Methods for treating chronic spontaneous urticaria by administering an IL-4R antagonist

Abstract

A method for treating or preventing chronic spontaneous urticaria in a subject is provided, comprising administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or an antigen-binding fragment thereof.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 225,716, filed July 26, 2021, U.S. Provisional Application No. 63 / 240,734, filed September 3, 2021, U.S. Provisional Application No. 63 / 313,041, filed February 23, 2022, U.S. Provisional Application No. 63 / 353,654, filed June 20, 2022, and EP Priority Application No. 22315049.1, filed March 4, 2022, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] FIELD OF THEINVENTION The present disclosure relates to the treatment and / or prevention of chronic spontaneous urticaria (CSU) 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 CSU in a subject in need thereof. [Background technology]

[0003] Chronic spontaneous urticaria, formerly known as chronic idiopathic urticaria and chronic urticaria, is one of the most frequent skin diseases. At any given time, 0.5% to 1% of the population is affected by the disease. (See Non-Patent Document 1). Chronic spontaneous urticaria is characterized by the spontaneous appearance of pruritic wheals (urticaria) and sudden skin reactions that last for more than 6 weeks without an identified cause and may be accompanied by angioedema. All age groups can be affected, but the peak incidence is between 20 and 40 years of age. The duration of the disease is generally several years, but tends to be longer in more severe cases, those with angioedema, and is accompanied by physical urticaria or positive autoserum skin tests (autoreactivity). Chronic spontaneous urticaria has a significant negative impact on quality of life, with sleep deprivation and psychiatric comorbidities frequently occurring. It also has a significant impact on society in terms of direct and indirect medical costs, as well as impaired performance at work and in personal life (ibid.).

[0004] Patients with chronic spontaneous urticaria, with or without angioedema, experience debilitating urticaria and pruritus secondary to dysregulation of mast cells and basophils. Degranulation of these cell types by activation of Fc gamma receptors (FcεRI) via agonistic autoantibodies or antigen-crosslinked cell surface-bound immunoglobulin E (IgE) releases histamine and other inflammatory mediators, causing local tissue edema and pruritus. Many symptoms of urticaria are mediated primarily by the action of histamine (a mast cell mediator) on H1-receptors, and treatment with H1-antihistamines (H1-AH) is the mainstay of treatment. (See Non-Patent Document 2). Approximately 50% of patients achieve symptom control with conventional H1-AH therapy. (See Non-Patent Document 3). Even with increased doses of antihistamines, approximately 40%-50% of patients remain symptomatic. The mechanism by which omalizumab exerts its therapeutic effect is thought to be limited by the reduction of serum IgE and the associated downregulation of IgE receptors. Targeting IgE with omalizumab has been successful in treating CSU patients, but not all patients respond equally to this treatment. (See Non-Patent Document 4). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Maurer M et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report. Allergy. 2011;66(3):317~30 [Non-Patent Document 2] Zuberbier T et al. The EAACI / GA2LEN / EDF / WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393~414 [Non-Patent Document 3] Kaplan AP. Chronic spontaneous urticaria: pathogenesis and treatment considerations. Allergy Asthma Immunol Res. 2017;9(6):477~82 [Non-Patent Document 4] Maurer M et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-35 Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is an unmet need. Thus, there is a need for new therapies to treat CSU. [Means for solving the problem]

[0007] In one aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, and wherein the subject has not previously been effectively treated with H1 antihistamine therapy and anti-IgE antibody therapy.

[0008] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0009] In certain exemplary embodiments, an H1 antihistamine is administered in combination with an antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0010] In certain exemplary embodiments, the subject is intolerant to omalizumab or remains symptomatic despite the use of omalizumab.

[0011] In certain exemplary embodiments, the subject is an adult.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 second doses.In certain exemplary embodiments, the initial dose is about 600mg, and each second dose is about 300mg.In certain exemplary embodiments, each second dose is administered every two weeks.

[0012] In certain exemplary embodiments, the subject is 12 to less than 18 years of age. 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. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0013] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0014] In certain exemplary embodiments, the subject is under the age of 6 to 12. 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.

[0015] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0016] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks.

[0017] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 300 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks. In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0018] In certain exemplary embodiments, the subject has a body weight of less than 15 kg and at least 5 kg, the initial dose is about 200 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks. In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old. In certain exemplary embodiments, the subject is at least 2 years old and less than 12 years old. In certain exemplary embodiments, the subject is at least 6 years old and less than 12 years old.

[0019] In certain exemplary embodiments, the subject weighs less than 60 kg. In certain exemplary embodiments, the subject weighs at least 30 kg and less than 60 kg.

[0020] In certain exemplary embodiments, the treatment results in an improvement in one or more patient-reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 dimensions (EQ-5D), Euroqol-5 dimensions Youth version (EQ-5D Y).

[0021] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0022] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0023] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0024] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0025] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0026] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0027] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0028] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0029] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0030] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0031] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0032] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0033] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0034] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0035] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0036] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0037] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0038] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0039] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0040] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0041] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0042] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0043] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0044] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0045] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 12 to 18 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, and wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage.

[0046] In certain exemplary embodiments, the subject has a body weight of less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0047] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0048] In certain exemplary embodiments, the subject has a body weight of less than 60 kg.

[0049] In certain exemplary embodiments, each second dose is administered every two weeks.

[0050] In certain exemplary embodiments, the subject has a body weight of at least 5 kg but less than 15 kg, the initial dose is about 200 mg, each second dose is about 200 mg, and each second dose is administered every 4 weeks.

[0051] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0052] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0053] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0054] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0055] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0056] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0057] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0058] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0059] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0060] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0061] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0062] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0063] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0064] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0065] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0066] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0067] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0068] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0069] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0070] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0071] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0072] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0073] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0074] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0075] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0076] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 6 to 12 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, and wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage.

[0077] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0078] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks.

[0079] In certain exemplary embodiments, the subject has a body weight of less than 60 kg.

[0080] In certain exemplary embodiments, the subject has a body weight of at least 5 kg but less than 15 kg, the initial dose is about 200 mg, each second dose is about 200 mg, and each second dose is administered every four weeks.

[0081] In certain exemplary embodiments, an H1 antihistamine is administered in combination with an antibody or antigen-binding fragment thereof.

[0082] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0083] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0084] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0085] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0086] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0087] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0088] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0089] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0090] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0091] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0092] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0093] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0094] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0095] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0096] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0097] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0098] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0099] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0100] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0101] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0102] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0103] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0104] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. 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 does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0107] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 12 to 18 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with antihistamine therapy.

[0108] In certain exemplary embodiments, the subject has a body weight of less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0109] In certain exemplary embodiments, the subject has a body weight of at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0110] In certain exemplary embodiments, the subject has a body weight of less than 60 kg.

[0111] In certain exemplary embodiments, each second dose is administered every two weeks.

[0112] In certain exemplary embodiments, the subject has a body weight of at least 5 kg but less than 15 kg, the initial dose is about 200 mg, each second dose is about 200 mg, and each second dose is administered every four weeks.

[0113] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0114] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0115] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0116] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0117] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0118] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0119] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0120] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0121] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0122] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0123] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0124] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0125] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0126] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0127] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0128] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0129] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0130] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0131] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0132] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0133] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0134] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0135] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0136] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0137] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0138] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 6 to 12 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with antihistamine therapy.

[0139] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0140] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks.

[0141] In certain exemplary embodiments, the subject has a body weight of less than 60 kg.

[0142] In certain exemplary embodiments, the subject has a body weight of at least 5 kg but less than 15 kg, the initial dose is about 200 mg, each second dose is about 200 mg, and each second dose is administered every four weeks.

[0143] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0144] In certain exemplary embodiments, an H1 antihistamine is administered in combination with an antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0145] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0146] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0147] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0148] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0149] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0150] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0151] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0152] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0153] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0154] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0155] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0156] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0157] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0158] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0159] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0160] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0161] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0162] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0163] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0164] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0165] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0166] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0167] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0168] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0169] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0170] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 12 to 18 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with anti-IgE antibody therapy.

[0171] In certain exemplary embodiments, the subject has a body weight of less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0172] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0173] In certain exemplary embodiments, each second dose is administered every two weeks.

[0174] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0175] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0176] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0177] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0178] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0179] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0180] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0181] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0182] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0183] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0184] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0185] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0186] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0187] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0188] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0189] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0190] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0191] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0192] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0193] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0194] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0195] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0196] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0197] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0198] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0199] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 6 to 12 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with anti-IgE antibody therapy.

[0200] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0201] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks.

[0202] In certain exemplary embodiments, the subject is intolerant to omalizumab or remains symptomatic despite the use of omalizumab.

[0203] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0204] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0205] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0206] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0207] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0208] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0209] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0210] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0211] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0212] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0213] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0214] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0215] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0216] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0217] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0218] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0219] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0220] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0221] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0222] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0223] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0224] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0225] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0226] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0227] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0228] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 12 to 18 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with H1 antihistamine therapy and anti-IgE antibody therapy.

[0229] In certain exemplary embodiments, the subject has a body weight of less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0230] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0231] In certain exemplary embodiments, each second dose is administered every two weeks.

[0232] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0233] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0234] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0235] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0236] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0237] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0238] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0239] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0240] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0241] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0242] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0243] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0244] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0245] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0246] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0247] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0248] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0249] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0250] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0251] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0252] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0253] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0254] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0255] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0256] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0257] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 6 to 12 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage, and wherein the subject has not previously been effectively treated with H1 antihistamine therapy and anti-IgE antibody therapy.

[0258] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every two weeks.

[0259] In certain exemplary embodiments, the subject weighs less than 30 kg and at least 15 kg, the initial dose is about 600 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every 4 weeks.

[0260] In certain exemplary embodiments, the subject is intolerant to omalizumab or remains symptomatic despite the use of omalizumab.

[0261] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0262] In certain exemplary embodiments, an H1 antihistamine is administered in combination with an antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0263] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0264] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0265] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0266] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0267] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0268] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0269] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0270] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0271] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0272] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0273] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0274] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0275] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0276] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0277] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0278] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0279] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0280] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0281] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0282] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0283] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0284] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0285] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0286] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0287] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0288] In another aspect, a method is provided for treating a subject having chronic spontaneous urticaria (CSU), comprising administering to the subject 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, wherein the subject is less than 2 to 6 years of age, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more second doses, and wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dosage.

[0289] In certain exemplary embodiments, the subject weighs at least 15 kg but less than 30 kg, the initial dose is about 300 mg, and each second dose is about 300 mg. In certain exemplary embodiments, each second dose is administered every four weeks.

[0290] In certain exemplary embodiments, an H1 antihistamine is administered in combination with an antibody or antigen-binding fragment thereof.

[0291] In certain exemplary embodiments, the subject weighs at least 5 kg and less than 15 kg, the initial dose is about 200 mg, and each second dose is about 200 mg. In certain exemplary embodiments, each second dose is administered every four weeks.

[0292] In certain exemplary embodiments, the subject has a body weight of at least 30 kg but less than 60 kg, the initial dose is about 400 mg, each second dose is about 200 mg, and each second dose is administered every two weeks.

[0293] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0294] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0295] In certain exemplary embodiments, the treatment results in an improvement in one or more patient reported outcomes (PROs) selected from the group consisting of Itch Severity Score (ISS), Urticaria Severity Score (HSS), Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Urticaria Control Test (UCT), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), Euroqol-5 Inventory (EQ-5D), Euroqol-5 Inventory Pediatric Version (EQ-5D Y).

[0296] In certain exemplary embodiments, the PRO is Itch Severity Score (ISS) and the subject has a reduction in Itch Severity Score over 7 days (ISS7). In certain exemplary embodiments, the reduction in ISS7 is at least 5.

[0297] In certain exemplary embodiments, the PRO is Urticaria Severity Score (HSS) and the subject has a reduction in Urticaria Severity Score over 7 days (HSS7).

[0298] In certain exemplary embodiments, the PRO is urticaria activity score (UAS), and the subject has a reduction in urticaria activity score (UAS7) over 7 days. In certain exemplary embodiments, the reduction in UAS7 is at least 10. In certain exemplary embodiments, the subject's UAS7 is 0.

[0299] In certain exemplary embodiments, the PRO is Urticaria Activity Score (UAS), and the subject's UAS is 6 or less.

[0300] In certain exemplary embodiments, the PRO is the Angioedema Activity Score over 7 days (AAS7), and the subject has a decrease in the AAS score.

[0301] In certain exemplary embodiments, the PRO is Urticaria Control Test (UCT) and the subject has an increased UCT score. In certain exemplary embodiments, the subject's UCT is 12 or greater.

[0302] In certain exemplary embodiments, the PRO is the Dermatology Life Quality Index (DLQI) and the subject has a decrease in DLQI score.

[0303] In certain exemplary embodiments, the PRO is the Pediatric Dermatology Life Quality Index (CDLQI) and the subject has a decrease in CDLQI score.

[0304] In certain exemplary embodiments, the PRO is the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) and the subject has a reduction in CU-Q2oL score.

[0305] In certain exemplary embodiments, the PRO is Patient Global Impression of Change (PGIC) and the subject has a decrease in PGIC score.

[0306] In certain exemplary embodiments, the PRO is Global Patient Impression of Severity (PGIS) and the subject has a reduction in PGIS score.

[0307] In certain exemplary embodiments, the PRO is the Euroqol-5 inventory (EQ-5D) or the Euroqol-5 inventory Pediatric version (EQ-5D Y) and the subject has an increase in EQ visual analog scale (EQ VAS) score.

[0308] In certain exemplary embodiments, improvement in PRO occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, improvement in PRO occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0309] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has a UAS7 score of 16 or greater.

[0310] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has an ISS7 score of 8 or greater.

[0311] In certain exemplary embodiments, prior to treatment with the antibody or antigen-binding fragment thereof, the subject has angioedema.

[0312] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of itch-free days experienced by the subject.

[0313] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of hives-free days experienced by the subject.

[0314] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids. In certain exemplary embodiments, a reduced dose of oral corticosteroid is required. In certain exemplary embodiments, the number of days oral corticosteroid treatment is required is reduced.

[0315] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue medication. In certain exemplary embodiments, a reduced dosage of antihistamine rescue medication is required. In certain exemplary embodiments, the number of days that antihistamine rescue medication is required is reduced.

[0316] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the antibody is dupilumab.

[0317] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0318] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0319] In certain exemplary embodiments, the subject does not have active atopic dermatitis or chronic induced cold urticaria (CICU).

[0320] The foregoing and other features and advantages of the present disclosure will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0321] [Figure 1]FIG. 1 is a schematic depiction of the study design overview of Example 1. Studies A and C have participants who are omalizumab naive. Study B has participants who are intolerant or incomplete responders to omalizumab. Dupilumab 300 mg Q2W / Q4W, one SC injection of 300 mg (2 mL) of dupilumab is administered. Dupilumab 200 mg Q2W, one SC injection of 200 mg (1.14 mL) of dupilumab is administered. Matching placebos are prepared in the same formulation without added protein (i.e., active agent). Adults: 300 mg Q2W; Adolescents: 200 mg Q2W for <60 kg or 300 mg Q2W for ≥60 kg; (Studies A and C only) Children 6-<12 years: 200 mg Q2W for ≥60 kg or 300 mg for <30 kg and ≥15 kg. EOS=end of study; EOT=end of treatment; R=randomized; SC=subcutaneous; Q2W=every 2 weeks; Q4W=every 4 weeks. [Figure 2A] FIG. 1 shows a table of activity schedules for two randomized, placebo-controlled trials (Example 1) of dupilumab in patients with CSU who remain symptomatic despite the use of H1 antihistamine treatment. [Figure 2B] FIG. 1 shows a table of activity schedules for two randomized, placebo-controlled trials (Example 1) of dupilumab in patients with CSU who remain symptomatic despite the use of H1 antihistamine treatment. [Figure 2C] FIG. 1 shows a table of activity schedules for two randomized, placebo-controlled trials (Example 1) of dupilumab in patients with CSU who remain symptomatic despite the use of H1 antihistamine treatment. [Diagram 3] FIG. 1 shows the questionnaire used to determine the urticaria activity score, a CSU-associated patient-reported outcome measure. [Figure 4] Figure 1 shows the questionnaire used in the Urticaria Control Trial, a CSU-related patient-reported outcome measure. [Figure 5A] Figure 1 shows a CSU-related patient-reported outcome measure, the Chronic Urticaria Quality of Life Questionnaire. [Figure 5B]Figure 1 shows a CSU-related patient-reported outcome measure, the Chronic Urticaria Quality of Life Questionnaire. [Figure 5C] Figure 1 shows a CSU-related patient-reported outcome measure, the Chronic Urticaria Quality of Life Questionnaire. [Figure 6] A diagram outlining Study A is shown. Study A included omalizumab-naive participants treated with dupilumab for 24 weeks. [Figure 7] FIG. 1 shows the statistical testing hierarchy for Study A. The figure shows p-values ​​for the primary endpoint at 12 and 24 weeks. [Figure 8] FIG. 13 graphically depicts the reduction in ISS7 in least squares mean (LSmean) change from baseline at weeks 12 and 24 for dupilumab treatment groups versus placebo. [Figure 9] FIG. 13 shows plots of the mean change in ISS7 over time from baseline to week 36 in both the placebo and dupilumab treatment groups. [Figure 10] FIG. 13 graphically depicts the reduction in UAS7 in least squares mean (LSmean) change from baseline at weeks 12 and 24 in dupilumab treatment groups versus placebo. [Figure 11] FIG. 13 shows plots of the mean change in UAS7 over time from baseline to week 36 in both the placebo and dupilumab treatment groups. [Figure 12] FIG. 10 graphically depicts the percentage of UAS7 partial responders (patients with UAS7 ≦6) in both the placebo and dupilumab treatment groups at weeks 12 and 24. The dupilumab treatment group had a higher percentage of UAS7 partial responders at both time points. [Figure 13] FIG. 10 graphically depicts the percentage of UAS7 complete responders (patients with UAS7 equal to 0) in both the placebo and dupilumab treatment groups at weeks 12 and 24. The dupilumab treatment group had a higher percentage of UAS7 complete responders at both time points. [Figure 14]FIG. 10 graphically depicts the percentage of patients who reached the ISS7 minimally important difference (MID) (patients with a decrease in ISS7 of ≥ 5) in both the placebo and dupilumab treatment groups at weeks 12 and 24. The dupilumab treatment group had a higher percentage of patients who reached the ISS7 MID at both time points. [Figure 15] FIG. 1 depicts a plot of the proportion of patients with a ≥ 5 point reduction in ISS7 from baseline over time through Week 36 in both the placebo and dupilumab groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0322] Before describing the present disclosure, it is to be understood that the present disclosure is not limited to the particular methods and experimental conditions described, since 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.

