Methods for treating prurigo nodularis by administering IL-4R antagonist

Abstract

Methods for treating or preventing prurigo nodularis (PN) in a subject are provided. Provided are methods comprising administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 257,876, filed on October 20, 2021, U.S. Provisional Application No. 63 / 300,492, filed on January 18, 2022, and European Application No. EP22315048.3, filed on March 4, 2022, each of which is incorporated by reference in its entirety. Technical Field

[0002] The present disclosure relates to treating and / or preventing prurigo nodularis (PN) in a subject in need thereof. The present disclosure relates to administering an interleukin-4 receptor (IL-4R) antagonist to treat or prevent PN in a subject in need thereof. Background Art

[0003] Prurigo nodularis (PN) is a skin disease characterized by the appearance of multiple, intensely itchy rashes in symmetrically distributed areas on the extremities. (Zeidler C et al., Chronic prurigo of nodular type: A Review. Acta Dermatol Venereol 2018; 98(2): 173-9). The main symptoms are prolonged, recurrent and uncontrollable rubbing, scratching and uncontrollable itching, resulting in the appearance of hyperkeratotic, erosive papules and nodules on the skin. The European Academy of Dermatology and Venereology (EADV) has published a widely accepted definition of chronic prurigo. (Pereira MP et al., European academy of dermatology and venereologyEuropean prurigo project: expert consensus on the definition, classification and terminology of chronic prurigo. J Eur Acad Dermatol Venereol. 2018; 32(7): 1059-65). The experts agreed that chronic prurigo should be used as an umbrella term for a range of clinical presentations (e.g. papular, nodular, plaque or umbilical). Prurigo nodularis is considered a distinct disease defined by the presence of a history and / or signs of chronic prurigo lasting ≥ 6 weeks, recurrent scratching and multiple localized / systemic prurigo skin lesions (whitish, hyperpigmented or pink papules, nodules and / or plaques).

[0004] The disease is difficult to treat and carries a high disease burden. Approximately 50% of patients have a past or current history of atopic dermatitis (AD) or another atopic disorder. (Iking A et al., S. Prurigo as asymptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients. J Eur Acad Dermatol Venereol 2013;27(5):550-7).

[0005] PN carries a significant burden of disease, as it is primarily manifested by pruritus. (Pereira MP et al., European Academy of Dermatology and Venereology European Prurigo Project: Expert consensus on the definition, classification and terminology of chronic prurigo. J Eur Acad Dermatol Venereol 2018; 32(7): 1059-65). The impact of PN on quality of life is reported to be higher than that of other common skin diseases, such as AD and psoriasis. (Steinke S et al., Humanistic burden of chronic pruritus in patients with inflammatory dermatoses: Results of the European Academy of Dermatology and Venereology Network on Assessment of Severity and Burden of Pruritus (PruNet) cross-sectional trial. J Am Acad Dermatol 2018;79(3):457-63). Patients report chronic insomnia due to persistent pruritus; persistent burning, stinging, and pain in the affected areas; and chronic depression, anxiety, anger, disgust, and shame; thus, overall having a significant impact on their quality of life. PN is a key factor in the development of mood disorders such as anxiety and depression, according to a 5-year cross-sectional study of 909 adult PN patients in the Johns Hopkins Hospital system (Boozalis E et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients J Am Acad Dermatol 2018;79(4):714-9).

[0006] Data on the epidemiology of PN are limited. Most studies show that the median age is over 50 years old. (Iking A et al., Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients. J Eur Acad Dermatol Venereol. 2013; 27 (5): 550-7). Nodular prurigo is only occasionally observed in young patients, in whom it is usually associated with atopic conditions. (Tanaka M et al., Prurigonodularis consists of two distinct forms: early-onset atopic and late-onset non-atopic. Dermatology. 1995; 190(4): 26976).

[0007] There are currently no United States (US) Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved targeted therapies for the treatment of either atopic or non-atopic forms of PN. Therefore, new therapies are needed to treat PN. Summary of the invention

[0008] In one aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising administering to the subject an initial dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0009] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0010] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0011] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0012] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0013] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0014] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0015] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0016] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0017] In certain exemplary embodiments, the antibody is dupilumab.

[0018] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0019] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0020] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0021] In certain exemplary embodiments, the subject is an adult.

[0022] In another aspect, a method for treating prurigo nodularis is provided, the method reducing or eliminating the dependence of a patient with prurigo nodularis on low to moderate potency topical corticosteroids and / or topical calcineurin inhibitors, the method comprising (a) selecting a patient with prurigo nodularis who is not controlled with background therapy comprising low to moderate potency topical corticosteroids and / or topical calcineurin inhibitors; (b) administering to the patient a defined dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) at a defined frequency for an initial treatment period, while maintaining the patient's background therapy for the initial treatment period; and (c) gradually reducing or eliminating the dose of the low to moderate potency topical corticosteroid and / or topical calcineurin inhibitor administered to the patient during a subsequent treatment period, while continuing to administer the antibody or antigen-binding fragment thereof at the defined frequency and dose used during the initial treatment period, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and a 1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1 Three light chain complementarity determining region (LCDR) sequences of NO:6, 7 and 8.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0024] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0025] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0026] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0027] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0028] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0029] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0030] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0031] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0032] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0033] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0034] In certain exemplary embodiments, the antibody is dupilumab.

[0035] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0036] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0037] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0038] In certain exemplary embodiments, the subject is an adult.

[0039] In another aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with a super-potent topical corticosteroid rescue medication.

[0040] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0041] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0042] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0043] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0044] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0045] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0046] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0047] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0048] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0049] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0050] In certain exemplary embodiments, the antibody is dupilumab.

[0051] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0052] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0053] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0054] In certain exemplary embodiments, the subject is an adult.

[0055] In another aspect, a method for treating pruritus associated with nodular prurigo in a subject is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with a super-potent topical corticosteroid rescue medication.

[0056] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0057] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0058] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0059] In certain exemplary embodiments, the pruritus is refractory to topical therapy.

[0060] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0061] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0062] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0063] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0064] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0065] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0066] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0067] In certain exemplary embodiments, the antibody is dupilumab.

[0068] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0069] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0070] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0071] In certain exemplary embodiments, the subject is an adult.

[0072] In another aspect, a method for treating a subject having prurigo nodularis is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with a systemic immunosuppressant.

[0073] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0074] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0075] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0076] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0077] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0078] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0079] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0080] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0081] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0082] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0083] In certain exemplary embodiments, the antibody is dupilumab.

[0084] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0085] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0086] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0087] In certain exemplary embodiments, the subject is an adult.

[0088] In another aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, and wherein the treatment results in a decrease in the subject's Worst Itch Numerical Rating Scale (WI-NRS) score.

[0089] In certain exemplary embodiments, the reduction in WI-NRS score is selected from the group consisting of 4, 5, 6, 7, 8, 9, and 10.

[0090] In certain exemplary embodiments, the reduction in WI-NRS score occurs at 12 weeks of treatment.

[0091] In certain exemplary embodiments, the reduction in WI-NRS score occurs at 24 weeks of treatment.

[0092] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0093] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0094] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0095] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0096] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0097] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0098] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0099] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0100] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0101] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0102] In certain exemplary embodiments, the antibody is dupilumab.

[0103] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0104] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0105] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0106] In certain exemplary embodiments, the subject is an adult.

[0107] In another aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the treatment results in a decrease in the subject's Investigator's Global Assessment of Prurigo Nodularis (IGAPN) score.

[0108] In certain exemplary embodiments, the reduction in IGA PN score is selected from the group consisting of 5, 4, 3, 2, and 1.

[0109] In certain exemplary embodiments, the subject receives an IGA PN score of 0 or 1.

[0110] In certain exemplary embodiments, the reduction in IGA PN score occurs at 12 weeks of treatment.

[0111] In certain exemplary embodiments, the reduction in IGA PN score occurs at 24 weeks of treatment.

[0112] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0113] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0114] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0115] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0116] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0117] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0118] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0119] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0120] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0121] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0122] In certain exemplary embodiments, the antibody is dupilumab.

[0123] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0124] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0125] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0126] In certain exemplary embodiments, the subject is an adult.

[0127] In another aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the subject has comorbid mild atopic dermatitis.

[0128] In certain exemplary embodiments, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

[0129] In certain exemplary embodiments, the initial dose is about 600 mg and each secondary dose is about 300 mg.

[0130] In certain exemplary embodiments, two doses are administered every other week (q2w).

[0131] In certain exemplary embodiments, the subject has previously failed treatment with mid- to ultra-potent topical corticosteroids.

[0132] In certain exemplary embodiments, the subject has a baseline WI-NRS score of 7 or greater.

[0133] In certain exemplary embodiments, the subject has a minimum total of 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

[0134] In certain exemplary embodiments, the subject has a baseline IGA PN score of 3 or greater.

[0135] In certain exemplary embodiments, the subject suffers from PN that is not adequately controlled by topical therapies or for which the use of those therapies is inappropriate.

[0136] In certain exemplary embodiments, the subject is a candidate for systemic therapy.

[0137] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0138] In certain exemplary embodiments, the antibody is dupilumab.

[0139] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0140] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0141] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0142] In certain exemplary embodiments, the subject is an adult.

[0143] In another aspect, a method for treating a subject with prurigo nodularis is provided, the method comprising selecting a subject with prurigo nodularis, and administering to the subject an initial dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0144] On the other hand, an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for use in treating prurigo nodularis is provided, the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8, and comprising an initial dose of about 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0145] On the other hand, provided is a use of an antibody or an antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for the manufacture of a medicament for treating prurigo nodularis, the antibody or the antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8, wherein the use comprises administering an initial dose of about 600 mg of the antibody or the antigen-binding fragment thereof, and one or more secondary doses of about 300 mg of the antibody or the antigen-binding fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0146] The foregoing and other features and advantages of the present disclosure will be more fully understood by the following detailed description of illustrative embodiments in conjunction with the accompanying drawings. The file of this patent contains at least one color drawing / photograph. Upon request and payment of the necessary fee, the Patent Office will provide a copy of this patent with one or more color drawings / photographs.

[0147] Figure 1 An overview of the study design of Example 1 is schematically depicted. The study was a multicenter, 24-week treatment, parallel, double-blind, randomized, placebo-controlled study to evaluate the use of dupilumab in patients with PN who were inadequately controlled by topical prescription therapies or who were inappropriate for those therapies. Participants received a 600 mg loading dose of dupilumab followed by 300 mg or matching placebo every other week (q2w).

[0148] Figure 2A-2D The timeline of activities for two randomized, placebo-controlled studies of dupilumab in patients with PN who were inadequately controlled by topical prescription therapies or who were not candidates for those therapies is depicted (Example 1).

[0149] Figure 3 Depicted is the questionnaire used to determine the Worst Itch Numerical Rating Scale (WI-NRS).

[0150] Figure 4 Depicted is the questionnaire used to determine the Investigator's Global Assessment of Prurigo Nodularis (IGA PN).

[0151] Figure 5 Depicted is the questionnaire used to determine the Pruritus Activity Score (PAS).

[0152] Figure 6 Schematically depicted are two Phase 3 studies of similar design and population described in Example 1. Both studies evaluated the use of dupilumab in patients with PN that was inadequately controlled by topical prescription therapies or in patients for whom topical prescription therapies were inappropriate.

[0153] Fig. 7A -B is a table depicting the statistical test hierarchy for the PRIME and PRIME2 studies of Example 1. Fig. 7A As shown, for PRIME, the primary endpoint and all multiplicity-adjusted secondary endpoints met statistical significance, including WI-NRS ≥4, IGA PN-S score of 0 or 1, WI-NRS ≥4 and IGA PN-S score of 0 or 1, percent change from baseline in WI-NRS (itch), change from baseline in DLQI, change from baseline in Skin Pain-NRS, and change from baseline in HADS (all at 24 weeks). Figure 7BAs shown, for PRIME2, the primary endpoint, key secondary endpoints, and other multiplicity-controlled endpoints met statistical significance, including WI-NRS ≥4 at weeks 12 and 24, IGA PN-S scores of 0 or 1 at weeks 12 and 24, WI-NRS ≥4 and IGA PN-S scores of 0 or 1 at week 24, mean percentage change from baseline in WI-NRS at week 24, DLQI at week 24, and Skin Pain-NRS at week 24.

[0154] Fig. 8A -D Graphically depicts the proportion of patients with WI-NRS ≥ 4 in both the placebo and durpilumab treatment groups. For PRIME, Fig. 8A As shown, the proportion of participants who achieved a ≥4-point reduction in the WI-NRS score (0-10) at week 24 was 45 (60.0%) in the dupilumab group and 14 (18.4%) in the placebo group, p<0.0001. Figure 8B As shown, the proportion of participants who achieved a ≥4-point reduction in WI-NRS (0-10) at Week 12 was 29 (37.2%) on dupilumab and 18 (22.0%) on placebo, p = 0.0216. The proportion of participants who achieved a ≥4-point reduction in WI-NRS (0-10) at Week 24 was 57.7% on dupilumab and 19.5% on placebo (p < 0.0001). Figure 8C -D graphically depicts the results of the PRIME study ( Figure 8C ) and PRIME2 studies ( Fig.8D ) with an improvement of ≥4 from baseline on the WI-NRS over time through Week 36.

[0155] Fig.9A -D Graphically depicts the proportion of participants in the durpilumab and placebo treatment groups who achieved an Investigator Global Assessment PN-Stage (IGA PN-S) score of 0 or 1. For PRIME, Fig.9A As shown, the proportion of participants achieving an IGA PN-S score of 0 or 1 at week 24 was 48.0% in the dupilumab group and 18.4% in the placebo group (p=0.0004). Fig. 9B As shown, the proportion of participants achieving an IGA PN-S score of 0 or 1 at Week 24 was 44.9% in dupilumab and 15.9% in placebo (p<0.0001). For Week 12, the proportions were 25.6% in dupilumab and 12.2% in placebo (p=0.0194). Fig. 9C-D graphically depicts the results of the PRIME study ( Fig. 9C ) and PRIME 2 studies ( Fig.9D ) with an IGA PN-S score of 0 or 1 over time from baseline to Week 36.

[0156] Fig. 10A -D Graphically depicts the proportion of participants in the dupilumab and placebo treatment groups with a concomitant WI-NRS improvement (decrease) from baseline of ≥4 and an IGA PN-S score of 0 or 1. For PRIME, as Fig. 10A As shown, the proportion of participants with an improvement (decrease) of ≥4 on the WI-NRS from baseline to Week 24 and an IGA PN-S score of 0 or 1 at Week 24 was 38.7% on dupilumab and 9.2% on placebo (p<0.0001). Fig. 10B As shown, the proportion of participants with an improvement (reduction) of ≥4 in the WI-NRS from baseline to Week 24 and an IGAPN-S score of 0 or 1 at Week 24 was 32.1% on durpilumab and 8.5% on placebo (p=0.0001). Fig. 10C -D graphically depicts the results of the PRIME study ( Fig. 10C ) and PRIME2 studies ( Fig. 10D ) with an improvement (reduction) from baseline of ≥4 on the WI-NRS and an IGA PN-S score of 0 or 1 over time through Week 36.

[0157] Fig.11A -D Graphically depicts the WI-NRS least squares (LS) mean delta percentage relative to baseline in the dupilumab and placebo treatment groups. For PRIME, Fig.11A As shown in Figure 2, at Week 24, the LS mean percentage change from baseline was -48.89 in the dupilumab-treated group and -22.22 in the placebo-treated group (p<0.0001). Fig. 11B As shown, at Week 24, the LS mean percentage change from baseline was -59.34 in the durpilumab-treated group and -36.18 in the placebo-treated group (p<0.0001). Fig. 11C -D graphically depicts the results of the PRIME study ( Fig. 11C ) and PRIME2 studies ( Fig.11D ) over time up to Week 36.

[0158] Fig. 12A-B graphically depicts the time to first use of rescue and / or contraindication drugs or procedures. Fig. 12A ) and PRIME2( Fig. 12B ) In both, durpilumab treatment reduced the time to first use of rescue and / or contraindication medications or procedures compared with placebo.

[0159] Fig.13A -B depicts the baseline ( Fig.13A ) and at week 24 after initiation of treatment with 300 mg dupilumab administered q2w ( Fig. 13B ) at baseline. At baseline, the patient's IGA PN-S score was 4, and the average WI-NRS score was 9.4. At 24 weeks of treatment, the patient's IGA PN-S score was 0, and the average WI-NRS score was 1.3.

