RU2822134C2 - Treatment of skin lesions and itching in patients with prurigo nodosum - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed is a method of treating skin lesions and pruritus in a subject with chronic pruritus (CP), including prurigo nodosum. Method involves administering to a subject an effective amount of nemolizumab. Also disclosed are pharmaceutical compositions for treating pruritus in a subject with CP, comprising nemolizumab, and use of nemolizumab in the manufacture of a drug for treating skin lesions and pruritus in a subject with CP.

EFFECT: invention can find further application in therapy.

54 cl, 29 dwg, 7 tbl, 1 ex

Description

RELATED APPLICATIONS

[0001] This application claims priority under 35 USC § 119(e) to US Provisional Application No. 62/797803, filed January 28, 2019, and US Provisional Application No. 62/809404, filed February 22, 2019, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] Described herein are methods of treating skin lesions and itching in a subject having chronic prurigo (CP), including pruritus nodularis (NP), pharmaceutical compositions for use in treating skin lesions and itching in a subject having CP, the use of nemolizumab or its equivalent in the manufacture of a medicinal product for the treatment of skin lesions and itching in a subject having CP.

BACKGROUND OF THE ART

[0003] The following discussion is provided to assist the reader in understanding the invention, and is not considered to constitute prior art.

[0004] Chronic prurigo (CP) is a skin disease due to neuronal sensitization to itch and the development of the itch-scratch cycle. Prurigo nodularis (NP) is a subtype of CP and is a skin disorder that results in the formation of hard, itchy lumps (nodules) on the skin. The itching (itching) can be intense, causing people to scratch until it bleeds or becomes painful. Scratching may cause additional skin lesions. Itching worsens with fever, sweating, or irritation from clothing. In some cases, people with UP have a history of other conditions, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or kidney disease.

[0005] The exact cause of CP or AP is unknown. Although scratching is known to cause more nodules to appear, it is not clear what causes the itching in the first place. The diagnosis of the disease is based on the identification of signs, such as extremely itchy skin with the formation of nodules. In some cases, a skin biopsy is used to confirm the diagnosis. Treatments available today may include corticosteroid creams, oral medications, cryotherapy, or photochemotherapy.

[0006] There remains a need to develop new therapeutic regimens for the treatment of patients with UP, in particular those suffering from chronic prurigo.

BRIEF DESCRIPTION OF THE INVENTION

[0007] Provided herein are methods of treating skin lesions and itching in a subject having chronic prurigo (CP), including prurigo nodosa (NP), pharmaceutical compositions for use in treating skin lesions and itching in a subject having CP, including UP, uses nemolizumab or its equivalent in the manufacture of a medicament for the treatment of skin lesions and itching in a subject having CP, including UP.

[0008] In accordance with some embodiments, methods are provided for treating skin lesions and itching in a subject having CP, comprising, consisting of, or consisting primarily of administering to the subject an effective amount of nemolizumab or an equivalent thereof.

[0009] In some embodiments of the methods, the subject has prurigo nodularis (NP). In some embodiments of the methods, AP has been diagnosed in the subject for at least about 6 months. In specific embodiments of the methods, the subject has at least about 20 nodules on his body with a bidirectional distribution. In specific embodiments of the methods, the subject has prurigo-related lesions on the upper extremities with or without lesions on the torso or lower extremities. In specific embodiments of the methods, the itch is assigned a score of at least 4, while in some embodiments, the itch is assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments of the methods, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments of the methods, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0010] In some embodiments of the methods, the subject does not have atopic dermatitis. In some embodiments of the methods, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis , bullous disease. In some embodiments of the methods, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, or pathomimia.

[0011]In some embodiments of the methods, the effective amount of nemolizumab or its equivalent is in the range from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In specific embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2. 5 mg/kg. In specific embodiments, the effective amount of nemolizumab or its equivalent is a constant dose of 40 mg. In other specific embodiments, the effective amount of nemolizumab or its equivalent is 30 mg with a loading dose of 60 mg. In other specific embodiments, the effective amount of nemolizumab or its equivalent is a constant dose of 6-60 mg, which is administered once every 4 weeks. In some embodiments of the methods, nemolizumab or its equivalent is administered by topical or parenteral routes. In some embodiments of the methods, nemolizumab or its equivalent is administered subcutaneously. In some embodiments, nemolizumab or its equivalent 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, or once every eight weeks. In certain embodiments, nemolizumab is administered over a period of at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months or more.

[0012] In accordance with some embodiments, pharmaceutical compositions are provided for use in the treatment of skin lesions and itching in a subject having chronic pruritus (CP), containing, consisting of, or consisting predominantly of nemolizumab or its equivalent.

[0013] In some embodiments of the pharmaceutical compositions, the subject has prurigo nodularis (PK). In some embodiments of the compositions, the AP has been diagnosed in the subject for at least about 6 months. In specific embodiments of the compositions, the subject has at least about 20 nodules on his body with a bidirectional distribution. In specific embodiments of the compositions, the subject has prurigo-related lesions on the upper extremities with or without lesions on the torso or lower extremities. In specific embodiments of the compositions, the itch is assigned a score of at least 4, while in some embodiments, the itch is assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments of the compositions, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments of the compositions, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0014] In some embodiments of the pharmaceutical compositions, the subject does not have atopic dermatitis. In some embodiments of the compositions, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bites, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis , bullous disease. In some embodiments of the compositions, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, pathomimia.

[0015] In some embodiments, the pharmaceutical composition further comprises a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier.

[0016] In some embodiments of the pharmaceutical compositions, nemolizumab or its equivalent is administered according to a constant dose regimen, while in some embodiments, nemolizumab or its equivalent is administered according to a loading dose regimen, in which the loading dose may be higher than subsequent serial doses (eg, 60 mg loading dose followed by 30 mg serial doses).

[0017] In some embodiments of the pharmaceutical compositions, nemolizumab or its equivalent is administered at a dose of about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.5 mg/kg, or from about 2.5 mg/kg to about 10 mg/kg, then as in some embodiments, nemolizumab or its equivalent is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg nemolizumab or its equivalent.

[0018] In accordance with some embodiments, the use of nemolizumab or its equivalent in the manufacture of a medicament for the treatment of prurigo in a subject having UP is provided.

[0019] In some embodiments, pruritus is moderate to severe. In some embodiments, the AP has been diagnosed in the subject for at least 6 months. In specific embodiments of the applications, the subject has at least 20 nodules on his body with a bilateral distribution. In specific embodiments, the subject has prurigo-related lesions on the upper extremities with or without lesions on the torso or lower extremities. In certain embodiments, the itch is assigned a score of at least 4, while in some embodiments, the itch is assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0020] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis , bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, pathomimia.

[0021] In some embodiments, nemolizumab or its equivalent is administered according to a constant dose regimen, while in some embodiments, nemolizumab or its equivalent is administered according to a loading dose regimen, in which the loading dose may be higher than subsequent doses. serial doses (eg, 60 mg loading dose followed by 30 mg serial doses).

[0022] In some embodiments, nemolizumab or its equivalent is administered at a dose of about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg, whereas in some embodiments, nemolizumab or its equivalent is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg , about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg nemolizumab or its equivalent.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0023] FIG. 1 Review of a clinical trial for the treatment of pruritus in patients with prurigo nodosa (NP) with nemolizumab. A multicentre (20 centers in the EU and US), randomized, double-blind, placebo-controlled, parallel group study was conducted with approximately 70 patients randomized into 2 groups (35 per group) and stratified for atopy. Enrolled patients received nemolizumab or placebo at a dose of 0.5 mg/kg every 4 weeks from baseline to week 8.

[0024] FIG. Figure 2 illustrates the percentage change from baseline in the weekly mean numeric rating scale (NRS) rating of maximum itching at week 4.

[0025] FIG. Figure 3 illustrates the percentage change from baseline in the weekly mean NRS score of maximum pruritus over 18 weeks.

[0026] FIG. Figure 4 illustrates the absolute change from baseline in the weekly mean NRS score of maximum pruritus over 18 weeks.

[0027] FIG. Figure 5 illustrates the absolute change from baseline in the weekly mean NRS score of maximum pruritus over 18 weeks in patients without atopy.

[0028] FIG. Figure 6 illustrates the absolute change from baseline in the weekly mean NRS score of maximum pruritus over 18 weeks in atopic patients.

[0029] FIG. Figure 7 illustrates the proportion of subjects achieving success based on Investigator Overall Assessment (IOI) (0/1). Investigator global assessment (IOR) values range from 0 (clear) to 4 (severe disease) and are presented as a percentage of patients in the specified population.

[0030] FIG. Figure 8 illustrates the distribution of TBI in patients over 18 weeks of treatment.

[0031] FIG. Figure 9 illustrates the percentage change in Verbal Rating Scale (VRS) over 18 weeks of treatment. The Verbal Rating Scale (VRS) is a unidimensional scale that allows patients to describe the intensity of itching in terms of gradually increasing dimensions.

[0032] FIG. 10 illustrates patients with Dermatologic Quality of Life Index (DQL) response (≥ 4) at week 4 and week 12. Dermatologic Quality of Life Index (DQOL) scores range from 0 to 30, with higher scores indicating lower quality of life.

[0033] FIG. Figure 11 illustrates the change from baseline DIQL at 4 weeks and 12 weeks.

[0034] FIG. 12 illustrates a comparison of whole body images of patients before treatment with nemolizumab (A and C) and after treatment for 16 weeks (B and D).

[0035] FIG. 13 illustrates a comparison of whole body images of patients before treatment with nemolizumab (A and C) and after treatment for 16 weeks (B and D).

[0036] FIG. 14 illustrates a comparison of whole body images of patients before treatment with nemolizumab (A and C) and after treatment for 16 weeks (B and D).

[0037] FIG. 15 illustrates the percentage change in Numerical Rating Scale (NRS) itching scores over 18 weeks of treatment.

[0038] FIG. 16 illustrates the proportion of subjects with a prurigo activity score (PAS) of 75% cured within 18 weeks of treatment.