[0323] 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.

[0324] As used herein, the term "about" when used in reference to a particular recited numerical value means that the value may vary from the recited value by up to 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0325] As used herein, the terms "treat," "treating," and the like mean to alleviate a symptom, temporarily or permanently remove the causal effect of a symptom, or prevent or slow the onset of a symptom of a specified disorder or condition.

[0326] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the disclosure herein, exemplary methods and materials are described herein. All publications mentioned herein are incorporated by reference in their entirety.

[0327] The present disclosure provides methods and compositions for treating chronic spontaneous urticaria (CSU).

[0328] As used herein, "urticaria" refers to a skin condition characterized by the formation of wheals (i.e., hive(s)) and / or the development of angioedema that may last for minutes or hours. As used herein, "chronic urticaria" or "CU" refers to urticaria defined by recurrent episodes occurring at least twice a week for six weeks.

[0329] As used herein, "chronic spontaneous urticaria" or "CSU" refers to a subset of CU in which a subject develops or develops wheals and / or angioedema for at least six weeks, and CSU does not have a specific cause or trigger.

[0330] As used herein, "wheal" refers to a raised, itchy (i.e., pruritic) area of ​​skin. Wheal can be used interchangeably with "hives." The intensity of a wheal can be characterized using a variety of assessment tools known in the art, including those discussed below.

[0331] As used herein, "angioedema" refers to areas of swelling of the underlying layers of skin or tissue immediately beneath the skin or mucous membranes. Swelling may occur, for example, in the face, tongue, larynx, abdomen, arms, and / or legs. Onset typically lasts minutes to hours and typically resolves within hours to days.

[0332] Methods for improving CSU-related patient-reported outcome (PRO) measures Also provided is a method for improving one or more CSU-associated 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.

[0333] Examples of CSU-related PRO measures include: (1) Urticaria Activity Score (UAS), (2) Angioedema Activity Score (AAS), (3) Urticaria Control Trial (UCT) score, (4) Dermatology Life Quality Index (DLQI), (5) Pediatric Dermatology Life Quality Index (CDLQI), (6) Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) score, (7) Patient Global Impression of Change (PGIC), (8) Patient Global Impression of Severity (PGIS), (9) Euroqol-5 Item (EQ-5D) score, and (10) Euroqol-5 Item Pediatric version (EQ-5D Y) score.

[0334] "Improvement of CSU-related PRO index" refers to an increase from baseline in one or more of the UCT score and EQ visual analog scale (EQ VAS) score, and / or a decrease from baseline in one or more of the following scores: Urticaria Activity Score (UAS), Angioedema Activity Score (AAS), Dermatology Life Quality Index (DLQI), Pediatric Dermatology Life Quality Index (CDLQI), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Patient Global Impression of Change (PGIC), and Patient Global Impression of Severity (PGIS). As used herein, the term "baseline" with respect to a CSU-related PRO index refers to the value of the patient's PRO index before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0335] To determine whether a CSU-related parameter is "improved", the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein. For example, the CSU-related parameter can be measured on the first day, second day, third day, fourth day, fifth day, sixth day, seventh day, eighth day, ninth day, tenth day, eleventh day, twelfth day, or on the third week, fourth week, fifth week, sixth week, seventh week, eighth week, ninth week, tenth week, eleventh week, twelfth week, thirteenth week, fourteenth week, fifteenth week, sixteenth week, seventeenth week, eighteenth week, nineteenth week, twentieth week, twenty-first week, twenty-second week, twenty-third week, twenty-fourth week, 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" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured) of the CSU-related parameter.

[0336] As used herein, the term "obtain" or "obtaining" refers to taking possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, e.g., a CSU-related parameter. "Directly obtaining" refers to performing a method (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 party or source (e.g., a third-party laboratory where the physical entity or value is obtained directly). Directly obtaining a physical entity includes performing a method that involves a physical change of a material entity, 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 in a mixture, and performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Obtaining a value directly includes performing a method that involves a physical change of a sample or another substance, such as performing an analytical method that involves a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis").

[0337] Indirectly obtained information can be provided in the form of a report, for example, provided in written or electronic form, such as an online database or application ("App"), etc. The report or information can be provided, for example, by a medical institution, such as a hospital or clinic; or a medical provider, such as a doctor or nurse.

[0338] Itch-free days: According to certain embodiments, administering IL-4R antagonist to patient causes the increase from baseline of the number of itch-free days experienced by subject.For example, administering IL-4R antagonist to the subject in need thereof causes the increase from baseline of the number of itch-free days experienced by subject by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days per month.

[0339] Urticaria-free days: according to certain embodiments, administering IL-4R antagonist to patient causes the number of urticaria-free days experienced by subject to increase from baseline.For example, administering IL-4R antagonist to subject in need thereof causes the number of urticaria-free days experienced by subject to increase from baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days per month.

[0340] Itch Severity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the Itch Severity Score (ISS). ISS7 is defined as the sum of the daily ISS scores (ranging from 0=none to 3=severity) recorded at the same time of day for 7 days. ISS7 ranges from 0 to 21, with higher scores indicating worse disease. The minimal important difference (MID) for ISS7 is 4.5 to 5.

[0341] Therapeutic methods are provided that result in a reduction in ISS7 score from baseline.For example, administering an IL-4R antagonist to a subject in need thereof reduces the ISS7 score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 points from baseline.

[0342] Urticaria Severity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in urticaria severity score (HSS). HSS7 is defined as the sum of the daily HSS scores (from 0=none to 3=>50 urticaria) recorded at the same time of day for 7 days. HSS7 ranges from 0 to 21, with higher scores indicating worse disease. The minimal important difference (MID) for HSS7 is 5 to 5.5.

[0343] Provided is a method of treatment that causes the reduction of HSS7 score from baseline.For example, administering an IL-4R antagonist to a subject in need thereof reduces HSS7 score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 points from baseline.

[0344] Urticaria Activity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the Urticaria Activity Score (UAS). The UAS, or Urticaria Activity Score (UAS), is a validated patient-reported outcome (PRO) measure. The daily UAS is the sum of the daily Urticaria Severity Score (HSS, ranging from 0=none to 3=50 or more hives) and the daily Itch Severity Score (ISS, ranging from 0=none to 3=intense), with the two main urticaria signs and symptoms being wheals and itch. The daily UAS score ranges from 0 to 6 points / day. The daily UAS score is summed over 7 days, with the UAS7 ranging from 0 to 42 and composed of the HSS7 and ISS7 components. The UAS7 is an established and widely accepted PRO tool that prospectively measures CSU activity. (See Mlynek A et al. How to assess disease activity in patients with chronic urticaria? Allergy. 2008;63(6):777-80.) It has been used as the primary outcome parameter and medical intervention in most recent clinical trials of CSU. (See Maurer M et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-35; Casale TB et al. Similar efficacy with omalizumab in chronic idiopathic / spontaneous urticaria despite different background therapy. J Allergy Clin Immunol Pract. 2015;3(5):743-50.) To aid in the interpretation of changes in scores in CSU participants, a minimally important difference (MID) value ranging from 9.5 to 10.5 has been defined.(See Hollis K et al. Comparison of urticaria activity score over 7 days (UAS7) values ​​obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study. Am J Clin Dermatol. 2018;19(2):267-74; Hawro T et al. The urticaria activity score-validity, reliability, and responsiveness. J Allergy Clin Immunol Pract. 2018;6(4):1185-90; Mathias SD et al. Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(1):20-4.) The UAS7 ranges from 0 to 42, with higher scores indicating higher disease activity. A score of 1 to 6 indicates that urticaria is well controlled. A score of 7 to 15 indicates mild urticaria. A score of 16 to 27 indicates moderate urticaria activity. A score of 28 to 42 indicates severe urticaria activity. If the UAS7 score is 6 or less, the urticaria is considered well controlled. Complete responders (no pruritus or urticaria) have a UAS7 of 0.

[0345] Provided is a method of treatment that causes the reduction of UAS or UAS7 score from baseline.For example, administering IL-4R antagonist to the subject in need thereof causes the reduction of UAS7 score from baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42 points.

[0346] Angioedema Activity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the Angioedema Activity Score (AAS). The Angioedema Activity Score (AAS) is a validated PRO measure that assesses the activity of angioedema (see Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92). The AAS involves the patient recording the presence or absence of angioedema in the past 24 hours. If angioedema is present, the patient answers five additional questions regarding the time of day when the swelling episode occurred, as well as the severity that this swelling episode caused and its impact on daily function and appearance. Each AAS item is scored between 0 and 3 points, i.e., the minimum and maximum daily AAS values ​​are 0 and 15 points. Daily AAS are summed into a 7-day score (AAS7), which ranges from 0 to 105 points (supra). A MID for AAS7 of approximately 8 points has been established (supra).

[0347] Therapeutic methods are provided that result in a reduction in AAS or AAS7 score from baseline.For example, administration of an IL-4R antagonist to a subject in need thereof can result in a reduction in AAS or AAS7 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, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, resulting in a decrease of 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, or 105 points.

[0348] Urticaria Control Test: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in the Urticaria Control Test score. The Urticaria Control Test (UCT) is a validated PRO measure for assessing urticaria control (Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92) and is based on four items (urticaria symptoms pruritus and wheal severity, insufficient frequency of treatment, impaired QoL, overall urticaria control). Each item is rated on a 5-point Likert-type scale (scored 0-4 points). A low score indicates high disease activity and low disease control. The UCT total score is calculated by adding up all the scores of the four individual items. Thus, the minimum UCT score is 0 points and the maximum score is 16 points, with a score of 16 points indicating complete disease control (see Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92). A UCT score of 12 or greater indicates adequate disease control. The MID for UCT is 3.

[0349] Provided is a method of treatment that causes the increase in UCT score from baseline.For example, administering IL-4R antagonist to a subject in need thereof causes the increase in UCT score from baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 points.

[0350] Dermatology Life Quality Index (DLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction 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 a skin condition on the participant's health-related quality of life (HRQoL) over the past week. Items cover symptoms, leisure activities, work / school or holiday spending, relationships including intimate relationships, side effects of treatment, and emotional reactions to having a skin condition. This is a validated questionnaire used in clinical and clinical trials (see 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 for 9 items (0=“not at all”, 3=“very much”). The remaining item, regarding work / exams, asks whether work / exams were disturbed and (if “no”) to what extent the skin condition caused problems at work / exams, rated on a 3-point Likert scale (“not at all” to “very much”). Overall scoring ranges from 0 to 30 points, with higher scores indicating poor HRQoL.The MID of the DLQI in participants with chronic idiopathic urticaria was reported to range from 2.24 to 3.10 points using a pooled analysis of distribution and anchor-based approaches using changes in DLQI total score and participant-rated itch severity score (Shikiar R et al. Minimal important difference (MID) of the dermatology life quality index (DLQI): results from patients with chronic idiopathic urticaria. Health Qual. Life Outcomes. 2005; 3:36).

[0351] Provided is a treatment method that causes DLQI score to decrease from baseline.For example, administering IL-4R antagonist to the subject in need thereof causes DLQI score to decrease by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 from baseline.

[0352] Pediatric Dermatology Life Quality Index (CDLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in CDLQI scores. The Pediatric Dermatology Life Quality Index (CDLQI) is a validated questionnaire designed to measure the impact of skin disease on children's HRQoL (see Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial validation and practical use. Br J Dermatol. 1995;132(6):942-9). Patients respond to 10 questions (perception of symptoms associated with the disease, impact of the disease on leisure, school or holidays, relationships, sleep, and side effects of treatment for the skin disease). The collection period for this instrument is 7 days. Nine of the 10 questions are scored on a 4-point Likert scale ranging from 0=not at all / not answering the question to 3=very much. Question 7 has one further answerable item (school absenteeism), which is assigned a score of 3. The CDLQI total score is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL. Patients complete the DLQI (>= 16 years) or the CDLQI (>= 12 to < 16 years).

[0353] Provided is a treatment method that causes the CDLQI score to decrease from baseline.For example, administering IL-4R antagonist to the subject in need thereof causes the CDLQI score to decrease by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 from baseline.

[0354] Chronic Urticaria Quality of Life Questionnaire (CU-QoL): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in CU-Q2oL scores. The CU-Q2oL is a disease-specific instrument used to assess the QoL of adult participants with CSU. (See Baiardini I et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire(CU-QoL). Allergy. 2005;60(8):1073-8). The CU-Q2oL is a 23-item self-administered questionnaire that includes six QOL components: itching, swelling, impact on activities of life, sleep problems, limitations, and appearance. Each item is scored on a 5-point Likert scale (1=not at all, 5=very much) to indicate how much each component bothers the participant. The individual items were summed to produce a total CU-Q2oL score, which was then converted to a scale of 0–100, with higher scores indicating greater QoL impairment.

[0355] Methods of treatment are provided that result in a reduction in CU-Q2oL score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof may result in a reduction in CU-Q2oL 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, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, resulting in a decrease of 5, 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.

[0356] Patient Global Impression of Change (PGIC): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction 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 change in CSU on a 7-point scale, compared to just before the participant starts study treatment. Response options are as follows: 0="very much better", 1="moderately better", 2="slightly better", 3="no change", 4="slightly worse", 5="moderately worse", 6="very much 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).

[0357] Provided is a method of treatment that results in a reduction in PGIC score from baseline.For example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in PGIC score of about 1, 2, 3, 4, 5 or 6 from baseline.

[0358] Global Patient Impression of Severity (PGIS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in PGIS score from baseline. Global Patient Impression of Severity (PGIS) is a one-item questionnaire that asks participants to give a global self-assessment of the severity of their illness over the past week on a 4-point scale. Answer options are as follows: 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).

[0359] Provided is a method of treatment that results in a reduction in PGIS score from baseline.For example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in PGIS score of about 1, 2 or 3 from baseline.

[0360] Euroqol-5 Items (EQ-5D) and EQ-5D Pediatric Version (EQ-5D Y): According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in EQ-5D or EQ-5D Y scores. The Euroqol-5 Items (EQ-5D) is a standardized PRO measure of health status developed by the EuroQol Group, providing a simple, 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 written form and an EQ visual analog scale (EQ VAS). The EQ-5D 5L written form includes five components: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each component has five problem perception levels: "no problems", "mild problems", "moderate problems", "severe problems", and "unable to do activities". (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). The respondent indicates his / her health status by checking (or crossing) a box against the most appropriate statement in each of the five components, resulting in a single-digit number representing the level of that component. The numbers for the five components can be combined into a five-digit number representing the respondent's health status. The EQ VAS records the respondent's self-rated health status on a vertical VAS with endpoints labeled "best imaginable health (100)" and "worst imaginable health (0)". This information can be used as a quantitative measure of health outcomes judged by the individual respondent. The EQ-5DYouth version (EQ-5D Y) is administered to children ≥6-<12 years of age and adolescents 12-15 years of age. (Wille N et al. Qual. Life Res. 2010;19(6):875-86). The EQ-5D-Y is based on the EQ-5D-3L and essentially consists of two pages, the EQ-5D narrative and the EQ VAS.The EQ-5D-Y descriptor includes five components: mobility, taking care of oneself, usual activities, pain or discomfort, and anxiety, sadness or unhappiness. Each component has three levels: no problems, some problems and a lot of problems. The EQ VAS records the respondent's self-rated health on a vertical VAS with endpoints labeled "best health you can imagine" and "worst health you can imagine". Patients complete the EQ-5D Y or EQ-5D questionnaire.

[0361] 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 can 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, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, resulting in an increase of 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.

[0362] Pediatric Dermatology Life Quality Index (C-DLQI) The C-DLQI is a validated questionnaire designed to measure the impact of skin diseases on children's health-related quality of life (HRQoL). The C-DLQI is validated in children ≥4 years to <16 years of age. The C-DLQI is recommended for children aged 4-12 years and participants should complete the questionnaire themselves, although young children may complete the questionnaire with assistance from a parent / caregiver. Participants provide answers to 10 questions (perception of symptoms associated with the disease, impact of the disease on leisure, school or holidays, relationships, sleep, and side effects of treatment for the skin disease). The collection period for the instrument is one week (7 days). Nine of the 10 questions are scored on a 4-point Likert scale ranging from 0 = not at all / not answering the question to 3 = very much. Question 7 has one further answerable item (school absenteeism), which is assigned a score of 3. The C-DLQI total score is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL.

[0363] Infant Dermatology Quality of Life Index (IDQOL) The IDQOL is a validated questionnaire designed for use in children <4 years of age. The questionnaire is completed by the child's caregiver / guardian. The questionnaire collection period is 1 week (7 days). There are 11 questions in total, 10 of which focus on the Life Quality Index topic scored on a 4-point Likert scale, and one on Dermatitis Severity scored on a 5-point Likert scale. For Life Quality Index questions 1, 5-10, the scoring range is always = 3 to never = 0. For question 2, the scoring range is always crying = 3, very bothersome = 2, slightly bothersome = 1, and in a good mood = 0. For question 3, the scoring range is >2 hours = 3, 1-2 hours = 2, 15 minutes to 1 hour = 1, and 0-15 minutes = 0. For question 4, the scoring range is >5 hours = 3, 3-4 hours = 2, 1-2 hours = 1, and <1 hour = 0. For the severity of dermatitis, a 5-point Likert scale is scored from very severe = 4 to none = 0. The IDQOL total score is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL.