[0160] Fig.14 Table depicting baseline disease characteristics of patients in the PRIME / EFC16459 and PRIME2 / EFC16460 studies. The mean (SD) WI-NRS at baseline for all enrolled patients in both studies was 8.5 (1.0). DETAILED DESCRIPTION

[0161] Before describing the present disclosure, it should be understood that the present disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0162] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0163] As used herein, when used with respect to a particular recited value, the term "about" means that the value may differ from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0164] As used herein, the terms "treat," "treating," and the like mean to relieve symptoms, temporarily or permanently eliminate the cause of symptoms, or prevent or slow the onset of symptoms of a specified disorder or condition.

[0165] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the disclosure herein, typical methods and materials are now described.All publications mentioned herein are incorporated by reference in their entirety.

[0166] The present disclosure provides methods and compositions for treating prurigo nodularis (PN).

[0167] As used herein, "prurigo nodularis" refers to the presence of chronic pruritus for ≥ 6 weeks in a subject, as well as a history and / or signs of recurrent scratching and multiple localized / systemic prurigo skin lesions.

[0168] As used herein, "pruritic skin lesions" refers to whitish, hyperpigmented, or pink papules, nodules, and / or plaques on a subject.

[0169] As used herein, "treating prurigo nodularis" refers to treating one or more symptoms of prurigo nodularis, including but not limited to reducing the number of lesions, reducing the size of lesions, reducing the itching associated with prurigo nodularis, and the like.

[0170] In certain embodiments, the subject with prurigo nodularis has one or more comorbid atopic inflammatory conditions. As used herein, "atopic inflammatory conditions" include, but are not limited to, one or more of allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), allergic conjunctivitis, allergic rhinoconjunctivitis, asthma, eosinophilic esophagitis, atopic conjunctivitis, atopic dermatitis, aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease or NSAID-ERD), perennial allergic rhinitis (PAR), atopic dermatitis (AD), food allergies, hives or urticaria, and exercise-induced bronchospasm. In certain exemplary embodiments, the subject having prurigo nodularis has comorbid atopic dermatitis, such as mild atopic dermatitis, moderate atopic dermatitis, moderate to severe atopic dermatitis, or severe atopic dermatitis. Methods for improving PN-related patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) measures

[0171] Methods for improving one or more PN-related patient-reported outcome (PRO) measures in a subject in need thereof are provided, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. Methods for improving one or more PN-related clinician-reported outcome (ClinRO) measures in a subject in need thereof are provided, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.

[0172] Examples of PN-related PRO measures include: (1) Worst Itch Numerical Rating Scale (WI-NRS), (2) Dermatology Life Quality Index (DLQI), (3) Pain Numerical Scale, (4) Sleep Numerical Scale, (5) Hospital Anxiety and Depression Scale, (6) Patient Global Impression of Change (PGIC), (7) Patient Global Impression of Severity (PGIS), and (8) European Health Dimension 5D (EQ-5D) score.

[0173] "Improvement in PN-related PRO measures" means an increase in one or more of the sleep numerical rating scale score and the European five-dimensional health scale (EQ-5D) score relative to baseline and / or a decrease in one or more of the worst pruritus numerical rating scale score (WI-NRS), the pain numerical rating scale score, the Hospital Anxiety and Depression Scale (HADS) score, the Dermatology Life Quality Index (DLQI) score, the Patient Global Impression of Change (PGIC) score, and the Patient Global Impression of Severity (PGIS) score relative to baseline. As used herein, the term "baseline" with respect to PN-related PRO measures means the numerical value of the PRO measure of the patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0174] Examples of PN-related ClinRO measures include: (1) Investigator Global Assessment of Prurigo Nodularis (IGA PN) and (2) Prurigo Activity Score (PAS).

[0175] "Improvement in a PN-related ClinRO measure" means a decrease in one or more of the Investigator's Global Assessment of Prurigo Nodularis (IGA PN) score or the Prurigo Activity Score (PAS) relative to baseline. As used herein, the term "baseline" with respect to a PN-related ClinRO measure means the value of a patient's ClinRO measure before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0176] To determine whether a PN-related parameter has been "improved," the parameter is quantified at baseline and at time points after administration of a pharmaceutical composition as described herein. For example, a PN-related parameter can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer after initial treatment with a pharmaceutical composition. The difference between the parameter value at a particular time point after the start of treatment and the parameter value at baseline is used to determine whether a PN-related parameter has been "improved" (e.g., increased or decreased, as the case may be, depending on the specific parameter being measured).

[0177] As used herein, the term "acquire" or "acquiring" refers to the possession of a physical entity or value (e.g., a numerical value) obtained by "directly acquiring" or "indirectly acquiring" a physical entity or value (such as a PN-related parameter). "Direct acquisition" means performing a process (e.g., performing a synthesis or analysis method) to obtain a physical entity or value. "Indirect acquisition" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly acquires a physical entity or value). Direct acquisition of a physical entity includes performing a process that includes a physical change of a physical substance (e.g., a starting material). Exemplary changes include preparing a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, and performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Direct acquisition of a value includes performing a process that includes a physical change of a sample or another substance, such as performing an analytical process (sometimes referred to herein as "physical analysis") that includes a physical change of a substance (e.g., a sample, an analyte, or a reagent).

[0178] The indirectly acquired information may be provided in the form of a report, for example, in paper or electronic form, such as from an online database or an application ("App"). The report or information may be provided, for example, by a healthcare institution, such as a hospital or clinic, or a healthcare provider, such as a doctor or nurse.

[0179] Itch-free daysAccording to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase in the number of itch-free days experienced by the subject relative to baseline. For example, administration of an IL-4R antagonist to a subject in need thereof results in an increase in the number of itch-free days experienced by the subject relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days / month.

[0180] Number of PN nodules According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in PN nodules (i.e., lesions) relative to baseline. For example, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in PN nodules relative to baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 6, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 , 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 8, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 nodules.

[0181] In some embodiments, the patient has a minimum of 20 PN lesions total on both legs and / or both arms and / or trunk at baseline prior to administration of the IL-4R antagonist.

[0182] Worst Itch Numerical Rating ScaleAccording to some embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the Worst Itch Numerical Rating Scale (WI-NRS) score relative to baseline. The WI-NRS is a PRO consisting of a single item rated from 0 ("no itch") to 10 ("worst itch imaginable") ( S et al., Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J Am Acad Dermatol. 2019;80(5):1395-402). Participants were asked to rate the intensity of their worst pruritus (itching) in the past 24 hours using the scale. Daily WI-NRS scores were summed over 7 days to obtain a mean weekly WI-NRS score.

[0183] Treatment methods are provided that result in a decrease in WI-NRS score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in WI-NRS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In some embodiments, prior to treatment with the IL-4R antagonist, the subject has a baseline WI-NRS score of 7 or greater.

[0184] Investigator's Global Assessment of Prurigo Nodularis According to some embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the Investigator Global Assessment of Prurigo Nodularis (IGA PN) score relative to baseline. IGA PN is a clinician-reported outcome (ClinRO) that allows clinicians to assess the activity of PN (IGAPN-A) using a 5-point scale from 0 (no problems) to 4 (severe); and to assess the stage of the disease (IGA PN-S) using a 5-point scale from 0 (no problems) to 4 (severe): 0 = no problems, no nodules; 1 = almost no problems, 1-5 nodules; 2 = mild, 6-19 nodules; 3 = moderate, 20-99 nodules; and 4 = severe, ≥100 nodules.

[0185] Treatment methods are provided that result in a decrease in IGA PN score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in IGA PN score relative to baseline by about 1, 2, 3, or 4 points.

[0186] Prurigo Activity ScoreAccording to some embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the Prurigo Activity Score (PAS) relative to baseline. The Prurigo Activity Score (PAS) is a ClinRO measurement. The original PAS questionnaire version 0.9 consisted of 7 items developed by PN expert clinicians ( J et al., Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo. J Eur Acad Dermatol Venereol. 2018;32(10):1754-60. The items of the PAS evaluate the following aspects of prurigo lesions: type (visible lesions: item 1a; predominant lesions: item 1b); estimated number (item 2); distribution (items 3, 4); and size (largest lesion: item 6a; representative lesions: item 6b). Other items evaluate the representative body area and the exact number of lesions (item 5), the percentage of prurigo lesions with excoriation / crusting on the surface (reflecting active scratching; item 7a), and the percentage of healed prurigo lesions (reflecting healing of chronic prurigo; item 7b).

[0187] Treatment methods are provided that result in a decrease in PAS score relative to baseline.

[0188] Dermatology Life Quality Index (DLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in DLQI score relative to baseline. Dermatology Life Quality Index (DLQI) A PRO developed to measure dermatology-specific HRQoL in adult participants. (See Finlay AY, Khan GK. Dermatology life quality index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994; 19: 210-6). The tool includes 10 items to assess the impact of skin disease on the participant's health-related quality of life (HRQoL) in the previous week. These items cover symptoms, leisure activities, work / school or holiday time, interpersonal relationships (including intimate relationships), side effects of treatment, and emotional reactions after suffering from skin disease. It is a validated questionnaire for clinical practice and clinical trials. (See Chernyshov PV. The evolution of quality of lifeassessment and use in dermatology. Dermatology. 2019; 235(3): 167-74). The response scale is a 4-point Likert scale (0 = "not at all", 3 = "very much") with 9 items. The remaining 1 item about work / study asks whether work / study is hindered and then (if "no") asks the extent of problems caused by the skin condition in work / study; this item is rated on a 3-point Likert scale ("not at all" to "very much"). The overall score ranges from 0 to 30, with high scores indicating poor HRQoL.

[0189] Treatment methods are provided that result in a decrease in DLQI score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in DLQI score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 points.

[0190] Numerical pain rating scaleAccording to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in pain numerical rating scale (NRS) score relative to baseline. In the pain NRS, participants are asked to rate the worst skin pain in the past 24 hours using a numerical rating scale (NRS) from 0 to 10, where 0 = no pain and 10 = the worst possible pain.

[0191] Treatment methods are provided that result in a decrease in pain NRS scores relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in pain NRS scores relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0192] Numerical sleep rating scale According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase in a Numerical Rating Scale (NRS) score for Sleep relative to baseline. In the Sleep NRS, participants are asked to rate the quality of their sleep over the past night upon waking using a 0 to 10 NRS, where 0 = worst possible sleep and 10 = best possible sleep.

[0193] Treatment methods are provided that increase sleep NRS scores relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof increases pain NRS scores by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points relative to baseline.

[0194] Hospital Anxiety and Depression ScaleAccording to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the Hospital Anxiety and Depression Scale (HADS) score relative to baseline. The Hospital Anxiety and Depression Scale (HADS) is a PRO tool used to screen for anxiety and depression in non-psychiatric populations. Repeated administration also provides information about changes in the patient's mood state. (Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67(6): 361-70 and Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a review of validation data and clinical results. J Psychosom Res. 1997; 42(1): 17-41). The HADS consists of 14 items, 7 each for anxiety and depression symptoms. The possible score range for each subscale is 0 to 21. For both subscales, the following cutoff scores are recommended: 0 to 7: normal; 8 to 10: borderline abnormal (borderline case); and 11 to 21: abnormal.

[0195] Treatment methods are provided that result in a decrease in HADS score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in HADS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

[0196] Use of antidepressants According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in antidepressant use relative to baseline. Treatment methods are provided that result in a reduction or elimination of antidepressant use relative to baseline. In certain embodiments, administration of an IL-4R antagonist to a subject in need thereof results in a reduction in the subject's use of antidepressants by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% or more. In other embodiments, administration of an IL-4R antagonist to a subject in need thereof results in the subject's elimination of antidepressant use.

[0197] Patient Global Impression of Change (PGIC)According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in PGIC score relative to baseline. The Patient Global Impression of Change (PGIC) is a single-item questionnaire that asks participants to provide an overall self-assessment of the overall change in PN compared to before the participant began study treatment on a 7-point scale. Response options are: 0 = "very good", 1 = "somewhat better", 2 = "a little better", 3 = "no change", 4 = "a little worse", 5 = "somewhat worse", 6 = "very worse". (See Guy W et al., ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, Rockville, Maryland, 1976).

[0198] Treatment methods are provided that result in a decrease in PGIC score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in PGIC score relative to baseline by about 1, 2, 3, 4, 5, or 6 points.

[0199] Patient Global Impression of Severity (PGIS) According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the PGIS score relative to baseline. The Patient Global Impression of Severity (PGIS) is a single-item questionnaire that asks participants to provide an overall self-assessment of the severity of illness over the past week on a 4-point scale. Response options are: 1 = "none", 2 = "mild", 3 = "moderate", 4 = "severe". (See Guy W et al., ECDEU Assessment Manual for Psychopharmacology. [ECDEU Psychopharmacology Assessment Manual] Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration [US Department of Health, Education and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, Rockville, Maryland], 1976).

[0200] Treatment methods are provided that result in a decrease in PGIS score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a decrease in PGIS score of about 1, 2, or 3 relative to baseline.

[0201] European Health Dimension (EQ-5D) :According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase in EQ-5D relative to baseline. The European Five-Dimension Health Scale (EQ-5D) is a standardized PRO measure of health status developed by the European Quality of Life Research Group (EuroQol Group) to provide a simple, universal measure of health for clinical and economic assessments. The adult version of the questionnaire is suitable for patients aged 16 years and above. EQ-5D consists of 2 parts: a descriptive system and an EQ visual analog scale (EQVAS). The EQ-5D 5L descriptive system includes the following 5 dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has 5 levels of perceived problems: "no problem", "slight problem", "moderate problem", "severe problem" and "unable to perform activity" (see Herdman M et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) . [Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)] Qual. Life Res. [Journal of Quality of Life Research] 2011; 20(10): 1727-36). The respondent is asked to indicate his / her health status by checking (or crossing) the box next to the most appropriate statement in the 5 dimensions; this produces a 1-digit number representing the level of that dimension. The numbers for the 5 dimensions can be combined into a 5-digit number to describe the respondent's health status. The EQ VAS records the respondent's self-rated health on a vertical VAS, where the endpoints are marked as "best imaginable health state (100)" and "worst imaginable health state (0)". This information can be used as a quantitative measure of the health outcomes judged by each respondent.

[0202] Treatment methods are provided that result in an increase in EQ VAS score relative to baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in an increase in EQ VAS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Interleukin-4 receptor antagonists

[0203] The methods described herein include administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R when IL-4R is expressed on a cell in vitro or in vivo and inhibits the normal biological signaling function of IL-4R. Non-limiting examples of classes of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, IL-4R antagonists include anti-IL-4R antibodies that can be used in the context of the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises the heavy and light chain (complementarity determining regions) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively.

[0204] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4), such as IL-4Rα.

[0205] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and the heavy chain constant region. The heavy chain constant region contains three domains CH 1. C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and the light chain constant region. The light chain constant region consists of a domain (C L 1). V H Area and V L The V region can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be natural or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0206] The term "antibody" also includes the antigen binding fragment of a complete antibody molecule. As used herein, the term "antigen binding portion thereof", "antigen binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen binding fragment of an antibody can be derived from a complete antibody molecule using, for example, any suitable standard technique (such as proteolytic digestion or the recombinant genetic engineering techniques involving manipulation and expression of DNA encoding antibody variable domains and optionally constant domains). Such DNA is known and / or easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biological techniques, for example, to arrange one or more variable domains and / or constant domains into a suitable configuration or to introduce codons, produce cysteine ​​residues, modify, add or delete amino acids, etc.

[0207] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementary determining regions (CDRs), such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed within the expression "antigen-binding fragment".

[0208] The antigen-binding fragment of an antibody will generally contain at least one variable domain. A variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame with one or more framework sequences. L Domain-associated V H In the antigen-binding fragment of the structural domain, V H Domain and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a monomer V H or V L Structural domain.

[0209] In certain embodiments, the antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragments of antibodies described herein include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) VH -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of variable domains and constant domains (including any of the exemplary configurations listed above), the variable domains and constant domains may be directly connected to each other or may be connected by a complete or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that create a flexible or semi-flexible connection between adjacent variable domains and / or constant domains in a single polypeptide molecule, and typically the hinge region may be composed of 2 to 60 amino acids, typically 5 to 50 or typically 10 to 40 amino acids. In addition, the antigen-binding fragments of the antibodies described herein may comprise the above-listed constant domains, each other and / or with one or more monomeric V H or V L Any configuration of homodimers or heterodimers (or other multimers) of variable and constant domains in which the domains are non-covalently associated (e.g., by disulfide bonds).