[0039] FIG. 17 illustrates the proportion of subjects with a prurigo activity score (PAS) of 50% cured within 18 weeks of treatment.

[0040] FIG. 18 illustrates the proportion of subjects with a prurigo activity score (PAS) of 0-24% cured over 18 weeks of treatment.

[0041] FIG. Figure 19 illustrates the percentage change from baseline in sleep disturbance measured by the NRS at week 4.

[0042] FIG. Figure 20 illustrates the percentage change in sleep disturbance according to the NRS at week 4.

DETAILED DESCRIPTION OF THE INVENTION

[0043] In the following, embodiments in accordance with the present invention will be described more fully. However, aspects of the invention may be embodied in various forms and should not be construed as limited to the embodiments provided herein. Rather, these embodiments are provided in order for this description to be thorough and complete and to fully convey the scope of the invention to those skilled in the art. The terminology used in the description herein is intended to describe specific embodiments only and is not intended to be limiting.

[0044] Unless otherwise specified, all terms used herein (including technical and scientific terms) have the same meanings as commonly understood by one skilled in the art to which this invention relates. It should be further understood that terms, such as those defined in conventional references, should be interpreted to have meanings consistent with their meanings in the context of the application submitted and the relevant prior art, and should not be interpreted in an idealized or overly formal sense unless clearly defined in this document. Although not expressly defined below, these terms should be interpreted in accordance with their generally accepted meaning.

[0045] The terminology used in the description herein is intended to describe specific embodiments only and is not intended to limit the invention. All publications, patent applications, patents and other literature references herein are incorporated by reference in their entirety.

[0046] Unless the context otherwise requires, it is expressly understood that the various features of the invention described herein can be used in any combination. In addition, the invention also provides that in some embodiments, any feature or combination of features provided herein may be excluded or omitted. By way of illustration, if the text states that a complex contains components A, B, and C, it is expressly implied that any of A, B, or C, or a combination thereof, may be omitted and omitted individually or in any combination.

[0047] Unless otherwise expressly stated, all specific embodiments, features and terms are intended to include both the embodiment, feature or term specified and their biological equivalents.

Definitions

[0048] As used herein, singular forms denote both singular and plural unless explicitly stated to denote exclusively the singular.

[0049] It should be understood that, although not always explicitly stated, all numerical designations are preceded by the term “about.” The term “about” means that the number included is not limited to the specific number given herein and is intended to refer to numbers approximating the number therein without departing from the scope of the invention. As used herein, the term "about" will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. When this term is used in a manner that is not clear to those skilled in the art in the context in which it is used, "about" means plus or minus 15%, 10%, 5%, 1%, or 0.1% of the specific term.

[0050] Also as used herein, the term “and/or” refers to and includes each and all possible combinations of one or more related enumerated items, as well as the absence of combinations when interpreted as an alternative (“or”).

[0051] As used herein, the terms “administer” or “administration” refer to (1) provision, provision, dosing and/or prescription, for example, by or under the direction of a healthcare professional or his or her authorized agent, and (2) administration, intake or use, for example by a healthcare professional or subject. Administration includes, but is not limited to, oral, parenteral (e.g., by intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), nasal by inhalation spray, vaginal, rectal, sublingual, urethral (e.g. by urethral suppository) or by local routes of administration (e.g., gel, ointment, cream, aerosol, etc.), and may be formulated, separately or together, in suitable unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients and stock solutions for each route of administration. The invention is not limited by route of administration, composition or dosage regimen.

[0052] As used herein, the terms “treat” or “cure” include alleviating, mitigating, or reducing UP, prurigo, or one or more symptoms thereof, regardless of whether UP and/or prurigo are considered “cured” or “healed.” , and regardless of whether all symptoms are resolved. These terms also include reducing or preventing the progression of UP and/or prurigo or one or more symptoms thereof, inhibiting or preventing the underlying mechanism of UP and/or prurigo or one or more symptoms thereof, and achieving any therapeutic and/or prophylactic benefit.

[0053] Interleukin 31 receptor alpha subunit ("IL-31RA", also known as NR10, glm-r and GPL) is a protein that forms a heterodimer with the oncostatin M receptor (OSMR) and functions as an IL-31 receptor. There are several known splice variants of human IL-31RA (WO 00/075314): NR10.1 consists of 662 amino acids and contains a transmembrane domain. NR10.2 is a soluble receptor-like protein consisting of 252 amino acids without a transmembrane domain. However, known IL-31RA splice variants that function as transmembrane receptor proteins include NR10.3 and IL-31RAv3. Preferred IL-31RA variants include NR10.3 (also called ILRAv4 (Nat Immunol 5, 752-60, 2004) and IL-31RAv3. NR 10.3 (IL31RAv4) consists of 662 amino acids (WO 00/075314; Nat Immunol 5, 752-60 60, 2004), and IL31RAv3 consists of 732 amino acids (GenBank accession number: NM-139017).

[0054] The amino acid sequence of IL31RAv4 is:

MKLSPQPSCVNLGMMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKN QTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQAT NWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSIL QYGLESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDK LNLKESDDSVNTEDRILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGTRILSSCPTSI (SEQ ID NO: 1)

[0055] The amino acid sequence of IL31RAv3 is:

MMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKNQTYNLTGLQPFTEY VIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQATNWTIQQDKLK PFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTS YIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTED RILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGYVTCPFRPDCPLGKSFEELPVSPEIPPRKSQYLRSRMPEGTRPEAKEQLLFSGQSLVPDHLCEEGAPNPYLKNSVTAREFLVSEKLPEHTKGEV (SEQ ID NO: 2)

[0056] Murine IL-31RA includes proteins containing the amino acid sequence:

MWTLALWAFSFLCKFSLAVLPTKPENISCVFYFDRNLTCTWRPEKETNDTSYIVTLTYSYGKSNYSDNATEASYSFPRSCAMPPDICSVEVQAQNGDGKVKSDITYWHLISIAKTEPPIILSVNPICNRMFQIQWKPREKTRGFPLVCMLRFRTVNSSRWTEVNFENCKQVCNLTGLQAFTEYVLALRFRFNDSRYWSKWSKEETRVT MEEVPHVLDLWRILEPADMNGDRKVRLLWKKARGAPVLEKTFGYHIQYFAENSTNLTEINNITTQQYELLLMSQAHSVSVTSFNSLGKSQEAILRIPD VHEKTFQYIKSMKAYIAEPLLVVNWQSSIPAVDTWIVEWLPEAAMSKFPALSWESVSQVTNWTIEQDKLKPFTCYNISVYPVLGHRVGEPYSIQAYAKE GTPLKGPETRVENIGLRTATITWKEIPKSARNGFINNYTVFYQAEGGKELSKTVNSHALQCDLESLTRRTSYTVWVMASTRAGGTNGVRINFKTLSISVFEIVLLTSLVGGGLLLLSIKTVTFGLRKPNRLTPLCCPDVPNPAESSLATWLGDGFKKSNMKETGNSGDTEDVVLKPCPVPADLIDKLVVNFENFLEVVLTEEAGKG QASILGGEANEYVTSPSRPDGPPGKSFKEPSVLTEVASEDSHSTCSRMADEAYSELARQPSSSCQSPGLSPPREDQAQNPYLKNSVTTREFLVHENIPEHSKGEV (SEQ ID NO: 3)

[0057] Cynomolgus IL-31RA includes proteins containing the amino acid sequence:

MMWTWALWMFPLLCKFGLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTAKRTYAFGKKHDNCTTSSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSDMTCWRLEDIAKTEPPEIFSVKPVLGIKRMIRIEWIKPELAPVSSDLKYALRFRTVNSTSWMEVNFAKNRKDTNQTYNLMGLQAFTEYVV ALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPTEVDGRRPVRLLWKKARGAPVLEKTLGYNIWYFPENNTNLTETVNTTNQQLELHLGGESYWVSMISYNSLGKSPVTTLRIPAIQEKSFRCIEVMQACLAEDQLVVKWQSSALDVNTWMIEWFPDMDSEHPTLSWESVSQATNWTIQQDKLKPFWCY NISVYPMLHDKVGEPYSIQAYAKEGIPSKGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYTVRVMA STSAGGINGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPSVPNPAESSIATWRGDDFKDKLNLKESDDSVNTEDRILKPCST (SEQ ID NO: 4)

[0058] As used herein, the term “subject” is used interchangeably with the term “patient” and means a mammal, particularly a human, equine, bovine, porcine, feline, canine, mouse, rat, or non-human primate. In preferred embodiments, the subject is a human. In some embodiments, UP has been diagnosed in the subject for at least 6 months. In specific embodiments, the subject has at least 20 nodules on his body with a bilateral distribution. In specific embodiments, the subject has prurigo-related lesions on the upper extremities with or without lesions on the trunk or lower extremities. In specific embodiments, the subject has an itch that has been assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0059] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, pathomimia.

[0060] As used herein, the term “chronic prurigo” or (“CP”) is as defined in the art and means a severe disease defined by the presence of chronic pruritus and multiple localized or generalized prurigo-related lesions. The chronic pruritus condition is characterized by the presence of abraded, scaly or crusty plaques and/or papules and/or nodules, often with a whitish or pink center and hyperpigmented edges and scars. There are four subtypes of chronic pruritus: nodular type (nodular pruritus or UP), papular type (papular pruritus), plaque type, and depressed type (Kierle type). CP occurs due to neuronal sensitization to itching and the development of the itch-scratch cycle. CP can be of dermatological, systemic, neurological, psychiatric/psychosomatic, multifactorial or undetermined origin. The term CP includes all stages and manifestations of chronic prurigo. The most well-known subtype of CP is prurigo nodularis (NP). See Pereira et al., Journal of European Academy of Dermatology and Venereology (2018) 32:1059–1065.

