Treatment of skin lesions and pruritus in patients with prurigo nodularis

Abstract

To provide methods for selectively treating pruritus in a subject having chronic prurigo (CP), including prurigo nodularis (PN), and pharmaceutical compositions therefor.SOLUTION: The method comprises administering an effective amount of nemolizumab or an equivalent thereof to a subject, who has been diagnosed of PN for at least about 6 months.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 797,803, filed January 28, 2019, and U.S. Provisional Application No. 62 / 809,404, filed February 22, 2019, the entire contents of which are incorporated herein by reference.

[0002] Field Described herein are methods for treating skin lesions and pruritus in subjects with chronic prurigo (CP), including prurigo nodularis (PN), pharmaceutical compositions for use in treating skin lesions and pruritus in subjects with CP, and the use of nemolizumab or an equivalent thereof in the manufacture of a medicament for treating skin lesions and pruritus in subjects with CP. [Background technology]

[0003] background The following discussion is provided to aid the reader's understanding of the present disclosure, and is not admitted to describing or constituting prior art thereto.

[0004] Chronic prurigo (CP) is a skin disorder caused by neural sensitization to itch and the development of an itch-scratch cycle. Prurigo nodularis (PN), a subtype of CP, is a skin disorder that causes the formation of hard, itchy lumps (nodules) on the skin. The itching (pruritus) can be intense, leading to scratching to the point of bleeding or pain. Scratching can cause the appearance of more skin lesions. The itch is worsened by irritation from heat, sweating, or clothing. In some cases, people with PN have a history of other diseases, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or kidney disease.

[0005] The exact cause of CP or PN is unknown. It is unclear what triggers the onset of itch in the first place, although scratching is known to cause the appearance of more nodules. Diagnosis of the disease is based on observation of symptoms such as extreme itching of the skin with nodule formation. In some cases, a skin biopsy is used to confirm the diagnosis. Current treatments may include corticosteroid creams, oral medications, cryotherapy, or photochemotherapy.

[0006] There remains a need to develop therapeutic regimens for treating patients with PN, particularly those suffering from chronic pruritus. Summary of the Invention

[0007] overview Provided herein are methods for treating skin lesions and pruritus in subjects with chronic prurigo (CP), including prurigo nodularis (PN), pharmaceutical compositions for use in treating skin lesions and pruritus in subjects with CP, including PN, and use of nemolizumab or an equivalent thereof in the manufacture of a medicament for treating skin lesions and pruritus in subjects with CP, including PN.

[0008] According to some embodiments, a method of treating skin lesions and pruritus in a subject with CP is provided comprising, consisting of, or consisting essentially of administering to the subject an effective amount of nemolizumab or an equivalent thereof.

[0009] In some embodiments of the method, the subject has prurigo nodularis (PN). In some embodiments of the method, the subject has been diagnosed with PN for at least about 6 months. In certain embodiments of the method, the subject has at least about 20 nodules on the body in a bilateral distribution. In certain embodiments of the method, the subject has prurigo lesions on the upper limbs, with or without lesions on the trunk or lower limbs. In certain embodiments of the method, the pruritus is assigned a score of at least 4 on the Numeric Rating Scale (NRS), while in some embodiments, the pruritus is assigned a score of at least 7. In certain embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other certain embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0010] In some embodiments of the method, the subject does not have atopic dermatitis.In some embodiments of the method, the subject does not have chronic pruritus caused by pathologies other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease.In some embodiments of the method, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0011] In some embodiments of the method, the effective amount of nemolizumab or its equivalent is in the range of about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is a 40 mg flat dose. In other specific embodiments, the effective amount of nemolizumab or its equivalent is 30 mg, with a 60 mg loading dose. In other specific embodiments, the effective amount of nemolizumab or its equivalent is six 60 mg flat doses administered once every four weeks. In some embodiments of the method, nemolizumab or its equivalent is administered by topical or parenteral route. In some embodiments of the method, nemolizumab or its equivalent is administered subcutaneously. In some embodiments, nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In certain embodiments, numolizumab is administered for at least 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months, or more.

[0012] According to some embodiments, there is provided a pharmaceutical composition for use in treating skin lesions and pruritus in a subject with chronic prurigo (CP), comprising, consisting of, or consisting essentially of nemolizumab or an equivalent thereof.

[0013] In some embodiments of the pharmaceutical composition, the subject has prurigo nodularis (PN). In some embodiments of the composition, the subject has been diagnosed with PN for at least about 6 months. In certain embodiments of the composition, the subject has at least about 20 nodules on the body in a bilateral distribution. In certain embodiments of the composition, the subject has prurigo lesions on the upper limbs with or without lesions on the trunk or lower limbs. In certain embodiments of the composition, the pruritus is assigned a score of at least 4 on the Numeric Rating Scale (NRS), while in some embodiments, the pruritus is assigned a score of at least 7. In certain embodiments of the composition, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other certain embodiments of the composition, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0014] In some embodiments of the pharmaceutical composition, the subject does not have atopic dermatitis.In some embodiments of the composition, the subject does not have chronic pruritus caused by pathologies other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease.In some embodiments of the composition, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0015] In some embodiments, the pharmaceutical composition further comprises a carrier, hi some embodiments, the carrier is a pharma- ceutically acceptable carrier.

[0016] In some embodiments of the pharmaceutical composition, nemolizumab or its equivalent is administered according to a flat dosing regimen, while in some embodiments, nemolizumab or its equivalent is administered according to a loading dose regimen, where the loading dose may be higher than subsequent consecutive doses (e.g., a loading dose of 60 mg, followed by consecutive doses of 30 mg).

[0017] In some embodiments of the pharmaceutical composition, 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, 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, while 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 of nemolizumab or its equivalent.

[0018] According to some embodiments, there is provided a use of nemolizumab, or an equivalent thereof, in the manufacture of a medicament for the treatment of pruritus in a subject with PN.

[0019] In some embodiments of this use, the pruritus is moderate to severe. In some embodiments of this use, the subject has been diagnosed with PN for at least 6 months. In certain embodiments of this use, the subject has at least 20 nodules on the body in a bilateral distribution. In certain embodiments of this use, the subject has prurigo lesions on the upper limbs, with or without lesions on the trunk or lower limbs. In certain embodiments of this use, the pruritus is assigned a score of at least 4 on the Numeric Rating Scale (NRS), while in some embodiments, the pruritus is assigned a score of at least 7. In certain embodiments of this use, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other specific embodiments of this use, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0020] In some embodiments of this use, the subject does not have atopic dermatitis.In some embodiments of this use, the subject does not have chronic pruritus caused by pathologies other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease.In some embodiments of this use, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0021] In some embodiments of this use, nemolizumab or its equivalent is administered according to a flat dosing regimen, while in some embodiments, nemolizumab or its equivalent is administered according to a loading dose regimen, where the loading dose may be higher than subsequent consecutive doses (e.g., a loading dose of 60 mg, followed by consecutive doses of 30 mg).

