-31 receptor A is administered according to a flat dose regimen.

26. The preventative or therapeutic agent of claim 25, wherein the subject is greater than or equal to 90 kg.

27. The preventative or therapeutic agent of claim 24, wherein the antibody against IL-31 receptor A is administered according to a loading dose regimen.Atty. Dkt. No.: 105153-285128. The preventative or therapeutic agent of claim 27, wherein the loading dose comprises about 60 mg of the antibody against IL-31 receptor A.

29. The preventative or therapeutic agent of claim 28, wherein the about 60 mg of the antibody against IL-31 receptor A is administered as two about 30 mg doses.

30. The preventative or therapeutic agent of any one of claims 1-29, wherein the subject has had CPUO for at least 6 months.

31. The preventative or therapeutic agent of any one of claims 1-30, wherein the subject has pruritus at one or more of left lower limb, right lower limb, left upper limb, right upper limb, anterior trunk, posterior trunk.

32. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improved Peak Pruritus Numeric Rating Scale (PP-NRS) score after at least one dose.

33. The preventive or therapeutic agent of any one of claims 1-31, wherein the subjects weekly average Peak Pruritus Numeric Rating Scale (PP-NRS) score is improved compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score.

34. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improvement of greater than or equal to 4 Peak Pruritus Numeric Rating Scale (PP-NRS) score compared to a baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score.

35. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has a Peak Pruritus Numeric Rating Scale (PP-NRS) score of less than 2 after the last dose.

36. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose.

37. The preventive or therapeutic agent of any one of claims 1-31, wherein the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score.Atty. Dkt. No.: 105153-285138. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improvement of greater than or equal to 4 Sleep Disturbance Numeric Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score.

39. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improved Sleep Disturbance Numeric Rating Scale (SD-NRS) score after at least one dose.

40. The preventive or therapeutic agent of any one of claims 1-31, wherein the subjects weekly average Sleep Disturbance Numeric Rating Scale (SD-NRS) score is improved compared to a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score.

41. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improvement of greater than or equal to 4 Sleep Disturbance Numeric Rating Scale (SD-NRS) compared a baseline Sleep Disturbance Numeric Rating Scale (SD-NRS) score.

42. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improved Dermatology Life Quality Index (DLQI) score after at least one dose.

43. The preventive or therapeutic agent of any one of claims 1-31, wherein the subjects Dermatology Life Quality Index (DLQI) score is improved compared to a baseline Dermatology Life Quality Index (DLQI) score.

44. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improvement of greater than or equal to 4 Dermatology Life Quality Index (DLQI) score compared a baseline Dermatology Life Quality Index (DLQI) score.

45. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has a Dermatology Life Quality Index (DLQI) score of 0 or 1 after the last dose.

46. The preventive or therapeutic agent of any one of claims 1-31, wherein the subject has an improved ItchyQoL™ score compared to a baseline ItchyQoL™ score.Atty. Dkt. No.: 105153-285147. A method for treating or preventing chronic pruritus of unknown origin (CPUO) in a subject greater than or equal to 18 years old, comprising administering to the subject about 30 mg to about 60 mg of an antibody against IL-31 receptor A.

48. The method of claim 47, wherein the antibody is an antibody having a neutralizing activity against IL-31 receptor A.

49. The method of claim 47 or 48, wherein the antibody is:(1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6;(2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or(3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

50. The method of any one of claims 47-49, wherein the antibody is administered subcutaneously.

51. The method of any one of claims 47-50, wherein the antibody is administered once per 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, or once every eleven weeks; preferably once every eight weeks or once every four weeks.

52. The method of any one of claims 47-51, wherein the antibody against IL-31 receptor A is Nemolizumab.Atty. Dkt. No.: 105153-285153. Use of the antibody of any one of claims 1-46 for treating chronic pruritus of unknown origin (CPUO) in a subject, wherein the subject is greater than or equal to 18 years old.

54. A pharmaceutical composition comprising about 30 mg to about 60 mg of an antibody against IL-31 receptor A and a pharmaceutically acceptable carrier for treatment of chronic pruritus of unknown origin (CPUO) in a subject in need thereof, wherein the subject is greater than or equal to 18 years old.

55. The pharmaceutical composition of claim 54, wherein the antibody is an antibody having a neutralizing activity against IL-31 receptor A.

56. The pharmaceutical composition of claim 54 or 55, wherein the antibody is:(1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 4, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 6;(2) an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or(3) an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

57. The pharmaceutical composition of any one of claims 54-56, wherein the pharmaceutical composition is formulated for subcutaneous administration.

58. The pharmaceutical composition of any one of claims 54-57, wherein the antibody against IL-31 receptor A is Nemolizumab.

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