[0061] As used herein, the term "nodular prurigo" (or "NP") is as defined in the art and refers to a skin condition that results in the formation of hard, itchy lumps (nodules) on the skin. The itching (itching) can be intense, causing people to scratch until it bleeds or hurts. Scratching may cause additional skin lesions. Itching worsens with fever, sweating, or irritation from clothing. In some cases, people with UP have a history of other conditions, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or kidney disease. The exact cause of UP is not fully understood. It is believed that nodules are most likely to form when the skin has been scratched or irritated in some way. Consequently, the actions of a person scratching the skin can lead to the formation of nodules. However, the reason why the skin becomes intensely itchy is unclear. Many people with UP have a history of eczema (atopic dermatitis), other skin conditions, or allergies. The main symptom of nodular prurigo (NP) is the formation of hard, highly itchy lumps (nodules) on the skin. The size of the nodules can range from very small to about half an inch in diameter. The nodules often have a hard, dry surface, and their number can range from several to hundreds. Most often, nodules form on the outside of the arms, shoulders and legs. Nodules can also form on the neck and torso and rarely form on the face and palms of the hands. They may be lighter or darker in color than the surrounding skin. After the nodules begin to heal, scarring may occur. Symptoms of UP can appear at any age, but most often in adults 20-60 years old. People with UP may be very concerned about the appearance of the nodules, and intensely itchy skin may make it difficult to sleep or perform daily activities. This can lead to the development of stress and depression in people with PM.

[0062] As used herein, the term “itch” is as defined in the art and refers to itchy skin and/or the sensation of itching. Itching can be caused by UP or other diseases or conditions such as dry skin. In some cases, itching includes generalized itching of the skin throughout the body. In some cases, the itching is localized to specific areas of the body, such as the arms or legs. Itching can be chronic or acute. Symptoms of itching include, but are not limited to, excoriation of the skin, redness, blisters, spots, blisters, dry skin, cracking of the skin, and a hard or scaly skin texture. In some cases, itching does not lead to detectable skin changes. Behavioral responses to itching include, but are not limited to, scratching the skin and/or massaging the skin. In some cases, scratching the skin can result in mild to severe excoriation. In some cases, patients with itching will refrain from scratching and/or massaging the skin. Traditional treatment options for itching include, but are not limited to, skin moisturizers, topical emollients, antihistamines such as diphenhydramine, corticosteroids such as topical hydrocortisone cream, soothing agents such as peppermint oil, menthol or camphor, crotamiton, antipruritic an agent often used to treat scabies, local anesthetics such as topical benzocaine cream, and phototherapy. The common type of light used for phototherapy is UVB.

[0063] As used herein, the term “antibody” generally refers to immunoglobulins or immunoglobulin-like molecules, including, for example and without limitation, IgA, IgD, IgE, IgG and IgM, combinations thereof, or fragments thereof. Antibody fragments include, for example and without limitation, Fab fragments and single chain variable fragments (scFv), as well as similar molecules produced during the immune response in any vertebrate, for example, mammals such as humans, goats, rabbits and mice, as well as non-mammalian species, for example, shark immunoglobulins.

[0064] In terms of antibody structure, an immunoglobulin generally has heavy (H) chains and light (L) chains linked together by disulfide bonds. There are two types of light chain, lambda (λ) and kappa (κ). There are five main classes (or isotypes) of the heavy chain that determine the functional activity of the antibody molecule: IgM, IgD, IgG, IgA and IgE. Each heavy and light chain contains a constant region and a variable region (regions are also known as "domains"). In combination, the heavy and light chain variable regions, also called the “Fab region,” specifically bind antigen. The heavy and light chain variable regions contain a “framework” region interspersed with three hypervariable regions, also called “complementarity determining regions” or “CDRs”. The framework volume and CDR were determined (see Kabat et al., Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, 1991, which is incorporated herein by reference). The Kabat database is available online. The framework sequences of the various light or heavy chains are relatively conserved within species. The antibody framework region, which is the combined framework regions of the constituent light and heavy chains, generally adopts a β-sheet conformation, and the CDRs form loops that connect and, in some cases, form part of the β-sheet structure. Thus, the framework regions form a scaffold that ensures that the CDRs are positioned in the correct orientation through interchain non-covalent interactions.

[0065] CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are usually designated CDR1, CDR2 and CDR3, numbered sequentially starting from the N-terminus, and are also usually identified by the chain on which the particular CDR is located. Thus, V _H CDR3 is located in the variable domain of the heavy chain of the antibody in which it is located, while V _L CDR1 is CDR1 from the variable domain of the light chain of the antibody in which it is located. An antibody that binds IL-31RA has a specific V _H region and V _L region sequence and thus specific CDR sequences. Antibodies with different specificities (i.e., different combination sites for different antigens) have different CDRs. Although the CDRs differ between antibodies, only a limited number of amino acid positions in the CDRs are directly involved in antigen binding. These positions in the CDR are called specificity-determining residues (SDRs). The antibody backbone plays a role in modulating immune cell activity. This region is called the Fc region (Fc) and consists of two heavy chains that contain two or three constant domains depending on the class of antibody. The function of the Fc region is to ensure that each antibody generates an appropriate immune response against a given antigen by binding to a specific class of proteins found on specific cells, such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils and etc., and are called “Fc receptors”. Because heavy chain constant domains make up the Fc region of an antibody, the classes of heavy chains in antibodies determine their class effects. Antibody heavy chains include alpha, gamma, delta, epsilon, and mu and correlate with antibody isotypes IgA, G, D, E, and M, respectively. This gives different antibody isotypes different class effects due to the presence of different Fc regions that bind and activate different types of receptors.

[0066] There are four subclasses of IgG, which is the most common antibody isotype found in human serum. The four subclasses IgG1, IgG2, IgG3 and IgG4 are highly conserved. In general, see the information on the Internet: ncbi.nlm.nih.gov/pmc/articles/PMC4202688/ . The amino acid sequences of the constant regions of these peptides are known in the art, for example, see Rutishauser, U. et al. (1968) “Amino acid sequence of the Fc region of a human gamma G-immunoglobulin” PNAS 61(4):1414-1421; Shinoda et al. (1981) “Complete amino acid sequence of the Fc region of a human delta chain” PNAS 78(2):785-789; and Robinson et al. (1980) “Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511)” PNAS 77(8):4909-4913.

Therapeutic antibodies

[0067] Nemolizumab is a humanized monoclonal antibody that binds to IL-31RA. Nemolizumab is annotated as follows: immunoglobulin G2-kappa, anti-[Homo sapiens IL31RA (interleukin 31 receptor subunit alpha)], humanized monoclonal antibody; heavy chain gamma 2 (1-445) [humanized VH (Homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -Homo sapiens IGHG2*01 ( CH1 C10>S (135), R12>K (137), E16>G (141), S17>G (142) (122-219), hinge C4>S (223) (220-231), CH2 H30> Q (268) (232-340), CH3 R11>Q (355), Q98>E (419) (341-445)) (122-445)], (224-214')-disulfide with kappa light chain ( 1'-214') [humanized V-kappa (Homo sapiens IGKV1-39*01 (82.10%) - IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'- 214')]; dimer (227-227":230-230")-bidisulfide. Nemolizumab has disulfide bridges in the following positions: inside H (C23-C104) 22-96 148-204 261-321 367-425 22''-96''148''-204''261''-321''367''-425''; inside L (C23-C104) 23'-88'134'-194'23'''-88'''134'''-194'''; between HL (h 5-CL 126) 224-214'224''-214'''; between HH (h 8, h 11) 227-227''230-230''. Nemolizumab has N-glycosylation sites at the following positions: H CH2 N84.4: 297, 297''. Nemolizumab lacks the C-terminal glycine and lysine H chains (CHS G1>del, K2>del).

[0068] Amino acid sequence of nemolizumab heavy chain:

QVQLVQSGAEVKKPGASVKVSCKASGYTFT GYIMN WVRQAPGQGLEWMG LINPYNGGTDYNPQFQD RVTITADKSTSTAYMELSSLRSEDTAVYYCAR DGYDDGPYTLET WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 5)

[0069] Amino acid sequence of nemolizumab light chain:

DIQMTQSPSSLSASVGDRVTITC QASEDIYSFVA WYQQKPGKAPKLLIY NAQTEAQ GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QHHYDSPLT FGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 6)

[0070] The variable domains of the heavy and light chain sequences are highlighted above in bold and the CDR sequences are underlined/italicized.

[0071] Nemolizumab-equivalent antibodies include, but are not limited to: (i) antibodies with heavy chains having at least 55%, at least 65%, at least 70%, at least 75%, at least 80 %, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100% amino acid sequence identity with the nemolizumab heavy chain sequence, ( ii) antibodies with light chains having at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100% amino acid sequence identity with the nemolizumab light chain sequence, (iii) antibodies with variable regions having at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least at least 98%, at least 99% or 100% amino acid sequence identity with the sequences of the variable regions of nemolizumab, (iv) antibodies with CDRs having at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100% amino acid sequence identity with nemolizumab CDR sequences, (v) antibodies that bind to the same isoform of IL-31RA as nemolizumab (e.g., IL31-RAv3), optionally the same epitope of IL-31RA, (vi) antibodies that block or neutralize IL -31RA, (vii) antibodies that bind to the oncostatin M receptor (OSMR), and (viii) combinations thereof. For example, suitable equivalents include immunoglobulins or immunoglobulin-like molecules with the same or substantially similar heavy and light chain amino acid sequences as nemolizumab. Additional examples of nemolizumab equivalents are described, for example, in WO 2010/064697.

[0072] Nemolizumab equivalents 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 using IL31-RA or a fragment thereof, which is obtained from a mammal, as an antigen. such as human or mouse, by known methods, after which antibodies having IL31-RA binding and/or neutralizing activity are selected from the anti-IL31-RA monoclonal antibodies thus obtained. In particular, the desired antigen or cells expressing the desired antigen are used as a sensitizing antigen for immunization in accordance with conventional immunization methods. Anti-IL31-RA monoclonal antibodies can be produced by fusing the resulting immune cells with known parent cells using traditional cell fusion methods and screening them against monoclonal antibody-producing cells (hybridoma) using traditional 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 obtained using the known gene sequence of IL31-RA, in accordance with known methods, for example, methods using baculoviruses (eg WO 98/46777).