[0364] Modified Urticaria Activity Score (UAS) The urticaria activity score (UAS) is a validated patient-reported outcome (PRO) measure. In this study, a modified version of the UAS (mUAS) is used to account for the small body surface area of ​​pediatric and adolescent patients. The mUAS is derived from the sum of the daily urticaria severity score (HSS, ranging from 0 to 3 (0=none, 1=mild: (1 to <10 wheals / 24 h), 2=moderate: (10 to 30 wheals / 24 h), and 3=intense: (>30 wheals / 24 h or large confluent areas of wheals)) and the daily itch severity score (ISS, ranging from 0=none to 3=intense). Wheals and itch are the two major symptoms of urticaria. The daily mUAS total score is calculated on a scale from 0 to 6 (itch severity score). The core score ranges from 0 to 3, and the urticaria severity score ranges from 0 to 3. Daily mUAS scores are summed over 7 days, resulting in the UAS7, which ranges from 0 to 42 and is comprised of the urticaria severity score over 7 days (HSS7) and itch severity score over 7 days (ISS7) components. Completion of the mUAS7 should be completed by the child or parent / caregiver / legal guardian for participants aged 4 years or older, and by a parent / caregiver for participants under 4 years of age.

[0365] The UAS7 is an established and widely accepted PRO tool that prospectively measures CSU activity. A minimally important difference (MID) value ranging from 9.5 to 10.5 has been defined to aid in the interpretation of score changes in CSU participants.

[0366] The itch severity score (ISS) is a single-item scale scored on a 0-3 Likert scale ranging from 0 = none to 3 = strong. The ISS is collected daily and used to derive the mUAS as described above.

[0367] The urticaria severity score (HSS) is a single-item scale scored on a 0–3 Likert scale ranging from 0 = none to 3 = severe. The HSS is collected daily and used to derive the mUAS score as described above.

[0368] 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 when expressed on a cell in vitro or in vivo, and inhibits the normal biological signaling function of IL-4R. 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 can be used in the context of the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises 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.

[0369] The term "human IL-4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), e.g., IL-4Rα.

[0370] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (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 (herein 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), and can be 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: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. 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 side-by-side analysis of two or more CDRs.

[0371] The term "antibody" also includes antigen-binding fragments of complete antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, for example, from complete antibody molecules using any suitable standard technique, for example, proteolytic digestion or recombinant genetic engineering techniques using DNA-encoded antibody variable and, optionally, constant domain manipulation and expression. 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, by using chemical or molecular biology techniques to arrange 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.

[0372] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity determining regions (CDRs), such as CDR3 peptides, or constrained FR3-CDR3-FR4 peptides). Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetraspecific antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the scope of the term "antigen-binding fragment".

[0373] An antigen-binding fragment of an antibody generally comprises at least one variable domain. The variable domain may be of any size or amino acid composition and generally comprises at least one CDR adjacent to or in frame with one or more framework sequences. L V related to domain H In an antigen-binding fragment having a domain, H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody contains a monomeric V dimer. H or V L It may include a domain.

[0374] In certain embodiments, an antigen-binding fragment of an antibody can comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that can be found within the antigen-binding fragments of an antibody described herein include: (i) a 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 H 2-C H 3; and (xiv) V L -C LIn any arrangement of variable and constant domains, including any of the exemplary arrangements 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. The 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 linkage between adjacent variable and / or constant domains in a single polypeptide molecule, and typically the hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Additionally, 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 domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above in non-covalent association (eg, via disulfide bonds).

[0375] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally contain at least two different variable domains, each capable of specifically binding to a separate antigen or to 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.

[0376] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0377] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies described herein may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) that are not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. 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, are grafted onto human framework sequences.

[0378] The term "recombinant human antibody" includes all human antibodies produced, expressed, created or isolated by recombinant means, e.g., 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 produced, expressed, created or isolated by any other means involving splicing of human immunoglobulin gene sequences into 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 antibody. H and V L The amino acid sequence of the region is H and V L When derived from and related to the sequences, they are sequences that cannot naturally occur within the human antibody germline repertoire in vivo.

[0379] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a suitable four-chain construct of approximately 150-160 kDa in which dimers are linked by inter-chain heavy chain disulfide bonds. In the second form, dimers are not linked by inter-chain disulfide bonds and molecules of approximately 75-80 kDa composed of covalently linked light and heavy chains (half-antibodies) are formed. These forms are extremely difficult to separate, even after affinity purification.

[0380] 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 antibody hinge region isotype. Single amino acid substitutions in the hinge region of human IgG4 hinges can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels commonly observed with human IgG1 hinges. For example, in manufacturing, it may be desirable to improve the yield of a desired antibody form, such as by substituting the hinge, C. H 2, or C H Antibodies with one or more mutations in three regions are provided.

[0381] By "isolated antibody" is meant 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 an antibody that has been separated or removed 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 in 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.

[0382] The term "specifically binds" and the like means 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" IL-4R as characterized in the present invention includes an antibody, or a portion thereof, that binds to IL-4R, and is capable of binding to the IL-4R. D is 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 in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules obtained from other (non-human) species.

[0383] Anti-IL-4R antibodies useful for 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 were 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 involving 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 CDR regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) are 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 with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce a large number of antibodies and antigen-binding fragments containing 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 in the domain are mutated back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, only the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues in a different germline sequence (i.e., a different germline sequence from the germline sequence from which the antibody is originally derived). Furthermore, the antibody may contain any combination of two or more germline mutations in the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residues in a particular germline sequence, and certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residues 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 antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0384] Methods involving the use of anti-IL-4R antibodies that include variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions, e.g., no more than 10, no more than 8, no more than 6, no more than 4, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein are provided.

[0385] The term "surface plasmon resonance" refers to an optical phenomenon that allows analysis of real-time interactions by detecting alterations in protein concentration within a biosensor matrix, for example, using a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0386] The term “K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0387] 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 in an antigen and have different biological effects. Epitopes may be 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 carbohydrate, phosphoryl, or sulfonyl moieties in an antigen.

[0388] The terms "substantial identity" or "substantially identical," when referring to a nucleic acid or a fragment thereof, indicate that when optimally aligned with another nucleic acid (or its complementary strand), with appropriate nucleotide insertions or deletions, there is nucleotide sequence identity in at least about 95%, or at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below.

[0389] The term "substantial similarity" or "substantially similar", when applied to polypeptides, means that two peptide sequences have at least 95% sequence identity, or at least 98% or 99% sequence identity, when optimally aligned, for example by GAP or BESTFIT programs, using default gap weights. In exemplary embodiments, non-identical residue positions differ by conservative amino acid substitutions. A "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with 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 are not expected to 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 skilled in the art. (See, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331, incorporated herein by reference.) Examples of groups of amino acids having 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 and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid, and (7) sulfur-containing side chains, cysteine ​​and methionine. Exemplary conservative amino acid substitutions are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative replacement is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443 at p. 45, which is incorporated herein by reference.A "moderately conservative" replacement is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0390] 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 a measure of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For example, GCG software contains programs such as Gap and Bestfit, which can be used with default parameters to determine the sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species, or between a wild-type protein and its mutant protein. (See, for example, GCG version 6.1). Polypeptide sequences may also be compared using FASTA, using default or recommended parameters, a program in GCG version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignment and percent sequence identity of the best overlap region 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 multiple 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.)

[0391] Human antibody production Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to generate human antibodies that specifically bind human IL-4R.

[0392] Using VELOCIMMUNE® technology (see, for example, U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high affinity chimeric antibody to IL-4R with a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the generation of a transgenic mouse with a genome that includes human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody that includes a human variable region and a mouse constant region in response to antigenic stimulation. DNA encoding the variable regions of the antibody's heavy and light chains 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.

[0393] Generally, VELOCIMMUNE® mice are exposed to an antigen of interest, and lymphoid cells (e.g., B cells) are harvested from the mice that express the antibody. The lymphoid cells can be fused with a myeloma cell line to produce an immortal hybridoma cell line, which is 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, e.g., CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0394] 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 produce a fully human antibody, such as wild-type or modified IgG1 or IgG4, as described herein. The constant region selected may vary depending on the particular use, and the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0395] Generally, the antibody that can be used in this method has high affinity as described above, as measured by binding to the antigen immobilized in solid phase or in solution phase.The mouse constant region is replaced with the desired human constant region to produce the fully human antibody described herein.The constant region selected may vary depending on the specific use, and the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0396] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R that can be used in the context of the methods described herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment can 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 the designated 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. In general terms, the Kabat definition is based on sequence diversity, 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 for identifying CDR sequences within antibodies.

[0397] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) derived from the heavy and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0398] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0399] 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.

[0400] In certain embodiments, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:1 and 2.

[0401] In one particular embodiment, the antibody sequence is dupilumab and comprises the heavy / light chain amino acid sequence pair of SEQ ID NOs:9 and 10.

[0402] Dupilumab HCVR amino acid sequence: EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 1).

[0403] Dupilumab LCVR amino acid sequence: DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 2).

[0404] Dupilumab HCDR1 amino acid sequence: GFTFRDYA (sequence number 3).

[0405] Dupilumab HCDR2 amino acid sequence: ISGSGGNT (sequence number 4).

[0406] Dupilumab HCDR3 amino acid sequence: AKDRLSITIRPRYYGL (sequence number 5).

[0407] Dupilumab LCDR1 amino acid sequence: QSLLYSIGYNY (sequence number 6).

[0408] Dupilumab LCDR2 amino acid sequence: LGS (sequence number 7).

[0409] Dupilumab LCDR3 amino acid sequence: MQALQTPYT (sequence number 8).

[0410] Dupilumab HC amino acid sequence: EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 9) (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant).

[0411] Dupilumab LC amino acid sequence: DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10) (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant).

[0412] 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-57 / SCB-VH-81;SCB-VL-57 / SCB-VH-82;SCB-VL-57 / SCB-VH-83;SCB-VL-57 / SCB-VH-84;SCB-VL-57 / S CB-VH-85;SCB-VL-57 / SCB-VH-86;SCB-VL-57 / SCB-VH-87;SCB-VL-57 / SCB-VH-88;SCB-VL-57 / SCB- VH-89; SCB-VL-57 / SCB-VH-90; SCB-VL-57 / SCB-VH-91; SCB-VL-58 / SCB-VH-91; SCB-VL-58 / SCB-VH-92; and SCB-VL-58 / SCB-VH-93;

[0413] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair SCB-VL-44 / SCB-VH-92.

[0414] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair SCB-VL-54 / SCB-VH-92.

[0415] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair SCB-VL-55 / SCB-VH-92.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] The antibodies listed in Table 1 below are described in more detail in US Pat. No. 10,774,141, which is incorporated herein by reference in its entirety for all purposes.

[0420] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0421] In certain embodiments, an antibody or antigen-binding fragment thereof of the present 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.

[0422] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises the LCVR / HCVR sequence pair MEDI-37GL-VL / MEDI-37GL-VH.

[0423] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises a HCVR comprising the HCDR1 sequence of MEDI-37GL-HCDR1, the HCDR2 sequence of MEDI-37GL-HCDR2, and the HCDR3 sequence of MEDI-37GL-HCDR3, and a LCVR comprising the LCDR1 of MEDI-37GL-LCDR1, the LCDR2 of MEDI-37GL-LCDR2, and the LCDR3 of MEDI-37GL-LCDR3.

[0424] 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.

[0425] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0426] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair AJOU-90-VL / AJOU-83-VH.

[0427] 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.

[0428] The antibodies listed in Table 3 below are described in more detail in WO2020 / 096381 and Kim et al. (Scientific Reports. 9:7772.2019), which are incorporated by reference in their entireties for all purposes.

[0429] [Table 3-1] [Table 3-2] [Table 3-3]

[0430] In certain embodiments, an antibody or antigen-binding fragment thereof of the present 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.

[0431] The antibodies listed in Table 4 below are described in more detail in US Pat. No. 7,605,237 and US Pat. No. 7,608,693, which are incorporated by reference in their entireties for all purposes.

[0432] [Table 4-1] [Table 4-2]

[0433] Pharmaceutical Compositions Methods are provided that include administering an IL-4R antagonist to a patient, the IL-4R antagonist being contained within a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, additives, and other agents that provide suitable transport, delivery, tolerance, etc. A large number of suitable formulations can be found in a formulary known to all pharmacists: 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 (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent 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.

[0434] 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 generally calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be empirically determined, e.g., the progress of the patient can be monitored by periodic evaluation and dosage adjusted accordingly. Furthermore, inter-species scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0435] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other bioactive agents.

[0436] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously with a standard needle and syringe. Furthermore, for subcutaneous delivery, a pen delivery device (e.g., a pen autoinjector) is easily applied 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 containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, a disposable pen delivery device is pre-filled with the pharmaceutical composition that is held in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0437] Numerous reusable pen and autoinjector delivery devices find use in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, 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™, to name just a few. 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 BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, and the like.

[0438] For direct administration to the sinuses, the pharmaceutical compositions described herein may be administered, for example, using a microcatheter (e.g., endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. The method includes administering an IL-4R antagonist in the form of an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-4R may be administered to treat CSU in a patient. The aerosolized antibody may be produced, for example, as described in U.S. Pat. No. 8,178,098, the entirety of which is incorporated herein by reference.

[0439] 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; see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. vol. 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 other embodiments, 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. 2:115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science vol. 249:1527-1533.

[0440] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, intravenous drip infusions, and the like. These injectable preparations can be manufactured by known methods. For example, the injectable preparations can be manufactured by dissolving, suspending or emulsifying, for example, the antibody or the above-mentioned salts thereof in a sterile aqueous or oily medium commonly used for injections. Examples of aqueous media for injection include physiological saline, isotonic solutions containing glucose, and other adjuvants, which can be used in combination with suitable solubilizers, such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil), and the like. Examples of oily media include sesame oil, soybean oil, and the like, which may be used in combination with solubilizers, such as benzyl benzoate, benzyl alcohol, and the like. Thus, the injections manufactured are generally filled into suitable ampoules.

[0441] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms with unit doses suitable for the dosage of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0442] 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.

[0443] 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 CSU-related PRO indicators (as defined elsewhere herein). "Therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of CSU in a subject.

[0444] In the case of an anti-IL-4R antibody, a therapeutically effective amount is about 0.05 mg to about 700 mg of an anti-IL-4R antibody, 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 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, Approximately 190mg, approximately 200mg, approximately 210mg, approximately 220mg, approximately 230mg, approximately 240mg, approximately 250mg, approximately 260mg, approximately 270mg, approximately 280mg, approximately 290m g, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 4 00mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg , about 510 mg, 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 certain embodiments, 300 mg of an anti-IL-4R antibody is administered.

[0445] The amount of IL-4R antagonist contained within an individual dose range can be expressed in terms of milligrams of antibody per kilogram of subject's 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 per kg of subject's body weight. For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0446] In certain embodiments, the initial dose is approximately the same as the loading dose. In certain embodiments, the initial dose is about 1.1x, about 1.2x, about 1.3x, about 1.4x, about 1.5x, about 1.6x, about 1.7x, about 1.8x, about 1.9x, about 2.0x, about 2.5x, about 3.0x, or more than the loading dose.

[0447] In certain embodiments, two or more doses (e.g., 2, 3, 4, or 5 or more) are administered at the beginning of the treatment regimen as an "initial dose" or "loading dose", followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the maintenance doses may be less than the loading dose or initial dose. For example, one or more loading doses of 600 mg of an IL-4R antagonist may be administered, followed by a maintenance dose of about 75 mg to about 300 mg. In certain embodiments, the method includes an initial dose or loading dose of about 400 mg or about 600 mg of an IL-4R antagonist. In certain embodiments, the method includes one or more second doses or maintenance doses of about 200 mg or about 300 mg of an IL-4R antagonist.

[0448] In certain exemplary embodiments, the subject is a pediatric subject having a body weight of more than 30 kg, and the IL-4R antagonist is administered at a dose of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In certain exemplary embodiments, the subject is a pediatric subject having a body weight of more than 30 kg, and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more second doses of about 400 mg, the second doses being administered every other week (q2w). In certain exemplary embodiments, the subject is a pediatric subject having a body weight of more than 30 kg, and the IL-4R antagonist is administered at an initial dose of about 300 mg and one or more second doses of about 300 mg, the second doses being administered every other week (q2w). 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 an initial dose of about 200 mg and one or more second doses of about 400 mg, the second doses being administered every other week (q2w). In a particularly exemplary embodiment, 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 second or maintenance doses of about 200 mg, the second doses being administered every other week (q2w).

[0449] In certain exemplary 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 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 certain exemplary 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 of about 600 mg and one or more second doses of about 600 mg, the second doses being administered every four weeks (q4w). In certain exemplary 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 of about 500 mg and one or more second doses of about 500 mg, the second dose being administered every four weeks (q4w). In certain exemplary 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 of about 400 mg and one or more second doses of about 400 mg, the second dose being administered every four weeks (q4w). In certain exemplary 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 of about 300 mg and one or more second doses of about 300 mg, the second dose being administered every four weeks (q4w). In a particularly exemplary embodiment, 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 of about 600 mg and one or more second or maintenance doses of about 300 mg, the second dose being administered every four weeks (q4w).

[0450] In certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 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 certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 300 mg and one or more second doses of about 300 mg, the second doses being administered every four weeks (q4w). In certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 250 mg and one or more second doses of about 250 mg, the second dose being administered every four weeks (q4w). In particularly exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 200 mg and one or more second doses of about 200 mg, the second dose being administered every four weeks (q4w).