[0022] In some embodiments of the use, 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, 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, while 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 of nemolizumab or its equivalent. [The present invention 1001] A method for treating skin lesions and pruritus in a subject with chronic prurigo (CP), comprising administering to the subject an effective amount of nemolizumab or an equivalent thereof. [The present invention 1002] The method of claim 1001, wherein the subject has prurigo nodularis (PN). [The present invention 1003] The method of claim 1002, wherein the subject has been diagnosed with PN for at least about 6 months. [The present invention 1004] Any of the aforementioned methods of the present invention, wherein the subject has at least about 20 nodules on the body in a bilateral distribution. [The present invention 1005] Any of the methods of the present invention, wherein the subject has prurigo lesions on the upper extremities. [The present invention 1006] Any of the methods of the invention, wherein the itch is assigned a score of at least 4 on a Numeric Rating Scale (NRS). [The present invention 1007] Any of the aforementioned methods of the present invention, wherein the itch is assigned a score of at least 7 on a Numeric Rating Scale (NRS). [The present invention 1008] Any of the methods of the present invention, wherein the subject does not have atopic dermatitis. [The present invention 1009] Any of the methods of the present invention, wherein the effective amount of nemolizumab or its equivalent is about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [The present invention 1010] Any of the methods of the present invention, wherein the effective amount of nemolizumab or its equivalent 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, or about 90 mg. [The present invention 1011] Any of the methods of the present invention, wherein the nemolizumab or equivalent is administered according to a flat dosing regimen. [The present invention 1012] Any of the methods of the present invention, wherein the nemolizumab or equivalent is administered according to a loading dose regimen. [The present invention 1013] Any of the methods of the invention, wherein said nemolizumab or said equivalent is administered by topical or parenteral route. [The present invention 1014] Any of the methods of the present invention, wherein said nemolizumab or said equivalent is administered subcutaneously. [The present invention 1015] Any of the methods of the present invention, wherein the nemolizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [The present invention 1016] A pharmaceutical composition for use in treating skin lesions and pruritus in a subject with chronic prurigo (CP), comprising nemolizumab or an equivalent thereof. [The present invention 1017] The pharmaceutical composition of the present invention 1016, wherein the subject has prurigo nodularis (PN). [The present invention 1018] The pharmaceutical composition of the present invention 1017, wherein the subject has been diagnosed with PN for at least about 6 months. [The present invention 1019] Any of the pharmaceutical compositions of claims 1016 to 1018, wherein the subject has at least about 20 nodules on the body in a bilateral distribution. [The present invention 1020] The pharmaceutical composition of any one of claims 1016 to 1019, wherein the subject has a prurigo lesion on the upper limbs. [The present invention 1021] The pharmaceutical composition of any of claims 1016 to 1020, wherein the pruritus is assigned a score of at least 4 on a numerical rating scale (NRS). [The present invention 1022] The pharmaceutical composition of any of claims 1016 to 1021, wherein the pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). [The present invention 1023] The pharmaceutical composition of any one of claims 1016 to 1022, wherein the subject does not have atopic dermatitis. [The present invention 1024] The pharmaceutical composition of any one of claims 1016 to 1023, further comprising a carrier. [The present invention 1025] The pharmaceutical composition of the present invention, wherein said carrier is a pharma- ceutically acceptable carrier. [The present invention 1026] The pharmaceutical composition of any of claims 1016 to 1025, wherein said nemolizumab or its equivalent is administered according to a flat dosing regimen. [The present invention 1027] The pharmaceutical composition of any of claims 1016 to 1025, wherein said nemolizumab or its equivalent is administered according to a loading dose regimen. [The present invention 1028] Any of the pharmaceutical compositions of the present inventions 1016 to 1027, comprising about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg of nemolizumab or an equivalent thereof. [The present invention 1029] Any of the pharmaceutical compositions of the present invention 1016 to 1027, comprising about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg of nemolizumab or an equivalent thereof. [The present invention 1030] Use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of skin lesions and pruritus in a subject with chronic prurigo (CP). [The present invention 1031] The use of the present invention 1030, wherein the subject has prurigo nodularis (PN). [The present invention 1032] The use of invention 1031, wherein said subject has been diagnosed with PN for at least about 6 months. [The present invention 1033] The use of any of claims 1030 to 1032, wherein the subject has at least about 20 nodules on the body in a bilateral distribution. [The present invention 1034] The use of any one of claims 1030 to 1033, wherein the subject has a prurigo lesion on the upper limbs. [The present invention 1035] The use of any of claims 1030 to 1034, wherein said pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). [The present invention 1036] The use of any of claims 1030 to 1035, wherein said pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). [The present invention 1037] The use of any one of claims 1030 to 1036, wherein the subject does not have atopic dermatitis. [The present invention 1038] The use of any of claims 1030 to 1037, wherein said nemolizumab or its equivalent is administered according to a flat dosing regimen. [The present invention 1039] The use of any of claims 1030 to 1037, wherein said nemolizumab or its equivalent is administered according to a loading dose regimen. [The present invention 1040] The use of any of claims 1030 to 1039, wherein the nemolizumab or an equivalent thereof 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, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg. [The present invention 1041] The use of any of claims 1030 to 1039, wherein the 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, or about 90 mg. [Brief description of the drawings]

[0023] [Figure 1]This is an overview of a clinical study of nemolizumab to treat pruritus in patients with prurigo nodularis (PN).A multicenter (20 sites in the EU and US), randomized, double-blind, placebo-controlled, parallel-group study was performed with approximately 70 randomized patients in two groups (35 per group), stratified by atopic background.Enrolled patients received nemolizumab at a dose of 0.5 mg / kg or placebo once every 4 weeks from baseline to week 8. [Diagram 2] Percentage change from baseline in mean weekly peak pruritus numerical rating score (NRS) at week 4 is shown. [Diagram 3] The percentage change from baseline in mean weekly peak pruritus NRS over 18 weeks is shown. [Figure 4] Absolute change from baseline in mean weekly peak pruritus NRS over 18 weeks is shown. [Diagram 5] Absolute change from baseline in mean weekly peak pruritus NRS over 18 weeks in patients without atopy. [Figure 6] 1 shows the absolute change from baseline in mean weekly peak pruritus NRS over 18 weeks in patients with atopy. [Figure 7] The proportion of subjects achieving Investigator Global Assessment (IGA) success (0 / 1) is shown. Investigator Global Assessment (IGA) scores range from 0 (clear) to 4 (severe disease) and are presented as a percentage of patients within the population shown. [Figure 8] 1 shows the IGA distribution in patients over 18 weeks of treatment. [Figure 9] Shown is the percentage change in the Verbal Rating Scale (VRS) over 18 weeks of treatment. The Verbal Rating Scale (VRS) is a one-dimensional scale that allows patients to describe their itch intensity with ascending adjectives. [Figure 10]Dermatological Life Quality Index (DLQI) responders (4 or greater) are shown at weeks 4 and 12. Dermatological Life Quality Index (DLQI) scores range from 0 to 30, with higher scores indicating lower quality of life. [Figure 11] Changes from baseline in DLQI at weeks 4 and 12 are shown. [Figure 12] Compare whole-body images of the patient before nemolizumab treatment (A and C) and after 16 weeks of treatment (B and D). [Figure 13] Compare whole-body images of the patient before nemolizumab treatment (A and C) and after 16 weeks of treatment (B and D). [Figure 14] Compare whole-body images of the patient before nemolizumab treatment (A and C) and after 16 weeks of treatment (B and D). [Figure 15] The percentage change in mean pruritus numerical rating scale (NRS) over 18 weeks of treatment is shown. [Figure 16] The percentage of subjects with a Prurigo Activity Score (PAS) of 75% healing over 18 weeks of treatment is shown. [Figure 17] The percentage of subjects with a Prurigo Activity Score (PAS) of 50% healing over 18 weeks of treatment is shown. [Figure 18] The percentage of subjects with a Prurigo Activity Score (PAS) of 0-24% healed over 18 weeks of treatment is shown. [Figure 19] The percentage change from baseline in Sleep Disturbance NRS at week 4 is shown. [Figure 20] The percentage change in sleep disturbance NRS at week 4 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description The embodiments according to the present disclosure are described more fully below. However, aspects of the present disclosure may be embodied in different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terms used in the description of this specification are merely for the purpose of describing specific embodiments, and are not intended to be limiting.

