Methods of Treating Prurigo Nodularis by Administering an IL-4R Antagonist - Patent application

Abstract

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

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 257,876, filed October 20, 2021, U.S. Provisional Patent Application No. 63 / 300,492, filed January 18, 2022, and European Patent No. 22315048.3, filed March 4, 2022, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates to the treatment and / or prevention of prurigo nodularis (PN) in a subject in need thereof.The present disclosure relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent PN in a subject in need thereof. [Background technology]

[0003] Prurigo nodularis (PN) is a skin disease characterized by multiple intensely itchy skin rashes in symmetrically distributed areas of the limbs (Zeidler C, et al. Chronic prurigo of nodular type: A Review. Acta Dermatol Venereol 2018;98(2):173-9). The main symptoms are long-term, recurrent and uncontrollable rubbing, scratching and uncontrollable itch, which results in hyperkeratotic erosive papules and nodules on the skin. A widely accepted definition of chronic prurigo has been published by the European Academy of Dermatology and Venereology (EADV) (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 invited experts agreed that chronic prurigo should be used as an umbrella term for a range of clinical manifestations (e.g., papular, nodular, macular or umbilicate). Prurigo nodularis is considered a distinct disease defined by the presence of chronic pruritus for more than 6 weeks, a history and / or signs of repeated scratching, and multiple focal / generalized prurigo skin lesions (whitish, hyperpigmented, or pink papules, nodules, and / or plaques).

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

[0005] Due to the central symptom of pruritus, PN is associated with a high burden of disease (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 has been reported to be higher than other common skin disorders 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 sleep deprivation due to constant itching; persistent burning, stinging and pain in the affected areas; and chronic depression, anxiety, anger, disgust and shame; thus, overall, significantly impacting their quality of life. 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), PN is a significant contributor to mood disorders such as anxiety and depression.

[0006] Data on the epidemiology of PN are limited. Most studies show a predominance of elderly patients with a median age above 50 years (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). Prurigo nodularis is only occasionally observed in younger patients, in whom it is more often associated with atopic symptoms (Tanaka M, et al. Prurigo nodularis consists of two distinct forms: early-onset atopic and late-onset non-atopic. Dermatology. 1995;190(4):26976).

[0007] There are no targeted therapies approved by the United States (US) Food and Drug Administration (FDA) or European Medicines Agency (EMA) for the treatment of PN, whether atopic or nonatopic, and therefore new therapies for treating PN are needed. Summary of the Invention [Means for solving the problem]

[0008] In one aspect, a method is provided for treating a subject having 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 the interleukin-4 receptor (IL-4R) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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.

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

[0010] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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, the method comprises: (a) selecting a patient with prurigo nodularis not controlled on background therapy comprising a low-to-moderate potency topical corticosteroid and / or a topical calcineurin inhibitor; (b) administering to the patient a defined dose of an antibody or antigen-binding fragment thereof that specifically binds interleukin-4 receptor (IL-4R) at a defined frequency during an initial treatment period while maintaining the patient's background therapy during the initial treatment period; (c) administering to the patient a defined dose of an antibody or antigen-binding fragment thereof that specifically binds interleukin-4 receptor (IL-4R) at a defined frequency during an initial 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. A method of treating prurigo nodularis comprising gradually reducing or eliminating the dosage of low- to medium-potency topical corticosteroids and / or topical calcineurin inhibitors administered to the patient over the course of a subsequent treatment period, thereby reducing or eliminating the patient's dependency on low- to medium-potency topical corticosteroids and / or topical calcineurin inhibitors, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the 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, the secondary doses are administered every other week (q2w).

[0027] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject having prurigo nodularis comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 results in a reduced need for treatment of the subject with super-potent topical corticosteroid rescue therapy.

[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, the secondary doses are administered every other week (q2w).

[0043] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 of treating prurigo nodularis in a subject is provided, comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 results in a reduced need for treatment of the subject with super-potent topical corticosteroid rescue therapy.

[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, the secondary 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 been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject with prurigo nodularis, comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 results in a reduced need for treatment of 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, the secondary doses are administered every other week (q2w).

[0076] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject with prurigo nodularis, comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 results in the subject having a decrease in 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 within 12 weeks of treatment.

[0091] In certain exemplary embodiments, the reduction in WI-NRS score occurs within 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, the secondary doses are administered every other week (q2w).

[0095] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject with Prurigo Nodularis comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 the subject having a decrease in Investigator Global Assessment of Prurigo Nodularis (IGA PN) 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 achieves an IGA PN score of 0 or 1.

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

[0111] In certain exemplary embodiments, a reduction in IGA PN score occurs over 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, the secondary doses are administered every other week (q2w).

[0115] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject with prurigo nodularis, comprising administering to the subject an initial dose of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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 concomitant 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, the secondary doses are administered every other week (q2w).

[0131] In certain exemplary embodiments, the subject has previously been treated ineffectively with mid- to extra-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, subjects have a minimum of 20 PN nodules total in 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 has PN that is not adequately controlled by local therapies or where those therapies are inadvisable.

[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 the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the 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 is provided for treating a subject with prurigo nodularis, 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) comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity 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] In another aspect, there is provided an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, for use in the treatment of prurigo nodularis, 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] In another aspect, there is provided a use of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 3, 4, and 5, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 6, 7, and 8, for the manufacture of a medicament for treating prurigo nodularis, the use comprising 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.

[0146] The foregoing and other features and advantages of the present disclosure will be more fully understood from the following detailed description of exemplary embodiments, taken in conjunction with the accompanying drawings. The file of this patent contains at least one drawing / photograph executed in color. Color Drawings / Photographs Copies of this patent will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0147] [Figure 1] Figure 1 shows a schematic overview of the study design in Example 1. 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 inadequately controlled with local prescription therapy or when such therapy is inadvisable. Participants received either 300 mg dupilumab or matching placebo every other week (q2w) after a 600 mg loading dose. [Figure 2A] 2A-2D show tables of the activity schedules of two randomized, placebo-controlled trials of dupilumab in patients with PN inadequately controlled with local prescription therapy or when such therapy is inadvisable (Example 1). [Figure 2B] 2A-2D show tables of the activity schedules of two randomized, placebo-controlled trials of dupilumab in patients with PN inadequately controlled with local prescription therapy or when such therapy is inadvisable (Example 1). [Figure 2C]2A-2D show tables of the activity schedules of two randomized, placebo-controlled trials of dupilumab in patients with PN inadequately controlled with local prescription therapy or when such therapy is inadvisable (Example 1). [Figure 2D] 2A-2D show tables of the activity schedules of two randomized, placebo-controlled trials of dupilumab in patients with PN inadequately controlled with local prescription therapy or when such therapy is inadvisable (Example 1). [Diagram 3] FIG. 1 shows the questionnaire used to determine the Worst Itch Numeric Rating Scale (WI-NRS). [Figure 4] FIG. 1 shows the questionnaire used to determine Investigator's Global Assessment of Prurigo Nodularis (IGA PN). [Figure 5-1] FIG. 1 shows the questionnaire used to determine the Prurigo Activity Score (PAS). [Figure 5-2] Continued from Figure 5-1. [Figure 6] Two Phase 3 studies of similar design and population are outlined in Example 1. Both studies evaluated the use of dupilumab in patients with PN not adequately controlled with local prescription therapy or in patients for whom local prescription therapy was not an option. [Figure 7A]7A-7B show a table of the statistical testing hierarchy for the PRIME and PRIME2 studies of Example 1. As shown in FIG 7A, for PRIME, the primary and all multiplicity-adjusted secondary endpoints met statistical significance, including WI-NRS > 4, IGA PN-S score 0 or 1, WI-NRS > 4 and IGA PN-S score 0 or 1, WI-NRS (itch) percent change from baseline, DLQI change from baseline, Skin Pain-NRS change from baseline, and HADS change from baseline (all at week 24). As shown in Figure 7B, for PRIME2, primary, important secondary, and other multiplicity controlled endpoints met statistical significance, including WI-NRS ≥ 4 at weeks 12 and 24, IGA PN-S score 0 or 1 at weeks 12 and 24, WI-NRS ≥ 4 and IGA PN-S score 0 or 1 at week 24, mean change from baseline in WI-NRS % at week 24, DLQI at week 24, and Cutaneous Pain-NRS at week 24. [Figure 7B] 7A-7B show a table of the statistical testing hierarchy for the PRIME and PRIME2 studies of Example 1. As shown in FIG 7A, for PRIME, the primary and all multiplicity-adjusted secondary endpoints met statistical significance, including WI-NRS > 4, IGA PN-S score 0 or 1, WI-NRS > 4 and IGA PN-S score 0 or 1, WI-NRS (itch) percent change from baseline, DLQI change from baseline, Skin Pain-NRS change from baseline, and HADS change from baseline (all at week 24). As shown in Figure 7B, for PRIME2, primary, important secondary, and other multiplicity controlled endpoints met statistical significance, including WI-NRS ≥ 4 at weeks 12 and 24, IGA PN-S score 0 or 1 at weeks 12 and 24, WI-NRS ≥ 4 and IGA PN-S score 0 or 1 at week 24, mean change from baseline in WI-NRS % at week 24, DLQI at week 24, and Cutaneous Pain-NRS at week 24. [Figure 8A]Figures 8A-8D graphically show the percentage of patients with a WI-NRS ≥ 4 for both placebo and dupilumab treatment groups. For PRIME, as shown in Figure 8A, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 24 was 45 (60.0%) compared to 14 (18.4%) with placebo, p<0.0001. For PRIME2, as shown in Figure 8B, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 12 was 29 (37.2%) compared to 18 (22.0%) with placebo, p=0.0216. The percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab and placebo at week 24 was 57.7% compared to 19.5% with placebo, p<0.0001. 8C-8D graphically show the proportion of participants with WI-NRS improvement from baseline ≧4 over time to week 36 in the PRIME ( FIG. 8C ) and PRIME2 ( FIG. 8D ) trials. [Figure 8B] Figures 8A-8D graphically show the percentage of patients with a WI-NRS ≥ 4 for both placebo and dupilumab treatment groups. For PRIME, as shown in Figure 8A, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 24 was 45 (60.0%) compared to 14 (18.4%) with placebo, p<0.0001. For PRIME2, as shown in Figure 8B, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 12 was 29 (37.2%) compared to 18 (22.0%) with placebo, p=0.0216. The percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab and placebo at week 24 was 57.7% compared to 19.5% with placebo, p<0.0001. 8C-8D graphically show the proportion of participants with WI-NRS improvement from baseline ≧4 over time to week 36 in the PRIME ( FIG. 8C ) and PRIME2 ( FIG. 8D ) trials. [Figure 8C]Figures 8A-8D graphically show the percentage of patients with a WI-NRS ≥ 4 for both placebo and dupilumab treatment groups. For PRIME, as shown in Figure 8A, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 24 was 45 (60.0%) compared to 14 (18.4%) with placebo, p<0.0001. For PRIME2, as shown in Figure 8B, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 12 was 29 (37.2%) compared to 18 (22.0%) with placebo, p=0.0216. The percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab and placebo at week 24 was 57.7% compared to 19.5% with placebo, p<0.0001. 8C-8D graphically show the proportion of participants with WI-NRS improvement from baseline ≧4 over time to week 36 in the PRIME ( FIG. 8C ) and PRIME2 ( FIG. 8D ) trials. [Figure 8D] Figures 8A-8D graphically show the percentage of patients with a WI-NRS ≥ 4 for both placebo and dupilumab treatment groups. For PRIME, as shown in Figure 8A, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 24 was 45 (60.0%) compared to 14 (18.4%) with placebo, p<0.0001. For PRIME2, as shown in Figure 8B, the percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab at week 12 was 29 (37.2%) compared to 18 (22.0%) with placebo, p=0.0216. The percentage of participants who achieved a 4-point or greater reduction in WI-NRS score (0-10) with dupilumab and placebo at week 24 was 57.7% compared to 19.5% with placebo, p<0.0001. 8C-8D graphically show the proportion of participants with WI-NRS improvement from baseline ≧4 over time to week 36 in the PRIME ( FIG. 8C ) and PRIME2 ( FIG. 8D ) trials. [Figure 9A]9A-9D graphically depict the percentage of participants who achieved an Investigator Global Assessment PN Stage (IGA PN-S) score of 0 or 1 for the dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 9A, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 48.0% compared to 18.4% for placebo (p=0.0004). For PRIME2, as shown in FIG. 9B, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 44.9% compared to 15.9% for placebo (p<0.0001). At week 12, the percentage was 25.6% for dupilumab and 12.2% for placebo (p=0.0194). 9C-9D graphically show the proportion of participants with an IGA PN-S score of 0 or 1 from baseline over time to week 36 in the PRIME (FIG. 9C) and PRIME2 (FIG. 9D) studies. [Figure 9B] 9A-9D graphically depict the percentage of participants who achieved an Investigator Global Assessment PN Stage (IGA PN-S) score of 0 or 1 for the dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 9A, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 48.0% compared to 18.4% for placebo (p=0.0004). For PRIME2, as shown in FIG. 9B, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 44.9% compared to 15.9% for placebo (p<0.0001). At week 12, the percentage was 25.6% for dupilumab and 12.2% for placebo (p=0.0194). 9C-9D graphically show the proportion of participants with an IGA PN-S score of 0 or 1 from baseline over time to week 36 in the PRIME (FIG. 9C) and PRIME2 (FIG. 9D) studies. [Figure 9C]9A-9D graphically depict the percentage of participants who achieved an Investigator Global Assessment PN Stage (IGA PN-S) score of 0 or 1 for the dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 9A, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 48.0% compared to 18.4% for placebo (p=0.0004). For PRIME2, as shown in FIG. 9B, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 44.9% compared to 15.9% for placebo (p<0.0001). At week 12, the percentage was 25.6% for dupilumab and 12.2% for placebo (p=0.0194). 9C-9D graphically show the proportion of participants with an IGA PN-S score of 0 or 1 from baseline over time to week 36 in the PRIME (FIG. 9C) and PRIME2 (FIG. 9D) studies. [Figure 9D] 9A-9D graphically depict the percentage of participants who achieved an Investigator Global Assessment PN Stage (IGA PN-S) score of 0 or 1 for the dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 9A, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 48.0% compared to 18.4% for placebo (p=0.0004). For PRIME2, as shown in FIG. 9B, the percentage of participants who achieved an IGA PN-S score of 0 or 1 for dupilumab and placebo at week 24 was 44.9% compared to 15.9% for placebo (p<0.0001). At week 12, the percentage was 25.6% for dupilumab and 12.2% for placebo (p=0.0194). 9C-9D graphically show the proportion of participants with an IGA PN-S score of 0 or 1 from baseline over time to week 36 in the PRIME (FIG. 9C) and PRIME2 (FIG. 9D) studies. [Figure 10A]10A-10D graphically depict the percentage of participants with a concurrent improvement (decrease) in WI-NRS ≥4 from baseline and an IGA PN-S score of 0 or 1 for dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 10A, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 38.7% for dupilumab and 9.2% for placebo (p<0.0001). For PRIME2, as shown in FIG. 10B, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 32.1% for dupilumab and 8.5% for placebo (p=0.0001). 10C-10D graphically show the proportion of participants with both a WI-NRS improvement (decrease) of 4 or more from baseline and an IGA PN-S score of 0 or 1 over time to week 36 in the PRIME (FIG. 10C) and PRIME2 (FIG. 10D) studies. [Figure 10B] 10A-10D graphically depict the percentage of participants with a concurrent improvement (decrease) in WI-NRS ≥4 from baseline and an IGA PN-S score of 0 or 1 for dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 10A, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 38.7% for dupilumab and 9.2% for placebo (p<0.0001). For PRIME2, as shown in FIG. 10B, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 32.1% for dupilumab and 8.5% for placebo (p=0.0001). 10C-10D graphically show the proportion of participants with both a WI-NRS improvement (decrease) of 4 or more from baseline and an IGA PN-S score of 0 or 1 over time to week 36 in the PRIME (FIG. 10C) and PRIME2 (FIG. 10D) studies. [Figure 10C]10A-10D graphically depict the percentage of participants with a concurrent improvement (decrease) in WI-NRS ≥4 from baseline and an IGA PN-S score of 0 or 1 for dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 10A, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 38.7% for dupilumab and 9.2% for placebo (p<0.0001). For PRIME2, as shown in FIG. 10B, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 32.1% for dupilumab and 8.5% for placebo (p=0.0001). 10C-10D graphically show the proportion of participants with both a WI-NRS improvement (decrease) of 4 or more from baseline and an IGA PN-S score of 0 or 1 over time to week 36 in the PRIME (FIG. 10C) and PRIME2 (FIG. 10D) studies. [Figure 10D] 10A-10D graphically depict the percentage of participants with a concurrent improvement (decrease) in WI-NRS ≥4 from baseline and an IGA PN-S score of 0 or 1 for dupilumab and placebo treatment groups. For PRIME, as shown in FIG. 10A, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 38.7% for dupilumab and 9.2% for placebo (p<0.0001). For PRIME2, as shown in FIG. 10B, the percentage of participants with an improvement (decrease) in WI-NRS ≥4 from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 32.1% for dupilumab and 8.5% for placebo (p=0.0001). 10C-10D graphically show the proportion of participants with both a WI-NRS improvement (decrease) of 4 or more from baseline and an IGA PN-S score of 0 or 1 over time to week 36 in the PRIME (FIG. 10C) and PRIME2 (FIG. 10D) studies. [Figure 11A]11A-11D graphically depict the WI-NRS least squares (LS) mean %Δ from baseline for the dupilumab and placebo arms. For PRIME, as shown in FIG. 11A, at week 24, the LS mean % change from baseline was −48.89 for the dupilumab arm and −22.22 for the placebo arm (p<0.0001). For PRIME2, as shown in FIG. 11B, at week 24, the LS mean % change from baseline was −59.34 for the dupilumab arm and −36.18 for the placebo arm (p<0.0001). FIGS. 11C-D graphically depict the mean percent change from baseline in WI-NRS over time through week 36 in the PRIME (FIG. 11C) and PRIME2 (FIG. 11D) studies. [Figure 11B] 11A-11D graphically depict the WI-NRS least squares (LS) mean %Δ from baseline for the dupilumab and placebo arms. For PRIME, as shown in FIG. 11A, at week 24, the LS mean % change from baseline was −48.89 for the dupilumab arm and −22.22 for the placebo arm (p<0.0001). For PRIME2, as shown in FIG. 11B, at week 24, the LS mean % change from baseline was −59.34 for the dupilumab arm and −36.18 for the placebo arm (p<0.0001). FIGS. 11C-D graphically depict the mean percent change from baseline in WI-NRS over time through week 36 in the PRIME (FIG. 11C) and PRIME2 (FIG. 11D) studies. [Figure 11C]11A-11D graphically depict the WI-NRS least squares (LS) mean %Δ from baseline for the dupilumab and placebo arms. For PRIME, as shown in FIG. 11A, at week 24, the LS mean % change from baseline was −48.89 for the dupilumab arm and −22.22 for the placebo arm (p<0.0001). For PRIME2, as shown in FIG. 11B, at week 24, the LS mean % change from baseline was −59.34 for the dupilumab arm and −36.18 for the placebo arm (p<0.0001). FIGS. 11C-D graphically depict the mean percent change from baseline in WI-NRS over time through week 36 in the PRIME (FIG. 11C) and PRIME2 (FIG. 11D) studies. [Figure 11D] 11A-11D graphically depict the WI-NRS least squares (LS) mean %Δ from baseline for the dupilumab and placebo arms. For PRIME, as shown in FIG. 11A, at week 24, the LS mean % change from baseline was −48.89 for the dupilumab arm and −22.22 for the placebo arm (p<0.0001). For PRIME2, as shown in FIG. 11B, at week 24, the LS mean % change from baseline was −59.34 for the dupilumab arm and −36.18 for the placebo arm (p<0.0001). FIGS. 11C-D graphically depict the mean percent change from baseline in WI-NRS over time through week 36 in the PRIME (FIG. 11C) and PRIME2 (FIG. 11D) studies. [Figure 12A] 12A-12B graphically depict the time to first use of rescue and / or prohibited medications or procedures. In both PRIME (FIG. 12A) and PRIME2 (FIG. 12B), dupilumab treatment compared to placebo reduced the time to first use of rescue medication and / or prohibited medication or procedure. [Figure 12B]12A-12B graphically depict the time to first use of rescue and / or prohibited medications or procedures. In both PRIME (FIG. 12A) and PRIME2 (FIG. 12B), dupilumab treatment compared to placebo reduced the time to first use of rescue medication and / or prohibited medication or procedure. [Figure 13] 13A-13B show the skin of patients in the PRIME study at baseline (FIG. 13A) and at 24 weeks (FIG. 13B) after initiating treatment with 300 mg dupilumab q2w. At baseline, patients had an IGA PN-S score of 4 and a mean WI-NRS score of 9.4. At 24 weeks of treatment, patients had an IGA PN-S score of 0 and a mean WI-NRS score of 1.3. [Figure 14] Figure 14 shows a table of baseline disease characteristics of patients in the PRIME / EFC 16459 and PRIME2 / EFC 16460 studies. Total enrolled patients in both studies had a mean (SD) WI-NRS of 8.5 (1.0) at baseline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0148] Before describing the present disclosure, it is to be understood that the disclosure is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0149] Unless otherwise defined, 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.