[0210] As with complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will generally comprise at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Conventional techniques available in the art can be used to transform any multispecific antibody format for use in the context of the antigen-binding fragments of an antibody described herein.

[0211] The constant region of an antibody is important for the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody can be selected based on whether it is desired that the antibody mediate cytotoxicity.

[0212] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the human antibodies described herein may, for example, include amino acid residues that are not encoded by human germline immunoglobulin sequences in the CDR region and specifically in the CDR3 region (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been transplanted onto human framework sequences.

[0213] The term "recombinant human antibody" includes all human antibodies prepared, expressed, generated or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described further below), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), antibodies isolated from human immunoglobulin gene transgenic animals (e.g., mice) (see, e.g., Taylor et al., (1992) Nucl. Acids Res. [Nucleic Acids Research] 20: 6287-6295), or antibodies prepared, expressed, generated or isolated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, when using human Ig sequence transgenic animals, undergo in vivo somatic mutagenesis), so that the V H Area and V L The amino acid sequence of the region is as follows: H Sequence and V L Sequences that are related to them but may not naturally exist within the human antibody germline repertoire in vivo.

[0214] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150-160 kDa, in which the dimer is held together by an interchain heavy chain disulfide bond. In the second form, the dimer is not connected via an interchain disulfide bond and forms a molecule of about 75-80 kDa, which is composed of a covalently coupled light chain and a heavy chain (half antibody). Even after affinity purification, these forms are extremely difficult to separate.

[0215] The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level normally observed with the human IgG1 hinge. H Zone 2 or C H Antibodies having one or more mutations in region 3, which mutations may be desirable, for example, in production to increase the yield of a desired antibody form.

[0216] An "isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism or from a tissue or cell in which the antibody naturally occurs or naturally occurs is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has undergone at least one purification or separation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0217] The terms "specifically bind" and the like mean that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4R includes an antibody that binds to IL-4R with a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. D An antibody that binds IL-4R or a portion thereof as measured in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0218] The anti-IL-4R antibodies useful in these methods may comprise one or more amino acid substitutions, insertions and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. Methods are provided involving the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 in the case of a tetrameric antibody, or 1, 2, 3, 4, 5, or 6 in the case of the HCVR and LCVR of an antibody) within one or more framework and / or CDR regions are mutated to the corresponding residues of the germline sequence from which the antibody is derived, or to the corresponding residues of another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of ordinary skill in the art can readily generate a number of antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V L All frameworks and / or CDR residues in the domain are mutated back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only some residues (e.g., only the mutated residues found in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2 or CDR3) are mutated back to the original germline sequence. In other embodiments, one or more mutations in the framework and / or CDR residues are mutated to the corresponding residues of different germline sequences (i.e., germline sequences different from the germline sequence from which the antibody is initially derived). In addition, the antibody may contain any combination of two or more germline mutations in the framework and / or CDR region, such as wherein some single residues are mutated to the corresponding residues of a specific germline sequence, while maintaining some other residues different from the original germline sequence or mutating to the corresponding residues of different germline sequences. Once antibodies and antigen-binding fragments containing one or more germline mutations are obtained, they can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Use of antibodies and antigen-binding fragments obtained in this general manner is encompassed within the present disclosure.

[0219] Methods of using anti-IL-4R antibodies are contemplated, comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, uses of anti-IL-4R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein are provided.

[0220] The term "surface plasmon resonance" refers to the ability to detect surface plasmon resonance using, for example, BIAcore TM The system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) detects changes in protein concentration within a biosensor matrix to analyze optical phenomena of interactions in real time.

[0221] The term "K D ” refers to the equilibrium dissociation constant for a specific antibody-antigen interaction.

[0222] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, called a paratope. A single antigen may have more than one epitope. Therefore, different antibodies may bind to different regions on the antigen and may have different biological effects. Epitopes may be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues in a polypeptide chain. In some cases, an epitope may include a portion of a sugar, phosphoryl, or sulfonyl group on the antigen.

[0223] The terms "substantial identity" or "substantially identical" when referring to nucleic acids or fragments thereof mean that when optimally aligned with another nucleic acid (or its complementary strand) by appropriate nucleotide insertions or deletions, at least about 95%, or at least about 96%, 97%, 98% or 99% of the nucleotide bases have nucleotide sequence identity as measured by any of the well-known sequence identity algorithms such as FASTA, BLAST or Gap, as discussed below.

[0224] When applied to polypeptides, the term "substantially similar" or "substantially similar" means that two peptide sequences share at least 95% sequence identity or at least 98% or 99% sequence identity when optimally aligned, such as by the program GAP or BESTFIT using the default gap weights. In an exemplary embodiment, the residue positions that are not identical differ by conservative amino acid substitutions. "Conservative amino acid substitutions" are amino acid substitutions in which one amino acid residue is substituted by another amino acid residue having a similar side chain (R group) of chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions do not significantly change the functional properties of proteins. In the case where two or more amino acid sequences differ from each other due to conservative substitutions, the sequence identity percentage or degree of similarity may be adjusted upward to correct the conservative nature of the substitution. The means for making such adjustments are well known to those skilled in the art. (See, for example, Pearson (1994) Methods Mol. Biol. [Molecular Biology Methods] 24: 307-331, which is incorporated herein by reference). Examples of amino acid groups with chemically similar side chains include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains are cysteine ​​and methionine. Exemplary conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45, incorporated herein by reference. A "moderately conservative" substitution is any change having a non-negative value in the PAM250 log-likelihood matrix.

[0225] Sequence analysis software is usually used to measure the sequence similarity of polypeptides, also referred to as sequence identity. Protein analysis software uses similarity measures assigned to various substitutions, deletions and other modifications (including conservative amino acid substitutions) to match similar sequences. For example, GCG software contains programs such as Gap and Bestfit, which can be used with default parameters to determine the sequence homology or sequence identity between closely related polypeptides (such as between homologous polypeptides from different organism species or between wild-type proteins and their mutant proteins). (See, for example, GCG version 6.1). FASTA (a program in GCG version 6.1) can also be used to compare polypeptide sequences using default or recommended parameters. FASTA (for example, FASTA2 and FASTA3) provides comparison and sequence identity percentage of the best overlapping region between query sequence and search sequence (Pearson (2000), supra). When the sequence of the present disclosure is compared with a database containing a large number of sequences from different organisms, another exemplary algorithm is a computer program BLAST using default parameters, especially BLASTP or TBLASTN. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each of which is incorporated herein by reference). Preparation of human antibodies

[0226] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used to prepare human antibodies that specifically bind to IL-4R.

[0227] use High affinity chimeric antibodies against IL-4R having human variable regions and mouse constant regions are initially isolated using the ELISA technique (see, e.g., US 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies. The technology involves producing a transgenic mouse with a genome comprising human heavy and light chain variable regions, which are operably linked to endogenous mouse constant region loci, so that the mouse produces antibodies comprising human variable regions and mouse constant regions in response to antigenic stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is separated and operably linked to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing complete human antibodies.

[0228] Generally, challenge with the antigen of interest Mouse, and reclaim lymphocytes (such as B cells) from the mouse expressing the antibody. Lymphocytes can be fused with myeloma cell lines to prepare infinite hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. The DNA encoding heavy chain and light chain variable regions can be separated and connected to the desired heavy chain and light chain isotype constant regions. This antibody protein can be produced in cells such as CHO cells. Alternatively, the DNA encoding antigen-specific chimeric antibodies or light chain and heavy chain variable domains can be directly separated from antigen-specific lymphocytes.

[0229] Initially, high-affinity chimeric antibodies with human variable regions and mouse constant regions are isolated. Antibodies are characterized and selected using standard procedures known to those skilled in the art to obtain desired characteristics, including affinity, selectivity, epitopes, etc. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody as described herein, such as a wild-type or modified IgG1 or IgG4. Although the selected constant region may vary depending on the specific use, high-affinity antigen binding and target-specific characteristics are present in the variable region.

[0230] In general, antibodies that can be used in the methods described herein have high affinity as described above when measured by binding to an antigen immobilized on a solid phase or in a solution phase. Mouse constant regions are substituted with desired human constant regions to generate fully human antibodies as described herein. Although the selected constant region may vary depending on the specific use, high affinity antigen binding and target specificity characteristics are present in the variable region.

[0231] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R that can be used in the context of the methods described herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within a given HCVR and / or LCVR amino acid sequence disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases can also be used to identify CDR sequences within antibodies.

[0232] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0233] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequence of SEQ ID NO: 3 / 4 / 5 / 6 / 7 / 8.

[0234] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0235] In certain embodiments, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0236] In certain embodiments, the antibody sequence is dupilumab, which comprises the heavy chain / light chain amino acid sequence pair of SEQ ID NOs: 9 and 10. Dupilumab HCVR amino acid sequence:

[0237] EVQLVESGGGLEQPGGSLRLSCAGSGFFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 1). Dupilumab LCVR amino acid sequence:

[0238] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 2). Dupilumab HCDR1 amino acid sequence:

[0239] GFTFRDYA (SEQ ID NO: 3). Dupilumab HCDR2 amino acid sequence:

[0240] ISGSGGNT (SEQ ID NO: 4). Dupilumab HCDR3 amino acid sequence:

[0241] AKDRLSITIRPRYYGL (SEQ ID NO: 5). Dupilumab LCDR1 amino acid sequence:

[0242] QSLLYSIGYNY (SEQ ID NO: 6). Dupilumab LCDR2 amino acid sequence:

[0243] LGS (SEQ ID NO: 7). Dupilumab LCDR3 amino acid sequence:

[0244] MQALQTPYT (SEQ ID NO: 8). Dupilumab HC amino acid sequence:

[0245] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO:9) (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant region). Dupilumab LC amino acid sequence:

[0246] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10) (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant region).

[0247] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of: SCB-VL-39 / SCB-VH-92; SCB-VL-40 / SCB-VH-92; SCB-VL-41 / SCB-VH-92; SCB-VL-42 / SCB-VH-92; SCB-VL-43 / SCB-VH-92; SCB-VL-44 / SCB-VH-92; SCB-VL-44 / SCB-VH-62; SCB-VL-44 / SCB-VH-68; SCB-VL-44 / SCB-VH-72. H-72;SCB-VL-44 / SCB-VH-82;SCB-VL-44 / SCB-VH-85;SCB-VL-44 / SCB-VH-91; SCB-VL-44 / SCB-VH-93; ;SCB-VL-47 / SCB-VH-92;SCB-VL-48 / SCB-VH-92;SCB-VL-49 / SCB-VH-92;SCB-VL-50 / SCB-VH-92;SCB-VL-51 / SCB-VH-92;SCB-VL-51 / SCB-VH-93;SCB -VL-52 / SCB-VH-92;SCB-VL-52 / SCB-VH-62;SCB-VL-52 / SCB-VH-91;SCB-VL-53 / SCB-VH-92;SCB-VL-54 / SCB-VH-92;SCB-VL-54 / SCB-VH-62;SCB-VL- 54 / SCB-VH-68; SCB-VL-54 / SCB-VH-72; SCB-VL-54 / SCB-VH-82; SCB-VL-54 / SCB-VH-85; CB-VH-62;SCB-VL-55 / SCB-VH-68;SCB-VL-55 / SCB-VH-72;SCB-VL-55 / SCB-VH-82;SCB-VL-55 / SCB-VH-85;SCB-VL-55 / SCB-VH-91;SCB-VL-56 / SCB-V H-92;SCB-VL-57 / SCB-VH-92;SCB-VL-57 / SCB-VH-93;SCB-VL-57 / SCB-VH-59;SCB-VL-57 / SCB-VH-60;SCB-VL-57 / SCB-VH-63; SCB-VL-57 / SCB-VH-64; SCB-VL-57 / SCB-VH-65; SCB-VL-57 / SCB-VH-66; SCB-VL-57 / SCB-VH-67; SCB-VL-57 / SCB-VH-68; SCB-VL-57 / SCB-VH-69; SCB-VL-57 / SCB-VH-70; SCB-VL-57 / SCB-VH-71; SCB-VL-57 / SCB-VH-72; SCB-VL-57 / SCB-VH-73; SCB-VL-57 / SCB-VH-74; SCB-VL-57 / SCB-VH-75; SCB-VL-57 / SCB-VH-76; SCB-VL-57 / SCB-VH-77; SCB-VL-57 / SCB-VH-78; SCB-VL-57 / SCB-VH-79; SCB-VL-57 / SCB-VH-80; SCB-VL-57 / SCB-VH-81; SCB-VL-57 / SCB-VH-82; SCB-VL-57 / SCB-VH-83; SCB-VL-57 / SCB-VH-84; SCB-VL-57 / SCB-VH-85; SCB-VL-57 / SCB-VH-86; SCB-VL-57 / SCB-VH-87; SCB-VL-57 / SCB-VH-88; SCB-VL-57 / SCB-VH-89; SCB-VL-57 / SCB-VH-90; SCB-VL-57 / SCB-VH-91; SCB-VL-58 / SCB-VH-91; SCB-VL-58 / SCB-VH-92; and SCB-VL-58 / SCB-VH-93. ;

[0248] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the LCVR / HCVR sequence pair of SCB-VL-44 / SCB-VH-92.

[0249] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the LCVR / HCVR sequence pair of SCB-VL-54 / SCB-VH-92.

[0250] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the LCVR / HCVR sequence pair of SCB-VL-55 / SCB-VH-92.

[0251] In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and a LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-55-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0252] In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and a LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0253] In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and a LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-44-LCDR3.

[0254] The antibodies listed in Table 1 below are described in more detail in US 10,774,141, which is incorporated herein by reference in its entirety for all purposes. Table 1.

[0255] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of: MEDI-1-VL / MEDI-1-VH to MEDI-42-VL / MEDI-42-VH.

[0256] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the LCVR / HCVR sequence pair of MEDI-37GL-VL / MEDI-37GL-VH.

[0257] In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a HCVR comprising the HCDR1 sequence of MEDI-37GL-HCDR1, the HCDR2 sequence of MEDI-37GL-HCDR2, and the HCDR3 sequence of MEDI-37GL-HCDR3, and a LCVR comprising LCDR1 of MEDI-37GL-LCDR1, LCDR2 of MEDI-37GL-LCDR2, and LCDR3 of MEDI-37GL-LCDR3.

[0258] The antibodies listed in Table 2 below are described in more detail in US Pat. No. 8,877,189, which is incorporated herein by reference in its entirety for all purposes. Table 2.

[0259] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise the LCVR / HCVR sequence pair of AJOU-90-VL / AJOU-83-VH.

[0260] In certain embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a HCVR comprising the HCDR1 sequence of AJOU-84-HCDR1, the CHDR2 sequence of AJOU-85-HCDR2, and the HCDR3 sequence of AJOU-32-HCDR3, and a LCVR comprising the LCDR1 of AJOU-96-LCDR1, the LCDR2 of AJOU-60-LCDR2, and the LCDR3 of AJOU-68-LCDR3.

[0261] The antibodies listed in Table 3 below are described in more detail in WO 2020 / 096381 and Kim et al. (Scientific Reports. [Science Report] 9:7772.2019), which are incorporated herein by reference in their entirety for all purposes. Table 3.

[0262] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of: 11 / 3, 27 / 19, 43 / 35, 59 / 51, 75 / 67, 91 / 83, 107 / 99, 123 / 115, 155 / 147 and 171 / 163.

[0263] The antibodies listed in Table 4 below are described in more detail in US Pat. No. 7,605,237 and US Pat. No. 7,608,693, which are incorporated herein by reference in their entirety for all purposes. Table 4.

[0264] The antibodies listed in Table 5 below are described in more detail in WO 2022 / 052974, which is incorporated herein by reference in its entirety for all purposes. Table 5.