[0025] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. It is further understood that terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of this application and the relevant art, and should not be interpreted in an ideal or overly formal sense unless expressly defined to that effect herein. Such terms are not expressly defined below, but should be interpreted according to their general meaning.

[0026] The terms used in the description of this specification are for the purpose of describing particular embodiments only and are not intended to limit the specification. All publications, patent applications, patents, and other references mentioned in this specification are incorporated by reference in their entirety.

[0027] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.Furthermore, the present disclosure also contemplates that in some embodiments, any feature or combination of features specified herein can be excluded or omitted.To explain, if the present specification states that a complex comprises components A, B, and C, it is specifically intended that any of A, B, or C, or combinations thereof, alone or in any combination, can be omitted and disclaimed.

[0028] Unless expressly stated otherwise, all specific embodiments, features, and terms are intended to include the recited embodiment, feature, or term, and biological equivalents thereof.

[0029] definition As used herein, the singular forms "a," "an," and "the" designate both the singular and the plural, unless expressly stated to designate only the singular.

[0030] Although not always explicitly indicated, it should be understood that all numerical designations are preceded by the term "about". The term "about" means that the numbers encompassed are not limited to the exact numbers set forth herein, but are intended to refer to numbers substantially around the recited numbers without departing from the scope of the present invention. As used herein, "about" is understood by those of ordinary skill in the art and varies to some extent with the context in which it is used. If the use of this term is not clear to those of ordinary skill in the art in light of the context in which it is used, "about" means up to plus or minus 15%, 10%, 5%, 1%, or 0.1% of the particular term.

[0031] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items as well as the absence of combinations when interpreted in the alternative ("or").

[0032] As used herein, "administer", "administration", "administering" refers to (1) providing, giving, dispensing, and / or prescribing (such as by or under the direction of a medical practitioner or his / her authorized agent), and (2) taking, taking, or consuming (such as by a medical practitioner or a subject). Administration includes, but is not limited to, oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implantation), by nasal inhalation spray, intravaginal, rectal, sublingual, urethral (e.g., urethral suppository), or topical routes of administration (e.g., gels, ointments, creams, aerosols, etc.), which may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmacologic acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration. The present invention is not limited by route of administration, formulation, or dosing schedule.

[0033] As used herein, "treat," "treating," or "treatment" includes reducing, ameliorating, or alleviating PN, pruritus, or one or more symptoms thereof, regardless of whether the PN and / or pruritus is considered "cured" or "cured," and regardless of whether all symptoms are resolved. These terms also include reducing or preventing the progression of PN and / or pruritus, or one or more symptoms thereof, impeding or preventing the underlying mechanisms of PN and / or pruritus, or one or more of them, as well as achieving any therapeutic and / or prophylactic benefit.

[0034] Interleukin-31 receptor subunit alpha ("IL-31RA", also known as NR10, glm-r, and GPL) is a protein that forms a heterodimer with oncostatin M receptor (OSMR) and functions as an IL-31 receptor. There are several known splice variants of human-derived IL-31RA (WO00 / 075314), and NR10.1 is composed of 662 amino acids and contains a transmembrane domain. NR10.2 is a soluble receptor-like protein composed of 252 amino acids that does not have a transmembrane domain. Meanwhile, 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 Immunol5,752-60,2004)) and IL-31RAv3. NR10.3 (IL31RAv4) consists of 662 amino acids (WO00 / 075314, Nat Immunol 5, 752-60, 2004), and IL31RAv3 consists of 732 amino acids (GenBank accession number NM-139017).

[0035] The amino acid sequence of IL31RAv4 is The file is TIFF0007671822000001.tif85170.

[0036] The amino acid sequence of IL31RAv3 is The file is TIFF0007671822000002.tif92169.

[0037] Mouse-derived IL-31RA has the amino acid sequence: Contains protein containing TIFF0007671822000003.tif92170.

[0038] The amino acid sequence of cynomolgus monkey-derived IL-31RA is Contains protein containing TIFF0007671822000004.tif92167.

[0039] As used herein, the term "subject" is used interchangeably with "patient" and refers to a mammal, specifically a human, horse, cow, pig, cat, dog, mouse, rat, or non-human primate. In preferred embodiments, the subject is a human. In some embodiments, the subject has been diagnosed with PN for at least 6 months. In certain embodiments, the subject has at least 20 nodules on the body in a bilateral distribution. In certain embodiments, the subject has prurigo lesions on the upper extremities with or without lesions on the trunk or lower extremities. In certain embodiments, the subject has pruritus assigned a score of at least 7 on the Numeric Rating Scale (NRS). In certain embodiments, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other specific embodiments, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0040] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic pruritus resulting from a condition other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0041] The term "chronic prurigo" or ("CP") is used herein as it is used in the art to refer to a characteristic disorder defined by chronic pruritus and the presence of multiple localized or generalized pruritic lesions. Chronic prurigo pathology is characterized by peeling, scaly, or crusted plaques and / or papules and / or nodules, often with whitish or pale pink centers and hyperpigmented borders and scars. There are four subtypes of chronic prurigo: nodular type (prurigo nodularis, or PN), generalized type (prurigo papularis), and plaque type, and umbilical type (Killer-type). CP results from neuronal sensitization to itch and the development of a cycle of itch-scratching. CP may 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 (PN). See Pereira et al., Journal of European Academy of Dermatology and Venereology (2018) 32:1059-1065.

[0042] "Prurigo nodularis" (or "PN"), as it is used in the art, herein means a skin disease that causes the formation of hard, itchy lumps (nodules) on the skin. The itching (pruritus) can be intense, leading to scratching to the point of bleeding or pain. Scratching can cause the appearance of more skin lesions. The itching is made worse by heat, sweating, or irritation from clothing. In some cases, people with PN have a history of other diseases, including eczema (atopic dermatitis), diabetes, lymphoma, HIV infection, severe anemia, or kidney disease. The exact cause of PN is poorly understood. It is thought that the nodules likely form when the skin is scratched or irritated in some way. Thus, the act of a person scratching their skin may cause the nodules to form. However, what causes the skin to become intensely itchy in the first place is unclear. Many people with PN have a history of eczema (atopic dermatitis), other skin conditions, or allergies. The main symptom of prurigo nodularis (PN) is the formation of hard, very itchy lumps (nodules) on the skin. The nodules can range in size from very small to about half an inch in diameter. The nodules often have a rough, dry top and can range in number from a few to hundreds. The nodules most commonly form on the outer arms, shoulders, and legs. Nodules can also form on the neck and trunk, and they rarely form on the face and palms of the hands. They may be lighter or darker in color than the surrounding skin. Scarring may occur after the nodules begin to heal. Symptoms of PN can begin at any age, but are most common in adults between the ages of 20 and 60. People with PN may be very concerned about the appearance of the nodules, and the intense itching of the skin may interfere with sleep or daily activities. This can cause people with PN to develop stress and depression.