[0150] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary by no more than 1% from the recited value. 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.).

[0151] As used herein, the terms "treat", "treating" and the like mean to alleviate the symptoms, to eliminate the cause of the symptoms, either temporarily or permanently, or to prevent or delay the onset of symptoms of the specified disorder or condition.

[0152] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0153] The present disclosure provides methods and compositions for treating prurigo nodularis (PN).

[0154] As used herein, "prurigo nodularis" refers to the presence of chronic pruritus for 6 weeks or more and a history and / or symptoms of recurrent scratching and multiple localized / generalized prurigo skin lesions in a subject.

[0155] As used herein, "prurigoid skin lesions" refers to whitish, hyperpigmented or pink papules, nodules and / or plaques on a subject.

[0156] As used herein, "treating prurigo nodularis" refers to treating one or more of the symptoms of prurigo nodularis, including, but not limited to, reducing the number of lesions, reducing the size of the lesions, reducing the pruritus associated with prurigo nodularis, and the like.

[0157] In certain embodiments, the subject with prurigo nodularis has one or more coexisting atopic inflammatory conditions.As used herein, "atopic inflammatory conditions" include, but are not limited to, one or more of allergic rhinitis, allergic fungal rhinosinusitis, 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 allergy, urticaria or hives, and exercise-induced bronchospasm. In certain exemplary embodiments, the subject with prurigo nodularis has coexisting atopic dermatitis, e.g., mild atopic dermatitis, moderate atopic dermatitis, moderate-severe atopic dermatitis, or severe atopic dermatitis.

[0158] Methods for improving PN-related patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) measures Methods for improving one or more PN-related patient-reported outcome (PRO) measures in a subject in need thereof, the method comprising 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, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.

[0159] Examples of PN-related PRO measures include: (1) Worst Itch Numeric Rating Scale (WI-NRS), (2) Dermatological Life Quality Index (DLQI), (3) Pain Numeric Scale, (4) Sleep Numeric Scale, (5) Hospital Anxiety and Depression Scale, (6) Patient Global Impression of Change (PGIC), (7) Patient Global Impression of Severity (PGIS), and (8) Eurocor-5 Dimension (EQ-5 D) score.

[0160] "Improvement of PN-related PRO scale" means an increase from baseline in one or more of the sleep numeric scale score and Euroqol-5 Dimension (EQ-5 D) score, and / or a decrease from baseline in one or more of the Worst Itch Numeric Rating Scale score (WI-NRS), Pain Numeric Scale score, Hospital Anxiety and Depression Scale (HADS) score, Dermatology Life Quality Index (DLQI) score, Patient Global Impression of Change (PGIC) score, and Patient Global Impression of Severity (PGIS) score. As used herein, the term "baseline" with respect to a PN-related PRO scale refers to the value of the patient's PRO scale before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0161] Examples of PN-related ClinRO measures include: (1) Investigator Global Assessment for Prurigo Nodularis (IGA PN) and (2) Prurigo Activity Score (PAS).

[0162] "Improvement in a PN-related ClinRO measure" refers to a reduction from baseline in one or more of the Investigator's Global Assessment of Prurigo Nodularis (IGA PN) scores or Prurigo Activity Score (PAS). As used herein, the term "baseline" with respect to a PN-related ClinRO measure refers to the value of the ClinRO measure of the patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0163] To determine whether a PN-related parameter has been "improved," the parameter is quantified at baseline and at time points following administration of a pharmaceutical composition described herein. For example, the PN-related parameter may be measured on 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 at 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 more after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" in the PN-related parameter (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured).

[0164] The term "obtain" or "obtaining" as used herein refers to gaining possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" a physical entity or value, such as a PN-related parameter. "Directly obtaining" means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving a physical entity or value from another entity or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Obtaining a physical entity directly includes performing a process that involves a physical change of a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Obtaining a value directly includes performing a process that involves a physical change of a sample or another substance, such as performing an analytical process that involves a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis").

[0165] Indirectly obtained information may be provided in the form of a report, such as provided in paper or electronic format from an online database or application (an "Application"). The report or information may be provided, for example, by a medical institution, such as a hospital or clinic, or a health care provider, such as a doctor or nurse.

[0166] Pruritus-free days: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in pruritus-free days experienced by the subject. For example, administration of an IL-4R antagonist to a subject in need thereof causes an increase from baseline in pruritus-free days experienced by the subject 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, or 31 days / month.

[0167] PN nodule count: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in PN nodules (i.e., lesions) from baseline. For example, administration of an IL-4R antagonist to a subject in need of administration of an IL-4R antagonist results in a reduction in PN nodules from 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, 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, 1 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, 7 8, 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, 1 19, 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 nodes.

[0168] 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.

[0169] Worst Itch Numeric Rating Scale: According to some embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the Worst Itch Numeric Rating Scale (WI-NRS) score. The WI-NRS is a PRO consisting of a single item rated on a scale of 0 ("no itch") to 10 ("worst itch imaginable") (Staender 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 are asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. Daily WI-NRS scores are summed over 7 days to create an average weekly WI-NRS score.

[0170] Methods of treatment are provided that result in a reduction in WI-NRS score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof reduces the WI-NRS score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points from baseline. In some embodiments, the subject has a baseline WI-NRS score of 7 or greater prior to treatment with an IL-4R antagonist.

[0171] Investigator Global Assessment of Prurigo Nodularis: According to some embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the Investigator Global Assessment of Prurigo Nodularis (IGA PN) score. 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 from 0 (clear) to 4 (severe) and a 5-point scale of disease stage (IGA PN-S): 0 = clear, no nodules; 1 = almost clear, 1-5 nodules; 2 = mild, 6-19 nodules; 3 = moderate, 20-99 nodules; 4 = severe, 100 or more nodules.

[0172] Treatment methods are provided that result in a reduction in IGA PN score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in IGA PN score of about 1, 2, 3, or 4 points from baseline.

[0173] Prurigo Activity Score: According to some embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the Prurigo Activity Score (PAS). The Prurigo Activity Score (PAS) is a ClinRO measurement. The original PAS questionnaire version 0.9 consists of seven items developed by clinicians specialized in PN (Poelking 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 PAS items assess 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). Other items assess activity in terms of representative body area and exact lesion count (item 5), the percentage of prurigo lesions with an abrasion / eschar on top (reflecting active scratching; item 7a) and the percentage of prurigo lesions that are healed (reflecting healing of chronic prurigo; item 7b).

[0174] Methods of treatment that result in a decrease in PAS scores from baseline are provided.

[0175] Dermatology Life Quality Index (DLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in DLQI scores. The Dermatology Life Quality Index (DLQI) is 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 instrument includes 10 items that assess the impact of skin disease on the participant's health-related quality of life (HRQoL) over the previous week. Items cover symptoms, leisure activities, work / school or holiday time, relationships including intimacy, side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials. (See Chernyshov PV. The evolution of quality of life assessment and use in dermatology. Dermatology. 2019;235(3):167-74). Response scale is a 4-point Likert scale (0='not at all' and 3='very much') for 9 items. One remaining item on work / exam asks if work / exam was interfered with and then (if 'no') how much of a problem the skin condition caused at work / exam. Items are rated on a 3-point Likert scale ('not at all' to 'a lot of'). Overall scoring ranges from 0 to 30, with higher scores indicating lower HRQoL.

[0176] Therapeutic methods are provided that result in a reduction in DLQI score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof causes a reduction in DLQI score from 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 or 30 points.

[0177] Pain Numeric Rating Scale: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in pain numerical rating scale (NRS) scores. For pain, NRS participants are asked to rate their worst skin pain in the past 24 hours using a 0 to 10 numerical rating scale (NRS), with 0 = no pain to 10 = worst possible pain.