[0451] 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 exemplary 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 second or maintenance doses of about 200 mg, the second dose being administered every other week (q2w). In certain exemplary 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 exemplary 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 second or maintenance doses of about 200 mg, and the second dose is administered every other week (q2w).

[0452] 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 a particularly exemplary embodiment, 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 second or maintenance doses of about 300 mg, the second dose being administered every other week (q2w).

[0453] 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 particularly 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 second or maintenance doses of about 300 mg, the second dose being administered every other week (q2w).

[0454] 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 solution of the IL-4R antagonist in a prefilled device is used to deliver 300 mg of the IL-4R antagonist in an injection of 2 mL. 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 solution of the IL-4R antagonist in a prefilled device is used to deliver 200 mg of the IL-4R antagonist in an injection of 1.14 mL.

[0455] Combination therapy Certain embodiments of the methods described herein include administering to a subject one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the 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 for treating CSU or related conditions or complications are provided, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0456] 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. Administration "concurrently 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 of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising an IL-4R antagonist, or is administered to the subject as a combined single-dose formulation comprising the additional therapeutic agent and the IL-4R antagonist.

[0457] In an exemplary embodiment, the additional therapeutic agent administered in combination with the IL-4R antagonist is a basic therapy. In an exemplary embodiment, the basic therapy comprises one or both of an antihistamine and an anti-IgE antibody. In certain embodiments, the method reduces the need for basic therapy. For example, in certain embodiments, the method reduces the dose and / or frequency of basic therapy.

[0458] The additional therapeutic agent may be, for example, another IL-4R antagonist (e.g., one or more suitable IL-4R antagonists listed in Tables 1-4), an IgE antagonist, an antihistamine, 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, the anti-IL-6R antibodies described in U.S. Pat. No. 7,582,298), or an IL-17 antagonist.

[0459] In an exemplary embodiment, the additional therapeutic agent is an H1 antihistamine. In some embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0460] In further exemplary embodiments, the additional therapeutic agent is an anti-IgE antibody. In some embodiments, the anti-IgE antibody is omalizumab. In some embodiments, the anti-IgE antibody is ligelizumab.

[0461] In some embodiments, the additional therapeutic agent administered in combination with IL-4R antagonist is a vaccine.In certain exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine.In certain exemplary embodiments, the vaccine is a live (e.g., live attenuated) viral vaccine or a live (e.g., live attenuated) bacterial vaccine.

[0462] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (e.g., HepB (Engerix-B, Recombivax)). HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also called IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (MMR II), MMRV (ProQuad)), meningococcal (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMRII), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcus (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax Rabies, RabAvert), Rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), Rubella (e.g., MMR (MMR II), MMRV (ProQuad)), Herpes Zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), Smallpox (e.g., Vaccinia (ACAM2000)), Tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), Tuberculosis, Typhoid (e.g., Typhoid Oral (Vivotif), Typhoid Polysaccharide (Typhim Vi), Chickenpox (e.g., VAR (Varivax), MMRV (ProQuad)), Yellow Fever (e.g., YF (YF-Vax)), and the like. Suitable vaccines are also listed in the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes. In some embodiments, the vaccine is for tetanus, diphtheria, whooping cough and / or seasonal trivalent / quadrivalent influenza vaccines.

[0463] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, the subject treated with the vaccine is treated with an IL-4R antagonist for CSU at the same time.

[0464] In certain embodiments, treatment with the IL-4R antagonist is discontinued or terminated prior to treatment with the vaccine. In certain embodiments, treatment with the IL-4R antagonist is discontinued for about 1 to about 9 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9 or more) weeks prior to administration of the vaccine. In some embodiments, treatment with an IL-4R antagonist is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 1 about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days.

[0465] In certain embodiments, treatment with the IL-4R antagonist is resumed after treatment with the vaccine. In certain embodiments, treatment with the IL-4R antagonist is resumed about 1 to about 14 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, about 9½, about 10, about 10½, about 11, about 11½, about 12, about 12½, about 13, about 13½, about 14, about 14½, or more) weeks after administration of the vaccine. In some embodiments, treatment with an IL-4R antagonist is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about or about 90 days.

[0466] In certain embodiments, the effectiveness of the IL-4R antagonist is not diminished by administration in combination with a vaccine or by subsequent administration of the vaccine.

[0467] In some embodiments, the efficacy of the vaccine is not diminished by administration in combination with an IL-4R antagonist, or by prior and / or subsequent administration of an IL-4R antagonist, in some embodiments, subjects develop seroprotective neutralizing titers to the vaccine when the vaccine is co-administered with an IL-4R antagonist.

[0468] In certain exemplary embodiments, a subject is administered a vaccine described herein, where the subject is administered at least one dose of an IL-4R antagonist prior to, during, or after administration of the vaccine.

[0469] 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 to a patient a single initial dose of an IL-4R antagonist, followed by one or more second doses of the IL-4R antagonist, optionally followed by one or more third doses of the IL-4R antagonist.

[0470] Provided are methods 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 2 weeks (every 2 weeks is used synonymously with every other week, once every 2 weeks or q2w), once every 3 weeks (once every 3 weeks or q3w), once every 4 weeks (monthly or q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 7 weeks (q7w), once every 8 weeks (q8w), once every 9 weeks (q9w), once every 10 weeks (q10w), once every 11 weeks (q11w), once every 12 weeks (q12w), or less frequently, so long as a therapeutic response is achieved.

[0471] In certain embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a weekly administration 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 employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a biweekly administration 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 employed (biweekly is used synonymously with every other week, biweekly, or q2w). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a triweekly administration 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 employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, administration once every four weeks (monthly administration) 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 employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, administration 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 employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, administration 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 employed. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, administration may be performed once every 8 weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, administration may be performed once every 12 weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. In certain exemplary embodiments, the route of administration is subcutaneous.

[0472] The term "week" refers to a period of (n x 7 days) ± 3 days, e.g., (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 weeks or more.

[0473] The terms "initial dose", "second dose" and "third dose" refer to the time sequence of administration of IL-4R antagonist. Thus, "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as "baseline dose" or "loading dose"); "second dose" is the dose administered after the initial dose; and "third dose" is the dose administered after the second dose. The initial dose, second dose and third dose can all contain the same amount of IL-4R antagonist and can differ from each other in terms of the number of administrations. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial dose, second dose and / or third dose varies from each other during treatment (e.g., adjusted up or down as necessary). In certain embodiments, two or more doses (e.g., 2, 3, 4, or 5) are administered at the beginning of the treatment regimen as a "loading dose", followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the maintenance dose may be less than the loading dose. For example, one or more initial or loading doses of 600 mg or 400 mg of the IL-4R antagonist may be administered, followed by a second or maintenance dose of about 75 mg to about 400 mg. In one embodiment, the second dose / 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 the IL-4R antagonist may be administered, followed by a second / maintenance dose of about 300 mg or about 200 mg, respectively. In one embodiment, the loading dose is 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.

[0474] 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.

[0475] In certain embodiments, the second dose is about 50 mg to about 600 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist.

[0476] 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.

[0477] In some embodiments, the subject is a child and weighs less than 15 kg and at least 5 kg, and the initial dose comprises 200 mg of the antibody or antigen-binding fragment thereof and one or more second doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0478] In some embodiments, the subject is a child and weighs 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 second doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0479] In some embodiments, the subject is a child and weighs 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 second doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0480] In some embodiments, the subject is a child and weighs more than 30 kg, and the initial dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more second 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, once every 2 weeks or q2w).

[0481] 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 the one or more second doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, once every two weeks or q2w). In an exemplary embodiment, the subject is an adolescent, weighs greater than or equal to 30 kg and less than 60 kg, and the initial dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and the one or more second doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, once every two weeks or q2w).

[0482] 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 second doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, once every two weeks, or q2w).

[0483] 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 second doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, once every two weeks or q2w).

[0484] In an exemplary embodiment, each second and / or third 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 a dose of an IL-4R antagonist administered to a patient prior to administration of the next dose in a series of multiple doses in a sequence that does not interrupt that dose.

[0485] The method can include administering multiple second and / or third doses of IL-4R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. For example, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0486] In embodiments that include multiple second doses, each second dose may be administered at the same times as the other second doses. For example, each second dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments that include multiple third doses, each third dose may be administered at the same times as the other third doses. For example, each third dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the number of times that the second and / or third doses are administered to the patient may vary during the treatment regimen. The number of administrations may also be adjusted during treatment by the physician according to the needs of the individual patient after clinical testing.

[0487] Methods are provided that involve sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient to treat CSU or an associated condition. In some embodiments, the methods involve administering one or more doses of an IL-4R antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of a second therapeutic agent. For example, one or more doses of about 75 mg to about 600 mg of an IL-4R antagonist can be administered, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of a second therapeutic agent (e.g., an H1 antihistamine or an anti-IgE antibody, as described elsewhere herein) to treat, alleviate, relieve or ameliorate one or more symptoms of CSU. In some embodiments, the IL-4R antagonist is administered in one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses resulting in the improvement of one or more CSU-related parameters, and then the second therapeutic agent is administered to prevent the recurrence of at least one symptom of CSU. Alternative embodiments involve the simultaneous administration of the IL-4R antagonist and the second therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the IL-4R antagonist are administered, and the second therapeutic agent is administered in a separate dosage at similar or different times relative to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0488] 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 once every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks or more. In a detailed embodiment, the IL-4R antagonist is administered for at least 24 weeks.

[0489] In certain embodiments, a kit is provided that includes a dosage form of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), where 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, for the treatment of CSU. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain embodiments, the antibody is dupilumab.

[0490] The kit can include a label or package insert, which includes instructions for administering the dosage form for the treatment of CSU. The instructions can describe a dosing regimen as further described herein for the treatment of CSU.

[0491] Treatment population The methods provided herein include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. The phrase "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of CSU or that has been diagnosed with CSU.

[0492] In a related embodiment, the "subject in need thereof" is a subject who has been prescribed or is currently taking an antihistamine prior to receiving the IL-4R antagonist. In some embodiments, the subject is currently taking an H1 antihistamine. In an exemplary embodiment, the subject is currently taking an H1 antihistamine selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine. For example, a method is provided that includes administering an IL-4R antagonist to a patient who has been taking an H1 antihistamine regularly for at least 6 weeks immediately prior to administering the IL-4R antagonist (such prior treatment is referred to herein as "basal treatment").

[0493] In another exemplary embodiment, the "subject in need thereof" is a subject who has been prescribed or is currently taking an IgE antagonist prior to receiving the IL-4R antagonist. A therapeutic method is provided in which baseline therapy is continued in combination with administration of an IL-4R antagonist. For example, a method is provided that includes administering an IL-4R antagonist to a patient who has been receiving a regular course of an IgE antagonist (such treatment history is referred to herein as "baseline therapy") immediately prior to administration of the IL-4R antagonist.

[0494] In yet other embodiments, the amount of H1 antihistamine, IgE antagonist, or both, is tapered before or after initiation of IL-4R antagonist administration.

[0495] In another exemplary embodiment, the "subject in need thereof" has a diagnosis of CSU refractory to H1 antihistamines prior to receiving the IL-4R antagonist. In some embodiments, the subject's CSU symptoms persist despite treatment with an H1 antihistamine (i.e., the subject is resistant to treatment with an H1 antihistamine).

[0496] In a further exemplary embodiment, the "subject in need thereof" is naive to an IgE antagonist, such as omalizumab (ie, the subject has not been previously treated with an IgE antagonist). In another embodiment, the "subject in need thereof" is intolerant to an IgE antagonist, such as omalizumab (i.e., the subject experiences adverse effects associated with IgE antagonist treatment). In another embodiment, a "subject in need thereof" is a poor responder to an IgE antagonist, including omalizumab (i.e., the subject continues to experience CSU symptoms despite treatment with an IgE antagonist).

[0497] 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), subjects 2-11 years of age (2-<12 years of age), and subjects 2-5 years of age (2-<6 years of age). In some embodiments, the "patient in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "patient in need thereof" is selected from the group consisting of adults age 18 years of age or older, adolescents age 12-17 years of age (12-<18 years of age), children age 6-11 years of age (6-<12 years of age), and children age 2-5 years of age (2-<6 years of age). The subject may be under 2 years of age, e.g., 12-23 months of age, or 6-11 months of age. In particularly exemplary embodiments, the subject is a child aged 6-<12 years of age (also referred to herein as a "child" subject). In certain embodiments, the subject in need thereof is a child aged 2-<6 years old having a weight of at least 5 kg and less than 15 kg. In certain embodiments, the subject in need thereof is a child aged 6-<12 years old having a weight of more than 30 kg. In certain embodiments, the subject in need thereof is a child aged 6-<12 years old having a weight of 30 kg or less and at least 15 kg. In certain embodiments, the subject in need thereof is an adolescent aged 12-<18 years old having a weight of at least 60 kg. In an exemplary embodiment, the subject in need thereof is an adolescent aged 12-<18 years old having a weight of less than 60 kg. In another exemplary embodiment, the subject in need thereof is an adolescent aged 12-<18 years old having a weight of 30 kg or more and less than 60 kg.

[0498] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a subject exhibiting a blood eosinophil level of at least 300 cells / microliter; and (b) administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.

[0499] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a patient exhibiting a blood eosinophil level of between 200 and 299 cells / microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0500] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 200 cells / microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0501] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 150 cells / microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0502] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 100 cells / microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0503] In certain embodiments, a method for treating CSU is provided, the method comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 100 cells / microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0504] In some embodiments, a "subject in need thereof" is a subject to be treated with a vaccine, e.g., a viral or bacterial vaccine. In some embodiments, the vaccine is a live vaccine, e.g., a live (e.g., live attenuated) viral vaccine or a live (e.g., live attenuated) bacterial vaccine.

[0505] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (e.g., HepB (Engerix-B, Recombivax)). HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also called IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (MMR II), MMRV (ProQuad)), meningococcal (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMRII), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcus (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax Rabies, RabAvert), Rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), Rubella (e.g., MMR (MMR II), MMRV (ProQuad)), Herpes Zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), Smallpox (e.g., Vaccinia (ACAM2000)), Tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), Tuberculosis, Typhoid (e.g., Typhoid Oral (Vivotif), Typhoid Polysaccharide (Typhim Vi), Chickenpox (e.g., VAR (Varivax), MMRV (ProQuad)), Yellow Fever (e.g., YF (YF-Vax)), etc. Suitable vaccines are also listed in the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes.

[0506] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, the subject treated with the vaccine is treated with an IL-4R antagonist simultaneously for CSU. In some embodiments, the subject discontinues treatment with the IL-4R antagonist prior to administration of the vaccine.

[0507] In certain embodiments, the subject discontinues treatment with an IL-4R antagonist for about 1 to about 9 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, or more) weeks prior to administration of the vaccine. In certain embodiments, the subject discontinues treatment with an IL-4R antagonist for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 28, about 30, or more) weeks prior to administration of the vaccine. 7, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days.

[0508] In certain embodiments, the subject resumes treatment with the IL-4R antagonist after treatment with the vaccine. In certain embodiments, the subject resumes treatment with the IL-4R antagonist 1 to 14 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, about 9½, about 10, about 10½, about 11, about 11½, about 12, about 12½, about 13, about 13½, about 14, about 14½, or more) weeks after administration of the vaccine. In certain embodiments, the subject receives treatment with an IL-4R antagonist for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 2, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90 days.

[0509] Methods for assessing pharmacodynamic CSU-related parameters A method is provided for evaluating one or more pharmacodynamic CSU-related parameters in a subject in need thereof, which is caused by administering a pharmaceutical composition comprising an IL-4R antagonist.A reduction in the incidence of CSU symptoms or an improvement in one or more CSU-related PRO indicators may be correlated with an improvement in one or more pharmacodynamic CSU-related parameters; however, such a correlation is not necessarily observed in all cases.

[0510] Examples of "pharmacodynamic CSU-related parameters" include, for example: (a) biomarker expression levels; and (b) serum protein and RNA analysis. "Improvement of pharmacodynamic CSU-related parameters" refers to, for example, a decrease from baseline in one or more biomarkers, such as IgE, eosinophil levels, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9. As used herein, the term "baseline" with respect to pharmacodynamic CSU-related parameters refers to the value of the pharmacodynamic CSU-related parameter for a patient before or at the time of administration of a pharmaceutical composition described herein.

[0511] To assess the pharmacodynamic CSU-related parameters, the parameters are quantified at baseline and at a time point after administration of the pharmaceutical composition.For example, the pharmacodynamic CSU-related parameters may be measured at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 14 days, or about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or later after the first treatment with the pharmaceutical composition. The difference between the parameter value at a particular time point after the start of treatment and the parameter value at baseline is used to establish whether there is a change, e.g., "improvement" (e.g., increase or decrease, as the case may be, depending on the particular parameter being measured), in the pharmacodynamic CSU-related parameter.

[0512] In certain embodiments, administration of an IL-4R antagonist to a patient causes changes, such as a decrease or increase in the expression of certain biomarkers. CSU-associated biomarkers include, but are not limited to, total IgE, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9. For example, administration of an IL-4R antagonist to a CSU 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. Expression of biomarkers 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).

[0513] As discussed above, expression of biomarkers 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, and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0514] compound 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, 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 centipoise.

[0515] 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 centipoise.

[0516] 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.

[0517] In a specific embodiment, the antibody comprises dupilumab. The term "dupilumab" also includes any biosimilars thereof, unless otherwise specified.

[0518] Suitable stabilized formulations are also described in US Pat. No. 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[0519] 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.