[0043] The term "pruritus" is used herein as it is used in the art and refers to itching and / or itchy sensation of the skin. Itching can be caused by PN and other diseases or conditions, such as dry skin. In some cases, itching involves generalized skin itching throughout the body. In some cases, itching can be localized to a specific area of ​​the body, such as the arms or legs. Itching can be chronic or acute. Symptoms of pruritus include, but are not limited to, peeling, redness, bumps, spots, blisters, dry skin, cracked skin, and leathery or scaly texture of the skin. In some cases, itching does not result in detectable changes to the skin. Behavioral responses to itching include, but are not limited to, scratching and / or massaging the skin. In some cases, scratching the skin can result in peeling ranging from mild to severe. In some cases, patients with pruritus refrain from scratching and / or massaging the skin. Traditional treatments for pruritus include, but are not limited to, skin moisturizers, topical emollients, antihistamines (such as diphenhydramine), corticosteroids (such as hydrocortisone topical cream), counterirritants (such as mint oil, menthol, or camphor), crotamiton, an antipruritic agent often used to treat scabies, local anesthetics (such as benzocaine topical cream), and phototherapy. A common type of light used in phototherapy is UVB.

[0044] As used herein, the term "antibody" collectively refers to immunoglobulin or immunoglobulin-like molecules, including, by way of example and without limitation, IgA, IgD, IgE, IgG, and IgM, combinations thereof, or fragments thereof. Antibody fragments include, by way of example and without limitation, Fab fragments and single chain variable fragments (scFv), and similar molecules produced during an immune response in any vertebrate, for example, in mammals such as humans, goats, rabbits, and mice, as well as in non-mammalian species such as shark immunoglobulins.

[0045] With respect to antibody structure, immunoglobulins generally have heavy (H) and light (L) chains interconnected by disulfide bonds. There are two types of light chains, lambda (λ) and kappa (κ). The five major heavy chain classes (or isotypes) that determine the functional activity of antibody molecules are IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain contains a constant region and a variable region (the regions are also known as "domains"). In combination, the heavy and light chain variable regions, also called "Fab regions", specifically bind to antigens. The light and heavy chain variable regions contain a "framework" region interrupted by three hypervariable regions, also called "complementarity determining regions" or "CDRs". The extent of the framework regions and CDRs has been defined (see Kabat et al., Sequences of Proteins of Immunological Interest, USDepartment of Health and Human Services, 1991, hereby incorporated by reference). Kabat's database is currently maintained online. The sequences of framework regions of different light or heavy chains are relatively conserved within a species. The framework regions of antibodies, which are the combined framework regions of the constituent light and heavy chains, mostly adopt a β-sheet conformation, and the CDRs form loops that connect and sometimes form part of the β-sheet structure. Thus, the framework regions act to form a scaffold that provides the positioning of the CDRs in the correct orientation by non-covalent interactions between the chains.

[0046] CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3, are numbered consecutively starting from the N-terminus, and are typically identified by the chain in which the particular CDR is located. Thus, V H CDR3 is located within the variable domain of the heavy chain of the antibody in which it is found, whereas V L CDR1 is the CDR1 derived from the variable domain of the light chain of the antibody in which it is found. Antibodies that bind to IL-31RA have a particular VH Area and V L Each antibody has a specific CDR sequence, and therefore a specific CDR sequence. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although it is the CDRs that vary from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity determining residues (SDRs). The base of an antibody plays a role in regulating the activity of immune cells. This region is called the Fc fragment region (Fc) and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. The Fc region is found on certain cells, such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, and neutrophils, and functions to ensure that each antibody generates an appropriate immune response to a given antigen by binding to a specific class of proteins called "Fc receptors". The constant domains of the heavy chains make up the Fc region of an antibody, so the class of the heavy chains of an antibody determines their class effect. Antibody heavy chains include alpha, gamma, delta, epsilon, and mu, which correlate with the antibody's isotypes IgA, G, D, E, and M, respectively. This leads to the speculation that antibodies of different isotypes have different class effects because their different Fc regions bind to and activate different types of receptors.

[0047] IgG, the most abundant antibody isotype found in human serum, has four subclasses. The four subclasses, IgG1, IgG2, IgG3, and IgG4, are highly conserved. See generally on the World Wide Web at ncbi.nlm.nih.gov / pmc / articles / PMC4202688 / . The amino acid sequences of the constant regions of these peptides are known in the art, see, for example, Rutishauser, U. et al. (1968) "Amino acid sequence of the Fc region of a human gamma G-immunoglobulin" PNAS 61(4): 1414-1421, Shinoda et al. (1981) "Complete amino acid sequence of the Fc region of a human delta chain" PNAS 78(2): 785-789, and Robinson et al. (1980) "Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC511)" PNAS 77(8): 4909-4913.

[0048] therapeutic antibodies "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; gamma 2 heavy chain (1-445) [humanized VH (Homo sapiens IGHV1-2*02 (83.70%)-(IGHD)-IGHJ5*01) [8.8.14] (1-121)-Homo sapiens IGHG2*01 (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")-bisdisulfide. Nemolizumab has disulfide bridges at the following positions: Intra-H(C23-C104) 22-96 148-204 261-321 367-425 22''-96'' 148''-204'' 261''-321'' 367''-425''; Intra-L(C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194''''; Inter-HL(h5-CL126) 224-214' 224''-214''''; Inter-HH(h8,h11) 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 of the heavy chain (CHS G1>deletion, K2>deletion).

[0049] Nemolizumab heavy chain amino acid sequence: TIFF0007671822000005.tif63170

[0050] Nemolizumab light chain amino acid sequence: TIFF0007671822000006.tif26170

[0051] The variable domains of the heavy and light chain sequences are shown above in bold, with the CDR sequences underlined / italicized.

[0052] Equivalent antibodies to nemolizumab include (i) antibodies having a heavy chain that comprises at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the heavy chain sequence of nemolizumab; (ii) antibodies having a light chain that comprises at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the light chain sequence of nemolizumab; (iii) antibodies having a light chain that comprises at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the variable region sequence of nemolizumab. (iv) antibodies having CDRs that comprise at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with the CDR sequences of nemolizumab; (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 (viiii) combinations thereof. For example, suitable equivalents include immunoglobulins or immunoglobulin-like molecules having the same or substantially similar heavy and light chain amino acid sequences as nemolizumab. Additional exemplary nemolizumab equivalents are described, for example, in WO2010 / 064697.

[0053] The equivalent of nemolizumab can be a monoclonal or polyclonal antibody. Such monoclonal antibodies having IL31-RA binding and / or neutralizing activity can be obtained, for example, by the following procedure. Anti-IL31-RA monoclonal antibodies are prepared by using antigen IL31-RA or a fragment thereof derived from a mammal such as human or mouse by known methods, and then antibodies having IL31-RA binding and / or neutralizing activity are selected from the anti-IL31-RA monoclonal antibodies thus obtained. Specifically, the desired antigen or cells expressing the desired antigen are used as sensitizing antigens for immunization according to conventional immunization methods. Anti-IL31-RA monoclonal antibodies can be prepared by fusing the obtained immune cells with known parent cells using conventional cell fusion methods and screening them for monoclonal antibody-producing cells (hybridomas) by conventional screening methods. Animals to be immunized include, for example, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses, and pigs. Antigens can be prepared according to known methods, for example by baculovirus-based methods, using known IL31-RA gene sequences (eg, WO98 / 46777).

[0054] Hybridomas can be prepared, for example, according to the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73:3-46). When the antigen is lowly immunogenic, the antigen may be linked to a macromolecule having immunogenicity such as albumin before immunization. The antigens used for the preparation of monoclonal antibodies having binding and / or neutralizing activity against human IL31-RA are not specifically limited, so long as they allow the preparation of antibodies having binding and / or neutralizing activity against human IL31-RA. For example, it is known that there are several mutants in human IL31-RA, and any mutant may be used as an immunogen, so long as it allows the preparation of antibodies having binding and / or neutralizing activity against human IL31-RA. Alternatively, under the same conditions, a peptide fragment of IL31-RA or a protein in which an artificial mutation has been introduced into natural IL31-RA may be used as an immunogen. Human IL31-RA.3 is one of the preferred immunogens for preparing antibodies having activity of binding to and / or neutralizing IL31-RA in the present disclosure.