[0178] Methods of treatment are provided that result in a reduction in pain NRS score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof reduces the pain NRS score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points from baseline.

[0179] Numerical Sleep Rating Scale: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in Numerical Sleep Rating Scale (NRS) scores. In the sleep NRS, participants are asked to rate the quality of their past night's sleep upon awakening using an NRS of 0 to 10, with 0 = worst possible sleep and 10 = best possible sleep.

[0180] Treatment methods are provided that result in a decrease in sleep NRS score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in pain NRS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.

[0181] Hospital Anxiety and Depression Scale: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the Hospital Anxiety and Depression Scale (HADS) score from baseline. The Hospital Anxiety and Depression Scale (HADS) is a PRO instrument for screening anxiety and depression in non-psychiatric populations. Repeated administration also provides information about changes in the patient's emotional 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. Possible scores range from 0 to 21 for each subscale. The following cut-off scores are recommended for both subscales: 0–7: normal; 8–10: borderline abnormal (borderline case); 11 to 21: abnormal.

[0182] Methods of treatment are provided that result in a decrease in HADS score from baseline. For example, administration of an IL-4R antagonist causes a decrease in HADS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 in a subject in need thereof.

[0183] Antidepressant use: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in antidepressant use from baseline. Treatment methods are provided that result in a reduction or elimination of antidepressant use from baseline. In certain embodiments, administration of an IL-4R antagonist results in a reduction of antidepressant use by the subject 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, by administering an IL-4R antagonist to a subject in need thereof. In other embodiments, administration of an IL-4R antagonist to a subject in need thereof results in the elimination of antidepressant use by the subject.

[0184] 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 from baseline. The Patient Global Impression of Change (PGIC) is a one-item questionnaire that asks participants to provide a global self-assessment of the overall change in their PN on a 7-point scale compared to just before the participant started study treatment. Response options are as follows: 0 = "much better", 1 = "slightly better", 2 = "slightly better", 3 = "no change", 4 = "slightly worse", 5 = "slightly 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, 1976).

[0185] Treatment methods are provided that result in a reduction in PGIC score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in PGIC score from baseline of about 1, 2, 3, 4, 5, or 6 points.

[0186] Patient Global Impression of Severity (PGIS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in PGIS scores from baseline. The Patient Global Impression of Severity (PGIS) is a one-item questionnaire that asks participants to provide an overall self-assessment of disease severity on a four-point scale over the past week. Response options are: 1=none, 2=mild, 3=moderate, 4=severe. (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, 1976).

[0187] Treatment methods are provided that result in a reduction in PGIS score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in PGIS score from baseline of about 1, 2, or 3.

[0188] Euroqol-5 Dimensions (EQ-5D): According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in EQ-5D. The Euroqol-5 Dimensions (EQ-5D) is a standardized PRO measure of health status developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic evaluation. The adult version of the questionnaire is adapted for patients aged 16 years and older. The EQ-5D consists of two parts: a descriptive system and an EQ visual analog scale (EQ VAS). The EQ-5D 5L descriptive system includes five dimensions: mobility, self-care, usual activity, pain / discomfort, and anxiety / depression. Each dimension has five levels of perceived problems: "no problems", "mild problems", "moderate problems", "severe problems", and "disabling". (See Herdman M, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual. Life Res. 2011;20(10):1727-36). Respondents are asked to indicate their health status by checking a box (or placing a cross) against the most appropriate statement for each of the five dimensions. This results in a single-digit number representing the level of that dimension. The five dimension numbers can be combined in a five-digit number that describes the respondent's health status. The EQ VAS records the respondent's self-rated health status on a vertical VAS, where the endpoints are labeled "best possible health status (100)" and "worst possible health status (0)". This information can be used as a quantitative measure of health outcomes as judged by the individual respondent.

[0189] Methods of treatment are provided that result in an increase in EQ VAS score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof may result in an increase in EQ VAS score from 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, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points increase in EQ VAS from baseline.

[0190] Interleukin-4 receptor antagonist The methods featured 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 and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on a cell in vitro or in vivo. Non-limiting examples of categories 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, the IL-4R antagonist includes an anti-IL-4R antibody that may be used in conjunction with 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 heavy and light chain (complementarity determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively.

[0191] The term "human IL 4 R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), such as IL-4Rα.

[0192] 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 contains a heavy chain variable region (referred to herein as HCVR or V H The heavy chain constant region is made up of three domains: H 1. C H 2, and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR 1, CDR 1, FR 2, CDR 2, FR 3, CDR 3, FR 4. In different embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0193] The term "antibody" also includes antigen-binding fragments of an intact antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding the antibody variable domains and optionally the constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and engineered, for example, chemically or using molecular biology techniques, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add or delete amino acids, and the like. 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; (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions (e.g. isolated complementarity determining regions (CDRs) such as CDR 3 peptides) of an antibody or the constraining FR 3-CDR 3-FR 4 peptide. Domain specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the expression "antigen binding fragment".

[0194] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. L V bound to domainH For antigen-binding fragments containing domains, V H Domain and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L Or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a dimer of monomer V H Or V L It may contain domains.

[0195] In certain embodiments, an antigen-binding fragment of an antibody may comprise 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 in the antigen-binding fragments of an antibody described herein include the following: (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)V H -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 H2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. A hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule, typically a hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Furthermore, antigen-binding fragments of antibodies described herein may be linked to each other and / or to one or more monomeric V H Or V L The variable domain and constant domain may comprise homodimers or heterodimers (or other multimers) of any of the variable domain and constant domain configurations listed above, non-covalently associated with the domains (e.g., by disulfide bonds).

[0196] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antigen-binding fragments of antibodies described herein using routine techniques available in the art.

[0197] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, an antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0198] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies described herein may include amino acid residues, e.g., in the CDRs, particularly CDR 3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation 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 grafted onto human framework sequences.

[0199] The term "recombinant human antibody" includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created or isolated by any other means including splicing of 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 are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) to thereby modify the V and V regions of the recombinant antibodies. H Area and V L The amino acid sequence of the region is human germline V H Sequence and V L These sequences are derived from and may not naturally occur within the human antibody germline repertoire in vivo.

[0200] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds and the approximately 75-80 kDa molecule is composed of covalently linked light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0201] The frequency of occurrence 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 typically observed using the human IgG1 hinge. Hinge, C H 2 or C H Antibodies with one or more mutations in three regions are provided, which may be desirable, for example in manufacturing, to improve the yield of the desired antibody form.

[0202] An "isolated antibody" refers to 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 it naturally occurs or is naturally produced, 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 been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0203] Terms such as "specifically bind" mean that an antibody or antigen-binding fragment thereof forms a complex with an 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 has 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 as measured by a surface plasmon resonance assay. D The present invention includes antibodies that specifically bind to IL-4R or a portion thereof. However, an isolated antibody that specifically binds to human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0204] Anti-IL-4R antibodies useful in the present methods may contain 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 are derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Methods are provided that include the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a tetrameric antibody, or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) within one or more framework and / or one or more CDR regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been mutated to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting from the heavy and light chain variable region sequences disclosed herein, one skilled in the art can readily produce a large number of antibodies and antigen-binding fragments thereof that contain one or more individual germline mutations or combinations thereof. In certain embodiments, the V H and / or V LAll of the framework and / or CDR residues within the domain are mutated back to the residue found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, for example only the mutated residues found within the first 8 amino acids of FR 1 or the last 8 amino acids of FR 4, or only the mutated residues found in CDR 1, CDR 2 or CDR 3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present disclosure.

[0205] Methods involving the use of anti-IL-4R antibodies that comprise variants of any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions, for example, the use of anti-IL-4R antibodies having HCVR, LCVR and / or CDR amino acid sequences that have, e.g., 10 or less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein is provided.

[0206] The term "surface plasmon resonance" refers to an optical phenomenon that allows analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example using a BIAcore™ (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) system.

[0207] "K D The term "antibody-antigen interaction" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0208] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are those generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include portions of sugars, phosphoryl groups, or sulfonyl groups on an antigen.

[0209] The terms "substantial identity" or "substantially identical" when referring to a nucleic acid or a fragment thereof, indicates that when optimally aligned with another nucleic acid (or its complementary strand), with appropriate nucleotide insertions or deletions, there is nucleotide sequence identity of at least about 95%, or at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known sequence identity algorithm, such as FASTA, BLAST or Gap, as discussed below.

[0210] As applied to polypeptides, the term "substantial similarity" 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 programs GAP or BESTFIT using default gap weights. In exemplary embodiments, non-identical residue positions differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions do not substantially change the functional properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art (see, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331, incorporated herein by reference). Examples of groups of amino acids with side chains with similar chemical properties 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, glutamine; (4) aromatic side chains: phenylalanine, tyrosine, tryptophan; (5) basic side chains: lysine, arginine, histidine; (6) acidic side chains: aspartic acid and glutamic acid, and (7) sulfur-containing side chains: 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 that has a positive value in the PAM 250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443 45, which is incorporated herein by reference. A "moderately conservative" substitution is any change that has a non-negative value in the PAM 250 log-likelihood matrix.

[0211] The sequence similarity of polypeptides, also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For example, GCG software includes programs such as Gap and Bestfit, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species or between a wild-type protein and its mutein (see, for example, GCG version 6.1). Polypeptide sequences can also be compared using FASTA, a program in GCG version 6.1, using default or recommended parameters. FASTA (e.g., FASTA 2 and FASTA 3) provides alignment and percent sequence identity of the region of best overlap between the query sequence and the search sequence (Pearson (2000) supra). Another exemplary algorithm for comparing the sequences of the present disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, using default parameters (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).

[0212] Preparation of human antibodies Methods for producing human antibodies in transgenic mice are known in the art. Any such known method can be used to produce human antibodies that specifically bind to human IL-4R.

[0213] Using VELOCIMMUNE® technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, a high affinity chimeric antibody against IL-4R with a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the creation of a transgenic mouse with a genome that includes a human heavy chain variable region and a human light chain variable region operably linked to an endogenous mouse constant region locus, such that the mouse produces an antibody containing a human variable region and a mouse constant region in response to antigenic stimulation. DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[0214] Generally, VELOCIMMUNE® mice are loaded with an antigen of interest and lymphoid cells (such as B cells) are harvested from the mice that express antibodies. Lymphoid cells can be fused with myeloma cell lines to prepare immortal hybridoma cell lines, which are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light chains can be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells, such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0215] First, a high affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for the desired characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to generate a fully human antibody as described herein, such as wild-type or modified IgG1 or IgG4. The constant region selected can vary according to the particular application, but the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0216] In general, the antibodies that can be used in the methods described herein have high affinity, as described above, as measured by binding to antigen immobilized on either a solid phase or in solution phase. The mouse constant region is replaced with the desired human constant region to generate the fully human antibody described herein. The constant region selected can vary according to the specific application, but the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0217] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds 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 the 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 the 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 specific HCVR and / or LCVR amino acid sequences 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. Generally speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the location 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 are also available to identify CDR sequences within antibodies.

[0218] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy chain variable region amino acid sequence pair and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0219] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acids of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0220] 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.

[0221] In a particular embodiment, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0222] In a particular embodiment, the antibody sequence is dupilumab comprising the heavy / light chain amino acid sequence pair of SEQ ID NOs:9 and 10.

[0223] Dupilumab HCVR amino acid sequence: [ka]

[0224] Dupilumab LCVR amino acid sequence: [ka]

[0225] Dupilumab HCDR1 amino acid sequence: GFTFRDYA (sequence number 3).

[0226] Dupilumab HCDR2 amino acid sequence: ISGSGGNT (sequence number 4).

[0227] Dupilumab HCDR3 amino acid sequence: AKDRLSITIRPRYYGL (sequence number 5).

[0228] Dupilumab LCDR1 amino acid sequence: QSLLYSIGYNY (sequence number 6).

[0229] Dupilumab LCDR2 amino acid sequence: LGS (sequence number 7).

[0230] Dupilumab LCDR3 amino acid sequence: MQALQTPYT (sequence number 8).

[0231] Dupilumab HC amino acid sequence: [ka] (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant)

[0232] Dupilumab LC amino acid sequence: [ka] (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant)

[0233] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are 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; 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-45 / SCB-VH-92; SCB-VL-46 / SCB-VH-92; 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; SCB-VL-54 / SCB-VH-91; SCB-VL-55 / SCB-VH-92; SCB-VL-55 / SCB-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-VH-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-61; SCB-VL-57 / SCB-VH-62; 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;SC B-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-5 7 / 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 / SC B-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;

[0234] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair SCB-VL-44 / SCB-VH-92.

[0235] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair SCB-VL-54 / SCB-VH-92.

[0236] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair SCB-VL-55 / SCB-VH-92.

[0237] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises 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.

[0238] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises 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.

[0239] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises 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.

[0240] The antibodies listed in Table 1 below are described in more detail in US Pat. No. 10,774,141, which is incorporated by reference in its entirety for all purposes.

[0241] [Table 1]

[0242] [Table 2]

[0243] [Table 3]

[0244] [Table 4]

[0245] [Table 5]

[0246] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a light chain variable region (LCVR) and 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.

[0247] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair MEDI-37 GL-VL / MEDI-37 GL-VH.

[0248] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a HCVR comprising the HCDR1 sequence of MEDI-37 GL-HCDR1, the HCDR2 sequence of MEDI-37 GL-HCDR2, and the HCDR3 sequence of MEDI-37 GL-HCDR3, and a LCVR comprising the LCDR1 of MEDI-37 GL-LCDR1, the LCDR2 of MEDI-37 GL-LCDR2, and the LCDR3 of MEDI-37 GL-LCDR3.

[0249] The antibodies listed in Table 2 below are described in more detail in US Pat. No. 8,877,189, which is incorporated by reference in its entirety for all purposes.

[0250] [Table 6]

[0251] [Table 7]

[0252] [Table 8]

[0253] [Table 9]

[0254] [Table 10]

[0255] [Table 11]

[0256] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair AJOU-90-VL / AJOU-83-VH.

[0257] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises 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.

[0258] The antibodies listed in Table 3 below are described in further detail in WO 2020 / 096381 and Kim et al. (Scientific Reports. 9:7772.2019), which are incorporated by reference in their entireties for all purposes.

[0259] [Table 12]

[0260] [Table 13]

[0261] [Table 14]

[0262] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a light chain variable region (LCVR) and 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. Nos. 7,605,237 and 7,608,693, which are incorporated by reference in their entireties for all purposes.