[0520] 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. See, e.g., Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, volumes I and II (D.N. Glover, eds., 1985); Oligonucleotide Synthesis (M.J. Gait, eds., 1984); Nucleic Acid Hybridization [B.D. Hames and S.J. Higgins, eds. (1985)]; Transcription And Translation [B.D. Hames and S.J. Higgins, eds. (1984)]; Animal Cell Culture [R.I. Freshney, ed. (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0521] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein are incorporated herein by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right to physically incorporate into this application any and all materials and information from such articles, patents, patent applications, or other physical and electronic documents.

[0522] Although the present invention has been described with reference to specific embodiments thereof, those skilled in the art should understand that various modifications can be made and equivalents can be substituted without departing from the true spirit and scope of the present invention. It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein can be made using appropriate equivalents without departing from the scope of the embodiments disclosed herein. In addition, many modifications can be made to adapt a particular situation, material, composition, process, process step(s) to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. Now, certain embodiments have been described in detail, but the same will be more clearly understood by reference to the following examples, which are intended to be illustrative only and not limiting. EXAMPLES

[0523] The following examples are presented 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 consider to be 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 indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0524] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1" or DUPIXENT®). EXAMPLES

[0525] Three randomized, double-blind, placebo-controlled, multicenter, parallel-group studies of dupilumab in omalizumab-naive patients and in patients who are omalizumab intolerant or incomplete responders and who have chronic spontaneous urticaria (CSU) that remains symptomatic despite the use of H1 antihistamine treatment

[0526] Rationale for the test Chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria (CIU), is a common condition characterized by pruritic wheals (urticaria) with or without angioedema that persist for more than six weeks without a specific known cause. Patients with chronic spontaneous urticaria experience debilitating urticaria and pruritus secondary to dysregulation of mast cells and basophils, with or without angioedema. Degranulation of these cell types by activation of Fc gamma receptors (FcεRI) via agonistic autoantibodies or antigen-crosslinked cell surface-bound immunoglobulin E (IgE) releases histamine and other inflammatory mediators, causing local tissue edema and pruritus. Many symptoms of urticaria are mediated primarily by the action of histamine (a mast cell mediator) on H1-receptors, and treatment with H1-antihistamines (H1-AH) is the mainstay of treatment (see Zuberbier T et al. The EAACI / GA2LEN / EDF / WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-414). Approximately 50% of patients achieve symptom control with conventional H1-AH therapy (see Kaplan AP. Chronic spontaneous urticaria: pathogenesis and treatment considerations. Allergy Asthma Immunol Res. 2017;9(6):477-82). Even with increased doses of antihistamines, approximately 40%-50% of patients remain symptomatic.

[0527] The mechanism by which omalizumab exerts its therapeutic effect is thought to be constrained by the reduction of serum IgE and the associated downregulation of IgE receptors. Although targeting IgE with omalizumab has been successful in treating patients with CSU, not all patients respond equally to this treatment (see Maurer M et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-35). Thus, there is an unmet need.

[0528] One possibility to meet this need is novel therapies that target signaling pathways important for mast cell and basophil survival and function. Blockade of IL-4 / IL-13 with dupilumab represents a new therapeutic approach for patients with CSU. Because this is a novel therapy that acts further upstream than IgE-targeted therapies, the clinical trial described here will demonstrate efficacy of dupilumab in patients who have failed antihistamines alone, in patients who have failed both antihistamines and omalizumab, or in patients who were intolerant to omalizumab. Each of the two trials is equally important to begin to address the extent to which dupilumab inhibits urticaria and / or angioedema by IgE-dependent and -independent mechanisms.

[0529] Dupilumab is a fully human monoclonal antibody (mAb) directed against the interleukin-4 receptor alpha subunit (IL-4Rα), a component of the interleukin (IL)-4 receptors types I and II, the latter of which is also the receptor for IL-13. Binding of dupilumab to IL-4Rα blocks both IL-4 and IL-13 signaling.

[0530] Test Overview The protocol includes three studies in CSU patients who still have symptoms despite the use of H1-AH treatment, one study includes omalizumab-naive patients (study A) and one includes patients who are intolerant or incomplete responders to omalizumab (study B). Study C will be performed in the same study population with a similar design as study A, fulfilling the health authorities' requirement to provide data from two adequate and well-controlled clinical trials. The three studies are of similar design, two studies (study A and study C) include participants who are omalizumab-naive, and one study (study B) includes participants who are intolerant or incomplete responders to omalizumab. Study A and study C include adults, adolescents (≥12–<18 years) and children (≥6–<12 years in some selected countries). Study B includes adults and adolescents. The selected dosing regimens are dupilumab 300 mg every 2 weeks (q2w) with a loading dose of 600 mg for adults, 300 mg q2w with a loading dose of 600 mg for adolescents >60 kg at screening, or 200 mg q2w with a loading dose of 400 mg for adolescents <60 kg at screening, and 200 mg q2w with a loading dose of 400 mg for children ≥6 to <12 years weighing ≥30 kg at screening, or 300 mg q4w with a loading dose of 600 mg for children ≥6 to <12 years weighing <30 kg and ≥15 kg at screening.

[0531] In all three trials, the target population consists of CSU patients who are still symptomatic despite treatment with H1-AH alone, and these patients have a significant unmet medical need. The updated international guideline for the definition, classification, diagnosis and management of urticaria (Zuberbier T et al. The EAACI / GA2LEN / EDF / WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy, 2018;73(7):1393-414) provides evidence-based recommendations and treatment algorithms. Steps 1 and 2 of this algorithm are the use of non-sedating H1-AH at approved doses or at increased doses (up to 4x), respectively. The treatment options in step 3 are omalizumab, cyclosporine A, or montelukast (LTRA). In this protocol, H1-AH up to 4x the approved dose can be used as background medication (steps 1 and 2).

[0532] The total number of participants expected across the three trials is approximately 384 randomized participants.

[0533] Approximately 130 participants will be randomized in Study A, which will take place in the omalizumab-naive population. This corresponds to approximately 65 participants randomly assigned to each intervention arm. Approximately 5% of participants enrolled will be adolescents, and up to approximately 5% of participants enrolled will be children ≥6-<12 years of age (some selected countries recruited both children and adolescents). The actual number of participants randomized in Study A was 138.

[0534] Approximately 104 participants were planned to be randomized in Study B, which will be conducted in the omalizumab intolerant or incomplete responder population. Approximately % of the enrolled participants were adolescents (recruited in some selected countries). Recruitment for the study has been closed, and the final number of randomized participants in Study B was 108. The original 83 randomized participants completed the 24-week treatment period by the interim analysis cutoff date, and an interim analysis was performed when the futility criteria were met. Participants still receiving study treatment will be discontinued, and all participants will be required to complete the follow-up period.

[0535] Omalizumab incomplete responders were defined as participants who were treated with at least 300 mg omalizumab every 4 weeks (q4w) for at least 3 months (minimum 3 injections) and had an inadequate response resulting in omalizumab discontinuation, as confirmed by investigator assessment.

[0536] the purpose Primary Objective To demonstrate efficacy of dupilumab in study participants with CSU who remain symptomatic despite use of H1-AH (Study A: omalizumab naive, Study B: omalizumab intolerant or incomplete responder).

[0537] Secondary Objectives - To demonstrate the effect of dupilumab on the composite endpoint of urticaria activity and on pruritus or urticaria separately at various time points. - To demonstrate efficacy of dupilumab for angioedema. - To demonstrate the efficacy of dupilumab in controlling urticaria. - Demonstrate improvement in health-related quality of life, overall disease status and severity. - To evaluate the ability of dupilumab to reduce the proportion of patients requiring treatment with oral corticosteroids (OCS). - Evaluate safety endpoints. - To evaluate the immunogenicity of dupilumab.

[0538] Other purposes - To validate the outcome measures in the Urticaria Composite Score and its components - Demonstrate health-related quality of life and health status indicators

[0539] Endpoints Primary Endpoint: - Change from baseline in weekly Itch Severity Score (ISS7) at Week 24 (excluding EU and EU Reference Countries). - In the EU and EU reference countries only: change from baseline in weekly urticaria activity score (UAS7, a patient-reported composite score of itch and urticaria) at Week 24.

[0540] Secondary Endpoints: - Week 12 * and change from baseline in weekly urticaria activity score (UAS7) at week 24 (excluding EU and EU reference countries). - Week 12 * and change from baseline in ISS7 at week 24 (EU and EU reference countries). - Change from baseline in weekly Urticaria Severity Score (HSS7) at Weeks 12 and 24. - Time to ISS7 Minimum Importance (MID) (ISS7 ≥ 5) response. - Week 12 * and the 24th week * Percentage of ISS7 MID (≥5 points) responders in the study. - Change from baseline in ISS7 at all time points (onset of effect assessed at the first p<0.05 and remaining significant for subsequent measures up to Week 24). - Week 12 * and 24th week * The proportion of patients with UAS7≦6. - Week 12 * and 24th week * Percentage of patients with UAS7=0. - Change from baseline in 7-day Angioedema Activity Score (AAS7) at Weeks 12 and 24. - Change from baseline in the Urticaria Control Trial (UCT) at Weeks 12 and 24. - Proportion of well-controlled patients (UCT ≥ 12) at weeks 12 and 24. - Change from baseline in Health-Related Quality of Life (HRQoL) by the Dermatology Life Quality Index (DLQI) in patients ≥ 16 years old and the Paediatric Dermatology Life Quality Index (CDLQI) in patients ≥ 6 to < 16 years old, at Weeks 12 and 24. - Patient Global Impression (PGIC) of change in CSU at weeks 12 and 24. - Change from baseline in Global Patient Impressions (PGIS) of CSU severity at Weeks 12 and 24. - Time-to-event and proportion of patients who received OCS versus CSU during the scheduled treatment period. - Proportion of participants who experienced treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs). - The incidence of treatment-emergent anti-drug antibodies (ADA) over time to dupilumab.

[0541] Measurement Appropriateness The assessments used in this study were standard for the evaluation of treatment in participants with CSU, which is characterized by recurrent episodes of pruritic urticaria, angioedema, or both for more than 6 weeks (Zuberbier T et al. Epidemiology of urticaria: a representative cross-sectional population survey. Clin Exp Dermatol. 2010; 35:869-73; Grob JJ et al. Comparative study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life. Br J Dermatol. 2005; 152:289-95).

[0542] The primary endpoints were the change from baseline in the weekly itch severity score (ISS7) at week 24 (except in EU and EU reference countries) and the change from baseline in the weekly urticaria activity score (UAS7, a patient-reported composite score of itch and urticaria) at week 24 (in EU and EU reference countries). Itch is one of the most important patient-related symptoms affecting quality of life in CSU and is highly related to how patients perceive their disease. ISS7 is one of the two components of the urticaria activity score UAS7 (a composite score assessing both itch and urticaria), which is an established and widely accepted patient-reported outcome tool to prospectively measure CSU activity (Mlynek A et al. How to assess disease activity in patients with chronic urticaria? Allergy. 2008; 63:777-80) and has been used as the primary outcome parameter in most clinical trials of CSU in recent years. (Maurer M et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.N Engl J Med.2013;368(10):924-35; Casale TB et al. Similar efficacy with omalizumab in chronic idiopathic / spontaneous urticaria despite different background therapy.J Allergy Clin Immunol Pract.2015;3(5):743-50).

[0543] Angioedema has been described as a very common clinical feature in CSU. Up to 40% of patients with CSU present with mixed urticaria and angioedema, and 10% present with angioedema alone. (Moolani Y, Lynde C, Sussman G.Advances in understanding and managing chronic urticaria [version 1; peer review:2 approved].F1000Res.2016;5.pii:F1000 Faculty Rev-177.Available from:URL:https: / / doi.org / 10.12688 / f1000research.7246.1). We investigated angioedema activity by evaluating the Angioedema Activity Score (AAS), a well-developed and well-validated instrument to measure angioedema activity in CSU patients (Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92).

[0544] In addition to the UAS and angioedema, which provide an overview of signs and symptoms, it is important to gain insight into the patient's self-assessment of disease control. To obtain a complete picture of the disease and to evaluate disease control over the course of treatment, we used the urticaria control test, a well-developed and validated instrument in CSU patients. (Weller K et al. Development and validation of the urticaria control test: A patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014; 133:1365-72).

[0545] Finally, patients with CSU experience considerable HRQoL impairment. Therefore, we assessed two instruments developed to measure dermatology-specific quality of life in adult and pediatric patients, the Dermatology Life Quality Index (DLQI) or the Pediatric Dermatology Life Quality Index (CDLQI), respectively (Finlay AY, Khan GK. Dermatology life quality index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6; Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial validation and practical use. Br J Dermatol. 1995;132(6):942-9).

[0546] Study design An overview of the study design is shown in Figure 1. The protocol included two studies of identical design, one in omalizumab-naive participants (Study A) and one in omalizumab-intolerant or incomplete responder participants (Study B). Study A included adults, adolescents (≥12 to <18 years) and children (≥6 to <12 years in some selected countries). Study B included adults and adolescents. Both studies were 24-week double-blind randomized placebo-controlled studies evaluating the use of dupilumab in patients with CSU who still had symptoms despite the use of H1-AH. The studies evaluated the effect of dupilumab on itch and urticaria scored separately once daily and on a 7-day average, frequency / severity of itch and urticaria by urticaria activity score (composite) scored on a 7-day average, angioedema activity, urticaria control, patients' health-related quality of life (HRQoL), and health status.

[0547] An omalizumab incomplete responder is defined as a patient who was treated with at least 300 mg omalizumab subcutaneously (SC) every 4 weeks (q4w) for at least 3 months (minimum 3 injections) and had an inadequate response resulting in omalizumab discontinuation, as confirmed by investigator assessment. Information on intolerance or incomplete response to omalizumab must be fully documented in the patient's medical record.

[0548] Both studies, A and B, evaluated the effects of dupilumab on itch and urticaria frequency / severity scored individually, on angioedema activity, urticaria control via a urticaria activity score (composite score), and on participants' HRQoL and health status.

[0549] Each study, A and B, is a two-arm parallel treatment study blinded / masked to participants and investigators, respectively. The studies are double-blind studies of treatment with dupilumab or placebo, but are not blinded to weight-based dose levels due to the different volume sizes (2 mL and 1.14 mL) of the dupilumab dose levels (300 mg / matching placebo or 200 mg / matching placebo) used for different weight categories in adolescents and children ≥6 to <12 years old. In addition, in children, they are not blinded to the dose regimen due to the different dosing frequency of IMP (q4w vs q2w). The activity schedule is shown in Figure 2.

[0550] Two (Studies A and B) consisted of three periods each: - Screening period (2-4 weeks). - IMP Treatment Duration (24 weeks ± 3 days): Approximately 234 participants (130 participants in Study A and 104 participants in Study B) will be randomized (1:1) to one of the following treatments: Dupilumab: Adults: 300 mg every 2 weeks (q2w); Adolescents: 200 mg q2w for adolescents <60 kg at screening or 300 mg q2w for adolescents ≥60 kg at screening; Study A: Children ≥6 to <12 years: 200 mg q2w for children ≥30 kg at screening and 300 mg q4w for children <30 kg to ≥15 kg at screening; Matched placebo

[0551] A loading dose equivalent to the assigned treatment arm will be administered on day 1. Patients assigned to dupilumab 300 mg q2w / q4w or matching placebo arm will receive two 2 mL injections on day 1. Patients assigned to dupilumab 200 mg q2w or matching placebo arm will receive two 1.14 mL injections on day 1. - Time period after IMP treatment (12 weeks ± 3 days).

[0552] In each of the two studies, participants continued their established standard-of-care background therapy with long-acting, non-sedating H1-AH at up to four times the recommended dose. If patients were taking more than four times the recommended dose at the screening visit (Visit 1), the investigators could adjust the patient's dose within the range specified at the screening visit (Visit 1). Patients continued to take the same dose daily for the duration of the study unless they experienced a relapse such that rescue treatment was initiated. All participants taking 1 to 3 times the approved H1-AH dose (the maintenance dose used at screening) were permitted to take additional doses of H1-AH medication as rescue treatment during the screening, treatment, and follow-up periods, as long as the dose did not exceed four times the recommended dose. If symptoms were still not controlled after increasing H1-AH to the maximum tolerated dose, participants could take OCS for short periods as rescue treatment during the treatment and follow-up periods. Participants already taking four times the approved H1-AH dose were allowed to take oral corticosteroids (OCS) for short periods as rescue treatment during the treatment and follow-up periods, but for the primary analysis, data collected after OCS use were considered missing and the worst post-baseline value before OCS use was used.

[0553] Scientific basis for study design In each of Studies A and B, a randomized placebo-controlled study design evaluating the effect of IMP in patients with CSU who have moderate to severe symptoms in addition to optimized background therapy was considered to be the most appropriate design to investigate the efficacy and safety of dupilumab in patients with CSU who remain symptomatic despite the use of H1-AH and who are omalizumab-naive or intolerant or incomplete responder.

[0554] Study A targeted omalizumab-naïve patients. More than 50% of CSU patients do not respond to H1 antihistamine treatment. (Zuberbier T et al. The EAACI / GA2LEN / EDF / WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-414; Zuberbier T et al. The EAACI / GA(2)LEN / EDF / WAO guideline for the definition, classification, diagnosis, and management of urticaria:the 2013 revision and update. Allergy. 2014;69(7):868-87).

[0555] Study B targeted omalizumab-treated CSU patients. Approximately 20%-40% of patients do not respond to omalizumab and remain without an effective third-line treatment, and these patients have the greatest unmet medical need. (Zuberbier T et al. The EAACI / GA2LEN / EDF / WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-414). This study also targeted omalizumab-intolerant patients.

[0556] The inclusion of approximately 5% of adolescent patients in Study A and approximately 5% of adolescent patients in Study B is consistent with the omalizumab clinical development program and approximates the prevalence of adolescent patients with CSU. (Zuberbier T, Abeler W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW et al. EAACI / GA(2)LEN / EDF / WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy. 2014;69(7):868-87).