[0073] Hybridomas can be obtained, for example, in accordance with the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46). When the immunogenicity of the antigen is low, immunization can be carried out after binding of the antigen to an immunogenic macromolecule such as albumin. Antigens used to produce monoclonal antibodies that have binding and/or neutralizing activity against human IL31-RA are not particularly limited as long as they produce antibody preparations that have binding and/or neutralizing activity against human IL31-RA. For example, it is known that there are a number of variants of human IL31-RA, and any variant can be used as an immunogen, provided that it produces antibody preparations that have binding and/or neutralizing activity against human IL31-RA. Alternatively, under the same conditions, an IL31-RA peptide fragment or a protein in which artificial mutations have been introduced into the natural IL31-RA sequence can be used as an immunogen. In the present invention, human IL31-RA is one of the preferred immunogens in the production of antibodies that have IL31-RA binding and/or neutralizing activity.

[0074] IL31-RA binding activity of 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), ELISA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay) and fluorescence antibody method. For example, if an 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 absorbance is measured to assess antigen binding activity. The binding and/or neutralizing activity of an equivalent anti-IL31-RA antibody can be measured, for example, by determining whether there is a growth inhibitory effect on an IL-31-dependent cell line. For example, the activity of purified mouse anti-IL-31 antibody can be assessed by analyzing IL-31-dependent growth of Ba/F3 cells transfected with mouse IL-31 receptor α and mouse OSMR genes.

[0075]The inventors hypothesized that an antipruritic drug may have a greater effect on UP in patients who have moderate to severe pruritus.

[0076] In some embodiments, itching is rated as none, mild, moderate, or severe. “Absent,” “mild,” “moderate,” and “severe” are terms in the art that describe the presence, extent, and/or intensity of excoriation. Those skilled in the art are aware of the limits and boundaries of these terms.

[0077]In some embodiments, the itch is characterized according to one or more of the following methods known to those skilled in the art. For example, a quick determination of intensity can be made using unidimensional scales that are commonly used in clinical practice. See Pereira et al., Allergology International (2017) 66:3–78, incorporated herein by reference. For example, patients may be asked to rate the intensity of itching from 0 (“no itching”) to 10 (“worst itch imaginable”) on a numerical rating scale (NRS). Another one-dimensional scale, the visual analogue scale (VAS), allows patients to indicate the intensity of itching using a mark on a 10 cm ruler-shaped scale. Both endpoints are designated by a number corresponding to the intensity, with 0 representing “no itch” and 10 representing “the worst itch imaginable.” Scores below 3.0 on the VAS/NRS are generally associated with mild itching, whereas scores above 6.9 illustrate severe itching. Scores above 9.0 represent very severe itching. The Verbal Rating Scale (VRS) is an additional unidimensional scale that allows patients to describe the intensity of itching in terms of gradually increasing characteristics (0—no itching, 4—worst itch imaginable). The NRS, VAS and VRS have been validated in large-scale studies involving patients with chronic pruritus with pruritic dermatoses or pruritus of various origins. These instruments have high reproducibility, and high correlations have been observed between scales 6, 7, 8. Chronic itching can greatly impair patients' quality of life. For this reason, the Dermatological Quality of Life Index (DQL) has been validated and is widely used. DQOL scores range from 0 to 30, with higher scores indicating lower quality of life. Investigator global assessment (IOR) values range from 0 (clear) to 5 (very severe disease) and are presented as a percentage of patients in the specified population. In the presented study, the OI scores range from 0 to 4.

Pharmaceutical compositions

[0078] Provided herein are pharmaceutical compositions for use in the treatment of skin lesions and itching in a subject having chronic pruritus (CP) containing, consisting of, or consisting predominantly of nemolizumab or its equivalent. In addition, the present invention provides therapeutic agents for CP that contain nemolizumab or its equivalent as an active ingredient.

[0079] In some embodiments, the subject has prurigo nodularis (NP). In some embodiments, UP has been diagnosed in the subject for at least about 6 months. In specific embodiments, the subject has at least about 20 nodules on his body with a bilateral distribution. In specific embodiments, the subject has prurigo-related lesions on the upper extremities with or without lesions on the trunk or lower extremities. In specific embodiments, the itch was assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0080] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, pathomimia.

[0081] The expression “contains nemolizumab or its equivalent as an active ingredient” means the content of nemolizumab or its equivalent as at least one of the active ingredients and does not limit the content of the antibody. In addition, the therapeutic agents for UP of the present invention may also contain, in combination with nemolizumab or its equivalent, other ingredients that enhance the treatment of UP. For example, the composition may contain one or more of topical corticosteroid creams or injections, menthol or phenol ointments to cool and soothe itchy skin, capsaicin cream, oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), and oral antihistamines.

[0082] The pharmaceutical compositions of nemolizumab or its equivalent of the present invention can be formulated in accordance with standard methods (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). In some embodiments, the pharmaceutical composition contains a carrier and/or an additive. In some embodiments, the carrier is a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical composition contains one or more of surfactants (eg, PEG and Tween), excipients, antioxidants (eg, ascorbic acid), colors, flavors, preservatives, stabilizers, buffering agents (eg, phosphoric acid , citric acid and other organic acids), chelating agents (e.g. EDTA), suspending agents, isotonic agents, binders, disintegrants, lubricants, flow agents, flavoring agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch , carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 contains 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.

[0083] When nemolizumab or its equivalent is provided as an aqueous solution for injection, nemolizumab or its equivalent can be dissolved in an isotonic solution containing, for example, physiological saline, dextrose or other adjuvants. Adjuvants may include, for example, D-sorbitol, D-mannose, D-mannitol and sodium chloride. In addition, solubilizing agents such as alcohols (eg ethanol), polyalcohols (eg propylene glycols and PEGs) and nonionic detergents (polysorbate 80 and HCO-50) can be used simultaneously.

[0084] If necessary, nemolizumab or its equivalent can be encapsulated in microcapsules (microcapsules of hydroxymethylcellulose, gelatin, polymethyl methacrylate, etc.) and enclosed in components of colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) ( for example, see “Remington's Pharmaceutical Science 16th edition” &, Oslo Ed. (1980)). In addition, methods for preparing sustained release drugs are known that can be applied to nemolizumab or its equivalent (Langer et al., J. Biomed. Mater. Res. (1981) 15, 167-277; Langer, Chem. Tech. ( 1982) 12, 98-105; US patent No. 3773919; European patent application (EP) No. 58481; Sidman et al., Biopolymers (1983) 22, 547-56).

[0085] The pharmaceutical compositions of the present invention can be administered orally or parenterally, but are preferably administered parenterally. In particular, pharmaceutical compositions are administered to patients by injection or transdermal administration. Injections include, for example, intravenous injections, intramuscular injections, and subcutaneous injections for systemic or local administration. Pharmaceutical compositions can be applied to areas where inflammation is desired to be suppressed, or areas surrounding these areas, by local infusion or intramuscular injection. In some embodiments, the pharmaceutical compositions are administered at or near the site of one or more cutaneous excoriations.

[0086] Administration methods can be appropriately selected according to the age and condition of the patient. The dose calculated per administration can be selected, for example, from the range from 0.0001 to 100 mg of active ingredient per kg of body weight. Alternatively, when the agents are administered to human patients, the dose of the active ingredient may be selected, for example, from the range of 0.001 to 1000 mg/kg body weight. In some embodiments, the composition is formulated to administer a dose containing, for example, from about 0.01 to 50 mg/kg, from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.05 mg/kg up to 0.15 mg/kg, from about 0.1 mg/kg to about 0.6 mg/kg, from about 0.1 mg/kg to about 1 mg/kg, from about 0.25 mg/kg to about 0.75 mg/kg, about 0.4 mg/kg to about 0.8 mg/kg, about 0.4 mg/kg to about 1.8 mg/kg, about 0.5 to about 2, 5 mg/kg, from about 0.8 mg/kg to about 2.2 mg/kg, from about 1 mg/kg to about 2.5 mg/kg, from about 1 mg/kg to about 3.5 mg/ kg, from about 1 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 2.5 mg/kg to about 10 mg/kg, from about 5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 20 mg/kg, from about 10 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 50 mg/kg, from about 25 mg/kg kg to about 75 mg/kg, about 50 mg/kg to about 100 mg/kg, or about 100 mg/kg to about 500 mg/kg, or about 100 mg/kg to about 1000 mg/kg body weight of nemolizumab or its equivalent. In preferred embodiments, the dose ranges from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.5 mg/kg, or from about 2.5 mg/kg to about 10 mg/kg. In some embodiments, the dose is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/ kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2 .9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/ kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 500 mg/kg or about 1000 mg/kg. In specific embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2. 5 mg/kg. In a preferred embodiment, the dose is about 0.5 mg/kg.

Treatment methods

[0087] In accordance with some embodiments, methods are provided for treating skin lesions and itching in a subject having prurigo nodularis (NP), comprising, consisting of, or consisting primarily of administering to the subject an effective amount of nemolizumab or an equivalent thereof.

[0088] In some embodiments, prurigo is moderate to severe. In some embodiments of the methods, AP has been diagnosed in the subject for at least 6 months. In specific embodiments of the methods, the subject has at least 20 nodules on his body with a bidirectional distribution. In specific embodiments of the methods, the subject has prurigo-related lesions on the upper extremities with or without lesions on the torso or lower extremities. In specific embodiments of the methods, itching was assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments of the methods, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments of the methods, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0089] In some embodiments of the methods, the subject does not have atopic dermatitis. In some embodiments of the methods, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis , bullous disease. In some embodiments of the methods, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, or pathomimia.

[0090] An "effective amount" is an amount sufficient to produce benefit or desired results, such as relief of at least one or more symptoms of UP and/or itching. As used herein, an effective amount also includes an amount sufficient to slow the progression of AD and/or pruritus, modify the course of symptoms of PM and/or pruritus (eg, sleep efficiency), or reverse symptoms of PM and/or pruritus. Therefore, it is impossible to determine the exact value of the "effective amount". However, in any given case, one skilled in the art will be able to determine the appropriate "effective amount" using only routine experimentation.