[0264] [Table 15]

[0265] [Table 16]

[0266] [Table 17]

[0267] The antibodies listed in Table 5 below are described in further detail in WO 2022 / 052974, which is incorporated by reference in its entirety for all purposes.

[0268] [Table 18]

[0269]

Table 19

[0270]

Table 20

[0271]

Table 21

[0272] In certain embodiments, the antibodies or antigen-binding fragments thereof of the disclosure include: 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 / 164-14;HV3-15-14 / KV4-14;HV3-15-14 / KV1-27-14;HV3-15-14 / KV1-9-14;HV 3-15-14 / KV1-NL1-14;HV3-15-14 / KV1D-43-14;HV3-48-14 / Y01-14;HV3-48-14 / 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;H V3-73*2-14 / KV1-NL1-14;HV3-73*2-14 / KV1D-43-14;HV3-72-14 / Y01-14;HV3-72-14 / 164-14;HV3-72-14 / KV4-14;HV3-72-14 / KV1-27-14;HV3-72-14 / KV1-9-14;HV3-72-14 / KV1-NL1-14;HV3-72-14 / KV1D-43-14;Y01-14 / Y01-1 4;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;162-14 / 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;

[0273] The antibodies listed in Table 6 below are described in more detail in WO 2021 / 213329, which is incorporated by reference in its entirety for all purposes.

[0274] [Table 22]

[0275] [Table 23]

[0276] [Table 24]

[0277] Pharmaceutical Compositions Methods are provided that include administering an IL-4R antagonist to a patient, where the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other agents that provide suitable entry, delivery, tolerance, etc. A large number of suitable formulations can be found in formularies known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. 52:238-311.

[0278] The dose of the antibody administered to the patient may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. The effective dose and schedule for administering the pharmaceutical composition containing the anti-IL-4R antibody can be empirically determined. For example, the progress of the patient can be monitored by periodic evaluation and the dose adjusted accordingly. Furthermore, inter-species scaling of the dose can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0279] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, for example, encapsulated in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (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, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents.

[0280] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously using a standard needle and syringe. Additionally, for subcutaneous delivery, pen delivery devices (e.g., autoinjector pens) readily find use in delivering the pharmaceutical compositions described herein. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge that contains the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0281] A number of reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of pharmaceutical compositions. Examples include the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN IV ... Examples of disposable pen delivery devices that have application in the subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, the SOLOSTAR Pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk), and KWIKPEN (Eli Lilly), SURECLICK Autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA Pen (Abbott Labs, Abbott Park IL), to name just a few.Examples of large volume delivery devices (e.g., large volume injectors) include, but are not limited to, bolus injectors, such as, for example, BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, etc.

[0282] Exemplary drug delivery devices may include needle-based injection systems as described in Table 1 of ISO 11608-1:2014(E) section 5.2. As described in ISO 11608-1:2014(E), needle-based injection systems may be broadly categorized as multi-dose container systems and single-dose (partial or full discharge) container systems. The containers may be replaceable or integral non-replaceable containers.

[0283] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based injection device with replaceable containers. In such systems, each container holds multiple doses and may be fixed or variable (pre-set by a user) in size. Other multi-dose container systems may include a needle-based injection device with an integrated non-replaceable container. In such systems, each container holds multiple doses and may be fixed or variable (pre-set by a user) in size.

[0284] As further described in ISO 11608-1:2014(E), the single dose container system may include a needle-based injection device with replaceable containers. In one example of such a system, each container holds one dose and the entire deliverable amount is expelled (full expelled). In another example, each container holds one dose and a portion of the deliverable amount is expelled (partial expelled). As also described in ISO 11608-1:2014(E), the single dose container system may include a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds one dose and the entire deliverable amount is expelled (full expelled). In another example, each container holds one dose and a portion of the deliverable amount is expelled (partial expelled).

[0285] An exemplary sleeve-triggered auto-injector with manual needle insertion is described in WO 2015 / 004052. An exemplary audible end-of-dose feedback mechanism is described in WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of the auto-injector is described in WO 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe auto-injector is described in WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of the syringe is described in WO 2016 / 193355.

[0286] For direct administration to the paranasal sinuses, the pharmaceutical compositions described herein can be administered, for example, using a microcatheter (e.g., endoscope and microcatheter), an aerosolization device, a powder dispenser, a nebulizer, or an inhaler. This method includes administration to a subject in need of administration of an IL-4R antagonist in an aerosolized formulation. For example, an aerosolized antibody against IL-4R can be administered to treat PN in a patient. The aerosolized antibody can be prepared, for example, as described in U.S. Pat. No. 8,178,098, the entirety of which is incorporated herein by reference.

[0287] In certain circumstances, 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. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed close to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). For other controlled release systems, see the review in Langer, 1990, Science 249:1527-1533.

[0288] The injectable preparation includes dosage forms for intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip infusion, and the like. These injectable preparations can be prepared by known methods. For example, the injectable preparation can be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous medium or oily medium conventionally used for injection. Examples of the aqueous medium for injection include isotonic solutions containing physiological saline, glucose, and other adjuvants, and the like, which can be used in combination with a suitable solubilizing agent such as alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactant (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)). Examples of the oily medium include sesame oil, soybean oil, and the like, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, and the like. The injectable preparation thus prepared is typically filled into a suitable ampoule.

[0289] Advantageously, the pharmaceutical compositions for oral or parenteral use are prepared in a dosage form of a unit dose suitable for the dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0290] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used as described herein are disclosed, for example, in US Pat. No. 8,945,559.

[0291] Dosage The amount of IL-4R antagonist (e.g., 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" refers to an amount of 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). "Therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of PN in a subject.

[0292] In the case of an anti-IL-4R antibody, the therapeutically effective amount is 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 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 20 0mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, About 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410 mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about The amount of anti-IL-4R antibody may be about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In a specific embodiment, 300 mg of anti-IL-4R antibody is administered.

[0293] The amount of IL-4R antagonist contained within an individual dose may be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist may 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 may 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.

[0294] In certain embodiments, the initial dose is about the same as the loading dose, hi 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 than the loading dose.

[0295] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of the treatment regimen as an "initial dose" or "loading dose", followed by subsequent doses administered on a less frequent basis (e.g., a "secondary dose" or "maintenance dose"). 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 the IL-4R antagonist may be administered, followed by a maintenance dose of about 75 mg to about 300 mg. In certain embodiments, the method includes an initial dose or loading dose of about 400 mg or about 600 mg of the IL-4R antagonist. In certain embodiments, the method includes one or more secondary doses or maintenance doses of about 200 mg or about 300 mg of the IL-4R antagonist.

[0296] In one embodiment, the maintenance dose is the same as the loading dose or the initial dose. For example, both the loading dose and the maintenance dose of the IL-4R antagonist may be administered at a dose of about 75 mg to about 300 mg. In a specific embodiment, the method includes an initial dose and a maintenance dose of about 300 mg of the IL-4R antagonist.

[0297] In certain exemplary embodiments, the subject is a pediatric subject having a body weight greater 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 having a body weight greater than 30 kg, and the IL-4R antagonist is administered at an initial or loading dose of about 400 mg and one or more secondary or maintenance doses of about 200 mg, the secondary doses being administered every other week (q2w). In some embodiments, the subject is a pediatric subject having a body weight greater than 30 kg, and the IL-4R antagonist is administered at an initial dose and a maintenance dose of about 200 mg, the maintenance doses being administered every other week (q2w).

[0298] In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and 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 at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, the secondary doses being administered every four weeks (q4w). In some embodiments, the subject is a pediatric subject having a body weight of 30 kg or less and a body weight of at least 15 kg, and the IL-4R antagonist is administered at an initial dose and a maintenance dose of about 300 mg, the maintenance dose being administered every four weeks (q4w).

[0299] 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 or maintenance doses of about 200 mg, the secondary doses being 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 a maintenance dose of about 200 mg, the maintenance doses being administered every other week (q2w). In certain embodiments, the subject is an adolescent subject weighing 30 kg or more 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 30 kg or more 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 or maintenance doses of about 200 mg, the secondary doses being administered every other week (q2w). In other embodiments, the subject is an adolescent subject weighing 30 kg or more and less than 60 kg, and the IL-4R antagonist is administered at an initial dose and a maintenance dose of about 200 mg, the maintenance doses being administered every other week (q2w).

[0300] In certain exemplary embodiments, the subject is an adolescent subject having a body weight of 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 having a body weight of at least 60 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, the secondary doses being administered every other week (q2w). In other embodiments, the subject is an adolescent subject having a body weight of at least 60 kg, and the IL-4R antagonist is administered at an initial dose and a maintenance dose of about 300 mg, the maintenance doses being administered every other week (q2w).

[0301] 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 or maintenance doses of about 300 mg, the secondary doses being 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, the maintenance doses being administered every other week (q2w).

[0302] In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 150 mg / mL using a prefilled device. In some embodiments, a 150 mg / mL IL-4R antagonist solution in a prefilled device is used to deliver 300 mg of IL-4R antagonist in a 2 mL injection. In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 175 mg / mL using a prefilled device. In some embodiments, a 175 mg / mL IL-4R antagonist solution in a prefilled device is used to deliver 200 mg of IL-4R antagonist in a 1.14 mL injection.

[0303] Combination therapy Certain embodiments of the methods described herein include administering to a subject one or more therapeutic agents in combination with an IL-4R antagonist. As used herein, the term "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent. Methods of treating PN or related conditions or complications are provided that include administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0304] For example, when administered "before" a pharmaceutical composition comprising an 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 IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an 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 IL-4R antagonist. "Concurrent administration" with a pharmaceutical composition comprising an 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) of administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0305] In exemplary embodiments, the additional therapeutic agent administered in combination with the IL-4R antagonist is a background therapy. In exemplary embodiments, the background therapy is one or more topical corticosteroids (TCS). In exemplary aspects, the background therapy is one or more oral corticosteroids (OCS). In other exemplary embodiments, the background therapy is one or more topical calcineurin inhibitors (TCIs). In some exemplary aspects, the background therapy is one or more low- to medium-potency topical corticosteroids (TCSs). In other exemplary embodiments, the background therapy is one or more low- to medium-potency topical calcineurin inhibitors (TCIs). In certain embodiments, the method results in a reduction in the need for background therapy. For example, in certain embodiments, the method results in a reduction in the dose and / or frequency of background therapy.

[0306] 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), a TCS, a TCI, an IL-1 antagonist (including, for example, the IL-1 antagonists 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, anti-IL-6R antibodies such as those set forth in U.S. Pat. No. 7,582,298), or an IL-17 antagonist.

[0307] In an exemplary embodiment, the additional therapeutic agent is mid-to-extra potency TCS.

[0308] In another exemplary embodiment, the additional therapeutic agent is low-medium potency TCS.

[0309] Suitable super-potency (i.e., Group 1) TCS include, but are not limited to, betamethasone dipropionate (boosted), clobetasol propionate, diflucortolone valerate, fluocinonide, flurandrenolide, halobetasol propionate, and the like.

[0310] Suitable high potency (i.e., Group 2) TCS include, but are not limited to, amcinonide, betamethasone dipropionate, clobetasol propionate, desoximethasone, diflorasone diacetate, fluocinonide, halcinonide, halobetasol propionate, and the like.

[0311] Suitable high potency (i.e., Group 3) TCS include, but are not limited to, amcinonide, betamethasone dipropionate, betamethasone valerate, desoximetasone, diflorasone acetate, diflucortolone valerate, fluocinonide, fluticasone propionate, mometasone furoate, mometasone furoate, and the like.

[0312] Suitable medium-potency (i.e., Group 4) TCS include, but are not limited to, betamethasone dipropionate, clocortolone pivalate, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone valerate, mometasone furoate, triamcinolone acetonide, etc. Particularly suitable medium-potency TCS include triamcinolone acetonide 0.1% cream and fluocinolone acetonide 0.025% ointment.

[0313] Suitable low-medium potency (i.e., Group 5) TCS include, but are not limited to, betamethasone dipropionate, betamethasone valerate, desonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone probutate, hydrocortisone valerate, predicarbate, triamcinolone acetonide, and the like.

[0314] Suitable low potency (ie, Group 6) TCS include, but are not limited to, alclometasone dipropionate, betamethasone valerate, desonide, fluocinolone acetonide, triamcinolone acetonide, and the like.

[0315] Suitable weakest (i.e., Group 7) TCS include, but are not limited to, hydrocortisone (base, >2%), hydrocortisone (base, <2%), hydrocortisone acetate, etc. A particularly suitable least potent TCS is hydrocortisone 1% cream.

[0316] In a further exemplary embodiment, the additional therapeutic agent is a mid-to-super potency TCI.

[0317] In a further exemplary embodiment, the additional therapeutic agent is a low- to medium-potency TCI.

[0318] Suitable TCIs include clobetasol propionate, betamethasone dipropionate, ASTAGRAF XL™ (i.e., tacrolimus extended release capsules), CEQUA™ (i.e., cyclosporine 0.09% eye drops), cyclosporine, cyclosporine ophthalmic, ELIDEL™ (i.e., pimecrolimus), ENVARSUS These include, but are not limited to, XR™ (i.e., tacrolimus extended release tablets), GENGRAF™ (i.e., cyclosporine), HECORIA™ (i.e., tacrolimus), LUPKYNIS™ (i.e., voclosporin), NEORAL™ (i.e., cyclosporine capsules and oral solution), pimecrolimus, PROGRAF™ (i.e., tacrolimus capsules), PROTOPIC™ (i.e., tacrolimus ointment), RESTASIS™ (i.e., cyclosporine 0.05% ophthalmic solution), SANDIMMUNE™ (i.e., cyclosporine capsules and oral solution), tacrolimus, tacrolimus ointment, VERKAZIA™ (i.e., cyclosporine ophthalmic emulsion), voclosporin, and the like.

[0319] A particularly suitable super potency TCS is clobetasol propionate 0.05% cream. A particularly suitable high potency TCS is betamethasone dipropionate 0.05% optimized ointment.

[0320] In a further exemplary embodiment, the additional therapeutic agent is an oral corticosteroid (ie, a systemic corticosteroid).

[0321] Suitable oral corticosteroids include, but are not limited to, prednisone, prednisolone, methylprednisolone, hydrocortisone, dexamethasone, cortisone acetate, and the like.

[0322] Dosing regimen 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, "sequentially administering" means that each dose of an IL-4R antagonist is administered to a subject at different times, e.g., on different days separated by a predefined interval (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering a single initial dose of an IL-4R antagonist to a patient, followed by one or more secondary doses of the IL-4R antagonist, and optionally followed by one or more tertiary doses of the IL-4R antagonist.