[0055] The IL31-RA binding activity of the equivalent antibody can be determined by methods known to those skilled in the art. Methods for determining the antigen-binding activity of an antibody include, for example, ELISA (enzyme-linked immunosorbent assay), EIA (enzyme immunoassay), RIA (radioimmunoassay), and fluorescent antibody method. For example, when an enzyme immunoassay is used, an antibody-containing sample, such as purified antibody and culture supernatant of antibody-producing cells, is added to a plate coated with an antigen. A secondary antibody labeled with an enzyme such as alkaline phosphatase is added, and the plate is incubated. After washing, an enzyme substrate such as p-nitrophenyl phosphate is added, and absorbance is measured to evaluate the antigen-binding activity. The binding and / or neutralizing activity of the equivalent antibody against IL31-RA can be measured, for example, by observing the effect of suppressing the growth of IL-31-dependent cell lines. For example, the activity of purified mouse IL-31 antibody can be measured by evaluating the IL-31-dependent growth of Ba / F3 cells transfected with mouse IL-31 receptor alpha and mouse OSMR gene.

[0056] We hypothesized that antipruritic drugs may have a greater impact on PN in patients with moderate to severe pruritus.

[0057] In some embodiments, itching is scored as none, mild, moderate, or severe. "None," "mild," "moderate," and "severe" are terms of art describing the presence, extent, and / or intensity of peeling. Those skilled in the art understand the boundaries of these terms.

[0058] In some embodiments, itch is characterized according to one or more of the following methods known to those skilled in the art. For example, intensity can be quickly measured using a unidimensional scale commonly used in clinical care. See Pereira et al., Allergology International (2017) 66:3-78, incorporated herein by reference. For example, patients can be asked to rate the intensity of their itch using a numerical rating scale (NRS) from 0 ("no itch") to 10 ("worst itch imaginable"). Another unidimensional scale, the visual analog scale (VAS), offers patients the opportunity to indicate the intensity of their itch by marking a ruler-shaped scale 10 cm long. Both endpoints are marked with numbers corresponding to intensity, with 0 representing "no itch" and 10 representing "worst itch imaginable". A VAS / NRS score of less than 3.0 points is generally associated with mild itch, while a score higher than 6.9 indicates severe itch. A score above 9.0 represents very severe itch. The verbal rating scale (VRS) is a more unidimensional scale that allows patients to describe the intensity of their itch by ascending adjectives (0 being no itch, 4 being the worst itch imaginable). The NRS, VAS, and VRS have been validated in a large study of patients with chronic itch, either with pruritic skin diseases or with itch of various origins. These instruments have a high degree of reproducibility, and there was a high correlation between scales 6, 7, and 8. Chronic itch can greatly reduce the quality of life of patients. For this reason, the Dermatological Quality of Life Index (DLQI) has been widely used and validated. DLQI scores range from 0 to 30, with higher scores indicating a lower quality of life. Investigator Global Assessment (IGA) scores range from 0 (clear) to 5 (very severe disease) and are presented as a percentage of patients within the indicated population. In this study, IGA scores range from 0 to 4.

[0059] Pharmaceutical Compositions Provided herein is a pharmaceutical composition for use in treating skin lesions and pruritus in subjects with chronic prurigo (CP), comprising, consisting of, or consisting essentially of nemolizumab or its equivalent.Furthermore, the present disclosure provides a therapeutic agent for CP, comprising nemolizumab or its equivalent as an active ingredient.

[0060] In some embodiments, the subject has prurigo nodularis (PN). In some embodiments, the subject has been diagnosed with PN for at least about 6 months. In certain embodiments, the subject has at least about 20 nodules on the body in a bilateral distribution. In certain embodiments, the subject has prurigo lesions on the upper limbs with or without lesions on the trunk or lower limbs. In certain embodiments, the pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). In certain embodiments, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other certain embodiments, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0061] In some embodiments, the subject does not have atopic dermatitis. In some embodiments, the subject does not have chronic pruritus resulting from a condition other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease. In some embodiments, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0062] The phrase "containing nemolizumab or its equivalent as an active ingredient" means containing nemolizumab or its equivalent as at least one of the active ingredients, and does not limit the percentage of the antibody. In addition, the therapeutic agent for PN in the present disclosure may also contain other ingredients that enhance the treatment of PN in combination with nemolizumab or its equivalent. For example, the composition may contain one or more topical corticosteroid creams or injections, ointments with menthol or phenol that cool and soothe skin itching, capsaicin creams, oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), and oral antihistamines.

[0063] The pharmaceutical composition of nemolizumab or its equivalent of the present disclosure can be prepared as a formulation according to standard methods (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). In some embodiments, the pharmaceutical composition includes a carrier and / or an additive. In some embodiments, the carrier is a pharma- ceutically acceptable carrier. For example, in some embodiments, the pharmaceutical compositions include one or more surfactants (e.g., PEG and Tween), excipients, antioxidants (e.g., ascorbic acid), colorants, flavoring agents, preservatives, stabilizers, buffers (e.g., phosphoric acid, citric acid, and other organic acids), chelating agents (e.g., EDTA), suspending agents, isotonicity agents, binders, disintegrants, lubricants, flow enhancers, flavoring agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, and inorganic salts. In some embodiments, the pharmaceutical composition comprises one or more other low molecular weight polypeptides, proteins (such as serum albumin, gelatin, and immunoglobulins), and amino acids (such as glycine, glutamine, asparagine, and lysine).

[0064] When preparing nemolizumab or its equivalent as an injectable aqueous solution, nemolizumab or its equivalent can be dissolved in an isotonic solution containing, for example, physiological saline, glucose, or other adjuvants.Adjuvants can include, for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride.In addition, suitable solubilizers can be used at the same time, for example, alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol and PEG), and nonionic surfactants (polysorbate 80 and HCO-50).

[0065] If desired, nemolizumab or its equivalent may be encapsulated in microcapsules (such as those made of hydroxymethylcellulose, gelatin, and polymethylmethacrylate) and made into a component of colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) (see, e.g., "Remington's Pharmaceutical Science 16th edition" &, Oslo Ed. (1980)). Additionally, methods for making sustained release drugs are known and can be applied to nemolizumab or its equivalents (Langer et al., J. Biomed. Mater. Res. (1981) 15, 167-277; Langer, Chem. Tech. (1982) 12, 98-105; U.S. Pat. No. 3,773,919; European Patent Application (EP) No. 58,481; Sidman et al., Biopolymers (1983) 22, 547-56; EP 133,988).

[0066] The pharmaceutical composition of the present disclosure can be administered either orally or parenterally, but is preferably administered parenterally.Specifically, the pharmaceutical composition is administered to the patient by injection or transdermal administration.Injection includes, for example, intravenous injection, intramuscular injection, and subcutaneous injection for systemic or local administration.The pharmaceutical composition can be given by local injection or intramuscular injection at the site where inflammation should be suppressed or in the area surrounding those sites.In some embodiments, the pharmaceutical composition is administered at one or more sites of skin peeling or proximal to one or more sites of skin peeling.