[0265] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region (HCVR) and a light chain variable region (LCVR) sequence pair (HCVR / LCVR) selected from the group consisting of: Y0188-1 / Y0188-1; Y0188-2 / Y0188-2; Y0188-3 / Y0188-3; Y0188-4 / Y0188-4; Y0188-6 / Y0188-6; Y0188-8 / Y0188-8; Y0188-9 / Y0188-9; Y0188-10 / Y0188-10; Y0188-14 / Y0188-14; HV3-15-14 / Y01-14; HV3-15-14 / Y01-16 4-14; HV3-15-14 / KV4-14; HV3-15-14 / KV1-27-14; HV3-15-14 / KV1-9-14; HV3-15-14 / KV1-NL1-14; HV3-15-14 / KV1D-43-14; HV3-48-14 / Y01-14; HV3-4 8-14 / 164-14; HV3-48-14 / KV4-14; HV3-48-14 / KV1-27-14; HV3-48-14 / KV1 -9-14;HV3-48-14 / KV1-NL1-14;HV3-48-14 / KV1D-43-14;HV3-73*2-14 / Y01 -14;HV3-73*2-14 / 164-14;HV3-73*2-14 / KV4-14;HV3-73*2-14 / KV1-27-14;HV3-73*2-14 / KV1-9-14;HV3-73*2-14 / KV1-NL1-14;HV3-73*2-14 / KV1D- HV3-72-14 / KV1-9-14; HV3-72-14 / KV1-NL1-14; HV3-72-1 4 / KV1D-43-14; Y01-14 / Y01-14; Y01-14 / 164-14; Y01-14 / KV4-14; Y01-14 / KV1-27-14; Y01-14 / KV1-9-14; Y01-14 / KV1-NL1-14; Y01-14 / KV1D-43-14; 1 62-14 / Y01-14;162-14 / 164-14;162-14 / KV4-14;162-14 / KV1-27-14;162- 14 / KV1-9-14; 162-14 / KV1-NL1-14; 162-14 / KV1D-43-1L; VH73-14 / Y01-14;VH73-14 / 164-14; VH73-14 / KV4-14; VH73-14 / KV1-27-14; VH73-14 / KV1-9-14; VH73-14 / KV1-NL1-14; and VH73-14 / KV1D-43-14. ;

[0266] The antibodies listed in Table 6 below are described in more detail in WO 2021 / 213329, which is incorporated herein by reference in its entirety for all purposes. Table 6. Pharmaceutical composition

[0267] Methods are provided comprising administering to a patient an IL-4R antagonist, wherein the IL-4R antagonist is contained in a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, etc. Many suitable formulations can be found in formulas known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN TM ), DNA conjugates, anhydrous absorption creams, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semisolid gels, and semisolid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. [Journal of Pharmaceutical Science and Technology] 52:238-311.

[0268] The dosage of the antibody administered to the patient may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. The dosage is generally calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment may be adjusted. The effective dosage and schedule for administering a pharmaceutical composition comprising an anti-IL-4R antibody may be determined empirically; for example, patient progress may be monitored by periodic assessments, and the dosage adjusted accordingly. In addition, interspecies scaling of dosages may be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0269] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered with other biologically active agents.

[0270] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, pen delivery devices (e.g., autoinjector pens) are readily applicable to delivering the pharmaceutical compositions described herein. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices typically utilize replaceable cartridges containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. In contrast, the disposable pen delivery device is pre-filled with a pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded.

[0271] Many reusable pen and auto-injector delivery devices are used for subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, AUTOPEN, to name a few. TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TMPen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM PEN (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM 、OPTIPEN PRO TM 、OPTIPEN STARLET TM and OPTICLIK TM (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices useful for subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, SOLOSTAR TM Pen (Sanofi), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjectors (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TMPen (Abbott Labs, Abbott Park IL). Examples of large volume delivery devices (e.g., large volume syringes) include, but are not limited to, push syringes such as, for example, BD Libertas West SmartDose, EnableInjections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, BespakLapas, etc.

[0272] Example drug delivery devices may involve needle-based injection systems, as described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly divided into multi-dose container systems and single-dose (partially or completely emptied) container systems. The container may be a replaceable container or an integrated non-replaceable container.

[0273] As further described in ISO 11608-1:2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container contains multiple doses, the sizes of which may be fixed or variable (preset by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container contains multiple doses, the sizes of which may be fixed or variable (preset by the user).

[0274] As further described in ISO 11608-1:2014 (E), a single-dose container system may relate to an injection device based on a needle with a replaceable container. In an example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely emptying). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially emptying). Also as described in ISO 11608-1:2014 (E), a single-dose container system may relate to an injection device based on a needle with an integrated non-replaceable container. In an example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely emptying). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially emptying).

[0275] An example sleeve-triggered autoinjector with a manual needle inserter is described in International Publication WO 2015 / 004052. An example audible end-of-dose feedback mechanism is described in International Publications WO 2016 / 193346 and WO 2016 / 193348. An example needle safety mechanism after use of an autoinjector is described in International Publication WO 2016 / 193352. An example needle sheath remover mechanism for a syringe autoinjector is described in International Publication WO 2016 / 193353. An example support mechanism for supporting the axial position of a syringe is described in International Publication WO 2016 / 193355.

[0276] For direct administration to the sinuses, the pharmaceutical compositions described herein can be administered using, for example, a microcatheter (e.g., an endoscope and microcatheter), a nebulizer, a powder dispenser, atomizer, or an inhaler. The method comprises administering an IL-4R antagonist to a subject in need thereof in the form of an aerosolized formulation. For example, an aerosolized antibody to IL-4R can be administered to treat PN in a patient. The aerosolized antibody can be prepared as described, for example, in US 8,178,098, which is incorporated herein by reference in its entirety.

[0277] In some scenarios, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. [CRC: Critical Reviews in Biomedical Engineering] 14: 201). In another embodiment, a polymeric material can be used; see, Medical Applications of Controlled Release [Controlled Release Medical Applications], Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. [CRC Press, Boca Raton, Florida]. In yet another embodiment, a controlled release system can be placed near the target of the composition, thus requiring only a small portion of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release [Controlled Release Medical Applications], supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in Langer's review (1990, Science [Science] 249: 1527-1533).

[0278] Injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, instillations, etc. These injectable preparations can be prepared by known methods. For example, the above-mentioned antibody or its salt can be dissolved, suspended or emulsified in a sterile aqueous medium or an oily medium commonly used for injection to prepare an injectable preparation. As an aqueous medium for injection, there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with appropriate solubilizers (such as alcohol (for example, ethanol), polyols (for example, propylene glycol, polyethylene glycol)), nonionic surfactants (for example, polysorbate 80, HCO-50 (polyoxyethylene (50mol) adducts of hydrogenated castor oil)), etc. As an oily medium, sesame oil, soybean oil, etc. are used, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. Usually the injection prepared in this way is filled in an appropriate ampoule.

[0279] Advantageously, the pharmaceutical composition for oral or parenteral use is prepared into a unit dosage form suitable for coordinating a certain dose of active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0280] Exemplary pharmaceutical compositions comprising an anti-IL-4R antibody that can be used as described herein are disclosed, e.g., in US Pat. No. 8,945,559. dose

[0281] The amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) administered to a subject according to the methods described herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of an IL-4R antagonist that results in an improvement in one or more PN-related PRO measures or PN-related ClinRO measures (as defined elsewhere herein). A "therapeutically effective amount" also includes an amount of an IL-4R antagonist that inhibits, prevents, alleviates, or delays the progression of PN in a subject.

[0282] For anti-IL-4R antibodies, a therapeutically effective amount can be from about 0.05 mg to about 700 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 51 In some embodiments, about 300 mg of the anti-IL-4R antibody is administered.

[0283] The amount of IL-4R antagonist included in each dose can be expressed as milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of subject body weight. For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0284] In certain embodiments, the initial dose is about the same as the loading dose. In certain embodiments, the initial dose is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.5 times, about 3.0 times or more of the loading dose.

[0285] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of a treatment regimen as an "initial dose" or "loading dose," followed by less frequent subsequent doses (e.g., "secondary doses" or "maintenance doses"). In one embodiment, the maintenance dose may be lower than the loading or initial dose. For example, one or more loading doses of 600 mg of an IL-4R antagonist may be administered, followed by a maintenance dose of about 75 mg to about 300 mg. In certain embodiments, these methods include an initial dose or loading dose of about 400 mg or about 600 mg of an IL-4R antagonist. In certain embodiments, these methods include one or more secondary doses or maintenance doses of about 200 mg or about 300 mg of an IL-4R antagonist.

[0286] In one embodiment, the maintenance dose is the same dose as the loading or initial dose. For example, both the loading dose and the maintenance dose of the IL-4R antagonist can be administered at a dose of about 75 mg to about 300 mg. In certain embodiments, the methods include an initial dose and a maintenance dose of the IL-4R antagonist of about 300 mg.

[0287] In certain exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg, and the IL-4R antagonist is administered at a dose of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some embodiments, the subject is a pediatric subject weighing more than 30 kg, and the IL-4R antagonist is administered at an initial dose or loading dose of about 400 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w). In some embodiments, the subject is a pediatric subject weighing more than 30 kg, and the IL-4R antagonist is administered at an initial dose and maintenance dose of about 200 mg, and the maintenance dose is administered every other week (q2w).

[0288] In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and weighing at least 15 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some embodiments, the subject is a pediatric subject weighing 30 kg or less and weighing at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary doses or maintenance doses of about 300 mg, and the secondary doses are administered every four weeks (q4w). In some embodiments, the subject is a pediatric subject weighing 30 kg or less and weighing at least 15 kg, and the IL-4R antagonist is administered at an initial dose and maintenance dose of about 300 mg, and the maintenance dose is administered every four weeks (q4w).

[0289] In certain exemplary embodiments, the subject is an adolescent subject weighing less than 60 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some embodiments, the subject is an adolescent subject weighing less than 60 kg, and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w). In other embodiments, the subject is an adolescent subject weighing less than 60 kg, and the IL-4R antagonist is administered at an initial dose and maintenance dose of about 200 mg, and the maintenance dose is administered every other week (q2w). In certain embodiments, the subject is an adolescent subject weighing greater than or equal to 30 kg and less than 60 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some embodiments, the subject is an adolescent subject weighing greater than or equal to 30 kg and less than 60 kg, and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w). In other embodiments, the subject is an adolescent subject weighing greater than or equal to 30 kg and less than 60 kg, and the IL-4R antagonist is administered at an initial dose and maintenance dose of about 200 mg, and the maintenance dose is administered every other week (q2w).

[0290] In certain exemplary embodiments, the subject is an adolescent subject weighing at least 60 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In exemplary embodiments, the subject is an adolescent subject weighing at least 60 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary doses or maintenance doses of about 300 mg, and the secondary doses are administered every other week (q2w). In other embodiments, the subject is an adolescent subject weighing at least 60 kg, and the IL-4R antagonist is administered at an initial dose and maintenance dose of about 300 mg, and the maintenance dose is administered every other week (q2w).

[0291] In certain exemplary embodiments, the subject is an adult and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In exemplary embodiments, the subject is an adult and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary doses or maintenance doses of about 300 mg, and the secondary doses are administered every other week (q2w). In other exemplary embodiments, the subject is an adult and the IL-4R antagonist is administered at an initial dose of about 300 mg and a maintenance dose of about 300 mg, and the maintenance dose is administered every other week (q2w).

[0292] In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 150 mg / mL using a pre-filled device. In some embodiments, 300 mg of the IL-4R antagonist is delivered in a 2 mL injection using a 150 mg / mL IL-4R antagonist solution in a pre-filled device. In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 175 mg / mL using a pre-filled device. In some embodiments, 200 mg of the IL-4R antagonist is delivered in a 1.14 mL injection using a 175 mg / mL IL-4R antagonist solution in a pre-filled device. Combination therapy

[0293] Certain embodiments of the methods described herein include administering to a subject one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the expression "in combination with" means administering the additional therapeutic agent before, after, or simultaneously with a pharmaceutical composition comprising an anti-IL-4R antagonist. In some embodiments, the term "in combination with" includes administering an IL-4R antagonist and a second therapeutic agent sequentially or simultaneously. The present invention provides methods for treating PN or related conditions or complications comprising administering an IL-4R antagonist in combination with a second therapeutic agent to obtain additive or synergistic activity.

[0294] For example, when administered "before" a pharmaceutical composition comprising an anti-IL-4R antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an anti-IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an anti-IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an anti-IL-4R antagonist. Administration "concurrently" with a pharmaceutical composition comprising an anti-IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the anti-IL-4R antagonist, or is administered to the subject as a single combination dose formulation comprising both the additional therapeutic agent and the anti-IL-4R antagonist.

[0295] In an exemplary embodiment, the additional therapeutic agent administered in combination with the IL-4R antagonist is a background therapy. In an exemplary embodiment, the background therapy is one or more topical corticosteroids (TCS). In an exemplary embodiment, the background therapy is one or more oral corticosteroids (OCS). In other exemplary embodiments, the background therapy is one or more topical calcineurin inhibitors (TCI). In some exemplary embodiments, the background therapy is one or more low to moderate potency topical corticosteroids (TCS). In other exemplary embodiments, the background therapy is one or more low to moderate potency topical calcineurin inhibitors (TCI). In certain embodiments, the method reduces the need for background therapy. For example, in certain embodiments, the method reduces the dosage and / or frequency of background therapy.

[0296] The additional therapeutic agent can be, for example, another IL-4R antagonist (e.g., one or more suitable IL-4R antagonists listed in Tables 1-4), TCS, TCI, an IL-1 antagonist (including, for example, an IL-1 antagonist as described in U.S. Pat. No. 6,927,044), an IL-5 antagonist, an IL-5R antagonist, an IL-6 antagonist, an IL-6R antagonist (including, for example, an anti-IL-6R antibody as described in U.S. Pat. No. 7,582,298), or an IL-17 antagonist.

[0297] In an exemplary embodiment, the additional therapeutic agent is a medium to ultra-high potency TCS.

[0298] In another exemplary embodiment, the additional therapeutic agent is a low to moderate potency TCS.

[0299] Suitable ultra-high potency (ie, Group 1) TCS include, but are not limited to, betamethasone dipropionate (boosted), clobetasol propionate, diflucortolone valerate, fluocinolone acetonide, flurandrenolide, halobetasol propionate, and the like.

[0300] Suitable high potency (ie, Group 2) TCS include, but are not limited to, amcinonide, betamethasone dipropionate, clobetasol propionate, desoximetasone, diflorasone diacetate, fluocinolone acetonide, halcinonide, halobetasol propionate, and the like.

[0301] Suitable high potency (ie, Group 3) TCS include, but are not limited to, amcinonide, betamethasone dipropionate, betamethasone valerate, desoximetasone, diflorasone diacetate, diflucortolone valerate, fluocinolone acetonide, fluticasone propionate, mometasone furoate, mometasone furoate, and the like.

[0302] Suitable intermediate potency (i.e., Group 4) TCS include, but are not limited to, betamethasone dipropionate, pitavaclocortolone, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone valerate, mometasone furoate, triamcinolone acetonide, etc. Particularly suitable intermediate potency TCS include triamcinolone acetonide 0.1% cream and fluocinolone acetonide 0.025% ointment.

[0303] Suitable lower intermediate potency (ie, Group 5) TCS include, but are not limited to, betamethasone dipropionate, betamethasone valerate, desonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone propionate, hydrocortisone valerate, prednicarbate, triamcinolone acetonide, and the like.

[0304] Suitable low potency (ie, Group 6) TCS include, but are not limited to, alclomethasone dipropionate, betamethasone valerate, desonide, fluocinolone acetonide, triamcinolone acetonide, and the like.

[0305] Suitable minimally potent (ie, Group 7) TCS include, but are not limited to, hydrocortisone (base, ≥±2%), hydrocortisone (base, <2%), hydrocortisone acetate, etc. A particularly suitable minimally potent TCS is hydrocortisone 1% cream.

[0306] In further exemplary embodiments, the additional therapeutic agent is a mid- to ultra-potent TCI.

[0307] In further exemplary embodiments, the additional therapeutic agent is a low to moderate potency TCI.

[0308] Suitable TCIs include, but are not limited to, clobetasol propionate, betamethasone dipropionate, ASTAGRAF XL TM (ie, tacrolimus extended-release capsules), CEQUA TM (i.e., Cyclosporine 0.09% Eye Drops), Cyclosporine, Cyclosporine Ophthalmic, ELIDEL TM (ie, pimecrolimus), ENVARSUS XR TM (ie, tacrolimus extended-release tablets), GENGRAF TM (i.e., cyclosporine), HECORIA TM (ie, tacrolimus), LUPKYNIS TM (cyclosporine), NEORAL TM (ie, cyclosporine capsules and oral solution), pimecrolimus, PROGRAF TM (ie, tacrolimus capsules), PROTOPIC TM (ie, tacrolimus ointment), RESTASIS TM (i.e., cyclosporine 0.05% eye drops), SANDIMMUNE TM (ie, cyclosporine capsules and oral solution), tacrolimus, tacrolimus ointment, VERKAZIA TM (i.e., cyclosporine ophthalmic emulsion), cyclosporine, etc.