[0091] An effective amount may be administered in one or more administrations, applications, or dosages. Such delivery depends on a number of variables, including the period of time over which the individual dosage unit is intended to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It should be understood that the specific dosage levels of the therapeutic agents of the present invention for any particular subject will vary. on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex and diet of the subject, time of administration, rate of elimination, drug combination and severity of the particular disease being treated and form of administration. Treatment dosages can generally be titrated to optimize safety and effectiveness. The dosage can be determined by a doctor and, if necessary, adjusted according to the observed effects of treatment. In general, dosage-response relationships from in vitro and/or in vivo tests can initially provide useful guidance on appropriate doses to administer to patients. In general, it is desirable to administer an amount of compound that is effective to achieve serum levels commensurate with concentrations that have been found to be effective in vitro . The determination of these parameters is within the competence of those skilled in the art. These aspects, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks.

[0092] Dosing regimens for the treatment of CP and UP may include a constant dose (i.e., repeated administration of the same dose at predetermined intervals) or a loading dose (i.e., an initial dose that is greater than or different from subsequent doses). serial doses). For purposes of any type of dosing regimen, the effective dose may be administered topically, parenterally, subcutaneously, subdermally, intradermally, or intramuscularly.

[0093] In some embodiments, the loading dose and subsequent serial doses may be administered by a single route (eg, subcutaneously), while in some embodiments, the loading dose and subsequent serial doses may be administered by different routes (eg, parenterally and subcutaneously, respectively). In some embodiments, the loading dose may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg or more. In some embodiments, the loading dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg or more. In some embodiments, the loading dose may be about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0 .06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/ kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1 .6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/ kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/ kg, about 500 mg/kg or about 1000 mg/kg. In some embodiments, the loading dose may be 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0 .5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg /kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/ kg, 2 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2 .7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 500 mg/kg or 1000 mg/kg. In some embodiments, the loading dose is administered as a single injection. In some embodiments, the loading dose is administered as a number of injections, which can be administered simultaneously or spaced out over time.

[0094] Subsequent serial doses of a loading dose regimen are generally lower than the loading dose. For example, in some embodiments, the dosing regimen may include a loading dose of 60 mg and a serial dose of 30 mg, which can be administered at specified intervals, for example, 4 weeks. In some embodiments, the serial dose of the dosing regimen may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg or more. In some embodiments, the serial dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg or more. In some embodiments, the serial dose may be about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0 .06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/ kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1 .6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/ kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/ kg, about 500 mg/kg or about 1000 mg/kg. In some embodiments, the serial dose may be 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0 .5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg /kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/ kg, 2 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2 .7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 500 mg/kg or 1000 mg/kg.

[0095] For purposes of a loading dose regimen, the first serial dose may be administered after 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days , 13 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10 weeks after the initial loading dose. In some embodiments, the serial dose is administered 4 weeks after the initial loading dose. In some embodiments, subsequent serial doses are administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10 weeks. In some embodiments, the serial doses are spaced out over 4 weeks (ie, nemolizumab or its equivalent is administered once every 4 weeks).

[0096] In some embodiments, the dose of nemolizumab or its equivalent administered to the subject is in the range of 0.001 to 1000 mg/kg of the subject's body weight. In some embodiments, the dose ranges from about 0.01 to 50 mg/kg, from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.05 mg/kg to 0.15 mg/kg kg, about 0.1 mg/kg to about 0.6 mg/kg, about 0.1 mg/kg to about 1 mg/kg, about 0.25 mg/kg to about 0.75 mg/kg , from about 0.4 mg/kg to about 0.8 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.5 to about 2.5 mg/kg, from about 0.8 mg/kg to about 2.2 mg/kg, from about 1 mg/kg to about 2.5 mg/kg, from about 1 mg/kg to about 3.5 mg/kg, from about 1 mg /kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 2.5 mg/kg to about 10 mg/kg, from about 5 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 20 mg/kg, from about 10 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 50 mg/kg, from about 25 mg/kg to about 75 mg/kg kg, about 50 mg/kg to about 100 mg/kg, or about 100 mg/kg to about 500 mg/kg, or about 100 mg/kg to about 1000 mg/kg body weight of nemolizumab or its equivalent. In preferred embodiments, the dose ranges from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.5 mg/kg, or from about 2.5 mg/kg to about 10 mg/kg. In some embodiments, the dose is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/ kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2 .9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/ kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 500 mg/kg or about 1000 mg/kg. In specific embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2. 5 mg/kg. In a preferred embodiment, the dose is about 0.5 mg/kg.

[0097] In some embodiments, the dose of nemolizumab or its equivalent administered to a subject is in the range of 1 to 100 mg, 25 to 75 mg, 30 to 60 mg, 40 to 80 mg, 20 to 80 mg, 1 to 25 mg, 1 to 50 mg, 10 to 90 mg, 15 to 85 mg, or ranges between these values. In some embodiments, the dose may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg , about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg or more. In some embodiments, the dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg or more.

[0098] In specific embodiments, a loading dose of about 60 mg of nemolizumab or its equivalent can be administered to a subject in need thereof, followed by subsequent serial doses of about 30 mg of nemolizumab or its equivalent once every 4 weeks.

[0099]In some embodiments of the methods, nemolizumab or its equivalent is administered by topical or parenteral routes. In some embodiments of the methods, nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the dose is administered subcutaneously at or near the site of one or more nodules.

[0100] In some embodiments, nemolizumab or its equivalent is administered daily, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice a year, once a year, and/or as needed based on the appearance and symptoms of atopic dermatitis or pruritus (eg, CP or UP). In preferred embodiments, nemolizumab or its equivalent is administered every four weeks or every eight weeks.

[0101] In some embodiments, the duration of treatment is about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed based on the appearance and symptoms of atopic dermatitis or itching (for example, HP or UP). In preferred embodiments, the duration of treatment is from about 12 weeks to about 24 weeks, from about 12 to about 36 weeks, from about 12 to about 48 weeks, or from about 24 to about 36 weeks.

[0102] In accordance with some embodiments, the use of nemolizumab or its equivalent in the manufacture of a medicament for the treatment of prurigo in a subject having prurigo nodosa (NP) is provided.

[0103] In some embodiments, pruritus is moderate to severe. In some embodiments, the AP has been diagnosed in the subject for at least 6 months. In specific embodiments of the applications, the subject has at least 20 nodules on his body with a bilateral distribution. In specific embodiments, the subject has prurigo-related lesions on the upper extremities with or without lesions on the torso or lower extremities. In specific embodiments of the methods, itching was assigned a score of at least 7 on a numeric rating scale (NRS). In specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 over the previous 3 days. In other specific embodiments, the average value of the NRS score for the worst daily intensity is at least 7 during the previous week.

[0104] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic prurigo as a result of a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis , bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic prurigo, such as notalgia paresthetica, brachioradialis prurigo, dilutional parasitosis, pathomimia.

EXAMPLES

Example 1: Determination of the effectiveness of nemolizumab in the treatment of pruritus in patients with UP.

[0105] A multicenter (20 centers in the EU and US), randomized, double-blind, placebo-controlled, parallel group study was conducted, including approximately 70 randomized patients in 2 groups (35 per group), stratified by atopy. Enrolled patients received subcutaneous nemolizumab or placebo at a dose of 0.5 mg/kg every 4 weeks. Patients were selected based on the following criteria.

[0106] Inclusion criteria:

[0107] 1. A man or woman at least 18 years of age at the time of screening.

[0108] 2. Clinical diagnosis of UP for at least 6 months with: (a) prurigo-related lesions on the upper extremities with or without lesions on the trunk or lower extremities, and (b) at least 20 nodules throughout the body with two-way distribution

[0109] 3. Severe itching according to the digital rating scale (DRS). NRS is determined both at the screening visit and at the baseline assessment visit. Screening visit: Average NRS score for worst daily intensity ≥ 7 during the previous 3 days. Baseline assessment visit: Average NRS score for worst daily intensity ≥ 7 during the previous week.

[0110] 4. Female subjects must meet the following criteria: (a) female subjects unable to bear children (post menopause, i.e. no menstrual bleeding for 1 year prior to screening without any other medical reason, hysterectomy or bilateral oophorectomy ); (b) female subjects of childbearing potential who have agreed to adhere to complete abstinence (if consistent with the subject's preferred and usual lifestyle) or to use an effective method of contraception throughout the clinical trial and for 120 days after the last administration of the study medicinal product.

[0111] Patients with the following pathological conditions are excluded.

[0112] Exclusion criteria:

[0113] 1. Chronic prurigo resulting from a pathological condition other than UP, such as scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual dermatillomania, lymphomatoid papulosis, chronic radiation dermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease .

[0114] 2. Unilateral prurigo-related lesions (eg, only one arm is affected).

[0115] 3. Skin bacterial or viral infection within 1 week prior to the baseline assessment visit.

[0116] 4. Infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 1 week before the screening visit or during the screening period if not fully resolved at the time of the screening/baseline assessment visit level, respectively.

[0117] 5. Any uncontrolled or serious disease or any medical or surgical condition that may interfere with the interpretation of the results of the clinical trial and/or expose the subject to a significant risk in the opinion of the Investigator (for example, solid cancer, AIDS, serious or uncontrolled cardiac disease), on at screening or at baseline.

[0118]6. Any active dermatoses that require immediate treatment.

[0119] 7. Active atopic dermatitis or recurrent outbreaks of atopic dermatitis.

[0120] 8. Neuropathic or psychogenic itching (notalgia paresthetica, brachioradial pruritus, dilutional parasitosis, pathomimia).

[0121] 9. Positive serologic results for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), hepatitis C antibodies, or human immunodeficiency virus (HIV) antibodies at the time of the screening visit.