[0067] The administration method can be appropriately selected according to the age and pathological condition of the patient. The single administration dose can be selected, for example, from the range of 0.0001-100 mg of active ingredient per kg of body weight. Alternatively, for example, when the drug is administered to a human patient, the dose of the active ingredient can be selected from the range of 0.001-1,000 mg / kg of body weight. In some embodiments, the composition may be administered in a dose range of, for example, about 0.01 to 50 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.05 mg / kg to 0.15 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 0.75 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 1.8 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.8 mg / kg to about 2.2 mg / kg, about 1 mg / kg to about 2.5 mg / kg, about 1 mg / kg to about 3.5 mg / kg, or about 3.5 mg / kg. The present invention is formulated to administer a dose containing about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 20 mg / kg to about 50 mg / kg, about 25 mg / kg to about 75 mg / kg, about 50 mg / kg to about 100 mg / kg, or about 100 mg / kg to about 500 mg / kg, or about 100 mg / kg to about 1000 mg / kg of body weight of nemolizumab or an equivalent thereof. In preferred embodiments, the dose ranges from about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.In some embodiments, the 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 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In a preferred embodiment, the dose is about 0.5 mg / kg.

[0068] Treatment method According to some embodiments, a method of treating pruritus in a subject with prurigo nodularis (PN) is provided comprising, consisting of, or consisting essentially of administering to the subject an effective amount of nemolizumab or an equivalent thereof.

[0069] In some embodiments, the pruritus is moderate to severe. In some embodiments of the method, the subject has been diagnosed with PN for at least 6 months. In certain embodiments of the method, the subject has at least 20 nodules on the body in a bilateral distribution. In certain embodiments of the method, the subject has prurigo lesions on the upper limbs, with or without lesions on the trunk or lower limbs. In certain embodiments of the method, the pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). In certain embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other certain embodiments of the method, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0070] In some embodiments of the method, the subject does not have atopic dermatitis.In some embodiments of the method, the subject does not have chronic pruritus caused by pathologies other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease.In some embodiments of the method, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering.

[0071] An "effective amount" is an amount sufficient to produce beneficial or desired results, such as the alleviation of at least one or more symptoms of PN and / or pruritus.As used herein, an effective amount also includes an amount sufficient to delay the onset of AD and / or pruritus, change the course of symptoms of PN and / or pruritus (e.g., sleep efficiency), or reverse symptoms of PN and / or pruritus.Therefore, it is not possible to specify an exact "effective amount".However, for any given case, a person skilled in the art can determine the appropriate "effective amount" using only routine experimental methods.

[0072] An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery depends on several variables, including the period for which the individual dosage units are to be used, the bioavailability of the therapeutic agent, the route of administration, and the like. However, it is understood that the specific dosage level of the therapeutic agent of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the particular compound used, the subject's age, weight, general health, sex, and diet, the time of administration, the rate of excretion, drug combinations, and the severity and form of administration of the particular disorder being treated. Therapeutic dosages can generally be titrated to optimize safety and efficacy. Dosages are determined by the physician and can be adjusted as necessary to match the observed therapeutic effect. Typically, dosage-effect relationships from in vitro and / or in vivo testing can provide useful guidance initially on the appropriate dosage for patient administration. In general, it is desired to administer an amount of the compound effective to achieve serum levels commensurate with the concentration found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations as well as effective formulations and administration procedures are well known in the art and are described in standard texts.

[0073] Dosage regimens for treating CP and PN may include plateau dosing (i.e., administering the same dose repeatedly at predetermined intervals) or loading doses (i.e., administering an initial dose that is higher or different than subsequent successive doses). For either type of dosing regimen, an effective dose can be administered topically, parenterally, subcutaneously, subdermally, intradermally, or intramuscularly.

[0074] In some embodiments, the loading dose and subsequent consecutive doses can be administered via the same route (e.g., subcutaneously), while in some embodiments, the loading dose and subsequent consecutive doses can be administered via different routes (e.g., parenteral and subcutaneous, respectively). In some embodiments, the loading dose can 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 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 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 ...1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 2.8 mg / kg, about g, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg.In some embodiments, the loading dose is 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, 2.0 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, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 ... / kg, 1.8mg / kg, 1.9mg / kg, 2mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.5mg / kg, 4mg / kg, 4.5mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 25mg / kg, 50mg / kg, 75mg / kg, 100mg / kg, 500mg / kg, or 1,000mg / kg. In some embodiments, the loading dose is administered as a single injection. In some embodiments, the loading dose is administered as multiple injections, which may be administered simultaneously or at defined intervals.

[0075] The subsequent successive doses of the loading dose regimen are generally lower than the loading dose.For example, in some embodiments, the dosing regimen may include a loading dose of 60mg and a successive dose of 30mg, which may be administered at a defined interval, for example, once every 4 weeks.In some embodiments, the successive doses of the dosing regimen may be about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg or more. In some embodiments, the continuous 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 continuous 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 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 ...1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about g, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg.In some embodiments, the sequential doses are 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, 2.0 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, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 ... / kg, 1.8mg / kg, 1.9mg / kg, 2mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.5mg / kg, 4mg / kg, 4.5mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 25mg / kg, 50mg / kg, 75mg / kg, 100mg / kg, 500mg / kg, or 1,000mg / kg.

[0076] For the loading dose regimen, the first consecutive dose can be administered 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 days, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks after the initial loading dose. In some embodiments, the first consecutive dose is administered 4 weeks after the initial loading dose. In some embodiments, the subsequent consecutive 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 consecutive doses are spaced 4 weeks apart (i.e., nemolizumab or its equivalent is administered once every 4 weeks).

[0077] In some embodiments, the dose of nemolizumab or its equivalent administered to a subject is within the range of 0.001 to 1,000 mg / kg of the subject's body weight. In some embodiments, the dose is about 0.01 to 50 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.05 mg / kg to 0.15 mg / kg, about 0.1 mg / kg to about 0.6 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 0.75 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.4 mg / kg to about 1.8 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.8 mg / kg to about 2.2 mg / kg, about 1 mg / kg to about 2.5 mg / kg, about 1 mg / kg to about 3. 5 mg / kg, about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 40 mg / kg, about 20 mg / kg to about 50 mg / kg, about 25 mg / kg to about 75 mg / kg, about 50 mg / kg to about 100 mg / kg, or about 100 mg / kg to about 500 mg / kg, or about 100 mg / kg to about 1000 mg / kg of 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, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.5 mg / kg, or about 2.5 mg / kg to about 10 mg / kg.In some embodiments, the 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 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 500 mg / kg, or about 1,000 mg / kg. In certain embodiments, the effective amount of nemolizumab or its equivalent is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, or about 2.5 mg / kg. In a preferred embodiment, the dose is about 0.5 mg / kg.

[0078] In some embodiments, the dose of nemolizumab or its equivalent administered to a subject is within the range of 1-100 mg, 25-75 mg, 30-60 mg, 40-80 mg, 20-80 mg, 1-25 mg, 1-50 mg, 10-90 mg, 15-85 mg, or any range therebetween. 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.

[0079] In certain embodiments, a loading dose of about 60 mg of nemolizumab or its equivalent may be administered to a subject in need thereof, followed by subsequent continuous doses of about 30 mg of nemolizumab or its equivalent once every four weeks.

[0080] In some embodiments of the method, nemolizumab or its equivalent is administered by topical or parenteral route. In some embodiments of the method, nemolizumab or its equivalent is administered subcutaneously. In some embodiments, the dose is administered subcutaneously or proximal to the site of one or more nodules.

[0081] In some embodiments, nemolizumab or its equivalent is administered daily, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, twice a year, once a year, and / or as needed based on the appearance of symptoms of atopic dermatitis or pruritus (e.g., CP or PN). In a preferred embodiment, nemolizumab or its equivalent is administered once every four weeks or once every eight weeks.