[0309] A particularly suitable super-high potency TCS is clobetasol propionate 0.05% cream. A particularly suitable high potency TCS is betamethasone dipropionate 0.05% optimized ointment.

[0310] In further exemplary embodiments, the additional therapeutic agent is an oral corticosteroid (ie, a systemic corticosteroid).

[0311] Suitable oral corticosteroids include, but are not limited to, prednisone, prednisolone, methylprednisolone, hydrocortisone, dexamethasone, cortisone acetate, and the like. Administration regimen

[0312] According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined time course. Such methods include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequential administration" means administering each dose of an IL-4R antagonist to a subject at different time points, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Provided are methods comprising sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of an IL-4R antagonist, and optionally followed by one or more tertiary doses of an IL-4R antagonist.

[0313] Methods are provided comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about four times a week, twice a week, once a week (q1w), once every two weeks (every two weeks is interchangeable with every other week, once every two weeks, or q2w), once every three weeks (once every three weeks or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or less frequently, as long as a therapeutic response is achieved.

[0314] In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once a week. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every two weeks (every two weeks may be used interchangeably with every other week, once every two weeks, or q2w). In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every three weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every four weeks (monthly administration). In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every five weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every six weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every eight weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg may be administered once every twelve weeks. In certain exemplary embodiments, the route of administration is subcutaneous.

[0315] The term "week" refers to a period of (n×7 days)±3 days, such as (n×7 days)±2 days, (n×7 days)±1 day or (n×7 days), where "n" represents the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0316] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order in which the IL-4R antagonist is administered. Thus, the "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose" or "loading dose"); the "secondary dose" is the dose administered after the initial dose; and the "tertiary dose" is the dose administered after the secondary dose. The initial dose, the secondary dose, and the tertiary dose may all contain the same amount of IL-4R antagonist, or may differ from one another in terms of the frequency of administration. However, in certain embodiments, during the course of treatment, the amount of IL-4R antagonist contained in the initial dose, the secondary dose, and / or the tertiary dose differs from one another (e.g., is adjusted up or down, as appropriate). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as "loading doses," followed by subsequent doses (e.g., "maintenance doses") administered at a less frequent frequency. In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more initial doses or loading doses of 600 mg or 400 mg of the IL-4R antagonist may be administered, followed by a secondary dose or maintenance dose of about 75 mg to about 400 mg. In one embodiment, the secondary dose / maintenance dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of 300 mg or 200 mg of the IL-4R antagonist may be administered, followed by a secondary dose / maintenance dose of about 300 mg or about 200 mg, respectively. In one embodiment, the loading dose may be separated, such as two or more doses administered at different time points, such as two loading doses, wherein the second loading dose is administered two weeks after the first loading dose.

[0317] In certain embodiments, the initial dose is about 50 mg to about 600 mg of the IL-4R antagonist. In one embodiment, the initial dose is 600 mg of the IL-4R antagonist. In another embodiment, the initial dose is 400 mg of the IL-4R antagonist. In still other embodiments, the initial dose is 300 mg of the IL-4R antagonist.

[0318] In certain embodiments, the second dose is about 50 mg to about 600 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist.

[0319] In certain embodiments, the initial dose is three times the maintenance dose. In certain embodiments, the initial dose is twice the maintenance dose. In certain embodiments, the initial dose is equal to the maintenance dose. In an exemplary embodiment, the initial dose is 300 mg and the maintenance dose is 300 mg.

[0320] In some embodiments, the subject is a child and weighs 30 kg or less and at least 15 kg, the initial dose comprises 600 mg of an antibody or its antigen-binding fragment, and one or more secondary doses comprise 300 mg of an antibody or its antigen-binding fragment administered every four weeks (q4w). In other embodiments, the subject is a child and weighs 30 kg or less and at least 15 kg, the initial dose comprises 300 mg of an antibody or its antigen-binding fragment, and one or more secondary doses comprise 300 mg of an antibody or its antigen-binding fragment administered every four weeks (q4w).

[0321] In some embodiments, the subject is a child and weighs more than 30 kg, the initial dose comprises 400 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 200 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In other embodiments, the subject is a child and weighs more than 30 kg, the initial dose comprises 200 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 200 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w).

[0322] In some embodiments, the subject is a teenager and weighs less than 60kg, the initial dose comprises 400mg of an antibody or an antigen-binding fragment thereof, and one or more secondary doses comprise 200mg of an antibody or an antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In other embodiments, the subject is a teenager and weighs less than 60kg, the initial dose comprises 200mg of an antibody or an antigen-binding fragment thereof, and one or more secondary doses comprise 200mg of an antibody or an antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In an exemplary embodiment, the subject is a teenager and weighs greater than or equal to 30kg and less than 60kg, the initial dose comprises 400mg of an antibody or an antigen-binding fragment thereof, and one or more secondary doses comprise 200mg of an antibody or an antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In other exemplary embodiments, the subject is an adolescent and weighs greater than or equal to 30 kg and less than 60 kg, the initial dose comprises 200 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, once every two weeks, or q2w).

[0323] In some embodiments, the subject is an adolescent and weighs more than 60 kg, the initial dose comprises 600 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In other embodiments, the subject is an adolescent and weighs more than 60 kg, the initial dose comprises 300 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w).

[0324] In some embodiments, the subject is an adult, the initial dose comprises 600 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w). In other embodiments, the subject is an adult, the initial dose comprises 300 mg of an antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of an antibody or antigen-binding fragment thereof administered every other week (every other week can be used interchangeably with every two weeks, every two weeks, or q2w).

[0325] In an exemplary embodiment, each secondary dose and / or tertiary dose is 1 to 14 weeks (e.g., 1, 1 1 / 2,2,2 1 / 2,3,3 1 / 2,4,4 1 / 2,5,5 1 / 2,6,6 1 / 2,7,7 1 / 2,8,8 1 / 2,9,9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 The phrase "previous dose" means the dose of the IL-4R antagonist administered to a patient in a sequence of multiple administrations prior to administration of the immediately next dose in the sequence, without intervening doses.

[0326] These methods may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to a patient. Similarly, in certain embodiments, only a single tertiary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to a patient.

[0327] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency of administering secondary and / or tertiary doses to the patient may vary over the course of the treatment regimen. The frequency of administration may also be adjusted during treatment by a physician depending on the needs of the individual patient after clinical examination.

[0328] Methods are provided comprising sequentially administering an IL-4R antagonist and a second therapeutic agent to a patient to treat PN or related conditions. In some embodiments, the methods comprise administering one or more doses of an IL-4R antagonist followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent. For example, one or more doses of about 75 mg to about 600 mg of an IL-4R antagonist may be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent (e.g., TCS or TCI) to treat, alleviate, reduce, or improve one or more symptoms of PN. In some embodiments, the IL-4R antagonist is administered at one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) such that one or more PN-related parameters are improved, followed by administration of a second therapeutic agent to prevent recurrence of at least one symptom of PN. Alternative embodiments involve administering an IL-4R antagonist and a second therapeutic agent simultaneously. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an IL-4R antagonist are administered, and a second therapeutic agent is administered at a separate dose at a similar or different frequency than the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0329] In certain embodiments, the IL-4R antagonist is administered every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks or more. In other embodiments, the IL-4R antagonist is administered every four weeks for 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks or more. In specific embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0330] In certain embodiments, a kit for treating CIndU is provided, the kit comprising a dosage form of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain embodiments, the antibody is dupilumab.

[0331] The kit may include a label or package insert, wherein the label or package insert includes instructions for administering the dosage form to treat PN. The instructions may list a dosing regimen for treating PN as further described herein. Treatment population

[0332] The methods provided herein include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. The expression "subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or signs of PN or has been diagnosed with PN.

[0333] In related embodiments, a "subject in need thereof" can be a subject who has been prescribed or is currently taking a TCI or TCS prior to receiving an IL-4R antagonist. In some embodiments, the subject is currently taking a low- to moderate-potency TCI or TCS. For example, methods are provided that include administering an IL-4R antagonist to a patient who has been regularly taking a low- to moderate-potency TCI or TCS for two weeks or more prior to administration of the IL-4R antagonist (such prior treatment is referred to herein as "background therapy").

[0334] In yet other embodiments, the amount of TCI or TCS is gradually reduced before or after the start of administration of the IL-4R antagonist. In other embodiments, the potency of the TCI or TCS is gradually reduced before or after the start of administration of the IL-4R antagonist.

[0335] In another exemplary embodiment, the "subject in need" is diagnosed with TCS- or TCI-refractory PN prior to receiving the IL-4R antagonist. In some embodiments, despite treatment with TCS or TCI, the subject's PN symptoms persist. In still another exemplary embodiment, the "subject in need" is diagnosed with moderate to super-high potency TCS- or TCI-refractory PN prior to receiving the IL-4R antagonist. In some embodiments, despite treatment with moderate to super-high potency TCS or TCI, the subject's PN symptoms persist. In yet another exemplary embodiment, the "subject in need" is diagnosed with low to moderate potency TCS- or TCI-refractory PN prior to receiving the IL-4R antagonist. In some embodiments, despite treatment with low to moderate potency TCS or TCI, the subject's PN symptoms persist.

[0336] In another embodiment, a "subject in need" is a subject whose PN cannot be adequately controlled by topical therapy. In other embodiments, a "subject in need" is a subject suffering from pruritus or PN refractory to topical therapy. In some embodiments, a "subject in need" is a subject for whom topical therapy is not suitable (i.e., the subject experiences side effects associated with topical therapy or is taking a drug that cannot be combined with topical therapy). In still other embodiments, a "subject in need" is a subject who is a candidate for systemic therapy for treating PN or pruritus.

[0337] In further exemplary embodiments, a "subject in need thereof" is a subject for whom TCS or TCI is medically inappropriate (ie, the subject has a history of allergies, adverse reactions, or other medical history in which administration of TCS or TCI is inappropriate).

[0338] In some embodiments, a "subject in need" is selected from the group consisting of: a subject 18 years of age or older, a subject 12 years of age or older, a subject 12 to 17 years of age (12 to <18 years of age), a subject 6 to 11 years of age (6 to <12 years of age), and a subject 2 to 5 years of age (2 to <6 years of age). In some embodiments, a "subject in need" is selected from the group consisting of: an adult, a teenager, and a child. In some embodiments, a "subject in need" is selected from the group consisting of: an adult 18 years of age or older, a teenager 12 to 17 years of age (12 to <18 years of age), a child 6 to 11 years of age (6 to <12 years of age), and a child 2 to 5 years of age (2 to <6 years of age). The subject may be less than 2 years of age, e.g., 12 to 23 months, or 6 to 11 months.

[0339] In some embodiments, a "subject in need thereof" may be a subject with comorbid atopic dermatitis or another atopic condition (i.e., the subject has a history of atopy). In an exemplary embodiment, the subject has comorbid mild atopic dermatitis. In other embodiments, the subject has comorbid moderate atopic dermatitis, moderate to severe atopic dermatitis, or severe atopic dermatitis.

[0340] In another exemplary embodiment, a "subject in need thereof" is a subject suffering from mild PN, moderate PN, moderate to severe PN, or severe PN. In some embodiments, the IGA PN-S score of a subject suffering from mild PN is 2 or mild. In some embodiments, the IGA PN-S score of a subject suffering from moderate PN is 3 or moderate. In some embodiments, the IGA PN-S score of a subject suffering from severe PN is 4 or severe. In some embodiments, the IGA PN-S score of a subject suffering from moderate to severe PN is 3 or 4 (moderate or severe). In some embodiments, a subject suffering from moderate to severe PN has a total of at least 20 PN nodules on both legs and / or both arms and / or trunk.

[0341] In other exemplary embodiments, a "subject in need" can be a subject with uncontrolled PN. In some embodiments, the subject with uncontrolled PN has failed to be treated with topical therapy. In some embodiments, the subject with uncontrolled PN has severe pruritus. In some embodiments, the subject with uncontrolled PN has more than 20 PN nodules.

[0342] In other exemplary embodiments, a "subject in need thereof" may be a subject having severe pruritus. Methods for assessing pharmacodynamic PN-related parameters

[0343] Methods for assessing one or more pharmacodynamic PN-related parameters in a subject in need thereof resulting from administration of a pharmaceutical composition comprising an IL-4R antagonist are provided. A reduction in the incidence of PN symptoms or an improvement in a PN-related PRO or ClinRO measure may be associated with an improvement in one or more pharmacodynamic PN-related parameters; however, such a correlation may not necessarily be observed in all cases.

[0344] Examples of "pharmacodynamic PN-related parameters" include, for example, the following: (a) biomarker expression levels and (b) serum protein and RNA analysis. "Improvement of pharmacodynamic PN-related parameters" means, for example, a decrease in one or more biomarkers (such as IgE, eosinophil levels, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9) relative to baseline. As used herein, the term "baseline" for pharmacodynamic PN-related parameters means the numerical value of the pharmacodynamic PN-related parameters of the patient before or at the time of administering the pharmaceutical composition described herein.

[0345] In order to evaluate the pharmacodynamic PN-related parameter, the parameter is quantified at the baseline and the time point after the administration of the pharmaceutical composition. For example, the pharmacodynamic PN-related parameter can be measured at about the 1st day, about the 2nd day, about the 3rd day, the 4th day, about the 5th day, about the 6th day, about the 7th day, about the 8th day, about the 9th day, about the 10th day, about the 11th day, about the 12th day, about the 14th day after the initial treatment with the pharmaceutical composition, or at about the 3rd week, about the 4th week, about the 5th week, about the 6th week, about the 7th week, about the 8th week, about the 9th week, about the 10th week, about the 11th week, about the 12th week, about the 13th week, about the 14th week, about the 15th week, about the 16th week, about the 17th week, about the 18th week, about the 19th week, about the 20th week, about the 21st week, about the 22nd week, about the 23rd week, about the 24th week or longer. The difference between the parameter value at a particular time point after the start of treatment and the parameter value at baseline is used to determine whether the pharmacodynamic PN-related parameter has changed, such as "improved" (e.g., increased or decreased, as appropriate, depending on the specific parameter measured).

[0346] In certain embodiments, administration of an IL-4R antagonist to a patient causes a change in the expression of a particular biomarker, such as a decrease or increase. PN-related biomarkers include, but are not limited to, total IgE, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9. For example, administration of an IL-4R antagonist to a PN patient can cause a decrease in total serum IgE levels. The decrease can be detected at about the first week, about the second week, about the third week, about the fourth week, about the fifth week, or longer after administration of the IL-4R antagonist. Biomarker expression can be determined by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured, for example, by reverse transcription-coupled polymerase chain reaction (RT-PCR).

[0347] Biomarker expression as described above can be analyzed by detecting proteins or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to treatment with IL-4R antagonists or IL-4 / IL-13 signaling (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, etc.). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), such as RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis). Preparations

[0348] In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 150 mg / mL of the antibody or antigen-binding fragment thereof that specifically binds to IL-4R; ii) about 20 mM histidine; iii) about 12.5 mM acetate; iv) about 5% (w / v) sucrose; v) about 25 mM arginine hydrochloride; vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9, and wherein the viscosity of the formulation is about 8.5 cPoise.

[0349] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of the antibody or antigen-binding fragment thereof that specifically binds to IL-4R; ii) about 20 mM histidine; iii) about 12.5 mM acetate; iv) about 5% (w / v) sucrose; v) about 50 mM arginine hydrochloride; and vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9, and wherein the viscosity of the formulation is about 8.5 cPoise.

[0350] In specific embodiments, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1 and a LCVR comprising the amino acid sequence of SEQ ID NO:2.

[0351] In a specific embodiment, the antibody comprises dupilumab. Unless otherwise indicated, the term "dupirocumab" also includes any biosimilars thereof.

[0352] Suitable stabilizing formulations are also described in US 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[0353] The present disclosure is further illustrated by the following examples, which should not be construed as further limiting.The contents of the figures, tables, and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0354] Moreover, in light of the present disclosure, conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art may be employed. Such techniques are fully explained in the literature. See, e.g., Green & Sambrook, Molecular Cloning: A Laboratory Manual, Fourth Edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (D. N. Glover, ed. 1985); Oligonucleotide Synthesis (M. J. Gait, ed. 1984); Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins, eds. (1985)); Transcription And Translation (B. D. Hames & S. J. Higgins, eds. (1984)); Animal Cell Culture (R. I. Freshney, ed. (1986)); Immobilized Cells And Enzymes (I. R. L. Smith, ed. (1987)); Press [IRL Press], (1986)]; B. Perbal, A Practical Guide To Molecular Cloning [Practical Guide to Molecular Cloning] (1984); FM Ausubel et al. (eds.), Current Protocols in Molecular Biology [Contemporary Molecular Biology Experimental Guide], John Wiley & Sons, Inc. [John Wiley and Sons Publishing Company] (1994). Examples

[0355] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and use the methods and compositions described in this disclosure, and are not intended to limit the scope of what the inventors consider to be their disclosures. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is at or near atmospheric pressure.