[0122] 10. Abnormal laboratory values listed below at the time of the screening visit: increased ALT/AST ≥ 3 VPN, increased CPK > 1.5 VPN, neutrophil count < 1.5 x 10 ³ /μl, creatinine clearance < 60 ml /min/1.73 m²;

[0123] 11. A history of asthma that meets any one or more of the following conditions: (i) worsening asthma requiring hospitalization in the last 12 months before the screening visit; (ii) asthma not under normal control (ie, symptoms > 2 days per week, awakening at night > 1–3 times per week, or some interference with usual activities) during the last 3 months before the screening visit; PEF <80% predicted at screening or baseline visit.

[0124] 12. Latent or active tuberculosis, determined by a positive quantiferon test for tuberculosis at the time of the screening visit.

[0125] 13. Receipt of any prohibited treatments within the specified time frame prior to the baseline assessment visit:

Table 1. Prohibited therapy

Local treatment Cleaning periods Calcineurin inhibitors (tacrolimus, pimecrolimus), TCS, vitamin D analogues, PDE-4 inhibitors 2 weeks Any topical treatment other than a moisturizer (eg, capsaicin, cryotherapy) 2 weeks Emollients or moisturizers with menthol, capsaicin, polidocanol or others with an "antipruritic" purpose 1 Week Systemic treatments Cleaning periods Corticosteroids, oral, injectable 4 weeks Immunosuppressive or immunomodulatory drugs (eg, azathioprine, methotrexate, thalidomide, cyclosporine) 8 weeks or 5 half-lives (whichever is longer) Antihistamines 1 Week Phototherapy 4 weeks Roxithromycin, erythromycin 1 Week Opioids (naltrexone, naloxone, nalbuphine, etc.), NK1 receptor antagonists (aprepitant), antiepileptic drugs (gabapentin, pregabalin) 4 weeks or 5 half-lives (whichever is longer) Biological drugs, retinoids 8 weeks or 5 half-lives (whichever is longer) Live vaccine 4 weeks Medicines with sedative effects such as benzodiazepines, imidazopyridines, hydroxyzine barbiturates or sedating antidepressants such as amitriptyline, paroxetine, unless these drugs have been taken at a stable dose for at least 3 months before screening 3 months

[0126] If the Investigator deems it medically necessary, emergency treatment options may be used with the study drug from day 29 onwards. All efficacy and safety assessments must be completed before emergency treatment options are initiated.

[0127] Table 2. Emergency treatment

Emergency therapy Action taken Antihistamines,
combined use of antihistamines and
ISS moderate strength Continuation of study drug cyclosporine, thalidomide, gabapentin, phototherapy, etc. Discontinuation of study drug

[0128] Endpoints:

[0129] The primary endpoint of the study was the percentage reduction from baseline (BI) in the CRS pruritus score at week 4.

[0130] The secondary endpoints of the study were the reduction at each visit to week 18 in CRS, VRS, or DPS. Safety assessments were also performed for a secondary endpoint. Prurigo remission was characterized by prurigo activity assessment (PDA) and PVA.

The pharmacokinetic (PK) profile of patients with UP was determined. The pharmacodynamic (PD) profile of patients with UP was determined from blood, biopsy, and D-scale samples of the patients. The quality of life of patients with UP was determined by the DQL. Actigraphy (using Actiwatch) was used to assess improvements in sleep and scratching. Photographs of patients with UP were obtained using the fotofinder system at selected centers.

[0131] The results of the clinical study are presented in the tables below.

Table 3. Demographics and baseline characteristics

Placebo
(N=36) Nemolizumab
0.5 mg/kg (N=34) Total (N=70) Floor
Male
Female
Race
White
Black/African American
Asians
Other
Age (in years)
Mean (SD)
Range 14 (38.9%)
22 (61.1%)
35 (97.2%)
1 (2.8%)
0
0
52.4 (17.47)
20-77 15 (44.1%)
19 (55.9%)
33 (97.1%)
1 (2.9%)
0
0
59.7 (13.16)
26-85 29 (41.4%)
41 (58.6%)
68 (97.1%)
2 (2.9%)
0
0
56.0 (15.85)
20-85 Weight
Mean (SD) (kg) 36
80.30 (20.716) 34
81.61 (21,766) 70
80.94 (21,088)

Note: Percentages are based on the number of subjects with a non-missing value in the corresponding treatment group.

[0132] As shown in Table 3, the placebo group and the nemolizumab treatment group had comparable study compositions for gender, race, age, and weight.

Table 4. Baseline clinical characteristics of the disease

Placebo
(N=36) Nemolizumab
0.5 mg/kg (N=34) Total (N=70) Mean baseline prurigo score (PRS) (SD)
Atopic background
Present
Absent
Number of nodules on the whole body, n (%)
20-100
> 100
Weekly assessment of CRS of maximum pruritus
Mean ± SD
Range
Weekly mean CRS score for itching
Mean (SD)
Overall Investigator Rating (ORR) , n (%)
Moderate
Strong
Baseline DQI score (range 0-30)
Mean ± SD 22.4 (17.50)
6 (16.7%)
30 (83.3%)
21 (58.3)
15 (41.7)
8.4 (1.18)
(7-9)
34
7.9 (1.28)
22 (61.1)
14 (38.9)
15.8 ± 6.0 17.1 (13.39)
5 (14.7%)
29 (85.3%)
21 (61.8)
13 (38.2)
8.4 (1.19)
(8-9)
33
7.8 (1.66)
16 (47.1)
18 (52.9)
16.9 ± 7.5 19.8 (15.76)
1
1 (15.7%)
59 (84.3%)
42 (60.0)
28 (40.0)
8.4 (1.17)
(8-9)
67
7.9 (1.47)
38 (54.3)
32 (45.7)

[0133] As shown in Table 4, the placebo group and the nemolizumab treatment group had comparable baseline levels of pruritus in the study, as measured by the number of total body nodules, weekly Numerical Rating Scale (NRS) maximum pruritus score, weekly mean NRS pruritus score, and overall assessment by the investigator (OI).

Table 5. Frequency of use of rescue medications

Placebo
(N=36) Nemolizumab, 0.5 mg/kg
(N=34) Total
(N=70) Subject with ≥ 1 rescue medication during the treatment period 4 (11.1%) 2 (5.9%) 6 (8.6%) Type of emergency assistance during the treatment period:
Local rescue drug (n)
Systemic rescue drug (n) 4 (11.1%)
3 (8.3%) 0
2 (5.9%) 4 (5.7%)
5 (7.1%)

[0134] As shown in Table 5, there was more use of topical rescue medications and systemic rescue medications in the placebo group.

[0135] The efficiency results are shown in FIG. 2-15. Specifically, in the primary endpoint, treatment with nemolizumab significantly reduced pruritus at week 4, as illustrated by the percentage change from baseline in the weekly mean CRS maximum pruritus score (Figure 2). In conclusion, treatment with nemolizumab 0.5 mg/kg was superior to placebo (-38%, 95% CI = [-51%, -25%], and the result was statistically significant (p < 0.001) at week 4.

[0136] In secondary endpoints, the nemolizumab treatment group correspondingly demonstrated a greater reduction in pruritus over the 18-week study period, as indicated by both the percentage change (Figure 3) and absolute change (Figure 4) in the CRS maximum pruritus score, and the results are statistically significant (p < 0.001). The same results were observed in both patients with and without atopic dermatitis (Figures 5 and 6).

[0137] Investigator Global Assessment (IOR) values range from 0 (clear) to 4 (severe disease) and are presented as a percentage of patients in the specified population. A much higher percentage of patients treated with nemolizumab achieved success in terms of TRI (TRI 0/1) compared with the placebo group (Figure 7). In addition, the distribution of TBI shows that the nemolizumab treatment group had a correspondingly higher percentage of patients with lower TBI than the placebo group (Figure 8). These results are statistically significant (p < 0.05) at 12 weeks and 18 weeks.

[0138] The Verbal Rating Scale (VRS) is a one-dimensional scale that allows patients to describe the intensity of itching in terms of gradually increasing ratings (1=no itching and 4=very severe itching). In other words, the nemolizumab treatment group showed a correspondingly greater percentage change in negative value, which translated into a greater reduction in pruritus over the 18-week study period compared to the placebo group (Figure 9). These results are statistically significant (p < 0.001).

[0139] Dermatologic Quality of Life Index (DQOL) scores range from 0 to 30, with higher scores indicating lower quality of life. As shown in FIG. 10, the nemolizumab treatment group had a greater percentage of patients responding with DQI ≥ 4 compared with the placebo group at both week 4 and week 12. As shown in FIG. 11, the change in DIQL from baseline was statistically significant (p < 0.01) in favor of nemolizumab at week 4 but not at week 12.

[0140] Whole body images were obtained for representative patients. As shown in FIG. 12-14, treatment with nemolizumab significantly reduced the number of nodules on the body of patients after 16 weeks.

[0141] Preliminary safety results

[0142] As shown in Tables 6 and 7, the nemolizumab treatment group and placebo group exhibited comparable rates of treatment-emergent adverse events (TEAEs) across all causes and comparable rates of TEAEs by system organ class (SOC) across all causes. Overall, nemolizumab was well tolerated.