[0557] Definition of Exam Completion Participants are considered to have completed the study if they completed all phases of the study, including the last end-of-study (EOS) visit. Participants are considered completers if they discontinue the treatment period early but complete follow-up until the scheduled EOS visit. Overall EOS is defined as the date of the last visit of the last participant in the study.

[0558] Study population Inclusion criteria For each of the two studies, A and B, participants are eligible to participate in the study only if they meet all of the following criteria: age I1. Study A and Study C: Participants must be ≥ 6-80 years old at the time of signing informed consent. Study B: Participants must be ≥ 12 years (or the legal minimum age for adolescents in the country where the investigational site is located) to 80 years at the time of signing the informed consent. Note: In countries where local regulations do not allow enrollment of children ≥6 to <12 years of age, recruitment is limited to those ≥12 years of age (or the minimum legal age for adolescents in the site's country). In countries where local regulations do not allow enrollment of children and adolescents ≥6 to <12 years of age, recruitment is limited to those ≥18 years of age.

[0559] Participant type and disease characteristics Participants with a diagnosis of refractory CSU for H1-AH at the time of randomization, as defined by all of the following: I2. Diagnosed with CSU >6 months prior to the screening visit (Visit 1). I3. Presence of pruritus and urticaria for >6 consecutive weeks at any time prior to the Screening Visit (Visit 1) despite use of H1-AH during this period. I4. Participants using study-defined H1-AH for CSU treatment. Note: Participants should maintain their pre-screening non-sedating H1-AH dose. Only up to 4x the recommended dose is permitted. If a participant is taking more than 4x the recommended dose at screening, the investigator may adjust the participant's dose to the prescribed range at the Screening Visit (Visit 1). The H1-AH dose must be stable for at least 3 consecutive days prior to the Screening Visit (Visit 1). I5. 7 days prior to randomization: - UAS7>16 - ISS7>8 Note: Eligibility for this study required complete electronic diaries (e-diaries) (UAS7 and ISS7) for 7 days prior to randomization. I6. Study A (Omalizumab-naive): Omalizumab-naive participants. Study B (Omalizumab Intolerance or Incomplete Responders): Omalizumab incomplete responders are defined as patients who were treated with at least 300 mg omalizumab every 4 weeks (q4w) for at least 3 months (minimum 3 injections) and had an inadequate response resulting in omalizumab discontinuation, as confirmed by investigator assessment. Note: Information regarding intolerance or incomplete response to omalizumab must be fully documented in the patient's medical record. I7. Participants are willing and able to complete an e-diary of symptoms daily for the duration of the study.

[0560] Test Overview Number of participants The total number of participants expected in the two trials was approximately 234 randomised participants.

[0561] In Study A, conducted in the omalizumab-naive population, approximately 130 participants were randomized, corresponding to approximately 65 participants randomly assigned to each intervention arm. Approximately 5% of participants enrolled were planned to be adolescents, and up to approximately 5% were planned to be children aged ≥6–<12 years (both children and adolescents were recruited in some selected countries).

[0562] Study B, conducted in the omalizumab intolerant or incomplete responder population, randomized approximately 104 participants, corresponding to approximately 52 participants randomly assigned to each intervention arm. Approximately 5% of enrolled participants were planned to be adolescents (recruited in several selected countries). An interim analysis was performed when the first 80 randomized patients completed the 24-week treatment period by the interim analysis cutoff date.

[0563] Approximately 30% to 40% of enrolled participants were expected to have angioedema.

[0564] Omalizumab incomplete responders were defined as participants who were treated with at least 300 mg omalizumab every 4 weeks (q4w) for at least 3 months (minimum 3 injections) and had an inadequate response resulting in omalizumab discontinuation, as confirmed by investigator assessment.

[0565] Intervention group and duration Patients who met the inclusion and exclusion criteria were randomized (1:1) to one of the following investigational medicinal product (IMP) treatment arms: - Dupilumab: - Adults: 300 mg every 2 weeks (q2w) Adolescents: 200 mg q2w for adolescents <60 kg at screening, 300 mg q2w for adolescents ≥60 kg at screening - Study A (only): Children ≥ 6 to < 12 years: 200 mg q2w for children ≥ 30 kg at screening, 300 mg q4w for children ≥ 15 kg at screening - Matched placebo

[0566] Study period (per participant) - Screening period (2~4 weeks) - Randomized IMP treatment period (24 weeks) - After IMP treatment (12 weeks)

[0567] Study intervention Investigational Drug: - Dupilumab 300 mg and matching placebo dupilumab 300 mg will be supplied in visually indistinguishable prefilled syringes. -Dupilumab 200 mg and matching placebo dupilumab 200 mg will be supplied in visually indistinguishable prefilled syringes. Dupilumab formulation: - Dupilumab 300 mg: Dupilumab solution at 150 mg / mL is loaded into a prefilled syringe to deliver 300 mg in 2 mL of injection, or - Dupilumab 200 mg: Dupilumab solution at 175 mg / mL is loaded into a prefilled syringe to deliver 200 mg in 1.14 mL of injection Route of administration: Subcutaneous (SC) injection Dosage regimen: - Two loading doses on day 1, followed by one injection q2w / q4w placebo: formulation: - Dupilumab 300 mg matched with placebo: 300 mg of the same formulation as the active drug without dupilumab was loaded into a prefilled syringe and placebo was delivered in a 2 mL injection, or - Dupilumab 200 mg matched with placebo: 200 mg of the same formulation as the active drug without dupilumab will be loaded into a prefilled syringe and delivered in 1.14 mL of injection Route of administration: SC injection Dosage regimen: - Two loading doses on day 1, followed by one injection q2w / q4w Participants continued their established standard of care background therapy with a long-acting, non-sedating H1-AH up to four times the recommended dose. If at the screening visit (Visit 1) the participant was taking more than four times the recommended dose, the investigator could adjust the participant's dose within the range specified at the screening visit (Visit 1). Participants continued to take the same dose daily for the duration of the study unless they experienced a relapse that would allow rescue treatment to be initiated. The following list of H1-AHs is permitted and includes recommended doses: - Cetirizine 10 mg once daily (qd). - Levocetirizine hydrochloride 5 mg qd - Fexofenadine 60 mg twice daily or 180 mg qd - Loratadine 10 mg qd - Desloratadine 5 mg qd - Bilastine 20 mg qd - Rupatadine 10 mg qd - Other H1-AH after consultation with sponsor

[0568] Study intervention Study intervention is defined as an investigational intervention, commercial product, placebo or medical device intended to be administered to participants in Study A, Study B or Study C according to the study protocol. A summary of study interventions administered is provided in Table 5 below.

[0569] [Table 5-1] [Table 5-2]

[0570] During the 24-week treatment period, the investigational product (IMP) will be administered every 14 ± 3 days (q2w) and every 28 ± 3 days (q4W) for children <30 kg and ≥15 kg.

[0571] The investigator or their designee trained the participant (or parent / legal representative / caregiver) on how to prepare and inject the IMP at Visit 2. Site staff injected the first of two injections. The participant (or parent / legal representative / caregiver) administered the second injection under the supervision of the investigator or designee.

[0572] When participants attend the study visit, IMP will be administered following clinical procedures and blood sampling. Patients should be monitored for at least 30 minutes. The monitoring period may be extended according to country- or site-specific requirements.

[0573] If the participant (or parent / legal authorized representative / caregiver) is unable or unwilling to administer the IMP, injections will be administered at the site via an unscheduled visit; alternatively, arrangements can be made for qualified site personnel and / or health professionals (e.g., visiting nurse services) to administer the IMP for doses that are not scheduled to be administered at the study site.

[0574] Subcutaneous injection sites will alternate between the upper thigh, abdominal quadrants, or upper arm, with no double injections in the same site during consecutive doses. Injections in the upper arm may only be administered by trained individuals (parent / legally authorized representative / caregiver trained by the investigator or co-investigator) or healthcare professionals, not by the participant themselves. IMP injections should be avoided in areas where patients have urticaria or angioedema.

[0575] Participants / guardians / legal representatives / caregivers should be trained by 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 as per national or local requirements), and in case of hypersensitivity symptoms, patients should contact their healthcare provider / emergency.

[0576] For off-site administration, a paper diary will be provided to record injection-related information, which will be kept as the source data for the patient's study file.

[0577] Non-investigational drugs Participants will continue their established standard of care background therapy with up to four times the recommended dose of a long-acting, non-sedating H1-AH. If the participant is taking more than four times the recommended dose at the screening visit (Visit 1), the investigator may adjust the participant's dose within the range specified at the screening visit (Visit 1). Participants should continue taking the same dose daily for the duration of the study unless they experience a relapse such that rescue treatment is initiated. The following list of H1-AHs is permitted and includes recommended doses: - Cetirizine 10 mg once daily (qd). - Levocetirizine hydrochloride 5 mg qd - Fexofenadine 60 mg twice daily or 180 mg qd - Loratadine 10 mg qd - Desloratadine 5 mg qd - Bilastine 20 mg qd - Rupatadine 10 mg qd - Other H1-AH after consultation with sponsor

[0578] For other information related to H1-AH, including safety precautions, see the National Product label.

[0579] How patients are assigned to treatment groups Patients were randomized to treatment arms in a 1:1 ratio. Randomization was first stratified by age (adults vs adolescents vs children in study A, adults vs adolescents in study B; children to approximately 5% of the total sample size in study A, and adolescents to approximately 5% of the total sample size in studies A and B, respectively). In adults, randomization was further stratified by country. In adolescents / children ≥ 6 to < 12 years, randomization was not further stratified.

[0580] Approximately 30% to 40% of enrolled participants were expected to have angioedema.

[0581] A randomized participant is defined as a participant who is assigned to a randomized intervention (i.e., a participant enrolled in the IRT), regardless of whether the treatment was administered. Participants will not be randomized more than once in the study.

[0582] Blinding method Dupilumab 300 mg / 200 mg and placebo-matched dupilumab 300 mg / 200 mg were provided in identically matched 2 mL / 1.14 mL prefilled syringes to ensure visual indistinguishability for each dose. Syringes and boxes were labeled with treatment kit numbers. These are double-blind studies of treatment with dupilumab or placebo, but are not blinded to weight-based dose levels due to the different volume sizes (2 mL and 1.14 mL) of the dupilumab dose levels (300 mg / matched placebo or 200 mg / matched placebo) used for different weight categories in adolescents and children ≥6 to <12 years of age. Additionally, children are not blinded to dose regimens due to the different dosing frequencies of IMP (q4w vs q2w).

[0583] Combination therapy Any medications or vaccines (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) that participants are taking at the time of enrollment or will receive during the study must be recorded together with the following: - Reasons for use - Dates of administration, including start and end dates. - Dosage information, including dose and frequency.

[0584] Long-acting, non-sedating H1-AHs are permitted as background medication and on demand as rescue medication at up to four times the recommended dose.

[0585] The following concomitant treatments are prohibited during the study. Participants receiving these treatments should discontinue study treatment: - Systemic immunosuppressants (immunosuppressants / immunomodulators) e.g., systemic corticosteroids (oral or parenteral [intravenous, intramuscular, SC]), cyclosporine, mycophenolate mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchicine, etc. NOTE: Short periods of OCS are permitted as rescue treatment, as are the antifibrinolytic drugs tranexamic acid and epsilon-aminocaproic acid. - Other monoclonal antibodies (which are biological response modifiers) - Phototherapy (including tanning beds) - IVIG - Plasmapheresis - Other investigational drugs

[0586] The following concomitant therapies were prohibited during the study, but participants receiving these therapies against the protocol did not need to discontinue study treatment: - Topical corticosteroids - Topical calcineurin inhibitors - Topical and oral antihistamines (except those approved as background therapy) - Regular doxepin treatment (daily or every other day for 5 or more consecutive days) - LTRAs and H2 receptor antagonists, unless stable and taken for a condition other than CSU.

[0587] Rescue medication All participants taking 1–3 times the approved nonsedating H1-AH dose (maintenance dose used at screening) were allowed to take additional doses of H1-AH medication as rescue treatment during screening, treatment, and follow-up, as long as the dose did not exceed 4 times the recommended dose. If symptoms were still not controlled after increasing H1-AH to the maximum tolerated dose, participants could take OCS for short periods as rescue treatment during the treatment and follow-up periods. Participants taking a stable dose of 4 times the approved H1-AH dose were allowed to take OCS for short periods as rescue treatment during the treatment and follow-up periods. To ensure consistency, it is recommended that OCS be used for 5–7 days starting at oral prednisone 40 mg (or clinically equivalent OCS), and then tapered at the investigator's discretion, if possible.

[0588] The initial antihistamine maintenance dose will remain stable for the duration of the study, and participants will continue on the maintenance dose even after rescue treatment is no longer required.

[0589] The use of permitted rescue medications should be delayed, if possible, for at least 8 weeks after the start of study treatment. The date and time of administration of rescue medications, as well as the name and dosage regimen of the rescue medication, must be recorded.

[0590] For other information about the H1-AH and OCS, including safety precautions, see National Product.

[0591] Discontinuation of study intervention In rare cases, it may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant should have all planned assessments at the End of Treatment (EOT) visit and complete an early Discontinuation visit.

[0592] Participants may discontinue IMP treatment at any time for any reason, this may be the Investigator's decision. Every effort should be made to document the reason for discontinuation and document it in the eCRF.

[0593] Patients are permanently withdrawn from study treatment for the following reasons: - At the request of the individual or their legally authorized representative (a legally authorized representative is an individual or judicial or other body authorized under applicable law to consent on behalf of the potential participant to the patient's participation in any procedure involving the trial). - If, in the opinion of the Investigator, continuation of the study would be detrimental to the participant's welfare. - At the special request of the sponsor. - Any deviations from the protocol are at the discretion of the investigator or sponsor. - If the investigator-required code is broken, study intervention will be permanently discontinued. - Pregnancy. - Anaphylactic or generalized allergic reaction associated with IMP requiring medical treatment. - Malignancy diagnosed during the study, except for cervical intraepithelial neoplasia, squamous cell carcinoma or basal cell carcinoma of the skin. - Opportunistic infections or other infections whose nature or course suggests an immunocompromised state. - Serum alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and total bilirubin >2×ULN. - Serum ALT >5×ULN if baseline ALT ≤2×ULN, or ALT >8×ULN if baseline ALT >2×ULN. - If a participant develops a medical condition that requires the use of prohibited substances.

[0594] Efficacy evaluation Efficacy data were collected using an electronic device. The e-diary was used for daily recording of PROs such as the UAS7 and AAS7 questionnaires, and the use of H1-AH medications. The device was distributed at the screening visit (Visit 1), including instructions for use, and participants / parents / caregivers / legal representatives were instructed on the use of the device. The recorded information was downloaded from the device every day. At the EOS visit, the e-diary was downloaded and returned to the site. Periodically, site staff should check the information downloaded from the participant's e-diary on the vendor's website. In particular, they should check the disease status reviewing UAS7 and AAS7, compliance with background therapy, and compliance with the e-diary overall. Sites should conduct appropriate follow-up of the subjects. The same questionnaire as for adolescents aged <16 years was also used for children aged 6–<12 years. For the UCT, DLQI (≥16 years) / CDLQI (≥6 to <16 years), CU-Q2oL, EuroQol 5-item questionnaire (EQ-5D-5L) (≥16 years) / EuroQol 5-item paediatric questionnaire (EQ-5D-Y) (≥6 to <16 years), PGIC, PGIS, and the questionnaire on days of absence / absence from work, participants completed the questionnaires on a tablet provided by the facility during their visit. This device was kept at the facility for the duration of the study.

[0595] Urticaria Activity Score The urticaria activity score (UAS) is a validated patient-reported outcome (PRO) measure. The daily UAS is the sum of the daily urticaria severity score (HSS, ranging from 0=none to 3=50 or more hives) and the daily itch severity score (ISS, ranging from 0=none to 3=intense), with the two main urticaria signs and symptoms being wheals and itch. The daily UAS score ranges from 0 to 6 points / day. The daily UAS score is summed over 7 days, and the UAS7 ranges from 0 to 42 and is composed of the HSS7 and ISS7 components. The UAS7 is an established and widely accepted PRO tool that prospectively measures CSU activity. (Mlynek A et al. How to assess disease activity in patients with chronic urticaria? Allergy.2008;63(6):777-80). It has been used as the primary outcome parameter and medical practice in most recent clinical trials of CSU (Maurer M et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-35; Casale TB et al. Similar efficacy with omalizumab in chronic idiopathic / spontaneous urticaria despite different background therapy. J Allergy Clin Immunol Pract. 2015;3(5):743-50). A minimally important difference (MID) value ranging from 9.5 to 10.5 has been defined to aid in the interpretation of changes in scores in CSU participants.(Hollis K et al. Comparison of urticaria activity score over 7 days (UAS7) values obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study. Am J Clin Dermatol. 2018;19(2):267-74; Hawro T et al. The urticaria activity score - validity, reliability, and responsiveness. J Allergy Clin Immunol Pract. 2018;6(4):1185-90; Mathias SD et al. Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(1):20-4).

[0596] Angioedema activity score The Angioedema Activity Score (AAS) is a validated PRO measure to assess angioedema activity. (Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92). The AAS is a diary in which participants document the presence or absence of angioedema during the past 24 hours on a daily basis. If angioedema is present, participants answer five additional questions regarding the time of day when a swelling episode occurred, and the severity that this swelling episode caused and its impact on daily function and appearance. Each AAS item is scored between 0 and 3 points, i.e., the minimum and maximum daily AAS values ​​are 0 and 15 points. Daily AAS are summed into a 7-day score (AAS7), which ranges from 0 to 105 points (supra). A MID for the AAS7 of approximately 8 points has been established (supra).