[0356] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1" or ). Example 1. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of dupilumab in patients with prurigo nodularis who were inadequately controlled with topical prescription therapies or who were inappropriate for those therapies (2 Phase 3 studies with similar design and populations—PRIME and PRIME2) Target Main Objectives :

[0357] To demonstrate the efficacy of dupilumab on the pruritus response in patients with PN who are inadequately controlled by topical prescription therapies or for whom those therapies are inappropriate. Secondary Objectives :

[0358] To demonstrate the efficacy of dupilumab for an additional pruritus endpoint in patients with PN who are inadequately controlled by topical prescription therapies or for whom those therapies are inappropriate.

[0359] To demonstrate the efficacy of dupilumab on PN skin lesions.

[0360] Demonstrate improvements in health-related quality of life (HRQoL).

[0361] Safety outcome measures were evaluated.

[0362] To evaluate the immunogenicity of dupilumab. end The primary endpoint of PRIME

[0363] Proportion of participants with an improvement (reduction) of ≥4 on the Worst Itch Numerical Rating Scale (WI-NRS) from baseline to Week 24. Primary endpoint of PRIME2 :

[0364] Proportion of participants with an improvement (decrease) of ≥ 4 on the Worst Itch Numerical Rating Scale (WI-NRS) from baseline to Week 12. Secondary End Points :

[0365] Proportion of participants with an improvement (reduction) of ≥4 on the WI-NRS from baseline to Week 24 (PRIME2 study).

[0366] Proportion of participants with a WI-NRS improvement (reduction) of ≥4 from baseline to Week 24 and an IGA PN-S score of 0 or 1 at Week 24. This endpoint captures the proportion of participants with a concomitant WI-NRS improvement (reduction) and an IGA PN-S score of 0 or 1 on the same day.

[0367] Time to efficacy for pruritus as measured by the proportion of participants with an improvement (reduction) of ≥4 from baseline in the WI-NRS during the 24-week treatment period.

[0368] Change from baseline in the WI-NRS at Week 24.

[0369] Change from baseline in the WI-NRS at Week 12.

[0370] Percent change from baseline in WI-NRS at Week 24.

[0371] Percent change from baseline in WI-NRS at Week 12.

[0372] Percent change from baseline in WI-NRS at Week 4.

[0373] Percent change from baseline in WI-NRS at Week 2.

[0374] Percent change from baseline in WI-NRS over time through Week 24.

[0375] Proportion of participants with a decrease in WI-NRS ≥4 at Week 4.

[0376] Proportion of participants with a decrease in WI-NRS of ≥4 over time through Week 24.

[0377] Onset of effect of change from baseline in WI-NRS through Week 12 (first p<0.05 difference from placebo in daily WI-NRS remained significant at subsequent measurements).

[0378] Proportion of participants with an Investigator Global Assessment of PN-S (IGA PN-S) score of 0 or 1 at Week 24.

[0379] Proportion of Participants with an IGA PN-S Score of 0 or 1 at Week 12.

[0380] Proportion of Participants with an IGA PN-S Score of 0 or 1 at Week 8.

[0381] Proportion of Participants with an IGA PN-S Score of 0 or 1 at Week 4.

[0382] Change from baseline in IGA PN-S scores at week 24.

[0383] Change from baseline in IGA PN-S scores at week 12.

[0384] Change from baseline in IGA PN-S scores at week 8.

[0385] Change from baseline in IGA PN-S scores at week 4.

[0386] Proportion of participants with an Investigator Global Assessment of PN-Activity (IGA PN-A) score of 0 or 1 at Week 24.

[0387] Proportion of Participants with an IGA PN-A Score of 0 or 1 at Week 12.

[0388] Proportion of Participants with an IGA PN-A Score of 0 or 1 at Week 8.

[0389] Proportion of Participants with an IGA PN-A Score of 0 or 1 at Week 4.

[0390] Change from baseline in HRQoL as measured by the Dermatology Life Quality Index (DLQI) through Week 24.

[0391] Change from baseline in HRQoL as measured by the DLQI to Week 12.

[0392] Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) from baseline to Week 24.

[0393] The incidence of treatment-emergent antidrug antibodies (ADA) to dupilumab over time. Study Design

[0394] This study was a multicenter, 24-week treatment, parallel, double-blind, randomized, placebo-controlled study designed to evaluate the use of durpilumab in patients with PN who were inadequately controlled by topical prescription therapies or who were not suitable for those therapies. The study evaluated the effect of durpilumab on improvement of pruritus and its effect on PN lesions, on patients' HRQoL, anxiety and depression, sleep quality and skin pain, and overall health status. Figure 1 As shown, this was a parallel treatment study with 2 groups, and the participants and investigators were blinded / masked.

[0395] Approximately 150 participants will be randomized 1:1. This corresponds to approximately 75 participants randomized to each intervention group. Participants who meet the inclusion and exclusion criteria will be randomly assigned (1:1) to one of the following investigational medicinal product (IMP) treatment groups: 300 mg of dupilumab and placebo. Active studies such as Figure 2A -D as shown. Duration of study period (per participant)

[0396] Screening period (2-4 weeks); Randomized IMP intervention period (24 weeks); and Follow-up period (12 weeks) Study Intervention Research Drugs:

[0397] Dupilumab 300 mg and dupilumab-matched placebo 300 mg were supplied in visually indistinguishable prefilled syringes. Dupilumab:

[0398] Formulation: Dupilumab 300 mg: 150 mg / mL dupilumab solution in a prefilled syringe, delivering 300 mg in a 2 mL injection.

[0399] Route of administration: Subcutaneous (SC) injection.

[0400] Dosage regimen: On day 1, an initial loading dose of 600 mg (2 injections of 300 mg) followed by 300 mg once every 2 weeks (Q2W). Placebo:

[0401] Formulation: Placebo is delivered as a 2 mL injection in a prefilled syringe identical to the active 300 mg formulation without durpilumab.

[0402] Route of administration: SC injection.

[0403] Dosage schedule: On day 1, after an initial loading dose (2 injections), inject once every 2 weeks. Non-investigational drugs

[0404] Participants were asked to apply a moisturizer (emollient) once or twice daily for at least 5 of the 7 consecutive days prior to Day 1 and continuing through Week 36.

[0405] If participants are on a stable regimen of low- to medium-potency TCS or TCI at the screening visit, they may continue to apply topical steroids once daily from screening to week 24 without tapering. If specific lesions resolve, participants may stop applying steroids to those sites, but continued application is permitted for persistent lesions. If participants are on a stable regimen of high-potency or ultra-potency steroids, participants should reduce the potency to medium-potency TCS and continue daily from screening to week 24. Occlusion is not permitted from screening to week 24.

[0406] Participants could be rescued with high-efficiency or ultra-high-efficiency TCS / TCI as needed throughout the study. Inclusion criteria

[0407] Participants were eligible for inclusion in the study only if all of the following criteria were met: age

[0408] Participants had to be between 18 and 80 years old at the time of signing the informed consent. Types of participants and disease characteristics Patients with a clinical diagnosis of PN, as defined by all of the following:

[0409] Diagnosed by a dermatologist at least 3 months prior to the screening visit.

[0410] Patients must have an average worst itch score of ≥7 in the 7 days prior to Day 1 on a WI-NRS scale of 0 to 10. (The baseline mean itch NRS score for worst itch intensity was determined based on the average of the daily NRS scores for worst intensity (daily scores range from 0 to 10) during the 7 days prior to randomization. At least 4 daily scores over 7 days were required to calculate the baseline mean score. For patients who did not report at least 4 daily scores during the 7 days prior to the planned randomization date, randomization was postponed until this requirement was met, but not to exceed the 28-day maximum duration of the screening period).

[0411] Patients were required to have a minimum of 20 PN lesions total on both legs and / or both arms and / or trunk at the Screening Visit and Day 1. (Patients were required to have bilaterally symmetrical lesions on all four extremities. Lesions were required to be present on at least 2 body surface areas).

[0412] Patients with a history of failure of a 2-week course of moderate to ultra-high potency TCS or who are medically unsuitable for TCS. (Failure is defined as the inability to achieve and / or maintain remission and low disease activity (similar to IGA PN-S score ≤2 [≤19 nodules]) despite treatment with a daily regimen of moderate to ultra-high potency TCS (±TCI, as appropriate) for at least 14 days or the maximum duration recommended in the product prescribing information, whichever is shorter).

[0413] A stable dose of a topical emollient (moisturizer) was applied once or twice daily for at least 5 of the 7 consecutive days prior to Day 1.

[0414] Participants had to be willing and able to complete a daily symptom electronic diary for the duration of the study. gender

[0415] Participants may be male or female. Contraception used by women complies with local regulations regarding contraceptive methods for those participating in clinical studies. Female participants are eligible to participate if they are not pregnant or breastfeeding and meet at least one of the following criteria: non-WOCBP or WOCBP and agree to use contraception during the study (at least until 12 weeks after the last dose of the study intervention). WOCBP must have a negative high-sensitivity pregnancy test (urine or serum, as required by local regulations) on day 1 before the first dose of the study intervention. Informed consent

[0416] Ability to sign an informed consent form. In countries where the legal age of majority is 18 years or older, the specific ICF must also be signed by the participant’s legally authorized representative. Exclusion criteria Participants were excluded from the study if any of the following criteria were met: Medical conditions

[0417] Presence of skin diseases other than PN and mild AD that may interfere with the assessment of study outcomes. Conditions include, but are not limited to, the following: scabies, insect bites, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual pruritus, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous diseases. (Note: Patients with mildly active AD will account for up to 10% of the atopic PN study population.)

[0418] PN secondary to medications (eg, opioids, angiotensin-converting enzyme [ACE] inhibitors).

[0419] PN secondary to a medical condition such as a neurological or psychiatric disorder (eg, dorsal paresthesia, brachioradialis pruritus, excoriations, obsessive-compulsive disorder, delusional parasitosis, etc.).

[0420] Patients with documented moderate to severe AD severity within 6 months prior to the screening visit or with a documented diagnosis of moderate to severe AD (e.g., IGA AD 3 or 4, Eczema Area and Severity Index [EASI] ≥16, Scoring of Atopic Dermatitis [SCORAD] ≥25) from the screening visit to the randomization visit.

[0421] Severe concomitant diseases that are poorly controlled and, in the investigator's judgment, would adversely affect the patient's participation in the study. Examples include, but are not limited to, patients with a life expectancy of less than 1 year, patients with uncontrolled diabetes (hemoglobin A1c ≥ 9% based on laboratory results within 3 months prior to the screening visit), patients with cardiovascular disorders (e.g., class III or IV heart failure according to the New York Heart Association classification), hepatobiliary disorders (e.g., class B or C Child-Pugh), neurological disorders (e.g., demyelinating diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic diseases.

[0422] Severe renal disease (e.g., uremic and / or dialysis patients).

[0423] Participants with uncontrolled thyroid disease.

[0424] Patients with active TB or nontuberculous mycobacterial infection or a history of incompletely treated TB were excluded from the study unless there was adequate documentation from the specialist that the participant had received adequate treatment and could be started with dupilumab based on the medical judgment of the investigator and / or infectious disease specialist. Tuberculosis testing was performed on a country-by-country basis according to local guidelines if required by regulatory authorities or ethics committees.

[0425] Diagnosed with active internal parasitic infection; suspected of having or at high risk for internal parasitic infection, unless clinical and (if necessary) laboratory evaluations exclude active infection prior to randomization.

[0426] Active chronic or acute infection (except HIV infection) requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks prior to the screening visit or during the screening period.

[0427] Known or suspected immunodeficiency, including a history of invasive opportunistic infection despite resolution of infection (e.g., TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), or recurrent infections of unusual frequency or prolonged duration, suggestive of an immunocompromised state, as judged by the investigator.

[0428] Active malignancy or history of malignancy within 5 years before the baseline visit, excluding completely treated carcinoma in situ of the cervix, completely treated and regressed nonmetastatic squamous cell carcinoma of the skin, or basal cell carcinoma.

[0429] History of systemic hypersensitivity or anaphylactic reaction to any biologic therapy, including any excipients.

[0430] Any other medical or psychological condition, including relevant laboratory abnormalities at screening, which, in the opinion of the Investigator, is suggestive of a new and / or underappreciated disease, would impose an unreasonable risk on the patient's participation in this clinical trial, might make the patient's participation unreliable, or might interfere with study assessments.

[0431] Have a history of drug and / or alcohol abuse.

[0432] Major surgical procedures were planned during the patient's participation in this study. Prior / concomitant therapy

[0433] Exposure to another systemic or topical investigational drug (monoclonal antibodies and small molecules) within a certain period before Visit 1 (Screening) as follows: for investigational monoclonal antibodies, the interval is less than 6 months or <5 PK half-lives (whichever is longer), and for investigational small molecules, the interval is less than 30 days or <5 PK half-lives (whichever is longer).

[0434] Any of the following treatments used within 4 weeks before the screening visit: systemic immunosuppressive / immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolic acid-mofetil, interferon-γ, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchicine, etc.); intralesional corticosteroid injections and cryotherapy; phototherapy, including tanning beds; naltrexone or other opioid antagonists; or gabapentin, pregabalin, and thalidomide.

[0435] Initiation of or change in dose of any of the following treatments within 3 months prior to the Screening Visit or anticipated change in dose of any of the following treatments during the study: paroxetine, fluvoxamine, or other selective serotonin reuptake inhibitors (SSRIs); serotonin and norepinephrine reuptake inhibitors (SNRIs); or Amitriptyline or other tricyclic or tetracyclic antidepressants.

[0436] Prior treatment with a biologic drug within the following timeframes: any cytodepleting agent, including but not limited to rituximab: within 6 months prior to the screening visit; omalizumab: within 5 months prior to the screening visit; or other immunomodulatory biologics: within 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer.

[0437] Treatment with a prescription moisturizer or a moisturizer containing additives such as ceramide, hyaluronic acid, urea, menthol, polidocanol, or filaggrin degradation products was initiated during the screening period (if initiated before the screening visit, patients could continue on a stable dose of such moisturizer).

[0438] Treatment with TCS / TCI (any potency) was initiated during the screening period or treatment with high-potency or super-potency TCS / TCI was initiated during the screening period.

[0439] For participants on a stable TCS / TCI regimen (same medication, same dose since 2 weeks before the screening visit) at the screening visit: TCS / TCI was taken for less than 6 days within 7 days before randomization or TCS / TCI of incorrect potency was taken within 7 days before Day 1.

[0440] Treatment with live (attenuated) vaccines within 4 weeks prior to the screening visit. (Note: For patients who plan to receive live attenuated vaccines during the study (based on national vaccination schedule / local guidelines), in consultation with the physician, determine whether the vaccine administration can be postponed until the end of the study or before the start of the study without affecting the patient's health: patients who can safely postpone the administration of live (attenuated) vaccines will be eligible for enrollment, or patients who receive the vaccine in advance will only be eligible for enrollment after a 4-week interval after the vaccine administration.)

[0441] Any prohibited medications and procedures are planned or anticipated during the screening and study treatment periods. Prior / concurrent clinical research experience

[0442] Previously participated in clinical studies with pilumab; previously received overtreatment with pilumab; previously used biologics to treat PN. Diagnostic evaluation

[0443] For subjects without a history of HIV infection prior to the screening visit, HIV serology was positive at screening.

[0444] For subjects with a history of HIV infection, CD4+ count ≤ 300 cells / μL and / or detectable HIV viral load at screening.

[0445] Participants with any of the following results at screening: HBs Ag positive (or indeterminate), total HBc Ab positive confirmed by positive HBV DNA, or HCV Ab positive confirmed by positive HCV RNA. Other exclusions

[0446] An individual who is placed in an institution by statute or legal order; a prisoner or legally committed subject.

[0447] Specific regulations related to any country that would prevent subjects from entering the study.

[0448] Participants who, in the judgment of the investigator, are unsuitable for participation in the study for any reason, including medical or clinical condition, or who may be at risk of noncompliance with study procedures.

[0449] Participants are clinical research center employees or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.

[0450] Participants are clinical research center employees or other individuals directly involved in the conduct of the study, or immediate family members of such individuals.