[0323] Methods are provided that include administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about 4 times per week, twice per week, once per week (q1w), once every two weeks (every two weeks is used interchangeably with every other week, biweekly or q2w), once every three weeks (3w 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 as less frequently as a therapeutic response is achieved.

[0324] In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, weekly dosing in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, biweekly dosing (every two weeks is used interchangeably with every other week, biweekly, or q2w) in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once every three weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be administered. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every four weeks (monthly dosing) in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every five weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every six weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. 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 can be administered once every 8 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 can be administered once every 12 weeks. In certain exemplary embodiments, the route of administration is subcutaneous.

[0325] The term "week" or "weeks" refers to a period of (n x 7 days) ± 3 days, for example (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, for example 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0326] The terms "initial dose", "secondary dose" and "tertiary dose" refer to the temporal order of administration of the IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also called a "baseline dose" or "loading dose"). A "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary and tertiary doses may all contain the same amount of IL-4R antagonist or may differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, secondary and / or tertiary doses differs from each other (e.g., adjusted up or down as necessary) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4 or 5) doses are administered as "loading doses" at the beginning of a treatment regimen, followed by subsequent doses (e.g., "maintenance doses") that are administered less frequently. In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more initial or loading doses of 600 mg or 400 mg of IL-4R antagonist may be administered, followed by a secondary or maintenance dose of about 75 mg to about 400 mg. In one embodiment, the secondary / maintenance dose may be equal to the initial / loading dose. For example, one or more initial / loading doses of 300 mg or 200 mg of IL-4R antagonist may be administered, followed by a secondary / maintenance dose of about 300 mg or about 200 mg, respectively. In one embodiment, the loading dose may be split, e.g., two or more doses administered at different times, e.g., two loading doses, with the second loading dose administered two weeks after the first loading dose.

[0327] 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 yet another embodiment, the initial dose is 300 mg of the IL-4R antagonist.

[0328] In certain embodiments, the secondary 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.

[0329] 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.

[0330] In some embodiments, the subject is a pediatric patient, weighing no more than 30 kg and at least 15 kg, and the initial dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks (q4w). In other embodiments, the subject is a pediatric patient, weighing no more than 30 kg and at least 15 kg, and the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks (q4w).

[0331] In some embodiments, the subject is a pediatric subject, weighing more than 30 kg, and the initial dose comprises 400 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 is used interchangeably with every 2 weeks, every other week, or q2w). In other embodiments, the subject is a pediatric subject, weighing more than 30 kg, and 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 is used interchangeably with every 2 weeks, every other week, or q2w).

[0332] In some embodiments, the subject is an adolescent, weighs less than 60 kg, and the initial dose comprises 400 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 is used interchangeably with every 2 weeks, every other week, or q2w). In other embodiments, the subject is an adolescent, weighs less than 60 kg, and 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 is used interchangeably with every 2 weeks, every other week, or q2w). In an exemplary embodiment, the subject is an adolescent, weighs 30 kg or more and less than 60 kg, and the initial dose comprises 400 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 is used interchangeably with every 2 weeks, every other week, or q2w). In another exemplary embodiment, the subject is an adolescent and weighs equal to or greater than 30 kg and less than 60 kg, and 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 and are administered every other week (biweekly is used interchangeably with every 2 weeks, biweekly or q2w).

[0333] In some embodiments, the subject is an adolescent and weighs more than 60 kg, and the initial dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every 2 weeks, every other week, or q2w). In other embodiments, the subject is an adolescent and weighs more than 60 kg, and the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every 2 weeks, every other week, or q2w).

[0334] In some embodiments, the subject is an adult and the initial dose comprises 600 mg of the antibody or antigen-binding fragment thereof and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every 2 weeks, every other week, or q2w). In other embodiments, the subject is an adult and the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every 2 weeks, every other week, or q2w).

[0335] In an exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" refers to the dose of IL-4R antagonist administered to a patient prior to administration of the very next dose in the series, without any intervening doses, in a multiple administration series.

[0336] The method may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0337] 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 1-2 weeks after the immediately preceding 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 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by the physician depending on the needs of the individual patient after clinical testing.

[0338] Methods are provided that include sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient to treat PN or an associated condition. In some embodiments, the methods include administering one or more doses of an IL-4R antagonist, followed by administration of one or more doses of a second therapeutic agent (e.g., 2, 3, 4, 5, 6, 7, 8, or more). 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 ameliorate one or more symptoms of PN. In some embodiments, the IL-4R antagonist is administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) to result in an improvement in one or more PN-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one symptom of PN. Alternative embodiments relate to the co-administration of an IL-4R antagonist and a second therapeutic agent. 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 in a separate dosage at a similar or different frequency to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0339] In certain embodiments, the IL-4R antagonist is administered every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or more. In other embodiments, the IL-4R antagonist is administered every 4 weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks or more. In certain embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0340] In certain embodiments, a kit is provided for the treatment of CIndU, comprising a formulation of an antibody or antigen-binding fragment thereof that specifically binds to the 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) of SEQ ID NO: 1 and a light chain variable region (LCVR) of SEQ ID NO: 2. In certain embodiments, the antibody is dupilumab.

[0341] The kit can include a label or package insert that includes instructions for administering the dosage form for the treatment of PN. The instructions can recite a dosing regimen, as further described herein, for the treatment of PN.

[0342] Treatment population The methods provided herein include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof, where "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of, or has been diagnosed with, PN.

[0343] In related embodiments, a "subject in need thereof" may be a subject who has been prescribed or is currently taking a TCI or TCS prior to administration of the IL-4R antagonist. In some embodiments, the subject is currently taking a low to medium potency TCI or TCS. For example, methods are provided that include administering an IL-4R antagonist to a patient who has been taking a regular course of low to medium potency TCI or TCS for at least two weeks immediately prior to administration of the IL-4R antagonist (such prior treatment is referred to herein as "background treatment").

[0344] In yet other embodiments, the amount of TCI or TCS is gradually decreased before or after the initiation of administration of the IL-4R antagonist. In other embodiments, the efficacy of the TCI or TCS is gradually decreased before or after the initiation of administration of the IL-4R antagonist.

[0345] In another exemplary embodiment, the "subject in need thereof" has a diagnosis of PN resistant to TCS or TCI prior to administration of the IL-4R antagonist. In some embodiments, the subject's PN symptoms persist despite treatment with a TCS or TCI. In yet another exemplary embodiment, the "subject in need thereof" has a diagnosis of PN resistant to mid- to high-potency TCS or TCI prior to administration of the IL-4R antagonist. In some embodiments, the subject's PN symptoms persist despite treatment with a mid- to high-potency TCS or TCI. In yet another exemplary embodiment, the "subject in need thereof" has a diagnosis of PN resistant to low- to medium-potency TCS or TCI prior to administration of the IL-4R antagonist. In some embodiments, the subject's PN symptoms persist despite treatment with a low- to medium-potency TCS or TCI.

[0346] In another embodiment, the "subject in need thereof" is a subject whose PN is not adequately controlled with topical therapy. In other embodiments, the "subject in need thereof" is a subject whose pruritus or PN is refractory to topical therapy. In some embodiments, the "subject in need thereof" is a subject for whom topical therapy is not advisable (i.e., the subject experiences adverse effects associated with topical therapy or is on medications that cannot be combined with topical therapy). In yet other embodiments, the "subject in need thereof" is a subject who is a candidate for systemic therapy to treat PN or pruritus.

[0347] In a further exemplary embodiment, a "subject in need thereof" is a subject for whom a TCS or TCI is medically inadvisable (i.e., the subject has an allergy, history of adverse reactions, or other medical history for which administration of a TCS or TCI is not recommended).

[0348] In some embodiments, the "subject in need thereof" is selected from the group consisting of subjects 18 years of age or older, subjects 12 years of age or older, subjects 12-17 years of age (12-18 years of age), subjects 6-11 years of age (6-12 years of age), and subjects 2-5 years of age (2-6 years of age). In some embodiments, the "subject in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "subject in need thereof" is selected from the group consisting of adults 18 years of age or older, adolescents 12-17 years of age (12-18 years of age), children 6-11 years of age (6-12 years of age), and children 2-5 years of age (2-6 years of age). The subject may be less than 2 years of age, e.g., 12 months to 23 months of age, or 6 months to 11 months of age.

[0349] 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 exemplary embodiments, the subject has comorbid mild atopic dermatitis. In other embodiments, the subject has comorbid moderate atopic dermatitis, moderate-severe atopic dermatitis, or severe atopic dermatitis.

[0350] In further exemplary embodiments, a "subject in need thereof" is a subject with mild PN, moderate PN, moderate-severe PN, or severe PN. In some embodiments, a subject with mild PN has an IGA PN-S score of 2 or mild. In some embodiments, a subject with moderate PN has an IGA PN-S score of 3 or moderate. In some embodiments, a subject with severe PN has an IGA PN-S score of 4 or severe. In some embodiments, a subject with moderate-severe PN has an IGA PN-S score of 3 or 4 (moderate or severe). In some embodiments, a subject with moderate to severe PN has a minimum of 20 PN nodules in total on both legs and / or both arms and / or trunk.

[0351] In other exemplary embodiments, the "subject in need thereof" may be a subject with uncontrolled PN. In some embodiments, the subject with uncontrolled PN has failed treatment 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.

[0352] In other exemplary embodiments, a "subject in need thereof" may be a subject with severe itch.

[0353] Methods for assessing pharmacodynamic PN-related parameters Provided is a method for evaluating one or more pharmacodynamic PN-related parameters in a subject in need thereof, which are caused by administering a pharmaceutical composition comprising an IL-4R antagonist.A reduction in the incidence of PN symptoms or an improvement in PN-related PRO or ClinRO measurements can be correlated with an improvement in one or more pharmacodynamic PN-related parameters.However, such a correlation is not necessarily observed in all cases.

[0354] Examples of "pharmacodynamic PN-related parameters" include, for example: (a) biomarker expression levels and (b) serum protein and RNA analysis. "Improvement of a pharmacodynamic PN-related parameter" refers to a decrease from baseline in one or more biomarkers, such as, for example, 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. As used herein, the term "baseline" with respect to a pharmacodynamic PN-related parameter refers to the numerical value of the pharmacodynamic PN-related parameter in a patient prior to or upon administration of a pharmaceutical composition described herein.

[0355] To assess the pharmacodynamic PN-related parameters, the parameters are quantified at baseline and at time points after administration of the pharmaceutical composition. For example, the pharmacodynamic PN-related parameters can be measured at about day 1, about day 2, about day 3, about day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or more after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" or other change in the pharmacodynamic PN-related parameter (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured).

[0356] In certain embodiments, administration of an IL-4R antagonist to a patient causes a change, e.g., a decrease or an increase, in the expression of certain biomarkers. PN-associated biomarkers include, but are not limited to, total IgE, c-reactive protein (CRP), IL-6, D-dimer, mid-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 about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or more after administration of the IL-4R antagonist. Biomarker expression can be assayed 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 to polymerase chain reaction (RT-PCR).

[0357] As described above, biomarker expression can be assayed by detection of protein 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), e.g., RNA levels of biomarkers; in other aspects, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0358] formulation In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 150 mg / mL of an 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; and vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 cPoise.

[0359] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising i) about 175 mg / mL of an 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 the viscosity of the formulation is about 8.5 cPoise.

[0360] In a specific embodiment, 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.

[0361] In a specific embodiment, the antibody comprises dupilumab. Unless otherwise specified, the term "dupilumab" also includes any biosimilars thereof.

[0362] Suitable stabilizing formulations are also described in US Pat. No. 8,945,559, which is incorporated by reference in its entirety for all purposes.

[0363] 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.

[0364] Moreover, in accordance with the present disclosure there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being fully explained in the literature. For example, 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 (DNGlover ed.1985); Oligonucleotide Synthesis (MJGait ed.1984); eds.(1985)];Transcription And Translation [BDHames & SJHiggins,eds.(1984)];Animal Cell Culture [RIFreshney,ed.(1986)];Immobilized Cells And Enzymes [IRL Press,(1986)];B.Perbal,A Practical Guide To Molecular Cloning(1984);FMAusubel et al.(eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). EXAMPLES

[0365] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0366] An exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody called dupilumab (also referred to herein as "mAb 1" or DUPIXENT®).

[0367] 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 Inadequately Controlled on Topical Prescription Therapies or When These Therapies Are Inadvisable (Two Phase 3 Studies of Similar Design and Populations-PRIME & PRIME 2) the purpose Main purpose: To demonstrate the efficacy of dupilumab for pruritic reactions in patients with PN inadequately controlled with topical prescription therapies or when such therapies are inadvisable.

[0368] Secondary purpose: To demonstrate the efficacy of dupilumab on additional pruritus endpoints in patients with PN inadequately controlled with topical prescription therapies or when these therapies are inadvisable.

[0369] To demonstrate the efficacy of dupilumab on the skin lesions of PN.

[0370] To demonstrate improvements in health-related quality of life (HRQoL).

[0371] To evaluate safety outcome measures.

[0372] To evaluate the immunogenicity of dupilumab.

[0373] Endpoints Primary endpoints of PRIME: Proportion of participants with an improvement (decrease) in Worst Itch Numeric Rating Scale (WI-NRS) of 4 or more from baseline to week 24.

[0374] Primary endpoint of PRIME2: Proportion of participants with an improvement (decrease) in Worst Itch Numeric Rating Scale (WI-NRS) of 4 or more from baseline to week 12.

[0375] Secondary endpoints: Proportion of participants who achieved an improvement of ≥4 in WI-NRS from baseline to week 24 (PRIME2 trial).

[0376] Proportion of participants with both a ≥4 improvement (decrease) in WI-NRS 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 improvement (decrease) in WI-NRS and IGA PN-S score of 0 or 1 on the same day.

[0377] Time to onset of effect on pruritus, as measured by the proportion of participants achieving an improvement (decrease) in WI-NRS of ≥4 from baseline during the 24-week treatment period.

[0378] Change from baseline in WI-NRS at week 24.

[0379] Change from baseline in WI-NRS at week 12.

[0380] Percent change from baseline in WI-NRS at week 24.

[0381] Percent change from baseline in WI-NRS at week 12.

[0382] Percent change from baseline in WI-NRS at week 4.

[0383] Percent change from baseline in WI-NRS at week 2.

[0384] Percent change from baseline in WI-NRS over time through week 24.

[0385] Proportion of participants with WI-NRS decline ≥ 4 at week 4.

[0386] Proportion of participants with WI-NRS decline ≥ 4 over time through week 24.