[0597] Urticaria Control Trial The Urticaria Control Test is based on four items: severity of urticaria symptoms pruritus and wheals, insufficient frequency of treatment, QoL impairment, and overall urticaria control, and is a validated PRO measure to assess urticaria control (Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92). Each item is rated on a 5-point Likert-type scale (scored 0-4 points). Low scores indicate high disease activity and low disease control. The UCT total score is calculated by adding all the scores of the four individual items. Thus, the minimum and maximum UCR scores are 0 and 16, with a score of 16 points indicating complete disease control. (Weller K et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92).

[0598] Dermatology Quality of Life Index and Pediatric Dermatology Quality of Life Index The Dermatology Life Quality Index (DLQI) is a PRO developed to measure dermatology-specific HRQoL in adult participants. (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 contains 10 items assessing the impact of skin disease on participants' HRQoL in the previous week. Items cover symptoms, leisure activities, work / school or how they spend their days off, relationships including intimate relationships, side effects of treatments, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical settings 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 for 9 items (0 = "not at all", 3 = "very much"). The remaining item, regarding work / exams, asks whether work / exams were interfered with and (if "no") to what extent the skin condition caused problems at work / exams; this item is rated on a 3-point Likert scale ("not at all" to "very much"). Overall scoring ranges from 0 to 30 points, with higher scores indicating poorer HRQoL. Using a pooled analysis of distribution- and anchor-based approaches using the change in DLQI total score and participant-rated itch severity score, the MID of the DLQI in participants with chronic idiopathic urticaria was reported to range from 2.24 to 3.10 points. (Shikiar R et al. Minimal important difference (MID) of the dermatology life quality index (DLQI): results from patients with chronic idiopathic urticaria.Health Qual.Life Outcomes.2005; p. 3:36).

[0599] The pediatric dermatology life quality index (CDLQI) is a validated questionnaire designed to measure the impact of skin disease on children's HRQoL. (Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial validation and practical use. Br J Dermatol. 1995;132(6):942-9). Patients respond to 10 questions (perception of symptoms associated with the disease, impact of the disease on leisure, school or holidays, interpersonal relationships, sleep, and side effects of treatment for the skin disease). The instrument has a 7-day collection period. Nine of the 10 questions are scored on a 4-point Likert scale ranging from 0=not at all / not answering the question to 3=very much. Question 7 has one further answerable item (absenteeism from school), which is assigned a score of 3. The CDLQI total score is the sum of the scores of each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL. Patients complete the DLQI (≥16 years) or CDLQI (≥12 to <16).

[0600] Chronic Urticaria Quality of Life Questionnaire The CU-Q2oL is a disease-specific instrument used to assess the QoL of adult participants with CSU. (Baiardini I et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire(CU-QoL).Allergy.2005;60(8):1073-8). The CU-Q2oL is a 23-item self-administered questionnaire that includes six QoL components: itching, swelling, impact on activities of life, sleep problems, limitations, and appearance. Each item is scored on a 5-point Likert scale (1=not at all, 5=very much) to indicate how much each component bothers the participant. The individual items are summed to give a total CU-Q2oL score, which is then converted to a scale of 0–100, with higher scores indicating greater QoL impairment.

[0601] Patients' general perception of changes in CSU disease and their general perception of the severity of CSU disease The Patient Global Impression of Change (PGIC) is a one-item questionnaire that asks participants to give a global self-assessment of the change in CSU on a 7-point scale compared to just before the participant started study treatment. Response options are: 0 = "much better", 1 = "moderately better", 2 = "slightly better", 3 = "no change", 4 = "slightly worse", 5 = "moderately worse", 6 = "much worse".

[0602] The Global Patient Impression of Severity (PGIS) is a one-item questionnaire that asks participants to give an overall self-assessment of the severity of their illness over the past week on a 4-point scale. Response options are: 1 = "none", 2 = "mild", 3 = "moderate", 4 = "severe". Patients complete the PGIC and PGIS.

[0603] EuroQol 5-item questionnaire The Euroqol-5 Items (EQ-5D) is a standardized PRO measure of health status developed by the EuroQol Group to provide a brief, 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 written form and an EQ visual analog scale (EQ VAS). The EQ-5D 5L written form includes five components: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each component has five problem perception levels: "no problems," "mild problems," "moderate problems," "severe problems," and "unable to do activities." (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 (or crossing) the most appropriate statement for each of the five dimensions. This results in a single-digit number that represents the level of that dimension. The numbers for the five dimensions can be combined into a five-digit number that represents the respondent's health status. The EQ VAS records the respondent's self-rated health on a vertical VAS with endpoints labeled "best imaginable health (100)" and "worst imaginable health (0)". This information can be used as a quantitative measure of health outcomes as judged by individual respondents.

[0604] The EQ-5D Pediatric Version (EQ-5D Y) is administered to children aged 6 to 12 years and adolescents aged 12 to 15 years. (Wille N et al. Qual. Life Res. 2010;19(6):875-86). The EQ-5D-Y is based on the EQ-5D-3L and essentially consists of two pages, the EQ-5D written form and the EQ VAS. The EQ-5D-Y written form includes five components: mobility, taking care of oneself, usual activities, pain or discomfort, and anxiety, sadness or unhappiness. Each component has three levels: no problems, some problems, and many problems. The EQ VAS is a vertical VAS with endpoints of "best imaginable health" and "worst imaginable health" to record the young patient's self-assessed health. Patients complete the EQ-5D Y or the EQ-5D questionnaire.

[0605] Number of days absent Patients who were working or studying were asked to report the number of sick / absent days since the last study assessment. Safety assessment Physical Examination - A complete physical examination will include examination of the skin, nasal passages, eyes, ears, respiratory, circulatory, gastrointestinal, neurological, lymphatic and musculoskeletal systems. - Investigators should pay particular attention to clinical signs related to any previous serious illness. - Any new findings or worsening of previous findings should be reported as a new adverse event. Vital Signs - Vital signs will be measured after 5 minutes of rest in a semi-recumbent or sitting position and will include axillary or oral temperature (temperature measurements will be taken in the same manner throughout the study), systolic and diastolic blood pressure, pulse and respiratory rate. - Blood pressure and pulse measurements should be assessed in the same arm using a fully automated device. Use manual techniques only if an automated device is not available. - Weight (kg) will be measured at Screening (Visit 1) and at the EOT / EOS visit. Height will be measured at Screening (Visit 1). Height and weight will be measured in indoor clothing and without shoes. electro-cardiogram - Obtain a single standard 12-lead ECG using an ECG device that automatically calculates heart rate and measures PR, QRS, QT, and QTc intervals. The ECG should be recorded after 10 minutes of rest in the supine position. Clinical Safety Laboratory Evaluation - The Investigator must review the laboratory reports, document this review, and record in the AE section of the CRF any clinically relevant changes that occurred during the study. Laboratory reports must be submitted with the source documentation. A clinically significant laboratory abnormality is one that is not related to an underlying disease unless the Investigator judges it to be more severe than would be expected for the participant's condition. - All laboratory tests that produce values ​​considered clinically significant abnormal during study participation should be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. - If there is no return to normal / baseline within a time period deemed reasonable by the investigator, the etiology must be identified and the sponsor notified. - If a laboratory value other than the protocol-defined laboratory value performed at the site's local laboratory requires a change in participant management or is deemed clinically important by the investigator (e.g., SAE, AE, or dose change), this must be recorded on the CRF.

[0606] Adverse events and serious adverse events Adverse events of particular interest Adverse Events of Special Interest (AESI) are AEs (serious or non-serious) of scientific and medical concern specific to the sponsor's product or program that require ongoing monitoring and prompt notification by the investigator to the sponsor. Such events may require further investigation to be characterized and understood. Adverse events of special interest may be added, modified, or removed during the study by protocol amendments.

[0607] For these AESIs, even if they do not meet the severity criteria, they will be notified to the sponsor immediately (i.e., within 24 hours) in response to the SAE notification using the appropriate page of the CRF (to be sent) or the e-CRF screen. - Anaphylactic reactions - Systemic hypersensitivity reactions - Helminth infections - Severe conjunctivitis or blepharitis - keratitis - Clinically symptomatic eosinophilia (or clinically symptomatic eosinophilia) - Significant increase in ALT - In participants with baseline ALT ≤ 2 × ULN, ALT > 5 × ULN, or - If baseline ALT is >2×ULN, ALT is >8×ULN. - Pregnancy in females and female partners of males participating in IMP / NIMP studies - Pregnancy occurring to a female participant in a clinical trial or the female partner of a male participant in a clinical trial. Only one of the severity criteria must be met for an SAE to be recognized. - In the event of pregnancy in a female participant, IMP should be discontinued. - Pregnancy follow-up in female participants or female partners of male participants Participation is mandatory until outcomes are determined. - Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital abnormalities, ectopic pregnancy). - Symptomatic overdose with IMP / NIMP (serious or non-serious) - IMP overdose (accidental or intentional) is defined as an event suspected by the Investigator or spontaneously reported by the participant as at least twice the intended dose during an interval of dosing less than 11 days. The circumstances (i.e., accidental or intentional) should be specified on the Overdose Form. - An overdose (accidental or intentional) with any NIMP is defined as an event suspected by the investigator or spontaneously notified by the participant, of at least twice the maximum prescribed daily dose, within the intended treatment interval. "The circumstances (i.e., accidental or intentional) should be clearly defined on the overdose form."

[0608] Adverse events are reported by the participant (or, where appropriate, the caregiver, parent, surrogate, or legally authorized representative of the participant). The investigator and qualified designee are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE, and for following up on AEs that are serious, considered related to the study intervention or procedures, or that cause the participant to discontinue the study intervention.

[0609] Pharmacodynamics IgE was the only pharmacodynamic parameter evaluated in this study.

[0610] Determining sample size The total number of participants expected across the three trials is approximately 384 randomized participants.

[0611] Population for analysis For the analyses performed separately for each study (A, B and C), the following populations were defined separately for each study (A, B and C) (Table 6):

[0612] [Table 6]

[0613] statistical analysis This section summarizes the statistical analyses of the primary and secondary endpoints. Table 7 below shows the efficacy analysis results.

[0614] [Table 7-1] [Table 7-2]

[0615] Safety analysis All safety analyses were performed on the safety population. Safety outcomes were summarized by treatment group. Baseline values ​​are generally defined as the last available value prior to randomization. Safety analyses are summarized below in Table 8.

[0616] [Table 8-1] [Table 8-2]

[0617] Summary of methods, results, and conclusions of Study A Methods: LIBERTY-CSU CUPID Study A (NCT04180488), a randomized, placebo-controlled, 24-week phase 3 trial, evaluated the efficacy and safety of dupilumab in patients ≥6 years with CSU who remained symptomatic despite treatment with antihistamines. Patients taking standard or ≤4th doses of antihistamines were randomized to receive dupilumab 300 mg (adults / adolescents ≥60 kg) or 200 mg (adolescents <60 kg / children ≥30 kg) subcutaneously every 2 weeks (n=70) or matching placebo subcutaneously every 2 weeks (n=68). Primary and ranked secondary endpoints included change from baseline in 7-day itch severity score (ISS7) and 7-day urticaria activity score (UAS7) at 24 weeks. Other secondary endpoints included change from baseline at week 24 in the 7-day Urticaria Severity Score (HSS7).

[0618] Test A results As shown in Figure 6 , Study A included omalizumab-naive participants who were treated with dupilumab for 24 weeks.

[0619] The statistical testing hierarchy for Study A is summarized in Figure 7, which shows p-values ​​for the primary endpoints at 12 and 24 weeks.

[0620] Baseline characteristics were generally balanced between treatment groups. Mean baseline ISS7, UAS7, and HSS7 (dupilumab / placebo) scores were 15.7 / 16.1, 30.8 / 31.9, and 15.0 / 15.8, respectively. At week 24, the least squares (LS) mean change from baseline in ISS7 (range: 0-21) was -10.2 / -6.0 (dupilumab / placebo, respectively) (LS mean difference -4.2; P = .0005), and in UAS7 (range: 0-42) was -20.5 / -12.0 (difference -8.5; P = .0003).

[0621] The primary endpoint, ISS7, met clinical and statistical significance. The results of ISS7 in least squares mean (LSmean) change from baseline are depicted graphically in Figure 8. At week 12, ISS7 (range 0-21) (LSmean from baseline) was -8.37 in the dupilumab group and -6.01 in the placebo group (difference -2.37, p=0.0377). At week 24, ISS7 (LSmean from baseline) was -10.24 in the dupilumab group and -6.01 in the placebo group (difference -4.23, p=0.0005). Figure 9 shows a plot of the mean change in ISS7 over time from baseline to week 36 in both the placebo and dupilumab treatment groups. The ISS7 scores ranged from 0 to 21, with a minimally important difference (MID) range of 4.5 to 5.

[0622] The primary endpoint, UAS7, met clinical and statistical significance. The results of UAS7 in least squares mean (LSmean) change from baseline are depicted graphically in Figure 10. At week 12, UAS7 (range: 0-42) (LSmean from baseline) was -16.81 in the dupilumab group and -11.79 in the placebo group (difference: -5.02, p=0.0223). At week 24, UAS7 (LSmean from baseline) was -20.53 in the dupilumab group and -12 in the placebo group (difference: -8.53, p=0.0003). Figure 11 shows a plot of the mean change in UAS7 over time from baseline to week 36 in both the placebo and dupilumab treatment groups. The UAS7 scores range from 0 to 42, with a minimally important difference (MID) range of 9.5 to 10.5.

[0623] The percentages of UAS7 partial and complete responders at 24 weeks in the dupilumab and placebo arms were statistically significant. Figure 12 graphically depicts the percentages of UAS7 partial responders (patients with UAS7 equal to or less than 6) in both the placebo and dupilumab arms at 12 weeks and 24 weeks. At 12 weeks, 18% of the placebo arm were partial responders and 34% of the dupilumab arm were partial responders (p=0.0215). At 24 weeks, 24% of the placebo arm were partial responders and 46% of the dupilumab arm were partial responders (p=0.0075). Figure 13 graphically depicts the percentages of UAS7 complete responders (patients with UAS7 equal to 0) in both the placebo and dupilumab arms at 12 weeks and 24 weeks. At week 12, 9% of patients in the placebo group were partial responders and 16% of patients in the dupilumab group were partial responders (p=0.2152).At week 24, 13% of patients in the placebo group were partial responders and 31% of patients in the dupilumab group were partial responders (p=0.0199).

[0624] The percentage of patients with a minimally important difference (MID) in ISS7 (patients with a reduction in ISS7 of 5 or more points) was statistically significant at week 24 in the dupilumab treatment group versus the placebo group. Figure 14 graphically depicts the percentage of patients who reached the ISS7 MID at weeks 12 and 24 in the placebo and dupilumab treatment groups. At week 12, 53% of placebo and 70% of dupilumab sampled patients reached the ISS7 MID (p=0.0971). At week 24, 43% of placebo and 73% of dupilumab sampled patients reached the ISS7 MID (p=0.0014). Figure 15 depicts a plot of the percentage of patients with a reduction in ISS7 from baseline of 5 or more points over time through week 36 in both the placebo and dupilumab groups.

[0625] The LS mean change from baseline in HSS7 (range: 0-21) at week 24 was -10.3 in the dupilumab group and -5.9 in the placebo group (difference -4.4, P = 0.0003).

[0626] Dupilumab significantly reduced itch as measured by ISS7 at week 24 whether baseline serum total IgE was <100 IU / mL or ≥100 IU / mL (median baseline serum total IgE in the entire population was 101.0 IU / mL): ISS7 LS mean differences (95% CI) vs placebo were -4.24 (-7.86, -0.62) and -4.63 (-8.22, -1.04), respectively. Furthermore, dupilumab significantly reduced urticaria activity as measured by UAS7 at week 24, regardless of baseline serum total IgE levels: mean differences (95% confidence intervals) vs placebo for LS in UAS7 were -8.17 (-15.04, -1.29) and -10.63 (-17.72, -3.54) for IgE < 100 IU / mL or ≥ 100 IU / mL, respectively; for HSS7, -4.2 (-7.60, -0.70) / -6.1 (-9.95, -2.33); and for UAS7, -8.2 (-15.04, -1.29) / -10.6 (-17.72, -3.54). The incidence of treatment-emergent adverse events (TEAEs) for dupilumab / placebo was 35 (50.0%) / 40 (58.8%), injection site reactions were 8 (11.4%) / 9 (13.2%), conjunctivitis was 0 / 1 (1.5%), and serious TEAEs were 2 (2.9%) / 5 (7.4%).

[0627] Dupilumab demonstrated clinically meaningful and statistically significant improvements in patients with H1 antihistamine-resistant CSU, regardless of baseline IgE levels, and was well tolerated.

[0628] Safety Results Study A Overall treatment-emergent adverse events (TEAEs) were similar between dupilumab and placebo, 35 (50.0%) / 40 (58.8%), with incidence of injection site reactions of 8 (11.4%) / 9 (13.2%), conjunctivitis of 0 / 1 (1.5%), and serious TEAEs of 2 (2.9%) / 5 (7.4%). TEAEs, serious TEAEs, TEAEs leading to treatment discontinuation, and SAEs were observed more frequently with dupilumab versus placebo (1 death (suicide) with placebo, 1 conjunctivitis with placebo, and a higher incidence of skin disorders (18 vs. 9) with dupilumab treatment compared to placebo (including angioedema with 1 with dupilumab treatment vs. 5 with placebo). Site reactions had a similar incidence (9 with placebo vs. 8 with dupilumab treatment). Two AESIs were observed in the dupilumab treatment group (pregnancy and hypersensitivity). An overview of TEAEs is shown below in Table 9. A detailed breakdown of TEAEs is provided in Table 10. Overall treatment-emergent adverse events reported in at least 5% of patients in either treatment group were similar with placebo and dupilumab.

[0629] [Table 9]

[0630] [Table 10]

[0631] Overall, dupilumab was well tolerated and demonstrated an acceptable safety profile in CSU. The safety profile was consistent with the known safety profile of dupilumab observed in approved populations and indications. No new safety signals were reported in CSU patients. No suspected unexpected serious adverse events (SUSARs), serious cardiovascular events, or malignancies were observed.