[0451] Patients who are sensitive to any study intervention or its components, or have allergies to drugs or other factors, are deemed by the investigator to be unsuitable for study participation. Study Intervention

[0452] Study interventions are defined as any investigational intervention, commercially available product, placebo, or medical device intended to be administered to study participants according to the study protocol. A summary of study interventions is provided in Table 7 below. Table 7 - Summary of Study Interventions Administered aSubcutaneous injection sites should be alternated between the upper thigh, 4 quadrants of the abdomen, or upper arm to avoid injecting the same site twice during consecutive administrations. Upper arm injections should only be done by trained personnel (parents / legally authorized representatives / caregivers trained by the investigator or representative) or healthcare professionals and not by participants themselves. IMP: investigational medicinal product; NIMP: non-investigational medicinal product.

[0453] The investigator or representative trains the patient (or caregiver) at Visit 2 how to prepare and inject the IMP. He / she injects the first of two injections. The participant (or caregiver) injects the second injection under the supervision of the investigator or representative. Patients are also trained by site staff to recognize potential signs and symptoms of hypersensitivity reactions to self-monitor at home for at least 30 minutes after the injection (or longer based on country-specific requirements or local site-specific requirements). Patients are advised to contact their healthcare provider / emergency room if symptoms of hypersensitivity reactions occur.

[0454] When participants came in for a study visit, the IMP was administered after clinical procedures and blood collection. Patients were monitored for at least 30 minutes.

[0455] Participants were allowed to self-inject the IMP at home between protocol-scheduled site visits. Participants who preferred to have their IMP administered by a healthcare professional had the option of having the injections administered at home by a nurse or at the study center. Non-investigational drugs

[0456] Beginning at the screening visit, participants were instructed to use their daily moisturizer, provided that the moisturizer did not contain any compounds with known antipruritic effects (such as menthol, polidocanol, pramoxine, lidocaine, prilocaine, capsaicin, naltrexone, N-palmitoylethanolamine, etc.) No changes in emollients or moisturizers or application of antipruritic products were allowed during the study.

[0457] Participants were asked to apply moisturizers (emollients) once or twice daily for at least 5 of the 7 consecutive days prior to Day 1 and continuing through Week 36. All types of moisturizers were permitted, but patients could not initiate new treatment with prescription moisturizers or over-the-counter moisturizers containing additives during the screening period or the intervention period. Patients could continue to use a stable dose of such moisturizers if started before the screening visit.

[0458] If the participant is on a stable regimen of low to medium potency TCS or TCI at the screening visit, they can continue to apply topical steroids once a day from screening to week 24 without tapering. If a specific lesion resolves, the participant can stop applying steroids to these sites, but is allowed to continue applying persistent lesions. If the participant is on a stable regimen of high-potency or ultra-high-potency steroids, the participant should reduce the potency to medium-potency TCS and continue applying it every day from screening to week 24. The stable regimen for TCS is to keep using the same medication (low to medium potency TCS) and keep the same treatment frequency (once or twice a day) from 2 weeks before screening. The stable regimen for TCI is to keep the same TCI medication and treatment frequency (once or twice a day) from 2 weeks before screening. If the participant's previous regimen was applied once a day, the participant will keep applying it every day during the study, and for participants who were applied twice a day before screening, participation will keep a regimen of twice a day during the study. If a specific lesion resolves, the participant can stop applying steroids to these sites, but is allowed to continue applying persistent lesions. Occlusion was not allowed from Screening to Week 24.

[0459] Patients are advised to use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment as intermediate potency and hydrocortisone 1% cream as low potency. If rescue with TCS is required, patients are advised to use betamethasone dipropionate 0.05% optimized ointment as high potency TCS or clobetasol propionate 0.05% cream as ultra-high potency TCS. If patients have tolerability issues with either of these steroids or if these steroids are not commercially available in some countries, they can be substituted with products of equal potency from the list provided by the sponsor.

[0460] For areas treated with TCS, moisturizer must be applied once a day only when TCS is not applied (i.e., moisturizer and TCS should not be used on the same area at the same time of day). For example, if TCS is applied at night, moisturizer is not applied to areas treated with TCS at night, but moisturizer is applied to those areas in the morning. For areas not treated with TCS, moisturizer is applied twice a day (morning and evening). Storage and handling

[0461] The investigator or designee must confirm that all study interventions received maintain appropriate temperature conditions during transport and that any discrepancies are reported and resolved prior to use of the study intervention.

[0462] Only participants enrolled in the study should receive the study intervention, and only authorized site personnel should provide or administer the study intervention. All study interventions must be stored in a secure, environmentally controlled, and monitored (manual or automated) area according to labeled storage conditions, with access limited to investigators and authorized site personnel.

[0463] The investigator, institution, or medical facility head, as applicable, is responsible for research intervention accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition records). Randomization and Blinding

[0464] All participants were centrally assigned to randomized study interventions using an interactive response technique (IRT). Participants were randomly assigned in a 1:1 ratio to treatment groups as described in Table 7.

[0465] Randomization was stratified by the following factors: history of documented atopy (atopic or nonatopic) (atopic: patients with a physician-documented history of atopic comorbidity (defined as AD, allergic rhinitis / rhinoconjunctivitis, asthma, or food allergy) or a current diagnosis of at least one of these atopic comorbidities according to the investigator's judgment, and nonatopic: patients without a physician-documented history of atopic comorbidity (defined as AD, allergic rhinitis / rhinoconjunctivitis, asthma, or food allergy) and not currently diagnosed with at least one of these atopic comorbidities according to the investigator's judgment); stable use of TCS / TCI (yes or no); and country / regional code.

[0466] Randomized participants were defined as those assigned to the randomized intervention, regardless of whether an intervention kit was used (i.e., participants enrolled via IRT). Participants could not be randomized more than once during the study. Blind method

[0467] Dupilumab 300 mg and dupilumab-matched placebo 300 mg were provided in visually indistinguishable identical matched 2 mL prefilled syringes. The syringe and box were labeled with the treatment kit number. Study intervention compliance

[0468] The investigator or his / her representative must ensure that the IMP is administered to each participant according to the label instructions.

[0469] Participants returned the intervention device at each visit. The investigator counted the number of remaining kits / prefilled syringes and completed the IMP Accountability and Inventory Form. The investigator or their representative recorded dosing information on the appropriate pages of the eCRF. Participant adherence to the study intervention was assessed at each visit. Adherence was assessed by counting returned kits / prefilled syringes. Deviations from the prescribed dosing regimen were recorded in the eCRF. Concomitant therapy

[0470] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that the participant is receiving at enrollment or receives during the study must be recorded along with: reason for use; dates of administration, including start and end dates; and dosing information, including dose and frequency.

[0471] In addition to the treatment of AD or PN, concomitant use of non-sedating antihistamines was allowed during the study, but no change in the dose of non-sedating antihistamines was allowed from week 11 to week 12 and from week 23 to week 24.

[0472] The following therapies were prohibited from being used concurrently throughout the study. Participants receiving these treatments were required to discontinue study treatment: systemic immunosuppressive / immunomodulatory drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolic acid-mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchicine, etc.); other monoclonal antibodies (which are biological modulators); phototherapy, including tanning beds; naltrexone or other opioid antagonists; and gabapentin, pregabalin, and thalidomide.

[0473] Concomitant use of the following therapies is prohibited unless the dose has been stable for at least 3 months prior to screening, but participants receiving the following do not need to discontinue study treatment: paroxetine, fluvoxamine, or other selective serotonin reuptake inhibitors (SSRIs); serotonin and norepinephrine reuptake inhibitors (SNRIs); and amitriptyline or other tricyclic or tetracyclic antidepressants. Doses should be kept stable (and may be reduced or discontinued if medically indicated), but should not be started or increased throughout the study.

[0474] Concomitant use of the following therapies was also prohibited throughout the study, but participants who received the following did not need to discontinue study treatment: intralesional corticosteroid injections and cryotherapy; sedating antihistamines; and nonsedating antihistamines specifically used to treat pruritus secondary to AD or PN. Rescue medication

[0475] The following rescue medications are available: high- or ultra-high-potency dermatologic preparations of TCS and TCI.

[0476] Rescue PN therapy may be offered to study patients at the investigator's discretion if medically necessary (ie, to control intolerable PN symptoms).

[0477] Although rescue medication is permitted at any time during the study, its use should be delayed, if possible, for at least 14 days after the start of study treatment. The date and time of rescue medication administration, as well as the name and dosing regimen of the rescue medication, should be recorded in the eCRF.

[0478] For the purpose of efficacy responder analysis, rescue was categorized using a prespecified algorithm (see SAP for details). In addition, a blinded review of all post-baseline medications was performed based on medical judgment to adjudicate rescue therapy. Patients who received rescue therapy during the study according to this adjudication were considered treatment failures. Stopping the study intervention

[0479] In rare cases, it may be necessary for a participant to stop the study intervention. If the study intervention is stopped permanently, the participant will remain in the study for safety evaluations.

[0480] If a participant decides to withdraw from IMP treatment, he or she may do so at any time, for whatever reason, or it may be the investigator's decision. Every effort will be made to document the reason for discontinuation of treatment, and this should be recorded in the eCRF.

[0481] Participants must permanently withdraw from study treatment for the following reasons: at their own request or at the request of their legally authorized representative (a legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a potential participant to the patient's participation in the procedures involved in the study); if the investigator believes that continuing the study would be harmful to the participant's health; at the specific request of the sponsor; if the participant is receiving a specific contraindicated medication; if the participant misses more than 2 consecutive doses of IMP; in the event of a protocol deviation, at the discretion of the investigator or sponsor; violation of any code of conduct at the request of the investigator; pregnancy; anaphylaxis or allergic reaction related to the IMP that requires treatment; a malignancy diagnosed during the study, excluding carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin; any opportunistic infection or other infection whose nature or course may indicate an immunocompromised state; serum alanine aminotransferase (ALT) >3 upper limits of normal (ULN) and total bilirubin >2ULN; or serum ALT >5ULN (if baseline ALT ≤2ULN) or ALT >8ULN (if baseline ALT >2ULN). Efficacy evaluation

[0482] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator maintains a screening log to record the details of all participants screened and to confirm eligibility or record the reason for screening failure, if applicable.

[0483] Participants completed patient-reported outcome questionnaires, including the NRS, in a quiet place before their medical visit and / or clinical testing. Participants were not dependent on their physicians, study nurses, or any other medical staff and completed the questionnaires on their own without any help from friends or relatives. Worst Itch Numerical Rating Scale

[0484] The Worst Itch Numerical Rating Scale (WI-NRS) is a PRO consisting of a single item rated from 0 (“no itch”) to 10 (“worst itch imaginable”). Participants are asked to rate the intensity of the worst itch (itching) they have experienced in the past 24 hours using this scale. Figure 3 Shown in. Investigator's Global Assessment of Prurigo Nodularis

[0485] The Investigator Global Assessment of Prurigo Nodularis (IGA PN) is a clinician-reported outcome (ClinRO) that allows clinicians to assess the activity of PN (IGA PN-A) using a 5-point scale ranging from 0 (no problem) to 4 (severe); and to assess the stage of disease (IGA PN-S) using a 5-point scale ranging from 0 (no problem) to 4 (severe). Figure 4 Shown in. Prurigo Activity Score

[0486] The Pruritus Activity Score (PAS) is a ClinRO measure. The original PAS questionnaire version 0.9 consisted of 7 items developed by PN expert clinicians ( J et al., Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo. J Eur Acad Dermatol Venereol. 2018;32(10):1754-60. The items of the PAS evaluate prurigo lesions in terms of: type (visible lesions: item 1a; predominant lesions: item 1b); estimated number (item 2); distribution (items 3, 4); and size (largest lesion: item 6a; representative lesion: item 6b).

[0487] Other items assess representative body area and exact number of lesions (item 5), activity expressed as the percentage of prurigo lesions with excoriation / crusting surfaces (reflecting active scratching; item 7a), and the percentage of prurigo lesions healed (reflecting healing of chronic prurigo; item 7b).

[0488] A simplified version of the 5-item PAS was used in this study. Specifically, items 3 (lesion distribution) and 6 (lesion monitoring) of the original PAS were deleted, and the response options were slightly modified and refined. Figure 5 Clinicians completed the screening / baseline version at the screening and baseline visits and the follow-up version of the modified PAS at other visits. Dermatology Life Quality Index

[0489] The Dermatology Life Quality Index (DLQI) is a PRO that was developed to measure dermatology-specific health-related quality of life (HRQoL) in adult patients (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6). The tool consists of 10 items that assess the impact of the skin disease on the patient's HRQoL during the previous week. The items cover symptoms, leisure activities, time spent at work / school or on holidays, interpersonal relationships (including intimate relationships), side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire for use in clinical practice and clinical trials (Chernyshov PV. The evolution of quality of life assessment and use indermatology. Dermatology. 2019; 235(3): 167-74). The response scale is a 4-point Likert scale (0 = "not at all", 3 = "very") with nine items. The remaining one item about work / study asks whether work / study is hindered, and then (if "no") asks the extent of problems caused by the skin condition in work / study; this item is rated on a 3-point Likert scale ("not at all" to "a great extent"). The overall score ranges from 0 to 30, with high scores indicating poor HRQoL.

[0490] Efficacy data were collected via an electronic device. Participants' responses to the WI-NRS, pain-NRS, and sleep-NRS questionnaires were recorded daily using an electronic diary. The device, including instructions for use, was distributed at the screening visit (visit 1). Participants were instructed to use the device. The recorded information was downloaded from the device daily. At the end of the study (EOS) visit, the electronic diary was downloaded and returned to the study center.

[0491] Participants completed the DLQI, HADS, EQ-5D-5L, PGIC, PGIS, and the absence days questionnaire on a tablet provided on site during the site visit. The device remained at the site for the duration of the study. Pain and sleep numerical rating scale

[0492] Participants were asked to rate their worst skin pain in the past 24 hours using a numerical rating scale (NRS) from 0 to 10, where 0 = no pain and 10 = worst possible pain.

[0493] Additionally, participants were asked to rate the quality of their sleep over the past night upon waking using a 0 to 10 NRS, where 0 = worst possible sleep and 10 = best possible sleep.

[0494] Participants completed a skin pain NRS and sleep quality NRS once daily. Hospital Anxiety and Depression Scale

[0495] The Hospital Anxiety and Depression Scale (HADS) is a PRO instrument used to screen for anxiety and depression in non-psychiatric populations; repeated administration also provides information about changes in the patient's mood state (Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 1983; 67(6): 361-70 and Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a review of validation data and clinical results. J Psychosom. Res. 1997; 42(1): 17-41). The HADS consists of 14 items, 7 each for anxiety and depression symptoms; the possible score range for each subscale is 0 to 21. For both subscales, the following cutoff scores are recommended: 0 to 7: normal; 8 to 10: borderline abnormal (borderline case); and 11 to 21: abnormal. Patient's overall impression of disease change and patient's overall impression of severity

[0496] The Patient Global Impression of Disease Change (PGIC) is a single-item questionnaire that asks patients to provide an overall self-assessment of the overall change in PN compared to before the patient started receiving study injections on a 7-point scale. Response options are: 0 = "very good", 1 = "somewhat better", 2 = "a little better", 3 = "no change", 4 = "a little worse", 5 = "somewhat worse", and 6 = "very bad".