[0387] Onset of effect in change from baseline in WI-NRS by week 12 (initially p<0.05 difference from placebo in daily WI-NRS that remained significant at subsequent measures).

[0388] Proportion of participants with an Investigator Global Assessment of 0 or 1 score for PN stage (IGA PN-S) at Week 24.

[0389] Proportion of participants with an IGA PN-S score of 0 or 1 at Week 12.

[0390] Proportion of participants with an IGA PN-S score of 0 or 1 at week 8.

[0391] Proportion of participants with an IGA PN-S score of 0 or 1 at week 4.

[0392] Change from baseline in IGA PN-S score at week 24.

[0393] Change from baseline in IGA PN-S score at week 12.

[0394] Change from baseline in IGA PN-S score at week 8.

[0395] Change from baseline in IGA PN-S score at week 4.

[0396] Proportion of participants with an investigator global assessment of PN activity (IGA PN-A) score of 0 or 1 at Week 24.

[0397] Proportion of participants with an IGA PN-A score of 0 or 1 at Week 12.

[0398] Proportion of participants with an IGA PN-A score of 0 or 1 at week 8.

[0399] Proportion of participants with an IGA PN-A score of 0 or 1 at week 4.

[0400] Change from baseline to week 24 in HRQoL as measured by the Dermatology Life Quality Index (DLQI).

[0401] Change from baseline in HRQoL to week 12 as measured by the DLQI.

[0402] Proportion of participants who experienced a treatment-emergent adverse event (TEAE) or serious adverse event (SAE) from baseline to week 24.

[0403] Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time.

[0404] Test Design This study was a multicenter, 24-week, treatment-parallel, double-blind, randomized, placebo-controlled study to evaluate the use of dupilumab in patients with PN inadequately controlled with topical prescription therapy or when those therapies are inadvisable. The study evaluated the effect of dupilumab on improving pruritus, as well as its effect on PN lesions, patients' HRQoL, anxiety and depression, sleep quality and skin pain, and overall health status. As shown in Figure 1, this was a treatment-parallel study with two arms that were blinded / masked for participants and investigators.

[0405] Approximately 150 participants were randomized 1:1. This corresponds to approximately 75 participants randomly assigned to each intervention arm. Participants who met the inclusion and exclusion criteria were randomized (1:1) to one of the following investigational medicinal product (IMP) treatment arms: 300 mg dupilumab or placebo. Activity studies are shown in Figures 2A-2D.

[0406] Length of study period (per participant) Screening period (2-4 weeks); Randomized IMP intervention period (24 weeks); Follow-up period (12 weeks)

[0407] Study intervention Investigational Drug: Dupilumab 300 mg and matching placebo dupilumab 300 mg delivered in visually indistinguishable prefilled syringes.

[0408] Dupilumab: Formulation: Dupilumab 300 mg: 150 mg / mL dupilumab solution in a prefilled syringe (2 mL injection delivers 300 mg).

[0409] Route of administration: Subcutaneous (SC) injection.

[0410] Dosage regimen: An initial loading dose of 600 mg (two injections of 300 mg) on ​​day 1, followed by 300 mg every 2 weeks (q2w).

[0411] placebo: Formulation: Identical formulation to the active 300 mg formulation without dupilumab in a prefilled syringe (placebo delivered in a 2 mL injection).

[0412] Route of administration: SC injection.

[0413] Dosage regimen: Initial loading dose (2 injections) on day 1 followed by 1 injection q2w.

[0414] Non-investigational drugs Participants were required to apply a moisturizer (emollient) once or twice daily for at least 5 of the 7 consecutive days immediately preceding Day 1, and to continue through Week 36.

[0415] If participants were on a stable regimen of low- to medium-potency TCS or TCI at the screening visit, they could continue topical steroid application once daily from screening until week 24 without tapering. If certain lesions resolved, participants could stop applying steroid to those sites but were allowed to continue application to persistent lesions. If participants were on a stable regimen of high- or ultra-potency steroids, they should taper down to a medium-potency TCS and continue applying it daily from screening until week 24. No occlusions were allowed from screening until week 24.

[0416] Participants may be rescued with high or suprapotent TCS / TCI as needed throughout the study.

[0417] Inclusion criteria Participants were eligible for inclusion in the study only if all of the following criteria applied:

[0418] age Participants must be between 18 and 80 years old at the time of signing the informed consent.

[0419] Participant types and disease characteristics Patients with a clinical diagnosis of PN defined by all of the following:

[0420] Have been diagnosed by a dermatologist for at least 3 months prior to the screening visit.

[0421] Patients must have had a mean worst itch score of 7 or greater for the 7 days prior to Day 1, on a WI-NRS ranging from 0 to 10. (Baseline Pruritus NRS mean score for maximum itch intensity was determined based on the average of the daily NRS scores for maximum intensity (daily scores range from 0 to 10) for the 7 days immediately prior to randomization. A minimum of four daily scores out of 7 days are required to calculate a baseline mean score. For patients who did not report at least four daily scores in the 7 days immediately prior to the planned randomization date, randomization should be delayed until this requirement was met, but not beyond the maximum duration of the 28-day screening period.)

[0422] 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 on Day 1. (Patients were required to have bilateral symmetric lesions on all extremities. Lesions were required to be present on at least two body surface areas.)

[0423] A 2-week history of failure of intermediate- to very-potent TCS or if TCS is medically not advisable. (Failure was defined as the inability of patients to achieve and / or maintain remission and low disease activity (similar to an IGA PN-S score of ≤2 [≤19 nodules]) despite treatment with a daily regimen of intermediate- to very-potent TCS (± TCI as needed) applied for at least 14 days or the maximum duration recommended by the product prescribing information, whichever is shorter).

[0424] A stable dose of topical emollient (moisturizer) was applied once or twice daily for at least 5 of the 7 consecutive days immediately preceding Day 1.

[0425] Participants must be willing and able to complete a daily symptom eDiary for the duration of the study.

[0426] sex Participants could be male or female. Contraception use by women was consistent with local regulations regarding contraception methods for people participating in clinical trials. Female participants were eligible to participate if they were not pregnant or breastfeeding and at least one of the following conditions applied: WOCBP or not WOCBP agreed to use a contraception method during the study (minimum until 12 weeks after the last dose of study intervention). WOCBP must have had a negative high-sensitivity pregnancy test (urine or serum as required by local regulations) one day before the first dose of study intervention.

[0427] Informed consent be able to give signed informed consent. In countries where the legal age is greater than 18 years, the specific ICF must also be signed by the participant's legally authorized representative.

[0428] Exclusion criteria Participants were excluded from the study if any of the following criteria applied:

[0429] Medical conditions Presence of skin pathologies other than PN and mild AD that may interfere with the assessment of study results. Conditions include, but are not limited to: eschars, insect bites, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual excoriation, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, and bullous disease. (Note: Patients with mild active AD represent up to 10% of the atopic PN study population.)

[0430] PN is secondary to drugs (e.g., opioids, angiotensin-converting enzyme [ACE] inhibitors).

[0431] PN occurs secondary to medical conditions such as neurological or psychiatric disorders (eg, paresthesia, brachioradial pruritus, pruritus nervousis, obsessive-compulsive disorder, delusions of parasitosis, etc.).

[0432] Patients with documented moderate-to-severe AD severity within 6 months prior to the screening visit or a documented diagnosis of moderate-to-severe AD between the screening visit and the randomization visit (e.g., IGA AD score of 3 or 4, Eczema Area and Severity Index [EASI] ≥ 16, or Scoring of Atopic Dermatitis [SCORAD] ≥ 25).

[0433] Uncontrolled severe comorbidities that, in the opinion of the investigator, would have adversely affected 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 disease (e.g., class III or IV heart failure according to the New York Heart Association classification), patients with hepatobiliary disease (e.g., Child-Pugh Class B or C), patients with neurological disease (e.g., demyelinating disease), patients with active major autoimmune disease (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic disease.

[0434] Severe renal conditions (e.g., uremic and / or dialysis patients).

[0435] Participants with uncontrolled thyroid disease.

[0436] Patients with active TB or nontuberculous mycobacterial infection, or a history of incompletely treated TB, were excluded from the study unless the participant was adequately treated and, in the medical judgment of the investigator and / or infectious disease specialist, was satisfactorily demonstrated by experts to be eligible to initiate treatment with dupilumab. TB testing was performed by country, according to local guidelines, if required by regulatory authorities or ethics committees.

[0437] Diagnosed with active endoparasitic infection; suspected or at high risk for endoparasitic infection unless active infection is excluded by clinical and (if necessary) laboratory evaluation prior to randomization.

[0438] Active chronic or acute infection (excluding HIV infection) requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks prior to the screening visit or during the screening period.

[0439] Known or suspected immune deficiency, as determined by the investigator, includes, for example, a history of invasive opportunistic infection (e.g., TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumococcosis, aspergillosis) despite resolution of infection, or recurrent infections of unusual frequency or prolonged duration, indicating an immunocompromised state.

[0440] Active malignancy or history of malignancy within 5 years prior to the baseline visit (excluding completely treated intraepithelial carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin).

[0441] History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any excipients.

[0442] Other medical or psychological conditions, including relevant laboratory abnormalities at screening, that, in the opinion of the Investigator, suggested a new and / or poorly understood disease, presented an unreasonable risk to the study patient as a result of participation in this clinical trial, made the patient's participation unreliable, or may have interfered with the study evaluations.

[0443] History of substance and / or alcohol abuse.

[0444] Major surgical procedures planned during the patient's participation in the study.

[0445] Prior / concomitant therapy Exposure to another systemic or local investigational drug (monoclonal antibodies and small molecules) within a period of time prior to Visit 1 (Screening) as follows: less than 6 months or less than 5 PK half-lives, whichever is longer, for investigational monoclonal antibodies, and less than 30 days or less than 5 PK half-lives, whichever is longer, for investigational small molecules.

[0446] Have used any of the following procedures within 4 weeks prior to the screening visit: systemic immunosuppressants / immunomodulators (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon gamma, 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.

[0447] Initiated use of the following treatments 3 months prior to the screening visit, or changed the dose of the following treatments, or were expected to change the dose of the following treatments throughout 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.

[0448] Prior treatment with a biologic within the following time frames: any cell depleting 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: 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer.

[0449] Initiation of treatment with prescription moisturizers or moisturizers containing additives such as ceramides, hyaluronic acid, urea, menthol, polidocanol, or filaggrin degradation products during the screening period (patients may continue using a stable dose of such moisturizers if started prior to the screening visit).

[0450] Initiation of treatment with a TCS / TCI (any potency) during the screening period or treatment with a high- or ultra-potency TCS / TCI during the screening period.

[0451] For participants who were on a stable regimen of TCS / TCI (maintaining the same medication and dose for 2 weeks prior to the screening visit) at the screening visit: application of TCS / TCI on <6 days in the 7 days immediately prior to randomization or application of an incorrect potency of TCS / TCI within the 7 days prior to Day 1.

[0452] Treatment with live (attenuated) vaccines within 4 weeks prior to the screening visit. (Note: For patients who have been vaccinated with live attenuated vaccines planned during the course of the study (based on national vaccination schedule / local guidelines), it was decided after consultation with the physician whether administration of the vaccine could be postponed until after the end of the study or before the start of the study without compromising the patient's health: patients who can safely postpone administration of live (attenuated) vaccines are eligible to enroll in the study or patients who have been vaccinated only after a gap of 4 weeks after vaccine administration can be enrolled in the study).

[0453] Planned or anticipated use of prohibited medications and procedures during screening and treatment periods.

[0454] Pre-clinical / concurrent clinical trial experience participation in a previous dupilumab clinical trial; previously treated with dupilumab; prior use of a biologic agent for PN.

[0455] Diagnostic evaluation and positive HIV serology at screening for participants with no history of HIV infection prior to the screening visit.

[0456] Participants with a history of HIV infection who had a CD4+ count ≤300 cells / μL and / or detectable HIV viral load at screening.

[0457] Participants with any of the following results at screening: positive (or indeterminate) HBs Ag, positive total HBc Ab confirmed by positive HBV DNA, or positive HCV Ab confirmed by positive HCV RNA.

[0458] Other Exclusions An individual held in an institution because of regulation or legal order; a detainee who is legally held in an institution.

[0459] Specific country-related regulations that prevent subjects from participating in the study.

[0460] Patients who are deemed unsuitable for participation by the investigator for any reason Participants who are potentially at risk for: (including medical or clinical conditions) or non-compliance with study procedures.

[0461] Participants may be employees of a clinical trial site or other individuals directly involved in the conduct of the study, or the immediate family members of such individuals.

[0462] Participants may be employees of a clinical trial site or other individuals directly involved in the conduct of the study, or the immediate family members of such individuals.

[0463] Sensitivity to any of the study interventions or components thereof, or to any drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.

[0464] Study intervention A study intervention was defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol. A summary of study interventions administered is provided in Table 7 below.

[0465] [Table 25]

[0466] The investigator or representative trained the patient (or caregiver) how to prepare and inject the IMP at Visit 2. He / she injected the first of two injections. The participant (or caregiver) administered the second injection under the supervision of the investigator or representative. Patients were also trained by on-site staff to recognize potential signs and symptoms of a hypersensitivity reaction, to self-monitor at home for at least 30 minutes after injection (or longer per country-specific or region-specific requirements). In case of hypersensitivity symptoms, patients were advised to contact their healthcare provider / emergency.

[0467] When participants arrived at the study clinic, IMP was administered after clinical procedures and blood draws. Patients were monitored for at least 30 minutes.

[0468] Between protocol-scheduled site visits, participants were able to self-inject the IMP at home. Participants who preferred to have a healthcare professional administer the IMP could choose to have the injection administered at home by a nurse or at the study site.

[0469] Non-investigational drugs Beginning at the screening visit, participants were instructed to use a daily moisturizer if it did not contain compounds with known anti-itch effects (e.g., menthol, polidocanol, pramoxine, lidocaine, prilocaine, capsaicin, naltrexone, N-palmitoylethanolamine, etc.) During the course of the study, participants were not permitted to change emollients or moisturizers or apply products for itch relief.

[0470] Participants were required to apply a moisturizer (emollient) once or twice daily for at least 5 of the 7 consecutive days immediately preceding Day 1 and to continue through Week 36. All types of moisturizers were permitted, but patients could not start new treatment with prescription moisturizers or over-the-counter moisturizers containing additives during the screening or intervention periods. Patients could continue using a stable dose of such a moisturizer if started before the screening visit.