[0082] In some embodiments, the treatment period is about 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, or as needed based on the appearance of symptoms of atopic dermatitis or pruritus (e.g., CP or PN). In preferred embodiments, the treatment period is about 12 weeks to about 24 weeks, about 12 to about 36 weeks, about 12 to about 48 weeks, or about 24 to about 36 weeks.

[0083] According to some embodiments, there is provided a use of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of pruritus in a subject with prurigo nodularis (PN).

[0084] In some embodiments of this use, the pruritus is moderate to severe. In some embodiments of this use, the subject has been diagnosed with PN for at least 6 months. In certain embodiments of this use, the subject has at least 20 nodules on the body in a bilateral distribution. In certain embodiments of this use, the subject has prurigo lesions on the upper limbs, with or without lesions on the trunk or lower limbs. In certain embodiments of this method, the pruritus is assigned a score of at least 7 on the Numeric Rating Scale (NRS). In certain embodiments of this use, the average of the worst daily intensity of the NRS score is at least 7 over the past 3 days. In other certain embodiments of this use, the average of the worst daily intensity of the NRS score is at least 7 over the past week.

[0085] In some embodiments of this use, the subject does not have atopic dermatitis.In some embodiments of this use, the subject does not have chronic pruritus caused by pathologies other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease.In some embodiments of this use, the subject does not have neuropathic or psychogenic pruritus, such as dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, and malingering. EXAMPLES

[0086] Example 1 Determine the efficacy of nemolizumab in treating pruritus in patients with PN A multicenter (20 sites in the EU and the US), randomized, double-blind, placebo-controlled, parallel-group study was performed involving approximately 70 randomized patients in two groups (35 per group) stratified by atopic background. Enrolled patients received subcutaneous nemolizumab at a dose of 0.5 mg / kg or placebo once every 4 weeks. Patients were selected based on the following criteria:

[0087] Inclusion Criteria: 1. Male or female, at least 18 years of age at the time of screening.

[0088] 2. Clinical diagnosis of PN for at least 6 months with: (a) prurigo lesions on the upper extremities with or without involvement of the trunk or lower extremities, and (b) at least 20 nodules over the whole body in a bilateral distribution.

[0089] 3. Severe pruritus on the Numeric Rating Scale (NRS). NRS is determined by both screening and baseline visits. Screening visit: Mean worst daily intensity of NRS score is 7 or more for the past 3 days. Baseline visit: Mean worst daily intensity of NRS score is 7 or more for the past week.

[0090] 4. Female subjects must meet one of the following criteria: (a) female subjects of non-childbearing potential (postmenopausal, i.e., absence of menses for one year prior to screening, hysterectomy, or bilateral oophorectomy, not for any other medical reason), (b) female subjects of childbearing potential who are abstinent (if consistent with the subject's preferred usual lifestyle) or who agree to use effective contraceptive methods throughout the clinical trial and for 120 days after administration of the final study drug.

[0091] Patients with the following conditions will be excluded:

[0092] Exclusion criteria: 1. Chronic pruritus resulting from another condition other than PN, such as scabies, insect bites, localized neurodermatitis, psoriasis, acne, folliculitis, excoriation disorder, lymphomatoid papulosis, chronic photosensitive dermatitis, dermatitis herpetiformis, sporotrichosis, or bullous diseases.

[0093] 2. Unilateral involvement of prurigo (e.g., only one arm affected).

[0094] 3. Bacterial or viral skin infections within 1 week prior to the baseline visit.

[0095] 4. Infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or antifungals within 1 week prior to the Baseline visit or during the Baseline period unless completely resolved at the Screening / Baseline visits, respectively.

[0096] 5. Any uncontrolled or serious disease, or any medical or surgical condition that may interfere with interpretation of the clinical trial results and / or that, in the judgment of the investigator at screening or baseline, may place the subject at significant risk (e.g., solid cancer, AIDS, serious or uncontrolled cardiac disease).

[0097] Any active skin condition requiring immediate treatment.

[0098] 7. Known active atopic dermatitis or recurrent erythema of atopic dermatitis.

[0099] 8. Neuropathic and psychogenic pruritus (dorsalgia paresthesia, brachioradial pruritus, delusional parasitosis, malingering).

[0100] 9. Positive serology results, hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), hepatitis C antibody, or human immunodeficiency virus (HIV) antibody, at the screening visit.

[0101] 10. Abnormal laboratory criteria at the screening visit, as listed below: ALT / AST elevation above upper limit of normal ≥3, CPK elevation above upper limit of normal >1.5, ≥1.5×10 3 Neutrophil count less than 60 ml / min / 1.73 m 2 Creatinine clearance of less than .

[0102] 11. Medical history of asthma with any or more of the following conditions: (i) having had an asthma exacerbation requiring hospitalization within the past 12 months prior to the screening visit, (ii) having poorly controlled asthma (i.e., symptoms >2 days per week, more than 1-3 nighttime awakenings per week, or some interference with usual activities) during the past 3 months prior to the screening visit, with a PEF <80% of predicted at the time of the screening or baseline visit.

[0103] 12. Latent or active TB as determined by a positive, QuantiFERON-based TB test result at the screening visit.

[0104] 13. Having received any prohibited treatment within the specified time frame prior to the baseline visit.

[0105] (Table 1) Prohibited therapy TIFF0007671822000007.tif172168

[0106] If deemed medically necessary by the investigator, rescue treatment for pruritus may be associated with study drug beginning on Day 29. All efficacy and safety evaluations should be completed prior to the initiation of rescue treatment.

[0107] (Table 2) Rescue therapy TIFF0007671822000008.tif39167

[0108] Endpoints: The primary endpoint of the study was the percent reduction from baseline (BL) in the Pruritus NRS at week 4.

[0109] Secondary endpoints of the study were reductions at each visit up to week 18, as characterized by NRS, VRS, or DPS. Safety assessments were also performed as secondary endpoints. Relief of prurigo was characterized by Prurigo Activity Score (PAS) and IGA.

[0110] Pharmacokinetic (PK) profiles of PN patients were measured. Pharmacodynamic (PD) profiles of PN patients were measured in blood, biopsy, and D-squame samples of patients. Quality of life of PN patients was measured by DLQI. Actigraphy (by Actiwatch) was applied to evaluate sleep improvement and scratching. Photos of PN patients were taken at selected centers by FotoFinder.

[0111] The results of the clinical study are presented in the table below.

[0112] Table 3. Demographic and baseline characteristics TIFF0007671822000009.tif85160Note: Percentages are based on the number of subjects with non-missing values ​​in each treatment group.

[0113] As shown in Table 3, the placebo and nemolizumab treatment groups in this study presented comparable compositions in terms of gender, race, age, and weight.

[0114] Table 4. Baseline clinical disease characteristics TIFF0007671822000010.tif122170

[0115] As shown in Table 4, the placebo and nemolizumab treatment groups in this study presented with comparable baseline levels of pruritus as measured by the number of whole body nodules, 1-week peak value rating scale (NRS) score, 1-week mean pruritus NRS score, and Investigator Global Assessment (IGA) score.

[0116] Table 5. Incidence of rescue medication TIFF0007671822000011.tif63168

[0117] As shown in Table 5, the placebo group had a greater incidence of local and systemic rescue medications.

[0118] Efficacy results are shown in Figures 2-15. Specifically, at the primary endpoint, nemolizumab treatment significantly reduced pruritus at week 4, as shown by the percentage change from baseline in the mean peak pruritus NRS at 1 week (Figure 2). Thus, nemolizumab treatment at a dosage of 0.5 mg / kg is superior to placebo (-38% at week 4, 95% CI = [-51%, -25%], and statistically significant (p<0.001).