[0497] The Patient Global Impression of Severity (PGIS) is a single-item questionnaire that asks patients to provide an overall self-assessment of illness severity over the past week on a 4-point scale. Response options are: 1 = "none", 2 = "mild", 3 = "moderate", 4 = "severe". European five-dimensional health scale questionnaire

[0498] The European Five-Dimension Health Scale (EQ-5D) is a standardized PRO measure of health status developed by the European Quality of Life Research Group (EuroQol Group) to provide a simple and universal health measure for clinical and economic evaluation. (Herdman M et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). [Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)] Qual Life Res. [Journal of Quality of Life Research] 2011; 20 (10): 1727-36). EQ-5D consists of 2 parts: a descriptive system and an EQ visual analog scale (VAS). The EQ-5D descriptive system includes the following 5 dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has 5 levels of perceived problems: "no problem", "mild problem", "moderate problem", "severe problem" and "unable to perform activities". The respondent is asked to indicate his / her health status by checking (or crossing) the box next to the most appropriate statement in each of the five dimensions; this produces a 1-digit number representing the rating of that dimension. The numbers for the five dimensions can be combined into a single 5-digit number to describe the respondent's health status. The EQ VAS records the respondent's self-rated health on a vertical VAS, with endpoints labeled "best imaginable health state (100)" and "worst imaginable health state (0)". This information can be used as a quantitative measure of the health outcomes judged by individual respondents. Number of days of absence from school / work

[0499] Participants who were employed or enrolled in school were asked to report the number of sick leave / absentee days since the last study assessment. Photograph

[0500] Decision of the selected study center Participants participating in this substudy will need to provide separate consent. One or several lesions will be photographed at baseline. The same lesions will be photographed at subsequent visits to assess their progression. Safety Assessment Physical examination

[0501] A comprehensive physical examination included at least evaluation of the skin (full body skin examination), nasal cavity, eyes, ears, respiratory system, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. Investigators paid special attention to clinical signs associated with preexisting serious illness. Any new findings or worsening of previous findings were reported as new AEs. Vital signs

[0502] Vital signs, including temperature, SBP and DBP, as well as pulse and respiratory rate, were measured in the semi-supine or sitting position after 5 minutes of rest. Blood pressure and pulse measurements were assessed using fully automated devices on the same arm. Manual techniques were used only when automated devices were not available. Weight (kg) was measured at Screening (Visit 1), EOT, and EOS Visits. Height was measured at Screening (Visit 1). Height and weight were measured in indoor clothing but without shoes. Electrocardiogram

[0503] A single 12-lead ECG was obtained using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT, and QTcF intervals. The ECG was recorded after resting in the supine position for 10 minutes. Results for PRIME / EFC16459

[0504] like Figure 6 PRIME / EFC16459 is one of two Phase 3 studies. PRIME is a global trial with N=151 patients, 33% / 50 from Asia, 27% / 41 from Latin America, 25% / 38 from Western countries / regions, and 15% / 22 from Eastern Europe. Baseline disease characteristics of patients in the PRIME / EFC16459 study are as follows Fig.14 The mean (SD) WI-NRS of all enrolled patients at baseline was 8.5 (1.0).

[0505] The primary endpoint met clinical and statistical significance. Fig. 8A As shown, the proportion of participants who achieved a ≥4-point reduction in WI-NRS (0-10) at Week 24 was 45 (60.0%) on dupilumab and 14 (18.4%) on placebo, p<0.0001. Thus, more than three times as many participants treated with dupilumab experienced a clinically meaningful reduction in pruritus relative to baseline.

[0506] like Fig. 7A As shown, the primary endpoint and all multiplicity-adjusted secondary endpoints met statistical significance, including WI-NRS ≥4, IGA PN-S score of 0 or 1, WI-NRS ≥4 and IGA PN-S score of 0 or 1, and percentage change from baseline in WI-NRS (itch) ( Fig.11A ), change from baseline in DLQI, change from baseline in Skin Pain-NRS, and HADS (all at 24 weeks). In contrast to PRIME2, PRIME did not include 12-week endpoints or Sleep-NRS in the grading structure. Fig.9AAs shown, the proportion of participants who achieved an IGA PN-S score of 0 or 1 at Week 24 was 48.0% on dupilumab and 18.4% on placebo (p=0.0004). Thus, nearly three times as many participants treated with dupilumab achieved no or few skin problems at Week 24 (a key secondary endpoint). Fig. 10A As shown, the proportion of participants with an improvement (reduction) of ≥4 in the WI-NRS from baseline to Week 24 and an IGA PN-S score of 0 or 1 at Week 24 was 38.7% in the dupilumab group and 9.2% in the placebo group (p<0.0001).

[0507] The pruritus and lesion responder analyses also met nominal statistical significance at Week 12. Non-multiplicity-adjusted secondary endpoints (including the proportion of responders achieving a ≥4-point reduction in the WI-NRS at Week 12, the proportion of responders achieving an IGA PN-S score of 0 or 1 at Week 12, and the LS mean change in the Sleep NRS) were all p<0.003.

[0508] In addition, if Fig. 12A Results showed that treatment with dupilumab reduced the time to first use of rescue and / or contraindication medications or procedures compared with placebo. Overall, treatment with dupilumab reduced the use of rescue / contraindication treatments throughout the 24-week intervention period.

[0509] Of note, in the pruritus responder analysis, treatment with durpilumab showed a difference from placebo as early as week 4, did not plateau by week 24, and was consistent regardless of atopic status. It was also noted that symptoms began to recur after treatment was stopped.

[0510] Dupilumab showed an acceptable safety profile in patients with PN, with no new safety signals. The safety profile was consistent with the known safety profile of dupilumab observed in the approved population and indication. Results for PRIME2 / EFC16460

[0511] like Figure 6 PRIME2 / EFC16460 was one of two Phase 3 studies that included 78 participants treated with dupilumab and 82 participants treated with placebo and was conducted in the United States. 46% of patients enrolled in the trial had at least one coexisting type 2 inflammatory condition. Baseline disease characteristics of patients in the PRIME2 / EFC16460 study were as follows Fig.14The mean (SD) WI-NRS for all enrolled patients at baseline was 8.5 (1.0). Almost all patients in the trial had severe pruritus, and all had moderate to severe disease based on the number of lesions. 62% of enrolled patients had ≥20 to 100 nodules, and 38% had >100 nodules.

[0512] The primary endpoint met clinical and statistical significance. Figure 8B As shown, the proportion of participants who achieved a ≥4-point reduction in the Worst Pruritus Numerical Rating Scale (WI-NRS) (0-10) at week 12 was 18 (22.0%) in the placebo group and 29 (37.2%) in the durpilumab group, p=0.0216.

[0513] All key secondary endpoints met clinical and statistical significance. Figure 8B As shown, the proportion of participants who achieved a ≥4-point reduction in WI-NRS (0-10) at Week 24 was 19.5% on placebo and 57.7% on durpilumab (p<0.0001). Thus, at Week 24, nearly three times as many participants treated with durpilumab experienced a clinically meaningful reduction in itch relative to baseline. Fig. 9B As shown, the proportion of participants achieving an Investigator Global Assessment PN-Stage (IGA PN-S) score of 0 or 1 (0-4) at Week 24 was 15.9% in the placebo group and 44.9% in the durpilumab group (p<0.0001). Thus, nearly three times as many participants receiving durpilumab achieved no or few skin problems at Week 24. Fig. 10B As shown, the proportion of participants with an improvement (reduction) of ≥4 in the WI-NRS from baseline to Week 24 and an IGA PN-S of 0 or 1 at Week 24 was 8.5% on placebo and 32.1% on durpivolumab (p=0.0001).

[0514] like Figure 7B Several multiplicity-adjusted secondary endpoints and other efficacy endpoints were also met, including the proportion of responders achieving an IGA PN-S score of 0 or 1 at week 12, the mean delta percentage of WI-NRS from baseline at week 24 ( Fig. 11B ), DLQI, and skin pain-NRS. The hierarchical structure was broken at the penultimate item (sleep-NRS not significant; HADS nominal).

[0515] In addition, if Fig. 12B Results showed that treatment with durpilumab reduced the time to first use of rescue and / or contraindication medications or procedures compared with placebo.

[0516] Mildly active atopic dermatitis accounted for 9% of the atopic PN study population and 4.5% of the total study population.

[0517] Dupilumab was well tolerated and demonstrated an acceptable safety profile in patients with PN. The safety profile was consistent with the known safety profile of dupilumab observed in the approved population and indication. No new safety signals were reported with dupilumab, and no malignancies were reported.

[0518] Pharmacokinetics (PK) and ADA were consistent with the known characteristics of dupilumab. Conclusions of PRIME / EFC16459 and PRIME2 / EFC16460

[0519] Overall, dupilumab demonstrated clinically and statistically significant efficacy in patients with prurigo nodularis (PN) who were inadequately controlled by topical prescription therapies or who were inappropriate for those therapies. Dupilumab also demonstrated replication of efficacy between the PRIME and PRIME2 studies. Dupilumab was effective and safe in this population, demonstrating an acceptable safety profile.

[0520] At week 24, approximately three times as many patients had a significant reduction in pruritus and skin lesions with durpilumab compared with placebo. Durpilumab is the first and only biologic to show positive phase 3 results in prurigo nodularis.

[0521] Dupilumab significantly improved pruritus and skin clarity at week 12, and both nearly threefold at week 24. The significant reductions in pruritus and skin lesions observed are important because nearly all patients had severe pruritus before enrollment, and nearly 40% had 100 or more nodules covering their entire body.

[0522] At week 24, significant and sustained treatment effects with durpilumab were observed across all disease components, including pruritus and lesion severity, regardless of baseline atopic status. In addition, durpilumab improved quality of life and psychological well-being. At week 24, patients treated with durpilumab experienced significantly greater improvements in measures of health-related quality of life and skin pain. Patients treated with durpilumab experienced significantly greater improvements in measures of health-related quality of life, skin pain, and anxiety and depression symptoms.

[0523] Treatment with dupilumab reduced the use of rescue / contraindication therapy throughout the 24-week intervention period.

[0524] At 24 weeks, approximately three times as many dupilumab patients (60% and 58%) experienced a clinically meaningful reduction in pruritus from baseline, the primary endpoint in PRIME, compared with 18% and 20% on placebo.

[0525] At 12 weeks, 44% and 37% of dupilumab patients experienced a clinically meaningful reduction in itch from baseline, compared with 16% and 22% on placebo, which was the primary endpoint in PRIME2.

[0526] At 24 weeks, more than twice as many dupilumab patients (48% and 45%) achieved no or few skin problems compared with 18% and 16% on placebo.

[0527] At 24 weeks, more than three times as many dupilumab patients (39% vs 32%) experienced a clinically meaningful reduction in itch and had no or few skin problems, compared with 9% and 9% of placebo patients.

[0528] The FDA has approved dupilumab for the treatment of PN: "DUPIXENT is indicated for the treatment of adult patients with prurigo nodularis (PN). The recommended dose for adult patients is an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week (Q2W)." Example 2: Validation of the Worst Itch Numerical Rating Scale for Pruritus Nodularis (PN) (WI-NRS) based on a clinical study of dupilumab in adults with PN Materials and methods:

[0529] The content validity of the WI-NRS was assessed by qualitative interviews with adult PN patients (N=20; age: 19-72 years).Pooled blinded data from a Phase 3 trial (N=311) were used to evaluate the measurement properties and within-patient clinically meaningful changes (responder definition) of the WI-NRS in patients with PN. result:

[0530] Patients rated the questions, recall period, and response scale as understandable and relevant. Adequate test-retest reliability was observed between screening and baseline (intraclass correlation coefficient = 0.72, using Patient Global Impression of Severity (PGIS) to define stable patients). Convergent and divergent validity was supported by moderate to strong correlations with other conceptually related measures (r = 0.34-0.73) and weaker correlations with less relevant measures (r = 0.06-0.32), respectively. The WI-NRS was sensitive to change as shown by differences in change from baseline between groups (by PGIS change and PGI change (PGIC); P < 0.001). Using an anchor-based approach with PGIS and PGIC, the threshold for improved responder definition was 4 points (range: 3.0-4.5). in conclusion:

[0531] The WI-NRS is a tool suitable for use in support of efficacy endpoints to measure itch intensity in adults with PN that is uncontrolled by topical therapies.

Claims

1. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and One or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

2. The method of claim 1, wherein the two doses are administered every other week (q2w).

3. A method for treating prurigo nodularis, which method reduces or eliminates the dependence of a patient with prurigo nodularis on low to moderate potency topical corticosteroids and / or topical calcineurin inhibitors, the method comprising: (a) Select patients with prurigo nodularis that is not controlled with background therapy consisting of low- to moderate-potency topical corticosteroids and / or topical calcineurin inhibitors; (b) administering to the patient a defined dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) at a defined frequency for an initial treatment period, while maintaining the patient's background therapy for the initial treatment period; and (c) gradually reducing or eliminating the dose of low-to-moderate potency topical corticosteroids and / or topical calcineurin inhibitors administered to the patient during the subsequent treatment period while continuing to administer the antibody or antigen-binding fragment thereof at the defined frequency and dose used during the initial treatment period, The antibody or antigen-binding fragment thereof comprises three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8.

4. The method of claim 3, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses.

5. The method of claim 4, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

6. The method of claim 4, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

7. The method of any one of claims 4 to 6, wherein the two doses are administered every other week (q2w).

8. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, Wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with a super-potent topical corticosteroid rescue medication.

9. The method of claim 8, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

10. The method of claim 8, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

11. The method of any one of claims 8 to 10, wherein the two doses are administered every other week (q2w).

12. A method for treating pruritus associated with prurigo nodularis in a subject, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, Wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with a super-potent topical corticosteroid rescue medication.

13. The method of claim 12, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

14. The method of claim 12, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

15. The method of any one of claims 12 to 14, wherein the two doses are administered every other week (q2w).

16. The method of any one of claims 12 to 15, wherein the pruritus is refractory to topical therapy.

17. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, Wherein treatment with the antibody or antigen-binding fragment thereof reduces the need to treat the subject with systemic immunosuppressants.

18. The method of claim 17, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

19. The method of claim 17, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

20. The method of any one of claims 17 to 19, wherein the two doses are administered every other week (q2w).

21. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, and wherein the treatment results in a reduction in the subject's Worst Itch Numerical Rating Scale (WI-NRS) score.

22. The method of claim 21, wherein the reduction in the WI-NRS score is selected from the group consisting of 4, 5, 6, 7, 8, 9 and 10.

23. The method of claim 21 or 22, wherein the reduction in WI-NRS score occurs at 12 weeks of treatment.

24. The method of claim 21 or 22, wherein the reduction in WI-NRS score occurs at 24 weeks of treatment.

25. The method of any one of claims 21 to 24, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

26. The method of any one of claims 21 to 24, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

27. The method of any one of claims 21 to 26, wherein the second doses are administered every other week (q2w).

28. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the treatment results in a reduction in the subject's Investigator's Global Assessment of Prurigo Nodularis (IGA PN) score.

29. The method of claim 28, wherein the reduction in the IGA PN score is selected from the group consisting of 5, 4, 3, 2, and 1.

30. The method of claim 28 or 29, wherein the subject obtains an IGA PN score of 0 or 1.

31. The method of any one of claims 28 to 30, wherein the reduction in the IGA PN score occurs at 12 weeks of treatment.

32. The method of any one of claims 28 to 30, wherein the reduction in the IGA PN score occurs at 24 weeks of treatment.

33. The method of any one of claims 28 to 32, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

34. The method of any one of claims 28 to 32, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

35. The method of any one of claims 28 to 34, wherein the second doses are administered every other week (q2w).

36. A method for treating a subject suffering from prurigo nodularis, the method comprising administering to the subject: an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5 and three light chain complementary determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, and one or more secondary doses of the antibody or antigen-binding fragment thereof, The subject had comorbid mild atopic dermatitis.

37. The method of claim 36, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

38. The method of claim 36, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

39. The method of any one of claims 36 to 38, wherein the second doses are administered every other week (q2w).

40. The method of any of the preceding claims, wherein the subject has previously failed treatment with mid- to super-potent topical corticosteroids.

41. The method of any of the preceding claims, wherein the subject has a baseline WI-NRS score equal to or greater than 7.

42. methods as described in any one of the preceding claims, wherein the subject has a total of at least 20 PN nodes on both legs and / or both arms and / or trunk at baseline.

43. The method of any of the preceding claims, wherein the subject has a baseline IGAPN score greater than or equal to 3.

44. The method of any of the preceding claims, wherein the subject suffers from PN that is not adequately controlled by topical therapies or for which those therapies are inappropriate.

45. The method of any of the preceding claims, wherein the subject is a candidate for systemic therapy.

46. ​​The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO:

2.

47. The method of claim 46, wherein the antibody is dupilumab.

48. The method of any of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

49. The method of claim 48, wherein the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

50. The method of claim 48 or 49, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

51. The method of any of the preceding claims, wherein the subject is an adult.

52. A method for treating a subject suffering from prurigo nodularis, the method comprising: Subjects with prurigo nodularis were selected; as well as The subject is administered an initial dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

53. An antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) for use in treating prurigo nodularis, the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8, and comprising an initial dose of about 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

54. Use of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) for the manufacture of a medicament for treating prurigo nodularis, the antibody or antigen-binding fragment thereof comprising three heavy chain complementary determining region (HCDR) sequences including SEQ ID NOs: 3, 4 and 5 and three light chain complementary determining region (LCDR) sequences including SEQ ID NOs: 6, 7 and 8, wherein the use comprises administering an initial dose of about 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of about 300 mg of the antibody or antigen-binding fragment thereof.

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