[0632] Patient outcomes: Patient outcomes in Study A are shown in Table 11 below. Three times more dropouts were observed in the placebo group (27%) vs. the dupilumab treatment group (9%). The treatment approach was to use available data after dropout. MI represents missing data. Worst Observed Value Extension (WOCF) was used for missing data when due to lack of efficacy by the investigator.

[0633] [Table 11-1] [Table 11-2]

[0634] Demographics: The demographics of patients in Study A are shown in Table 12 below. There were a total of six pediatric patients, including two children aged 6-11 years in the dupilumab group and two adolescents aged 12-17 years in the placebo and dupilumab groups, respectively. Study A included 12 elderly patients over 65 years old. There were more female patients (66%).

[0635] [Table 12-1] [Table 12-2]

[0636] Disease Characteristics: Disease characteristics of patients in Study A are summarized in Table 13 below. Baseline ISS7 was approximately 16 in both dupilumab and placebo arms. Baseline UAS7 was approximately 31 in both dupilumab and placebo arms. Baseline HSS7 was approximately 15 in both dupilumab and placebo arms. Approximately 45% of patients in Study A had angioedema. Baseline total IgE was approximately 50% <100 and approximately 50% >100 in both dupilumab and placebo arms. Baseline H1-antihistamine was approximately 50% at standard dose and approximately 50% at higher than standard dose in both dupilumab and placebo arms.

[0637] [Table 13-1] [Table 13-2] [Table 13-3]

[0638] Predefined Medical / Surgical History: The medical / surgical history of participants in Study A is shown below in Table 14. The medical / surgical history of these patients is consistent with published literature regarding CSU and comorbid atopic diseases. Active atopic dermatitis was an exclusion criterion.

[0639] [Table 14]

[0640] Rescue Medications: A summary of rescue medications recorded by the investigator during the 24-week treatment period is shown in Table 15 below.

[0641] [Table 15]

[0642] Summary of pediatric patient data for Study A: A total of six pediatric patients were randomized. Four adolescents aged 12-17 years were included. Two adolescent patients received dupilumab and showed a reduction in signs and symptoms of CSU. In two adolescent patients in the placebo group, one patient stopped treatment at the patient's discretion due to lack of efficacy and one patient reported a reduction in signs and symptoms of CSU. Two children aged 6-11 years who received dupilumab treatment stopped treatment early at the patient's discretion due to lack of efficacy (one at week 4 and the other at week 10). Dupilumab had an overall favorable safety profile in pediatric CSU patients. No TEAEs were reported in any pediatric patients.

[0643] Conclusion of Test A Overall, dupilumab demonstrated clinically meaningful and statistically significant efficacy and was well tolerated in patients with CSU who remained symptomatic despite the use of H1 antihistamines.

[0644] Furthermore, these results were unexpected because the role of IL-4 and IL-13 in the pathogenesis of CSU was unknown. (See Gimenez-Arnau AM et al. The Pathogenesis of Chronic Spontaneous Urticaria:The Role of Infiltrating Cells J Allergy Clin Immunol Pract 2021 Jun;9(6):2195~2208). In particular, "the pathogenesis of chronic spontaneous urticaria (CSU)typically focuses[ed] on mechanisms by which cutaneous mast cells (MCs)may be activated to initiate the process." (Ibid., p. 2195). Furthermore, "the basophil is thought to have an important role in the pathogenesis of CSU given its similarities to the MC as a major source of histamine and expression of the high-affinity receptor for IgE." (Ibid., p. 2199). Furthermore, it is also known that "circulating IL-4, as well as IL-4 produced by PBMCs, does not seem elevated in the majority of patients with CSU" and "no correlation with disease activity or ASST [autologous serum skin test] could be made."(Cited above are Degirmenci et al. Analysis of the Association of Chronic Spontaneous Urticaria with Interlekin-4,-10, Transforming Growth Factor-β1, Interferon-γ, Interleukin-17A and-23 by Autologous Serum Skin Test. Postepy Dermatol Alergol. 2017 Feb;34(1):70-76 and Confino-Cohen R et al. Low Stimulated IL-4 Secretion in PBMC from Patients with Chronic Idiopathic Urticaria. Cytokine. 2004 Jul 21-Aug 7;27(2-3):74-80). "IL-13 serum levels in patients with CSU do not correlate with disease activity" is also known. (Citing Gimenez-Arnau AM et al. The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells J Allergy Clin Immunol Pract 2021 Jun;9(6):2195-2208; Chen et al. Different Expression Patterns of Plasma Th1-, Th2-, Th17- and Th22-related Cytokines Correlate with Serum Autoreactivity and Allergen Sensitivity in Chronic Spontaneous Urticaria. J Eur Acad Dermatol Venereol. 2018 Mar;32(3):441-448). Thus, the results provided in this study demonstrating that antibodies that inhibit IL-4 and IL-13 are effective in treating CSU were unexpected.

[0645] The Phase 3 CSU clinical trial met its primary endpoint and all ranked secondary endpoints. At 24 weeks, dupilumab reduced itch and urticaria activity scores (itch and urticaria) by nearly 2-fold, regardless of baseline IgE levels. The addition of dupilumab to standard-of-care antihistamines significantly reduced itch and urticaria in biologic-naive patients compared with those treated with antihistamines alone (placebo) in Study A.

[0646] In this study (n=138), the addition of dupilumab to standard of care antihistamines resulted in approximately half the reduction in itch and urticaria activity (itch and urticaria) compared to standard of care alone at 24 weeks, with sustained effects observed beyond the effective treatment period. Results from the study showed a 63% reduction in itch severity with dupilumab versus 35% with standard of care (antihistamines) as measured by a 22-point itch severity scale (10.24-point improvement with dupilumab vs. 6.01-point improvement with standard of care, p=0.0005), which was the primary endpoint in the US (secondary endpoint in the EU).

[0647] Results of the study showed a 65% reduction in the severity of urticaria activity (itch and hives) with dupilumab compared to 37% with standard of care, as measured by a 43-point urticaria activity scale (20.53 points with dupilumab vs. 12.00 points with standard of care, p=0.0003), which was the primary endpoint in the EU (secondary endpoint in the US). Additionally, of patients treated with dupilumab, 73% experienced a clinically meaningful difference in itch and 31% experienced complete disease control, compared to 43% and 13% of standard of care patients, respectively (p<0.02).

[0648] Other endpoints, including responder analyses of UAS7 and ISS7 responders, were met at week 24. ISS7 and UAS7 at week 12 were also statistically significant.

[0649] Notably, dupilumab treatment did not plateau through week 24, was sustained over the 12-week follow-up period, and was consistent regardless of baseline IgE levels.

[0650] The study demonstrated safety results consistent with the known safety profile of dupilumab in its approved dermatology indications. Over the 24-week treatment period, the overall rates of treatment-emergent adverse events were generally similar in the dupilumab and placebo groups (50% dupilumab vs. 59% standard of care). The most common adverse events were injection site reactions (11% dupilumab vs. 13% standard of care). Conjunctivitis was reported in 0 dupilumab and 1 standard of care patients. Overall adverse events, serious adverse events, adverse events leading to treatment discontinuation, and SAEs were more common in the placebo and dupilumab groups.

[0651] Conclusion of Test B Study B of the CSU clinical program evaluated dupilumab in patients with chronic spontaneous urticaria (CSU) refractory to omalizumab and was recently halted due to futility based on a prespecified interim analysis, although numerical improvements in key endpoints were observed. Safety data were generally consistent with Study A and the known safety profile of dupilumab in approved dermatology indications. EXAMPLES

[0652] A multicenter, single-arm study investigating the pharmacokinetics and safety of dupilumab in male and female participants ≥2 to <12 years of age with uncontrolled chronic spontaneous urticaria (CSU)

[0653] Rationale for the test Chronic urticaria is defined as the appearance of itchy wheals (hives) with or without angioedema for more than 6 weeks. Chronic spontaneous urticaria (CSU) is hives without an identified precipitating factor. Blockade of IL-4 / IL-13 with dupilumab represents a potential new treatment for patients with CSU.

[0654] Antihistamines are the mainstay of treatment, but up to 50% of patients remain uncontrolled with antihistamines alone. IgE-targeted therapy with omalizumab has been successful in treating patients with CSU, but not all patients respond to this therapy and it is not approved for patients under 12 years of age. Treating pediatric patients with CSU remains challenging, as their pathophysiology is thought to be the same in all age groups, with antihistamines being the first-line treatment. However, there remains a high unmet need for novel treatments for these indications, especially in the pediatric population.

[0655] Study design This is a multicenter, single-arm, 24-week Phase 3 study evaluating the PK and safety of dupilumab in patients ≥2 to <12 years of age with chronic spontaneous uncontrolled CSU.

[0656] The primary objective of this study is to characterize the PK profile and the secondary objective is to evaluate the safety profile of dupilumab in children ≥2 to <12 years of age with uncontrolled CSU. The study will collect clinical information on response to treatment in this age group, but all efficacy analyses will be descriptive.

[0657] The study consists of three periods: - Screening period (2~4 weeks) - Study intervention period (24 weeks) - Follow-up period (12 weeks) - Study duration is 38-40 weeks (including screening and follow-up) - There will be 8 study visits.

[0658] Screening Period Prior to screening, participants must have been treated with a non-sedating H1-antihistamine for CSU.

[0659] The screening period is 2 to 4 weeks.

[0660] Duration of treatment After successful completion of the screening period, participants will begin the treatment period. All participants will receive dupilumab subcutaneously every 4 weeks (Q4W) or every 2 weeks (Q2W) with or without a loading dose based on weight and age.

[0661] After the treatment period All participants will complete a 12-week post-treatment follow-up period after the treatment period without receiving any study intervention. Investigational Drug - Dupilumab (SAR231893; DUPIXENT). formulation - Solutions for injection. Route of administration - Subcutaneous (SC)

[0662] the purpose Main purpose To characterize serum concentrations of dupilumab over time. Secondary Objectives - To evaluate the safety of dupilumab. - To evaluate the immunogenicity of dupilumab. - To evaluate improvements in health-related QoL in participants receiving dupilumab with CSU who still have symptoms despite the use of H1-antihistamines or appropriate precautions. - To assess the effect of dupilumab on urticaria activity, itch, and urticaria severity scores in patients with CSU who remain symptomatic despite the use of H1-antihistamines. Endpoints - C at 12 and 24 weeks trough Including dupilumab concentrations in serum over time. - Safety and tolerability assessment: incidence of TEAEs or SAEs. - Incidence of ADAs over time in response to dupilumab. - Change from baseline in C-DLQI at week 24 in children aged 4 to 12 years. - Change from baseline in IDQOL at 24 weeks in children aged 2 to 4 years. - Change from baseline in modified UAS7 at Week 24. - Change from baseline in modified ISS7 at Week 24. - Change from baseline in Modified HSS7 at Week 24.

[0663] Inclusion criteria Participants are eligible to participate in this study only if they meet all of the following criteria:

[0664] age Participants must be ≥2 years old and <12 years old at the time of signing the informed consent.

[0665] Participant type and disease characteristics Participants with a documented diagnosis of CSU >6 months prior to the screening visit.

[0666] Participants with CSU Patients with CSU (characterized by recurrent pruritic wheals with or without angioedema) who remained symptomatic at screening despite regular H1-antihistamine treatment.

[0667] body weight Weight ≧5kg~<60kg.

[0668] compliance Participant / parents / carers / legally authorized representatives of the participant (if appropriate) who are willing and able to comply with study visits and related procedures.

[0669] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria:

[0670] Medical conditions Underlying etiologies of chronic urticaria other than CSU.

[0671] The presence of skin morbidity other than CSU that may compromise the assessment of outcomes in this study.

[0672] Participants who received both CSU and CICU diagnoses simultaneously.

[0673] Participants with active AD.

[0674] Serious complications that adversely affect a patient's participation in the study.

[0675] Patients with active tuberculosis or nontuberculous mycobacterial disease, or a history of incompletely treated TB.

[0676] Have been diagnosed with, are suspected of having, or are at high risk of having an internal parasitic infection.

[0677] Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks prior to the screening visit (V1) or during the screening period.

[0678] Known or suspected immunodeficiency.

[0679] Active malignancy or history of malignancy within 5 years prior to the baseline visit.

[0680] History of systemic hypersensitivity or anaphylaxis to dupilumab (including any excipients).

[0681] Previously participated in a clinical trial of dupilumab or been treated with commercially available dupilumab.

Claims

**Claim 1** A pharmaceutical composition for use in the treatment of a subject having chronic spontaneous urticaria (CSU), the composition comprising an antibody that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody comprises three heavy chain CDR sequences, each comprising SEQ ID NO: 3, 4, and 5, and three light chain CDR sequences, each comprising SEQ ID NO: 6, 7, and 8, wherein the antibody is administered to the subject as a first dose, followed by one or more second doses, each second dose being administered every two weeks, wherein the subject has not been previously effectively treated by H1 antihistamine therapy. **Claim 2** The pharmaceutical composition according to claim 1, wherein the subject still has symptoms despite the use of an H1 antihistamine. **Claim 3** The pharmaceutical composition according to claim 1 or 2, wherein the subject has not been previously effectively treated by anti-IgE antibody therapy. **Claim 4** The H1 antihistamine is administered in combination with the antibody, and optionally, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine. The pharmaceutical composition according to any one of claims 1 to 3. **Claim 5** The pharmaceutical composition according to any one of claims 1 to 4, wherein the subject is intolerant to omalizumab or still has symptoms despite the use of omalizumab. **Claim 6** The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject is between 12 and less than 18 years old. **Claim 7** The subject has a body weight of 30 kg or more and less than 60 kg, the first dose is about 400 mg, and each second dose is about 200 mg, or The subject has a body weight of 60 kg or more, the first dose is about 600 mg, and each second dose is about 300 mg. The pharmaceutical composition according to any one of claims 1 to 6. **Claim 8** The pharmaceutical composition according to any one of claims 1 to 7, wherein treatment with the antibody results in an improvement in one or more patient-reported outcomes (PROs) selected from the group consisting of itch severity score (ISS), urticaria severity score (HSS), urticaria activity score (UAS), angioedema activity score (AAS), urticaria control test (UCT), dermatology life quality index (DLQI), pediatric dermatology life quality index (CDLQI), chronic urticaria quality of life questionnaire (CU-Q2oL), global patient impression of change (PGIC), global patient impression of severity (PGIS), Euroqol-5 Dimensions (EQ-5D), and Euroqol-5 Dimensions Pediatric version (EQ-5D-Y).

9. The PRO is an itch severity score (ISS), and the subject has a decrease in itch severity score (ISS7) over 7 days, and optionally, the decrease in ISS7 is at least 5; The PRO is a urticaria severity score (HSS), and the subject has a decrease in urticaria severity score (HSS7) over 7 days, and optionally, the decrease in HSS7 is at least 10 at 24 weeks of treatment; The PRO is a urticaria activity score (UAS), and the subject has a decrease in urticaria activity score (UAS7) over 7 days, and optionally, the decrease in UAS7 is at least 10 or the subject's UAS7 is 0, or the PRO is a urticaria activity score (UAS), and the subject's UAS is 6 or less; The PRO is an angioedema activity score (AAS7) over 7 days, and the subject has a decrease in the AAS score; The PRO is a urticaria control test (UCT), and the subject has an increase in the UCT score, and optionally, the subject's UCT is 12 or more; The PRO is a dermatology life quality index (DLQI), and the subject has a decrease in the DLQI score; The PRO is a pediatric dermatology life quality index (CDLQI), and the subject has a decrease in the CDLQI score; The PRO is a chronic urticaria quality of life questionnaire (CU-Q2oL), and the subject has a decrease in the CU-Q2oL score; The PRO is a global patient impression of change (PGIC), and the subject has a decrease in the PGIC score; The PRO is a global patient impression of severity (PGIS), and the subject has a decrease in the PGIS score; or The PRO is the Euroqol-5 Dimensions (EQ-5D) or the Euroqol-5 Dimensions Pediatric Version (EQ-5D-Y), and the subject is the pharmaceutical composition according to claim 8 that has an increase in the EQ Visual Analogue Scale (EQ VAS) score.

10. The improvement of the PRO occurs with 12 weeks of treatment with the antibody; or The improvement of the PRO occurs with 24 weeks of treatment with the antibody, the pharmaceutical composition according to claim 9.

11. Before treatment with the antibody, the subject has a UAS7 score of 16 or more; Before treatment with the antibody, the subject has an ISS7 score of 8 or more; Before treatment with the antibody, the subject has angioedema; Treatment with the antibody results in an increase in the number of days without itching experienced by the subject; Treatment with the antibody results in an increase in the number of days without urticaria experienced by the subject; or Treatment with the antibody results in a decrease in the need for treatment of the subject with oral corticosteroids, the pharmaceutical composition according to any one of claims 1 to 10.

12. The dosage of oral corticosteroids required is decreased and / or the number of days for which oral corticosteroid treatment is required is decreased, the pharmaceutical composition according to claim 10.

13. Treatment with the antibody results in a decrease in the need for treatment of the subject with antihistamine rescue medication, the pharmaceutical composition according to any one of claims 1 to 12.

14. The dosage of antihistamine rescue medication required is decreased or The number of days for which antihistamine rescue medication is required is decreased, the pharmaceutical composition according to claim 11.

15. The antibody 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, the pharmaceutical composition according to any one of claims 1 to 14.

16. The antibody is dupilumab, the pharmaceutical composition according to claim 15.

17. The antibody is administered using an autoinjector, needle and syringe, or pen; or The antibody is administered using a prefilled device, the pharmaceutical composition according to any one of claims 1 to 16.

18. The antibody is administered subcutaneously, the pharmaceutical composition according to any one of claims 1 to 17.

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