Table 6. Overall safety summary for all-cause treatment-emergent adverse events (TEAEs)

Placebo
(N=36) Nemolizumab
0.5 mg/kg (N=34) Total
(N=70) Number of adverse events
Subjects with at least one TEAE
Serious NEVL
Severe NEVL
Lethal NEVL
TEAE that led to temporary discontinuation of the drug
TEAE that led to permanent discontinuation of the drug
TEAE that led to study discontinuation 69
24 (66.7%)
3 (8.3%)
1 (2.8%)
0
1 (2.8%)
1 (2.8%)
2 (5.6%) 77
23 (67.6%)
4 (11.8%)
5 (14.7%)
0
0
2 (5.9%)
2 (5.9%) 146
47 (67.1%)
7 (10.0%)
6 (8.6%)
0
1 (1.4%)
3 (4.3%)
4 (5.7%)

Table 7. Frequency of adverse events by system organ class (SOC) (> 5%), all cases

Placebo (N=36) Nemolizumab
0.5 mg/kg (N=34) Total (N=70) Infections and parasites
Skin and subcutaneous tissue disorders
Gastrointestinal disorders
Musculoskeletal and connective tissue disorders
General disorders and conditions at the injection site
Damage, poisoning and procedural complication
Renal and urinary tract disorders
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
Disorders of the circulatory and lymphatic system
Metabolic and nutritional disorders
Psychiatric disorders
Vascular disorders 12 (33.3%)
12 (33.3%)
5 (13.9%)
5 (13.9%)
4 (11.1%)
2 (5.6%)
2 (5.6%)
1 (2.8%)
3 (8.3%)
2 (5.6%)
0
2 (5.6%)
2 (5.6%) 10 (29.4%)
10 (29.4%)
7 (20.6%)
6 (17.6%)
5 (14.7%)
4 (11.8%)
2 (5.9%)
2 (5.9%)
0
0
2 (5.9%)
0
0 22 (31.4%)
22 (31.4%)
12 (17.1%)
11 (15.7%)
9 (12.9%)
6 (8.6%)
4 (5.7%)
3 (4.3%)
3 (4.3%)
2 (2.9%)
2 (2.9%)
2 (2.9%)
2 (2.9%)

--->

LIST OF SEQUENCES

<110> Nestle Skin Health S.A.