[0471] If participants were on a stable regimen of low- to medium-potency TCS or TCI at the screening visit, they could continue topical steroid application once daily without tapering from screening to week 24. If certain lesions resolved, participants could stop applying steroids to those sites, but were allowed to continue application to persistent lesions. If participants were on a stable regimen of high- or ultra-potency steroids, they were tapered to medium-potency TCS and should continue applying daily from screening to week 24. A stable regimen of TCS was to maintain the same agent (low- to medium-potency TCS) and the same treatment frequency (once or twice daily) used from 2 weeks prior to screening. A stable regimen of TCI was to maintain the same agent and treatment frequency (once or twice daily) of TCI used from 2 weeks prior to screening. If a participant's previous regimen was once daily application, they would maintain daily application during the study, and for participants who were twice daily before screening, they would maintain their twice daily regimen during the study. If certain lesions resolved, participants could stop applying steroid to those sites, but were allowed to continue application to persistent lesions. No occlusions were allowed from screening until week 24.

[0472] Patients were recommended to use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency and hydrocortisone 1% cream for low potency. If rescue with TCS was required, patients were recommended to use either betamethasone dipropionate 0.05% optimized ointment for high-potency TCS or clobetasol propionate 0.05% cream for ultra-potency TCS. If patients had tolerance problems with any of these steroids or if they were not commercially available in some countries, patients could substitute a product of the same potency from a list provided by the sponsor.

[0473] In areas treated with TCS, moisturizer had to be applied once a day only at times when TCS was not applied (i.e. moisturizer and TCS should not be used on the same area at the same time during the day). For example, if TCS was applied in the evening, moisturizer was not used in the evening on TCS-treated areas, but was applied to those areas in the morning. In areas not treated with TCS, moisturizer was applied twice a day (morning and evening).

[0474] Storage and handling The investigator or designee must ensure that proper temperature conditions were maintained during transport for all study interventions received, and any discrepancies were reported and resolved prior to use of the study intervention.

[0475] Only participants enrolled in the study may receive the study intervention, and only authorized site staff may 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 limited access to the investigator and authorized site staff.

[0476] The investigator, site or head of clinical facility (if applicable) was responsible for accountability, coordination and record-keeping of the study interventions (i.e., receipt, reconciliation, and final disposition records).

[0477] Randomization and blinding All participants were centrally assigned to the randomized study intervention using automated response technology (IRT). Participants were randomized in a 1:1 ratio to the treatment arms listed in Table 7.

[0478] Randomization was stratified by the following factors: documented atopic history (atopic or nonatopic) (atopic: patients with a physician-documented history of an atopic comorbidity defined as AD, allergic rhinitis / rhinoconjunctivitis, asthma, or food allergy, as determined by the investigator, or with a current diagnosis of at least one of these atopic comorbidities, and nonatopic: patients with no physician-documented history of an atopic comorbidity defined as AD, allergic rhinitis / rhinoconjunctivitis, asthma, or food allergy, as determined by the investigator, and without a current diagnosis of at least one of such atopic comorbidities); stable use of TCS / TCI (yes or no); and country / region code.

[0479] Randomized participants were defined as participants who were assigned to the randomized intervention, regardless of whether the intervention kit was used (i.e., participants enrolled by the IRT). Participants could not be randomized more than once in the study.

[0480] Blinding method Dupilumab 300 mg and matching placebo dupilumab 300 mg were delivered in identically matched, visually indistinguishable 2 mL prefilled syringes. The syringes and boxes were labeled with the treatment kit number.

[0481] Study intervention compliance The investigator or his / her designee must ensure that the IMP was administered to each participant according to the labeling instructions.

[0482] Intervention units were returned by participants at each visit. The investigator counted the number of remaining kits / prefilled syringes and recorded them on the IMP Accountability and Inventory Form. The investigator or his / her designee recorded medication information on the appropriate page of the eCRF. Participants' adherence to the study intervention was assessed at each visit. Compliance was assessed by counting returned kits / prefilled syringes. Deviations from the prescribed medication regimen were recorded in the eCRF.

[0483] Combination therapy Any medications or vaccines (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) that participants were receiving at the time of enrollment or during the study had to be recorded, along with the reason for use; dates of administration, including start and end dates; and dosage information, including dose and frequency.

[0484] Concomitant use of nonsedating antihistamines was permitted throughout the study, except for treatment of AD or PN, but dose changes of nonsedating antihistamines were not permitted during both weeks 11-12 and 23-24.

[0485] Concomitant use of the following therapies was prohibited throughout the study. Study treatment had to be discontinued in participants receiving these therapies: systemic immunosuppressants / immunomodulators (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchicine, etc.); other monoclonal antibodies (which are biological modifiers); phototherapy, including tanning beds; naltrexone or other opioid antagonists; and gabapentin, pregabalin, and thalidomide.

[0486] Concomitant use of the following therapies was prohibited unless the dose had been stable for at least 3 months prior to screening, but participants receiving the following did 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 needed to remain stable (which may be reduced or discontinued if medically indicated) but should not be initiated or increased throughout the study.

[0487] Concomitant use of the following treatments was also prohibited throughout the study, but participants receiving the following did not need to discontinue study treatment: intralesional corticosteroid injections and cryotherapy; sedating antihistamines; non-sedating antihistamines used specifically to treat pruritus secondary to AD or PN.

[0488] Rescue medication The following rescue medications may be used: dermatological preparations of high or extra potency TCS and TCI.

[0489] If medically necessary (i.e., to control intolerable PN symptoms), rescue PN treatment may be provided to study patients at the investigator's discretion.

[0490] The use of rescue medication was permitted at any time during the study, but rescue medication use should be delayed for at least 14 days after the start of study treatment, if possible. The date and time of rescue medication administration, as well as the name and dosing regimen of the rescue medication, were recorded in the eCRF.

[0491] For the purposes of efficacy response analyses, rescue was classified using a pre-specified algorithm (SAP details). In addition, rescue was adjudicated by conducting a blinded review of all post-baseline medications to adjudicate rescue treatment based on medical judgment. Patients who received rescue treatment according to this adjudication during the study were considered treatment failures.

[0492] Discontinuation of study intervention In rare instances, it may have been necessary for a participant to permanently discontinue the study intervention. If the study intervention was permanently discontinued, the participant would remain in the study to be evaluated for safety.

[0493] Participants could discontinue treatment with the IMP at any time, regardless of reason, if they decided to do so or this could have been the investigator's decision. Every effort was made to document the reason for discontinuation of treatment, which should be documented in the eCRF.

[0494] Participants had to be permanently withdrawn from the study treatment for the following reasons: at their own request or at the request of a legally authorized representative (legally authorized representative means an individual or judicial or other institution authorized under applicable law to consent on behalf of the potential participant to the procedures involved in the study); if, in the investigator's opinion, continuation in the study would have been detrimental to the participant's health; at the specific request of the sponsor; if being treated with certain prohibited substances; if more than two consecutive IMP doses were missed; at the discretion of the investigator or sponsor in case of deviations from the protocol; a destroyed code at the request of the investigator; pregnancy; an anaphylactic or generalized allergic reaction related to IMP and requiring treatment; a diagnosis of malignancy during the study, except for intraepithelial carcinoma of the cervix, or squamous cell or basal cell carcinoma of the skin; any opportunistic infection or other infection whose nature or course may suggest an immunocompromised state; a serum alanine aminotransferase (ALT) >3 upper limit of normal (ULN) and total bilirubin >2 ULN; or serum ALT >5 ULN if baseline ALT ≤ 2 ULN, or ALT >8 ULN if baseline ALT >2 ULN.

[0495] Efficacy evaluation All screening assessments were required to be completed and reviewed to ensure potential participants met all eligibility criteria. Investigators maintained a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as appropriate.

[0496] Patient-reported outcome questionnaires, including the NRS, were completed by participants before the consultation and / or clinical trial in a quiet place. The questionnaires were completed by the participants themselves, independently of the physician, study nurse or any other medical personnel, and without help from friends or relatives.

[0497] Worst Itch Numeric Rating Scale The Worst Itch Numeric Rating Scale (WI-NRS) is a PRO consisting of a single item rated on a scale of 0 ("no itch") to 10 ("worst itch imaginable"). Participants are asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The WI-NRS is shown in Figure 3.

[0498] Investigator's Global Assessment of Prurigo Nodularis Investigator Global Assessment for 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 (clear) to 4 (severe) and the stage of the disease (IGA PN-S) using a 5-point scale ranging from 0 (clear) to 4 (severe); IGA PN is shown in Figure 4.

[0499] Prurigo activity score The Prurigo Activity Score (PAS) is a ClinRO measurement. The original PAS questionnaire version 0.9 consists of seven items developed by clinicians with expertise in PN (Poelking 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 PAS items assess prurigo lesions with respect to: 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).

[0500] Other items assess activity in terms of representative body area and exact lesion count (item 5), the percentage of prurigo lesions with an abrasion / eschar on top (reflecting active scratching; item 7a) and the percentage of prurigo lesions that are healed (reflecting healing of chronic prurigo; item 7b).

[0501] A 5-item abbreviated version of the PAS was used in this study. Notably, items 3 (lesion distribution) and 6 (lesion monitoring) from the original PAS were deleted, and response options were slightly modified and refined. This assessment tool is shown in Figure 5. Clinicians completed the screening / baseline version at screening and baseline visits and follow-up versions of the modified PAS at other visits.

[0502] Dermatology Quality of Life Index The Dermatology Life Quality Index (DLQI) is a PRO 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 instrument contains 10 items assessing the impact of skin disease on the patient's HRQoL over the previous week. Items cover symptoms, leisure activities, work / school or holiday time, relationships including intimacy, side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials (Chernyshov PV. The evolution of quality of life assessment and use in dermatology. Dermatology. 2019;235(3):167-74). The response scale is a 4-point Likert scale (0 = "not at all" and 3 = "very much") for 9 items. The remaining item, regarding work / exam, asks if work / exam was interfered with and then (if "no") how much of a problem the skin condition caused at work / exam. Items are rated on a 3-point Likert scale ("not at all" to "a lot"). Overall scoring ranges from 0 to 30, with higher scores indicating poorer HRQoL.

[0503] Efficacy data were collected via an electronic device. An electronic diary was used for daily recording of participants' responses to the WI-NRS, Pain-NRS, and Sleep-NRS questionnaires. The device was distributed at the screening visit (Visit 1) containing instructions for use. Participants were instructed on the use of the device. Recorded information was downloaded from the device daily. At the end-of-study (EOS) visit, the electronic diary was downloaded and returned to the site.

[0504] Participants completed the DLQI, HADS, EQ-5 D-5 L, PGIC, PGIS, and missed school / workplace questionnaires during the site visit on a tablet provided at the site. This device was kept on-site for the duration of the study.

[0505] Numerical Rating Scales for Pain and Sleep Participants were asked to rate their worst skin pain in the past 24 hours using a 0–10 numeric rating scale (NRS), with 0 = no pain to 10 = worst possible pain.

[0506] Additionally, participants were asked to rate the quality of their past night's sleep upon awakening using a 0 to 10 NRS, with 0 = worst possible sleep and 10 = best possible sleep.

[0507] Participants completed the Cutaneous Pain NRS and Sleep Quality NRS once daily.

[0508] Hospital Anxiety and Depression Scale The Hospital Anxiety and Depression Scale (HADS) is a PRO instrument for screening anxiety and depression in non-psychiatric populations; repeated administration also provides information about changes in the patient's emotional 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. Possible scores range from 0 to 21 for each subscale. The following cut-off scores are recommended for both subscales: 0-7: normal; 8-10: borderline abnormal (borderline case); 11-21: abnormal.

[0509] Patient's global impression of disease progression and patient's global impression of disease severity The Patient Global Impression of Disease Change (PGIC) is a one-item questionnaire that asks patients to provide a global self-assessment of the overall change in their PN on a 7-point scale compared to just before they started the study injections. Response options are as follows: 0 = "much better," 1 = "slightly better," 2 = "slightly better," 3 = "no change," 4 = "slightly worse," 5 = "slightly worse," and 6 = "very worse."

[0510] The Patient Global Impression of Severity (PGIS) is a one-item questionnaire that asks patients to provide an overall self-assessment of disease severity on a 4-point scale for the past week. Response options are: 1 = "none", 2 = "mild", 3 = "moderate", 4 = "severe".

[0511] Euroqol-Five Dimensions Questionnaire The Euroqol-5 dimensions (EQ-5D) is a standardized PRO measure of health status developed by the EuroQol Group to provide a simple and generic measure of health 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). Qual Life Res. 2011;20(10):1727-36). The EQ-5 D consists of two parts: a description system and an EQ visual analog scale (VAS). The EQ-5D description system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels of perceived problems: "no problems", "mild problems", "moderate problems", "severe problems", and "disabling". Respondents are asked to indicate their health status by checking a box (or putting a cross) against the most appropriate statement for each of the five dimensions. This results in a single-digit number representing the level of that dimension. The five dimensions can be combined into a five-digit number that describes the respondent's health status. The EQ VAS records the respondent's self-assessed health status on a vertical VAS, where the endpoints are labeled "best possible health status (100)" and "worst possible health status (0)." This information can be used as a quantitative measure of health outcomes as judged by individual respondents.

[0512] Days not attending school / work Participants employed or enrolled in a school were asked to report the number of sickness absences / absences from school since the last study assessment.

[0513] photo shoot Participants at selected centers who decided to take part in this substudy had to give separate consent. One or several lesions were photographed at baseline. The same lesions were photographed at subsequent visits to assess their progression.

[0514] Safety assessment Physical Examination A complete physical examination included, at a minimum, evaluation of the skin (total skin exam), nasal passages, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. Investigators paid particular attention to clinical signs related to previous serious illness. New findings or worsening of previous findings were reported as new AEs.

[0515] Vital signs Vital signs were measured in semi-supine or sitting position after 5 min of rest and included temperature, SBP and DBP, and pulse and respiratory rate. Blood pressure and pulse measurements were assessed using the same arm with a fully automated device. Manual techniques were used only if the automated device was not available. Weight (kg) was measured at Screening (Visit 1), EOT and EOS visits. Height was measured at the Screening visit (Visit 1). Height and weight were measured in indoor clothing but without shoes.

[0516] electro-cardiogram 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 a 10-minute rest in the supine position.

[0517] PRIME / EFC 16459 Results As shown in Figure 6, PRIME / EFC 16459 is one of two Phase 3 studies. PRIME was a global study with N=151 patients, 33% / 50 from Asia, 27% / 41 from Latin America, 25% / 38 from Western Europe, and 15% / 22 from Eastern Europe. The baseline disease characteristics of patients in the PRIME / EFC 16459 study are shown in Figure 14. Total enrolled patients had a mean (SD) WI-NRS of 8.5 (1.0) at baseline.