[0119] In secondary endpoints, the nemolizumab treatment group consistently demonstrated greater reductions in pruritus throughout the 18-week study, as evidenced by both the percentage change (Figure 3) and absolute change (Figure 4) in peak pruritus NRS, with results that were statistically significant (p<0.001). The same results were observed in patients with and without atopic dermatitis (Figures 5 and 6).

[0120] Investigator Global Assessment (IGA) scores range from 0 (clear) to 4 (severe disease) and are presented as the percentage of patients within the indicated population. Compared to the placebo group, a much higher percentage of nemolizumab-treated patients achieved IGA success (IGA 0 / 1) (Figure 7). In addition, the IGA distribution shows that the nemolizumab-treated group consistently had a higher percentage of patients with lower IGA than the placebo group (Figure 8). These findings are statistically significant at weeks 12 and 18 (p<0.05).

[0121] The verbal rating scale (VRS) is a one-dimensional scale that allows patients to describe their itch intensity by ascending adjectives (1 = no itch, and 4 = very severe itch). In other words, the nemolizumab treatment group consistently showed a higher percentage change in negative values, which translates into a greater reduction in itch throughout the 18-week study compared to the placebo group (Figure 9). The results are statistically significant (p<0.001).

[0122] Dermatological Life Quality Index (DLQI) scores range from 0 to 30, with higher scores indicating lower quality of life. As shown in Figure 10, at both weeks 4 and 12, the nemolizumab treatment group had a higher percentage of responders rating with a DLQI of 4 or higher compared to the placebo group. As shown in Figure 11, the change from baseline in DLQI was statistically significant (p<0.01) in favor of nemolizumab at week 4, but not at week 12.

[0123] Representative patient whole body images were taken. As shown in Figures 12-14, nemolizumab treatment significantly reduced the number of nodules on the patient's body after 16 weeks.

[0124] Preliminary safety results As shown in Tables 6 and 7, the nemolizumab-treated and placebo groups had similar numbers of all-cause treatment-emergent adverse events (TEAEs) and similar incidences of all-cause TEAEs by system organ class (SOC). Overall, nemolizumab was well tolerated.

[0125] Table 6. Safety - Overall Summary of All-Cause Treatment-Emergent Adverse Events (TEAEs) TIFF0007671822000012.tif73167

[0126] Table 7. Incidence of TEAEs (>5%) by System Organ Class (SOC), all causes TIFF0007671822000013.tif108167

[0127] Sequence information SEQUENCE LISTING <110> Galderma Holdings SA Chugai Seiyaku Kabushiki Kaisha <120> TREATMENT OF SKIN LESIONS AND PRURITUS IN PRURIGO NODULARIS PATIENTS <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> PRT <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> PRT <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> PRT <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> PRT <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> PRT <213> Artificial Sequence <220> <223> Nemolizumab heavy chain amino acid sequence <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> PRT <213> Artificial Sequence <220> <223> Nemolizumab light chain amino acid sequence <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

1. A pharmaceutical composition formulated for subcutaneous administration comprising an effective amount of nemolizumab for use in treating skin lesions and pruritus in a subject with prurigo nodularis (PN), comprising: the subject does not have atopic dermatitis; The pharmaceutical composition.

2. The pharmaceutical composition described in claim 1, characterized in that the pharmaceutical composition is administered to a subject once every four weeks.

3. The pharmaceutical composition of claim 1 or 2, wherein the effective amount of nemolizumab is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg.

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the subject achieves at least about a 55% reduction in average peak pruritus numerical rating score (NRS) over one week.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the subject has been diagnosed with PN for at least about 6 months.

6. The pharmaceutical composition described in any one of claims 1 to 5, wherein the subject has at least about 20 nodules on the body in a bilateral distribution or the subject has prurigo lesions on the upper extremities.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein the pruritus is assigned a score of at least 4 on the Numeric Rating Scale (NRS).

8. The pharmaceutical composition of any one of claims 1 to 7, further comprising a pharma- ceutically acceptable carrier.

9. A pharmaceutical composition described in any one of claims 1 to 8, characterized in that the nemolizumab is administered to a subject according to a flat dosing regimen.

10. A pharmaceutical composition described in any one of claims 1 to 8, characterized in that the nemolizumab is administered to a subject according to a loading dose regimen.

11. A pharmaceutical composition described in any one of claims 1 to 10, comprising 30 mg or 60 mg of nemolizumab.

12. A pharmaceutical composition formulated for subcutaneous administration comprising about 60 mg or less of nemolizumab for use in treating skin lesions and pruritus in subjects with prurigo nodularis (PN).

13. The pharmaceutical composition described in claim 12, characterized in that the pharmaceutical composition is administered to a subject once every four weeks.

14. A pharmaceutical composition described in claim 12 or 13 containing 30 mg or 60 mg of nemolizumab.

15. The pharmaceutical composition of any one of claims 12 to 14, wherein the effective amount of nemolizumab is 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, or about 60 mg.

16. A pharmaceutical composition described in any one of claims 12 to 15, wherein the subject has been diagnosed with PN for at least about 6 months.

17. The pharmaceutical composition described in any one of claims 12 to 16, wherein the subject has at least about 20 nodules on the body in a bilateral distribution or the subject has prurigo lesions on the upper extremities.

18. A pharmaceutical composition described in any one of claims 12 to 17, wherein the pruritus is assigned a score of at least 4 on a numerical rating scale (NRS).

19. The pharmaceutical composition of any one of claims 12 to 18, further comprising a pharma- ceutically acceptable carrier.

20. A pharmaceutical composition described in any one of claims 12 to 19, characterized in that the nemolizumab is administered to a subject according to a flat dosing regimen.

21. A pharmaceutical composition described in any one of claims 12 to 19, characterized in that the nemolizumab is administered to a subject according to a loading dose regimen.

22. Use of nemolizumab in the manufacture of a medicament for the treatment of skin lesions and pruritus in a subject with prurigo nodularis (PN), comprising: the drug is formulated for subcutaneous administration; the subject does not have atopic dermatitis; The above uses.

23. The use of claim 22, characterized in that the drug is administered to the subject once every four weeks.

24. The use of claim 22 or 23, wherein the drug comprises nemolizumab in the range of about 5 mg to about 60 mg.

25. The use described in any one of claims 22 to 24, characterized in that the drug is used to administer nemolizumab to a subject at a dose of 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, or about 60 mg.

26. Use of nemolizumab in the manufacture of a medicament for the treatment of skin lesions and pruritus in a subject with prurigo nodularis (PN), comprising: The medicament comprises about 60 mg or less of nemolizumab and is formulated for subcutaneous administration. The above uses.

27. The use of claim 26, characterized in that the drug is administered to the subject once every four weeks.

28. The use described in claim 26 or 27, characterized in that the drug is used to administer nemolizumab to a subject at a dose of 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, or about 60 mg.

29. The use described in any one of claims 22 to 28, wherein the subject achieves at least about a 55% reduction in average peak pruritus numerical rating score (NRS) per week.

30. The use described in any one of claims 22 to 29, wherein the subject has been diagnosed with PN for at least about 6 months.

31. The use described in any one of claims 22 to 30, wherein the subject has at least about 20 nodules on the body in a bilateral distribution or the subject has prurigo lesions on the upper extremities.

32. The use described in any one of claims 22 to 31, wherein the pruritus is assigned a score of at least 4 on the Numeric Rating Scale (NRS).

33. The use described in any one of claims 22 to 32, characterized in that the nemolizumab is administered to a subject according to a flat dosing regimen.

34. The use described in any one of claims 22 to 32, characterized in that the nemolizumab is administered to a subject according to a loading dose regimen.

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