Christophe, Piketty

<120> TREATMENT OF SKIN LESIONS AND ITCHING IN PATIENTS WITH PRIGGIES NODOLOUSY

<130> 105153-3004

<150> US 62/797,803

<151> 2019-01-28

<150>US 62/809,404

<151> 2019-02-22

<160> 6

<170> PatentIn, version 3.5

<210> 1

<211> 662

<212> Protein

<213> Homo sapiens

<400> 1

Met Lys Leu Ser Pro Gln Pro Ser Cys Val Asn Leu Gly Met Met Trp

1 5 10 15

Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe Ser Leu Ala

20 25 30

Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr Tyr Tyr Arg

35 40 45

Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr Ser Tyr Thr

50 55 60

Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys His Asp Asn

65 70 75 80

Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser Cys Ser Phe

85 90 95

Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile Glu Val Glu

100 105 110

Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr Tyr Trp Arg

115 120 125

Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe Arg Val Lys

130 135 140

Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp Ile Lys Pro

145 150 155 160

Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu Arg Phe Arg

165 170 175

Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala Lys Asn Arg

180 185 190

Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln Pro Phe Thr

195 200 205

Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp

210 215 220

Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu Glu Ala Pro

225 230 235 240

Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu Ala Asp Gly

245 250 255

Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly Ala Pro Val

260 265 270

Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro Glu Ser Asn

275 280 285

Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln Leu Glu Leu

290 295 300

His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser Tyr Asn Ser

305 310 315 320

Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala Ile Gln Glu

325 330 335

Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val Ala Glu Asp

340 345 350

Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val Asn Thr Trp

355 360 365

Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr Thr Leu Ser

370 375 380

Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln Gln Asp Lys

385 390 395 400

Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro Met Leu His

405 410 415

Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala Lys Glu Gly

420 425 430

Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile Gly Val Lys

435 440 445

Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu Arg Lys Gly

450 455 460

Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly Gly Lys Gly

465 470 475 480

Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly Leu Glu Ser

485 490 495

Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala Ser Thr Ser

500 505 510

Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr Leu Ser Phe

515 520 525

Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly Gly Gly Leu

530 535 540

Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys Lys Pro Asn

545 550 555 560

Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro Ala Glu Ser

565 570 575

Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys Leu Asn Leu

580 585 590

Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile Leu Lys Pro

595 600 605

Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu Val Val Asn

610 615 620

Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala Arg Thr Gly

625 630 635 640

Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Thr Arg Ile Leu Ser

645 650 655

Ser Cys Pro Thr Ser Ile

660

<210> 2

<211> 732

<212> Protein

<213> Homo sapiens

<400> 2

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe

1 5 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr

20 25 30

Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr

35 40 45

Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys

50 55 60

His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser

65 70 75 80

Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile

85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr

100 105 110

Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe

115 120 125

Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp

130 135 140

Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu

145 150 155 160

Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala

165 170 175

Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln

180 185 190

Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser

195 200 205

Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu

210 215 220

Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu

225 230 235 240

Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly

245 250 255

Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro

260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln

275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser

290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala

305 310 315 320

Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val

325 330 335

Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val

340 345 350

Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr

355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln

370 375 380

Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro

385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala

405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile

420 425 430

Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu

435 440 445

Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly

450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly

465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala

485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr

500 505 510

Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly

515 520 525

Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys

530 535 540

Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro

545 550 555 560

Ala Glu Ser Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys

565 570 575

Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile

580 585 590

Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu

595 600 605

Val Val Asn Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala

610 615 620

Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Tyr Val

625 630 635 640

Thr Cys Pro Phe Arg Pro Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu

645 650 655

Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg

660 665 670

Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gln Leu Leu

675 680 685

Phe Ser Gly Gln Ser Leu Val Pro Asp His Leu Cys Glu Glu Gly Ala

690 695 700

Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Ala Arg Glu Phe Leu Val

705 710 715 720

Ser Glu Lys Leu Pro Glu His Thr Lys Gly Glu Val

725 730

<210> 3

<211> 716

<212> Protein

<213> Mus musculus

<400> 3

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser

1 5 10 15

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr

20 25 30

Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn

35 40 45

Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn

50 55 60

Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys

65 70 75 80

Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly

85 90 95

Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile

100 105 110

Ala Lys Thr Glu Pro Pro Ile Ile Leu Ser Val Asn Pro Ile Cys Asn

115 120 125

Arg Met Phe Gln Ile Gln Trp Lys Pro Arg Glu Lys Thr Arg Gly Phe

130 135 140

Pro Leu Val Cys Met Leu Arg Phe Arg Thr Val Asn Ser Ser Arg Trp

145 150 155 160

Thr Glu Val Asn Phe Glu Asn Cys Lys Gln Val Cys Asn Leu Thr Gly

165 170 175

Leu Gln Ala Phe Thr Glu Tyr Val Leu Ala Leu Arg Phe Arg Phe Asn

180 185 190

Asp Ser Arg Tyr Trp Ser Lys Trp Ser Lys Glu Glu Thr Arg Val Thr

195 200 205

Met Glu Glu Val Pro His Val Leu Asp Leu Trp Arg Ile Leu Glu Pro

210 215 220

Ala Asp Met Asn Gly Asp Arg Lys Val Arg Leu Leu Trp Lys Lys Ala

225 230 235 240

Arg Gly Ala Pro Val Leu Glu Lys Thr Phe Gly Tyr His Ile Gln Tyr

245 250 255

Phe Ala Glu Asn Ser Thr Asn Leu Thr Glu Ile Asn Asn Ile Thr Thr

260 265 270

Gln Gln Tyr Glu Leu Leu Leu Met Ser Gln Ala His Ser Val Ser Val

275 280 285

Thr Ser Phe Asn Ser Leu Gly Lys Ser Gln Glu Ala Ile Leu Arg Ile

290 295 300

Pro Asp Val His Glu Lys Thr Phe Gln Tyr Ile Lys Ser Met Lys Ala

305 310 315 320

Tyr Ile Ala Glu Pro Leu Leu Val Val Asn Trp Gln Ser Ser Ile Pro

325 330 335

Ala Val Asp Thr Trp Ile Val Glu Trp Leu Pro Glu Ala Ala Met Ser

340 345 350

Lys Phe Pro Ala Leu Ser Trp Glu Ser Val Ser Gln Val Thr Asn Trp

355 360 365

Thr Ile Glu Gln Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn Ile Ser

370 375 380

Val Tyr Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser Ile Gln

385 390 395 400

Ala Tyr Ala Lys Glu Gly Thr Pro Leu Lys Gly Pro Glu Thr Arg Val

405 410 415

Glu Asn Ile Gly Leu Arg Thr Ala Thr Ile Thr Trp Lys Glu Ile Pro

420 425 430

Lys Ser Ala Arg Asn Gly Phe Ile Asn Asn Tyr Thr Val Phe Tyr Gln

435 440 445

Ala Glu Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu

450 455 460

Gln Cys Asp Leu Glu Ser Leu Thr Arg Arg Thr Ser Tyr Thr Val Trp

465 470 475 480

Val Met Ala Ser Thr Arg Ala Gly Gly Thr Asn Gly Val Arg Ile Asn

485 490 495

Phe Lys Thr Leu Ser Ile Ser Val Phe Glu Ile Val Leu Leu Thr Ser

500 505 510

Leu Val Gly Gly Gly Leu Leu Leu Leu Ser Ile Lys Thr Val Thr Phe

515 520 525

Gly Leu Arg Lys Pro Asn Arg Leu Thr Pro Leu Cys Cys Pro Asp Val

530 535 540

Pro Asn Pro Ala Glu Ser Ser Leu Ala Thr Trp Leu Gly Asp Gly Phe

545 550 555 560

Lys Lys Ser Asn Met Lys Glu Thr Gly Asn Ser Gly Asp Thr Glu Asp

565 570 575

Val Val Leu Lys Pro Cys Pro Val Pro Ala Asp Leu Ile Asp Lys Leu

580 585 590

Val Val Asn Phe Glu Asn Phe Leu Glu Val Val Leu Thr Glu Glu Ala

595 600 605

Gly Lys Gly Gln Ala Ser Ile Leu Gly Gly Glu Ala Asn Glu Tyr Val

610 615 620

Thr Ser Pro Ser Arg Pro Asp Gly Pro Pro Gly Lys Ser Phe Lys Glu

625 630 635 640

Pro Ser Val Leu Thr Glu Val Ala Ser Glu Asp Ser His Ser Thr Cys

645 650 655

Ser Arg Met Ala Asp Glu Ala Tyr Ser Glu Leu Ala Arg Gln Pro Ser

660 665 670

Ser Ser Cys Gln Ser Pro Gly Leu Ser Pro Pro Arg Glu Asp Gln Ala

675 680 685

Gln Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu Phe Leu Val

690 695 700

His Glu Asn Ile Pro Glu His Ser Lys Gly Glu Val

705 710 715

<210> 4

<211> 735

<212> Protein

<213> Macaca fascicularis

<400> 4

Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe

1 5 10 15

Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr

20 25 30

Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr

35 40 45

Ser Tyr Thr Gln Tyr Thr Ala Lys Arg Thr Tyr Ala Phe Gly Lys Lys

50 55 60

His Asp Asn Cys Thr Thr Ser Ser Ser Thr Ser Glu Asn Arg Ala Ser

65 70 75 80

Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile

85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser Asp Met Thr

100 105 110

Cys Trp Arg Leu Glu Asp Ile Ala Lys Thr Glu Pro Pro Glu Ile Phe

115 120 125

Ser Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Arg Ile Glu Trp

130 135 140

Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Ala Leu

145 150 155 160

Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala

165 170 175

Lys Asn Arg Lys Asp Thr Asn Gln Thr Tyr Asn Leu Met Gly Leu Gln

180 185 190

Ala Phe Thr Glu Tyr Val Val Ala Leu Arg Cys Ala Val Lys Glu Ser

195 200 205

Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu

210 215 220

Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Thr Glu

225 230 235 240

Val Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly

245 250 255

Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Phe Pro

260 265 270

Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gln Gln

275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met Ile Ser

290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg Ile Pro Ala

305 310 315 320

Ile Gln Glu Lys Ser Phe Arg Cys Ile Glu Val Met Gln Ala Cys Leu

325 330 335

Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val

340 345 350

Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro

355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln

370 375 380

Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro

385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala

405 410 415

Lys Glu Gly Ile Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn Ile

420 425 430

Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu

435 440 445

Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly

450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly

465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Thr Val Arg Val Met Ala

485 490 495

Ser Thr Ser Ala Gly Gly Ile Asn Gly Thr Ser Ile Asn Phe Lys Thr

500 505 510

Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly

515 520 525

Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys

530 535 540

Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Ser Val Pro Asn Pro

545 550 555 560

Ala Glu Ser Ser Ile Ala Thr Trp Arg Gly Asp Asp Phe Lys Asp Lys

565 570 575

Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile

580 585 590

Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Ser

595 600 605

Val Val Asn Phe Gly Asn Val Leu Gln Glu Met Phe Thr Asp Glu Ala

610 615 620

Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Glu Tyr Val

625 630 635 640

Thr His Pro Phe Arg Ala Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu

645 650 655

Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg

660 665 670

Ser Arg Met Pro Glu Gly Thr Cys Leu Glu Ala Glu Glu Gln Leu Leu

675 680 685

Val Ser Gly Gln Ser Leu Glu Ser Leu Ala Pro Asp His Val Arg Glu

690 695 700

Ala Ala Ala Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu

705 710 715 720

Phe Leu Val Ser Gln Lys Leu Pro Glu His Thr Lys Gly Glu Val

725 730 735

<210> 5

<211> 445

<212> Protein

<213> Artificial sequence

<220>

<223> Amino acid sequence of nemolizumab heavy chain

<400> 5

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe

50 55 60

Gln Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys

210 215 220

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser

290 295 300

Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

<210> 6

<211> 214

<212> Protein

<213> Artificial sequence

<220>

<223> Amino acid sequence of nemolizumab light chain

<400> 6

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Phe

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asn Ala Gln Thr Glu Ala Gln Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Asp Ser Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<---

Claims (54)

1. A method of treating skin lesions and itching in a subject having chronic pruritus (CP), comprising administering to the subject an effective amount of nemolizumab. 2. The method according to claim 1, characterized in that the subject has nodular prurigo (NP). 3. The method according to claim 2, characterized in that UP has been diagnosed in the subject for at least about 6 months. 4. The method according to any of the preceding claims, characterized in that the subject has at least about 20 nodules on his body with a bilateral distribution. 5. A method according to any one of the preceding claims, characterized in that the subject has prurigo-related lesions on the upper extremities. 6. The method according to any of the preceding claims, characterized in that the itching was assigned a score of at least 4 on a digital rating scale (NRS). 7. A method according to any of the preceding claims, characterized in that the itching has been assigned a score of at least 7 on a numerical rating scale (NRS). 8. The method according to any of the preceding claims, characterized in that the subject does not have atopic dermatitis. 9. The method of any one of the preceding claims, wherein the effective amount of nemolizumab is in the range of about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg /kg, from about 0.5 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.5 mg/kg or from about 2.5 mg/kg to about 10 mg/ kg. 10. A method as claimed in any one of the preceding claims, wherein the effective amount of nemolizumab is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. 11. A method according to any one of the preceding claims, characterized in that nemolizumab is administered according to a constant dose schedule. 12. The method according to any of the preceding claims, characterized in that nemolizumab is administered in accordance with a loading dose schedule. 13. The method according to any of the preceding claims, characterized in that nemolizumab is administered locally or parenterally. 14. The method according to any of the preceding claims, characterized in that nemolizumab is administered subcutaneously. 15. A method according to any of the preceding claims, characterized in that nemolizumab is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks or once every eight weeks. 16. The method according to any of the preceding claims, characterized in that the effective amount of nemolizumab is from 30 to 60 mg. 17. The method according to claim 16, characterized in that nemolizumab is administered once every four weeks. 18. A pharmaceutical composition for use in the treatment of skin lesions and itching in a subject having chronic pruritus (CP), containing nemolizumab and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition according to claim 18, characterized in that the subject has prurigo nodularis (NP). 20. The pharmaceutical composition according to claim 19, characterized in that AP has been diagnosed in the subject for at least about 6 months. 21. Pharmaceutical composition according to any one of paragraphs. 18-20, characterized in that the subject has at least about 20 nodules on his body with a bilateral distribution. 22. Pharmaceutical composition according to any one of paragraphs. 18-21, characterized in that the subject has prurigo-related lesions on the upper extremities. 23. Pharmaceutical composition according to any one of paragraphs. 18-22, characterized in that the itching was assigned a score of at least 4 on a digital rating scale (NRS). 24. Pharmaceutical composition according to any one of paragraphs. 18-23, characterized in that the itching was assigned a score of at least 7 on a digital rating scale (NRS). 25. Pharmaceutical composition according to any one of paragraphs. 18-24, characterized in that the subject does not have atopic dermatitis. 26. Pharmaceutical composition according to any one of paragraphs. 18-25, characterized in that nemolizumab is administered in accordance with a constant dose schedule. 27. Pharmaceutical composition according to any one of paragraphs. 18-25, characterized in that nemolizumab is administered in accordance with a loading dose regimen. 28. Pharmaceutical composition according to any one of paragraphs. 18-27, characterized in that the composition contains from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg /kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg nemolizumab. 29. Pharmaceutical composition according to any one of paragraphs. 18-27, characterized in that the composition contains about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg nemolizumab. 30. Pharmaceutical composition according to any one of paragraphs. 18-29, where the composition contains from 30 to 60 mg of nemolizumab. 31. The pharmaceutical composition according to claim 30, where the composition is administered once every four weeks. 32. Use of nemolizumab in the manufacture of a medicament for the treatment of skin lesions and itching in a subject having chronic pruritus (CP). 33. Use according to claim 32, characterized in that the subject has nodular prurigo (NP). 34. Use according to claim 33, characterized in that UP has been diagnosed in the subject for at least about 6 months. 35. Application according to any one of paragraphs. 32-34, characterized in that the subject has at least about 20 nodules on his body with a bilateral distribution. 36. Application according to any one of paragraphs. 32-35, characterized in that the subject has prurigo-related lesions on the upper extremities. 37. Application according to any one of paragraphs. 32-36, characterized in that the itching was assigned a score of at least 4 on a digital rating scale (NRS). 38. Application according to any one of paragraphs. 32-37, characterized in that the itching was assigned a score of at least 7 on a digital rating scale (NRS). 39. Application according to any one of paragraphs. 32-38, characterized in that the subject does not have atopic dermatitis. 40. Application according to any one of paragraphs. 32-39, characterized in that nemolizumab is administered in accordance with a constant dose schedule. 41. Application according to any one of paragraphs. 32-40, characterized in that nemolizumab is administered in accordance with a loading dose regimen. 42. Application according to any one of paragraphs. 30-39, characterized in that nemolizumab is administered at a dose of from about 0.01 mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. 43. Application according to any one of paragraphs. 30-42, characterized in that nemolizumab is administered at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. 44. Application according to any one of paragraphs. 32-43, wherein the drug is used such that nemolizumab is administered to a subject in an amount of 30 to 60 mg. 45. Use according to claim 44, wherein the medicament is used such that nemolizumab is administered to the subject once every four weeks. 46. A pharmaceutical composition comprising nemolizumab and a pharmaceutically acceptable carrier, for use in the treatment of skin lesions and itching in a subject having pruritus nodularis (NP), where the subject does not suffer from atopic dermatitis. 47. A pharmaceutical composition comprising nemolizumab and a pharmaceutically acceptable carrier, for use in the treatment of skin lesions and itching in a subject having prurigo nodularis (NP). 48. The pharmaceutical composition according to claim 46 or 47, characterized in that the subject has at least about 20 nodules on his body with a bilateral distribution. 49. Pharmaceutical composition according to any one of paragraphs. 46-48, characterized in that the subject has prurigo-related lesions on the upper extremities. 50. Pharmaceutical composition according to any one of paragraphs. 46-49, characterized in that nemolizumab is administered in accordance with a constant dose schedule. 51. Pharmaceutical composition according to any one of paragraphs. 46-49, characterized in that nemolizumab is administered in accordance with a loading dose regimen. 52. Pharmaceutical composition according to any one of paragraphs. 46-51, where the composition is once every four weeks. 53. Pharmaceutical composition according to any one of paragraphs. 46-52, where the composition contains from 30 to 60 mg of nemolizumab. 54. Pharmaceutical composition according to any one of paragraphs. 46-52, where the composition contains 30 or 60 mg of nemolizumab.

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