[0518] The primary endpoint was met with clinical and statistical significance. As shown in Figure 8A, at week 24, the proportion of participants who achieved a 4-point or greater reduction in WI-NRS (0-10) with dupilumab was 45 (60.0%) compared with 14 (18.4%) with placebo, p<0.0001. Thus, more than three times as many dupilumab-treated participants experienced a clinically significant reduction in itch from baseline.

[0519] As shown in Figure 7A, the primary endpoint and all multiplicity-adjusted secondary endpoints met statistical significance including WI-NRS >= 4, IGA PN-S score 0 or 1, WI-NRS >= 4 and IGA PN-S score 0 or 1, WI-NRS (itch) percent change from baseline (Figure 11A), DLQI change from baseline, Skin Pain-NRS change from baseline, and HADS (all at week 24). Compared to PRIME2, PRIME did not include week 12 endpoints or sleep-NRS in the strata. As shown in Figure 9A, the proportion of participants who reached an IGA PN-S score of 0 or 1 with dupilumab at week 24 was 48.0% compared to 18.4% with placebo (p=0.0004). Thus, nearly three times as many dupilumab-treated participants achieved clear or almost clear skin at week 24, the key secondary endpoint. As shown in Figure 10A, the proportion of participants who achieved an improvement (decrease) of ≥4 in WI-NRS from baseline to week 24 and an IGA PN-S score of 0 or 1 at week 24 was 38.7% for dupilumab and 9.2% for placebo (p<0.0001).

[0520] Analyses of itch and lesion responders at week 12 also met nominal statistical significance. Non-multiplicity adjusted secondary endpoints including the proportion of responders achieving a 4-point or greater 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.

[0521] Additionally, dupilumab treatment compared to placebo reduced the time to first use of rescue and / or prohibited medications or procedures, as shown in Figure 12 A. Overall, dupilumab treatment reduced the use of rescue / prohibited medications throughout the 24-week intervention period.

[0522] Notably, treatment with dupilumab differentiated from placebo as early as week 4 in the itch responder analysis, 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 discontinued.

[0523] Dupilumab demonstrated a tolerable safety profile in patients with PN with no new safety signals that were consistent with the known safety profile of dupilumab observed in approved populations and indications.

[0524] PRIME2 / EFC 16460 results As shown in Figure 6, PRIME2 / EFC 16460 was one of two phase 3 trials that included 78 participants for treatment with dupilumab and 82 participants for treatment with placebo and was conducted in the United States. 46% of patients enrolled in the study had at least one coexisting type 2 inflammatory condition. The baseline disease characteristics of patients in the PRIME2 / EFC 16460 study are shown in Figure 14. Total enrolled patients had a mean (SD) WI-NRS of 8.5 (1.0) at baseline. Almost all patients in the study had severe pruritus, and all patients had moderate to severe disease based on the number of lesions. 62% of enrolled patients had 20 to 100 nodules, and 38% had more than 100 nodules.

[0525] The primary endpoint was met with clinical and statistical significance. As shown in Figure 8B, the proportion of participants who achieved a 4-point or greater reduction in the Worst Itch Numeric Rating Scale, WI-NRS (0-10), at week 12 with placebo was 18 (22.0%) and with dupilumab was 29 (37.2%), p=0.0216.

[0526] All key secondary endpoints were met with clinical and statistical significance. As shown in Figure 8B, the percentage of participants who achieved a WI-NRS reduction of 4 points or more (0-10) at week 24 with placebo was 19.5% compared to 57.7% with dupilumab (p<0.0001). Thus, at week 24, nearly three times as many dupilumab-treated participants experienced a clinically significant reduction in itch from baseline. As shown in Figure 9B, the percentage of participants who achieved an Investigator Global Assessment PN Stage (IGA PN-S) score of 0 or 1 (0-4) at week 24 with placebo was 15.9% compared to 44.9% with dupilumab (p<0.0001). Thus, at week 24, nearly three times as many dupilumab-treated participants achieved clear or almost clear skin. As shown in FIG. 10B, the percentage of participants with a WI-NRS improvement (decrease) from baseline of 4 or greater at week 24 and a concomitant IGA PN-S score of 0 or 1 at week 24 with placebo was 8.5% compared with 32.1% with dupilumab (p=0.0001).

[0527] As shown in Figure 7B, several multiplicity-adjusted secondary endpoints and other efficacy endpoints were also met, including the proportion of responders who achieved an IGA PN-S score of 0 or 1 at week 12, WI-NRS %mean delta from baseline at week 24 (Figure 11B), DLQI, and cutaneous pain-NRS. Ranking started second to last (sleep-NRS not significant; HADS nominal).

[0528] Additionally, as shown in FIG. 12B, dupilumab treatment compared to placebo reduced the time to rescue and / or first use of a prohibited medication or procedure.

[0529] Mild active atopic dermatitis accounted for 9% of the atopic PN study population and 4.5% of the total study population.

[0530] 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 approved populations and indications. No new safety signals or malignancies were reported with dupilumab.

[0531] Pharmacokinetics (PK) and ADA were consistent with the known profile of dupilumab.

[0532] Conclusions of PRIME / EFC 16459 and PRIME2 / EFC 16460 Overall, dupilumab demonstrated clinically and statistically significant efficacy in patients with prurigo nodularis (PN) who were inadequately controlled with topical prescription therapies or for whom these therapies are not advisable. Dupilumab also demonstrated replication of efficacy between the PRIME and PRIME2 trials. Dupilumab was effective and safe in this population and demonstrated a tolerable safety profile.

[0533] Patients who received approximately three times as much dupilumab experienced significantly less pruritus and skin lesions compared with placebo at week 24. Dupilumab is the first and only biologic to demonstrate positive Phase 3 results in prurigo nodularis.

[0534] Dupilumab significantly improved itch and skin clearance at week 12, and nearly tripled both at week 24. A significant reduction in itch and skin lesions was observed, which was important considering that nearly all patients had severe itch and nearly 40% had more than 100 nodules covering their bodies prior to enrollment.

[0535] Significant and sustained treatment benefits with dupilumab were observed at 24 weeks across all disease components, including itch and lesion severity, regardless of baseline atopic status. Additionally, dupilumab improved quality of life and mental health. Dupilumab-treated patients experienced significantly greater improvements in measures of health-related quality of life and cutaneous pain at 24 weeks. Dupilumab-treated patients experienced significantly greater improvements in measures of health-related quality of life, cutaneous pain, and symptoms of anxiety and depression.

[0536] Dupilumab treatment reduced the use of rescue / ban-on therapies throughout the 24-week intervention period.

[0537] Nearly three times as many dupilumab patients (60% and 58%) experienced a clinically meaningful reduction in itch from baseline at 24 weeks compared with 18% and 20% on placebo, the primary endpoint of PRIME.

[0538] Forty-four percent and 37% of dupilumab patients experienced a clinically significant reduction in itch from baseline at 12 weeks, compared with 16% and 22% on placebo, the primary endpoint of PRIME2.

[0539] More than twice as many dupilumab patients (48% and 45%) achieved clear or almost clear skin at 24 weeks compared with 18% and 16% with placebo.

[0540] At 24 weeks, more than three times as many dupilumab patients (39% and 32%) experienced both itch and a clinically meaningful reduction in clear or almost clear skin compared with 9% and 9% of placebo patients.

[0541] The US Food and Drug Administration has approved dupilumab for the treatment of PN, stating: "DUPIXENT is indicated for the treatment of adult patients with prurigo nodularis (PN). The recommended dosage for adult patients is 300 mg every other week (Q2W) following an initial dose of 600 mg (two 300 mg injections)."

[0542] Example 2: Validation of the Prurigo Nodularis (PN) Worst Itch Numeric Rating Scale (WI-NRS) from a Clinical Trial of Dupilumab in Adults with PN Materials and Methods: The content validity of the WI-NRS was assessed by qualitative interviews with adult PN patients (N=20; age: 19-72 years). The measurement properties and within-patient clinically meaningful change (responder definition) of the WI-NRS in PN patients were evaluated using pooled blinded data from a phase 3 study (N=311).

[0543] result: Patients found the questions, recall period, and response scales easy to understand and relevant. Adequate test-retest reliability was observed between screening and baseline (intraclass correlation coefficient = 0.72, Patient Global Impression of Severity (PGIS) was used to define stable patients). Convergent and divergent validity was supported by moderate to strong correlations with other conceptually related scales (r = 0.34-0.73) and weaker correlations with less related scales (r = 0.06-0.32), respectively. The WI-NRS was sensitive to change, as demonstrated by differences in change from baseline between groups (PGIS change and PGI per change (PGIC); P < 0.001). Using a fixation-based approach with PGIS and PGIC, the responder definition threshold for improvement was 4 points (range: 3.0-4.5).

[0544] Conclusion: The WI-NRS is a fit-for-purpose instrument to support efficacy endpoints measuring pruritus intensity in adults with uncontrolled PN with topical therapy.

Claims

1. 1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in treating a subject with prurigo nodularis, comprising: the IL-4R antagonist is a fully human IgG4 antibody comprising 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; A pharmaceutical composition wherein an IL-4R antagonist is administered to said subject at an initial dose of about 600 mg, followed by one or more maintenance doses of about 300 mg, each maintenance dose being administered every other week (q2w).

2. 2. The pharmaceutical composition of claim 1, wherein the antibody comprises a heavy chain variable region (HCVR) amino acid sequence comprising SEQ ID NO: 1 and a light chain variable region (LCVR) amino acid sequence of SEQ ID NO:

2.

3. 2. The pharmaceutical composition of claim 1, wherein the antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO:9 and a light chain sequence comprising the amino acid sequence of SEQ ID NO:

10.

4. 2. The pharmaceutical composition of claim 1, wherein the antibody is dupilumab.

5. The pharmaceutical composition of claim 1 , wherein the subject is an adult.

6. 10. The pharmaceutical composition of claim 1, wherein the subject has prurigo nodularis that is not adequately controlled by topical therapies or for which such therapies are not advisable.

7. 10. The pharmaceutical composition of claim 1, wherein the subject has prurigo nodularis that is not adequately controlled by topical prescription therapies or for which such therapies are not advisable.

8. 10. The pharmaceutical composition of claim 1, wherein the subject does not respond adequately to treatment with topical corticosteroids (TCS).

9. The pharmaceutical composition of claim 1, wherein treatment with TCS is not recommended.

10. administering the antibody A 4-point or greater reduction in the Worst Itch Numerical Rating Scale (WI-NRS) from baseline to week 24 of treatment; or Improvement in Investigator's Global Assessment of Prurigo Nodularis Stage (IGA PN-S) score to an IGA PN-S score of 0 or 1 at 24 weeks of treatment The pharmaceutical composition of claim 1 ,

11. 11. The pharmaceutical composition of claim 10, wherein the reduction in WI-NRS score is a reduction of 4, 5, 6, 7, 8, 9, or 10 points.

12. 11. The pharmaceutical composition of claim 10, wherein the improvement in IGA PN-S score is a decrease of 1, 2, 3, 4, or 5 points.

13. The object is Having a WI-NRS score of 7 or greater at baseline; and / or Have a minimum of 20 nodular prurigo lesions at baseline; and / or have an IGA PN-S score of 3 or 4 at baseline; The pharmaceutical composition of claim 1.

14. 14. The pharmaceutical composition of claim 13, wherein the prurigo nodular lesions are present on at least two body surface areas on both legs, and / or both arms, and / or the trunk.

15. 10. The pharmaceutical composition of claim 1, wherein administration of the antibody results in an improvement in one or more patient-reported outcomes (PROs) selected from the group consisting of Worst Itch Numerical Rating Scale (WI-NRS) score, Dermatology Life Quality Index (DLQI) score, Pain Numerical Scale score, Sleep Numerical Scale score, Hospital Anxiety and Depression Scale score, Patient Global Impression of Change (PGIC) score, Patient Global Impression of Severity (PGIS) score, and Eurocor-5 Dimension (EQ-5D) score.

16. 10. The pharmaceutical composition of claim 1, wherein the antibody is contained in a reusable or disposable pen, autoinjector pen, or syringe.

17. 17. The pharmaceutical composition of claim 16, wherein the antibody is contained in a syringe, and the syringe is a prefilled syringe.

18. The pharmaceutical composition of claim 1 , wherein the antibody is administered subcutaneously.

19. 1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in treating a subject with prurigo nodularis that is not adequately controlled by topical therapy or for which such therapy is inadvisable, comprising: The subject is an adult, the IL-4R antagonist is dupilumab; A pharmaceutical composition wherein an IL-4R antagonist is administered to said subject at an initial dose of about 600 mg, followed by one or more maintenance doses of about 300 mg, each maintenance dose being administered every other week (q2w).

20. The prurigo nodularis does not respond adequately to topical prescription therapies or if such therapies are not advisable.

20. The pharmaceutical composition of claim 19, wherein

21. 20. The pharmaceutical composition of claim 19, wherein the subject does not respond adequately to treatment with topical corticosteroids (TCS).

22. 20. The pharmaceutical composition of claim 19, wherein treatment with TCS is not recommended.

23. said administering A 4-point or greater reduction in the Worst Itch Numerical Rating Scale (WI-NRS) from baseline to week 24 of treatment; or Improvement in Investigator's Global Assessment of Prurigo Nodularis Stage (IGA PN-S) score to an IGA PN-S score of 0 or 1 at 24 weeks of treatment 20. The pharmaceutical composition of claim 19, wherein

24. 24. The pharmaceutical composition of claim 23, wherein the reduction in WI-NRS score is a reduction of 4, 5, 6, 7, 8, 9, or 10 points.

25. 24. The pharmaceutical composition of claim 23, wherein the improvement in IGA PN-S score is a decrease of 1, 2, 3, 4, or 5 points.

26. The object is Having a WI-NRS score of 7 or greater at baseline; and / or Have a minimum of 20 nodular prurigo lesions at baseline; and / or have an IGA PN-S score of 3 or 4 at baseline; 20. The pharmaceutical composition of claim 19.

27. 27. The pharmaceutical composition of claim 26, wherein the prurigo nodular lesions are present on at least two body surface areas on both legs, and / or both arms, and / or the trunk.

28. 20. The pharmaceutical composition of claim 19, wherein the IL-4R antagonist is contained in a reusable or disposable pen, autoinjector pen, or syringe.

29. 29. The pharmaceutical composition of claim 28, wherein the IL-4R antagonist is contained in a syringe, and the syringe is a prefilled syringe.

30. 20. The pharmaceutical composition of claim 19, wherein the IL-4R antagonist is administered subcutaneously.

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